MXPA01001053A - Chemically induced intracellular hyperthermia - Google Patents

Abstract

An invention relating to therapeutic pharmacological agents and methods to chemically induce intracellular hyperthermia and/or free radicals for the diagnosis and treatment of infections, malignancy and other medical conditions. The invention relates to a process and composition for the diagnosis or killing of cancer cells and inactivation of susceptible bacterial, parasitic, fungal, and viral pathogens by chemically generating heat, and/or free radicals and/or hyperthermia-inducible immunogenic determinants by using mitochondrial uncoupling agents, especially 2,4 dinitrophenol and, their conjugates, either alone or in combination with other drugs, hormones, cytokines and radiation.

Description

-neither-. ^ INTRACELLULAR HYPERTHERMIA INDUCED CHEMICALLY CROSS REFERENCE TO RELATED REQUESTS This application claims the priority benefit for the provisional patent application of E. U.A. series No. 60 / 094,286, filed July 27, 1998, which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION This invention relates to therapeutic pharmacological agents and methods for chemically inducing intracellular hyperthermia and / or free radicals for the diagnosis and treatment of infections, malignancies and other medical conditions. This invention also relates to a process and composition for the diagnosis or annihilation of cancer cells and inactivation of susceptible bacteria, parasitic, fungal and viral pathogens chemically generating heat, free radicals and immunogenic determinants. capable of induction by hyperthermia. Said pathogens, infected or transformed cells are inactivated or annihilated without irreparable damage to normal, non-infected, non-transformed cells. More specifically, this invention relates to the diagnosis and treatment of cancer; AIDS treatment; and other diseases and conditions using mitochondrial non-coupling agents, -i especially 2,4-dimitrophenol and its conjugates, either alone or in combination with other drugs, hormones, cytosine and radiation.

GENERAL BACKGROUND 5 Systemic hyperthermia, local heat and fever therapy have been empirically used as effective treatments for malignant, infectious diseases and other diseases since antiquity. The therapeutic hyperthermia was first documented in 0 surgical papyri by Edwin Smith in the 17th century, D.C. Toxin extracts of Streptococcus erysipelatis (group A streptococcus) and Coley's Bacillus prodigiosus (Serratia marcescens) were used to induce fever for the treatment of patients with advanced cancer. The novel prize was awarded for 5 using fever therapy in the treatment of neurosyphilis with the injection of malarial blood. At the end of 1955, the Mayo Clinic advocated using malariotherapy or heat therapy for cases of "penicillin-resistant" tertiary syphilis. Long-term referrals with patients with inoperable carcinomas who were treated with 0 hot baths and local heat applications have also been reported. The published observations on the disappearance of malignancies such as a soft tissue sarcoma in a patient experiencing high fever due to erysipelas and tumor lysis of Burkitt lymphomas after malignant hyperthermia during surgical anesthesia are known. A historical review Comprehensive on anecdotal and intuitive rational observations for the empirical use of therapeutic hyperthermia has been published by Myer, J.L. The temperature of a body can be intentionally elevated either through pyrogens to produce fever (fever therapy) or, through induction hyperthermia (therapeutic hyperthermia). Fever raises body temperature by raising the thermoregulatory "fixation point" located in the preoptic region of the anterior hypothalamus. By doing this, it is body physiologically, it works to maintain the highest temperature setting. The temperature of the high core body increased by fever may or may not be elevated above the value of the highest setting point. In contrast, induced hyperthermia always raises the body temperature above the hypothalamic thermoregulatory fixation point and the physiologically intact body attempts to reduce its core temperature back to the baseline of the fixation point. The renewed clinical interest in hyperthermia has occurred over the past 35 years due to the continuing failure of standard therapies to treat various forms of cancer and emerging infections. Except for few exaggeratedly rare forms of cancer such as childhood leukemias and testicular cancer or immune response infections, chemotherapy, radiation, and drug therapy usually provide very little survival and are briefly extended. U not the main obstacles to "cure" cancer «?, disseminated and infections, has been the innate or acquired resistance of tumor cells and emerging microbes to antibiotics, drugs and treatments given in tolerable doses. The intensification of treatments, or the use of multiple drugs to overcome resistance is invariably prevented by concomitant toxicities or development of resistance to multiple drugs. In addition, in contrast to drugs, which represent an individual molecular species that biochemically interacts with specific enzymes or receptors of viruses, prokaryotes and eukaryotes, The action of hyperthermia is biophysical and global. Hyperemia does not have any specific thermal receiver. Therefore, the possibility of a point mutation causing a functional change in a receptor and conferring resistance to hyperthermia is unlikely, and may be equivalent to the development of resistance to the process of in vitro pasteurization. Among pathogenic bacteria, it has been reported that only one variable in 1 x 106 cells from an original population is resistant to hyperthermia. Hyperthermia has been used alone or together with radiation and chemotherapy in the treatment of a variety of malignancies.

Overgaard et al. Reported that a combination of heat and radiation results in complete double control in many melanoma lesions compared to radiation alone. Maeda, M., N. Et al. , published in Japónica Gastroenterology, that hyperemia with tumor necrosis factor resulted in a successful treatment of hepatocellular carcinoma. Studies Randomized prospectuses of hyperthermia combined with chemoradiotherapy for esophageal carcinoma demonstrated three-year cumulative survival regimens that were greater than doubled with the addition of hyperthermia to chemoradiotherapy. The combination of chemotherapy with hyperthermia in metastatic breast cancer refractory to common therapies, that is, failure before hormone therapy and chemotherapy, resulted in 39% complete remissions and 23% partial remissions: pain relief Bones was awesome. Fujimoto, S., Takahashi, M. Et al. , demonstrated that the five-year survival rate of patients with peritoneal carcinomatosis of gastric carcinoma treated with hyperthermic intraperitoneal chemoperfusion was 41.6%, while 50% of the survival duration of the group that did not receive intraperitoneal hyperthermia was 1%. 10 days. Preoperative hyperaemia with chemotherapy and radiation is also known to improve long-term outcomes in patients with rectal carcinoma, especially those with advanced disease. Clinically it is known that regional hyperthermic infusions, that is, extremities, with chemotherapy is useful for the treatment of melanoma. Combination therapy with hyperthermia and radiation has been successful in the treatment of non-Hodgkins lymphomas. More recently, a survival benefit of hyperemia was shown in a prospective randomized trial for patients with glioblastoma multiforme who ?? they undergo radiotherapy. However, there have been no rigorous clinical prospective trials with hyperthermia alone or, in combination with agents out of use with radiation therapy. 5 The scientific rationale for therapeutic hyperthermia in cancer therapy is supported by known data from preclinical, in vitro and animal studies. It has been shown that tumor cells in a tissue culture are directly more sensitive to heat as compared to their non-malignant counterparts.

Cells that undergo mitosis, DNA sintering in the "S phase" are especially more sensitive to hyperthermia. It has been shown that human leukaemic progenitor cells can be selectively killed by hyperemia and, in vitro use has been shown to purge the spinal cord from tumor cells residuals before the autologous spinal cord transplant. Microcalorimetric measurements confirm that the tumor tissues produce more heat and are "warmer" than their non-tumor counterparts. As a consequence, they are less able to tolerate additional heat loads. 20 Tumor cells are also annihilated through heat indirectly. Tumor angiogenesis is inhibited through heat. The hyperthermia causes the tumors to have a high heat retention with increased cytotoxicity due to the neovasculature of the tumor lacking smooth muscle and precursors of vessel wall needed to cool through vaso dilatation.

Increased hypoxia, acidity, death signaling of the Fos gene, reduced nutrient supply and improved immunological cytotoxicity have also been reported to be caused by hyperthermia and contribute to improved tumor cell death. In addition, the combination of hyperthermia with chemotherapy and / or radiation has been shown to be supra-additive or cinergistic in the annihilation of tumors. It has been shown that human gastric carcinoma cells are selectively annihilated through a combination of cisplatin, tumor necrosis factor and hyperthermia: a 40% increase in DNA damage was observed by cisplatin in the presence of the combination of three agents on cisplatin alone or any double combination. Numerous animal studies, including the initial publication by Crile, showed that transplanted neoplasms in mice returned when treated with hyperthermia without irreparable damage to adjacent tissues. Body temperature is a critical factor in determining host susceptibility, location of lesions and the natural history of many infectious diseases. Temperature has direct effects on the development of all microorganisms, including those that are pathogenic. Almost all bacteria that cause diseases in humans develop optimally within the range of 33-41 ° C and, their temperature growth characteristics are not easily altered in vitro. For example, lesions of Hansen's disease (leprosy) caused by Mycobacterium leprae characteristically develop and they destroy the colder, more acral parts of the body such as fingers, big toes, outer ear, nasal orifice cooled by air current and larynx. Leprosy organisms proliferate and follow the coldest temperature gradients in the body, 25-33 ° C. In animals, leprosy organisms can only develop in the armadillo or the paw pads of mice, where the in situ injury temperatures are 27-30 ° C. Spontaneous improvement in leprosy lesions has been reported in patients after of febrile illness. The therapy of fever, hot baths and local heat therapy were initially used for the treatment of this disease. Hypothermia is also known to destroy Treponema pallidum, the causative agent of syphilis, by heating for five hours at 39 ° C, three hours at 40 ° C, two hours at 41 ° C or one hour at 41.5 ° C. The spirochetes responsible for displacement, begel, pinta and Lyme disease show a similar temperature sensitivity. Other bacteria that predominantly cause lesions in cold places and are susceptible to heat inactivation include, Neisseria gonorrhea, Hemophillus (chancroid), Mycobacterium ulcerans, Mycobacterium marinum (granuloma of "pools"), diphtheria, etc. In addition, it has been reported that hyperthermia can be cynergy with antibiotics and chemotherapy in the treatment of several bacterial diseases. The elevated body temperature potentiates the effect of penicillin on staphylococcus and syphilis. Hyperthermia makes sulfadiazene bactericidal for streptococci. However, recent controlled studies show that when antipyretics are used in animals with experimentally induced infections, severe, there is a high mortality. However, systemic hyperthermia has generally been abandoned as a treatment for bacterial infections with the advent of antibiotics. Hyperthermia has remained an effective treatment for many fungal infections. Superficial dermatophytosis blooms in cooler regions of the body and heat treatment is sometimes the only viable therapy for chronic granulomatous lesions. For example, Sporothrix schenkii, the causative agent of sporotrichosis, has an optimal temperature growth below 37 ° C and is successfully eliminated through local hyperthermia. Similarly, patients with pesudo scheriosis insensitive to antifungal antibiotics are cured with hyperthermic treatments. In Japan, cavity heaters, hot water and infrared heating remain as current and effective treatments for several fungal infections. Systemic hyperthermia, using a Liebel-Flarsheim hyperthermia fever cabinet (Kettering), dramatically treated a case of disseminated sporotrichosis with periodic iridocyclitis, the cultures after repeated treatment of the patient remained negative. The role of hyperthermia in modulating the clinical course of other fungal infections, including histoplasmosis, blastomycosis American, chromomycosis, cryptococcosis, paracoccidiodomicosis, Wolves disease and candidiasis, has been described. Fungi, such as Nocardia, Actinomyces and Aspergillus also proliferate in cooler regions of the body causing jaw injuries (actinomycosis) and foot injuries (Mature feet) respectively. The in vitro heat sensitivity data for many of the previous fungi and other pathogenic fungi have been reported by Mackinnon et al. , Silva, and others. The effect of temperature and hyperthermia in the pathogenesis of parasitic disease is also well known. Leishmaniasis, a widely disseminated parasitic disease transmitted by the picket line of a mosquito, clinically infects 12 million people around the world. Cutaneous and mucocutaneous lesions, ie, oriental pain, Baghdad boil, Delhi boil, chiclero ulcer, and espundia, are usually very destructive and permanently disfigure. Hyperthermia with moist heat of 39 ° to 41 ° C applied for 20 hours for several days has proven to be an effective treatment. In vitro, human macrophages infected with Leishmania mexicana are completely destroyed by heating at 39 ° C for 3 days. All mucocutaneous Leishmania spp., Without considering the subspecies, demonstrate optimal growths of 35 ° C only with L. tropic and L. donovani sepals surviving at temperatures of 39 ° C. Clinical observations have shown that hyperthermal treatment of a Leishmania lesion usually it evokes an immune response and results in the healing of other lesions over a period of 5-6 weeks. The effect of hyperthermia on other parasites, including Trypanosoma cruzi, malaria, microfilaria, acantamoeba, tramtódos and cestodes, has been published. The elevated temperature of the body is also recognized as a major factor in the recovery of viral infections. Many viruses multiply best at temperatures below 37 ° C and their multiplication is inhibited or stopped if the body temperatures exceed 39 ° C. In in vitro replication of Rhinovirus for example, there are falls of units of 106 records with an upward temperature shift of 2 ° C (from 37 ° to 39 ° C). The replication of herpes viruses, as well as the concentration of intracellular and extracellular herpes viruses, are markedly reduced when the incubation temperature rises to 40 ° C. The production of the varicella virus in a human fibroblast cell culture is optimal at 37 ° C and ceases at 39 ° C. The beneficial effects of hyperthermia in the onset of viral disease in laboratory animals infected with myxomatosis, encephalomyocarditis, herpes, gastroenteritis, rabies and the common cold, in man, have also been documented. Influenza and viruses that cause upper respiratory infections, such as the common cold, thrive in a cold environment of 30-35 ° C. The temperature gradients in this scale exist in the autumn and winter within the oral, nasal, tracheal and laryngeal mucosa and lead to epidemics of influenza and flu. Live respiratory virus vaccines have been developed for influenza, through the use of heat-sensitive mutants that can not be duplicated again or cause clinical disease at 36-37 ° C. It is also known that as a difference of 0.5 ° C in the Higher replication temperature of a virus can have a dramatic effect on virulence and pathogenicity. Other animal viruses such as Newcastle disease in chickens, rabbit papilloma, feline leukemia, rabbit pustule rash, hoof and muzzle disease in cattle, hand, foot and mouth disease, warts on the sole of the human foot , and the "fat" of horses due to the involvement of pustular eruption of horses from the colder acral extremities above the spurs, are known to be very simple to heat inhibition. The heat treatment of cells infected with human immunodeficiency virus (HIV-1) at 39 ° C for 2 days has been documented to significantly reduce viral production and reduce the activity of the reverse transcriptase enzyme marker30 times The in vitro hyperthermia of 42.0 ° C for 1 hour, 4 days of separation selectively reduces the loads of RNA VI VI in chronically infected (latent) lymphocytes. Hyperthermia of 42 ° C for 3 hours combined with tumor necrosis factor has been published to selectively kill all acute and chronically infected VI H cells in tissue culture.laC It has been reported that the use of whole body hyperthermia causes regression of Kaposis sarcoma, clarifies oral candidiasis, eliminates hepatitis C, causes remission of varicella-zoster, increases weight gain and improves CD4 lymphocyte counts in patients with acquired immunodeficiency (SI DA). A dramatic improvement with hyperthermia therapy has been documented in a patient infected with debilitating Verruca vulgaris and HIV. The FDÁ has approved clinical trials involving hyperthermia for the treatment of AIDS with a patented extracorporeal blood heating machine to induce hyperthermia of the entire body. The FDA has recently expanded trials of extracorporeal heating machine to allow the treatment of 40 patients infected with HIV. Hyperthermia can increase cytotoxicity and reverse drug resistance to many chemotherapeutic agents. In addition, it has also been shown that hyperthermia improves the delivery of many novel cancer therapeutics, ie, monoclonal antibodies to neoplasms with a resultant improvement in an anti-tumor effect, improves the delivery of gene therapy with the use of viral vectors; and increases drug delivery and anti-tumor effects when liposomes containing the drug are used. In addition to increasing the rate of extravasation of liposomes from the vascular compartment by a factor of 40-50, hyperthermia can also be used to selectively release chemotherapeutic agents from liposomes designed to be thermosensitive. Thermosensitive liposomes are small vesicles composed of portions of lipid phosphatidylcholine constructed to contain and transport a variety of drugs. Liposomes are designed to remain stable in blood and tissues at physiological temperatures. When they pass through a hot tissue area, however, they dissolve and effectively release their encapsulated contents. Thermosensitive liposomes are used to trap and carry drugs whose systemic toxicity is desired to be limited to a particular tumor, organ or tissue heated. Examples of drugs that have been encapsulated in liposomes include metrotexatro, doxorubicin, amphotericin B, cisplatin, and others. The liposomes can be designed in order to release their contents at predetermined temperatures. Hyperthermia has also been a solution for the treatment of a variety of heat-labile toxins or poisonous deteriorations. For example, an easy treatment for deterioration of Scorpaenidae and Siganidae is the local application of heat. The main poisonous component of these and many other venoms of lionfish, spiny coto, barber fish, scorpion fish, stonefish, halibut, etc. , is a protein that is not capable of dialysis, very heat labile. Opposed to the nuances of using specific anti-venom, immersing the damaged area or the patient in hot water, or applying other forms of hyperthermia, is a simple and fast treatment. Standard clinical methods for hyperthermia they depend on the exogenous heat deposition to that normally produced by the metabolism. All current, deliberate and controlled methods of heat require an external energy source. Non-surgical heating methods include: hot air, ultrasound, microwaves, paraffin wax baths, hot water blankets, radiant heat devices, high temperature hydrotherapy and combinations thereof. Invasive means of induction hyperthermia include surgical insertion of various heating devices, infusion of hot solutions into the peritoneal cavity through catheters or heating of the blood extracorporeally through a heat exchanger. The last method, developed by Parks et al., Involves the surgical pment of a femoral arterio-venous shunt for removal., heating and replacement of blood to induce complete hyperthermia of the body. A more recent experimental improvement in this method has been the induction of total body hyperthermia with veno-venous bypass perfusions. Several machines have been patented for the extracorporeal heating of blood to induce hyperthermia (see patents of US Pat. No. 5,391, 142 and 5,674, 190). Endogenous heating creating induced fevers with toxins, pyrogens and microorganisms has been used in the past and has recently been attempted again. Heimlich has reported the use of malaria therapy for the treatment of Lyme disease, SI DA and malignancy. Pontiggia et al. , they treated patients with AIDS combining fever, induced by parenteral injections of streptococcal lysate preparations, with hyperthermia generated through an infrared heating bed. Another way in which the technique has been in agreement with the induction of hyperthermia has been to introduce micron-sized magnetic particles and subject them to either magnetic fields or hyperbaric oxygen (see U.S. Patent No. 4,569,836). This method was designed for the treatment of cancer based on the belief that cancer cells could absorb the particles and concentrate them intracellularly. Then, a magnetic field could be applied to heat the particles and generate lethal hyperthermia within the cancer cells. One modification of this technology is the use of magnetic cationic liposomes to induce intracellular hyperthermia. This technology was based on the observation that glioma cells have a higher affinity for positively charged magnetic liposomes instead of "neutral" ones. A more recent variation of this science has been developed in Germany using "activated" magnetoliposomes. This methodology has been developed in an attempt to treat AIDS, using magnetic nanoparticles coupled either to CD4 lymphocytes or anti-HIV gp120 antibodies. Magnetic nanoparticles are intended to selectively bind either to the envelope of the HIV protein or to HIV-infected cells, and then be heated by external, high-frequency alternating magnetic fields.

Either invasive or non-invasive, all current methods for inducing hyperthermia depend on an external energy source and can not safely deliver adequate energy to result in therapeutic heating. The supply of heat to obtain the actual desired temperature for deep target tissues has not been possible due to the current physics involved in thermodynamics, heat transfer from the outside to the cell. Warming tissues deeper than five centimeters below the skin with microwaves, radiofrequency or ultrasound devices is difficult because the absorption of energy is not uniform or is not focused. Radiating heat, hot water, molten wax and other methods cause excessive heating of the subcutaneous fat that acts as a barrier to gain heat to the body. Common adverse effects of such external heating methods include superficial skin burns, blister formations, ulcer formation secondary opportunistic infections, and pain. In addition, many tumors have a high cooling of blood flow, which nullifies any potential therapeutic gain that can be obtained through the use of such systemic, extracellular hyperthermia devices. Also, insufficient heating energy prolongs the induction time required to reach the actual therapeutic temperature. This promotes resistance to heat treatment through the development of thermal shock response and thermotolerance.

The high frequency electromagnetic devices used to heat intracellular magnetic particles invariably induce eddy currents within the body making it difficult to provide a uniform, controlled and safe heating without toxic effects to normal cells. Furthermore, not all tumors have characteristics that selectively pick up magnetic particles or have an affinity for positively charged magnetic liposomes. Also, the magnetic cationic liposome particles are subjected to several neutralization interactions with anions, giving them a short half charged life. In addition, the complexity of using specific anti-VI H antibodies bound to electromagnetic particles also assumes a non-mutated VI H genome with stable antigenic determinants. On the contrary, a high mutation rate in the VI H genome and its protein antigenic determinants are known to exist and is the main obstacle to the development of an effective vaccine. Therefore, said treatments do not selectively heat transformed cells without heating and damaging normal cells. The extracorporeal blood heating methods require surgery and anesthesia. Furthermore, as with all external heating methods, temperature variations and toxic driving thermogradients from the initial heating point to the target tissue can not be avoided. For example, it is consciously known that the temperature of the marrow The spinal cord is 1 ° -2 ° C below the average body core temperature achieved by extracorporeal blood hyperthermia. This is a major problem in systemic hyperthermic therapy, as the marrow is a common reservoir of metatatic cancer cells and infectious microorganisms. The therapeutic temperatures of the spinal cord can not be obtained due to the fact that the intermediate tissues between the blood and the marrow create a temperature gradient by cooling the blood before it reaches the spinal cord. Since the effectiveness and toxicity of hyperthermia depends on both the actual temperature and the duration of heating, the supply of the desired temperature and heating duration (thermal doses) to the spinal cord may require that the blood and intervening tissues be heated beyond what is safe for normal, healthy cells. A European trial of multiple trials documented that only 14% of all protocols achieve target temperatures required. In addition, the methodology of current extracorporeal heating and equipment is a lot of work, time consuming and expensive. The use of fever induction agents such as live microorganisms, pyrogens and toxin lysates is clinically uncontrollable, not predictable or insufficient both for the degree and duration of the temperature increase. Other reasons why hyperthermia has not been accepted as a mode of therapy, is because the heating machine Current are not compatible with non-invasive temperature measurement technology. The measurement of the actual temperatures reached in target tissues is critical to the heating efficiency, that is, determining the thermal dose. Recently, non-invasive thermometry with magnetic resonance imaging (MRI), ultrasonic backscattering, electrical impedance, electromagnetic adaptive feedback and advanced, high-precision pixel infrared temperature imaging have been developed. To use the magnetic resonance imaging or other equipment to verify hyperthermia in real time, however, it is necessary to combine a hyperthermia device with an MRI unit. This has proven to be difficult and very costly, since each device is functionally altered, if not damaged, by the presence of the other. The exact molecular and cellular mechanism through which heat kills or inactivates tumor cells and microorganisms is unknown. Heat is an entropic agent and acts globally on each molecule that constitutes the cell. It is known that heating causes conformational changes in proteins, denatures enzymes and affects the fluidity of the cell membrane. For example, the herpes simplex virus thymidine kinase (type 1) has a shortened half-life at 40 ° C for only 30 minutes. The enzyme product of transforming gene of Rous sarcoma virus (protein phosphatase), a critical protein for the Cellular regulation is completely inactivated in 30 minutes at 41 ° C. It is known that hyperthermia increases the formation of free oxygen radicals, including superoxide, hydroxyl, hydroperoxyl, hydrogen peroxide and lipid peroxides. These reactive oxygen species react indiscriminately and oxidize many organic molecules, causing DNA damage, denaturation of the protein, lipid peroxidation and other reactions of destructive chains. Acid microenvironments, known to exist in tumors and microorganisms with high glycolysis regimes (Embden-Meyerhof path) and production of lactic acid, favor the protonation of the superoxide radical to form the highly reactive and toxic hydroperoxyl radical. In this way, the thermal sensitivity of many tumors increases with the reduction of the intracellular pH value. As compared to normal cells, many malignant and virally transformed cells have a reduced total functional capacity to withstand the increased flow of free oxygen radicals produced by hyperthermia. At the intracellular level, it is known that moderate heating activates phospholipase, A2, which increases the formation of pro-inflammatory mediators such as leukotrienes, prostaglandins and eicosanoids. The heat also increases the release of intracellular calcium through the stimulation of phospholipase C. The calcium cyclization through the mitochondrial membrane seems critical for the increased production of free radicals by oxygen. Elevated intracellular calcium also inhibits the anti-apoptotic, mitochondrial Bc1 -2 protein, and induces the production of heat shock proteins, and mediates thermotolerance. Heat damage to the intracellular tubulin network, lysosomes, Golgi bodies, mitochondria and the control of RNA cleavage are some of the most well-known subcellular systems affected by heat. Although the initial primary event leading to cell death through hyperthermia is unknown, a reduction in mitochondrial membrane potential followed by decoupling of oxidative phosphorylation and generation of reactive oxygen species in the uncoupled respiratory chain are the first alterations detectable biochemicals in cells irreversibly consigned to apoptosis. The cytotoxic effect of hyperthermia in this way is believed to be caused by numerous changes and complex damage to multiple vital functions of the cells. Those biochemical products altered by heat and essential for the function or viability of the cell are the pivotal objectives of therapeutic heating. The hyperthermic cell damage mode depends on the severity of the heat stress, temperature and duration of the heating. A moderate heating of the 39-42 ° C heating is used therapeutically and is known to promote programmed cell death through apoptosis, an active process to selectively remove heat-sensitive cells without inflammation, cell death, or subsequent fibrosis of the cell. tissue. Malignant cells or other transformed cells undergo apoptosis through the suppression or activation of one or more genes such as bd -2, c-myc, p53, TRPM-2, RP-2, RP-8, raf, abl, APO -1 1 FAS, ced-3, ced-4, ced-9, etc. The drugs (methotrexate, cisplatin, colchicine, etc.) hormones (glucocorticoids), cytokines (tumor necrosis factor-alpha), radiation (free radicals) and hyperthermia can all start apoptosis. The increase in temperature or duration of heating, or both, leads to the death of cells through necrosis. This physical process to indiscriminate the annihilation of cells is associated with inflammation and causes major damage to normal, healthy cells. For the purposes of systemic hyperthermia, the target cell apoptosis is selection therapy. In the clinical setting, it must be controlled under moderate heating conditions in order to selectively differentiate and eliminate target cells with minimal toxicity to normal cells. Such controlled driver heating through external technologies is inherently possible. The thermal and thermophysiological physical properties of cells vary and depend on their thermal conductivity, specific heat, density and blood perfusion between the various organs and tissues. Based on these properties, the actual temperatures in some of these sites are usually "divided" independently of one another and do not represent the average "core" temperature, verified during therapy. Furthermore, it is well recognized that it is the real intracellular temperature increase, with its associated internal physical and chemical changes, that is critical for the successful use of hyperthermia to exploit the fundamental biochemical differences between normal and heat-sensitive cells. Unfortunately, the initial cellular targets of all extracorporeal heating methods are the cell membrane and its integrated proteins. The internal contents of the cell, including mitochondria, compartment enzymes, other organelles and any intracellular pathogens, etc. , are progressively heated in sequence through thermal conduction from the outside. In this way, to sufficiently heat the inside of the cell, the external temperature must overcome the cell membranes and mitrocondricas, each composed of a double layer of lipid that acts as an effective thermal barrier. Thus, by necessity, the heating methods of the prior art require high external temperatures to establish a sufficient gradient to overcome conduction heat loss that is not isotropic and that is not homogeneous between internal tissues and the membrane isolation barrier cellular and mitochondrial. For example, the Organetics PSI® device (now First Circle Medical Inc.) has to warm the blood externally to 48 ° C before returning it directly to the patient's tilting system. Other extracorporeal circuit perfusion devices need to achieve ex vivo temperatures of 49 ° C.

Animal studies require temperatures of 54 ° C during the induction phase to achieve adequate target tissue temperatures. The safety in said prior art, therefore, is limited by the incipient destruction of surrounding tissues at the sites of the high temperature heating phases. When lower temperatures are attempted, the effectiveness is compromised either by inadequate temperatures or the duration of heating or the development of thermotolerance. As a result, only regional hyperthermia has been widely used clinically and only in combination with more traditional techniques, such as radiation and chemotherapy. Currently, none of the known heating technologies provide clinically safe and effective hyperthermia to treat systemic or disseminated disease. In order for systemic hyperthermia to be used more widely and clinically, current heating methods must also overcome the use of laborious and complex equipment, including invasive extracorporeal infusion and related toxicity problems for interposed tissues. In addition, the new hyperthermic technology must be compatible with non-invasive real-time thermometry. The present invention avoids the problems of heat toxicity, inadequate heating of the target tissue, excessive cost, surgery, anesthesia and incompatibility with non-invasive temperature measuring devices: problems that are inherent to all therapeutic methods that supply extracellular heat, from outside-in. This invention, therefore, is an intracorporeal intracellular heating system, which has additional distinct advantages. First, the human body is biochemically and physiologically designed to tolerate higher temperatures when heated from the inside out as opposed to from the outside-in. For example, compared to extracorporeal heating, which can safely generate a maximum body core temperature of 42 ° C, intracorporeal hyperthermia caused by persistent exercise induces physiological temperatures of up to 45 ° C in the muscle and liver at temperatures core of the body up to 44 ° C. Patients with exerted thermal attack have survived rectal body temperatures as high as 46.5 ° C without any permanent clinical sequelae. Although the maximum critical temperature that humans can tolerate is unknown, the physiological hyperthermal temperature induced under controlled conditions with adequate hydration has not shown any permanent adverse effects. Liver biopsies of subjects with such temperatures have not shown any significant microscopic abnormality. Second, since heating with the present invention is chemically induced from within the cell, the actual intracellular therapeutic temperature will be greater than the measured core temperature. As a result, intracellular organelles, including mitochondria, are heated at higher temperatures, experience greater decoupling and generate an increased flow of reactive oxygen species. Since free oxygen radicals, including superoxide, improve and probably mediate the effects of hyperthermia, improved therapeutic gain will be obtained at lower body core temperatures. In addition, it is known that for every 0.5 ° C increase in body temperature, the metabolic rate and oxygen consumption increases by 7%. This increase will help the heating of the same body. Third, the safety and control temperatures with the present invention are more than superior to those of the exogenous methods. The body is naturally designed to dissipate heat from the inside out. This is evident from the fact that a temperature gradient of 3.5 ° - 4.5 ° C exists between the visceral nucleus and the skin. This gradient represents the transfer of heat from regions of high temperature to regions of low temperature, with loss of final heat from the skin to the environment through conduction, convection, radiation and sweat induced by evaporation. The margin of safety and control represented by the "feedback gain" of this intact physiological heat dissipation system is extremely high, approaching 27-33. This cooling regime can balance an influx of heat in the body of a naked human being in a dry room at about 120 ° C. In this way, the heat flow system of the human being allows the body to get rid of the excessive endogenous heat very quickly and effectively. As a result, there is a wide margin of safety in case the target temperature is exceeded. In contrast, exogenous heating contravenes the natural physiological flow of heat and its dissipation mechanisms. The natural heat dissipation mechanisms are killed and compromised. Control and safety over hyperthermia induced by extracellular media in this way is fragile with little margin for error.

COMPENDIUM OF THE INVENTION The present invention comprises a composition and method for using micondrial decoupling agents, especially DNP, DNP with free radical production drugs, DNP with liposomes, DN P conjugated to free radical formers, and DN P with other therapeutic pharmaceutical agents, which are activated intracellularly by heat or reaction with mitochondrial electrons or free radicals to cause the release of active drugs for the treatment of cancer, HIV, other viruses, parasites, bacteria, fungi and other activities. Although not intended to be bound by theory, it is said that the use of mitochondrial uncoupling agents, to increase intracellular heat and free radicals, as a treatment for unrelated cancers, viruses and other pathogens presupposes that the mechanism of action is non-specific for enzymes and receptors, but is specific for interference with cell and pathogen viability and induction of programmed cell death. The degree of intracellular heating, free radical formation, complete hypothermia of the body and release of active drug molecules is controlled through the DNP dose. Based on the amount of oxygen consumed, the dose of DN P is adjusted to achieve the desired degree of hyperthermia. Safety and effectiveness are also controlled by manipulating metabolic regimes of target tissues, the duration of treatment and permission to cool the body. In accordance with the present invention, the intracellular mitochondrial heat is generated through the use of DNP, other uncouplers, their conjugates, either alone or in combination with other drugs for the treatment of thermosensitive cancers such as non-Hodgkins lymphoma, prostate carcinoma, glioblastoma multiforme, Kaposi's sarcoma, etc.; bacteria such as Borrelia burgdorferi, Mycobacterium leprae, Treponema pallidum, etc.; viruses such as VI H, hepatitis C, herpes virus, papillomavirus, etc.; fungi such as Candida, Sporothrix schenkii, Histoplasma, Paracoccidiodes, Aspergillus, etc.; and parasites such as Leishmania, malaria, acontomoeba, cestodes, etc. 2,4-Dinitrophenol was selected as the decoupler of choice, since it can be used at relatively high concentrations, allowing a uniform distribution in organs and tissues. This invention also encompasses the use of DN P to selectively increase energy metabolism and heat production in incipient malignancies for the purpose of increasing the sensitivity of positron emission tomography. of diagnosis, magnetic resonance sensitive to temperature and infrared imaging of high precision pixel temperature to differentiate normal cell metabolisms from aberrant ones. A further object of the invention is the use of DNP to increase the transcription of heat shock proteins, especially HSP 72, as a form of cellular preconditioning to reduce restenosis after angioplasty, increase the successful outcome of other surgeries, and facilitate processing of antigen and presentation of immunogenic determinants in infectious agents, virally transformed cells and tumors in order to increase the natural or biologically activated immune response. According to another aspect of the invention, DNP-controlled thermogenesis is combined with other agents used to treat infectious diseases, malignancies and other diseases. Examples of other agents include antifungal drugs, antiviral, antibacterial, antiparasitic and antineoplastic. Such drugs, including inhibitors of angiogenesis and radiation have an increased kinergic or additive activity when combined with hyperthermia in the treatment of cancer. The method can also be used to improve the sensitivity of positron emission tomography, nuclear magnetic resonance spectroscopy and infrared thermography in the diagnosis and verification of the treatment of various diseases, including cancer. Similarly, the method can be used to improve the identification of coronary plaques and of the "hot" carotid artery not stable, predisposed to break or suffer thrombosis. This methodology of diagnosis and treatment verification is based on the fact that most tumors have higher metabolic rates and generate more heat than normal tissues. Likewise, it is presumed that the unstable atherosclerotic plaques are broken, since they have a dense infiltration of macrophages that have high metabolic regimes and generate enzymes in excess and heat, causing the plaque to degrade and loosen. In both cases, controlled doses of DNP or other uncouplers can also increase metabolic rates and heat production to raise diagnostic sensitivity. The controlled heating with DN P and the recombinant tissue-type plasminogen activators, fibrinolytics, can also be used therapeutically to accelerate fibrinolysis of plugged arteries.

In another aspect of the invention, DNP is administered in controlled doses and in time to provide physiological stress, "chemical exercise", in order to induce the synthesis of autologous thermal shock proteins (HSPs). The intracellular heat exposure associated with autologous HSP induction has an important cytoprotective effect against ischemia and cellular trauma and acts as a form of cellular thermal preconditioning in patients who are going to undergo surgery. The induction of HSPs through DNP in patients from 8 to 24 hours before angioplasty, coronary bypass surgery, organ transplants and other forms of high-risk surgery, could provide an improved clinical outcome with intimate thinning after reduced angioplasty or restenosis, high myocardial protection after infarction, improved musculocutaneous survival in plastic reconstruction and reduced ischemia / reperfusion injury in cases of organ transplant. Another aspect of the invention provides controlled doses of DNP to induce whole-body, moderate, long-lasting hyperthermia (6 to 8 hours), (39.0 40.0 ° C) to offer maximum expression of the immunogenic HSPs or peptides associated with HSPs . The antigenic properties of HSPs and HSP-peptide complexes, induced by DNP in infectious agents, especially those located intracellularly, or in tumors, can be exploited to improve the immune response. This aspect of the present invention provides a process for modulating a patient's immune system with other therapies, comprising the steps of: (1) raising the expression of HSPs proteins through the process described above, and (2) administering antibodies monoclonal or humanized polyclonal, or (3) administer cytosines, lymphokines, recombinant interferons, etc. , or (4) administer standard anti-infective or anti-neoplastic therapy. The additional objects and advantages of the invention will be set forth in part in the description of the drawings that follow, and in part will be obvious from the description, or may be learned by practicing the invention. The objects and advantages can be obtained and made through the uses and compositions particularly pointed out in the detailed description of the preferred embodiments and in the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows aspects of glycolysis with the formation of pyruvic acid and release of energy as heat. Figure 2 illustrates the conversion of pi ruvic acid to acetyl CoA and the 2 carbon fragments entering the TSA cycle. Figure 3 shows the electron transfer downstream of the electron transport chain during the oxidative phosphorylation process. Figure 4 shows oxidative phosphorylation as a coupling of 2 different processes, the oxidation of reduction equivalents and the formation of ATP. Both processes are "coupled" through a potential electro-chemical membrane created by passing electrons down the electron transport chain. Figure 5 shows the chemosmosis process. The electrons that pass to the electron transport chain create energy to pump H + out of the internal mitochondrial membrane. This process creates a proton motive force that causes the formation of ATP through protons that invade the membrane through ATP-synthase.

Figure 6 illustrates the decoupling of oxidative phosphorylation through damage to the inner mitochondrial membrane. Figure 6 (a) shows how oxidative phosphorylation is coupled by DN P in undamaged intact mitochondrial membranes. Figure 7 shows the initial formation of superoxide radicals through the univalent reduction of oxygen in the electron transport chain. Figure 7 (a) illustrates the formation of hydrogen peroxide and hydroxyl radicals through the Heber-Weiss reaction. Figure 7 (b) shows a summary of mitochondrial oxygen utilization and free radical formation. Figure 8 illustrates the heating effects on mitochondrial decoupling and the correlation of decoupling with superoxide free radical formation. Figure 9 illustrates the increased formation of free oxygen radicals after the termination of DN P decoupling and normalization of oxygen consumption. Figure 10 shows the overall intracellular effects of DNP, including the dominant foci of increased heat generation. Figure 1 1 shows the relative powers of several decouplers. Figure 1 1 (a) shows the effect of body temperature on a metabolic scale. Figure 1 2 shows six of the hottest organs in the human body and their relative blood flow.

Figure 13 shows the effect of successive doses of 2,4-DNP on oxygen consumption. Figure 14 shows a typical flow diagram of a hyperthermia patient induced by DN P. Figure 15 shows a flow chart of a patient verified after successive infusions of DNP and glucagon for the treatment of parasitic liver disease. Figure 16 shows the annihilation of UT-78 H cells chronically infected with HIV with varying concentrations of DN P. Figure 1 7 shows a flow chart of the patient after infusion of norpinfrin and successive intravenous doses of DN P for the treatment of disease by VI H. Figure 1 7 (a) illustrates substitute parameters in relation to VI H disease before and after treatment with DN P. Figure 18 shows a patient flow chart verified after a successive infusion of DN P for the treatment of Lyme's desease. Figure 1 9 shows a patient flow chart verified using an alpha-1 adrenergic agonist with DNP to induce hyperthermia in a patient with disseminated cancer. Figure 20 shows several survival studies of tumor growth regression animals treated with DN P and a drug encapsu thermosensitive liposome side. Figure 21 shows the protective effects of pretreatment with DN P in balloon-induced arterial catheter damage. Figure 22 shows the protective effects of pretreatment of DN P on survival after prolonged hepatic ischemia induced by the Pringle maneuver. Figure 23 shows the improved survival effect of musculocutaneous flat skin after pretreatment with DNP. Figure 24 shows the effects of oral DNP on oxygen consumption before a patient undergoes a PET scan. Figure 25 shows a flow chart of DN P verified with increasing increases in oxygen consumption before a patient experiences diagnostic thermography. Figure 26 shows a verified patient flow diagram using dinitrophenol and methylene blue for the treatment of prostate carcinoma. Figure 27 shows biochemical and clinical response of androgen-independent prostatic carcinoma to dinitrophenol and treatment of methylene blue. Figure 28 shows a verified patient flow diagram using interferon-alpha and dinitrophenol for the treatment of chronic hepatitis C infection. Figure 29 shows the effects of treatment of dinitrophenol and interferon-alpha on liver enzymes and viral loads of hepatitis C. Figure 30 shows an illustrative method of synthesis of conjugates and novel derivatives of 2,4-dinitrophenol. Figure 31 shows the synthesis of an expanded combination collection of uncoupling agents.

DETAILED DESCRIPTION OF THE INVENTION The elements of electron transfer, transport and energy conversion are ubiquitous and necessary for life. All eukaryotic and prokaryotic organisms depend on electron transfer and transport elements such as hemes containing metal and non-metallic portions such as flavins and adenine nucleotides. These biochemical entities convert stored energy into chemical bonds of food into potential cellular and organelle membranes, molecules that contain high energy such as adenosine triphosphate (ATP), creatinine phosphate, and other forms of chemical energy necessary to maintain the state of Entropic life highly negative. The most common form of biological energy is adenosine triphosphate (ATP). Adenosine triphosphate, ATP, is produced either anaerobically through the path of Embden-Myerhoff (glycolysis) or through oxidative phosphorylation. The latter, an oxygen-dependent chemical energy conversion process, is generally associated with the Tricarboxylic Acid Cycle [(TCA), Krebs Cycle or Citric Acid Cycle]. The acid cycle tricarboxylic links the glycolysis products to a coupled series of multiple enzymes of electron carriers called an electron transport chain (ETS). The electron transport chain is coupled for the production of adenosine triphosphate. The entire tricarboxylic acid cycle and the oxidative phosphorylation process is located in intracellular organelles known as mitochondria. Although the release of energy from food can come from a variety of biochemical means, the most important means through which the release of energy is initiated is through the division of glucose into two molecules of pyruvic acid. This occurs through the non-oxygen dependent process of glycolysis in a series of ten chemical steps illustrated in Figure 1. The total efficiency of trapping energy in the form of adenosine triphosphate, ATP, through this anaerobic process It is 43%. The remaining released energy (57%) is discharged in the form of heat. The pyruvic acid molecules derived from glucose, as well as final products of fat and protein breakdown, are transported to the mitochondrial matrix where they are converted to two carbon fragments of acetyl-coenzyme A, Figure 2. As illustrated, these fragments of acetyl enter the tricarboxylic acid cycle if their hydrogen atoms are removed and released either as hydrogen ions (H +) or combined with nicotinamide and flavin adenine dinucleotides (NAD + and FADH) to produce large equivalent quantities of usable reductions (NADH and FADH2). The skeleton or carbon structure is converted to carbon dioxide (CO2) which is dissolved in body fluids. Finally, the dissolved CO2 is transported to the lungs and expired from the body. As seen in Figure 2, the flow of reagents in the tricarboxylic acid cycle is always the same direction, since NADH and FADH2 are constantly being removed as the hydrogen is oxidized by the mitochondrial electron transport chain. It is the electron transport chain that provides approximately 90% of the total adenosine triphosphate formed through glucose catabolism. During this process, known as oxidative phosphorylation, the hydrogen atoms that were released during glycolysis, the tricarboxylic acid cycle, and converted to NADH and FADH2, are oxidized through a series of enzymatic redox complexes (electron transport chain). ) located in the inner mitochondrial membrane, Figure 3. The energy released in these steps is captured by a chemosmotic mechanism that is dependent on the final reduction of O2 to form H2O. As illustrated in Figure 4, oxidative phosphorylation is two distinct processes: (1) oxidation NADH and FADH2; and (2) the formation of adenosine triphosphate. Both processes are interdependent or "coupled" by a high energy bound proton gradient (H +, pH) and membrane potential through the inner mitochondrial membrane provided by electrons as they pass through the electron transport chain. The energy released by the electrons pumps hydrogen ions (H +) from the internal matrix of the mitochondrion into the space between the outer membrane, Figure 5. This process is known as chemosmosis and creates a high concentration of H + outside the internal mitochondrial membrane and a powerful negative electric potential in the internal matrix. This transmembrane proton gradient (proton motive force) causes hydrogen ions to flow back into the mitochondrial matrix through an integral membrane protein (adenosine triphosphate tape) to form ATP from ADP and ionic phosphate free. The efficiency of oxidative phosphorylation in the capture of energy as adenosine triphosphate is approximately 69%. The remaining released energy (31%) is dissipated as heat. The total efficiency of energy transfer to adenosine triphosphate from glucose through glycolysis, the tricarboxylic acid cycle and oxidative phosphorylation is 66%, with approximately 34% of the energy being released as heat. Heat is continuously produced by the body as a byproduct of metabolism and finally all the energy expended by the body is converted to heat. On a thermodynamic basis, the body's total heat production is the algebraic sum of the enthalpy changes of all biological processes in the body. The trajectories with inapplicable, although in the body the oxidation involves numerous reactions catalyzed by enzyme that is present at 37 ° C. Biochemically, around 95% of all oxygen (O2) consumed is used by the mitochondria to stoichiometrically couple the reduction of oxygen to adenosine triphosphate and production of heat through oxidative phosphorylation. The speed of consumption of O2 (VO2) can be measured through indirect calometry and in this way be related to the production of heat in the body. Although this method does not include anaerobic processes such as glycolysis, indirect calorimetry is closely in agreement with direct measurements of heat in the body and it is generally accepted that one liter of VO2 generates 4,825K calories (kilocalories of energy), 5/6 of which can be detected as heat. In human adults, elevated VO2 and endogenous heat production can occur through muscle thermogenesis (work or chills) and / or chemistry [(catecholamines, thyroid, etc.) without chill]. Since muscle activity can increase heat production by 4-10 times, thermogenesis without chills can only increase heat production by up to 15%. However, oxygen consumption and thermogenesis without chills can increase dramatically when moderate damage to the inner mitochondrial membrane occurs, so that no intact proton leaks or re-enters the mitochondrion, uncoupled to the synthesis of the triphosphate of the mitochondrion. adenosine Heating, endotoxin, osmotic imbalance, etc. , can cause such damage, that is, loss of coupling, resulting in respiration and metabolism of adenosine triphosphate preceding independently and maximally, previous respiration, phosphorylation in reverse. Figure 6 compares normal coupled respiration and the formation of adenosine triphosphate with that which occurs there has been damage to the inner mitochondrial membrane. The increased reduction of oxygen results in a high heat production. In addition, certain chemicals, including biological products, can selectively elevate proton transport through intact, undamaged internal mitochondrial membranes, and dramatically increase VO2 and heat production. These compounds dissipate the proton electrochemical-motor proton transmembrane potential of the mitochondria and decouple the electron transport chain from the synthesis of adenosine triphosphate. Figure 6 (a) illustrates said decoupling agent, DNP, which cyclizes protons through an intact mitochondrial membrane. The DNP and other decouplers allow each of the different processes involved in oxidative phosphorylation to "separate" and increase their velocities according to their own separate kinetic and thermodynamic signals, Figure 6 (b). The decouplers increase the breathing regimes, electron transport, VO2, heat production and increase the utilization of food substrates through glycolysis and the tricarboxylic acid cycle. Controlled doses of a decoupler will increase O2 consumption and heat production with a reduction or none at all. reduction in adenosine triphosphate levels, due to the intracellular equilibrium displacement in criatinin phosphate, oxidative phosphorylation reagents and high production of adenosine triphosphate through the anaerobic, glycolytic path. Excessive or toxic doses of virtually all uncouplers, however, will produce adverse side effects, including decreased respiration, decreased heat production and ultimately cell death. In addition to the fact that heat is a by-product of oxidative phosphorylation, reactive oxygen species are also continuously produced by the mitochondrial electron transport chain. Oxygen free radicals are produced during aerobic oxidation as the electrons are finally transported by the electron carriers to reduce O2 to H2O. As illustrated in Figure 7, superoxide radicals (O2.) Are generated by electrons spilled through the univalent reduction of oxygen. Figure 7 (a) shows that the superoxide dismutase then converts the superoxide radical to hydrogen peroxide. Additional hydrogen peroxide (H2O2) and hydroxyl radicals (OH-) are formed through the Haber-Weiss reaction, the hydroxyl radical being the most reactive species, reacting with any biological portion instantaneously. Figure 7 (b) illustrates the total scheme of oxygen metabolism and free radical formation at the level of the mitochondria. As the mitochondria warm up progressively, the Decoupling occurs with increased flow of free oxygen radicals. The effects of heat on mitochondrial decoupling and generation of superoxide radicals are illustrated in Figure 8. A linear correlation of 0.98 (P <0.01) is obtained for the relationship between the percentage of decoupling and the percentage of generation of superoxide. Similar to the body temperature increased by exercise and VO2 induced hyperthermia through decoupling agents appears to inhibit electron transport at the cytochrome c level in the redox chain. Normal rat liver, infused with DN P, increases the formation of reactive oxygen species to three times after the end of decoupling, Figure 9. In general, uncouplers are agents that are ionophores, hydrophobic binding protons and transverse biological membranes to dissipate the proton in transmembrane (pH) and potential membrane gradients (??, Delta Psim). By doing this, decouplers increase the rate of metabolism (utilization of substrates) in intact animals and isolated tissues by increasing the oxygen reduction regime through the high availability of protons. The consumption of O2 is increased and remains fast as long as the mitochondrial respiratory chain (electron transport) tries to overcome the effects of the uncoupler to maintain a pH gradient. The energy is still being used to pump protons through the mitochondrial membrane, but the protons are carried back through the membrane through the decoupler as illustrated in Figure ?(to). This creates a useless cycle and the energy is released as heat. This chemical heat release process is comparable to the heating that occurs when a power cord is "short-circuited". Depending on the degree of external heat dissipation of the body, the body temperature rises 30 to 60 minutes after the increase in O2 consumption. The rapid onset of actions after an intravenous injection of a decoupler. Depending on the intravenous dose, human oxygen consumption is high in approximately 1 5-20 minutes and the production of intracellular heat is proportionally high. Metabolic regimens as high as 10 times normal have been reported. The increases persist in the metabolic regime and can continue as long as 12 to 36 hours, due to the long hydrophobic half-life of the decouplers in the tissues. Increases in temperature can be seen from 10 minutes to 15 minutes in subjects whose heat dissipation mechanisms have been compromised. So far, it has not been reported that hyperthermia induced by decoupling compounds have any therapeutic application. Although there are three general classes of decoupling agents, each contains specific decouplers of oxidative phosphorylation. The present invention uses 2,4-dinitrophenol (DN P) as the preferred embodiment. This is because 2,4-d initrofenol has been extensively studied. DN P was commonly used in food grade dyes at the end of from the 1800s and in the ammunition industry of the First World War. A rapid high respiration and hyperthermia, up to 49 ° C, was observed in man and animals that were accidentally intoxicated. Said dramatic physiological effects by dinitro-aromatic dyes, especially 2,4-dinitrophenol, caused these to remain inextricably linked to modern and later studies of metabolism and bioenergetics. In the 1930s, 2,4-dinitrophenol was introduced to clinical medicine for the purpose of losing weight. However, it was sold as a secret panacea for runners and seriously misused. If its long half-life in tissues has been recognized and the medical supervision implemented, it can become an accepted drug. 2,4-dinitrophenol has been reported in innumerable different enzyme, cellular and metabolic studies. The review of such large published studies has documented a very specific mechanism of 2,4-dinitrophenol with common action and proton ionophore, with all the effects of its direct pharmacological extension. DNP is not mutagenic through the modified Ames and Ames tests; it has not been found to be carcinogenic or teratogenic; and, the levels in the blood plasma of DNP can be easily determined. 2,4-Dinitrophenol can be used at pharmacological doses that achieve therapeutic concentrations in tissues. In addition 2,4-dinitrophenol is stable, inexpensive and commercially available in a purity of reagent grade. However, it is understood that other decouplers and combinations of other decouplers with other drugs, hormones, cytosines and radiation can potentially be used under clinical fixation and appropriate doses to induce intracellular hyperthermia and promote additive or cynergy effects. Figure 10 shows the total intracellular mechanism of the action of 2,4-dinitrophenol (and other uncouplers). High-intracellular foci of high heat and oxygen-free radical flow are illuminated. The numbers enclosed in circles in the Figure indicate both direct and indirect effects of DNP: the effects with circles 1 and 2 show that after their intercalation in the inner mitochondrial membrane, DN P releases H + (hydrogen ions) through the membrane [see Figure 6 (a)], this short circuits (de-energizes) the proton gradient established by the H + pumping action of the mitochondrial electron transport system (see Figure 5). As a consequence, the internal mitochondrial membrane potential is reduced from -180 to -145 mV. The effects of circles 3, 4, 5 and 6 show that the normal oxygen consumption and flow of NADH and FADH2 (reduction equivalents) through the electron transport system is coupled to the additional input of H + through the mitochondrial availability of ADP to re-synthesize adenosine triphosphate (see Figure 4). By freely returning the protons in the mitochondrial matrix without the concomitant dependence in the reformation of ADP to ATP, 2,4-dinitrophenol increases oxygen consumption proportionally to the degree of decoupling. The oxygen consumption regime remains linked, however, to the flow of electrons provided by NADH and FADH2 through the electron transport chain [see Figure 6 (a)]. The use of NADH and FADH2 (re-oxidation) is concomitantly increased. The effects in circles 7, 8, 9 and 10 show that the use of oxygen and electron transfer proceed at increasing speeds to accelerate proton pumping against the added hydrogen ion charge introduced by 2,4-dinitrophenol. As a result, NADH and FADH2 are continually diminished by the oxidation region to NAD + and FAD ++. The high "oxidation pressure" NAD + and FAD ++ increase the oxidation of the substrate and the flow of two carbon segments through the tricarboxylic acid cycle (TCA). The consumption of acetyl-CoA increased at the same time is maintained by an increased glycolysis regimen through the reduction of pyruvate. If the oxygen supply is inadequate or the dose of 2, 4-dinitrophenol is excessive, the concentration of reduced NADH is increased, the oxidation of pyruvate through CoA and the tricarboxylic acid cycle is inhibited and the lactic acid will accumulate. Lactate is overproduced when cellular hypoxia is not present per se, but glycolysis exceeds pyruvate oxidation. Said intracellular lactic acidosis exists in neoplastic cells, where there is a lack of insulin, when the fructose is infused and in other conditions or use of drugs that increase glycolysis and / or inhibit the mitochondrial electron transport system. Although it is understood that the intracellular heat generated by 2,4-dinitrophenol is the algebraic sum of enthalpy changes of all metabolic processes within the cell, the Effects enclosed in circles in 1 1, 12 and 13 illustrate the most important intracellular foci of heat generated by 2,4-dinitrophenol. Total hyperthermia of the intracellular body results when 2,4-dinitrophenol releases energy at a faster rate than it can be dissipated. The heat is generated mainly in the inner mitochondrial membrane (electron transport system) the tricarboxylic acid cycle and cytoplasmic glycolysis sites. Initially, DNP generates heat in the inner mitochondrial membrane by discharging a portion of the energy stored in its electrochemical gradient. Optionally, said heat is from the "chemical short circuit" created by 2,4-dinitrophenol that releases protons to the negative side (matrix) of the polarized internal mitochondrial membrane [see Figure 6 (a)]. By usurping the controlled proton reentry and energy capture as ATP of the availability of ADP through ATP synthase, 2,4-dinitrophenol causes reoxidation of NADH and FADH2 (higher concentrations of NAD + AND FAD ++) at speeds much higher than those needed for oxidative phosphorylation. This causes an increased drop of electrons through the electron transport chain with rapid reduction of oxygen to water (see Figure 3). The resulting energy is released as heat within the mitochondrial membrane. The rate of heat production from the tricarboxylic acid cycle is increased as it operates at a higher flow to maintain decreased amounts of reduced NADH and FADH2 used to reduce molecular oxygen. The flow of Acetyl-CoA and all metabolites through the tricarboxylic acid cycle (see Figure 2) is increased by the activation of enzymes that sequentially degrade hydrogen containing 2 carbon fragments to CO2, NAHD, FADH2 and heat. Glycolysis and its associated heat production in the cytoplasm is also increased by 2,4-dinitrophenol. The glycolytic activity is elevated through reduced concentration ratios of ATP to ADP, activating pyruvate dehydrogenase and phosphofructokinase respectively (see Figure 1). These enzymes increase the rate of catabolism from glucose to pyruvate and its conversion to acetyl-CoA to enter the tricarboxylic acid cycle. Giicolysis is very "inefficient in energy" to develop the energy balance deficit created by DNP. The non-captured energy of the glycolytic exergonic reactions accelerated by DNP is released as heat in the cytoplasm. The production of anaerobic heat stimulated by 2,4-dinitrophenol through glycolysis can sometimes be greater than that produced by the mitochondria. For example, many tumors and normal fibroblasts treated with DNP increase heat production by 83%, with only a 36% increase in oxygen consumption. It is known that glycolysis contributes to more than 62% of the total heat produced by human lymphocytes. The effect with circle 14 shows that the mitochondrial electron transport chain normally produces reactive oxygen species through univalent oxygen reduction [see Figure 7, 7 (a) and 7 (b)]. Under physiological conditions, 2 to 4% of mitochondrial oxygen is converted to superoxide. The induced partial decoupling of DN P and mitochondrial heating increases the production number of reactive oxygen species. It is known that cytochrome oxidase and reductase are inhibited by heating the electron transport system. As a result, the hot mitochondrial membranes produce a high amount of free oxygen radicals when the decoupling induced by DN P is stopped and the oxygen consumption is normalized (see Figure 9). Reactive oxygen species act in synergy with heat to alter proteins, induce membrane changes and initiate apoptosis in susceptible cells. The effects with circles 1 5 and 16 show the effects of DN P on intracellular calcium homeostasis. Usually, calcium is stored in the mitochondrial matrix, being pumped through the energized mitochondrial membrane. By de-energizing the mitochondria directly through DN P, and indirectly inducing the heating of the membrane and pro-oxidant tension, the permeability of the inner mitochondrial membrane is elevated not specifically with the flow and calcium cycle. This activates intramitochondrial dehydrogenases to produce more reduction equivalents in the form of NADH and FADH2 to coincide with high energy demands. The production of heat is high as a by-product of the increased tricarboxylic acid cycle. Other known decouplers that are considered as "classics" in the same category and which act as DNP, include clofazimine, albendazole, cambendazole, oxybendazole, triclabendazole (TCZ), 6, chloro-5- [2,3-dichlorophenoxy] -2-methylthio-benzimidazole and its metabolites of sulfoxide and sulfone, thiobendazole, rafoxanide, bithionol, niclosamide, eutipine, various lichen acids (hydroxybenzoic acids) such as (+) usnic acid, vulpinic acid and atranorine, 2 ', 5-dichloro-3-t-butyl-4' -nitrosalicylanilide (S-¡#), 3, 4 \ 5-triclorasalicilanilide (DCC), silvernetin, 2-trifluoromethyl-4,5,6,7-tetrachlorobenzimidazole (TTFB), 1799, AU-1421, 3,4,5 , 6,9, 10-hexahydro-14,16-dihydroxy-3-methyl-iH-2-benzoxacyclotetradecin-1,7 (8H) -dione (zearalenone), N, N 1 -bis- (4-trifluoromethylphenyl) -urea , resorclic acid lactone and its derivatives, 3,5, -di-t-butyl-hydroxybenzyldenemalonontrile (SF6847), 2,2, -bis- (hexafluoroacetonyl) acetone, triphenylboron, carbonyl cyanide (4-trifluoromethoxyphenylhydrazone) (FCCP) , tributylamine (TBA), 3-chlorof carbonyl cyanide enylhydrazone (CICCP), 1, 3,6,8-tetranitrocarbazole, tetrachlorobenzotriazole, 4-iso-octyl-2,6-dinitrophenol (Octyl-DNP), 4-hydroxy-3,5-diidobenzonitrile, mitoguazone, (Methylglyoxal bisguanilhydrazone), pentachlorophenol (PCP), 5-chloro-2-mercatobenzothiazole (TBI), N- (3-trifluoromethylphenyl) -anthranilic acid (flufenamic acid), 4-nitrophenol, 4,6-dinothrocresol, 4-isobutyl- 2,6-dinitrophenol, 2-azido-4-nitrophenol, 5-nitrobenzotriazole, 5-chloro-4-nitro-benzotriazole, tetrachlorobenzotriazole, methyl-o-phenyl-hydrazone, N-phenylanthranilic acid, N- (3-nitrophenyl) anthranilic acid, acid N- (2,3-dimethylphenyl) anthranilic, mefenamic acid, diflunisal acid, phlephenamyxic acid, N- (3-chlorophenyl) anthranilic acid, carbonyl cyanide 4-trifluoromethoxyphenylhirazone (FCCP), SR-4233 (Ti rapazamine), atovaquone, 4- (6'-methyl-2'-benzothiazyl) -phenylhydrazone carbonyl cyanide (BT-CCP), ellipticine, olive oil, ellipcinium, isoelipticine and related isomers, methyl-0-phenylhydrazonocyanoacetic acid, methyl-0- (3-chlorophenylhydrazono) cyanoacetic acid 2- (3'-chlorophenylhydrazone) -3-oxobutyronitrile , thiosalicylic acid, 2- (2 ', 4-dinitrophenylhydrazone) -3-oxo-4,4-demethylvaleronitrile) relanium, melipramine, and various other chemical entities including unsaturated fatty acids (optimally up to 14 carbon atoms), sulflaramide and its metabolite suifonamide perfluoroctane (DESFA), perfluoroctane, clofibrate, Wy-14, 643, ci profibrate, and fluoroalcohol. The conventional unnamed additional uncouplers can include any analog that generally has a removable, weakly acidic proton and a lipophilic, electron withdrawing moiety that is capable of delocalising charges. The hydrophilic character and the ability to exchange proton equivalents are integral aspects of classical DNP types of decouplers. A second class of decouplers are ionophore antibiotics. These molecules uncouple oxidative phosphorylation by inducing influx of cation or anion through the mitochondrial membranes and diffusing a protonated form. As a result, the useless chemical cyclization ensures the restoration of the initial membrane potential. The energy released is dissipated as heat.

Examples of ionosphores that release potassium ions (K +) through membranes include the antibiotics gramicidin, nigericin, thyrotricidin, tirocidin and valinomycin. Nystatin releases sodium ions. The calcium ionophore, compress A23187, is an ionophore soluble in lipids that mediates the electroneutral exchange of divalent cations for protons. Alamethycin, harizianin HA V, satuturnisoporin SA IV, zervamycins, magainin, cecropin, melittin, hipecilins, suzucalilins, monensins, tricotoxins, antiamoebins, crystal violet, cyanide dyes, cadmium ion, trichosporin-B and its derivatives are examples of decoupling ionophores that depend on the release of organic phosphate (PO =) through the mitochondrial membrane. A third class of uncouplers is a group of heterogeneous compounds that dissipate the proton gradient by binding or interacting with specific proteins in the inner mytochondrial membrane. Examples of said compounds include desadpifins, ionized calcium (Ca ++), decoupling proteins such as UCPI-1, UCP-2, UCP-3, PU MP (Mitochondrial Plant Decoupling Protein), histones, polylysines, and the protein antibiotic A206668-a that bind proteins of phosphoryl transfer. The examples and a power comparison of some uncouplers are illustrated in Figure 11. Various conjugates, ducts, analogues and derivatives of the aforementioned agents can be formulated and synthesized to improve intracellular uncoupling and heat production. In addition, several covalent uncoupling compounds can be synthesized as pro-drugs, which after redox or reaction with free radicals within the cell, will be activated to induce decoupling, heat production and free radical cyclization. Such derivatives and formulations may be desirable in the treatment of many tumors with higher mitochondrial membrane potentials and high total bio-reductive capacity. In this manner, the decoupling free radical pro-drug compounds can exert a selective higher kill of transformed cells by experiencing a greater flow of reduction or acceptance of electrons in tumor cells. In this regard, the contents of the patent of E. U.A. No. 5,428, 163 and the published methods of C-Alkylation of phenols and their derivatives by Hudgens, TL and Turnbull, KD are incorporated herein by reference, From a physico-chemical and thermodynamic point of view, the amount of heat produced by the Decoupling is proportional to the density and velocity of electron flow through the mitochondrial electron transport chains. Said electron flow is initially reflected by the magnitude of the electrochemical proton gradient through the inner mitochondrial membrane. Those cells, tissues or organs and organisms that are metabolically more active will generally have a high membrane potential and will respond with a greater amount of heat production for a given dose and type of decoupler. The Figure 12 lists the six most "hot" organs in a human body along with their blood flow velocities and heat production rates. The actual amount of intracellular hyperthermia produced by a decoupler depends on the dose of the decoupler, its relative potency and substrate availability such as glucose, glutamine, fatty acids and other substances that produce NADH or FACH2. Oxygen and the magnitude of the electrochemical gradient of the mitochondrial proton (? ΜH +) are additional factors that determine the amount of heat that can be potentially released by a decoupler. Among all the constituents,? ΜH + is the most clinically important. ? μH + is composed of the transmitochondrial membrane potential [?? (charge difference)] and the pH gradient (? pH (H + concentration difference) l,? μH + = F? - 2.3RT? pH, where F = Faraday constant, R = Gas constant and T = Kelvin Degrees In this way,? ΜH + represents the potential amount of heat that can be released by a decoupler when one mole of H + is dissipated through the inner mitochondrial membrane.This potential heat energy is normally expressed in millivolt units (mV) and is referred to as the motive force of the proton,? p =? μH + / F = ?? - 2.3 (RT / F)? pH. In vivo,? pH is generally one unit or less, so that 75 % or more of the total of? p is composed of ?? .. Consequently, the intracellular heat produced by a decoupler can be estimated only by the mitochondrial membrane potential (??).

Knowing the value of ??, is of practical importance since the biopsy specimens can be incubated with cationic organic probes to assess ?? and the degree of differential heating that will occur between normal and transformed tissues. Dyes such as rhodamine 123, mitoratrator green, calcein plus Co ++, 3,31-dihexyloxacarbocyanine, triphenylmethylphosphonium, JC-1, 5,51, 6,61-tetrachlor-1, 113,3 -tetrathylbenzimidazolecarbocyanine, etc. Do you all have an affinity for one? mitochondrial negative. Based on the amount of cationic dye consumption, the membrane potential of specific tissues, tumors and cells can be determined through the Nernst equation: ?? = - (RT / F) 1 n (Centered / Csa? gives). Which at physiological conditions of 37 ° C = -61 record (Cent / Csa? Da), where Centered / output is the concentration of the probe inside and outside the mitochondria and plasma membrane. For example, from 10 to 1 gradient = -60mV, 100 to 1 = -120mV. The decouplers dissipate, generate heat and release or edit the consumption of cationic dyes. Six years of systematic measurement of mitochondrial membrane potentials have been performed on human and mammalian cells, including some 200 cell types derived from human malignant tumors of kidney, ovary, pancreas, lung, dural cortex, skin, breast, prostate, cervix, vulva, colon, liver, testicles, esophagus, trachea and tongue. Based on this exhaustive study, a difference of ?? of at least 60 mV is known to exist between normal epithelial cells and carcinoma cells. This is important for the present invention, since the uncoupling or "short circuit" of a potential of 60 mV through a mitochondrial membrane of 5 nm could be equivalent to the amount of heat generated by short circuiting 120,000 V through 1 centimeter . By exploiting or raising the membrane potential between normal and transformed cells, the rate of intracellular heat production by a decoupler can be selectively increased in target tissues. In order for an intracellular hyperthermia induced by uncoupler to be of therapeutic benefit, the development of thermotolerance is also taken into account in the practice of this invention. Mammalian cells and prokaryotes become acclimated and acquire transient resistance or thermotolerance to gradual or non-lethal hyperthermia. Said adaptation is believed to occur through the high synthesis of highly conserved groups of proteins known as heat shock proteins (HSP). The amount of HSP present in tissues, cells and organisms subjected to non-lethal heat, or other forms of prolonged metabolic stress, is proportional to their survival at higher temperatures. In general, thermotolerance develops after 3 to 4 hours of continuous hyperthermia, peaks in 1 to 2 days and relapses back to normal thermosensitivity in 3 to 4 days. It is known that thermotolerance alters the lethality of hyperthermia by an increase of as much as 2 ° C or twice the heating time required to achieve the same cytotoxic temperature effect. Bliss Adaptive thermoresistance for human tumors is problematic for continuous or fractionated cytotoxic treatment with hyperthermia. Induction heating times with the present invention, therefore, are maintained at a minimum of 1 to 2 hours. In addition, the cytotoxic hyperthermia induced by the decoupler in the present invention induces relative tissue hypoxia, reduces the intracellular pH and limits the production of adenosine triphosphate, all of these decreasing the development of thermotolerance. Uncoupling of decoupler doses, which produce gradual heating, can be used to induce HSP synthesis and promote thermotolerance. The determination of the amount of 2,4-dinitrophenol in mg / kg of the body weight required to produce the desired level of cytotoxic hyperthermia is a safe and effective way, is established from the thermal equivalents (Kcal) of oxygen consumed ( VO2), and the specific heat capacity by known means of the human body. It is known that at standard temperature and barometric pressure, one liter of oxygen consumed per minute (VO2) generates approximately 4.862 Kcal. It is also known that the average specific heat capacity of human beings is approximately 0.83 of that required to raise one gram of H20 1 ° K = 4.184 J, a heat capacity of 3.47 Jg K "1. An initial estimate of the total energy required to be generated by 2,4-dinitrophenol, to induce a hyperthermia of 41 .0 ° C in one hour can be simply determined from the above, and adapted to a specific patient as follows: Patient Characteristics Body weight 70kg V02 rest 0.25L / min Basal energy expenditure 73.1 Kcal / hr (1754.4Kcal / 24 hrs.) Basal core temperature 37.0 ° C Target temperature 41 .0 ° C Energy required to raise the temperature to the target level in 1 hour (Weight in grams = 70x103) (human specific heat = 3.47 J g K "1) (Temperature increase = 41.0 ° -37.0 ° C) approximately 0.97 x 106 J Since 1 J = 4.184 x 10"4 Kcal, a total energy input of approximately 232 Kcal could be required to raise the patient's temperature to the target level in one hour less than the amount of heat generated by a hot metabolism mentioned above. ahead.

Increase in metabolic rate / heat production with elevation in body temperature The basal metabolic rate (BMR) is known to increase in patients with endogenous fevers by approximately 7% for each 0.5 ° C increase in temperature. This is represented graphically in Figure 1 1 a. As a result, the increase in the BM R in relation to the temperature itself will help achieve the objective level during the induction phase through the following equation: BMRTnúclß0 = 73.1 x 1 .07 (Tnúc, ßo -37) 70 5 In this way, at 41.0 ° C the metabolic rate will be 134.4 Kcal / hr, 61. 3 Kcal / hr above the level of basal energy expenditure. This increase in metabolic rate, therefore, will reduce the initial energy required to heat the patient by approximately 61 Kcal for a one-hour time frame.

Net initial energy input required to reach the target temperature in 1 hour 232 Kcal - 61 Kcal (per high BMR) = 171 Kcal Increase required in initial VO2 to obtain a heat input of 171 Kcal Since the equivalent of Kcal for one liter of oxygen consumed per minute is 4,862, then the initial increase in V02 required for general 171 Kcal can be calculated as follows: Heat in Kcal / minute = V02 x 4.862. Since the individual patient has a V02 at rest of 0.25 l / minute at which = 73.1 Kcal / hour of BMR, then X (V02) = 171 Kcal, or X = 0.25 x 171 /73.1 An initial minimum increase in V02 at approximately 0.60 l / minute is required.

Dosage of 2,4-dinitrophenol required to increase V02 to 0.60 l / min. The individual dose of 2,4-dinitrophenol DNP (mg / kg) required to produce an increase in oxygen consumption to 0.60 l / minute with the In order to achieve a heat production of 171 K / lime, it is achieved in the following way: (1) 2,4-dinitrophenol is prepared in a sterile aqueous solution of 200 mg / 100 ml. If it is not completely dissolved, it can be brought to a solution by regulating its pH with 1% NaHCO3, the pH must be maintained below 8 to avoid hydrolysis; (2) the dose of 2,4-dinitrophenol, DN P, for each intravenous infusion can vary from 0.5 to 4 mg / kg and will depend on the clinical situation, as well as the initial and subsequent increases in metabolic rate (V02). In an especially preferred embodiment, the patient is given an initial dose of DNP not greater than 1 mg / kg intravenously, infused for not less than a period of two minutes. Within approximately 10-15 minutes, a minimum of a 15% increase in V02 will occur. The V02 will continue to rise until a plateau is reached in an additional 5 to 10 minutes. After 5 minutes of plateau in V02, a subsequent dose of either 0.5, 1, 2, 2.5 or 3.0 mg / kg of DNP is administered and V02 is raised until a desired plateau is reached. Additional infusions of DNP or other medications are administered under clinical parameters of V02 respiratory regimen, pulse, blood pressure, urine output, cardiac output, core temperature, and clinical state of the patient in order to maintain a safe and effective heating control. If the heat dissipation mechanisms are neutralized, measurable increases in core temperature will occur approximately 20 to 30 minutes after an increase in V02. Figure 13 illustrates the V02 increases associated with repeated infusions of 2,4-dinitrophenol. Medications that raise total metabolic rate, or that of specific target tissue, and have short half-lives, can be used to increase the relative activity of DNP or other decouplers to further adjust V02 and heat production. Examples of such drugs are almost unlimited since any drug, hormone or biological response modifier that causes changes in entalphia (heat content) during the course of its chemical and intracellular biophysical activity and interaction in the life cycle of biological cells, They can be used. Some illustrative examples include glucagon (half-life of 9 minutes in the plasma), arbutamine (half-life of 10 minutes), dobutamine (half-life of 2 minutes), and vasopressin (half-life of 5 minutes). Various amino acids and fatty acids, for example, glutamine, proline, octanoate, etc. , increase V02 through the translocation reduction equivalents towards the mitochondrial matrix through the release of malate-aspartate, B-oxidation or proline metabolism. Agents such as methylene blue (tetramethylthionine), ubiquinone, menadione, hematoporphyrin, phenazine, methosulfate, 2,6-dichlorophenolindophenol, coenzyme Q 1, CoQ2, or other analogues of duroquinone and decilubiquinone, etc. , they can raise the heat and / or the production of free radical acting as artificial electron acceptors. Said agents, and numerous others, can be co-administered with DNP or other uncouplers to effectively elevate changes in enthalpy in the entire organism or specific target tissues.

Reduction of heat loss and temperature control The loss of radiation heat and elevated evaporative of man are two main dominant thermoregulatory mechanism for the cooling of the body. The body's methods for adjusting heat loss are vasoconstriction and vasodilation in the blood vessels of the skin. Radiation can represent 60% of the heat loss generated by the body, while evaporation sweating at 1.0 liters / hour can represent a potential heat loss of approximately 1,000 Kcal / hour. With a big difference, sweating and evaporation is the main mechanism that dissipates heat under conditions that induce large heat gains. Depending on the clinical circumstances, heat loss due to evaporation as well as radiation can be managed and controlled through a variety of methods including, but not limited to, using vasoconstriction agents, placing the patient in a surgical suit. scuba diving, moistened survival suit, or wrapping the patient in a blanket soaked in covered water or Containing a polyethylene liner to avoid evaporative heat losses. The use of ultrasonic nebulizers to induce continuous humidity and high humidity is also known to prevent evaporative heat losses. The evaporative and radiant heat loss of the skull is controlled through appropriate upper gears, shower caps and / or wet towels. The control of local air velocities and the handling of surrounding areas such as temperature, emission, winds and convection currents are important to avoid large heat losses. In those clinical circumstances, where a total hyperthermia of the body is required, the failure to adequately control the heat loss of the body will need to use higher doses of DNP in inducing a greater metabolic tension in the patient. If the core target temperature is exceeded or continues to rise after the target temperature is achieved, exposing a limb or body surface for a short interval will allow sufficient heat loss to reduce core temperature to the target scale. At target temperatures of 39-41 ° C, the residual decoupling through DNP will continue for approximately 3 hours. The production of heat with a by-product of glycolysis, and the hot metabolism also keeps the heat content in the body and compensates for any heat loss. Therefore, target plateau temperatures can be regulated with a large margin of safety and with little or no additional use of decoupler. The therapy is finished removing the patient's vapor barrier. The evaporative and radiant heat loss of the patient generally produces a drop in core temperature of approximately 2-2.5 C in approximately 20-30 minutes. Obese patients and those with compromised thermoregulation systems experience a slower drop in temperatures.

Patient supervision, fluid support and evaluation during treatment The placement of physiological monitoring sensors, intravenous fluids, supplemental oxygen (41 / minute) and optional oral diazepam sedatives (5-10 mg) is initiated before treatment. Patients receive 0.85 to 1.0 liters of 5% intravenous dextrose (IV) in 0.25 normal saline per hour alternating with 5% dextrose in 0.5 normal saline plus 7.5 to 10 meq KCl per liter to ensure urinary output Not less than 1 ml / kg / hr. The oxygen consumption, the caloric expenditure, rectal core temperature, heart rate, blood pressure, heart rate and respiratory rate are continuously displayed, supervised by a trained member of the treatment team. The data is automatically downloaded into a computer every 20 seconds to 3 minutes during the entire procedure and immediately represented in computer graphics and diagrams. Two hours after the treatment and 48 hours of post-treatment, the serum chemistries and blood profiles are repeated. A typical flow diagram of a Patient is illustrated in Figure 14.

Excessive heat treatment and antidotes In those rare cases where too much uncoupler is administered or the patient's metabolic rate unexpectedly increases and V02, hyperthermia, pulse rate and resulting patient fatigue, appropriate support measures of cooling should be instituted, intravenous hydration and administration of specific medications. The cooling should be instituted not covering the patient, spraying with warm water and ventilating with an industrial grade ventilator. If cooling is inadequate, ice packs should be considered immediately on surfaces, underarms and groin and intravenous cold glucose solutions. Bicarbonate 1 -2 mEq / kg should be administered in the absence of blood gas analysis. The urine output of > 1 ml / kg / hour should always be maintained to avoid prerenal azotemia and secondary oliguria for possible rhabdomyolysis and myoglobinuria. Mannitol should be administered if urine production is inadequate. Hypoglycemia should be corrected immediately with 50% saturated intravenous glucose. If it results in severe or persistent hypermetabolism, 1,000 mg of rectal propylthiouracil, hydrocortisone (100 mg q 6 hours) or dexamethasone 2 mg q 6 hours, and / or sodium iodide as sodium iodide of 1 g should be administered intravenously. (contrast agent) should be administered intravenously to induce iatrogenic hypothyroidism. The Reduced metabolic rate will dramatically decrease the physiological response of DN P. Agitation and restlessness of the patient can be avoided through an appropriate IV dose or IM of diazepam. Salicylates are of no value and can contribute to further decoupling. Medications that reduce sweating, for example, tricyclic antidepressants, antihistamines, anticholinergics, phenothiazines, or reduced vasodilation, for example, sympathomimetics, a-agonists, or that reduce cardiac output, eg, diuretics, beta-blockers, or induce depression hypothalamic, for example, neuroleptics, a-blockers, opioids, etc. , must be avoided before, during and immediately after treatment with decouplers. Hypermetabolic and hyperthermic activity of DNP can also be specifically reduced using calcium channel blockers such as nifedipine, verapamil and others, in intravenous doses that do not cause a drop in blood pressure or induce cardiac arrhythmias. Dihydrobenzperidol (a neuroleptic drug with adrenergic properties) can also be used to cause significant reductions, similar to hypermetabolism and DN P-induced hyperthermia. Doses of these anti-DN P agents are titrated at 5 mg to 30 mg increments and can be provided either by mouth or intravenously. In those cases where 2, 4-dinitrophenol appears to reduce electrical conduction or cause EKG conduction abnormalities, Coenzyme Q10, in a dose of 50mg / kg, can be used to restore normal electrical activity.

Patient selection and pretreatment evaluation It is imperative that in the practice of this invention patients be selected and evaluated before treatment. Criteria for inclusion and exclusion of recommended patients include: (1) patients who have a definitive histopathology or other laboratory-confirmed diagnosis of their disease; (2) the disease or condition must be sensitive to the treatment of intracellular hyperthermia; (3) patients must have a Karnofsky classification of 70% or more; (4) not be pregnant; (5) the weight should be within 45% (+/-) of the ideal body weight and patients should weigh at least 35kg; (6) there should be no history or findings of anhidrosis, scleroderma, ectodermal dysplasia, Riley-Day syndrome, multiple arthrogryposis, extensive psoriasis, serious dysrhythmiasmalignant hyperthermia or malignant neuroleptic syndrome, pheochromocytoma, hypocalcemia, repeated episodes of hypoglycemia, chronic or recurrent venous thrombosis, alcoholism, renal failure, cirrhosis, untreated hyperthyroidism, anaphylaxis associated with heat or exercise-induced cholinergic urticaria, induced angioedema for exercise or heat, schizophrenia, catatonia, stroke disorders, emotional instability, Parkinson's disease, and brain radiation, cystic fibrosis, unstable angina pectoris, congestive heart failure, patients with pacemakers heart disease, severe cerebrovascular disease, spinal cord damage, severe lung damage, hereditary muscle disease such as Duchenne muscle disease, central core muscle disease, congenital myotonia, King-Denborough syndrome, Scwanry-Jampol syndrome, or osteogenesis imperfecta; (6) non-immediate use of drugs that damage heat dissipation mechanisms in the body, such as phenothiazines, anticholinergics, antihistamines, antipakinsonians, glutethimide, hallucinogens, lithium, cocaine, or other use of illicit drug, inhibitors of monamine oxidase , sympathomimetics, phencyclidine, opioids, phenylephrine, INH, tricyclic antidepressants, withdrawal of dopamine agonists, or cardiovascular drugs that clinically damage the cardiac regimen or thermoregulatory vasodilation such as high doses of β-blockers, vasodilators, or calcium channel blockers; and, (7) the patient must not be anemic or otherwise have reduced oxygen absorption, carrying or using capacity. The pretreatment evaluation must include a complete medical history and physical examination focused on the selection criteria listed above. Laboratory evaluation should include pulmonary function tests, if indicated, complete hematologic monitoring with hemastatic profile, EKG, liver function tests, serum biochemical profile, thyroid panel, serum creatinine, calcium, phosphate, and strain-EGK or multiple gate radionucleotide expulsion scan by exercise in patients whose fraction of cardiac expulsion has suspicion of not being greater than 45% with probable deterioration by exercise. Although clinical exceptions for introducing laboratory values may exist, the following laboratory data should be a brand guide for the initiation of treatment: hemoglobin > = 1.0g / dl for men and > = 10.0g / dl for women, platelet count > = 75.00 platelets / mm3, bilirubin < = 2 X ULN (ULN = upper limit of normal). ALT (SGPT) < = 2 X ULN, AST (SGOT) < = 2 X U LN, pancreatic amylase < 1.5 X ULN, neutrophil count > = 1, 000 cells / mm3. The electrolytes in the serum and K + should be within normal limits since hypocalcemine reduces blood flow in the muscles, cardiovascular function, and function of the sweat glands. More generally, the method described above will be designed for an individual patient, how it was previously established, 2,4-dinitrophenol can be administered through intravenous infusion. Alternatively, the route of administration may also be oral, rectal or topically. The frequency and the optimal interval between administrations is individualized and determined by measuring VO2? as well as other parameters. For example, various lab, x-ray, CAT scan, MRI, PET scan, HIV load, CD4 + lymphocyte, HSP expression, prostate specific antigen (PSA) and other clinical production substitute markers can establish VO2, frequency and duration of therapy. A treatment, or treatments with a frequency of each day. or a day yes and a day no. and as far as a year or more may be required for sustained beneficial results. The optimal VO2, temperature, duration and frequency between treatments will likely vary from patient to patient and the specific disease or condition you are treating. One skilled in the art may be able to modify a protocol within the present invention, in accordance with standard clinical practice, to obtain optimum results. For example, VI H ratios between viral load, CD4 + lymphocyte counts, presence of opportunistic infections and the patient's clinical status can be used to develop more optimal regimes of 2,4-dinitrophenol administration. The studies of the applicants have revealed that the methods of the present invention can be effective in the diagnosis and treatment of a wide variety of disease states and conditions wherein the hypermetabolism induced by uncoupler, hyperthermia, oxidant stress, and its sequelae, play an important and beneficial role. For those skilled in the art, it is also contemplated that a variety of different veterinary applications as well as medical ones for treatment and diagnosis can be practiced with the present invention. It is contemplated that 2,4-dinitrophenol, or other uncouplers, may also be administered with other compounds used to treat infections, malignancies and other diseases. Examples of other agents include antifungal drugs, antibacterial, antiviral or anti-plastics, cell differentiation agents and, several biological response modifiers. Examples of antifungal agents include Amphotericin B, Griseofulvin, Fluconazole (Diflucan), Intraconazole, 5-fluoro-cytosine (Flutocytosine, 5-FC), Cetatoconazole and Miconazole. Examples of antibacterial agents include antibiotics such as those represented from the following classifications: β-lactam rings (penicillins), marciclocyclic lactone rings (macrolides), polycyclic naphthacenecarboxamide derivatives (tetracyclines), amino sugars in glycosidic linkages (aminoglycosides) , peptides (bacitracin, gramicedin, polymyxins, etc.), nitrobenzene derivatives of dichloroacetic acid, large ring compounds with conjugated double bond systems (polyenes), various sulfa drugs including those derived from sulfanilamide (sulfonamides, 5-nitro compounds) -2-furianyl (nitrofuran), quinolone carboxylic acids (nalidixic acid), fluorinated quinolones (ciprofloxane, enoxacin, ofloxacin, etc.), nitroimidazoles (metroindazole), and many others.These antibiotic groups are examples of preferred antibiotics, and the examples Within such groups include: peptide antibiotics, such as bacit racine, bleomycin, cactinomycin, capreomycin, colistin, dactionomycin, gramacidin A, enduracitin, amfomycin, gramicidin J, micamycins, polymyxins, stendomicin, actinomycin; aminoglycosides represented by streptomycin, neomycin, paromycin, gentamicin, ribostamycin, tobramycin, amikacin; Lividomycin beta-lactams represented by benzylpenicillin, methicillin, oxacillin, hetacilin, piperacillin, amoxicillin, and carbenacillin; lincosamides represented by clindamycin, lincomycin, celesticetin, desalicetin; Chloramphenicol; macrolides represented by erythromycins, lancamycin, leucomycin, picromycin; nucleosides such as 5-azacytidine, puromycin, septacidin and amicetin; phenazines represented by myxin, lomofungin, iodine; oligosaccharides represented by curamycin and everninomycin; sulfonamides represented by sulfathiazole, sulfadiazine, sulfanilimide, sulfapyrazine; polyenes represented by amphotericins, candicidins and nystatin; polyethers; tetracyclines represented by doxycyclines, minocyclines, metacyclines, chlortetracyclines, oxytetracyclines, demeclocyclines; nitrofurans represented by nitrofurazone, furazolidone, nitrofurantoin, furium, nitrovin and nifuroxime; quinolone carboxylic acids represented by nalidixic acid, pyromidic acid, pipemidic acid and oxolinic acid. The Encyclopedias of Chemical Technology, 3a. Edition, Kirk-Othmer, editors, Volume 2 (1978), which is hereby incorporated by reference in its entirety. Antiviral agents that can be used with 2,4-dinitrophenol include: interferons α, β and β, amantadine, rimantadine, arildone, ribaviran, acylcovir, abacavir, vidarabine (ARA-A) 9-1, 3, dihydroxy-2- propoxymethylguanine (DHPG), ganciclovir, enviroxima, foscarnet, ampligen, podophyllotoxin, 2, 3, -dideoxythidine (ddC), iododeoxyuridine (DI U), trifluorothymidine (TFT), dideoxyinosine (ddi), d4T, 3TC, zidovudine, efavirenz, protease inhibitors such such as indinavir, saquinavir, ritonavir, nelfinavir, amprenavir. etc. , and specific antiviral antibodies. Anti-cancer drugs that can be used with 2,4-dinitrophenol include, but are not limited to, various cell cycle-specific agents represented by structural analogues or antimetabolites of metoltrexate, mecaptpuorine, flurouracil, cytarabine, thioguanine, azacitidine; bleomycin peptide antibiotics such as podophyllin alkaloids including etoposide (VP-16) and teniposide (VM-26); and several plant alkaloids such as vincristine, vinblastine, and paclitaxel. Non-specific antineoplastic agents in the cell cycle such as various alkylation compounds such as busulfan, cyclophosphamide, mechlorethamine, melphalan, altaretamine, phosphamide, cisplatin, decarbazine, procarbazine, lomustine, carmustine, lomustine, semustine, chlorambucil, thiotepa and carboplatin. Anticancer antibiotics and several natural products and various agents that can be used with DNP include: dactinomycin, daunorubicin, plicamycin, mitomycin, idarubicin, amasacrine, asparaginase, quinacrine, retinoic acid derivatives (etretinate), phenylacetate, suramin, taxotere, tenizolamide, gencitabine, amonafide, streptozocin, mitoxantrone, mitotane, fludarabine, cytarabine, cladribine, paclitaxel (taxol), tamoxifen and hydroxyurea, etc. 2,4-dinitrophenol, DN P, can also be administered with various hormones, hormone agonists and biological response modifying agents, which include but are not limited to, flutamide. Prednisone ethinyl estradiol, diethylstilbestrol. hydroxyprogesterone caproate, medroxiprogressterone, megestrolactate, testosterone, fluoxymesterone and thyroid hormones such as di-, tri-, and tetraiodothyroidine. The aromatase inhibitor, amino glutetimide, the peptide hormone inhibitor octreotide and gonadotropin releasing hormone agonists such as goseriline acetate and leprolide can also be used with DNP. Biological response modifiers such as the various cytosines, interferon alfa-2a, interferon alfa-2b, interferon-gama, interferon-beta, interleukin-1. interleukin-2, interleukin-4, interleukin-10, monoclonal antibodies (anti-HER-2 / humanized antibody neu), tumor necrosis factor, granulocyte-macrophage colony stimulation factor, macrophage colony stimulation factor, various Prostaglandins, phenylacetates, retinoic acids, leukotrienes, thromboxanes and other fatty acid derivatives can also be used with DN P. The use of this invention must be under the strict direction of a qualified and specialized treatment group to ensure effectiveness and safety. The treatment group stays with the patient through the procedure to ensure that safe and controlled doses of a decoupler are administered by monitoring real-time changes in V02, metabolic rate, temperature, respiratory rate, heart rate, urine output and clinical status of the patient. patient. This invention is practiced in controlled steps in order to obtain a predetermined V02 and plateau of warm-up time for a disease of particular condition. For example, in cases where heat dissipation mechanisms do not have to be blocked, the specialized group will periodically re-verify V02, heart rate, blood pressure, CAT scan, MRI, etc. , and other laboratory and clinical parameters to ensure a safe and continuous efficacy of DNP therapy. It is preferred that the skilled group undergo a training period on the use of this invention prior to its administration to human patients. The present invention is further illustrated with reference to the following examples, which illustrate specific elements of the invention, but should not be construed as limiting the scope of the invention.

Example 1 Method to use 2,4-dinitrophenol (DNP) with glucagon to treat parasitic infections, liver hydatid disease History: A Swiss man, white 52-year-old trainer of European fox hunting dogs, presented a pain in the upper right quadrant and vomit. Past history revealed that he underwent hepatic "cyst" surgery about two years ago. Pre-operatively, he was treated with albendazole. Only one dose of albendazole was given due to a reaction anaphylactic "close to death". He denied history of weight loss, pulmonary, cardiac, neurological or thermoregulatory problems. There was no history of alcohol abuse or use of medications. The patient was adamantly opposed to any surgery or additional treatment with albendazole or mebendazole. Physical examination: Weight = 90 kg; height = 177.8 cm; BP = 140/80; HR = 76 & reg; Resp. = 18min; T = 37.0 An old well-healed scar consistent with anterior hepatic surgery was presented. The physical examination in another way was not considerable. Laboratory studies: EKG, chest x-rays, blood panel, including serum electrolytes, thyroid studies, and liver function tests were within normal limits (WN L). A complete blood count was not considerable except for 20% eosinophilia. Ultrasound and nuclear magnetic resonance revealed cysts with a diameter of 4.2 to 3 cm in the right middle lobe of the liver and a solitary semi-solid medulla cyst of 2 cm in the neck of the right humerus. The ELISA serology showed a diagnostic titration for hydatid disease. The review of previous reports of surgical liver pathology revealed a tapeworm compatible with Echinococcus multiocularis. Chemical determination and evaluation of treatment: The patient did not obtain any historical or physical contraindication to hyperthermia induced by DN P. Conventional therapy of the Hydatid disease is either surgical resection or medical therapy with albendazole for 4 weeks. Bone hydatid cysts can not be managed through surgery and respond poorly to standard medical therapy. It is known that Echinococcus multiocularis and the germ membranes of hydatid cysts are irreversibly destroyed by heating at 41 ° C for 15 minutes. Human liver and hepatocytes can withstand artificial temperatures of 42 ° C for more than 20 hours without irreversible damage. Acute treatment with glucagon is known to preferentially stimulate hepatocyte mitochondrial V02. The hepatocyte regimes decoupled by V02 are also known to be stimulated up to 100% in less than 6 minutes after glucagon hormonal action. It has been shown that acute treatment with glucagon selectively raises the pH gradient across the mitochondrial membranes of hepatocytes. In this way, it is empirically assumed that any increase in V02 from the administration of glucagon causes elevated thermogenesis, predominantly in the liver. Treatment protocol: The patient was given 10 mg of diazepam by mouth and dressed in a modified wet suit. The wet suit was cut longitudinally on the arms and legs. Sailboat strips were placed on the cuts to close, quick and remove and expose the extremities. After the placement of monitoring sensors, it was started intravenously with fluids of 5% dextrose, 0.5% normal saline with 7 meq of K +, infused at an initial speed of 12cc / kg / hr. The evaporative heat loss from the head was reduced to a minimum through a plastic bathing cap and towel. A temperature probe of 401 BC (YSI Incorported, Yellow Springs, Ohio) was inserted 1 cm into the rectum. The probe was connected to a model 4600 telethermometer (YSI 4600 Precision Thermometer) and readings were presented and recorded continuously within 0.1 ° C in the baseline and during treatment in Hewlett-Packard (HP) computer systems with software from custom developed by MR &S (Manalapan, New Jersey). A TEEM 100 metabolic analysis system (AeroSport Inc., Ann Arbor, Michigan), with a modified mask and oxygen delivery system (38-40% O2 saturation) for patient comfort and increased accuracy, was attached to the patient . Oxygen consumption (V02), carbon dioxide production ((VC02), expired air volume (VE), heart rate (HR), and Kcal of produced heat were measured in 20 second intervals and extrapolated to speeds of 1 minute or hours All patient data were monitored in real time, continuously displayed at baseline and during treatment and recorded on HP computer systems with custom MR &S software (Manalapan, New Jersey) Treatment procedure: After 10-minute baseline records, the required amount of DNP to raise V02 to obtain a patient temperature of 40 ° C was calculated as described under "dose of DN P required to increase V02". The patient was given an initial dose of 1 mg / kg of DN P, infused intravenously for a period of 3 minutes. After the V02 was stabilized at 40% above the baseline, an additional infusion of DNP of 3 mg / kg was provided. After obtaining a V02, 0.5 mg of glucagon was administered intravenously. After this stabilization of V02, a glucagon drip was variably infused from 0.5 to 5 mg / kg / hour to further control V02 and selectively increase heat production in the liver. The treatment procedure was discontinued after the patient was maintained at a rectal body temperature of 40 ° C for about one hour. The wet suit opened and the cover of the head was removed. After the patient's body temperature reached 38 ° C, the Foley catheter was removed and the intravenous fluids were discontinued. The evaporative and radiant heat loss reduced the body temperature to a normothermic level in 30 minutes. No toxicity was found after immediate or delayed treatment. The parameters of the supervised patient are shown in Figure 1 5. Treatment outcome: Studies of serial imaging revealed shrinkage of the hepatic and bone cyst with increased density at 2 and 4 weeks after treatment. The repetition of magnetic resonance imaging at 4 months showed a complete disappearance of the cyst in the liver and h u that Example 2 Method to use 2,4-dinitrophenol, DNP, to treat viral infections, HIV disease History: A 38-year-old white man, addicted to intravenous heroin in the past, was diagnosed approximately 8 years ago with HIV through of ELISA and positive Western staining for antigens p24 and gp41 of VI H after presenting weight loss and aphthae. His history included repeated treatment for cadidiasis, pneumocystis carnini, and several subcutaneous abscesses. Past medications included sulfamethoxazole, ketoconazole, fluconazole, zidovudine, didanosine, and several other antibiotics. During the past year and a half remained on highly active antiretroviral therapy (HAART) with several inhibitors of HIV protease combined with nucleoside and nonucleoside inhibitors of thymidine, purine, or cytosine. He was unable to tolerate nelfinavir due to diarrhea. The ritonavir caused intractable vomiting and abdominal pain. Current medications include indinavir, zidovudine and lamivudine. The review of the most recent viral load (VL) and CD4 + lymphocyte counts showed an initial drop in HIV RNA in plasma (copies / ml) from 200,000 to 2,000 over a 12-week period with viral load returning to 200,000 at week 16. The CD4 + lymphocyte counts remained between 10 to 200 cells / mm3. Approximately 5 months ago he was treated for oral and endobronchial Kaposi sarcoma (KS) with liposomal daunorubicin followed by doxorubicin liposomal Denied treatment with vincristine or bleomycin. There was no history of recent diarrhea, recent weight loss, hemoptysis, reduced breathing in mild expulsion, or cardiac problems. There was no illicit use of the drug during the last 2 years. The patient did not establish any or combination of HAART that was able to reduce their viral load and multiple side effects of the drugs so as to limit their comfort in taking the medications. No history of thermoregulation problems was presented. Physical examination: weight = 60 kg; height = 155 cm; BP = 128/72; Resp = 20; T = 38.2 ° C; and the pulse was 92 and reg. The examination revealed asthenia and generalized enlargement of lymph nodes, some with a diameter of 2 to 3 cm in the armpit and inguinal regions. There were diffuse oropharyngeal aphthae. Behind the canker sores, the oral cavity also contained several dark red, nodular plaque lesions on the hard palate and gum. The lesions were not bleached in the compression with the tongue shoulder. A crusted strawberry type mass, 1 by 2 cm, was present in the external orifice of the rectum. There were no neurological deficits or eye injuries. Laboratory studies: EKG, electrolytes in the serum, kidney and liver function tests were normal. The hematocrit was 35.5%, WBC was 9, 900 with 81% neutrophils, 4 bands, 1 1 lymphocytes and 4 monocytes. The platelets were 314,000 / mm3. The viral load was 400,000 copies / ml (Amplicor H IV Monitor test, Roche).

A CD4 + T cell count was quantified through flow cytometry at 250 / mm3. He was positive for the hepatitis C antibody. The chest x-ray showed some irregular opaque, apical, bilateral aspects. Pulmonary function tests showed all parameters, including forced expired volume, greater than 80% of the predicted. The Karnofsky classification was greater than 70. Biopsies of normal tissue and tumor were obtained, with a diameter of 3 to 6 mm from the oral cavity and the external orifice of the rectum. The tissues were equally divided, weighed and placed in a Ringer's Lactate solution at 4 ° C. Normal and histologically confirmed KS tissues were then subjected to microcalorimetric measurements on a thermal activity monitor (ThermoMetric, Jarfalla, Sweden). The registered heat production (μW / min) was 8.2-8.5 times higher for Kaposi sarcoma lesions than oral mucosal tissues without tumors. Repeated measurements with specimens from biopsies in 30 uM DNP increased heat production in tumor tissues 20, 5 times more than in non-tumor specimens. Clinical determination and evaluation of treatment: It is known that T cells infected with HIV and HIV are more sensitive to be annihilated by heat instead of uninfected lymphocytes. The susceptibility to annihilate with heat was improved with the high production of oxygen-free radical. Acute and chronically infected cells had reduced levels of mannose superoxide dismutase activity (MnSOD). The dismutase of Manganous superoxide is located exclusively in mitochondria. The mathematical modeling of human H IV production and CD4 + T cell rotation predicts that both free virus and actively infected cells will be reduced by a minimum of 40% with one hour of therapeutic hyperthermia at 42 ° C a day and a day. Day will not promote the recovery of the population of uninfected T cells. Studies of human HIV with extracorporeal hyperthermia of 41-42 ° C have reported isolated cases of extended patient survival, detectable virus elimination and improvement of Kaposi's sarcoma lesions. It is known that 2,4-dinitrophenol generates intracellular hyperthermia and oxygen free radicals from the level of the inner mitochondrial membrane. Studies on in vitro inactivation of HUT-78 cells chronically infected with VI H through various concentrations of DNP are graphically depicted in Figure 16. The patient has been and remains resistant to treatment with HAART. Opportunistic infections with candida and Kaposi's sarcoma herpes virus (KSHV, human herpes virus type 8) that cause canker sores and Kaposi's sarcoma are co-morbid conditions indicative of a worsening prognosis. Despite having AIDS with candidiasis and Kaposi's sarcoma, the patient maintains a good cardiac and pulmonary function. No history of thermoregulation problems was presented. It was discussed and agreed that hyperthermia treatments with core body temperatures of 41 ° C can be administered on a daily basis or a day if and not a day, as tolerated, for a minimum of 3 hours, not exceeding 5 hours. Pretreatment protocol: all medications were stopped two weeks before treatment. The patient refused to take diazepam, the placement of a Foley catheter and the oxygen mask. He dressed himself with an immersion suit for dry cold water (Strearns, ISS-5901, Universal Adult) designed to avoid heat loss and modify the easy placement of physiological monitors. The equipment to measure the heart rate, temperature, carbon dioxide production and Keal of the produced heat were conducted as summarized in example 1. An oral breathing tube was used to measure V02 of ambient air. Urine output was measured when the patient voluntarily urinated through a "Texas" catheter (a tightly fitting surface condom around the head of the penis with the tubing connected to the urine collection bag). The patient was informed that hyperthermia was administered as tolerated by its vigor and verified clinical parameters, not exceeding 5 hours on a daily basis or a day if and not, during a total of 5 sessions. Treatment procedure: The baseline reading for 5 minutes established an average V02 of 300 cc / minute. An initial dose of 2 mg / kg of DNP was administered for a period of 2 minutes. V02 was increased and stabilized at 1 5 minutes at 340-380cc / minute. An additional infusion of 2 mg / kg of DNP was provided, V02 was increased and stabilized at 610-630cc / minute. The core temperature of the body was increased to 39.4 ° C in 60 minutes. A gradual drop in blood pressure was observed at 90 minutes at 100-60m / hg. Norepinephrine bitartrate (Levophed) was intravenously given as a drip at a dose of 1 microgram / minute and adjusted to maintain blood pressure at 130/80. Approximately 1 minute after starting the vasopressor, the heart rate increased from 90 to 100 and V02 to 0.85 liters / minute. The temperature of the core body was increased by 20 minutes at 41.5 ° C. V02 was maintained at LOlitros / minute reducing and increasing the dose of norepinephrine. An additional infusion of 1 mg / kg of DNP was provided at 4 hours to correct the drop in V02. Occasionally when core temperature rises above 41.6 ° C, a lower limb was exposed for evaporative heat loss. The patient withstood the procedure without any adverse effect for a period of 7 hours. The protocol was repeated consecutively for 5 days without the additional use of vasopressors. Results of the treatment: Immediately after the first oral treatment, candidiasis was improved by 50%. The oral Kaposi lesions and the external rectum orifice exhibited marked erythema with circumferential areas of bleaching. On the second day of treatment, Kaposi's sarcoma erythema decreased. No evidence of oral candidiasis was observed on the third day of therapy. The anal tumor was incrusted and approximately 60% was decreased in size on the fifth day and the last day of therapy. Lymphadenopathy progressively reduced and resolved 2 weeks after treatment. At 30 days after treatment, a complete regression of both oral and anal Kaposi sarcoma lesions was presented. The repetition of the blood work in the days of treatment did not show any important hematological change of electrolyte, liver or kidney of the baseline. The viral load immediately after day 5 of treatment showed 50,000 copies of VI H-RNA copies / ml. VI H RNA was not detectable at 4, 6 and 1 2 weeks after treatment. The counts of the T-cell lymphocyte, CD4 +, increased to 380-420 cells / mm3 in the fourth week and remained stable at weeks 6 and 1 2. Figure 1 7 shows parameters of the supervised patient on day 1 of treatment. Figure 17 (a) shows changes in substitute markers • immediately after weeks 4, 6 and 12 of treatment.

EXAMPLE 3 Use of 2,4-dinitrophenol, DNP, to treat bacterial infections, Lyme disease H istoria: a 33-year-old white woman with a case from the textbook of Lyme borreliosis related to being bitten by acarus and developing a pathognomonic erythema on his right anterior thigh. The rash was determined in 2 weeks but 3 months later it developed verbal memory damage, m igrative arthritis of the knees, ankles and thi bias. They were fibromyalgia, tachycardia and Bell's palsy on the left side. Constitutional symptoms of fatigue, malaise and severe depression caused her to undergo psychiatric care for 1 year and a half before she was definitively diagnosed with chronic Borrelia burgdorferi infection. She was treated with ceftriaxone, 2 g intravenously every 12 hours for 14 days. 4 months after an apparent improvement he developed photophobia, headaches, pronounced loss of memory, depression, dysesthesia and a painful swollen left knee joint. The repeat ELISA Western blot and DNA-PCR were all positive for B. Burgdorferi. The spinal superior part showed pleocytosis with positive antibody and PCR tests for neuroborreliosis. During the following year, the patient received prolonged ceftriaxone, 2 g per day intravenously for 3 months, and 3 individual short courses of ciprofloxacin, minocilcin, and oral azithromycin. The symptoms failed for the determination. Two months after his last antibiotic regimen, a new ring-shaped erythematous rash occurred again, suggestive of erythema in the right thigh and developed under his left armpit. Doxycycline was instituted and the rash was reduced. The patient refused additional antibiotic therapy due to the associated uncontrollable diarrhea and made tentative plans to undergo "malariotherapy" in China. Physical examination: weight = 60kg; height = 160 cm; BP = 130/70; HR = 86 and reg, resp = 18; T = 37.3 ° C. The physical examination revealed a swollen and weak left knee. A hypopigmented area was presented Thin atrophic skin on the right thigh, typical of chronic acrodermatitis atropicans. The neurological examination showed some verbal memory deficit. Paresthesias of lower distant extremity, bilateral. Laboratory studies: EKG demonstrated a first atrioventricular block of first degree (internal PR> 0.2 sec), some widening of the QRS complex and Wenckeback periodicity. There was no fall of beats. Arthroscopy of the left knee showed synovial hypertrophy with early erosive arthritis. Synovial fluid analysis revealed a WBC of 50,000 cells / ml with 70% neutrophils and a positive DNA-PCR for Borrelia burgdorferi. The synovial tissue biopsy sections showed chronic non-specific synovitis. The staining histology of Warthin-Starry and silver revealed spirochete organisms consisting of Borrelia burgdorferi. Spinal fluid analysis of lumbar puncture showed pleocytosis, elevated gamma globulin and positive PCR for B. burgdorferi. Spinal fluid cultured for 2 months in a Barbour-Stoenner-Kelly medium was reported positive for B. burgdorferi. Electrolytes in the serum, kidney function, liver and hematological studies all were within normal limits. The patient experienced tension EKG obtaining a maximum heart rate of 165 without any evidence of arrhythmia or depression of the S-T segment. Clinical determination and treatment evaluation: Lyme disease is a zoonosis caused by a slow development of pathogenic spirochetes, Borrelia burgdorferi. In Several species of mammals, including humans, these organisms are known to invade heart, kidneys, bladder, vessel and brain. Borrelia spirochetes are very resistant to treatment with antibiotics, especially if there is evidence of the central nervous system or involvement of joints. It has been isolated viable B. burgdorferi from monolayers of fibroblasts treated with antibiotic. Borrelia spirochetes are known to be facultative intracellular pathogens in fibroblasts through confocal laser scanning microscopy. The tissue of the central nervous system, joints, frontal chamber of the eye and intracelular location can provide a spirochete of Borrelia burgdorferi with a protective environment against antibiotic therapy and Borrelia burgdorferi has reliably been cured in patients with chronic disease, even from those previous and aggressively treated. This patient confirmed chronic disease of the central nervous system and Lyme of the joint despite extensive antibiotic therapy. The Lyme spirochete was irreversibly inactivated through heating at 40 ° C for 3 hours, 41.0 ° C for 2 hours or 41.5 ° C for 1 hour. The susceptibility of all strains of Borrelia burgdorferi has penicillin and ceftriaxone was increased up to 16 times the temperature rise from 36 ° C to 38 ° C. At 40 ° C Borrelia burgdorferi increases the expression of at least 12 heat shock proteins (HSP), most of which are strongly immunogenic. The patient had no history of thermoregulation problems. He was informed that his body temperature can be raised from 40 to 41 ° C for a period of 3 hours, the actual level and time under hyperthermia may depend on his supervised clinical parameters. Pretreatment protocol: the night before treatment, the patient was instructed not to eat and to wear cotton underwear. Approximately 4 hours before treatment, 2 mg of alprazolam was administered by mouth. The patient visited himself in a dry cold immersion suit (Stearns, previously described) with head equipment. The monitoring sensors, including the presentation of EKG, intravenous fluids and the Foley catheter were attached and the suit was closed with a closure. The patient opted for oxygen supplementation. The modified mask was connected to the metabolic analysis system TEEM 100 for V02 measurements. The data was recorded as previously described. Treatment procedure: the 10-minute baseline record showed a V02 of 220 cc / min, 3.7 cc02 / kg / min. The patient was infused with 1 mg / kg of DNP for a period of 2 minutes. The V02 was increased and stabilized at 250 cc / min, 5.3cc / kg / min. A second dose of 2.0mg / kg was infused over a period of 2 minutes and V02 reached a peak at 400 cc / min, 8.8cc 02 / kg / min. An additional dose of 1.0 mg / kg DN P was provided 30 minutes after the second dose. The V02 increased and reached a stable plateau at 600cc / m in 10.8cc / kg / min.

The rectal temperature continued to rise until a scale of 40.2 to 40.6 ° C was reached at 70 minutes after the initial dose. A fall in V02 was observed at 90 minutes, a dopamine drip started at 2-3 mcg / kg / min. The V02 was increased back to 680-710 cc / min. The temperature remained stable between 40.1 ° C and 40.6 ° C through the 3 hour plateau treatment period. The patient periodically requested that the V02 monitoring mask be removed during the period of hyperthermia treatment. It was adapted with the removal of the mask on 2 occasions for periods of no more than 10 minutes. The patient did not experience any problems during the procedure, but he was notoriously fatigued in 3 hours. The treatment was terminated at 4 hours and 10 minutes after the initial dose of DNP. 25 minutes after the patient was removed from the neoprene survival suit, rectal core temperature dropped to 38.5 ° C. A normothermia was achieved approximately 60 minutes after the end of therapy and removal of the survival suit. Approximately 6.5 to 7 hours after the treatment, the patient experienced cold, an increase in oral temperature of 38.7 ° C and malaise. The intravenous fluids and the drip of dopamine at 2mcg / kg / min were restarted and the patient was closely observed. Her symptoms calmed for 3 hours and the next day she felt active and hungry. It was assumed that she experienced a delayed Jarish-Herxheimer reaction. The flow diagram of supervised treatment of patients is found in Figure 1 8.

Results of the treatment: 2 months later, the patient established that his deficits of arthralgia, myalgia, malaise, fatigue and memory disappeared. There were no more dysesthesias in the lower extremities. EKG showed resolution of its first-degree A-V block. The patient was informed of his positive culture of past positive cerebrospinal fluid for the spirochete of Lyme disease. It was suggested that a repeat spinal cap be made for B. burgdorferi for PCR and cultures. If it is positive, the patient agreed to be treated again with both hyperthermia induced by DNP, intravenous ceftriaxone for maximum synergism. The repeat spinal fluid analysis was normal, that is, no elevated protein, no detectable Borrelia DNA through PCR, and no pleocytosis. Three months later, the spinal fluid culture in the Barbour-Stoenner-Kelly I I medium was reported as negative.

Example 4 Method for using 2,4-dinitrophenol, DNP, with vasopressors and chemotherapy to treat neoplasia, peritoneal carcinomatosis. History: a 55-year-old woman presented a distended abdomen due to ascitos. Laparotomy revealed peritoneal dissemination of malignancy with histological findings of an undifferentiated adenocarcinoma of unknown origin. Physical examination: weight = 55 kg; height = 1 54 cm; BP = 1 40/90; H R = 88 and reg; Resp = 22; T = 37.6 ° C. The patient was an Islamic woman Well-developed and well-nourished with a midline laparotomy healing scar. Ballotable ascitos were detected in the abdomen. There was no lymphadenopathy. Laboratory studies: the laboratory test of the acyclic fluid showed high levels of amylase. She had a hemoglobin of 9.2. High levels of amylase and tumor markers, including CA15-3, CA 125 and CA72-4 were present in the serum. Blood chemistry, liver and kidney function tests were within normal limits. Chest x-rays and EKG were normal. MRI and abdominal ultrasound showed normal atrophic pancreas, liver and ovaries, well disseminated nodular lesions consistent with peritoneal carcinomatosis were seen. Clinical determination and evaluation of treatment: the patient presented an inoperable malignancy of unknown origin. Chemotherapy in such cases is only of marginal survival benefit. Hyperthermia, combined with chemotherapy, has been shown to be cystic with high tumor response and survival benefit. It is known that markers of tumor antigen are increased by the heat shock response and much improved immunological monitoring. The patient did not present any history of thermoregulation problems, but refused to be placed in a wet suit or survival suit due to a "phobia of hermetic enclosed garments".

It was chosen to treat the patient with hyperthermochemotherapy. The treatment consisted of 2,4-dinitrophenol, and combination chemotherapy with carboplatin, mitomycin, and doxifluridine. An a-1 energetic receptor agonist was used to minimize peripheral vascular dilation and heat loss. Pretreatment protocol: the patient received transfusions of 3 units of packed red blood cells. A Foley catheter was inserted on each day of treatment. It was covered with a mantle soaked in water containing a polyethylene liner. A shower cap with towel was used to prevent the loss of heat from the head. The intravenous lines were placed in both arms with intracatheters with a caliber of 19. EKG monitors, heart rate, rectal thermistor and V02 were attached. The mask supplemented with oxygen and the equipment were annexed and the data verified as previously described under example 1. Treatment protocol: the patient was given chemotherapy by mouth. The total doses of carboplatin and mitomycin were 450 mg and 24 mg IV respectively, on day 1 and last of week 6. 600 mg of doxifluridine were administered orally, daily for 5 days and repeated the last 5 days of week 6. On the infusion day of DN P, the records of baseline for 10 minutes. 30 mg of mefenteramine sulfate was given by intramuscular injection. 10 minutes later his heart rate increased to 96 and his V02 increased from 250 to 320 cc / min. The V02, rhythm Heart rate and blood pressure were stabilized after 20 minutes and given an initial dose of 1 mg / kg of DNP. Additional infusions of 0.5 mg / kg of DNP were administered in 3 successive infusions separated by 20 minutes. The V02 of the patients stabilized between 780-820 cc / min and their core temperature increased a maximum of 41.4 ° C. After a plateau temperature of 41.5 ° C ± 0.5 ° C was reached, its V02 level and temperature were maintained for a period of 2 hours and 30 minutes with additional infusion of 0.5 mg / kg of DNP given 50 minutes after the last dose. The DN P treatment protocol was repeated every 4 days for a period of 6 weeks. Figure 19 shows a supervised, representative flow chart. Treatment results: Through the combined treatments presented above, the ascites resolved at the end of the sixth week. Amylase levels in the serum and all tumor markers were reduced after the third week of treatment and were normal by week 6. Repetitive magnetic resonance imaging and further examination of the abdominal echo showed complete resolution of peritoneal metastasis. Nine and a half months after the treatment the patient was relieved without any evidence of a new tumor recurrence.

Example 5 Use of 2,4-dinitrophenol, DNP, with thermosensibie liposomes To overcome the toxicity in normal tissues of many anti-cancer agents such as doxorubicin and anti-infective drugs such as amphotericin B, liposomal formulations were developed. It is known that liposomal doxorubicin has reduced cardiotoxicity and increased antineoplastic efficacy. The thermosensitive liposomes can also improve tumor activation and reduce toxicity by releasing their contents of water soluble drugs in response to tumor hyperthermia. Various synthetic and natural lipids such as dipalmitoyl phosphatidyl choline and distearoyl phosphatidyl choline or egg phosphathidyl choline and cholesterol can be combined in different molar ratios with ethanol, or other agents having a two phase effect on the gel-to-liquid phase transition of the double layers of phosphatidyl choline, to produce leaking liposomes (undergo crystal-to-liquid crystal phase transitions) at a predetermined hyperthermal temperature. Thermosensitive liposomes were prepared from phosphatidyl choline (PC) and cholesterol (Ch) using the ethanol method of Tamura et al. A combination of PC: Ch at a molar ratio of 8: 1 in the presence of 6% (v / v) ethanol resulted in the formation of liposomes having a transition temperature of between 40.2 and 40.8 ° C. The anticancer drug dacarbazine, [5- (3, 3'-dimethyl-1-triazino) imidazole-4-carobxamide] was encapsulated in these liposomes sensitive to heat at a concentration of 3 mg / ml. The in vivo efficacy of dacarbazine encapsulated in thermosensitive iiposomes was tested in Swiss albino mice transplanted with fibrosarcoma of dimethyl benzo-dithionapheten-derived ascites subjected to hyperthermia induced by 2,4-dinitrophenol. Male Swiss albino mice with an age of 10-12 weeks were injected with 3x106 viable fibrosarcoma cells in the peritoneum. After 15 days, the animals were divided into several treatment and control groups receiving intraperitoneal injections of DNP-free dacarbazine alone, DNP + empty liposomes and DNP + dacarbizin encapsulated in liposomes. DNP-induced hyperthermia was recorded with neonatal rectum and 22 ga. of hypodermic YSI probes. Temperatures were recorded 30 minutes after an intraperitoneal dose of 20 mg / kg of DN P. The 2,4-dinitrophenol was administered every day for a total of 5 doses. In all cases, the intraperitoneal, hypodermic temperatures were 1 ° C higher than the rectal temperature. As shown in Figure 20, the survival curves of animals treated only with DN P and with liposomes containing DNP + drug were significantly improved compared to the controls. The animals treated with DNP-induced hyperthermia remained alive on day 100, while the animals treated with the substitute all died on day 60.

Example 6 Use of 2,4-dinitrophenol, DNP to induce autologous heat shock proteins as a form of thermal preconditioning before arterial balloon catheterization or ischemic surgical damage DN P was given orally at doses to increase V02 of 1.5. to 5 times above normal per day for a period of 2-6 days or, as an infusion at doses that can increase V02 and core body temperatures not greater than 39 ° C for periods of 5 to 6 hours or, intravenous doses of DNP alone, with vasopressors, or other short-acting metabolic stimulants, which can increase V02 at equivalent core temperatures of 40-41 ° C for periods of 1-530 minutes. After 8-48 hours of the DN P term, the patient may experience maximum heat shock protein production. Said stress induced by C N P can improve the clinical result through the induction of synthesis of cellular heat shock protein with protection of the organs, tissues and cells of the patient from subsequent ischemic surgical or traumatic procedures. This DN P-induced preconditioning method can be used to reduce intima thinning and restenosis after angioplasty, improve ischemia / reperfusion injury in organ and tissue transplantation, and improve the surgical outcome of procedures that require temporary occlusion. or prolonged arterial blood flow. Examples of said thermotolerance to utologist induced by DNP used as a form of preconditioning are illustrated in Figure 21, which shows the limitation of proliferative arterial catheter balloon damage in Sprague-Dawley rats pretreated with DNP-induced hyperthermia; Figure 22 shows the protective effect of pretreatment with DNP before ischemic liver damage caused by the Pringle maneuver; and Figure 23 illustrates improved cutaneous muscle skin survival after induction of heat shock proteins through DNP.

Example 7 Method to use 2,4-dinitrophenol, DNP to improve proton emission tomography (PET) in the diagnosis of malignancy and / or malignant transformation (Glioma) History: a 24-year-old white man with neurofibromatosis presented with a 6-month history of the loss of body sensation on the left side, emotional changes, sensory attacks, little attention to conversations and feelings of never seen. Physical examination: weight = 65 kg; height = 175cm; BP = 135/80 and reg; Resp = 18; T = 37.9 ° C. The patient was a well-developed and well-fed white man with sensory losses of the upper and lower left extremities, postural instability and loss of tactile discrimination. There was a frank astereognosis on the right. The examination of the eyes was normal without papillodema.

Laboratory studies: the complete blood count, blood chemistry and endocrine examination were all normal. EEG was within normal limits. MRI with gadolinium enhancement showed a reduced signal in the right temporoparietal region without any evidence of contrast enhancement. PET examination with [18F] fluoro-2-deoxy-D-glucose (FDG) revealed a homogeneous, hypometabolic (metabolic grade 1) area consisting of a low-grade glioma in the right temporoparietal region. No areas with high FDG consumption were presented. The non-invaded gray matter differentiation displaced from the tumor was not discernible through PET imaging. Clinical determination and diagnostic evaluation: although low grade gliomas generally present histological characteristics of a benign tumor, it is known that the presence of areas of high consumption of FDG through PET scanning in said gliomas is associated with a higher percentage of malignant transformation PET-FDG with evidence of tumor hypermetabolism is believed to be an early biochemical marker of cellular malignant transformation and is of prognostic value in high-grade gliomas. Biochemically, the use of a high glucose content (consumption of FDG) in the presence of oxygen, known as aerobic glycolysis, is thought to be the result of an overactive hexokinase linked to the tumor's mitochondria. Therefore, the high consumption of FDG represents a high hexokinase activity and is associated with increased aggressiveness in gliomas, menigonia and other neoplasms. Since DNP decouples oxidative phosphorylation, any short fall in the production of mitochondrial adenosine triphosphate must come from elevated glycolysis. As a result, the consumption of FDG will be proportionally increased in malignant cells treated with DNP over those that are normal in the white and gray matter of the contralateral brain. Since no abnormal consumption of FDG was detected in the tumor or through standard PET methodology and the PET scan was unable to clearly delineate the tumor boundaries it was chosen to give the patient a low dose of DNP to improve consumption of the tumor. FDG and repeat the PET scan. The hypermetabolic components of the tumor in this way can allow a stereotactic biopsy guided by PET, more focused. Pretreatment protocol: three days before DNP dosing and repeat PET-FDG scan, the patient's dose of phenytoin was increased from 100 mg 3 times a day daily to 200 mg three times a day. The same positron emission tomogram, CTI-Siemens 933 / 08-12 which provides adjacent slices of 6.75 mm and spatial resolutions in plane (full width to a maximum average) of about 5 mm was used. The highest level of FDG consumption stimulated without DNP and with DN P in the tumor area was compared and quantitatively graded by two radiologists. Independently, each researcher visually evaluated the positron emission tomogram and used the following scale of metabolic determination: I, FDG consumption it is less than the contralateral white matter; II, the consumption between the contralateral white and gray matter levels; Ill, consumption of FDG equal to or greater than the contralateral gray matter. Diagnostic-treatment protocol: the patient was given 300 mg of a DN P capsule (approximately 4 mg / kg of body weight) 3 hours before undergoing a PET-FDG scan. 40 minutes before the emission scan was injected intravenously with a bolus of FDG according to standard methodology. Immediately before the 20 minute emission scan, the V02 consumption of the patients was 40% above that in the baseline. A flow chart of DNP / V02 of patients is illustrated in Figure 24. Diagnostic results: Improved PET-FDG exploration by DNP revealed two areas of hypermetabolism. One of the areas exceeded the limits of the lesion in CT images and consequently only one of the objectives (classified as lll in FDG consumption) was selected in the area of "abnormal PET-normal CT". The plane that best represents the hypermetabolic consumption area of abnormal FDG was selected and the pixel located in the center of the area was interactively noted on a visual inspection. The coordinates of that hypermetabolic pixel induced by DN P were then calculated and fixed as a target for the biopsy. A PET-guided stereotactic biopsy was performed under the procedure described by Levivier et al., That is, the The objective of the PET image was projected onto the corresponding stereotactic computerized thermographic slice (CT) to control the reliability and precision of the target selection and trajectory. Serial stereotactic biopsies were performed along the trajectory through the method described by Kelly et al. In the pathological examination, including analysis of nuclear polymorphism and cell density, 2 foci or sites of anaplasia consistent with glioblastoma (grade III astrocytoma) were observed. Treatment results: Based on the diagnosis of improved PET-FDG screening by DNP presented above, it was found that this patient has a malignant transformation in his otherwise low grade glioma. This procedure of diagnostic treatment protocol to detect sites or foci of hypermetabolisms caused him to undergo systematic radiation therapy with chemotherapy (dibromodulcitol-procarbazine-carmustine) earlier in the course of his malignant process. One year after diagnosis and therapy, the patient again underwent PET scan. The improvement by DN P (repeated as presented under "previous" diagnosis) revealed a hypermetabolic component (metabolic grade II) in the tumor area. PET-guided repeated biopsy revealed the area that will be an area of radionecrosis. The remaining viable tumor, even with DNP improvement, continued to be a metabolic grade I. The patient remains alive a year and a half after his diagnosis, although with hemiparalysis on the left side.

Example 8 Method for using 2,4-dinitrophenol, DNP to improve the detection of malignant tumors through high-resolution digital infrared imaging (breast carcinoma) History: a 34-year-old white female with existing fibrocystic disease of the Chest experienced an annual mammogram and was found to have an equivocal opacity on the right chest, halfway up the air. Two past breast biopsies were negative for malignancy and consistent with fibroadenomatous breast disease. The patient was opposed to another breast biopsy (it could be the third), unless there is a definite indication of an injury to that of his known fibrocystic disease of the breaths. Physical examination: weight = 60 kg; height = 164cm; BP = 120/72; H R = 88 and reg; R = 18 / min; T = 37.7 ° C. The patient was a normal-looking white woman with nodularities explored to diffuse in both breasts. A non-soft protuberance, 3 X 2 cm, palpable was located 3 cm to the middle of the right air. There was a small absence of nozzle discharge, retraction, wart formation on the skin, rash or discoloration of both breasts. There was no palpable axillary lymphadenopathy. Laboratory studies: chest x-rays, EKG, blood chemistry, and blood count were normal. Mammography, Doppler ultrasound, MRI, and scintinamography failed to indicate or eliminate a possible hidden carcinoma in this young patient with dense, fibroadenomatous breast disease. A diffuse, non-cystic opacity on the right breast was the only definitive finding of these breast studies. Clinical determination and diagnostic evaluation: the patient has already undergone two previous open heart biopsies without evidence of malignancy. The early detection of breast carcinoma is of crucial importance in order to survive. False negative results of mammography (and other complementary studies) vary between 5-30%. The ability of infrared imaging technology to detect changes related to elevated metabolism (tumor) and angiogenesis has been greatly improved from that of 30 years ago. Now the high resolution digital computerized infrared equipment can detect focal increases in tumor temperature of as little as 0.05C, and increases in focal breast temperatures that can be as high as 1 -2 ° C in malignant tumors against breast sites contralateral normal.

Since it is known that infrared imaging has at least a 19% false-positive and 17% false-negative regimen, and mammography mistaken information from abnormal infrared images is not common in young women with dense breast tissue and diffuse fibrocystic disease, the use of DNP to improve tumor metabolism (infrared imaging) over that of normal tissue, can be of substantial diagnostic benefit. Specifically, the DNP can greatly improve the Tumor metabolism (infrared imaging) compared to improved infrared imaging without DNP and can greatly improve tumor detection when there is either insufficient production or detection of metabolic heat or vascular changes. In addition, the heat differential between improved DNP and infrared tumor imaging without DNP can also reduce the false positive rate seen in this procedure, especially in benign conditions such as fibrocystic breast disease. Since no infrared imaging without DNP is able to detect as much as 1 -3 ° C at the focal temperature, between normal and malignant tissue, the DNP enhancement can increase the temperature difference several times and improve both the sensitivity as the precision of infrared imaging technology currently available. The patient agrees to have both breasts examined non-invasively with infrared imaging, before and after administration of intravenous DNP to determine if there is elevated infrared signaling from the palpable lump, restless in its right breast. Prediagnostic protocol: the patient was undressed from the waist and sat with his hands locked on his head during a 5-minute equilibrium period in a thermally controlled room, free of wind, maintained between 18 ° C and 20 ° C. She did not take any oral medication, alcohol, coffee and does not smoke, she does Exercise uses deodorant before the test. A baseline of 4 images consisting of anterior views, below the surface and two side views of each breast were generated through an integrated infrared imaging station consisting of an optical scanning mirror system containing a mercury detector -cadmio-tellurium (Bales Scientific, CA). The infrared system had a spatial resolution of 600 optical lines, a central computer software processor providing multiple task capabilities and a high resolution color monitor capable of presenting 1024 by 768 resolution points with 1 10 colors or shades of gray per image . The images were stored in recoverable laser discs. Diagnostic treatment protocol: After the previous baseline studies were performed, the patient was given an initial intravenous dose of 1 mg / kg of 2,4-dinitrophenol and observed for a period of 20 minutes. After an additional 2 mg / kg of DNP was administered and 30 minutes later, a thermally controlled room was used for the repetition of improved infrared imaging by DNP. Immediately before the transfer of the patient to the thermally controlled room, the V02 of the patient was increased incrementally to 50% above its baseline V02, see Figure 25. After obtaining repeat infrared images under the exact protocol used to have baseline studies.

Diagnosis, treatment results: the formation of infrared images of baseline (improved without DNP) revealed a negligible vascular symmetry and no significant change in temperature when the results were reviewed and compared with the rest of the ipsilateral and contralateral chest sites. Improved infrared imaging by DNP resulted in a bilateral overall increase in chest temperature of approximately 0.5 ° C. An abnormal 2.5 ° C increase in temperature was observed in the palpable right breast lesion discovered by clinical examination. Since no cause of non-cancer for such dramatic temperature increase, it can be identified, ie, abscesses, traumas or recent surgery, this increase of 5 times in heat production (above the baseline increase of DN P of 0.5 ° C) was strongly suspected to be caused by a previous malignancy. The patient was admitted to the hospital and under general anesthesia underwent an open chest biopsy. The frozen section (and the last permanent tissue mounds) revealed a well-differentiated intraductal carcinoma. The progesterone and estrogen receptors as determined by immunocytochemical methods were negative. A simple right mastectomy was performed with lymph node dissection of the axilla. A total of 12 lymph nodes were identified: there was no evidence of tumor. The patient refused chemotherapy and radiotherapy. He was placed on long oral tamoxifen treatment term (10 mg twice a day).

Example 9 The use of finitrofenol with artificial electron receptors (and other free-radical-forming agents) in the treatment of hormone-resistant malignancy and chemotherapy (prostate cancer) History: a 68-year-old Mexican man developed a gradual increase in the low back pain, right hip pain and several episodes of hematuria over a period of 10 months. He was sent to a urologist and the diagnostic process revealed a carcinoma of the prostate with extension of the tumor into the bladder.

Bone metastasis was present in the right pelvis, fourth and fifth lumbar vertebrae, right femur, left humerus, sixth and seventh right ribs and right scapula. He rejected any form of surgery but experienced radiation therapy in the pelvis and symptomatic bone lesions. Treatment was started with megestrol acetate (640 mg / day), prednisone (20 mg / day) and leuprolide (7.5 mg / month). After 3 months of therapy, the patient continued to have progression of his disease manifested by the increase in bone pain, increased levels of prostate specific antigen (PSA) and increased acid phosphatase in the serum. Physiological examination: weight = 72kg; height = 1 .75cm; BP = 140/86; R = 22; T = 37.6 C; H R = 88 and reg. The examination revealed moderate emaciation with some bilateral lower extremity edema + 1 and scrotum. There were basilar, bilateral regimes spread in the br examination. Laboratory studies: EKG demonstrated a branch block of right partial group. The chest x-rays showed moderate chronic obstructive pulmonary dis with minimal fibrosis. Intersitial edema was observed in both fields of the lower lung. There was no pulmonary metastasis. The complete blood count showed moderate anemia with a hemoglobin of 10.5 and a hematocrit of 34%. The liver function tests were normal. The white blood cell count, the differential and platelet count, was within normal limits. The PSA level was 58mg / ml. The acid phosphatase in the serum was 2 X above normal. Blood electrolytes, including calcium, were within normal limits. Acid phosphatase, AST, ALT and bilirubin levels were normal. Bone scan of radionucleotide revealed multiple metastases in the axial skeleton and ribs. The revision of the past prosthetic biopsy slides showed a high degree of adenocarcinoma of the prostate with grade 8 Gln. The pulmonary function studies showed a moderate obstruction of the air flow with moderate hypoxemia and hypercarbia. Tension EKG was not performed due to its severe intolerance to exercise. Clinical determination and evaluation of treatment: the patient has hormone-refractory, metastatic prostate carcinoma with documented clinical progression incrng bone pain and raising the serial values of PSA. According to the TNM classification of American Joint Cancer: Committee for prostate cancer (T = degree of extension of primary tumor, N = involvement of the regional lymph node, and M = presence of distant metastasis), it has the highest stage ( T3 N3 M1). Histologically, the tumor is aggressive through the Gln classification system. Since death due to prostatic carcinoma is almost invariable as a result of failure to control metastatic dis and since prostate cancers are well known to be sensitive to thermal stress, the DNP therapy of the present was taken as a last effort to stop the progression of the tumor and / or improve the quality of life of the patients.

In view of patient age, lung problems and poor functioning status (Karnofsky's classification of 6), it was decided to treat the patient with moderate doses of DN P and a free radical cyclisation agent, methylene blue (MB) , to induce cinergistic tumor annihilation. The effect of methylene blue on the state of cellular reduction-oxidation (redox) is well known. Methylene blue ly traverses cell membranes and acts as an electron acceptor of major coenzymes. Unlike oxidizing drugs, it subtly transfers endogenous substrate electrons to oxygen. Depending on the redox state of a cell, methylene blue can act as either an intracellular electron acceptor or donor. Methylene blue directly catalyzes the reaction of reducing agents intracellular, NADPH, NADH and GSH (reduced glutathione) with oxygen causing the production of hydrogen peroxide, superoxide anions, and the formation of potent cytotoxic oxidizing species, peroxynitrite. In mitochondria partially decoupled by DNP, methylene blue also stimulates respiration due to its double action of providing reduction equivalents necessary for the ß-oxidation of fats and capacity for donation / rel of electrons, with respect to the mitochondrial respiratory chain. It is an effective drug, at a dose of 1 -3 mg / kg, in the treatment of nitrate-induced methemoglobinemia. Methylene blue is also used as a given antidote as a 100 mg bolus, IV, for encephalopathy associated with alkylation chemotherapy. Since the decoupling, heat and increase of MB, the flow of cellular free radicals and malignant cells has a high bioreductive capacity, the cinergistic effects of 2,4-dinitrophenol with MB can allow a maximum annihilation of the tumor with minimum to moderate levels of hyperthermia of the total induced body. Additional free radical cyclising agents can be used in place of MB, and include, but are not limited to: phenazine methosulfate, xenobiotics such as quinones (eg, menadione, semiquinone, naphthoquinone, duroquinone, indigo-carmine), compounds nitrous (for example, metronidazole, niridazole, nitrofurozone, flunitrazepam), eminium ions (for example, methyl viologen, benzyl viologen, etc.) and others. In this patient was administered DN P-MB therapy in order not to exceed the baseline VO2 level by 50-75%. Pretreatment protocol: the patient was transfused with 2 units of red blood cells packed 48 hours before undergoing treatment. Intravenous fluids (lactated Ringer's solution) were administered at a rate of 100cc / hour. The patient was dressed in cotton clothes and placed in an air-conditioned room. The equipment to monitor the heart rate and the regimen, temperature and oxygen consumption was used as presented in example 1. An oral breathing tube was used to conduct TEEM VO2 measurements. In addition, oxygen supplement and "shock car" were available. Treatment protocol: Baseline VO2 measurements for 8 minutes established an average VO2 of 250cc / minute. The 2,4-dinitrophenol, at a dose of 2. mg / kg, was infused intravenously over a period of 2 minutes. VO2 repeated at 20 minutes was stabilized at 340-360cc / minutes. An additional infusion of 1 mg / kg of DNP was administered, and 15 minutes later the VO2 was elevated and stabilized at 420cc / minute. 10 minutes later, an infusion of methylene blue, 2mg / kg (dissolved in 0.4% of a 35ml pyrogen-free isotonic saline solution) was administered in 20 minutes. The repeated measurement of VO2 at intervals of minutes showed that it was elevated and stabilized at 450-500cc / minute.

At the third hour, VO2 declined on a scale of 360-380cc / minute. An additional dose of 1 mg / kg of DN P was infused during a period of 2 minutes. Repeated VO2 measurements 20 minutes after this infusion showed an increase in VO2 back to 450-500cc / minute. The temperature of the rectal probe was raised to a maximum of 1.3 ° C above the baseline. Blood pressure and cardiac regimens remained within normal limits. The patient resisted the procedure without any adverse effects and the therapy was terminated 6 hours after the initial dose of DNP. The protocol was repeated one day a day, not for a total of 15 treatments (30 days). The therapy was discontinued for two weeks and the cycle was repeated again for 30 more days, the treatment being administered one day yes and one not. Results of treatment: there was no evidence of general toxicity at any time during the treatment. The patient observed a decrease in his lower back, hips and other areas of bone pain at the 6th. day after therapy. At 2 weeks, the patient was out of all the narcotic analgesics (morphine) and presented a markedly increased appetite. On day 8, repeated PSA levels were increased by approximately 120% to 125 mg / ml. The acid phosphatase remained unchanged. All the other blood chemistries, including CBC, showed no significant alterations. At 6 weeks after treatment, the PSA repeat values showed a significant reduction at 30mg / ml with a concomitant drop in acid phosphatase levels in the serum. In the final stage, 10 weeks after the start of the treatment, a prostate biopsy was performed. Histological examination revealed that 95% of the tumor is necrotic with only disseminated acini or a scar containing an occasional malignant cell. There was a significant increase in the stromal cells above that seen in his initial biopsy. One of the most important changes observed by the pathologist was the formation of cyst-like structures within the epithelial cells. The patient was observed for 3 months after the start of therapy, during this time he gained 8.2 kg of weight, remained without pain and established that he felt "normal". Figure 26 shows supervised treatment parameters. Figure 27 shows biochemical, biopsy and clinical responses. Oral DNP therapy (250mg twice daily, daily for 5 days and then recycle without any medication for 2 days) was started after his intravenous therapy and continued for up to 4 months. A repeated prostate biopsy was obtained at the end of the 4th. month. The pathological examination revealed disintegration of remaining tumor acini together with the formation of many epithelial cysts. Occasional residual tumor cells were fractured and separated with markedly reduced cytoplasm. Extensive fibrosis occurred with an apparent increase in the number of stromal cells. Cytoplasm volume was significantly reduced in both residual and normal tumor cells. In summary, there were very few intact acini or viable acinar cells.

Example 10 Method for using dinitrophenol with biological response modifiers (in the treatment of hepatitis infection C) History: a 32-year-old banker with chronic hepatitis C infection was evaluated. He provided a past history of intermittent jaundice, dark urine, moderate anorexia, nausea, and vomiting. This episode occurred 10 years ago, approximately 3 months after a transfusion (3 units of packed red blood cells) for a cesarean section. She is currently asymptomatic, but in a routine health insurance exam she was found to have in her ALT and AST levels (alanine and aspartate aminotransferase): 140IU / L and 90IU / L, respectively. I drank 5-8 glasses of wine per week. Additional laboratory tests identified anti-HCV antibodies with a HCV-RNA level of 5 X 106 / ml. The patient refused to undergo liver biopsy, but agreed with treatment with interferon alfa-2b (3 million units injected subcutaneously 3 times a week) and ribavirin (500 mg orally, twice daily). After 12 weeks of treatment he developed lethargy, severe headaches, fever, nausea and depression. Anemia was detected with a hemoglobin concentration of 9.2g / deciliter. As a result, their dose of interferon was reduced to 1.5 million units 3 times a week and the dose of ribavirin was reduced to a total of 600 mg / daily. After 6 months of treatment their ALT and AST levels were normal and the HCV-RNA was undetectable. However, an additional therapy of 6 months failed to sustain its clinical improvement and was found to have a relapse. HCV-RNA levels in the serum were increased to 5.2 million copies / ml and liver enzymes were increased to 2.5-3 times that of the normal scale. He was unable to tolerate any additional ribavirin due to severe anemia. He persistently refused to undergo a percutaneous liver biopsy. Physical examination: Weight = 48 kg; height = 150 cm; BP = 128/82; HR = 76 and reg; R = 18; T = 37.5 ° C. The physical examination failed to reveal any signs of chronic liver disease. She was found to have several disseminated areas of alopecia which she attributes to her anti-hepatitis C therapy. Laboratory studies: EKG levels and chest x-rays were normal. CBC revealed moderate anemia with a hemoglobin of 10.2 and a hematocrit of 34%. WBC, differential and platelet counts were within normal limits. The alkaline phosphatase was within normal limits. AST and ALT levels in the serum were raised 2.5-3 times those of the upper normal limits. It was found that the levels of HCV-RNA in the serum are at 5.8 million copies / ml. The infectious hepatitis C strain was genotype 1 b. The anti-mitochondrial antibody serology was negative (titration less than 1: 20). There were no other abnormalities of blood chemistry, hormone or urine laboratory. Clinical determination and evaluation of treatment: the patient has a chronic hepatitis C infection with relapse after the combination treatment of ribavirin and interferon alfa-2b. This is not uncommon since the relapse regimen after an end-of-treatment response to interferon-ribavirin therapy may exceed 50%. He was unable to tolerate additional ribavirin therapy, due to a related anemia. In addition, the dose scale of interferon at points that do not respond to initial interferon therapy was only successfully tested in a small number of cases. Despite the refusal to undergo any form of liver biopsy, he agreed to undergo a combination of DNP and interferon therapy for a period of 12 weeks. It is known that the liver is one of the "hottest" organs in the human body. Liver temperatures exceeding 44 ° C have been documented in humans experiencing vigorous exercise. The hepatitis C virus is an encoded sphere of RNA containing several polyproteins comprising a capsid, 2 cover proteins, and at least 6 enzymatic proteins with varied functions. The hepatitis C virus is known to be sensitive to heat and is inactivated through standard blood bank warming techniques. Reports of inactivation of hepatitis C with the use of extracorporeal hyperthermia are known. It has been reported that patients with positive VI H treated with hyperthermia Extracorporeal, many of which were also positive for hepatitis C, the hepatitis C virus was eliminated (as determined by PCR-viral RNA analysis in serum). Based on this, patients failed to respond to conventional treatment, anecdotal and case report studies showing beneficial results with total body hyperthermia, the patient underwent a combination of DNP therapy and interferon. He was informed that he should undergo daily treatments with intravenous DN P for 5 days per week and receive interferon-alfa at a dose of 1.5 million units subcutaneously every two days. This treatment protocol can be continued until your hepatitis C-RNA blood viremia is no longer detected. Pretreatment protocol: every night before treatment with the patient was instructed not to eat after 7 at night and get dressed in cotton clothes. Approximately 6 hours before the intravenous administration of DN P, 1.5 million units of subcutaneous interferon-alpha were provided every third day. Recurrent blood work, including CBC and platelet counts, AST, ALT, and hepatitis C-RNA levels could be initially obtained at 48 hours and then weekly. No effort was made to avoid the loss of heat in the body. An individual intravenous line was placed with a 21 gauge intercatheter. The monitoring of cardiac rhythm, rectal thermistor and VO2 was conducted during the therapy as it was resumed. Treatment procedure: the patient presented himself same for the treatment and was given a subcutaneous dose of 1.5 million units of interferon-alpha. Approximately 6 hours later, at 1 p.m., a baseline VO2 level recorded in 5 minutes was 160 cc / min. It was infused with u 1. mg / kg of DN P for a period of 2 minutes. At 20 minutes, its VO2 was increased and stabilized at approximately 210cc / minute. A second dose of 1 mg / kg of DNP was infused and the VO2 reached a peak 20 minutes later, at 250cc / minute. An additional dose of 2.0 mg / kg of DN P was provided 30 minutes after the 2nd. dose. The repetition VO2 showed an increase and stabilization 20 minutes later, at 360cc / minutes. The rectal temperature of the patient increased and never exceeded 1 .3 ° C above its normal baseline. 2 hours of his last dose of DN P his VO2 was decreased to 280cc / minute. An additional dose of 2 mg / kg of DNP was administered. In patients VO2 was increased and stabilized 20 minutes later at a level of 420cc / minute. It was observed that he was sweating deeply. Through the treatment, the patient was allowed to drink fluids ad libitum. He was noticeably fatigued after 5 hours of therapy. The supervised parameters and the flow chart are shown in Figure 23. The 5-day treatment protocol was repeated after a "DN P rest period" of 2 days. This regimen was repeated 3 times. Interferon-alpha was administered subcutaneously for a total of 10 weeks. Figure 28 shows the flow chart of patients with D N P / i interferon treatment. Treatment results: through the treatment regimen summarized above, the viral load of hepatitis C-RNA was decreased by approximately 2 records after 48 hours. During the next 5 days, the viral load was further decreased by an additional record. HCV-RNA remained undetectable and the HCV viral genome remained removed from the bloodstream in the second week, and afterwards. Alanine transaminase levels (ALT) were raised 7 times to 48 hours and remained elevated until week 3, at which time they returned to levels slightly below those that existed before therapy. CBC bilirubin and blood urea nitrogen (BU N) remained within normal limits. Alkaline phosphatase levels were raised 2 times to 48 hours but returned to pretreatment levels on day 7. The HCV viral genome of patients remained removed from their bloodstream 18 months after the therapy and there was a normalization of their ALT .

EXAMPLE 1 Method for Using Intracellular Hyperthermia Induced by Dinitrophenol to Increase Immunogenicity of Human Tumors DN P can be provided as an intravenous solution, or as an oral preparation, in order to increase oxygen consumption 2.5-5 times above the normal for a period of 2-3 hours. Said treatment can be administered a day if and one day not during a period of 5-10 days. At 8-24 hours after the last day of treatment, the patient may be given standard chemotherapy or specific monoclonal antibody immunotherapy directed against mutated or inappropriately expressed oncogenic proteins (eg, ras, p53, HER / neu, etc.) , or a combination of anti-oncogenic immunotherapy with chemotherapy or radiation. Heat shock proteins (HSPs) or stress-induced proteins are constitutively expressed in all living cells, and are among the most abundant proteins found. However, many members of the HSP family can also be expressed through conditions that cause cell stress such as heat, drugs, glucose deprivation, etc. Of importance for the method of the present invention is that the expression of HSPs proteins in tumors is associated with an immune and / or cytotoxic T-lymphocyte response. In particular, it is known that members of the HSP70 family (HSPs proteins are generally classified by their molecular weights, eg, HSP90 kdaltons, HSP27 kdaltons, HSP70 kdaltons, etc.) are expressed on cell surfaces. Due to the ability of DNP to induce intercellular hyperthermia, the enhanced expression of human HSPs proteins in tumors treated with DN P can greatly increase their immunogenicity. This method can be used to expand the specific antigen repertoire of many tumors poorly immunogenic elevating the expression of immunogenic determinants of HSP-peptide on its cell surface. These consequences can increase any endogenous specific antitumor immune response. In addition, immunogenic immunogenic targets intracellular-DNP can also increase the efficacy of monoclonal antibodies exogenously synthesized and administered. For example, patients with HER-2 / neu overexpressing metastatic breast cancer (25% of breast cancer patients) can be treated through the DN P method mentioned above. This treatment can then be followed by a standard loading dose in weekly infusions of anti-HER-2 / neu monoclonal antibodies. Clinical benefits can be evaluated through total regimens of response and response duration.

Example 12 Synthesis and use of novel 2,4-dinitrophenol conjugates and derivatives The formation of novel nitrophenol compounds is of importance since their alkyl, alekene, fatty acid, aromatic derivatives and other derivatives can significantly improve their biological activity and / or improve the therapeutic index. Many reactions of the benzene ring of phenols are known through halogenation, sulfonation and nitration. Novel procedures for the C-alkylation of phenols through the reduction of benzyl alcohol, aldehydes, benzonitriles and Mannich bases. Alkylations or other additions of the "R" group have also been performed on various phenolic substrates using Stille or Negishi coupling reactions. An example of converting a nitrophenol compound to the desired alkylated analogue (or other analogue of the "R" group) in a 2-step procedure using the Stille coupling reaction is illustrated in Figure 30. As shown in step 1, the DNP is first iodinated with the Barluenga reagent (IPy2 BF4) to produce 2,4-dinitro-3-5-diiodophenol. In step 2, the nitroiodophenol is then converted to the alkylated derivative (in this example an ethylated derivative) through a Stille co-catalytic palladium-copper reaction. Compound 3 shown in Figure 30 is an ethylated derivative of DN P and is designed to elevate decoupling activity by adding lipophilic alkyl substituents to the benzene ring. Such analogues with increased activity may be partially useful in the treatment of bulky tumors and malignancies that are high in fat., for example, liposarcoma, glioblastoma, etc. A representative aspect (step 2) to the co-catalytic ethylation of palladium-copper of a nitroiodophenol is illustrated through the conversion of 2,4-dinitro-3-, 5-diiodophenol to 2,4-dinitro-3,5 -diethylphenol. Nitroiodophenol (500mg, 934μmol) was added to a pressurized reaction to contain 1.5ml of N-ethylpyrrolidinone. HE they added Pd2dba3CHCL3 (27mg, 26μmol) and tripheninphosphine (50mg / 191μmol) to the stirring solution and heated slowly to approximately 50 ° C for 10 minutes. Copper iodide (17 mg, Ol μmoles) was added to the stirring solution. The mixture was again heated at 50 ° C for 10 minutes. The solution was cooled to 32 ° C and tetraethyl tin (28 μL, 2.05 mmol) was added to the stirring solution. The reaction tube was sealed and heated with continuous agitation at 65 ° C for 12-16 hours. Aqueous process and extraction of ethyl acetate with drying through magnesium sulfate (MgSO 4) and concentration produced the final product.

Example 13 Synthesis of an Expanded Combination Collection of Putative Decoupling Agents Capable of Inducing Intracellular Hyperthermia The spectrum of potential classical decoupling agents that can induce intracellular hyperthermia can be greatly expanded through a designed convergent synthetic appearance. An almost unlimited variety of decouplers can be synthesized through a "combination" scheme to produce an expanded "collection" of decoupling agents with related structures. The scheme specifically presented here illustrates the synthesis of 21 potential decoupling agents, but can be expanded from 1, 000 to 100, 000 putative decoupling agents Five classes of decouplers were prepared through the convergent route shown in Figure 31. The synthetic scheme shown in Figure 31 is designed as a combinatorial aspect to allow access to a collection of structurally related putative decouplers for biological evaluation. Although the given examples observed in Figure 31 will allow the formation of at least 21 novel decouplers, a simple variation in this synthetic scheme will allow the decoupler collection to be expanded to include 1,000 to 100,000 novel decoupling agents. After the discussion, the general synthetic aspect will be described in Figure 31, the simple synthetic variations designed to expand the decoupler collection. Said variations will be apparent to those skilled in the art of synthetic organic chemistry and pharmaceutical development. Beginning from benzaldeido (Figure 31, compound 1), the diiodination at positions 3-5-using the Barluenga reagent (IPy2BF4) offers compound 2, which is alkylated using a Coille-copper Streck cocaine reaction to produce a 3,5-unsubstituted compound. This second 2-step aspect is known to produce a variety of methylated phenols. The use of tetramethyl tin then produces the dimethyl derivatives [compound 3, wherein R = Me (methyl)]; tetrabutyl tin produces the dibutyl derivatives [compound 3, wherein R = Bu (butyl)]; and tetraphenyl tin produces the diphenyl derivatives [compound 3, wherein R = Ph (phenyl)]. A Baeyer-Villiger oxidation of compound 3 with meta-chlorobenzoic peracid (mCPBA) followed by alkaline hydrolysis [KOH (potassium hydroxide)] of the resulting format provides phenols, compound 4. 2,4-dinitro derivatives or 2,4 -dic homogeneous initially have access from an intermediate compound 4. The nitrosation of compound 4 with the nitrofuromethylsulfonate salt (NO2CF3SO3) gives the 3,5-disubstituted 2,4-dinotrophenols shown in compound 5. Three different decoupling agents were produced through this synthetic route. The diiodination of compound 4 in positions 2- and 4- produces compound 6, which is treated with copper cyanide (I) (CuCN) to give the derivative 2,6-dicyanate, compound 7. 3 additional decouplers were synthesized through this route. The heterocyclic nitro, and cyano decouplers are also accessed from intermediate compound 3. The 2-cyano, 4-nitro decouplers are activated, since the spherical effects of the cyano group in position 2 are less than the corresponding 2-nitro derivatives . Mono-iodination of compound 3 through the thallium intermediate provides the selective 2-iodine derivative compound 8. The conversion of compound 8 to phenol, compound 9, is achieved through the Baeyer-Villiger oxidation and hydrolysis of the resulting format. Selective 4-nitration produces compound 10 and is easily accomplished with a nitrofluoromethylsulfonate salt followed by cyanidation to provide decouplers-2-cyano-, 4nitro, compound 1 1. 3 additional decouplers were produced through of this route. Additional decouplers such as the 2,4,6-tricyano compounds can also be produced through the same convergent synthesis. The exhaustive iodination of Compound 4 offers the compound 2,4,6,6-triiodinated, which is then directly converted to triadin decouplers, compound 13, through catalysed copper exchange. 3 more decouplers were produced through this modification. A 2,4-dician uncoupler carrying 3 variable substituents at positions 33-, 5- and 6- are also easily produced through this convergent aspect. The initial selective monobromination of compound 4, phenol, in the ortho position provides compound 14, which is diiodinated at positions 2,4 to produce the derivatives of the compound 2,4-diiodo, 6-bromo-compound 15. The exchange of Selective cyano to the more reactive aryl iodide positions offers the derivatives of the compound of 16, dicyano. A final palladium-copper cocatalytic Stille reaction results in the formation of 3,4-dicylated 3,6,6-trisubstituted 2,4-dicylinkers. The use of the same previously described tin reagents allows the production of either methyl, ethyl, propyl, butyl, etc. , or phenyl in the 6-position. Together with the 3 different substituents in the 3- and 5- positions, 9 additional decouplers are provided by this additional expansive route. The synthesis of 21 novel decouplers illustrated by the convergent aspect in Figure 31 can be further modified. So that they experts in In this technical aspect, a simple variation in this illustrative synthetic aspect will allow a vastly expanded collection of potential decouplers to be synthesized. The expanded collection can be produced through the introduction of an alkyl and aryl substituent arrangement in the 3-, 5- positions. and / or 6-, while maintaining 2,4-dinitro, 2,4-dicyano, 2-cyano-4nitro-, and / or the 2,4,6-trityano-phenol substrate. This simple synthetic variation is achieved using a variety of well-known reactions mediated by palladium, zinc, or copper at the stage of incorporation of the alkyl or aryl group, i.e., Figure 31, compound 2 to 3 and compound 16 to 17, in conversions. This synthesis is a variation of the Stille reaction, the Heck reaction, the Negishi coupling, Suzuki couplings, Semmelhack reactions and cuprate reactions. Such variation may introduce an unrestricted arrangement of potential substituents in the phenol core of the decoupler. This combination aspect can still be further expanded through variable halogenation (ie, bromination or iodination) at positions 3 and 5 to allow 2 different substituents to be introduced at these two positions in the metal-mediated halogen exchange regions. . This "combinatorial collection" aspect will allow a large scale of potential decouplers to be synthesized and evaluated for potential biological activity, including safety and effectiveness. The activity of many different conjugates and derivatives of 2,4-dinitrophenol (and its decoupling agents) can be tested through known in vitro methods for oxygen consumption, for example, tissue or cell suspensions with Clark-type oxygen sensors. Toxicity, mutagenicity and studies of LD50 in animals can be performed under recognized protocols before using any of the novel compounds in humans. After establishing toxicity and safety criteria, the various novel conjugates and derivatives can be administered under dose scale assays as previously presented for the clinical use of dinitrophenol. It will be apparent to those skilled in the art that numerous modifications and variations can be made to the processes and compositions of this invention. Thus, it is intended that the present invention cover the modifications and variations of this invention as long as they are within the scope of the appended claims and their equivalents.

REFERENCES 1.) Coley, W. B. (1893) "The Treatment of Malignant Tumors by Repeated inoculations of Erysipelas" Am. Journal Medical Science; 105: 487-51 1. 2.) Sartin, JS, Perry, OH (1995) "From Mercury to Malaria to Penicillin: The History of the Treatment of Syphilis at the Mayo Clinic- 1916-1955" Journal of the American Academy of Pharmacology, February. 3.) O'Leary, P. A. (1955) "Neurosyphilis II: Treatment" Baker, A. B., Editor. Clinical Neurology. Volume 2. New York: Haeber-Harper: 846-865. 4.) Westermark, F. (1898) "Uber die Behandiung of Ulcerinded Cervixcarcinomas" Mittel Kontanter Warme. Zbe Gynak: 1335-1339. 5.) Busch, W. (1866) "Uber den Einfluss Welchen Heftigese Erysiphelen Zuwelen AVF Organisiete Neubildungen Amiben" Verhandlungen de Naturh: Preuss Rheinl; 23: 28-30. 6.) Suer, R. P., Fisher, W. B. et al. (1980) "Burkitt's Lymphoma: Tumor Lysis Following Malignant Hyperthermia" Cancer Treatment Reports: Volume 64. No. 2-3, February / March. 7.) Tsueda, K., Dubick, M. N. et al. (1978) "Intraoperative Hyperthermia Crisis in Two Children With Undifferentiated Lymphoma" Anesth. Analg. 57: 51 1 -14. 8.) Green, I. (1991) "Hyperthermia Alone or Combined With Chemotherapy for the Treatment of Cancer" Hyperthermia in Conjunction with Cancer Chemotherapy, No. 2, AHCPR, Health Technology Assessment Reports, U.S. Department of Heath and Human Services. 9.) Overgaard, J., González, M. C. et al. (1995) "Randomized Trial of Hyperthermia as Adjuvant to Radiotherapy for Recurrent or Metastatic Melanoma" The Lancet; 345: 540-43. 10.) Maeda, M., Watanabe, N., Yamauchi, N. et al. (1991) "Successful Treatment of a Case of Hepatocellular Carcinoma with Tumor Necrosis Factor and Local Hyperthermia" Japónica Gastroenterology, Volume 26, No. 6: 774-778. 1 1.) Kitamura, K., Kwano, H. , Watanabe, M. et al. (1995) "Prospective Randomized Study of Hyperthermia Combined with Chemoradiotherapy for Esophageal Carcinoma" Journal Surg. Oncol. Sept; 60 (1): 55-8. 12.) Kitamura, M., Sumiyoshi, K., Sonoda, K. et al. (1997) "The Clinical and Histopathological Contributing Factors Influencing the Effectiveness of Preoperative Hyperthermo-chemo-Radiotherapy for the Patients with Esophageal Cancer" Hepatogastroenterology, January / February; 44 (13): 175-180. 13.) Pontiggia, P., Curto, C. F. et al. (1995) "Is Metastatic Breast Cancer Refractory to Usual Therapy Curable?" Biomed. and Pharmacother. 49; 79-82. 14.) Myer, J. L. (1984) "Hyperthermia-A Historical Perspective". Front Radiat. Ther. Oncol. 18: 1-22 15.) Fujimoto, S. et al. (1997) "Improved Mortality Rate of Gastric Carcinoma Patients with Peritoneal Carcinomatosis Treated with Intraperitoneal Hyperthermia Chemoperfusion Combined with Surgery. "Cancer Mar. 1; 79 (5): 884-91 16.) Ohno, S., Tomoda, M. et al. (1997)" Improved Surgical Results After Combining Preoperative Hyperthermia with Chemotherapy and Radiotherapy for Patients with Carcinoma of the Rectum. "Dis.

Rectum Apr: 40 (4): 401-6. 17.) Gautherie, M. (Ed.), Robins, H. L, Cohen, J. D., Nevelle, A. J. (1997) "Whole Body Hyperthermia: Biological and Clinical Aspects, Clinical Thermology, Subseries Thermotherapy, New York; Springer-Verllag. 41 -46. 18.) Donato, V. et al. (1997) "Multicentre Experience with Combined Hyperthermia and Radiation Therapy in the Treatment of Superficially Located Non-Hodgkin's Lymphomas "J. Exp. Clin Cancer Res. 16 (1): 87-90 19.) Kim, S. et al. (1976)" The Enhanced Killing of Irradiated HeLa Cells in Synchronous Culture by Hyperthermia "Br. J. Radiol. 48: 872-874. 20.) Moriyama, Y. et al. (1986) "Application of Hyperthermia to the Treatment of Human Acute Leukemia: Purging Human Leukemic Progenitor Cells by Heat "Blood, Vol. 67, 3: 802804. 21.) Uranus, M. (1988)" Tumor Response to Hyperthermia " Hyperthermia and Oncology, Vol. I, Uranus, M. and Douple, E. Eds. , NSP BV. 162-200. 22.) Moyalan, D. J. et al. (1989) "Hyperthermia-Scientific Basis and Clinical Applications "Therapeutic Radiology, Manfield, C. M. Ed., Elsevier-New York. 531-541. 23.) Buell, J. F. et al. (1997) "Synergistic Effect and Possible Mechanisms of Tumor Necrosis Factor and Cisplatin Cytotoxicity Under Moderate Hyperthermia Against Gastric Cancer Cells "Ann.

Surg. Oncol. 4 (2): 141 -8. 24.) Crile, G. (1963) "The Effects of Heat and Radiation on Cancers Implanted on the Feet of Mice "Cancer Res. 23: 372-380.25) Brown, MRW et al. (1971)" Inhibition and Destruction of Microorganisms by Heat "Hugo, WB Ed., Inhibition and Destruction of the Microbial Cell Academic Press, New York, 1-37, 26.) Brand, PW (1959) Int. J. Lepr. 27: 1, 27.) Storrs, EE (1971) Int. J. Lepr: 39: 703 28. ) Muir, E. (1948) Manual of Leprosy, Baltimore, Williams &Wilkins, 29.) Bierman, W. (1942) "The History of Fever Therapy in Treatment of Disease" Bull NY Acad. Med. 18: 65- 75. 30.) Hollander, D. H et al. (1959) Am. J. Syphilis 3, 8: 489. 31) Schwemlein, T. J et al. (1948) Journal American Med. Assoc. : 1209. 32.) White, HJ et al (1938) J. Bacteriol 36: 481. 33.) Simon, H. B. et al. (1996) "Pathophysiology of Fever and Fever of Undetermined Origin" Scientific American Medicine Vol. 2. Dale, D.

C. et al. Eds. Scientific American, New York, Section 7, Subsection XXIV, 4. 34. ) Sutherland, G. E. et al. (1980) "Heat Treatment for Certain Chronic Granulomatosis Skin Infections "Southern Med. J. 73, 12: 1564-1565. 35.) Hiruma, M. et al. (1992) "Hyperthermic Treatment of Sporotrichosis" Mycoses, 35: 293-299. 36.) Thomas, C. C. et al. (1951) "Sporotrichosis Responding to Fever Therapy "JAMA 147: 1342- 1343. 37.) Rodbard, D. et al. (1980)" Temperature: A critical Factor Determining Localization and Natural History of Infectious, Metabolic, and Immunological Diseases "Perspectives in Biology &Medicine, Spring. 439-474. 38.) Mackinnon, J. E. (1968) "Systemic Mycosis", Wolstenholme, G.

E., and Porter, R. (Eds.) Boston: Little, Brown. 39.) Mackinnon, J. E. et al. (1962) Sabouraudia, 2:31. 40.) Silva, M. (1958) "Fungi and Heat Sensitivity" Trans. N. Y. Acad.

Sci., 2d series, 21: 46 41.) Dubos, R.J. (1952) "Bacterial and Mycotic Infections of Man" 2nd ed. Philadelphia: Lippencott. 42.) Kuhn, L. R. (1939) "Growth and Viability of Cryptococcus neoformans at Mouse and Rabbit Body Temperatures" Proc. Soc.

Exp. Biol. Med. 41: 573-574. 43.) Samady, J. A. et al. (1996) "Cutaneous and Mucocutaneous Leishmaniasis "Cutis 57: 13-20 44.) Sacks, D. L. et al. (1983)" Thermosensitivity Pattems of Old vs New World Cutaneous Strains of Leishmania Growing within Mouse Peritoneal Macrophages In Vitro "Am. J. Trop. Med. Hyg. 32 (2): 300-304. 45.) Junaid, A. J. N. (1986) "Treatment of Cutaneous Leishmaniasis With Heat "Int. J. Dermatol., 25: 470-472, 46.) Kakahashi, M. (1992)" Effect of Thermochemotherapy on Alveolar Hydadid Disease of the Liver "J. of the Japanese Surg. Soc., 93 (2): 1 50- 1 57. 47.) Baron, S. (1963) "Mechanism of Recovery from Viral Infection" Advan. Virus Res. 10: 39-64. 48.) Kim, A. et al. (1983) "How Viruses May Overeóme Non-specific Defense in the Host "Phil. Trans. R. Soc. Lond. B303, 115-122, 49.) Fenner, F. et al (1976) Medical Virology 2d ed. New York: Academic Press. 50.) Schmidt, J. R. et al (1960) "Temperature Effect on Herpes Simplex" J. Infecí. Dis. 107: 356-360. 51.) Vaczi, I. Et al. (1963) "Influence of Temperatures on the Multiplication of Varecella Virus "ACTA Virol. (Prague) 12: 109-1 15. 52. ) Carter, W. A. et al. (1974) "Viral Infection and Host Defense" Science, 186: 1 172-1 177. 53.) Schweitzer-Thumann, C. et al. (1994) "Effect of an Elevated Temperature on the Replication of HIV-1 and Monocytic Cell Line " Res. Virol. 145: 163-170. 54.) Lee, M. H. et al. (1996) "HIV-1 Load is Decreased in Chronic Infected ACH-2 Cell Line by Successive In Vitro Hyperthermia Treatment "XI International Conference On AI DS, Vancouver, Canada 55. ) Wong, G. H. et al. (1991) "Tumor Necrosis Factor to Selectively Sensitizes Human Immunodeficiency Virus-lnfected Cells to Heat and Radiation "Proc. Nati. Acad. Sci. USA 88: 4372- 4376. 56.) Alonso, K. et al. (1994)" Systemic Hyperthermia in the Treatment of HIV-Related Disseminated Kaposi's Sarcoma "Am. J.

Clin. Oncol 17 (4): 353-359. 57.) Alonso, K. et al. (1995) "Whole Body Hyperthermia and the Augmentation of Cellular Cytotoxic Repsonses in the Treatment of Acquired Immune Deficiency Syndrome "Southern Med. J. 88: S142 .58.) Schecterle, L.M. et al. (1995)" Potential Role of Whole Body Hyperthermia to Treat Lyme Disease "Southern Med. J. 88: 5142-143. 59. ) Stone, R. (1993) "CDC Chokes on AI DS Treatment Proposal" Science 260: 883. 60.) Ash, S. R. et al. (1994) "The Biologic-HT Sorbent System Maintains Normal Blood Chemistries During Whole-Body Hyperthermia "American Society for Artificial Internal Organs, 40, h Anniversary Meeting, San Francisco, California. 61.) Kakinuma, K. et al. (1996) "Drug Delivery to the Brain Using Thermosensitive Liposome and Local Hyperthermia "Int. J Hyperthermia 12 (1): 157-165 62.) Iga, K. (1992)" Optimum Formation of Thermosensitive Liposome for Targeted Tumor Drug Delivery "J of Takeda Research Lab. 5: 45-72. 63.) Merlin, J. L. et al. (1993) "proliferative of Thermosensitive Liposome-Encapsulated Doxorubicin Combined with 43 ° C Hyperthermia in Sensitive and Multi-Drug ResistMCT-7 Cells " Eur. J. Cancer 29A: 2264-2268. 64.) Kizer, K. W. (1992) "A Simple Solution to Scorpaenidae Stings" Emergency Medicine July, 209A-210-B. 65.) Hudgens, T. L., Tumbull, K. D. (1998) "C-Methylation of Phenols, Tyrosine Derivatives, and a Tyrosine Containing Peptide " Tetrahedron Letters 40: 2719-2722. 66.) Cortopassi, G. et al. (1995) "Modeling the Effects of Age-Related mtDNA Mutation Accumulation: Complex I Deficiency, Superoxide and Cell Death "Biochem. Biophys. Acta 1271: 171-176. 67. ) Koga, S. et al. (1990) "Extracorporeally Induced Total-Body Hyperthermia for Disseminated Cancer "Adv. Exp. Med. Biol. 267: 1 77- 1 88. 68.) Parks, L.C. et al. (1979) "Treatment of Far-Advanced Bronchogenic Carcinoma by Extracorporeally Induced Systemic Hyperthermia "J. Cardiovasc Surg. 78: 883-892 69.) Vertrees, R. E. et al. (1996)" Induction of Whole Body Hyperthermia and Venovenous Perfusion "American Society for Artificial Internal Organs J. 42 (4): 250-4. 70.) Pontiggia, P. et al. (1995) "Whole Body Hyperthermia Associated with Betacarotene Supplementation in Patients with AIDS " Biomed. And Pharmacother 5: 263-265. 71.) Müller-Scholte, D. P. et al (1996) "AI DS Therapy Using Encapsulated Magnetic Nanoparticles "RWTH-AACH EN, Rechnerbetrieb Informatik, Germany. (German Patent #?). 72. ) Colé, N. H. (1994) "Hyperthermia as AdjuvTreatment for Recurrent Breast Cancer and Primary MalignGlioma" JAMA 271 (10): 797-802. 73.) Gilden, D. (1995) "Hyperthermia Study Finds Little Effect" GMHC Treat Issues 9: 1 1. 74.) Roizen-Towle, L. et al. (1988) "Thermotolerance in Human Cells of Normal and Neoplastic Origin" Int. J. Hyperthermia 4 (6): 665-675. 75.) Gerwick, L. E. et al. (1980) "Influence of pH on the Response of Cells to Single and Split Doses of Hyperthermia" Cancer Research 40: 4019-4024. 76.) Hirokawa, K. et al. (1997) "Effect of Lactic Acid in Tumors on -tumor Activity of Hyperthermia "Int. J. Hyperthermia 13 (11): 1 15- 123. 77.) Yoshikawa, T. et al. (1993)" The Role of Active Oxygen Species and Lipid Peroxidation in the - Tumor Effect of Hyperthermia "Cancer Research 53: 2326-2329.78.) Kang, S. et al. (1994)" Debilitating Verruca Vulgaris in a Patient Infected with the Human Immunodeficiency Virus: Dramatic Improvement with Hyperthermia Therapy "Arch Dermatol. : 294-296 79.) Calderwood, SK et al. (1987) "Thermal Injury Causes Stimulation of Phospholipase A2 Activity in Mammalian Cells" Walden, T. Prostaglandin and Lipid Metabolism in Radiation Injury, New York, NY: Plenum Press; 201 -206.80) Stephenson, MA et al. (1986) "Rapid Increase in Inositol Triphosphate and Intracellular Ca + 2 After Heat Shock "Biochem.

Biophys. Res. Commun. 137: 826-833. 81.) Kroemer, G. et al. (1995) "The Biochemistry of Programmed Cell Death "The FASEB Journal 9: 1278-1287, 82.) Decaudin, D. et al. (1997)" Bcl-2 and Bcl-X Antagonize the Mitochondrial Dysfunction Preceding Nuclear Apoptosis by Chemotherapeutic Agents "Cancer Res. 57: 62-67 83.) Zamzami, N. et al. (1996)" Mitochondrial Control of Nuclear Apoptosis "J. Exp. Med. 183: 1533-1544 84.) Henry, K. et al. (1996)" Acute Effects of Whole Body Hyperthermia (WBH) on Plasma H IV RNA Levéis "3rd Conf. Retro.

And Opportun. Infect. 1: 122. 85.) McLaren, J. E. et al. (1990) "Consensus on Hyperthermia for 1990's "Adv. Exper. Med. Biol. 267: 21-36, 86.) Sessier, D. I, et al. (1990)" Skin-Surface Warming: Heat Flux and Central Temperature "Anesthesiology 73: 218-224. .) Gordon, RT et al. (1979) "Intracellular Hyperthermia" Medical Hippothesis 5: 83-102. 88.) González, G. D. et al. (1995) "Radiotherapy and Hyperthermia" Eur. J. Cancer 31A (7-8): 1351-1355. 89.) Strohbehn, J. W. (1994) "Hyperthermia Equipment Evaluation" Int. J. Hyperthermia 10 (3): 429-432. 90.) Multhoff, G. (1997) "Heat Shock Protein 72 (HSP72), A Hyperthermia-lnducible I mmunogenic Determinant On Leukemic K562 and Ewing's Sarcoma Cells "Int. J Hyperthermia 13: 39-48. 91. Brooks, G. A. et al. (1971) "Temperature.Skeletal Muscle Mitochondrial Functions, and Oxygen Debt "Am. J. Physiol. 220: 1053-1059. 92.) Brooks, G. A. et al. (1971) "Tissue Temperatures and Whole Animal Oxygen Consumption After Exercise" Am. J. Physiol. 221: 427-431. 93.) Hynynen, K. et al. (1997) "Thermal Effects of Focused Ultrasound on the Brain: Determination with MR Imaging "Radiology 204 (1): 247-53. 94.) Skinkal, M. et al. (1996) "Intracellular Hyperthermia for Cancer Using Magnetic Cationic Lipsomes: In Vitro Study "Jpn. J.

CancerRes. 87 (11): 1179-83. 95.) Khogali, M. et al. (1993) "Heat Stroke and Temperature Regulation "(eds M. Khogali and J. R. S. Hales) Academic Press, Sydney 96.) Benndorf, R. et al. (1997)" Cellular Stress Response: Stress Proteins-Physiology and Implication for Cancer "Recent Results Cancer Res. 143: 129-144. 97.) Sneed, P. K. et al, (1998) "Survival Benefit of Hyperthermia in A Prospective Randomized Trial of Brachytherapy Boost +/- Hyperthermia for Glioblastoma Multiforme" Int. J. Radiat. Oncol. Biol.

Phys. 40 (2): 287-95. 98.) Dahl, O. (1996) "Interaction of Heat and Drugs in vitro and in vivo" in Seegenschmidt, M. H. , Vernon, C.C. (eds) Thermoradiotherapy and Thermochemotherapy, Vol 1. Berlin, Germany, Springer, 103-122. 99.) Hauck, M. L. et ai (1995) "Enhancement of Radiolabeled Monoclonal Antibody Uptake in Tumors with Local Hyperthermia "in Torchlin, V. P. (ed): Targeted Delivery of Imaging Agents. Boca Raton, FL. , CRC, 335-361. 100.) Dewhirst, M.W. et al (1997) "Hyperthermic Treatment of Malignant Disease: Current Status and a View Toward the Future " Seminars in Oncology, 24 (6): 616-625. 101.) Gaber, M. H. et al, (1996) "Themosensitive Liposomes: Extravasation and Relase of Contents in Microvascular umor Networks "Int. J. Radiat Oncol. Biol. Phys. 36: 1 177-1 187. 102.) Kato, H. et al. (1998)" Research and Development of Hyperthermia Machines for Present and Future Clinical Needs "Int. J.

Hyperthermia 14 (1): 1 -1 1. 103.) Clegg, S.T. et al, (1996) "Verification of a Hyperthermia Model Method Using MR Thermometry "Int. J. Hyperthermia, 1 1: 409-424. 104. ) Keyserlingk, J.-R. (1998) "Is It Time To Reassess the Valué of Infrared Breat Imaging "Primary Care &Cancer, February Issue, 9. 105. ) Kamiya, M. et al (1998) "A Case of Cutaneous Pseudallescheriosis Resembling Sporotrichosis" Nippon Ishinkin Gakkai Zasshi, 39 (1): 33-36. 106.) Youngblood, D. et al (1998) "First Circie Tries to Advance" Minneapoplis Star Tribune, April 13 Issue, p. D2. 107.) Szreder, Z. et al (1991) "Acomparative Study on the Thermoregulatory Effects of Prazosin, Dihydrobenzperidol and Nifedipin on 2,4-Dinitrophenol Induced Hyperthermia in Rabbits "Gen.

Pharmac, Vol. 22 (6): 1139-1 142. 108.) Koga, S. et al (1990) "Extracorporeal Induced Total-Body Hyperthermia for Disseminated Cancer "Adv. Exp. Mod. Biol., 267: 177-188.109) Robins, H. I. Et al. (1990)" Whole Body Hyperthermia in the Treatment of Neoplastic Disease "Radiol Clin North, 17 (3): 603-610. 1 10.) Thrall, D. E. et al (1990) "A Comparison of Temperature in Canine Solid Tumors During Local and Whole-Body Hyperthermia Administered Alone and Simultaneously "Int. J. Hyperthermia, 6 (2): 305-317. 1 1 1.) Raaphorst, G. P. et al (1994) "Hyperthermia Radiosensitization in Human Giloma Cells Comparison of Recovery of Polymerase Activity Survival, and Potentially Lethal Damage Repair "Int. J. Radiat. Oncol. Biol. Phys., 29 (1): 133-139.12) Eisler, K. et al. (1990)" New Clinical Aspects of Whole Body Hyperthermia "Adv. Exp. Med. Biol. 267: 393-398.1 13.) Thrall, D. E. et al. (1989)" Whole Body Hyperthermia in Dogs Using a Radiant Heating Device: Effect of Surface Cooling on Temperature Uniformity "Int. J. Hyperthermia 5 (2): 137143. 1 14.) Young, R. A. et al (1989)" Stress Proteins, Infection, and Immune Survelliance "[Review] Cell 59 (1): 5-8.1 1) Lindquist, S et al (1988)" The Heat Shock Proteins "[Review] Annu. Rev. Genet. 22: 631 -677. 1 16.) Henle, K. J. et al (1980) "Time-Temperature Conversions Bioiogical Applications of Hyperthermia "Radiat, Res. 82 (1): 138-145. 1 17.) Riviere, J. E. et al (1986) "Effect of Hyperthermia on Cisplatin Pharmokinetics in Normal Dogs "Int. J. Hyperthermia. 2 (4): 351-358. 1 18.) Santinami, M. et al (1989) "Seven Year Experience with Hyperthermic Perfusion Extracorporeal Circulation for Melanoma of the Extremities" J. Surg. Oncol. 42 (3): 201-208. 1 19.) Yerushaimi, A. et al (1982) "Antitumor Effects of Combined Interferon and Hyperthermia in Mice "Proc. Soc. Exp. Biol. Med. 169 (3) 413-415. 120.) Kerr, J. F. et al 1994"Apoptosis, Its Significance in Cancer and Cancer Therapy "(Published erratum appears in Cancer 1994 Jun 15; 73 (12): 3108) [Review] Cancer 73 (8): 20132026. 121.) Kozak, W. (1993) "Fever a Possible Strategy for Membrane Homeostasis During Infection "[Review] Perspect, Biol. Med. 37 (1): 14-34. 122.) Villar, J. et al. (1994)" Induction of the Heat Shock Response Reduces Mortality Rate and Organ Damage in a Sepsis-lnduced Acute Lung Injury Model "(See Comments) Crit. Care Med. 22 (6): 914-921. 123.) Page, R. I. et al (1994) "Effect of Whole Body Hyperthermia on Carboplatin Disposition and Toxicity in Dogs "Int. J. Hyperthermia (6): 807-816. 124.) Jain, R. K. et al (1994) "Barriers to Drug Delivery in Solid Tumors "[Review] Sci. Am. 271 (1): 93-127. 125.) Bowler, K. (1981)" Heat Death and Cellular Heat Injury "J.

Therm. Biol. 6: 171-178. 126.) Heron, I. et al (1978) "The Actions of Interferon are Potentiated at Elevated Temperatures" Macmillan Journals Ltd. Nature 274: 508-510. 127.) Parks, LC et al (1995) "Systemic Hyperthermia by Extracorporeal Induction: Techniques and Results, In: Unk. Anonymous, Pp407-446, 128.) Harmon, BV et al (1990)" Cell Death Induced in a Murine Mastocytoma by 42-47 Degrees C Heating in Vitro Evidence that the Form of Death Changes from Apoptosis to Necrosis above to Critical Heat "Int. J. Radiat, Biol. 58 (5): 845-858. 129.) Gabriele, P et al (1990) "Hyperthermia Alone in the. Treatment of Recurrences of Malignant Tumors. Experience with 60 lessions "Cancer 66 (10): 2191 -2195. 130.) Brinnel, H. et al (1987)" Enhanced Brain Protection During Passive Hyperthermia in Humans "Eur. J. Appl. Physiol. 56 (5): 540-545 131.) Harmon, BV et al (1991) "The Role of Apoptosis in. The Response of Cells and Tumors to Mild Hyperthermia" Int. J. Radiat, Biol. 59 (2): 489-501. .) Cohen, J. D. et al (1990) "Whole Body Hyperthermia and Intraperitoneal Carboplatinum in Residual Ovarian Cancer" ln: Bicher, H 1, McLAren, J. R., Pigluicci, G. (eds) Consensus of Hyperthermia for the 1990's: Advances in Medicine and Biology Series, Plenum, New York, pp 197-202. 133. ) Sellins, K. S. et al (1991) "Hyperthermia Induces Apoptosis in Thymocytes (published erratum appears in Radiat, Res. 1992 Mar: 129 (3); 370-371). Radiat. Res. 126 (1): 88-95. 134.) Freeman, M.L. et al. (1977) "Effects of pH on Hyperthermic Cell Survival" J. Nati. Cancer Inst.5B (6): 1837-1839. 135.) Kamura, T. et al (1982) "Development of Thermotolerance During Fractionated Hyperthermia in a Solid Tumor in Vivo "Cancer Res.42 (5): 1744-1748. 136.) Reisinger, E. et al (1996) "Antiniotics and Increased Temperatures Against Borrelia Burgdorferi in vitro" Scand. J. Infecí.

Dis.28 (2): 155-7. 137.) Schecterle, L. M. et al (1995) "Altered Lipid Meibolism wiíh Hyperihermia "FASEB 9 (4): A646, 138.) Groom, R. C. eí al (1987)" Hyperihermic Treamenal Cancer: Systemic Hyperthermia and Isolated Limb Perfusion "Proc. Am.

Of Cardiov. Per.8: 105-111. 139.) Yang, H. X. el al (1991) "Hyperlhermic Inaclivation, Recovery and Induced Thermoloarance of Human Naural Killer Cell Lyiic Function "Iní. J. Hyperíhermia 7 (1): 35-49. 140.) Arkin, H. eí al (1994)" Receñí Developmenls in Modeling Heal Transfer in Blood Perfused Tissues "[Review] IEEE Trans. Biom. Eng. 41 (2): 97-107. 141.) St. Cyr et al (1996) "Whole Body Exlracorporeal Low Flow Hyperthermia in a Canine Model "J. Extracorporeal Technology 28 (3): 140-146. 142. ) Macy. D. W. (1985) "Physiological Studies of Whole-Body Hyperthermia of Dogs "Cancer Res. 45: 2769-2773, 143.) Schecterle, L. M. et al (1995)" Could Whole Body Hyperthermia Offer to Treatmení Option in Lyme Disease? "Alternative Med. J. Pp. 19-20, 144.) O'Leary, P. S. (1927)" Treatment of Neurosyphilis by Malaria: Report on the Three Year Observation of the First One Hundred Patienls Treated "JAMA 89: 95-100, 145.) Field, S. B. et al (1983)" The Relationship Between Heating Time and Temperature: Its Relevance to Clinical Hyperthermia " Rediother. Oncol. 1: 179-186. 146.) Omar, R. A. al (1987) "Antioxidant Enzymes and Survival of Normal and Simian Virus 40-Transformed Mouse Embryo Cells After Hyperthermia "Cancer Res. 47: 3473-3476, 147.) Rowell, L. B. (1974)" Human Cardiovascular Adjustments to Exercise and Thermal Stress "[Review] Physiol. Rev. 5 (1): 75-159. 148. ) Nadel, E. R. et al (1979) "Circulatory Regulation During Exercise in Different Ambient Temperatures. J. Appl. Physiol. 46 (3): 430-437. 149.) Frey, M. A. et al (1979) "Cardiac Response to Whole-Body Heating "Aviat, Space Envirn, Med 50 (4): 387-389, 150.) Rowell, L. B. (1983)" Cardiovascular Aspects of Human Thermoregulation "[Review] Circ. Res. 52 (4): 367-379.151.) Rowell, L. B. (1972)" Importance of the Splanchnic Vascular Bed in Human Blood 'Pressure Regulation "J. Appl. Physio. 32 (2): 213-220. 152.) Page, R. L. et al (1994) "Therapeutic Hyperthermia: Contribution from Clinical Studies in Dogs with Spontaneous Neoplasia" [Review] In Vivo 8 (5): 851-858. 153.) Gillette, S.M. et al (1992) "Response of Canine Soft Tissue Sarcomas to Radiation or Radiation Plus Hyperthermia: A Randomized Phase II Study" Int. J. Hyperthermia 8 (3): 309-320. 154.) Thrall, D. E. et al (1992) "Serious Toxicity Associated with Annular Microwave Array Induction of Whole-Body Hyperlhermia in Normal Dogs" Int. J. Hyperthermia 8 (1): 23-32. 155.) Meyer, R. E. et al (1991) "Effect of a Passive Heat and Moisture Exchanger on Esophageai Temperature in Tumor-Bearing Dogs During Whole-Body Hyperthermia" Am. J. Vet. Res. 52 (10): 1688-1691. 156.) Page, R. L. et al (1991) "Phase I Sludy of Melphalan Alone and Melphalan Plus Whole Body Hyperthermia in Dogs with Malignant Melanoma" Int. J. Hyperthermia 7 (4): 559-566. 157.) Herman, T. S. et al (1982) "Effect of Heating on Lethality Due to Hyperthermia and Selected Chemotherapeutic Drugs" J. Nati. Cancer Ins. 68 (3): 487-491. 158.) Overgaard, J. et al (1983) "The Importance of Thermololerance for the Clinical Clinic wiíh Hyperíhermia" Radiolher. Oncol 1 (2): 167-178. 159.) Mackowiak, P. A. (1981) "Direcl Effecls of Hyperlhermia on Pathogenic Microorganisms: Teologic Implications with Regard to Fever "[Review] Rev. Infecí. Dis. 3 (3): 508-520. 160.) Li, GC el al (1992)" Heal Shock Protein hsp70 Protects Cells from Thermal Stress even After Deletion of its ATP-Binding Domain " Proc. Nati Here. Sci. USA 89 (5): 2036-2040. 161.) Mitsudomi, T. et al (1993) "Transformation by Viral Oncogenes Increased Sensitivily to Heat in Rat 3Y1 Fibroblasts "Anticancer Res. 13 (4): 995-999. 162.) Clocca, DR et al (1993) "Biological and Clinical Implications of Heat Shock Protein 27,000 (Hsp27): a Review [Review] J. Nati, Instil Cancer 85 (19): 1558-1570.163.) Faulus , J. A. et al (1993) "Heat Shock Protein Response in a Prostate Tumor Model to Intersíiial Thermolherapy: Implicaíions for Clinical Trial "Proslaie 23 (3): 263-270 164.) Trieb, K. Al (1994)" Hyperlhermia Inhibits Proliferation and Stimulates the Expression of Differentiation Markers in Cultured Thyroid Carcinoma Cells "Letl Cancer 87 (1): 65-71 165.) Tauchi, K. et al (1991)" Expression of Heat Shock Protein in Human Breast Cancer: An Immunohistochemical Study "Jpn J. Clin.

Oncol. 21 (4): 256-263. 166.) Oleson, J. R. et al (1993) "Sensilivily of Hyperhermia Trial Ouícomes lo Temperaíure and Time: Implications for Thermal Goals of Treatment "Int. J. Radiat. Oncol. Biol. Phys. 25 (2): 289-297. 167.) Dickson, J. A. et al (1980)" Temperature Range and Selective Sensivitiy of Tumors to Hyperthermia: A Critical Review "Ann. N. Y. Acad. Sci. 335: 180-205. 168. ) Meyer, J. L. et al (1989) "Hyperthermic Oncology: Currenl Biology, Physics and Clinical Results "[Review] Pharmacol. Ther. 42 (2): 251-288. 169.) Sapareto, S.A. (1987): Thermal Isoeffect Dose: Addressing the Problem of Thermotolerance "Iní. J. Hyperlhermia 3 (4): 297-205 170.) Field, S. B. eí al (1983)" The Relalionship Beíween Healing Time and Temperalure: Its Relevance to Clinical Hyperlhermia " Radiolherap. Oncol. 1 (2): 179-186. 171.) Armor, M. al (1993) "A Sensilivity of Human Cells to Mild Hyperthermia" Cancer Res. 53 (12): 2740-2744. 172.) Amrani, M. et al (1996) "Kinetics of Induction and Protective Effect of Heat-Shock Proteins After Cardioplegic Arrest "Ann.

Surg. 61: 1407-1412. 173.) Marber, M. S. et al (1993) "Cardiac Stress Protein Elevation 24 Hours After Brief Ischemic or Heat Stress is Associated with Resistance to Myocardial Infarction "Circ 88: 12641272. 174.) Hulíer, M. M. eí al (1994)" A Direct Correlalion Belween íhe Amounl of Heal-Shock Prolein Induced and Ihe Degree of Myocardial Protection "Circ 89: 355-360, 175.) Donnelly, T. J et al. (1992)" Heat-Shcok Protein Induction in Rat Hearts. A Role for Improved Myocardial Salvage After Ischemic and Reperfusion? "Circ 85: 769-778 176.) Amran, M. et al. (1994)" Induction of Heat-Shock Proteins Enhancements Myocardial and Endothelial Functional Recovery After Prolonged Cardiologic Arrest "Ann Thorac, Surg. 57: 1 57- 160. 177. ) Liu, X. et al (1 .992) "Heat Shock: A New Approach for Myocardial Preservation in Cardiac Surgery "Circ 86 (suppl 2): 358-363. 178.) Waiker, DM et al (1993) "Heat Stress Limits Infarct Size in Isolale Perfused Rabbil Hearí: Cardiovasc. Res. 27: 962-967 179.) Downing, JF ee al (1987)" The Effecl of in vivo Hyperíhermia on Selected Lymphokines in Man "Lymphokine Res. 6: 103-109 180.) Englehardl, R. (1988)" Summary of Receñí Clinical Experience in Whole-Body Hyperíhermia Combined wiíh Chemolherapy "ln: lsseis, RD Wilmanns, W (eds) Applicafion of Hyperlhermia in íhe Trealmení of Cancer pp200-204 181.) Aloia, RC el al (1988) "Lipid Composilion and Fluidity of the Human Immunodeficiency Virus "Proc. Nati. Acad. Sci. 85: 900-904. 182. ) Hager, E. D. et al (1996) "Intraperitoneal Hyperthermic Perfusion (IPHP) Chemolherapy of Advanced Wiih Pairs Ovarian Cancer "Hyperfhermic Oncol. Proc. 7, h Int. Congress Hyperthermic Oncol. 11: 261 183.) Robins, H. I. et al (1993) "Phase I Clinical Triais of Carboplatin and 41.8 degrees C Whole-Body Hyperhermia in Cancer Palienls" J. Oncol. 1 1 (9): 1787-1794. 184.) Schecíerle, L. M. el al (1995) "Currenl and Future Prospects of Whole Body Hyperthermia for Deactivation of H IV "AIDS Patient Care 9 (2): 85-86. 185.) Zippel, D. et al (1996) "Continuous Hyperlhermic Periloneal Perfusion for Malignant Ascites and lrresectable_lntra Abdominal Cancer "Hyperthermic Oncol. Proc. 7th Int. Congress Hyperthermia Oncol. 1 1: 258-260. 186.) Schecterle, L. M. et ai (1995) "Hyperthermia as a Potential Treatmenl in H IV Disease "Alternative Med. J. 2 (3): 28-32, 187.) Schecterle, L. M. et al. (1997)" Hyperthermia Alters HIV Kinetics "Alternative Therapies in Clinical Practice 4 (5): 162-164 188.) Henry, K. et al (1996)" Accute Effects of Whole Body Hyperthermia (WBH) on Plasma HIV RNA Levéis "Third Conf. On Retroviruses and Opportunistic Infections "Abstract # 373, 189.) Schecterle, L.M. et al. (1995)" Rate of Temperature Rise Using a Hot Air Whole Body Hyperthermia Device "Southern Med. J. 88 (10): PS143. 190.) Scheclerle, L. M. et al (In Press) "Twelve Month Follow-up in Advanced H IV Patients Treated with Whole Body Hyperthermia "20, h Int. Mtg. On Clinical Hyperthermia 191.) St. Cyr, J. A. et al (1996)" Cranial Venous Effluent Temperature Assessment During Extracorporeal Whole Body Hyperthermia "FASEB j. 10 (3): A1 1 8. 192.) Schecterle, L. M. et al (1996)" Maintenance of Renal and Hepatic Function with Dopamine During and following Extracoporeal Whole Body Hyperthermia "SASEB j. 10 (3): A1 19. 193.) Schecterle, L. M. et al (1996)" Alterative HIV Therapies "The Scientist 1 1 (9): 10. 194.) Kapp, D. (1982) "Discussion: Hyperthermia and Drugs" NCI Monogr. 61: 322. 195. ) Martin. P. A. et al (1987) "Monitoring Body Site Temperature During Systemic Hyperthermia "Crit. Care Med. 15: 163-164, 196.) Ohnoshi, et al. (1985)" Combined Cytotoxicity Effect of Hyperthermia and Anthrcycline Antibiodics on Human Tumor Cells "JNCI 74: 275-281, 197.) Van der Zee, J. et al. (187)" Whole Body Hyperthermia as a Treatmenl Modality "In: Fields, S.B., Hand, J.W. (eds) An Introduction to the Practical Aspects of Clinical Hyperthermia. Taylor and Francis, London pp 185-212. 198.) Thrall, D. E. el al (1990) "A Comparison of Temperature in Canine Solid Tumors During Local and Whole-Body Hyperthermia Administered Alone and Simultaneously "Int. J. Hyperthermia 6: 305-317. 199.) Oleson, J. et al (1984) "Analysis of Prognostic Variables in Hyperthermia Treatment of 161 Patients" Int. J. Radial. Oncol. Biol.

Phys. 10: 2231-2240. 200.) Oslrow, S. et al (1981) "Physiologic Response and Toxicity in Patients Undergoing Whole-Body Hyperthermia for íhe Trealmení of Cancer "Treaí Cancer, Rep. 65" 323-325. 201.) Robins, H. I. el al (1986) "Inlerferon-alpha (IFN-alpha) and Whole Body Hyperthermia (WBH): a Phase I Trial "Am. Assoc. Cancer Res. 27: 205. 202.) Schonbaum, E. et al (1990) "Thermoregulation Physiology and Biochemistry "Pergamon, New York, pp. 1-506, 203.) Tamura, K. et al. (1991)" High Pressure Anlagonism of Alcohol Effecís on íhe Main Phase-Transition Temperaíure of Phospholipid Membranes: Biphasic Response "Biochemica eí Biophysica Acia, 1066, 219-224, 204.) Hayashi, H. el al (1998)" Temperalure-Dependent Associating Property of Liposomes Modified with a Thermosensitive Polymer "Bioconjug, Chem. May-June: 9 (3): 382-9, 205.) Liang, Chang-seng et al (1973)" Comparison of Cardiac Output Responses to 2,4 Dinilrophenol-lnduced Hypermetabolism and Muscular Work " The Journal of Clinical Investigation, September, Volume 52: 2283-2292, 206.) Matsuda, T. (1996) "The Presení Slaíus of Hyperíhermia in Japan" Ann. Acad. Med. Singapore, May; 25 (3): 420 -4, 207.) Ikeda, S. eí al (1998) "Enhancement of the Effecí of an Angiogenesis Inhibilor on Murine Tumors by Hyperlhermia" Oncol. Rep., Jan-Feb; 5 (1): 181 -4. 208. ) Kakeya, H. (1997) "Heal Shock Prolein of Cryptococcus Neoformans in Cryptococcosis" Abs. Gen. Meet, Am. Soc. Microbiol., May 408; 97: 271 (abstract No. F67) 209.) Mulíhoff, G . (1997) "Heal Shock Protein 72 (HSP72), a Hyperthermia-inducible Immunogenic Determinant on Leukemic K562 and Ewing's Sarcoma Cells" Int. J. Hyperthermia, Jan-Feb; 13 (1): 39-48. 210.) Kato, H. et al (1998) "Research and Development of H yperlhermia Machines for Present and Future Clinical Needs" Int. J. Hyperthermia, Volume 14: No. 1; 1 - 1 1. 21 1.) Monti, M. et al (1986) "Microcalorimetric Invesligalion of Cell Metabolism in Tumor Cells from Patients with Non-Hodgkin Lymphoma (NHL)" Scand. J. Haematol.; 36: 353-357. 212.) Kallerhoff, M. et al (1996) "Microcalorimetric Measurements Carried out on Isolated Tumorous and Nontumorous Tissue Samples from Organs in the Urogenital Tract in Comparison to Histological and Impulse-Cylophoiomelric Investigations" Urol. Res.; 24: 83-91. 213.) Alpard, S. K. et al (1996) "Therapeulic Hyperthermia" Perfusion 1 1: 425-435. 214.) Bachmann, Barbara et al (1995) "Target Structures for HIV-1 Inactivation by Methylene Blue and Light" Journal of Medical Virology 47: 172-178. 215.) Castedo, M. et al (1995) "Mitochondrial Perturbation Defines Lymphocytes Undergoing Apoptotic Depletion in Vivo" Eur. J. Immunol. 25: 3277-3284. 216.) Dryer, S. E. et al (1980) "Enhancement of Mitochondrial, Cyanide-Resistant Superoxide Dismutase in the Livers of Rats Treated with 2,4 Dinitrophenol" The Journal of Biol. Chem. 255 (3): 1054-1057. 217.) Gibellini, D. (1995) "Tat-expressing Jurkat Cells Shown an Increased Resistance to Different Apoptotic Stimuli, Including Acute Human Immunodeficiency Virus-lypel (HIV-1) Infection" Briish J. of Haema. 89: 24-33. 218.) Ho, D. D. et al (1995) "Rapid Turnover of Plasma Virions and CD4 Lymphocytes in HIV-1 Infection" Nature 373: 123-126. 219. ) Male. A. ef al. (1995) "Miíochondrial Dysfuncíions in Circulating T Lymphocyles from Human Immunodeficiency Virus-1 Carriers "Blood 86 (7): 2481 -2487. 220.) Ornsiein, M. H. to the" The Anliinflammayer and Anliviral Effecls of Hydroxychloroquine in Two Countries wilh Acquired Immunodeficiency Syndrome and Aclive Inflammatory Arthritis " Arthrilis and Rheumaíism 39 (1): 157-161. 221.) Owens, S. D. eí al (1995) "Hyperlhermic Therapy for HIV Infection "Medical Hypolheses 44: 235-242, 222.) Pennypacker, C. eí al (1995)" Localized or Sysèmic In Vivo HeaI Inactivation of Human Immunodeficiency Virus (HIV): A Mahemaíical Analysis "Journal of Acquired Immune Deficiency Syndrome and Human Reírovirology 8: 321 -329. 223.) Perelson, A. S. et al. (1994) "Does Hyperihermia Have a Therapeutic Role in HIV Disease" Science 271: 1582-1 1586. 224.) Schecferle, L. M. et al (1994) "Does Hyperfhermia Have a Therapeulic Role in HIV Disease "Research News, Journal of íhe Minn Here. Science 58 (2): 27-30. 225.) Sweiízer-Thumann, C. eí al (1994) "Effecls of an Elevated Temperalure on the Re fl ection of HIV-I in a Monocyclic Cell Line" Res. Virol. 145: 163-170. 226.) Somasundaran, M. eí al (1994) "Localizaíion of H IV RNA in Milochondria of Infecled Cells Poleníial Role in Cyclopaíhogenicily " The Journal of Cell Biology 126 (6): 1353-1360. 227.) Sperber, K. ei al. (1993) "Inhibilion of Human Immunodeficiency Virus Type I Replication by Hydroxychloroquine in T Cells and Monocytes "AIDS Research and Human Retroviruses 9 (1): 91-98, 228.) Spire, B. et al. (1985)" Inactivation of Lymphadenopathy-Associated Virus by Heat, Gamma Rays, and Ultraviolet Light "The Lancet, Jan. 26: 188-189, 229.) Steinhart, CP, et al. (1996)" Effect of Whole-Body Hyperthermia on AIDS Patienls wííh Karposi's Sarcoma: A Piloí Sludy "Journal of Acquired Immune Deficiency Syndrome and Human Relrovirology 11: 271-281, 230.) Ursini, MV (1993) "Enhanced Acíivily of Human G6PD Promoler Transfecíed in HeLa Cells Producing High Levéis of HIV-I Tal" Virology 196: 338-343. 231.) Weatherbum, H et al. (1990) "Joint Use of Hyperthermia and Chemotherapy in HIV Infection" International Journal of Immunopathology and Pharmacology 3 (2): 55-58, 232.) Westendorp, M. 0. et al. (1995) "HIV-1 Tat Potenial-induced TNF-KB Activation and Cytotoxicity by Altering Ihe Cellular Redox Slale" The EMBO Journal 14 (3): 546-554. 233.) Yamauchi, N. (1992) "Mechanism of Synergislíc Cyloioxic Effecí Belween Tumor Necrosis Facfor and hyperthermia" Jpn. J. Cancer Res. 83: 540-545. 234.) Yatvin, M. et al. (1995) "Whole Body Hyperthermia lo Treat H IV Infection (Meeting Abstract)" 18th International Symposium on Clinical Hyperthermia. p 12, Kiev, Ukraine. 235.) Flores, S.C. et al. (1996) "Alteralions and Redox Status by the HIV-1 TAT Proiein Affect Cellular Gene Expression and Function " Presentation, Oxidative and Redox Regulation Conference, Instiíul Pasleur, Paris, France. 236.) Chernin, E. (1984) "The Malariatherapy Of Neurosyphilis" J. Parasit. 70 (5): 61 1 -617. 237.) Shvets, M. A. (1974) "Oxidative Phosphorylation in the Skeletal Muscles of Rabbits During Dinitrophenol Hyperíhermia "Bulleíin of Experimental Biol. And Medicine, 242.) Wood, D. A. al (1934) "A Case of Failit Dinitrophenol Poisoning" J.A. M.A. 102: 1 147. 243.) Bachynsky, N. (1987) "A Testing Program Using the Thermogenic drug 2,4-Dinitrophenol save it Uves in Freezing Environmenls J. Environ. Sci. 30: 50-56. 244.) Hoch, Frederic L. et al (1973) "Hyperthermia, Muscle Rigidity, and Uncoupling in Skeltal Muscle Mitochondria in Rats Treated with Halothane and 2,4-Dinilrophenol "Anesth, Volume 38 (3): 237-243, 245.) Takehiro, T. N et al. (1979)" Effects of 2, 4-Dinitrophenol on the Body Temperature and Cardiopulmonary Functions in Unanaesthetized Rats "J. Therm. Biol. Volume 4: 297-301, 246.) Leutsker, R., Jr. Al (1935)" An Inslance of Circulatory Collapse Atlributed to Dinitrophenol "U. S. Navel Bulletin, Volume 33 (2): 394-395. 247.) Bachynsky, N. (1986) "A Reassessment of the Potenlial of 2, 4-Dinilrophenol in Weight Reduction "5th Int. Conf. On Obesity Jerusalem, Israel. 248. ) Schulte, T. L. et al (1934) "Chronic Toxicity of Dinitrophenol: Renal Function "Proc. Soc. Exper. Biol. Med., 31: 1 163. 249.) Blackburn, RV et al (1998)" Adenoviral-Mediated Transfer of a Heal-Inductible Double Suicide Gene inio Prostate Carcinoma Cells "Cancer Res 1; 58 (7): 1358-1362, 250.) Wierenga, PK et al (1998) "Enhanced Selectivily of Hyperthermic Purging of Human Progenitor Cells Using Goralatide, an Inhibitor of Cell Cycle Progression "Bone Marrow Transplant Jan; 21 (1): 73-78. 251.) Osman, Yasser et al (1995) "Enhanced Elimination of Ph + Chromosome Cells In Vitro by Combíned Hyperthermia and other Drugs (AZT, IFN-a, TNF, and quercetin): Its application to Autologous Bone Marrow Transplantation for CML "Exp Hema 23: 444-452, 252.) Carr, Andrew W. et al (1993)" Uncoupling of Rat Liver Mitochondrial Oxidative Phosphorylation by the Fasciolicide Triclabendazole and its Sulfoxide and Sulfone Metabolites "J.

Parasitol. , 79 (2); 198-204. 253.) Tainter, M. L. et al (1932) "Actions of Dinitrophenol" Proc. Soc.

Exper. Biol. Med. 29: 1268-1275. 254.) Tainter, M. L. et al (1933) "Febrile, Respiratory and Some Other Actions of Dinitrophenol "J. Pharmacol. Exp. Therap., 48: 410-418. 255. ) Tainter, M. L. (1933) "Dinitrophenol as a Metabolic Stimulant" Bull. Calif. Dielelic Assoc. , 1: 3-6. 256.) Tainter, M. L. et al (1934) "A Case of Fatal Dinitrophenol Poisoning" J .A. M.A. , 102: 1 147. 257. ) Tainter, M. L. (1934) "Dinitrophenol in Diet, on Growth and Duration of Life of the White Rat "Proc. Soc. Exper. Biol. Med., 31: 1161-1163. 258.) Tainter, M.L. et al. (1935) "Metabolic Aclivity of Compounds Related to Dinitrophenol" J. Pharmacol. Exper. Ther., 53: 58-62. 259.) Tainter, M. L. al (1934) "Metabolic Response of White Rats to Continued Administration of Dinitrophenol" J. Pharmacol. Exper.

Ther., 54: 454-458. 260.) Tainter, M. L. (1938) "Growth, Life-Span and Food Intake of White Rats Fed Dinitrophenol Throughout Life" J. Pharm. Exp. Ther., 63, No.1. 261.) Tainter, M. L. et al (1934) "Chronic Toxicily of Dinilrophenol: Renal Funcion "Proc. Soc. Exper. Biol. Med., 31: 1163-1166, 262.) Tainter, ML et al. (1935)" Dinitrophenol on Liver Function "Calif. And West. Med., 43: No.5 263.) Tainler, ML el al (1937) "Chronic Toxicily of Dinitrophenol: Functional and Morphological Changes in the Liver "J. Pharm. Exp.

Ther., 59: 419-423. 264.) Tainter, M.L. (1986) "Dinilrophenol: In Relrospect" Affidavit, Notarized by Marie J. Panella, Westchester County, New York, No. 60-4798577. 265.) Emge, L. A. et al (1933) "Effects of Dinitrophenol on anExperimental Sarcoma of the While Ral "Proc. Soc. Exper. Biol.

Med., 31: 152. 266.) Saiki, C. et al (1997) '? Ffect of 2,4-Dinitrophenol on the Hypometabolic Response to Hypoxia of Conscience Adull Rats "J.

Appl. Physiol. , 83 (2): 537-542. 267.) Williams, T. F. et al (1958) "Effects of 2,4-Dinitro? Henol on Respiration in the Dog "Am. J. Physiol., 193 (1): 181-188, 268.) Johannesen, J. et al. (1977)" Renal Energy Metabolism and Sodium Reabsorption after 2,4-Dinitrophenol Administration "Am. J.

Physiol., 233 (3): F207-F212. 269.) Rognstad, R. et al (1969) "The Effect of 2,4-Dinitrophenol on Adipose-Tissue Melabolism "Biochem J., 11: 431-444, 270.) Millhom, D. E. et al (1982)" Effects of Salicylate and 2,4-Dinitrophenol on Respiration and Metabolism "J. Appl. Physiol., 53: 925-929. 271.) Huch, A. D. et al (1969) "Oxygen Transport in Anesthetized Dogs in Hypoxia, wilh Oxygen Uplake Increased by 2,4-Dinitrophenol "Respir Physiol., 6: 187-201, 272.) Vollmer, RT et al (1999)" A prognostic score for hormone-refractory prostate cancer: analysis of two cancer and leukemia group B sludies "Clin Cancer Res., 5 (4): 831-7. 273.) Vollmer, RT et al (1998)" The dynamics of prostate specific antigen in hormone refractory prostate carcinoma: an analysis of cancer and leukemia group B study 9181 of megestrol acelate " Cancer, 83 (9): 1989-94. 274.) Hawkins, R.A. et al (1998) "Apoplic Dealh of Pancreatic Cancer Cells Induced by Polyunsaturated Fatly Acids Varies with Double Bond Number and Involves an Oxidative Mechanism "J. Of Pathology, 185: 61 -70. 275.) March, A. et al (1999) "Tumor Antigens are Constitutively Presented in the Draining Lymph Nodes" J. of Immunology, 162: 5838-5845. 276.) Asaumi, J. et al (1999) "Influence of Metabolic Inhibitors on the Intracellular Accumulation and Retention of Adriamycin" Anticancer Research, 19: 615-618. 277.) Linsinger, G. et al (1999) "Uncouplers of Oxidative Phosphorylation Can Enhance Fas Death Signal" Mol and Cell Biology, 19: 3299-3311. 278.) Issekutz, Jr., B. (1984) "Effects of Propanolol in Dinitrophenol Poisoning" Arch. Int. Pharmacodyn. , 272: 310-319. 279.) Marcus, M. (1988) "The Regulation of Myocardial Perfusion in Health and Disease" Hospital Practice, July 15: 203-230. 280.) U.S. Navy (1935) "Treatment of Obesity With Dinitrophenol" United Slates Naval Bulletin, XXXIII: 238-243. 281.) Scylhes, J. B., Jones, C.M. (1999) "Implicalions of the Recent Lyme Culture Technique for the Diagnosis of Syphilis" 12th International Conference on Lyme Disease and Other Spirochetal and Tick-Borne Disorders, New York, p.58. 282.) Phillips, S. E., Maltman, L. H. et al (1998) "A Proposal for the Reliable Culture of Borrelia burgdorfrei from Patients with Chronic Lyme Disease, Even from Those Previously Aggressively Treated" Infection 26: 364-367. 283.) Flanagan, S. et al (1998) "Increased flux of free radicals in cells subjected to hyperthermia: detection by electron paramagnetic resonance spin rapping "FEBS 431: 285-286, 284.) Kelly, P.J., Daumas-Duport C. et al (1987)" Imaging-based Stereotaxis Serial Biopsies in Untreated Intracranial Glial Neoplasms "J Neurosurg 66: 865-874, 285.) Levivier, M., Goldman S. al (1992)" Positron Emission Tomography-guided Stereotaxic Brain Biopsy "Neurosurgery 31: 792- 797 286.) Biaglow, J. et al (1998)" The Measurement of Bioreductive Capacity of Tumor Cells Using Methylene Blue "Int. J. Radiation Oncology Biol. Phys. 42: 769-773. 287.) Sibille, B. et al (1998) "2,4 Dinitrophenol-Uncoupling Effect on ?? in Living Hepatocytes Depends on Reducing-Equivalent Supply " Cytometry 32: 102-108. 288.) Jones, B. F. (1998) "A Reappraisal of the Use of Infrared Thermal Image Analysis in Medicine "I EEE Trans Med Imaging 17 (6): 1 01 9-27. 289.) Head, J. F. et al (1996) "Thermography.

Pathologic Characteristics, Vascularity, Proliferation Rate, and Survival of Patients With Invasive Dutal Carcinoma of the Breast " Cancer 77 (7): 1324-8. 290.) Head, J. F. et al (1993) "Breast Thermography is a Noninvasive Prognostic Procedure That Predicts Tumor Growlh Rale in Breast Cancer Patients "Ann N and Acad Sci 698: 1 53-8, 291.) Livertoux, M., Lagrange, P. al. (1996)" The Superoxide Production Mediated By The Redox Cycling Of Xenobiotics In Rat Brain Microsomes Is Dependent On Their Reduction Potential "Brain Research 725: 207-216. 292.) Flanagan, S. et al (1998) "Increased Flux of Free Radicáis in Cells Subjected to Hyperthermia: Detection by Electron Paramagnetic Resonance Spin Trapping "FEBS 431: 285-286, 293.) Daut, J., Elzinga, G. (1988)" Heat Production of Quiescent Ventricular Trabeculae Isolated From Guinea-Pig Heart "Journal of Physiology 398: 259-275. 294.) Yanase, M. et al (1998) "Intracellular Hyperthermia for Cancer Using Magnetite Cationic Liposomes: An in vivo Sludy "Jpn. J.

Cancer Res. 89: 463-469. 295.) Brenner, B. et al (1995) "Altered Constitutive and Stress-Regulated Heat Shock Protein 27 Expression in HIV Type 1 -infected Cell Lines "AIDS Research and Human Retroviruses 1 1: 713-717. 296.) Loven, D. P. et al (1988) "A Role for Reduced Oxygen Species in Heat Induced Cell Killing and the Induction of Thermotolerance" Medical Hypotheses 26: 39-50. 297.) McHutchison, J .G. et al (1998) "Intereon Alfa-2b Alone Or In Combination With Ribavirin As Initial Treatment For Chronic Hepatilis C "N EJM 339: 1485-1499, 298.) Bassett, D.J. P. et al (1976)" Stimulalion of Ral Lung Melabolism With 2, 4-dinitrophenol and Phenazine Methosulfale "American Journal of Physiology 231: 898-902. 299. ) Biaglow, J. E. et al (1998) "The Measurement Of Bioreductive Capacity of Tumor Cells Using Methylene Blue "Int. J. Radiation Oncology Biol. Phys. 42: 769-773. 300.) Lagrange, P et al (1994) "Superoxide Anion Production During Monoelectronic Reduction Of Xenobioíics By Preparations Of Rat Brain Coríex, Microvessels, And Choroid Plexus "Free Radical Biology & Medicine 17: 355-359. 301.) Visarius, T.M. ei al (1997) "Slimulaíion Of Respiralion By Melhylene Blue In Ral Liver Milochondria "FEBS Letters 412: 157-160, 302.) MacEwen, E.G. (1990)" Biologic Response Modifiers: The Future Of Cancer Therapy? "Vet Clin North Am Small Anim Pract : 1055-73. 303.) Blachere, N. E. et al (1995) "Heat Shock Protein-Based Cancer Vaccines and Relapsed Thoughts On Immunogenicity of Humor Tumors "Cancer Biology 6: 349-355, 304.) Tamura, Y. et al (1997)" Immunotherapy of Tumors Wilh Autologous Tumor-Derived Heat Shock Protein Preparations "Science 278: 1 17-120. 305.) Jatoi, A. et al (1999) "The Prognostic Effect of Increased Resling Energy Expenditure Prior to Trealmení for Lung Cancer " Lung Cancer 23: 153-8. 306.) Nakanoma, T. et al (1998) "Anti-Proliferaíive Effecís of Healing on íhe Human Prostatic Carcinoma Cells in Culture" Hum Cell 1 1 (3): 167-74 307. ) (a) Barluenga, J. et al (1996) G. Chem. Commun. 1505-1506. (b) Arsequell, G. et al (1998) Tetrahedron Lett. (39): 7393-7396. 308.) Fariña, V. et al (1999) J. Org. Chem., (59): 5905-5911. 309.) Godfrey, I.M. et al (1974) J. Chem. Soc. Perkin Trans I, 1353-1356. 310.) Coon, C.L. (1973) J. Org. Chem. (38): 4243-4248. 311.) Bacon, R.G.R. (1965) Quart. Rev. (19) 95. 312.) (a) Mitchell, T. N. et al (1992) Synthesis, 803-815. (b) Fariña, V. (1996) Puree & Appl. Chem., (68), 73-78. 313.) (a) de Meijere, A. et al (1994) Angew. Chem. Int. Engl., (33): 2379-2411. (b) Heck, R. F. (1982) Org. React., (27): 345-390. 314. ) (a) Knochel, P. et al (1998) Tetrahedron, (54): 8275-8319. (b) Knoehel, P. et al (1993) Chem. Rev., (93): 2117-2188. (c) Erdick, E. (1992) Tetrahedron, (48): 9577-9648. (d) Negishi, e.l. (1982) Acc. Chem. Res. (15): 340-348. 315.) Miyaura, N. et al (1995) A. Chem. Rev. (95): 2457-2483. 316.) Semmelhack, M.F. et al (1971) J. Am. Chem. Soc, (93): 5980. 317. ) Whitesides, G.M. et al (1969) J. Am. Chem. Soc, (91): 4871-4882.

Claims (54)

1. A method of inducing intracellular hyperthermia comprising the step of administering a canine of a sufficient mitochondrial decoupling agent to induce intracellular hyperthermia.

2. The method according to claim 1, wherein the mitochondrial decoupling agent is 2,4-dinitrophenol. The method according to claim 1, wherein the mitochondrial decoupling agent is selected from the group consisting of: classical decouplers, including 2,4-dinitrophenol, clofazimine, albendazole, cambendazole, oxybendazole, triclabendazole (TCZ), , chloro-5- [2,3-dichlorophenoxy] -2-methylthio-benzimidazole and its sulfoxide and sulphone metabolites, thiobendazole, rafoxanide, bithionol, niclosamide, eulipin, various lichen acids (hydroxybenzoic acids) such as (+) acid Ursin, Vulpinic acid and atranorine, 2 ', 5-dichloro-3-t-butyl-4'-nitrosalicylanilide (S-13), 3,4', 5-tricycloalkylanilide (DCC), silvernetin, 2-trifluoromethyl-4, 5,6,7-tetrachlorobenzimidazole (TTFB), 1799, AU-1421, 3,4,5,6,9, 10-hexahydro-14,16-dihydroxy-3-methyl-1 H-2-benzoxacyclotetradecin-1, 7 (8H) -dione (zearalenone), N, N 1 -bis- (4-trif luoromethyl-enyl) -urea, resorcyl acid lactones and their derivatives, 3,5-di-t-butyl-hydroxybenzyldenemalononlyl (SF6847), 2,2, -bis - (hexafluoroacetonyl) acetone, triphenylboron, carbonyl cyanide 4-lrifluoromeloxyphenylhydrazone (FCCP), butylamine (TBA), 3-chlorophenylhydrazone carbonyl cyanide (CICCP), 1, 3,6,8-n-nitrocarbazole, lelraclorobenzotriazole, 4-iso-octyl-2,6-dinitrophenol (Octyl-DNP), 4-hydroxy-3,5-diiodobenzonitrile, mitoguazone, (methylglyoxal) bisguanilhydrazone), pentachlorophenol (PCP), 5-chloro-2-mercatobenzothiazole (BZT-SH), tribromoimidazole (TBI), N- (3-l-trifluoromethylphenyl) -anlranyl acid (flufenamic acid), 4-niiophenol, 4,6-dinoiocresol , 4-isobuyl-2,6-dinopyrol, 2-azido-4-nyl-phenol, 5-niirobenzolriazole, 5-chloro-4-niirobenzolriazole, 1-chlorobenzolriazole, mephyl-o-phenylhydrazone, N-phenylalanylic acid, N- (3-) acid niiophenyl) aniranilic acid, N- (2,3-dimethylphenyl) anlyranilic acid, mefenamic acid, diflunisal, flefenamyxic acid, N- (3-chlorophenyl) anthranilic acid, 4-fluorifometylxyphenylhirazone carbonyl cyanide (FCCP), SR-4233 (Tirapazamine ), atovaquone, 4- (6'-methyl-2'-benzoliazyl) -phenylhydrazone of carbonyl cyanide (BT-CCP), elipycin, olivacin, elipycinium, isoelipycin and isomers r Labeled, melil-O-phenylhydrazonocyanoacetic acid, melil-0- (3-chlorophenylhydro) cyano-acetic acid 2- (3'-chlorophenylhydrazone) -3-oxobuyronyl-trile, thiosalicylic acid, 2- (2 ', 4-dinitrophenylhydrazono) -3- oxo-4, 4-demethylvaleronilyl), relanium, melipramine, and various other chemical substances including unsaturated fatty acids (optimally up to 14 carbon atoms), sulflaramide and its perfluorooctane sulfonamide metabolite (DESFA), perfluoroctane, clofibralo, Wy-14 , 643, ciprofibrafo, and fluoroalcohol; ionophore antibiotic decouplers, including gramicidin, nigericin, lyrotricin, tirocidin, valinomycin, alameycin, harzianin HA V, salurnisporin SA IV, zervamycins, magainin, cecropins, meliin, hypereknes, suzucacillins, monensins, urioxins, aniiamoebins, chrysalis violeia, cyanide colloran, cadmium ion, icosprosporin-B and its derivatives; and other heterogeneous coupling compounds, including desaspidin, ionized calcium (Ca ++), decoupling proteins such as UCPI-1, UCP-2, UCP

3, PUMP (Plant Uncoupling Milochondrial Protein, Mitochondrial Disengagement Protein from Pigeons), histones, polylysines, protein A206668-a, and compound K23187.

4. The method according to claim 1, wherein the mitochondrial uncoupling agent is a conjugate comprising 2,4-dinitrophenol.

The method according to claim 1, wherein the induced intracellular hyperthermia is used for the diagnosis or treatment of infections, malignancies or other medical conditions.

6. The method according to claim 5, wherein the induced intracellular hyperthermia is used in the diagnosis or treatment of infections, malignancies or other medical conditions selected from the group consisting of cancer, infections or infestions.

7. The method according to claim 5, wherein the induced intracellular hyper- ermia is used in the diagnosis or irradiation of cancer.

8. The method according to claim 5, wherein a The animal is administered the mifochondrial decoupling agent and a separate medication is administered, where the second medication elevates the animal's meiotic metabolic regime, the melabolic regimen of a specific objective fluid in the animal or an increase in free radical flow.

9. The method according to claim 8, wherein the second medicament is selected from the group consisting of glucagon, arbutiamine, dobu- amine, vasopressin, glu- amine, proline, oenanoafous, meleylene blue (ephimmelylionine), ubiquinone, menadione, hemayoprofirin, polyunsaturated fatty acids including linoleic acids (double bonds in carbons 9 and 12), alpha-linolenic (double bonds in carbons 9, 12 and 15), gamma-linolenic (double bonds in carbons 6, 9, and 12), arachidonic (double bonds in carbons 5, 8, 11, and 14), eicosapenlanic (double bonds in carbons 5, 8, 11, 14, and 17), docosahexenoic (double bonds in carbons 4, 7, 10 , 13, 16, and 19), cis-parinárico (double bonds in carbons 9, 11, 13, and 15) and, monounsaturated fatty acids including oleic acids (double bonds in carbon 9), erucic (double bonds in carbon 13), phenazine melosulfan, 2,6-dichlorphenolindophenol, coenzyme, Q1 , CoQ2, and its analogues, duroquinone and decilubiquinone. 1.

The method according to claim 5, wherein the induced indwelling hyperle- mia involves the induction of proleins of luermic shock. eleven .

The method according to claim 5, wherein administer a second therapeutic agent, or therapy.

The method according to claim 1, wherein the second therapeutic agent or therapy is selected from the group consisting of: antifungal agents including Amphotericin B, Griseofulvin, Fluconazole (Diflucan), Intraconazole, 5-fluoro-cytosine (Flutocytosine , 5-FC), Cetatoconazole and Miconazole; antibacterial agents, including antibiotics such as those represented from the following classifications: β-lactam rings (penicillins), marcrocyclic lactone rings (macrolides), polycyclic naphthacenecarboxamide derivatives (lelraciclins), amino sugars in glycosidic linkages (aminoglycosides), peptides (baciiracina, gramicedina, polymyxins, etc,), nitrobenzene derivatives of dichloroacetic acid, large ring compounds with conjugated double bond systems (polyenes), various sulfa drugs including those derived from sulfanilamide (sulfonamides, 5-nitro-2 compounds -furyanyl (nilrofuran), quinolone carboxylic acids (nalidixic acid), fluorinated quinolones (ciprofloxane, enoxacin, ofloxacin, ele), nilroimidazoles (metroindazole), peptide antibiotics, (such as bacitracin, bleomycin, cactinomycin, capreomycin, colistin, dactionomycin, gramacidin A, enduracitin, amfomycin, gramicidin J, micami Cinnamines, Polymyxins, Stendomicin, Actinomycin; aminoglycosides represented by streptomycin, neomycin, paromycin, gentamicin, ribostamycin, tobramycin, amikacin; beta-lactams of lividomycin represented by benzylpenicillin, methicillin, oxacillin, hetacilin, piperacillin, amoxicillin, and carbenacillin; lincosamides represented by clindamycin, lincomycin, celesykeine, desalicein; Chloramphenicol; macrocoids represented by erilromycins, lancamycin, yyucomycin, picromycin), nucleosides (such as 5-azacylidine, puromycin, sepyacidin and amicein, phenazines represented by myxin, lomofungin, iodine), oligosaccharides (including curamycin and everninomycin), sulfonamides represented by suifailazole, sulfadiazine, sulfanilimide, sulfapyrazine), polyenes (including ampholeinins, candicidins and nisiaine, polyethers, tetracyclines (including doxycyclines, minocyclines, metacyclines, chlorhetracyclines, oxytetracyclines, demeclocyclines), nylrofurans (including nilrofurazone, furazolidone, nilrofuranioin, furium, niirovin and nifuroxime), quinolone acid carboxylic acids (including nalidixic acid, pyromide acid, pipemidic acid and oxolinic acid); anthelminal agents including α, β and α, amanladine, rimanladine, arildone, ribaviran, acylcovir, abacavir, vidarabine (ARA-A) 9-1, 3, dihydroxy-2-propoxymethylguanine (DHPG), ganciclovir, enviroxime, foscarnei, ampligen, podofiloioxina, 2,3, -didesoxilidina (ddC), iododeoxyuridine (IDU), udifluoroimidine (TFT), dideoxyinosine (ddi), d4T, 3TC, zidovudine, efavirenz, inhibitors of proiease such as indinavir, saquinavir, rilonavir, nelfinavir, amprenavir, and specific anliviral antibodies; anli-cancer drugs including cell-cycle-specific agents (including melollrexalo eslruclural analogous or analogs, mecapipuorine, flurouracil, cyanarabine, lyoguanine, azacitidine), antibiotics bleomycin peptide, such as podophyllin alkaloids including etoposide (VP-16) and teniposide (VM-26); various alkaloids of plañís such as vincristine, vinblastine, and paclitaxel, non-specific anti-neoplastic agents in the cell cycle such as various alkylation compounds such as busulfan, cyclophosphamide, mechlorethamine, melphalan, altaretamine, ifosfamide, cisplafina, decarbazine, procarbazine, lomustine, carmustine, lomustine, semustine, chlorambucil, thiotepa and carboplatin; various hormones, hormone agonists, and biological response modifying agents, which include flutamide, prednisone, ethinyl estradiol, diethylstilbestrol, hydroxyprogesterone caproate, medroxyprogressterone, megestrolactate, testosterone, fluoxymesterone, and thyroid hormones such as di-, tri-, and tetraiodothyroid; the aromatase inhibitor, amino glutetimide, the peptide hormone inhibitor octreotide and gonadotropin releasing hormone agonists such as goserilin acetate and leprolide, biological response modifiers such as the various cytosines, interferon alfa-2a, interferon alfa-2b, interferon-gamma, interferon-beta, interleukin-1. interleukin-2, interleukin-4, interleukin-10, monoclonal antibodies (anti-HER-2 / humanized antibody neu), tumor necrosis factor, granulocyte-macrophage colony stimulation factor, macrophage colony stimulation factor, various prostaglandins, phenylalolas, retinoic acids, leukotrienes, thromboxanes and others derived from fatty acid; and radiation therapy.

13. The method according to claim 1. wherein the mitochondrial decoupling agent is an analogue of 2,4-dinitrophenol.

The method according to claim 1, wherein the mitochondrial uncoupling agent is a derivative of 2,4-dinitrophenol.

15. A method for inducing intracellular free radicals, comprising the step of administering a quantity of a sufficient mitochondrial decoupling agent to induce intracellular free radicals.

16. The method according to claim 15, wherein the mitochondrial decoupling agent is 2,4-dinitrophenol.

The method according to claim 15, wherein the mitochondrial decoupling agent is selected from the group consisting of: classical decouplers, including 2,4-dinitrophenol, clofazimine, albendazole, cambendazole, oxybendazole, triclabendazole (TCZ), , chloro-5- [2,3-dichlorophenoxy] -2-methylthio-benzimidazole and its sulfoxide and sulfone metabolites, thiobendazole, rafoxanide, bithionol, niclosamide, eutipine, various lichen acids (hydroxybenzoic acids) such as (+) acid Ursin, vulpinic acid and atranorine, 2 ', 5-dichloro-3-t-butyl-4'-nilrosalicylanilide (S-13), 3,4', 5-tricycloalkylanilide (DCC), silvernetin, 2-trifluoromethyl-4, 5,6,7-tetrachlorobenzimidazole (TTFB), 1799, AU-1421, 3, 4, 5,6,9, 10-hexahydro-14,16-dihydroxy-3-methyl-1 H-2-benzoxacyclotetradecin-1, 7 ( 8H) -dione (zearalenone), N, N 1 -bis- (4-trifluoromethylphenyl) -urea, lactones of resorcylic acid and its derivatives, 3,5, -di-t-butyl-hydroxybenzyldenemalonontrile (SF6847), 2,2, -bis- (hexafluoroacetonyl) acetone, triphenylboron, 4-lrifluoromeloxyphenylhydrazone of carbonyl cyanide (FCCP), butylamine (TBA), 3-chlorophenylhydrazone carbonyl cyanide (CICCP), 1, 3,6,8-yleraniicrocarbazole, leiraclorobenzolriazole, 4-iso-oclil-2,6-dinylphenol (Oclil-DN P), 4-hydroxy-3 , 5-diiodobenzoniírilo, mifoguazona, (melilglioxal bisguanilhidrazona), pentachlorophenol (PCP), 5-chloro-2-mercafobenzofiazol (BZT-SH), tribromoimidazol (TBI), acid N- (3-írifluoromeilil pyl) -anlranílico (fenfenámico acid), 4-nylrophenol, 4,6-diniolrocresol, 4-isobuyl-2,6-dinyl-phenol, 2-azido-4-nyl-phenol, 5-nyl-benzolriazole, 5-chloro-4-nyl-benzo-triazole, 1-chlorobenzoyriazole, meilyo-phenylhydrazone, N-acid -phenylanthranilic acid, N- (3-nylphenyl) anthranilic acid, N- (2,3-dimethylphenyl) aniluric acid, mefenamic acid, diflunisal, flefenamyxic acid, N- (3-chlorophenyl) anlyranilic acid, carbonyl cyanide 4-fluorifluorophoxyphenylhirazone (FCCP), SR-4233 (Tirapazamine), alovacuone, 4- (6'-melil-2'-benzoyiazyl) - carbonyl cyanide phenylhydrazone (BT-CCP), elipycin, olive oil, ellipcinium, isoelipticine and related isomers, melil-O-phenylhydrazonocyanoacetic acid, melil-0- (3-chlorophenylhydrazono) cyanoacetic acid 2- (3'-chlorophenylhydrazone) -3 -oxobulonyl iron, lyosalicylic acid, 2- (2 ', 4-diniofophenylhydrazono) -3-oxo-4,4-demellylvaleronilyl), relanium, melipramine, and various other chemical agents including unsaturated fatty acids (such as up to 14 carbon atoms) , sulflaramide and its metabolite perfluorocyanin sulfonamide (DESFA), perfluoroocyan, clofibralo, Wy-14, 643, ciprofibralo, and fluoroalcohol; ionophore antibiotic decouplers, including gramicidin, nigericin, tirolricin, tirocidin, valinomycin, alameicin, harzianin HA V, salurnisporin SA IV, zervamycins, magainin, cecropins, melilin, hypereknes, suzucacillins, monensins, tricotoxins, aniiamoebins, crislal violet, cyanide colorani , cadmium ion, glycosporin-B and its derivatives; and other heyrogeneous coupling compounds, including desaspidin, ionized calcium (Ca ++), decoupling proleins such as UCPI-1, UCP-2, UCP3, PUMP (Plant Uncoupling Mitochondrial Protein, Mitochondrial Disengagement Protein of Plañas), hisyones, polylysines, Prolein A206668-a, and the compound K23187.

18. The method according to claim 15, wherein the mitochondrial uncoupling agent is a conjugate comprising 2,4-dinitrophenol. 9.

The method according to claim 15, wherein the mitochondrial uncoupling agent is a derivative of 2,4-dinylphenol.

20. The method according to claim 1, wherein the mitochondrial uncoupling agent is a 2,4-dinitrophenol analogue. twenty-one .

The method according to claim 1, wherein the induced intracellular free radicals are used in the diagnosis or tracing of infections, m ig nities or other medical conditions

22. The method according to claim 13, wherein the induced intracellular free radicals are used in the diagnosis or treatment of infections, malignancies or other medical conditions selected from the group consisting of cancer, and bacterial, parasitic, fungal infections or infestations. and viral.

23. The method according to claim 21, wherein an animal is administered the mitochondrial uncoupling agent and a separate medicament is administered, wherein the second medicament increases the metabolic total regimen of the animal, in a tissue metabolic regimen specific target in the animal or an increase in free radical flow.

The method according to claim 23, wherein the second medicament is selected from the group consisting of glucagon, arbutamine, dobutamine, vasopressin, glutamine, proline, octanoate, methylene blue (tetramethylthionine), ubiquinone, menadione, hematoprofirin, polyunsaturated fatty acids including linoleic acids (double bonds in carbons 9 and 12), alpha-linolenic (double bonds in carbons 9, 12 and 15), gamma-linolenic (double bonds in carbons 6, 9, and 12), arachidonic (double bonds in carbons 5, 8, 11, and 14), eicosapentanoic (double bonds in carbons 5, 8, 1 1, 14, and 17), docosahexenoic (double bonds in carbons 4, 7, 10, 13, 16, and 19), cis-parinárico (double bonds in carbons 9, 1 1, 13, and 15) and, acids monounsaturated fats including oleic acids (double bonds in carbon 9), erucic (double bonds in carbon 13), phenazine melosulfate, 2,6-dichlorphenolindophenol, coenzyme, Q1, CoQ2, and their analogues, duroquinone and decilubiquinone.

25. The method according to claim 21, wherein the intracellular free radicals are used in diagnosis or tracing or Lyme disease.

26. The method according to claim 21, wherein the induced intracellular free radicals involve the induction of heat shock proteins.

27. The method according to claim 15, wherein a second therapeutic agent or therapy is administered.

The method according to claim 27, wherein the second therapeutic agent or therapy is selected from the group consisting of: antifungal agents including Amphotericin B, Griseofulvin, Fluconazole (Diflucan), Iniraconazole, 5-fluoro-cilosine (Flulocylosin, 5-FC), Cetatoconazole and Miconazole; Aniibacterial agendas, including aminoalicycles such as those represented from the following classifications: ß-laclama rings (penicillins), marcrocyclic laclone rings (macrolides), polycyclic derivatives of naftacenecarboxamide (tetracyclines), amino sugars in glycosidic bonds (aminoglycosides), peptides (bacitracin, gramicedin, polymyxins, etc.), nitrobenzene derivatives of dichloroacetic acid, large ring compounds with conjugated double bond systems (polyenes), various drugs sulfa including those derived from sulfanilamide (sulfonamides, compuesíos 5-Niiro-2-furianilo (niírofurano), quinolone carboxylic acids (nalidixic acid), fluorinated quinolones (ciprofloxan, enoxacin, ofloxacin, ele), nilroimidazoles (metroindazol), antibiólicos peptide, (such as bacitracin, bleomycin, cactinomycin, capreomycin, colistin, dactionomycin, gramacidin A, enduracillin, amfomycin, gramicidin J, micamycins, polymyxins, leleomycin, actinomycin, aminoglycosides represented by esrepfomycin, neomycin, paromycin, geniamycin, ribosiamycin, tobramycin, amikacin; beta-lacidia of lividomycin represented by benzylpenicillin, meicillin, oxacillin, heyacillin, piperacillin, amoxicillin, and carbenacillin, lincosamides represented by clindamycin, lincomycin, celeslicelin, desalicelline, chloramphenicol, macrolides represented by erythromycins, lancamycin, leucomycin, picromycin), nucleosides (ial) as 5-azaci idina, puromycin, seplacidina and amicelina; phenazines represented by myxin, lomofungin, iodine), oligosaccharides (including curamycin and everninomycin, sulfonamides represented by sulfaliazole, sulfadiazine, sulfanilimide, sulfapyrazine), polyenes (including amphotericins, candicidins and nystatin, polyethers, telcyclines (including doxycyclines, minocyclines, metacyclines, chlortetracyclines) , oxytetracyclines, demeclocyclines), nitrofurans (including nitrofurazone, furazolidone, nitrofurantoin, fury, nitrovine and nifuroxime), quinolone carboxylic acid (including nalidixic acid, pyromide acid, pipemidic acid and oxolinic acid); antivirals including α, β and β-interferons, amantadine, rimantadine, arildone, ribaviran, acylcovir, abacavir, vidarabine (ARA-A) 9-1, 3, dihydroxy-2-propoxymethylguanine (DHPG), ganciclovir, enviroxima, foscarnet, ampligen , podophyllotoxin, 2,3, -didesoxilidina (ddC), iododeoxyuridine (IDU), trifluorolimidina (TFT), dideoxyinosine (dDI), d4T, 3TC, AZT, efavirenz, lales proíeasa inhibitors such as indinavir, saquinavir, riíonavir, nelfinavir, amprenavir , and specific anliviral antibodies; drugs anii-cancer including specific ageníes of cell cycle (including analogs or aníimeíaboliíos esírucíurales of melollrexato, mecapípuorina, fluorouracil, cytarabine, thioguanine, azacitidine), aníibióíicos of pépíido bleomycin, SLEDAI as alkaloids podophyllin including efoposida (VP-16) and feniposide (VM-26); various alkaloids SLEDAI plañías as vincrisíina, vinblasíina, and paclitaxel, anti-neoplásíicos not specific in the cell cycle such as various compueslos of lales alkylation as busulfan, cyclophosphamide, mecloreíamina, melphalan, altaretamina, ifosfamide, cisplatin, dacarbazine, procarbazine, lomustine, carmustine, iomustine, semustine, chlorambucil, thiotepa and carboplatin; several hormones, hormone agonists and agents biological response modifier, which include flutamide, prednisone, ethinyl estradiiol, diethylstilbestrol, hydroxyprogesterone caproate, medroxyprogesterone, megeslrolaclalo, íesloslerona, fluoxymesterone and thyroid hormones such as di-, tri-, and felrayodotiroidina; the aromatase inhibitor, amino glutetimide, the inhibitor of peptide hormone octreolide and gonadotropin release hormone agonisfas such as acetylation of goseriiin and leprolide, biological response modifiers such as the various cyanosines, inferred alpha-2a, inlerferon alfa-2b, inerferon-gama, inlerferon-beía, inlerleucin-1. iníerleucina-2, inlerleucina-4, interleukin-10, monoclonal aníicuerpos (anli-H ER-2 / anlicuerpo humanized neu), facíor of íumoral necrosis, facíor of esíimulación colony granulociío-macrophage facfor of esíimulación macrophage colony, various prostaglandins, phenylacetates, reinoic acids, leucoirienes, ioboxboxes and others derived from fatty acid; and radiation therapy.

29. A method to treat disease in an animal by inducing in-cell hyperthermia, which comprises the step of administering a canine of a sufficient mitochondrial decoupling agency to induce in-cell hyperpermia.

30. The method according to claim 29, wherein the myochondrial uncoupling agent is 2,4-dinylphenol.

31. The method according to claim 29, wherein the mitochondrial decoupling agent is a conjugate comprising 2,4-dinitrophenol.

32. The method according to claim 29, wherein the disease selects from the group consisting of cancer and infections or infestations of Baclerian, parasite, fungal and viral pathogens.

33. The method according to claim 29, wherein the Intracellular induced hyperremia is used in the cancer allergy.

34. The method according to claim 29, wherein an animal is administered the myochondrial decoupling agent and a separate drug is administered, wherein the second drug increases the animal's metabolic rate, the metabolic rate of an animal. specific target in the animal, or an increase in free radical flow.

35. The method according to claim 34, wherein the second medicament is selected from the group consisting of glucagon, arbutiamine, dobu- amine, vasopressin, glu- amine, proline, ocfanoaio, meyylene blue (lely- caraillionin), ubiquinone, menadione, hemayoprofirin, polyunsaturated fatty acids including linoleic acids (double bonds in carbons 9 and 12), alpha-linolenic (double bonds in carbons 9, 1 2 and 1 5), gamma-linolenic (double bonds in carbons 6, 9, and 12 ), arachidonic (double bonds in carbons 5, 8, 1 1, and 14), eicosapenlanic (double bonds in carbons 5, 8, 1 1, 14, and 17), docosahexenoic (double bonds in carbons 4, 7 , 10, 1 3, 16, and 1 9), cis-parinárico (double bonds in carbons 9, 1 1, 1 3, and 1 5) and, monounsaturated fatty acids including oleic acids (double bonds in carbon 9) , erucic (double bonds in carbon 13), phenazine melosulfalo, 2,6-dichlorphenolindofen l, coenzyme, Q 1, CoQ2, and its aologians, duroq uinona and decilubiquinona.

36. The method according to claim 29, wherein the Intracellular hyperlensis induced by ionization involves the induction of thermal shock proteins.

37. A method for diagnosing a disease in an animal by chemically inducing in-cell hypererymia, comprising the step of administering a canine from a miiochondrial uncoupling agent sufficient to induce in-cell hypererymia.

38. The method according to claim 37, wherein the mitochondrial uncoupling agent is 2,4-dinitrophenol.

39. The method according to claim 37, wherein the mitochondrial uncoupling agent is a conjugate comprising 2,4-dinitrophenol.

40. The method according to claim 37, wherein the disease is selected from the group consisting of cancer, infections or infestations of bacterial, parasite, fungal and viral pathogens.

41 The method according to claim 37, wherein the induced intracellular hyper- ermia is used in the diagnosis or treatment of cancer.

42. The method according to claim 37, wherein an animal is administered the milochondrial decoupling agent and a separate medicament is administered, wherein the second medically increases the total metabolic rate of the animal, the metabolic rate of a specific target tissue in the animal or an increase in free radical flow.

43. The method according to claim 42, wherein the second drug is selected from the group consisting of glucagon, arbutamine, dobutamine, vasopressin, glutamine, proline, octanoate, methylene blue (tetramethillionine), ubiquinone, menadione, hematoprofirin, polyunsaturated fatty acids including linoleic acids (double bonds in carbons 9 and 12), alpha-linolenic (double bonds in carbons 9, 12 and 15), gamma-linolenic (double bonds in carbons 6, 9, and 12), arachidonic (double bonds in carbons 5, 8, 1 1, and 14), eicosapentanoic (double bonds in carbons 5, 8, 11, 14, and 17), docosahexenoic (double bonds in carbons 4, 7, 10, 13, 16, and 19), cis-parinárico (double bonds in carbons 9, 11, 13, and 15), and monounsaturated fatty acids including oleic acids (double bonds in carbon 9), erucic (double bonds in carbon 13), phenazine methosulfate, 2,6-dichlorphenolindophenol , coenzyme, Q 1, CoQ2, and its analogues, duroquinone and decilubiquinone.

44. The method according to claim 37, wherein the induced intracellular hyperthermia involves the induction of heat shock proteins.

45. The method according to claim 37, wherein the mitochondrial decoupling agent is selected from the group consisting of: classical decouplers, including 2,4-dinitrophenol, clofazimine, albendazole, cambendazole, oxybendazole, triclabendazole (TCZ), , chloro-5- [2,3-dichlorophenoxy] -2-methylthio-benzimidazole and its metabolites of sulfoxide and sulfone, thiobendazole, rafoxanide, bithionol, niclosamide, eutipine, various lichen acids (acids) hydroxybenzoics) such as (+) usnic acid, vulpinic acid and atranorine, 2 ', 5-dichloro-3-l-bulyl-4'-nitrosalicylanilide (S-13), 3,4', 5-tricycloalkylanilide (DCC), silvernetin, 2-trifluoromethyl-4,5,6,7-tetrachlorobenzimidazole (TTFB), 1799, AU-1421, 3,4,5,6,9, 10-hexahydro-14,16-dihydroxy-3-methyl-1 H-2-benzoxacyclotetradecin-1, 7 (8H) -dione (zearalenone), N, N1-bis- (4-trif luoromethyl-phenyl) -urea, resorcylic acid lactones and their derivatives, 3,5-di-t-butyl -hydroxybenzyldenemalonontrile (SF6847), 2,2, -bis- (hexafluoroacetonyl) acelone, triphenylboron, carbonyl cyanide 4-trifluoromethoxyphenylhydrazone (FCCP), tributylamine (TBA), carbonyl cyanide 3-chlorophenylhydrazone (CICCP), 1, 3 , 6,8-telraniylcarbazole, leiraclorobenzolriazole, 4-iso-oclil-2,6-diniofophenol (Ocíil-DNP), 4-hydroxy-3,5-diiodobenzonilrilo, miíoguazona, (meiilglioxal bisguanilhidrazona), pentachlorophenol (PCP), 5- chloro-2-mercatobenzoliazole (BZT-SH), iribromoimidazole (TBI), N- (3-lrifl) acid uoromethylphenyl) -anlranilic acid (flufenamic acid), 4-nilrophenol, 4,6-dinioorrocresol, 4-isobuyyl-2,6-dinylphenol, 2-azido-4-nylphenol, 5-nitrobenzolriazole, 5-chloro-4-nitrobenzotriazole, 1,2-chlorobenzoyriazole , melil-o-phenylhydrazone, N-phenylalanylic acid, N- (3-nyrophenyl) anlylenyl acid, N- (2,3-dimethylphenyl) aniranyl acid, mefenamic acid, diflunisai, flephenamyxic acid, N- (3-chlorophenyl) aníranílico, 4-lrifluoromeloxifenilhirazona of carbonyl cyanide (FCCP), SR-4233 (Tirapazamina), aiovacuona, 4- (6'-melil-2'-benzotiazil) -phenylhydrazona of carbonyl cyanide (BT-CCP), elipticina, olivacina , eliptcinio, isoelipticina and related isomers, meilyl-O-phenylhydrazonocyanoacetic acid, methyl-0- (3-chlorophenylhydrazono) cyanoacetic acid 2- (3'-chlorophenylhydrazone) -3-oxobuhylironyl, Iosalicylic acid, 2- (2 ', 4-dinyl-phenylhydrazono) -3-oxo-4 , 4-demelilvaleroniírilo), relanio, melipramina, and you will hear various chemical eniidades including unsaturated fatty acids (as opium had 14 carbon atoms), sulflaramide and its melabolioio perfluoroclano sulfonamide (DESFA), perfluorocíano, clofibralo, Wy-14, 643, ciprofibre, and fluoroalcohol; Inephobic anilibiotic decouplers, including gramicidin, nigericin, ioiroicricin, firocidin, valinomycin, alamelicin, harzianin HA V, salurnisporin SA IV, zervamycins, magainin, cecropins, meliiin, hi pelcinins, suzucacillins, monensins, uricoxins, aniiamoebins, crislal viólela, colóranles de cyanide, cadmium ion, uricosporin-B and its derivatives; and other heterogeneous coupling compounds, including desaspidin, ionized calcium (Ca + +), decoupling proleins such as UCPI-1, UCP-2, UCP3. PUMP (Plant Uncoupling Mitochondrial Protein, Mitochondrial Plant Decoupling Protein), histones, polylysines, protein A206668-a, and compound K231 87.

46. The method according to claim 37, wherein a second therapeutic agent or therapy is administered.

47. The method according to claim 46, wherein the second therapeutic agent or therapy is selected from the group consisting of: antifungal agents including Amphotericin B, G riseofulvi na, Fluconazole (Difl ucan), I ntraconazole, 5-fluoro -cytosine (Flutocytosine, 5-FC), Celanoconazole and Miconazole; antibacterial agents, including antibiotics such as those represented from the following classifications: ß-lactam rings (penicillins), marcrocyclic lactone rings (macrolides), polycyclic derivatives of naftacenecarboxamide (tetracyclines), amino sugars in glycosidic linkages (aminoglycosides), peptides (bacitracin, gramicedin, polymyxins, etc.), nilrobenzene derivatives of dichloroacetic acid, large ring compounds with conjugated double bond systems (polyenes), various sulfa drugs including those derived from sulfanilamide (sulfonamides, 5-nitro-2 compounds -furyanyl (nilrofuran), quinolone carboxylic acids (nalidixic acid), fluorinated quinolones (ciprofloxane, enoxacin, ofloxacin, ele), nitroimidazoles (metroindazole), peptide antibiotics, (such as bacitracin, bleomycin, cactinomycin, capreomycin, colistin, dactionomycin, gramacidin A, enduracitin, amfomycin, gramicidin J, micamycin s, polymyxins, esidomycin, acyinomycin; aminoglycosides represented by sclerephomycin, neomycin, paromycin, genlamycin, riboslamycin, бbramycin, amikacin; Lividomycin beia-laciams represented by benzylpenicillin, methicillin, oxacillin, hetacilin, piperacillin, amoxicillin, and carbenacillin; lincosamides represented by clindamycin, lincomycin, celeslicelin, desalicellin; Chloramphenicol; macrolides, represented by erythromycins, lancamycin, leucomycin, picromycin), nucleosides (such as 5-azacylidine, puromycin, seplacidin and amicetine; phenazines represented by mixina, lomofungna, iodine), oligosaccharides (including curamycin and everninomycin, sulfonamides represented by sulfathiazole, sulfadiazine, sulfanilimide, sulfapyrazine), polyenes (including amphotericins, candicidins and nystatin, polyethers, tetracyclines (including doxycyclines, minocyclines, metacyclines, chlortetracyclines, oxytetracyclines, demeclocyclines), nitrofurans (including nitrofurazone, furazolidone, nitrofurantoin, fury, nitrovine, and nifuroxime), quinolone carboxylic acid (including nalidixic acid, pyromide acid, pipemidic acid, and oxolinic acid), antiviral agents including α, β, and β interferons, amaníadin, rimantadine , arildone, ribaviran, acilcovir, abacavir, vidarabine (ARA-A) 9-1, 3, dihydroxy-2-propoxymethylguanine (DH PG), ganciclovir, enviroxima, foscarnet, ampligen, podophyllotoxin, 2,3, -dideoxydidine (ddC) ), iododeoxyuridine (IDU), trifluorothymidine (TFT), dideoxyinosine (ddi), d4T, 3TC, zidovudine, efavirenz, inhibitors of protease such as indinavir, saquinavir, ritonavir, nelfinavir, amprenavir, and specific anliviral antibodies; anticancer drugs including cell-cycle-specific agents (including melollrexalo scleroquinol analogs or anlimeiabolils, mecapiopurine, flurouracil, cytarabine, lyoguanine, azacilidine), bleomycin peptide antibiotics, such as podophyllin alkaloids including etoposide (VP-16) and feniposide (VM-26); several alkaloids of pure plains such as vincrisine, vinblaslin, and pacliaxel, non-specific anti-neoplastic agents in the cell cycle such as various alkylation compounds such as busulfan, cyclophosphamide, mechloreiamine, melphalan, alfareiamina, ifosfamida, cisplaíina, decarbazina, procarbazina, lomusíina, carmusíina, lomuslina, semusíina, chlorambucil, íioiepa and carboplalina; various hormones, hormone agonisies, and biological response modification agen- cles, which include flufamide, prednisone, ethyl esiradiol, diellyslilbestrol, hydroxyprogesterone caproalo, medroxyprogresterone, megliprallate, leslos- lerone, fluoximesyerone, and iodine-free iodine hormones such as di-, iri-, and lely- thiodothyroid; the aromatase inhibitor, amino gluteimide, the inhibitor of the pyreid hormone ocyreoid and gonadotropin-releasing hormone release agonies such as gosferiline and leprolide acephael, biological response modifiers such as the various cytosines, interferon alfa-2a, interferon alfa-2b, interferon-gama, inlerferon-bela, inerleucine-1. inleleucine-2, inleleucine-4, inerieucin-1 0, monoclonal antibodies (anli-H ER-2 / humanized neu antibody), tissue necrosis factor, granulocyte-macrophage colony-mimicking faclor, macrophage colony stimulation facfor , various proslaglandins, phenylaceae, reinoic acids, leukofrienes, ioboxboxes and others derived from fatty acid; and radiation therapy.

48. A method for inducing heat shock proleins in an animal, comprising the step of administering a sufficient amount of a mitochondrial decoupling agent to induce heat shock proteins.

49. The method according to claim 48, wherein the Mitochondrial uncoupling agent is 2,4-dinitrophenol.

50. The method according to claim 48, wherein the mitochondrial decoupling agent is selected from the group consisting of: classical decouplers, including 2,4-dinylphenol, clofazimine, albendazole, cambendazole, oxybendazole, andriclabendazole (TCZ), , chloro-5- [2,3-dichlorophenoxy] -2-methyl-benzimidazole and its sulfoxide and sulfone melabolies, fiobendazole, rafoxanide, biionion, niclosamide, euipyne, various lichen acids (hydroxybenzoic acids), such as acid (+) Ursin, Vulphenic acid and Alranorine, 2 ', 5-dichloro-3-l-bulyl-4'-niyrosalicylanilide (S-13), 3,4', 5-lyriclorasalicylanilide (DCC), plaryanelin, 2-trifluoromethyl-4, 5, 6, 7-eyrylorobenzimidazole (TTFB), 1799, AU-14213,4, 5,6,9,10-hexahydro-14,16-dihydroxy-3-methyl-1 H-2-benzoxacycloheiradecin-1, 7 (8H) -dione (zearalenone), N, N 1 -bis- (4 -frifluoromethylphenyl) -urea, resorcinyl acid and its derivatives, 3,5-di-t-butyl-hydroxybenzidenemalonontrile (SF6847), 2,2, -bis- (hexafluoroacetonyl) acetone, triphenylboro, 4-trifluoromethoxyphenylhydrazone cyanide carbonyl (FCCP), butyl ammonium (TBA), 3-chlorophenylhydrazone carbonyl cyanide (CICCP), 1, 3,6,8-tetranitrocarbazole, telraclorobenzolriazole, 4-iso-oclyl-2,6-dinylphenol (Oclil-DNP), 4 -hydroxy-3, 5-diiodobenzonyl-trile, miloguazone, (megliphoxal bis-guanylhydrazone), peniachlorophenol (PCP), 5-chloro-2-mercalobenzol-azole (BZT-SH), iribromoimidazole (TBI), N- (3-trifluoromethyl-phenyl) -antranilic acid ( flufenamic acid), 4-nitrophenol, 4,6-dinothrocresol, 4-isobutyl-2,6-dinylphenol, 2-azido-4-nitrophenol, 5- nilrobenzofriazol. 5-chloro-4-nitrobenzoyriazole, io-chlorobenzoyriazole, meilyo-phenylhydrazone, N-phenylalanylic acid, N- (3-nyl-phenyl) -annilic acid, N- (2,3-dimethy-phenyl) -annilic acid, mefenamic acid, diflunisal, flephenamy acid , N- (3-chlorophenyl) anlylenyl acid, carbonyl cyanide 4-fluorifomethyl-pheromazine (FCCP), SR-4233 (Tirapazamine), aiovaquone, 4- (6'-methyl-2'-benzoliazyl) -phenylhydrazone of carbonyl cyanide (BT-CCP), eliplicina, olivacina, eliplcinio, isoelipficina and related isomers, melil-O-phenylhydrazonocianoacélico acid, meíil-0- (3-chlorophenylhydrazono) cyanoacéíico acid 2- (3'-chlorophenylhydrazona) -3-oxobuíironifrilo, íiosalicílico acid , 2- (2 ', 4-diniofophenylhydrazono) -3-oxo-4, 4-demethylavaleronyryl), relanium, melipramine, and various chemical substances including unsaturated fatty acids (optimally up to 14 carbon atoms), sulflaramide and its metabolite perfluoroctane sulfonamide (DESFA), perfluoro tano, clofibrate, Wy-14, 643, ciprofibrate, and fluoroalcohol; antibiotic ionophore decouplers, including gramicidin, nigericin, tirotricin, tirocidin, valinomycin, alamelicin, harzianin HA V, saturnisporin SA IV, zervamycins, magainin, cecropins, melittin, hypereknes, suzucacillins, monensins, tricotoxins, antiamoebins, crystal violet, cyanide dyes , cadmium ion, trichosporin-B and its derivatives; and other heterogeneous coupling compounds, including desaspidin, ionized calcium (Ca + +), decoupling proteins such as UCPI-1, UCP-2, UCP3, PU MP (Plant U ncoupling Mitochondrial Protein, Mitochondrial Protein Decoupling of Plants), histones, polylysines, protein A206668-a, and compound K23187.

51 The method according to claim 48, wherein the mitochondrial uncoupling agent is a conjugate comprising 2,4-dinitrophenol.

52. The method according to claim 48, wherein the induced heat shock proteins condition the animal for a specific condition.

53. The method according to claim 52, wherein the specific condition is surgery.

54. The methods according to claims 1, 15, 29, 48 and 51, wherein the decoupling agent is produced using combinatorial technology.