JPH04502621A - Treatments and vaccines to stimulate immune responses - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Treatments and immune response stimulation vaccines This invention relates to the field of immunology, particularly to viruses and/or virus-infected cells. virus-infected CD, a method of inactivating and/or attenuating cells, using photophoresis; and the inactivated and/or poisoned virus and/or virus-infected cells by immune response. Patients infected with special HIV retrovirus and patients with abnormal white blood cell count , in combination with photophoresis and administration of a photoactive compound such as 8-methoxybutsoralen. regarding the treatment of Used in the manufacture of medicines for the treatment of viral infections such as Compounds are also described. This invention also applies to viruses, especially HTV retroviruses. and a method for producing this vaccine.

There are many debilitating infectious diseases caused by viral infections. Also, DNA viruses and There are many different types of viruses, including RNA viruses.

Retroviruses form a subgroup of RNA viruses, and in order to replicate, First, these genomic RNAs are reverse transcribed into DNA (TranSC'r2 p*ICrn) usually refers to the synthesis of RNA from DNA). No. Once in the form of DNA, the viral genome is introduced into the host cell genome. , exploiting the full advantages of the host cell transcription/transrayon machinery for reproduction purposes. be done. Once introduced into the host cell's DNA, the virus remains active for as long as the cell is alive. Lasts longer.

Certain retroviruses are known to cause a drop in white blood cell counts in infected patients. It is. This subset of retroviruses that causes a decrease in white blood cell counts may cause human immune deficiencies. known as the virus (HIV).

Certain species of HIV retroviruses cause acquired immunodeficiency syndrome (AIDS) isolated from patients with the symbols HIVI and HIV2, sometimes collectively “HTLVI[”, These retroviruses are referred to as “LAV” or simply HIV. CD, such as human T lymphocytes and mononuclear cells, infects cells that express the marker. That's probably why. These cells are involved in the functioning of the immune system. This infection is progressively decreases the CD, T-cell population and impairs the function of other CD, cells such as mononuclear cells. interfere with the patient's ability to fight other infections, and the patient is often fatal. This can be fatal, making you more susceptible to infections.

There are at least three clinical manifestations of AIDS infection.

Initially, in the “carrier” state, the only symptom of infection is the presence of HIV antibodies in the blood. presence or culture ability of the virus. The next stage is the AIDS-related complex (“A I D S related complex” (ARC)) It is known as These are fatigue, elevated body temperature and chronic infection. These symptoms affect the patient's ability to fight infection. It generally progresses to the final fatal ALDS condition when lost.

A particularly vexing problem associated with combating HIV retroviral infection is the The process of reverse transcription of DNA involves repeated mutations, causing the body's immune system to recognize the virus itself. This makes it extremely difficult to recognize and attack the accompanying infected cells.

Therefore, the purpose of this invention is to treat viral infections in patients with abnormally low white blood cell counts. The goal is to provide a method to treat the disease.

Another object of this invention is to provide a method for treating patients infected with HIV retrovirus. There are many things.

Furthermore, the purpose of this invention is particularly to prevent infection with retroviruses such as the HIV retrovirus. It provides a vaccine for viral infection when the virus is transmitted.

Other objects of this invention will become apparent from the following description of the invention.

l skin east prisoner Toyogo skin removal According to this invention, a patient infected with a virus, especially an HIV retrovirus, can be treated with a virus. In the case of infected cells, the cell membrane (e.g. cell membrane receptors and/or nucleic acid flags) ) and/or cell membrane nucleic acids may bind to cell cytoplasmic nucleic acids or – In the case of either a virus or a cell-associated virus, the surface of the virus (virus surface) to receptors and/or nucleic acid fragments on the surface) and/or to viruses. using a photoactive substance that binds to a nucleic acid (e.g. DNA or RNA) that has been certain spectra, such as ultraviolet light, to inactivate and/or attenuate viruses; This substance is activated by electromagnetic irradiation to trigger an immune response against viral infection. The treated virus and/or virus-infected cells are present in the patient's immune system. discovered a cure.

Psoralen compounds, especially 8-methoxybutsoralen, are particularly preferred for this purpose; UVA irradiation is preferred for activation.

The treatments described here should not be used in patients with abnormally low circulating lymphocytes or white blood cells. This is a particularly important feature of this invention.

In addition, the treatment method according to the invention may help regenerate immune system function in such patients. We have discovered that it can be used to This is due to HIV infection (untreated or extreme). In addition to patients with ARC/AIDS who have a weakened immune system It is very important for the treatment of patients. Such patients generally do not succumb to opportunistic infections. and an unacceptable decrease in the number of lymphocytes or white blood cells.

The treatment method according to this invention does not cause a harmful deterioration of the patient's immune system, and can treat abnormal whitening. Controlling HIV and other retroviral infections in patients with low blood cell levels I found it useful. Therefore, the method of this invention provides a method for treating patients with Can be used to treat ARC/AIDS-like conditions without causing opportunistic infections. I can do it. The treatment method according to this invention improves the function of the immune system in such patients. It can also be used to In addition, HJV retroviruses can be used for diseases other than AIDS. It can occur. The inventors believe that the method of this invention is also useful for treating such diseases. Ru.

According to this invention, photoactive compounds such as 8-methoxybutsoralen can be prepared in vitro or Administered to the patient's blood or a fraction thereof in vivo using the usual route of administration. be done. A portion of the patient's blood is then purified (preferably) using photophoresis. are treated (externally). This is ultraviolet light, preferably at a wavelength of 320 to 400 nm. Activates photoactive compounds such as long-wavelength ultraviolet light, (commonly referred to as UVA light) It consists of subjecting the blood to electromagnetic radiation at a wavelength suitable to cause the blood to become oxidized. treated blood or A fraction of verb) remain.

A vaccine against a virus and a method for producing the same are provided by the present invention. This issue According to Akira, photoactive compounds (such as those described herein) can be used to treat HIV retroviruses. donor infected with AIDS and/or AIDS or AIDS-related complex is administered to the blood or fraction thereof of a donor suffering from the disease. Then Donna - treating at least a portion of the blood using photophoresis as described above; treated blood or its Fractions (e.g., treated free virus isolates) can be used as vaccines. In the case of treatment of HIV infection, the treated virus can be used to obtain the desired immune response. It is preferred to use virus-infected cells with the treatment virus.

The treated blood is optionally processed in a conventional manner to substantially remove red blood cells.

The resulting processed fraction is used as a vaccine that can be administered to patients.

This invention is also useful for the treatment of viral infections in patients with abnormal leukopenia. for the treatment of HIV] or HIV2 infections and for patients with AIDS carriers. for the treatment of patients with AIDS or AIDS-related complexes. related.

1st year J koan FIG. 1 is a block diagram of a photophoresis device that can be used to carry out the method of this invention. .

Fig. 2 shows patient Na 3 (7) CD a cells, GP24 and G A diagram of changes in P120 antibody values.

FIG. 3 shows changes in GP24 antibody levels of five patients treated in Example.

FIG. 4 shows changes in GP120 antibody values of five patients treated in Example 2.

FIG. 5 shows the percentage of CD, helper cells for five patients treated in Example 2. Diagram of changes in stage.

3 pieces of concave porridge 1 plate Although the scope of this invention is not limited by any particular theory of operation, Infectious diseases, especially those that cannot be controlled by the patient's normal immunological response, can be treated with this invention. We believe that it can be treated using photophoresis treatment.

The photophoretic process according to this invention not only treats viral infections but also (i) treats Including non-viral infectious diseases of the patient's immune system (compromised by viral infection) restore the ability to survive other infections; (ii) restore the immune system's pre-existing response to previous infections; The inventor believes that it will recover.

The photophoretic treatment method of this invention is useful for treating retroviruses such as HTV retroviruses. It is particularly valuable in the treatment of viral infections that mutate frequently. The photophoresis method of this invention According to natural subunits of the gas itself (released upon cell break-up and/or flushed into the blood) ) and/or pathogenic non-infectious viruses are used.

Mutations in viral antigens are induced by photophoresis and subsequent immune responses to mutant forms of viral antigens. Do not use attenuation/inactivation defenses during generalization of answers. Thus, the treatment according to the invention The law provides a dramatic self-vaccination against viral infections.

The method of the invention is useful for treating patients with viral infections and patients with abnormal leukopenia. It has been found to be particularly useful for HIV retroviral infections. child The method also applies to AIDS carriers or AIDS or AIDS-related complexes. It is particularly useful in treating patients with cancer.

According to the claimed method, a photoactive compound is first introduced into the blood of a virally infected patient. Administer. Photoactive compounds can be administered in vivo (e.g. orally or intravenously) or It can be administered ex vivo to a portion of blood taken from a patient using routine blood collection methods.

Alternatively, free virus can be removed from infected cells using conventional virus isolation methods known in the art. Separate. Administering photoactive compounds to infected cells prior to virus isolation or free isolation Can be administered to viruses.

However, when treating HIV infection, the treatment virus and treatment virus can be used as described below. Preferably, it is used for both virus-infected cells.

According to the invention, in the case of virus-infected cells, the photoactive compound is applied to the cell membrane (e.g. binding to receptors and/or nucleic acid fragments of cell membranes) and/or cell nuclei. or those that bind to nucleic acids in the cytoplasm, in the case of free viruses or cell-associated viruses. on the virus surface (e.g. viral surface receptors and/or nucleic acid fragments). binds to nucleic acids (e.g. DNA or RNA) incorporated into viruses It uses a certain amount of light, such as ultraviolet light, to inactivate and/or attenuate the virus. Viruses activated and treated by exposure to spectral electromagnetic radiation Preferably, the virus-infected cells are present in the patient's immune system. this eye For this reason, bussoralen compounds, especially 8-methoxypsoralen, are particularly preferred; In this case, UVA irradiation is preferred for its activation.

A photoactive compound is then administered to a portion of the patient's blood or to the free dissociated cells. The free virus is subjected to photophoresis using electromagnetic irradiation, e.g. using ultraviolet light. Ru. The photophoresis step is preferably performed outside the body using an extracorporeal photophoresis device.

The photophoresis process according to the invention can also be performed in vivo.

A currently preferred extracorporeal photophoresis device for use in the method of this invention is the US Pencil Vanier, now made under the UVARO name by Therakos Company of Westchester. There are things that are true. The company's UVAR photophoresis device is described in U.S. Patent No. 4.683. ．． No. 889 (Granted August 14, 1987 to R.L. Edelson) , the entire content is included here as a reference.

As illustrated in FIG. A pump 10 for removing blood from the patient through the needle, an irradiation material 20, and a pump close to the irradiation room. irradiation source 30 and a centrifuge 40, preferably of the continuous type. patient's Tubing collection bags for blood, etc. that will come into contact with blood or its fractions The various parts of the device, such as the Replaceable to be discarded after each use to prevent the possibility of blood infection is preferred.

Exposure of blood or freely isolated virus to ultraviolet light in a photophoresis apparatus is within the skill of the art. power range.

When the photophoresis step is carried out in vitro, at least one of the treated blood or treated free-isolated virus A fraction is also returned to the patient after the procedure. The above treatment method is approximately Repeat once or at intervals of about once every four weeks. In the treatment of HIV infection , the above treatment method is performed for 2 consecutive days, and once a month (i.e., the patient is given 2 treatments each month). It is most preferable to undergo multiple treatments.

In view of the disclosure contained herein, those skilled in the art will be able to determine the treatment parameters, i.e., photoactivation. Doses of compound and electromagnetic radiation administered during each period, synchrony of treatment (e.g., monthly, weekly, etc.) The number of procedures (e.g., two per section for three consecutive days) should be determined based on the patient's condition and the patient's response to the procedure. could be adjusted depending on the response.

Preferred photoactive compounds for use in accordance with this invention include U.S. Pat. No. 4,321,919 The compound known as busoralen is disclosed in the patent, the disclosure of which is hereby incorporated by reference. Put it in.

Preferred compounds for use in this invention include:

8-Methoxybutsoralen 4.5°, 8-trimethylbusoralen, 5-methoxybusoralen, 4-methylbusoralen, 4.4-dimethylbusoralen, 4.5”-dimethylbusoralen and 4',8-dimethylbusoralen The most preferred photoactive compound for use in accordance with this invention is 8-methoxypsoralen. be.

Determination of effective doses for in vitro virus inactivation of freely isolated virus is within the skill of the art. is within the range of ability.

Oral administration is preferred when photoactive compounds are administered in vivo into the patient's blood, but static administration is preferred. Administration can also be by injection and/or other conventional routes of administration.

The preferred dosage of photoactive compound is in the range of about 0.3-04 mg/Kg body weight However, larger or smaller amounts can also be used.

The photoactive compound is administered in vitro to only a portion of the patient's blood or a fraction thereof. Based on the amount of blood or fraction thereof to be treated, a person skilled in the art will It would be possible to calculate a dose l equal to the above range.

For oral administration, the photoactive compound is administered at least about 1 hour prior to the photophoretic procedure. Preferably, the administration is performed within about 3 hours prior to administration.

The timing of administration will depend on the bioavailability of the photoactive compound, its expected half-life, etc. You can adjust it up and down as needed.

When given intravenously, the time period will generally be short.

Viral infection following administration of photoactive compounds across the spectrum of electromagnetic radiation Exposure of cells and/or their viruses to light effectively inactivates and/or must be of sufficient intensity/duration to attenuate. Appropriate wavelength and exposure for photophoresis The use of light is at the option of those skilled in the art, depending on the photoactive compound used and the treatment situation. Ru.

When the photoactive compound is 8-methoxybus psoralen, the virus and virus to be treated are Approximately 2 joules of UVA irradiation per m2 of surface area of R. rus infected cells is preferred. .

When performing the photophoretic procedure according to this invention in vivo, it is important to avoid causing unnecessary harm to the patient. Care should be taken to ensure maximum radiation exposure. The method for calculating the maximum irradiation exposure is It is known in the field and will not be described here.

In summary, this invention is directed to patients with viral infections and the immune system being compromised by such infections. patients with reduced levels, as well as patients infected with HIV retroviruses or AIDS or provides a novel treatment for patients developing AIDS-related complexes. like this patients cannot tolerate treatments that would weaken their immune systems.

The treatment method according to the present invention is effective and safe for human HIV infection. The inventor has discovered that. The invention also provides a method for making a vaccine. Therefore, H.I. Donors infected with viruses such as V retrovirus may experience symptoms such as: It can be used to produce vaccines against infectious diseases.

First, photoactive compounds such as those described above are used to treat free virus and/or virus. At least a portion of the donor blood containing R. rus-infected cells is administered orally prior to blood removal. or administered either intravenously or, after blood removal, ex vivo. Optionally, Red blood cells are removed from a portion of the nurse's blood in advance using a known method, and the resulting fluxon is added with a photoactive substance. Quality can also be administered.

In both cases, blood treated with photoactive substances (e.g. enriched with leukocytes) fractions) and/or portions of free isolated virus, as described above. subjected to photophoretic treatment using electromagnetic radiation in the spectrum, e.g. ultraviolet light, preferably UVA. . The treated blood, its parts or free virus (as the case may be) is then added to one source. It is administered back to the donor as a vaccine. According to this invention, the treated virus from the treated blood or parts thereof following photophoretic processing for use as a vaccine. You can also release it.

In addition, according to the invention, processed blood, i.e. peptides or polypeptides, e.g. For example, a mixture of various blood components containing sidekin, lymphokin, monokin, etc. Alternatively, the processed portion of the blood may be processed by those skilled in the art to treat the donor's viral infection. specific components that can be used as antiviral vaccines and/or as antiviral vaccines. .

Last 1L minus 1 He is 39 years old, weighs about 70 kg, and was diagnosed with an AIDS-related complex. A male patient was treated according to the present invention as follows.

During the afternoon of the first day of treatment, 8-methoxybutsoralen was administered at a dose of 30 mg (approximately 0.4 mg). /kg) was administered orally to patients. Has 8-methoxybus psoralen been administered to the patient? After about 1 o'clock darkness, photophoresis treatment was carried out using the above Terracos UVAR photophoresis device. , some of the patient's blood was removed.

Using a centrifuge integrated with a photophoresis device, virtually all of the extracted blood is removed. All red blood cells were separated and the separated red blood cells were then returned to the patient. Next, about 30 6 cycles of 0cc blood and 240cc buffy coat (containing T-lymphocytes) (40 cc of buffy coat per cycle) was removed. buffy coat and Straight line is Puffyco) After 40cc or the first cycle is collected, UV irradiation is performed. I was given a shot. Irradiation was continued for 6 cycles, resulting in a total irradiation time of approximately 4 hours. After that, it continued for another hour and a half. The irradiated buffy coat and plasma are then transferred to the patient. was returned to. The above steps were repeated on the morning of August 8, the following day.

Before receiving photophoresis treatment according to the present invention and after 5 weeks after receiving photophoresis treatment according to the present invention. Patients' blood parameters are shown in Table 1.

[Blood parameters of ARC patients who underwent photophoresis treatment according to the present invention]

Blood parameters Before treatment After treatment Normal range hemoglobin 11.7 G/DL 10.80/DL Hematolift 33.9% 33.6% □WB C5, 2/LIL 4.7/ULWB (2IL knee Band 16% 16% Segmented nucleus sphere 29% 23% Lymphocytes 43% 46% Abnormal lymphocytes 7% 7 parts Monocytes 5% 7% Platelets 208.000 241.000 yen CD, (T”) 17% 85% 56-78% CD, (T’) 4% 22% 32-50% CD, (T") 26% 62% 13-38% T'/T" Ratio 0.15 0.4 0.8 to 1.9 Furthermore, the treatment according to the present invention as described above Mumps treated by a method well known in the field before undergoing medical treatment Patients with negative skin tests developed mumps after six months of treatment according to the invention. Cold skin test was positive. This positive mumps skin test indicates delayed hypersensitivity. evidenced by skin biopsies that characterize the histological changes of the disease. The above conclusion The results show that the treatment method of the present invention resulted in the reconstitution of normal immunity. vinegar.

This patient was admitted for two consecutive days in one month as part of a clinical trial involving five patients. The patient continued to undergo the treatment described above. The results are described in Example 2 below. This disease This person is referred to as Patient 1 in Example 2.

Last JLIλ Fatigue, lymphomyopathies, fever, unresponsive skin test, and CD.

Five patients with ARC characterized by cell loss volunteered , Institutional Review Board at Morristown Memorial Hospital, Morristown, New Chassis, pursuant to the provisions. He underwent a clinical trial. The test group consisted of three same-sex men aged between 27 and 39 years old. Lover, a 42-year-old male correctional patient abusing intravenous drugs and a 27-year-old female correctional patient abusing intravenous drugs. consisting of people.

After you first discover that you are HIV antibody positive, you are registered as an HIV positive patient. The period is 1 to 4 years. Have not received any treatment for HIV infection in the past Only those patients who met the criteria will be included in the inclusion criteria.

Each patient receives the treatment described in Example 1 for two consecutive days per month. I received the Sesho method. The doses of 8-methoxypsorelan used ranged from 0.4 to 0. The dosage was in the range of 6+++g/kg and the administration was done orally.

The four patients received a total of 12 treatments over a 6-month study period. i.e. , I received treatment for 2 consecutive days a month for 6 months.

The fifth patient voluntarily stopped receiving transitional treatment in the 5th month and received only 10 treatments. received no medical treatment. Based on physical exam, monthly antibody and antigen tests and CD; All five patients had either stable disease or a positive response to treatment. Indicated. None of the patients suffered damage to their immune systems during treatment.

According to strict clinical criteria, all five patients improved with respect to muscle size. showed that. Four patients showed changes in energy index and general "well-being" state. I could see how good it was. At the beginning of treatment, the increase in energy levels lasted about a week after treatment. . By the third month of treatment, a consistent increase in energy levels persists. Ta.

Most notably, the first treated patient (patient of Example 1).

In other words, a homosexual patient who before treatment could only climb the stairs with great difficulty is now able to climb the stairs. One person can jog three and a half miles and can also do weight lifting. This is what happened.

One patient who had intermittent increases in energy levels or no She was a reformed female patient who abused intravenous drugs and had a young child. Her fatigue was tested Although chronic before treatment, intermittent changes in energy levels are still observed after treatment. It wasn't noticed.

As a result of further clinical observation, the patient lost 3.3 kg of body weight during the 6-month treatment period. Increased appetite and stabilization of weight were observed in 4 non-female patients. 3 pieces By April, lymphomuscular disease had disappeared in five patients, and there has been no recurrence since then. stomach. Four male patients recovered their delayed skin hypersensitivity after 6 months of treatment. During the treatment period, all patients showed no difficulty and no acquired symptoms in the general public. Community acquired) was able to treat upper respiratory tract infections.

In addition to normal changes, hemoglobin and hemorrhage, reticulocyte counts, and small blood Board counting has stabilized. In four male patients, white blood cell counts changed only slightly. The total number of circulating blood cells was stable, and one female patient had Decreased white blood cell count (from 4.000 before treatment to 2.000 after 6 months of treatment) The patient showed a decrease in the number of lymphocytes and lymphocytes. ESR1 urine analysis in all patients No change was observed in SMAC-20 and 5GOT serum and 5GPT serum. A slight increase was seen.

Corresponding to the increase in HIV antibody titer, TgG capsid antibody or 1:1280 tie Except for one patient, whose titer decreased from 1:160 to 1:160 (all patients' EBV , the titer remained constant. CMV titers remained unchanged in all patients. . Patients who tested negative for P24 antigen remained negative, and patients who tested positive remained negative. It remained as it was. Also, no change in titer has occurred by the end of the 6-month period. It was. Viral culture of blood for HIV was reported in one patient (patient 3) after treatment. The test turned negative in one patient, but remained positive in the other.

The course of the patient whose HIV culture turned negative (patient 3) is described in Figure 2. . The Gp antibody levels of the five patients during the course of treatment are shown in coordinates in Figure 3. There is. The Gp120 of the five patients during the course of treatment is shown in coordinates in Figure 4. ). Finally, five patients' CD a Hertzian cells during the treatment process. The rates are shown in coordinates in FIG.

A summary of clinical characteristics and experimental results are shown in Table 2 below.

Table 2 Summary of clinical characteristics and experimental results Miyukido Age: 38 years old gender two male Nature: homosexual Known period of HIV antibody positivity: 3 years Nisato E-1-ship Weight (kg) 71. 3 70. 5CDam cells (96) 4 34 GP24 antibody value (absorbance) 2.52 2.760 P120 antibody value (absorbance’) 2,22 1.68 Delayed skin test hypersensitivity Negative Positive Virus culture (blood) positive, ink 1”- Age: 30 years old gender two male Nature: homosexual Known period of HIV antibody positivity: 2 years LUJfL I-LUL Weight (kg) 64. 5 66, 0CD4 cells (%) 29 31 CP24 antibody value (absorbance) 0.12 0.740 P120 antibody value (absorbance) 0.83 0.14 Delayed skin test hypersensitivity Negative Positive Virus culture (blood) positive test 1 Age = 27 o gender male Nature: homosexual Known period of HIV antibody positivity: 4 years 5-riichi-mae Weight (kg) 63. 6 64. 7CD, 1m cell (%) 34' 33°0 GP24 antibody value (absorbance > 0.72 1.690 P120 antibody value (absorbance) 1,04 2.07 Delayed skin test hypersensitivity Negative Positive Virus culture (blood) positive negative * This patient's CD before treatment! cells (%) data is not available. The values shown in the table are for one month after receiving the first treatment. determined by blood taken from the patient.

**This patient only received 10 treatments because he voluntarily chose to discontinue treatment at 5 months. Not receiving medical treatment. Three months after voluntarily discontinuing treatment, this patient's CD, detailed The number of cysts (%) increased to 40, but decreased to 24 5 months after discontinuing treatment. Ta.

Yeongsado Age: 42 years old gender male Nature: Conversion IVDA Known period of HIV antibody positivity: 2 years 5-star-front member-1=back Weight (kg) 109 109 CD, cells (%) 11 33 GP24 antibody value (absorbance) 0.62 1.76 GP120 antibody gl (absorbance) 0.12 1.25 Delayed skin test hypersensitivity Negative Positive Virus culture (blood) Yang sex Yang Shuri Kodan Age, 27 o gender two female Nature: Conversion IVDA Known period of HIV antibody positivity: 2 years ゑ-yu plate　Re-riichi　 Weight (kg) 61. 0 57. 7CD, cells (%) 12 13 GP24 antibody value (absorbance) 1.42 2.89G P120 antibody value (absorbance ) 0.46 1.95 Delayed skin test hypersensitivity Negative Virus culture (blood) jii positive sex test ■1 Six months of treatment as described in Example 2, i.e. patient 1,2°4.5 every month. At the end of 6 months of treatment, 2 consecutive days of treatment will be given every month. Instead, the treatment process was changed for each patient so that they only received treatment for one day.

The inventors determined whether each patient's CD4 cells (%) had decreased significantly. Served. The original treatment process in which patients receive 2B consecutive treatments every month resumes. As a result, CD and cells (%) increased in patients 1 and 2. Patients 4 and 5 CD in.

Cell (%) data are not yet available. Individual results are shown below.

See 1 above As a result of the original 6-month treatment of twice a month, this patient's CD, cells (% ) was 34. After receiving treatment once a month for 5 months, CD, cells (%) decreased to 18. The original treatment process was resumed, and two months later, CD4 m cells ( %) was over 39. As a result of the original 6 months of treatment, this patient's CD4 Cells (%) were 31. CD after 4 months of monthly treatment.

Cells (%) decreased to 10. CD after two months after the original treatment process was resumed. , cells (%) rose to 27.

Mikōdo As a result of the original 6 months of treatment twice a month, this patient's CD4 cells (%) decreased to 3. It was 3. After 4 months of monthly treatment, CD and cells (%) decreased to 7. Book The previous treatment process has resumed, but CD,! Data on changes in cells (%) are not available.

Kenwako As a result of the original 6-month treatment twice a month, this patient's CD and cells (%) were 13. It was. After 4 months of monthly treatment, the CD4 cell count (%) dropped to 8. original cure Treatment was resumed, but no data on changes in CD or cells (%) were obtained.

Medicaments made using photoactive compounds herein can be prepared using standard techniques already known to those skilled in the art. Since it can be formulated using various techniques, it will not be described in detail here. For example, photoactivation The compound can be made into tablets, capsules, etc. suitable for oral administration using conventional excipients. Wear.

The photoactive compound may also be administered parenterally, intravenously or intramuscularly, if desired. It can be made into lumber. This drug is added to the blood fraction removed from infected donors. It can also be formulated into an injection solution or suspension solution for in vitro administration.

The above description is for the purpose of illustrating the invention, and those skilled in the art will appreciate the following claims: Various modifications may be made to the invention herein described without departing from its spirit and scope as defined herein. It should be understood that it is not intended to limit the scope of the invention, as the invention may be modified.

Fig, 1 Fig, 2 Fig, 3 Fig, 4' Fig, 5 international search report

Claims (67)

[Claims] 1. a. In the patient's blood, in the case of virus-infected cells, in the cell membrane (e.g. receptors and/or nucleic acid fragments) and/or cell nuclei or cells. to nucleic acids in cytoplasma, or in the case of free or cell-associated viruses. virus surface (e.g. viral surface receptors and/or nucleic acid fragments). to the virus) and/or to the nucleic acid (e.g. DNA or RNA) introduced into the virus. , viruses and/or viruses that have been inactivated and/or attenuated and treated. Exposure to electromagnetic radiation in a specified spectrum for the purpose of presenting infected cells to the patient's immune system. administering a photoactive compound that binds upon activation by light, and b. treating at least a portion of the patient's blood to which the photoactive compound has been administered; Photophoresis uses electromagnetic irradiation, and photoactive compounds and electromagnetic irradiation can cause viral infections. viral infection consisting of a process done in an amount that is pharmaceutically effective to control and methods of treating patients with abnormal lymphocytes or leukopenia. 2. 2. A method according to claim 1, wherein the administration of the photoactive compound is carried out ex vivo. 3. 2. The method according to claim 1, wherein the administration of the photoactive compound is carried out in vivo. 4. Photophoresis is carried out extracorporeally and the method includes step (b) followed by aliquoting a portion of the treated blood. 3. The method of claim 2 comprising the step of returning to the patient. 5. Photophoresis is carried out extracorporeally and the method includes step (b) followed by aliquoting a portion of the treated blood. 4. The method of claim 3 comprising the step of returning to the patient. 6. Claim 1 wherein the electromagnetic radiation is ultraviolet light and the photoactive compound is a psoralen compound. the method of. 7. The psoralen compound is psoralen, 8-methoxypsoralen, 4,5',8 -trimethylpsoralen, 5-methoxypsoralen, 4-methylpsoralen, 4 , 4-dimethylbusoralen, 4,5'-dimethylpsoralen and 4'8-dimethyl 7. The method of claim 6, wherein the method is selected from the group consisting of lupsoralen. 8. The psoralen compound is 8-methoxypsoralen, psoralen and 4,5',8- 8. The method of claim 7, wherein the method is selected from the group consisting of limethylpsoralen. 9. 9. The method of claim 8, wherein the psoralen compound is 8-methoxypsoralen. 10.8-Methoxypsoralen is administered at a dose of about 0.3 to about 0.7 mg/kg 10. The method of claim 9. 11. The method of claim 10, wherein the 11.8-methoxypsoralen is administered orally. 11. The method of claim 10, wherein the 12.8-methoxypsoralen is administered intravenously. 13. Steps a and b are performed on two consecutive days, and steps a and b are performed on the first day and then the next day. 10. The method of claim 9, wherein the two-day treatments are repeated at intervals of about 1 to 4 weeks. . 14. Steps a and b are performed on two consecutive days, and steps a and b are performed on the first day and then the next day. 11. The person of claim 10, wherein the treatment is repeated over and over again, and the interval between such two-day treatments is about 1 to 4 weeks. Law. 15. a. At least a portion of the donor's blood contains cells, in the case of virus-infected cells. membranes (e.g. interrogating receptors and/or nucleic acid fragments of cell membranes) and/or to nucleic acids in the cell nucleus or cytoplasm, or to free viruses or cells. In the case of virus-associated viruses, virus surface (e.g. virus surface receptors and /or nucleic acid fragments) and/or nucleic acids that have been introduced into a virus (e.g. virus that has been inactivated and/or attenuated and treated (DNA or RNA) designated space for the purpose of presenting viruses and/or virus-infected cells to the patient's immune system. administering a photoactive compound that binds upon activation by exposure to electromagnetic radiation of the vector; and b. treating at least a portion of the donor blood to which the photoactive compound has been administered; The method involves subjecting at least a fraction of the blood portion to photophoresis using said electromagnetic irradiation. photoactive compounds and electromagnetic radiation have been used medicinally to control viral infections. HIV retroviral infection in an infected donor comprising the steps of: How to make a vaccine against. 16. A claim in which the blood fraction is processed to substantially remove red blood cells. 15 ways. 17. The blood fraction is substantially free of red blood cells before carrying out step (b). 17. The method of claim 16. 18. The blood fraction is substantially free of red blood cells after carrying out step (b). 17. The method of claim 16. 19. The fraction treated in step (b) is essentially a free isolated HIV retrograde 16. The method of claim 15, wherein the method comprises: 20. Following step (b), the treated fraction of blood is infected with an HIV retrovirus. Claim 15 comprising further processing for isolation for use as a vaccine against the method of. 21. a. administering 8-methoxypsoralen to at least a portion of the patient's blood; b. Then, at least a portion of the patient's blood to which 8-methoxypsoralen was administered was exposed to UV light. subjected to extracorporeal photophoresis using A light; c. A small amount of blood processed in steps (a) and (b) At least one fraction is injected into the patient where it is treated with 8-methoxypsoralen. UVA light is given in a pharmaceutically effective amount to inhibit the progression of an AID patient infection. S carrier or infection with AIDS or AIDS-related complex How to treat patients. 22. The dose of 8-methoxypsoralen used in step (a) is Claim 21 wherein about 0.3 to about 0.7 mg/Kg is orally administered to the patient within about 3 hours. the method of. 23. a. Photoactive compounds are activated by exposure to ultraviolet light and bind to nucleic acids in white blood cells a photoactive compound that can be administered to infected white blood cells in a patient, and then b. Photophoresis using ultraviolet light to remove at least a portion of the patient's leukocytes to which the photoactive compound has been administered. photoactive compounds and ultraviolet light inhibit the progression of the patient's infection. an AIDS carrier or an AIDS carrier which is of pharmaceutically effective use for How to treat patients with S or AIDS-related complex and infected leukocytes Law. 24. 24. The method of claim 23, wherein the photoactive compound is 8-methoxypsoralen. 25. a. 8-methoxy at a dose of about 0.3 to about 0.7 mg/kg into the patient's blood. Administer psoralen and then b. exposing at least a fraction of the patient's blood to UVA light; - Methoxypsoralen and UVA light increase the number of uninfected T cells in patients, but Abnormal due to viral infection such as HIV infection, which consists of a process that is a pharmaceutically effective amount. A method for increasing the number of uninfected T cells in a patient with T cell depletion. 26. a. in the patient's blood, in the case of virus-infected cells, in the cell membrane (e.g. cell membrane). receptors and/or nucleic acid fragments) and/or cell nuclei or cells. to the nucleic acids in the cell cytoplasma, or to the site of free or cell-associated viruses. virus surface (e.g. viral surface receptors and/or nucleic acid fragments) nucleic acids (e.g. DNA or RNA) that have been introduced into Viruses and/or viruses that have been inactivated and/or weakened and treated of electromagnetic radiation in a given spectrum for the purpose of infecting virus-infected cells to the immune system of three parties. administering a photoactive biological compound that binds upon activation by light exposure, and b. treating at least a portion of the patient's blood to which the photoactive compound has been administered; Photophoresis uses electromagnetic irradiation, and photoactive compounds and electromagnetic irradiation are known to cause viral infections. an AIDS drug comprising steps taken in an amount that is pharmaceutically effective to control AIDS. Treatment of infected patients with AIDS or AIDS-related complex How to do it. 27. 27. The method of claim 26, wherein the administration of the photoactive compound is performed ex vivo. 28. 27. The method of claim 26, wherein the administration of the photoactive compound is performed in vivo. 29. Photophoresis or in vitro exposure of the treated blood portion to the patient following step (b) 28. The method of claim 27, comprising the step of reverting to . 30. Photophoresis or in vitro exposure of the treated blood portion to the patient following step (b) 29. The method of claim 28, comprising the step of reverting to . 31. 27. The compound of claim 26, which is a photoactive compound or a psoralen compound by electromagnetic irradiation or ultraviolet light. Method. 32. The psoralen compound is psoralen, 8-methoxypsoralen, 4,5', 8-trimethylpsoralen, 5-methoxybutsoralen, 4-methylpsoralen, 4,4 dimethylpsoralen, 4,5'-dimethylpsoralen and 4',8-dimethylpsoralen 32. The method of claim 31, wherein the method is selected from the group consisting of tilbutsoralen. 33. Psoralen compounds include 8-methoxypsoralen, psoralen and 4,5', 33. The method of claim 32, wherein the compound is selected from the group consisting of 8-trimethylpsoralen. 34. 34. The method of claim 33, wherein the psoralen compound is 8-methoxypsoralen. 35.8-Methoxypsoralen is administered at a dose of about 0.3 to about 0.7 mg/kg 35. The method of claim 34. 36. The method of claim 35, wherein the 8-methoxypsoralen is administered orally. 36. The method of claim 35, wherein the 37.8-methoxypsoralen is administered intravenously. 38. Steps (a) and (b) are performed on two consecutive days, and steps (a) and (b) are performed on the first day. repeated on the next day, with an interval of approximately 1 to 4 weeks between each such two-day treatment. 35. The method of claim 34, wherein the method is performed. 39. Steps (a) and (b) are performed on two consecutive days, and steps (a) and (b) are performed on the first day. repeated on the next day, with an interval of approximately 1 to 4 weeks between each such two-day treatment. 36. The method of claim 35, wherein the method is performed. 40. a. in the patient's blood, in the case of virus-infected cells, in the cell membrane (e.g. cell membrane). receptors and/or nucleic acid fragments) and/or cell nuclei or cells. to the nucleic acids in the cell cytoplasma, or to the site of free or cell-associated viruses. In some cases, viral surface (e.g. viral surface receptors and/or nucleic acid fragments) nucleic acids (e.g. DNA or RNA) that have been introduced into Viruses and/or viruses that have been inactivated and/or weakened and treated of electromagnetic radiation in a specified spectrum for the purpose of infecting the patient's immune system with virus-infected cells. administering a photoactive compound that binds upon activation by light exposure, and b. treating at least a portion of the patient's blood to which the photoactive compound has been administered; photophoresis using electromagnetic irradiation; photoactive compounds and electromagnetic irradiation are consisting of a process performed in an amount that is pharmaceutically effective to control virus infections. A method of treating patients with HIV retroviral infection. 41. 41. The method of claim 40, wherein the photoactive compound administration is performed ex vivo. 42. 41. The method of claim 40, wherein the administration of the photoactive compound is performed in vivo. 43. Photophoresis is carried out extracorporeally, and following step (b), the treated blood portion is 42. The method of claim 41, further comprising the step of returning to the patient. 44. Photophoresis is carried out extracorporeally, and following step (b), the treated blood portion is 43. The method of claim 42, further comprising the step of returning to the patient. 45. Claim 40, wherein the electromagnetic radiation is ultraviolet light and a photoactive compound or a psoralen compound. Method. 46. The psoralen compound is psoralen, 8-methoxybutsoralen, 4,5', 8-trimethylpsoralen, 5-methoxybutsoralen, 4-methylpsoralen, 4,4-dimethylpsoralen, 4,5'-dimethylpsoralen and 4',8-dimethylpsoralen 46. The method of claim 45, selected from the group consisting of tilpsoralen. 47. The psoralen compound is 8-methoxypsoralen, busoralen and 4,5', 47. The method of claim 46, wherein the compound is selected from the group consisting of 8-trimethylpsoralen. 48. 48. The method of claim 47, wherein the psoralen compound is 8-methoxypsoralen. 49.8-Methoxypsoralen is administered at a dose of about 0.3 to about 0.7 mg/kg 49. The method of claim 48. 50. The method of claim 49, wherein the 50.8-methoxypsoralen is administered orally. 51. The method of claim 49, wherein the 51.8-methoxypsoralen is administered intravenously. 52. Steps (a) and (b) are performed on two consecutive days, and steps (a) and (b) are performed on the first day. and repeated on the next day, with an interval of about 1 to 4 weeks between each such two-day treatment. 49. The method of claim 48. 53. Steps (a) and (b) are performed on two consecutive days, and steps (a) and (b) are performed on the first day. The treatment is repeated the next day, with approximately 1 to 4 weeks between such two-day treatments. The method of claim 49. 54. a. 8-Methoxypsoralen is added to at least a portion of the patient's blood in a photoactivated manner. In this section, substantially all free and/or cell-associated HIV retro administered in an amount sufficient to bind to the virus as well as infected cells, and then b. 8-Metho At least a portion of the blood of a patient administered xypsoralen will be collected to determine the progress of the patient's HIV infection. subjected to extracorporeal photophoresis using an amount of UVA light sufficient to inhibit cell lineage; c. Process (a ) and (b) injecting at least a fraction of the treated blood into the patient; A method of treating a patient with an HIV retroviral infection comprising: 55. Before photophoresis, the dose of 8-methoxypsoralen used in step (a) is approximately From about 0.3 to about 0.7 mg/kg for oral administration to a patient within 3 hours. 56. In the case of virus-infected cells, cell membranes (e.g. cell membrane receptors and/or binds to nucleic acids) and/or binds to nucleic acids in the cell nucleus or cytoplasm. In the case of viruses or cell-associated viruses, the surface of the virus (e.g. into the receptor and/or nucleic acid fragment) and/or into the virus. nucleic acids (e.g. DNA or RNA) to inactivate and/or attenuate the virus. A photoactive compound that is activated by exposure to a predetermined spectrum of electromagnetic radiation to The compound is used to treat viral infections in infected patients with abnormal lymphocytes and leukopenia. Use of a photoactive compound characterized in that it is used in the production of a medicament. 57. According to claim 56, the photoactive compound is a psoralen compound. Applications. 58. Claim characterized in that the photoactive compound is an 8-methoxypsoralen compound. Use according to claim 57. 59. In the case of virus-infected cells, cell membranes (e.g. cell membrane receptors and/or binds to nucleic acids) and/or binds to nucleic acids in the cell nucleus or cytoplasm. In the case of viruses or cell-associated viruses, the surface of the virus (e.g. into the receptor and/or nucleic acid fragment) and/or into the virus. nucleic acids (e.g. DNA or RNA) to inactivate and/or attenuate the virus. A photoactive compound that is activated by exposure to a predetermined spectrum of electromagnetic radiation to The compound is specifically designated for use in the manufacture of medicines for the treatment of HIV virus infection. Applications of photoactive compounds as characteristics. 60. According to claim 59, the photoactive compound is a psoralen compound. Applications. 61. A claim characterized in that the psoralen compound is 8-methoxypsoralen Uses according to Section 60. 62. In the case of virus-infected cells, cell membranes (e.g. cell membrane receptors and/or binds to nucleic acids) and/or binds to nucleic acids in the cell nucleus or cytoplasm. In the case of viruses or cell-associated viruses, the surface of the virus (e.g. into the receptor and/or nucleic acid fragment) and/or into the virus. nucleic acids (e.g. DNA or RNA) to inactivate and/or attenuate the virus. photoactive compounds that are activated to bind by exposure to a defined spectrum of electromagnetic radiation If the compound is an AIDS carrier or an AIDS or AIDS-related compound, Photoactivation characterized in that it is used in the production of a medicament for patient treatment having a plex. Uses of compounds. 63. According to claim 62, the photoactive compound is a psoralen compound. Applications. 64. A claim characterized in that the psoralen compound is 8-methoxypsoralen Uses according to Section 63. 65. Consisting of a pump (10), an irradiation chamber (20) and an irradiation source (30), it is Characterized by its use in the treatment of viral infections in infected patients with decreased counts of paracytosis or white blood cells. Applications of photophoresis devices. 66. It consists of a pump (10), an irradiation chamber (20), and an irradiation source (30). A use of a photophoresis device characterized in that it is used for the treatment of viral infections. 67. Pump (10), irradiation chamber (20), irradiation source (30), centrifuge (40) AIDS carrier or AIDS or AIDS-related complex A use of a photophoresis device characterized in that it is used for treatment of patients with.