JP4372723B2 - Compositions useful in the manufacture of a medicament for the treatment of chronic pain - Google Patents

Description

The present invention relates to pharmacology. More specifically, the present invention relates to compositions useful for the manufacture of a medicament for various stubborn disorders such as chronic pain.

  Many chronic diseases have symptoms that are known to be very difficult to treat and often do not respond to safe and non-addictive non-steroidal drugs. Diseases such as stubborn cough do not respond to normal medications and drugs such as codeine, morphine or the anti-inflammatory steroid prednisone must be used. These drugs cannot be used over long periods due to toxic side effects on the patient's health, long-term dangers, and habitual risks. Other diseases such as dermatitis have no satisfactory treatment for rashes that occur simultaneously with severe itching. Drugs such as prednisone, even tricyclic antidepressants, have been tried with topical application, but are not believed to provide substantial and consistent healing.

Chronic pain due to symptoms such as stroke, cancer, trauma, and neuralgia resulting from symptoms such as diabetes and herpes zoster are also problems that cannot be adequately treated. Chronic pain has been claimed to suffer millions of people. Various therapies have been attempted for this type of pain, but safe and effective treatments are needed.

The compound dextromethorphan, (+)-3-methoxy-N-methylmorphinan, has been used as an antitussive component in sexirop. Dextromethorphan has also been attempted as a potential therapeutic agent for stroke and progressive neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. However, since dextromethorphan is rapidly degraded in the liver and excreted by most people, the therapeutic effect is limited for any disease.

Detailed Description of the Invention

One object of the present invention is to provide a combination of compounds that are useful in the manufacture of a medicament that has been previously stubborn and can effectively treat conditions that do not respond to other drugs. It is also an object of the present invention to provide a safe and non-addictive drug with relatively few side effects for patients suffering from stubborn symptoms for a long time.

SUMMARY OF THE INVENTION The present invention provides compounds useful in the manufacture of a medicament for the treatment of various diseases including stubborn cough, dermatitis, chronic pain, tinnitus and sexual dysfunction. These compounds are a pharmaceutically effective amount of dextromethorphan, a pharmaceutically effective amount of a second agent and an inhibitor of enzymatic dextromethorphan oxidation. The combination of compounds can be administered together or individually. The preferred formulation is dextromethorphan and the antioxidant quinidine. Inhibitors that can be used also include quinine, yohimbine, fluorectin, haloperidol, ajmarin, lobeline and pipemperone.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Definitions The term dextromethorphan (hereinafter DM) means (+)-3-methoxy-N-methylmorphinan or a medically effective salt and its homologues.
The term “antioxidant” or “oxidation inhibitor” means an inhibitor capable of inhibiting the oxidation of DM by the liver enzyme debrisoquin hydroxylase.
The term “stubborn” or “incurable” cough means a cough that does not respond appropriately to non-addictive non-steroidal drugs.

  The term “dermatitis” or “eczema” refers to skin conditions including visible skin damage that may be accompanied by itchy and irritated skin. This condition does not easily respond to non-prescription drugs, lotions, or ointments.

The term “chronic pain” means pain due to symptoms such as stroke, cancer and trauma and neurological pain resulting from destruction of neural tissue such as postherpetic neuralgia due to shingles and diabetic neuropathy due to long-term diabetes.
The term “tinnitus” refers to a condition characterized by high pitch tinnitus that is believed to be due to the loss of motility of the outer hair cells of the umbilical tube of the ear.

  The present invention provides compositions for use in the manufacture of a medicament for effective treatment of various chronic and stubborn diseases that do not respond to other treatments. These compositions are enzymatically produced by a medically effective amount of dextromethorphan (DM), or a pharmaceutically acceptable salt or homolog thereof, by a medically effective amount of the liver enzyme debrisoquinine hydroxylase. Combined with an inhibitor of dextromethorphan oxidation. Chronic and stubborn diseases that respond to medication containing a dextromethorphan / antioxidant combination include stubborn cough, dermatitis, chronic pain and tinnitus. Relatively powerful antioxidants are quinidine and quinine. Other mild antioxidants include yohimbine, fluoretin, haloperidol, azimarin, lobeline, and pipemperone.

  Kinins and other antioxidants have been found to have a significant effect of increasing and stabilizing the amount of DM circulating in the patient's blood when administered in combination with DM. This effect is described in Smith, US Pat. No. 5,166,207, issued November 24, 1992, and Zhang, Y., Clin. Pharmacol. Ther, 51: 647-655 (1992), where Combine them as a reference.

  Dextromethorphan (hereinafter DM) is a common name for (+)-3-methoxy-methylmorphinan. This compound is described in detail in Rodd et al., Chemistry of Carbon Compounds, Elsevier Publ., New York (1960), which is incorporated by reference. It is a non-addictive opioid with a right-handing enantiomer (mirror image) of the morphinan ring structure that forms the molecular core of many opiates.

  DM is used as an antitussive component in general sexirop. The antitussive component of DM is thought to be derived primarily from its action as an antagonist to the neuronal receptors known as sigma receptors or high affinity dextromethorphan receptors. These receptors are sometimes referred to as sigma opiate receptors, but it is not clear whether they are actually opiate receptors. Sigma receptors are inhibitory receptors, and activation of these receptors by DM or other sigma antagonists causes some type of suppression of neural signals. Dextromethorphan is also thought to act on another type of receptor known as the N-methyl-D-aspartate (NMDA) receptor, which is one of the excitatory amino acid (EAA) receptors. Type. Unlike agonist activity at the sigma receptor, DM acts as an antagonist to the NMDA receptor and suppresses nerve impulse conduction regulated through the NMDA receptor. Since the NMDA receptor is an excitatory receptor, the action of DM as an NMDA antagonist results in suppression of neural signals. Furthermore, DM has been reported to suppress the action on the neuronal calcium channel. This is the antagonist activity of DM in NMDA and is considered to be one of the common combinations in various conditions that respond to drugs containing DM / antioxidant in combination.

  When used in medicine, DM rapidly disappears from the bloodstream in most patients, such as Dayer et al., Clin Pharmacol. Ther, 45: 34-40 (1989), Vetticaden et al., Pharmaceut. Res, 6: 13-19. (1989) and Ramachander et al., J. Pharm. Sci., 66: 1047-1048 (1977), which are incorporated herein by reference. DM is broken down in the liver into several metabolites. DM is oxidized by O-demethylation, removing one of the methyl groups and producing two metabolites, dextrophan and 3-methoxymorphinan. If the secondary methyl group is removed, the resulting metabolite is 5-hydroxymorphinan. Dextrophan is known to have many biological activities of DM. However, dextrophan and 5-hydroxymorphinan are covalently bound to other compounds in the liver, primarily to bind to S-containing compounds such as glucuronic acid or glutathione to form glucuronides or sulfate conjugates. However, it cannot easily cross the blood-brain barrier and disappears rapidly from the body in urine.

  The specific enzyme primarily responsible for DM-oxidation is debrisoquin hydroxylase, also known as spartin monooxygenase, and in various literature, cytochrome P-450DB, cytochrome P-450 dbl ( Or dbl), also referred to as cytochrome P-4502D6. Hereinafter, it is referred to as debrisoquin hydroxylase. Debrisoquin hydroxylase belongs to the family of “cytochrome P-450” or “cytochrome oxidase”. These enzymes are typically found at high concentrations in hepatocytes, especially liver microsomes, and are present at lower concentrations in various other organs or tissues, such as the lungs. By oxidizing lipophilic compounds, the cytochrome oxidase enzyme eliminates compounds from the body that act as toxins or accumulate at undesirable levels. Typically, oxidation makes lipophilic compounds more soluble in water and therefore more easily disappears from the urine or disappears with aerosols exiting the lungs. Debrisoquin hydroxylase is clearly present in brain tissue (Fonne-Pfister et al., Biochem. Biophys. Res. Communic, 148: 1144-1150 (1987), Niznik et al., Arch. Biochem. Biophys, 26: 424-432 (1990), Tyndale et al., Mol. Pharmacol, 40: 63-68 (1991)) its function in the brain is not fully understood.

  Dextromethorphan is a common drug that is widely used as a sexirop and doses up to about 120 mg / day for adults. In the present invention, the DM dose range is about 20-200 mg / day, preferably 20-150 mg / day, and varies depending on the patient's weight, severity of the disease, and the strength and amount of the antioxidant used in combination with DM. Come.

  Quinidine is the right-handing stereoisomer of quinine. Quinidine is used in the treatment of cardiac arrhythmias and is a relatively powerful cardiac medicine. Quinidine is commercially available from many companies, such as A.H. Robin, Richmond Virginia, but is used only by physician prescriptions. Both DM and quinidine are used in powders and specific dose capsules can be manufactured by commercial companies as desired. The dose of quinidine to increase mainly the DM concentration in the bloodstream of many patients was 150 mg / day or less, although individually different. The present invention contemplates a dose range of 50-300 mg / day, desirably 50-150 mg / day. In some patients, it has been found effective at about 50 mg / day. On the other hand, the amount used for the adjustment of antiarrhythmia in heart disease patients is 600-1200 mg / day.

  Many antioxidants other than quinidine have been shown in the literature using in vivo screening. These reports include Inaba et al., Drug Metabolism and Disposition 13: 443-447 (1985), Fonne-Pfister et al., Biochem. Pharmacol, 37: 3829-3835 (1988) and Broly et al., Biochem. Pharmacol, 39: 1045- 1053 (1990), all of which are incorporated herein by reference. As reported by Inaba et al., K1 values (Michaelis-Menton inhibition valus) of 50 micromolar or less, nortriptyline, chlorpromazine, domperidone, haloperidol, pipemperone, labetalol, metaprolol, oxprenolol, propranolol, timolol , Mexiletine, quinine, diphenhydramine, azimarin, lovelin, papaverine and yohimbine. Desirable compounds with particularly strong inhibitory activity are yohimbine, haloperidol, azimarin, lobeline and pipemperone, whose K1 values are between 4 and 0.33 μM. On the other hand, the K1 value of quinidine is 0.06 μM. Of these inhibitors, quinine sulfate, disulfiram, cimetidine, fluroxetine, propranolol and nortriptyline were tested for their ability to stabilize DM concentrations in the bloodstream as described in detail in Example 4 below. As expected, the results of these studies showed an increase in DM concentration that was not observed when DM was administered with quinidine. In addition, there were substantial differences between individuals in the effect of each antioxidant.

  Quinine having a skeleton similar to quinidine had the effect of increasing the DM / DRP ratio in each person tested. Other drugs showed greater differences for each person. This difference indicates that the doses described in Example 4 below should be tested in advance prior to use in patients for individual antioxidants. It should also be noted that many antioxidants have a wide range of changes and have a medicinal effect that the prescribing physician takes into account. The dosage of other antioxidants varies from antioxidant to antioxidant and must be determined using the protocol described in Example 4.

  In addition to the antioxidants described above, Lilly's Prozac trade name fluoxetine has also been found to be effective in increasing DM levels in the blood of some patients. For example, one patient who took 20 mg of fluoxetine twice daily recorded a blood concentration of DM of 40 ng / ml when DM was administered according to the study shown in Example 4.

  The optimal amount of dextromethorphan and antioxidant to be administered to a particular patient is determined by administering various amounts of each drug as follows. (1) Analyze blood samples to determine the DM concentration in the circulating blood; (2) Patient doses to determine the combination of doses that provides the best results in effectively suppressing the targeted symptoms. Observe the progression of the condition.

  Many factors affect the dose of DM and antioxidants that will be appropriate for a particular individual. One very important factor is the ability of each person to metabolize DM. It is known that 7-10% of the total population does not have a gene that functions properly to encode the debrisoquin hydroxylase enzyme. These people are “low metabolizers” by physicians or pharmacologists, while those who have the gene encoding debrisoquin hydroxylase are “very metabolizers”. “Low-metabolites” are overreacting to some drugs that can be completely administered to those who have complete cytochrome P450 enzymes, and therefore must be addressed with special consideration and caution. A patient.

  In addition to debrisoquin hydroxylase inhibition, other cytochrome P450 isozymes appear to be suppressed by quinidine or other inhibitors with varying levels of binding affinity. This is described in literature such as Kupfer et al., Lancet ii: 517-518 (1984) and Guttendorf et al., Ther. Drug. Monit., 10: 490-498 (1988), incorporated herein by reference. In addition, cytochrome P450 enzymes are non-specific in that a single isozyme can react to a large number of substrates having chemical structures that differ greatly, and that various isozymes have overlapping activities on a single substrate. It is. Thus, even though quinidine exerts its most prominent effect on debrisoquin hydroxylase, it can inhibit other cytochrome P450 enzymes as well, thereby causing a greater loss of normal and desirable liver activity. To bring.

  Since DM is considered a safe drug marketed as a general drug, it is used as a convenient means or reference drug for determining whether a patient is a high metabolite or a low metabolite. Such diagnostic tests are performed to find patients who are “low metabolizers” and protected from various drugs that cannot metabolize properly. However, if a patient is taking a drug such as quinidine, enzyme levels are inhibited and diagnostic tests to identify “low metabolizers” are inaccurate, reflecting the presence of inhibitors.

  In addition, DM can cause diarrhea, dry mouth, lightheadedness, loss of appetite, and in some cases impotence in male patients in some patients. These side effects are likely to occur and become heavier with antioxidants at a rate commensurate with their strength. Accordingly, it is contemplated that the DM-quinidine or DM-antioxidant formulations disclosed herein are currently used only under the supervision of a physician who will determine the appropriate treatment. All appropriate warnings must be made for the use of any antioxidant so that it can be appreciated by physicians and other persons skilled in the art. However, the dose of quinidine that results in a substantial increase in blood DM concentration is only a fraction of the amount normally used for antiarrhythmic effects.

  For some patients, the combination of antioxidants other than DM and quinidine is desirable for pharmaceutical manufacture. In some cases, the patient is not resistant to the quinidine or quinidine-DM combination, eg, is allergic to quinidine or suffers from a known heart condition with long QT intervals and is therefore not resistant to quinidine. Less potent oxidation inhibitors are also desirable when combined with DM. For example, quinidine is changed to a second drug to avoid increased tolerance that requires increasing doses of quinidine. Or in patients with moderate symptoms where cough does not respond appropriately to other treatments but is not severe enough to require a strong enzyme inhibitor.

  Unexpectedly, it has been discovered that the combination of DM and quinidine is very effective in reducing the symptoms of “emotional instability”. Emotional instability is a complex problem in patients with bilateral neuropathy typically derived from neurological disorders such as stroke, head injury, ALS or Alzheimer's disease, and convulsive, such as explosive laughter or uncontrollable crying There is an emotional outbreak. In patients with brain disorders that lead to emotional instability, such outbreaks often occur without warning at inappropriate times. The effect of adjusting the emotional instability of DM in combination with quinidine is described in US Pat. No. 5,206,248, issued April 27, 1993, which is incorporated herein by reference. This effect of DM-quinidine, which modulates emotional instability, has not been observed in patients taking DM alone.

  The combination of compounds described above is very effective as a drug in the treatment of other chronic diseases that do not respond well to other treatments. The DM / antioxidant combination can be used to effectively treat severe and stubborn cough that is not addictive, does not respond appropriately to non-steroidal drugs. Stubborn cough is the result of respiratory infections, asthma, emphysema and other respiratory diseases.

  A test using DM-quinidine formulation for the treatment of stubborn cough in human patients is described in Example 5 below. In all study patients, treatment with a combination of DM and antioxidants provided very beneficial results with minimal side effects. These results clearly confirm the effectiveness and benefit of using DM-antioxidants in the manufacture of a medicament for the treatment of stubborn cough.

  The invention also discloses the combined use of DM and antioxidants in the manufacture of a medicament for the treatment of dermatitis. “Dermatitis” or “eczema” is a skin condition characterized by visible skin damage and / or itching or burning on the skin. The effect of DM-quinidine formulation for the treatment of dermatitis was first observed as an unexpected beneficial side effect during the study of ALS patients who happened to suffer from severe dermatitis. After these initial results, an additional study was done by oral administration of DM-quinidine capsules to several patients with dermatitis. As a result, there was a marked remission of rash and itching. Medicaments containing DM or DM-antioxidants can be administered topically to patients with dermatitis. Details of the results are described in Example 6.

  DM alone is also effective in treating dermatitis in certain patients. These patients are “low metabolizers” due to a lack of genetic ability to express a functional copy of the debrisoquin hydroxylase enzyme. For these individuals, DM alone is a safe dose and is sufficient to effectively treat dermatitis without the need for concurrent use of antioxidants to increase blood DM levels.

  The present invention also provides the use of DM and antioxidants in medicaments for the treatment of chronic pain due to symptoms such as stroke, trauma, cancer, shingles, neuropathic pain such as diabetes.

  Neuropathic pain includes postherpetic neuralgia and diabetic neuropathy. Postherpetic neuralgia (PHN) is a complication of shingles that affects approximately 10% of patients with shingles. Diabetic neuropathy is a common complication of diabetes that increases with the duration of the disease. The pain of these types of neuropathies is a burning pain often accompanied by a stinging pain, a pin or tingling pain or a dental pain, as follows: The skin is sensitive with an abnormal sensation to light touch or clothing loss. Pain is exacerbated by activity, movement changes, or emotional uplift. This pain is so severe that daily activities are not possible, resulting in sleep disturbance or loss of appetite. The mechanisms that cause these types of pain are not well understood, but seem to involve degeneration of medullary nerve fibers. In diabetic neuropathy, small and large nerve fibers are destroyed, and the tolerance value of temperature sensation, pain, and vibration is lowered. Large and small fiber dysfunction is more severe in the lower limbs with pain progression. Many of the physiological measurements of nerves that can be routinely performed in patients with neuropathic pain indicate that the nerve conduction gradually becomes slower. To date, the treatment of neuropathic pain is far from successful.

  DM-quinidine was administered orally to patients with stroke, diabetes and chronic pain due to other causes. All patients took DM-quinidine and had some pain relief at 2-4 weeks. This study is described in Example 7 below.

  It should be noted that the side effects of male patients in the initial emotional study and dermatitis study described in Example 7 include the occurrence of impotence. This impotence continued until the patient discontinued DM-quinidine-containing drug therapy. Therefore, it is considered that DM-antioxidant-containing drugs can be used for the treatment of sexual dysfunction including persistent erection or premature ejaculation.

  One patient in the pain test also suffered from symptoms of tinnitus characterized by high pitch tinnitus. After DM / quinidine treatment, the patient stopped tinnitus. Thus, based on this fact and the involvement of NMDA receptors in the co-clear system, it is the use of DM / antioxidants in the present invention in the manufacture of a medicament for the treatment of tinnitus.

  The medicament used for the treatment of the various diseases described above is produced from DM and an appropriate antioxidant, or a salt or homologue of DM and various antioxidants. “Salts” and “homologs” are used in the usual pharmaceutical sense and are limited to pharmacologically acceptable and pharmaceutically effective salts and homologs of dextromethorphan and antioxidants. The term “pharmacologically acceptable” is characterized by making a practical salt or homologue suitable for administration to a human. For example, these compounds must be sufficiently chemically stable at the appropriate storage conditions to have a suitable shelf life, and are physiologically acceptable, non-addictive or acceptable when administered orally. Must not have side effects that cannot be done. Acceptable salts include alkali metal salts and salts of free acids or free bases.

  Acids that may be used to form acid addition salts include inorganic and organic acids such as sulfate or chloride salts. Alkali metal salts and alkaline earth metal salts may include, for example, sodium, potassium, calcium or magnesium salts. All of these salts are prepared by conventional methods. Various salts of the compounds described herein are widely used in pharmacy and are described in books such as The Merck Index, which are well known to those skilled in the art. The ingredients used to form the active agent salts described herein are not critical as long as they are non-toxic and do not substantially contribute to the desired efficacy.

  A pharmaceutical homolog is a molecule that is similar to the original compound, other parts or other that do not readily ionize or degrade, such that one or more parts of the original molecule occur in a salt. Refers to molecules that have been modified with alternative groups. For example, if the hydrogen or chlorine moiety is replaced with a methyl group, the resulting molecule will be considered a homolog. As included herein, homolog-product alternatives must not destroy the anti-cough, anti-dermatitis or other activities of the original compound.

  Administration of medicaments prepared from the compounds described in the present invention can be done by any method that can introduce the compounds into the blood. Administration is oral, parenteral, intravenous, subcutaneous, topical or inhalation. In particular, topical administration, such as lotion or pimple, is used to treat dermatitis. Similarly, inhaled aerosols are used to treat stubborn cough. Injectable, topical or inhalation formulations contain a pharmaceutically acceptable carrier or diluent in combination with the active compound. Various other formulations of oral and injectable pharmaceuticals are described in Smith's US Pat. No. 5,166,207, incorporated herein by reference.

Examples The first studies described in Examples 1 to 3 were performed in patients with amyotrophic lateral sclerosis (ALS, also called Low Gering disease). At that time, it was believed that DM should be effective in preventing the progression of ALS and other neurological diseases. The studies described in Examples 1 to 3 were conducted in patients suffering from ALS (mostly adults over 40 years old), but the metabolism of DM in ALS patients was well known as an adult knowledge report or control population. There was no difference compared to the daily trial of a healthy volunteer.

Example 1: Urinary DM / DR ratio Six patients suffering from ALS were orally administered a single 60 mg dextromethorphan dose. Several hours later, urine samples were collected and the urine concentrations of dextromethorphan (DM) and dextrophan (DR) were measured as follows to determine the DM / DR ratio. A low DM / DR ratio suggests that DM is rapidly metabolized to DR metabolites in the patient. At different weeks, DM 60 mg and quinidine 150 mg were orally administered to the same patient and urinary DM and DR levels and DM / DR ratio were measured again.

  DM and DR urine levels without quinidine were measured by adding 40 mg of thebaine as an internal standard to 1 mL of urine. To this was added 2000 units of β-galactosidase in 1 mL of acetate buffer (0.1 M, pH 5.0). The mixture was incubated for 18 hours at 37 ° C. and then extracted by adding 1 mL of phosphate buffer (pH 12, 0.10 M) and 7 mL of n-butanol / hexane (10:90 v / v). After mixing and centrifuging, the organic phase is transferred to a clean tube, acidified with 400 μL of 0.01 N HCl, and 20 microliters (μL) of the aqueous phase is injected into a high performance liquid chromatography (HPLC) system. For HPLC, a phenyl column (flow rate: 1.2 mL / min) in which the mobile phase was equilibrated with acetonitrile: water (51:49, v / v) containing 10 mM KHPO4, 10 mM hexanesulfonic acid, pH 4.0 was used. The detection of thebaine, dextromethorphan and dextrophan was achieved with a fluorescence excited at 228 nm (Kratos FS-980 Fluorometer) without an emission blocking filter.

  Gas chromatography / mass spectrum (gc / ms) assay was used to measure dextromethorphan and dextrophan in the presence of quinidine. Conveniently, 500 nanograms (ng) of dimethacrine was added to 0.5 ml of urea sample. The urea pH was adjusted to 5.0 with 0.1 M acetate buffer (usually about 1.0 ml) and β-glucuronidase was added (2000 units / urine ml). The mixture was incubated and shaken at 37 ° C. for 18 hours. The urine was subsequently adjusted to pH 10-11 with 1.0 mL phosphate buffer and urine was extracted with 5 mL dichloromethane. The dichloromethane extract was extracted under nitrogen, reconstituted in 300 μL of BSTFA and injected into a gc-ms analyzer equipped with a SE-30 column. The gas chromatography conditions were: injector and transfer line temperature 250 ° C., oven 70 ° C. to 260 ° C. 20 ° C./min and source temperature 180 ° C. Detection was performed by selective ion tracking at m / z 271 for dextromethorphan, 294 for internal standard and 329 for dextrophan. Typical standard curves for dextromethorphan and dextrophan were provided. The assay sensitivity was 100 ng / ml for dextromethorphan and 400 ng / ml for dextrophan.

引き続いての試験を、ＡＬＳ患者および、１日試験に志願した健康な対照を含む５０名以上のヒトで行った。ＡＬＳ患者は、ＤＭおよびキニジンを一日を基本にして数週間投与され、一方対照者は、各薬一回量のみ投与された。結果は、表１のものと非常に類似した。 The results in Table 1 suggest that quinidine is an effective inhibitor of dextromethorphan metabolism. The DM / DR ratio of all test substances increases by at least 2 in the intensity range, usually 3 or more.

Subsequent studies were conducted in more than 50 humans, including ALS patients and healthy controls volunteered for the 1-day study. ALS patients received DM and quinidine on a daily basis for several weeks, while controls received only a single dose of each drug. The results were very similar to those in Table 1.

続いて、血漿濃度を、長期間にわたりデキストロメトルファンおよびキニジンを投与されている約１５名の他のＡＬＳ患者について測定した。結果は表２のデータと非常に類似した。 Example 2: Plasma concentration of DM Five patients received 120 mg of DM orally without quinidine co-administration. Ten to twelve hours later, blood was collected, plasma was isolated by centrifugation, plasma was analyzed, and DM concentration was measured using the Thevine / HPLC method.
The same patient was orally dosed with 60 mg DM (half the control dose) and 150 mg quinidine for different weeks. After 10-12 hours, blood was collected and plasma was analyzed for DM using thebaine / HPLC.
The results in Table 2 suggest that quinidine results in a large increase in DM concentration in plasma.

Subsequently, plasma concentrations were measured for approximately 15 other ALS patients who have been administered dextromethorphan and quinidine over time. The results were very similar to the data in Table 2.

Example 3: Dose-response study Further studies were conducted using a range of doses of DM to determine the amount of DM orally administered to patients and plasma concentrations after 10-12 hours (as described in Example 2). A dose-response curve for (measurement) was established. All patients received 150 mg quinidine daily. The results of these studies are shown graphically in FIG. 1, with the mean values shown as open squares and the standard dispersion range as vertical bars. The ascending line through the mean is almost a straight line; a curve based on more rigorous data probably indicates horizontal asymptomaticity.

  The test results in the above examples show that when quinidine is co-administered with DM, DM circulation in the blood increases and prolongs without causing serious side effects. Thus, co-administration of an antioxidant such as quinidine with DM can increase the effect of DM in a situation that depends on the concentration of DM circulating in the blood.

Example 4: Use of Other Antioxidants Because one patient is not quinidine resistant, the ability of several other candidate antioxidants to inhibit DM oxidation in various humans was tested. In these studies, DM was administered to various individuals who were all healthy volunteers. DM was given before and after taking the candidate antioxidant, and urine samples were collected and analyzed at appropriate times to determine the amount of DM and its substantial metabolite dextrophan (DRP) in the urine. A DM / DRP ratio of zero means that substantially all DM has been metabolized to DRP in the patient. A ratio higher than zero indicates that DM is not completely metabolized and there is an obvious amount of DM remaining in the urine.

  Tested with 12 healthy volunteers. The first urine sample was taken after the first DM administration before the antioxidant administration, the basal value was determined for that human, and for all volunteers the DM / DRP ratio used to obtain the control was 1.338. It was confirmed that, except for one person who was a “low metabolite”, it was a “high metabolite” with a basal DM / DRP ratio of 0.06 or less. Urine samples were analyzed using high performance liquid chromatography (HPLC) to make a quantitative assessment of the area contained in the chromatographic peak indicated by DM and its substantial oxidative metabolite (dextrophan, DRP). A DM / DRP ratio higher than zero suggests that DM is not completely metabolized, and an obvious amount of DM remains in the patient's urine; a ratio of zero indicates that substantially all DM is DRP Means it was metabolized.

  Candidate antioxidants were administered after measuring the basal DM / DRP ratio for each volunteer. These reagents included quinine sulfate, disulfiram, cimetidine, fluoxetine, propranolol and nortriptyline. After an appropriate delay, a second urine sample was obtained and analyzed. Each reagent was administered to 2 patients.

  The strongest result observed in these tests was quinam (quinidine sulfate). In one patient, the DM / DRP ratio increased from 0.02 (pre-kinin basis) to 0.09; in the other patient, the DM / DRP ratio increased from 0.00 to 0.05. When other candidate reagents are tested, the results show a high level of change in different individuals. For example, in 2 patients taking fluoxetine, one increased from 0.00 (pre-drug basis) to 0.11, while in other humans decreased from 0.03 to 0.00. In two patients taking propranolol, the DM / DRP ratio increased from 0.00 to 0.02 for one person, while the other decreased from 0.02 to 0.00. In 2 patients taking disulfiram, the DM / DRP ratio decreased from 0.06 to 0.08 in one patient, while the other decreased from 0.06 to 0.00. These levels of variability are not surprising since it is well known that humans have significant variability in their oxidase.

Example 5: Trials in patients with stubborn cough Three patients suffering from stubborn cough, all lasting several months, were tested under physician supervision. One patient had been previously treated with prednisone, an anti-inflammatory steroid with long-term adverse side effects. The second patient coughs for 8 months after respiratory infection and responds only temporarily to cough syrup containing codeine that is addictive and cannot be taken for a long time. A third patient suffers from a severe cough after a respiratory infection that broke some ribs. Antibiotics and anti-inflammatory inhalants for respiratory infections were prescribed because of suspected asthma symptoms.

  The first trial of 3 patients with stubborn cough showed very effective results with virtually no side effects.

  The 70-year-old female patient EAR suffered from a recurrent persistent non-wet cough for several years. This cough responded to prednisone administration but recurred immediately after prednisone ceased and continuous administration of prednisone was considered unacceptable. She tried various cough syrups and had little effect, her cough was both albuterol (β-adrenergic bronchodilator) or ipratropium bromide (anticholine) both administered using a nebulizer inhaler. Did not respond to bronchodilator). When she received 1 capsule / day of 75 mg of quinidine and 60 mg of DM, her cough stopped initially but recurred several days later. When the dose was increased to 2 capsules / day, the cough stopped and did not recur. There were no reports of side effects from her.

  A 38 year old male patient SP who did not smoke and had no history of asthma had had a persistent non-wet cough for about 8 months. Temporarily stopped when penicillin and codeine cough syrup were ingested, but recurred after cessation of codeine intake. For the first time after taking one capsule of 75 mg and 60 mg DM, cough almost completely stopped after a few days and almost no cough a day. There are no reports of side effects from him.

  A 43-year-old male patient RC who did not smoke and had no history of asthma had had a cough that began with an upper respiratory cervical virus infection followed by a bacterial infection for about 5 months. The cough was so severe that the ribs broke. When he first began to pay attention to the symptoms, the cough drained a yellow sputum. Although sputum was removed with antibiotics, cough continued despite treatment of suspected asthma conditions with inhalation treatment with flunisolide (an anti-inflammatory steroid) and albuterol. The cough did not substantially improve when taking only 1 capsule / day, but improved only within 90% of the first day after taking 2 capsules / day. He sometimes coughs, but his condition has improved so that he sometimes forgets to take medicine. There are no reports of side effects from him.

  In all cases, the patient was pleased with the results. The combined DM-antioxidant treatment is very effective in almost completely eliminating coughs that cannot be fully treated with other medications, and DM-antioxidant treatment has reported few side effects. The results clearly demonstrate the effectiveness and practicality of the present invention.

Example 6: Treatment of dermatitis During the first experiment, a white female patient BT suffering from ALS from the age of 60 was suffering from severe dermatitis including a disorder that manifested small spots. Her condition was diagnosed as atopic dermatitis. Its etiology is unknown. The patient was very ill with the disorder and had been affected for about 10 years. She has been prescribed many drugs (including various steroids such as prednisone) to control itching; the most recent prescription is “Doxepin”, a tricyclic antidepressant. These medications did not help much.

  Patients began with the first treatment of quinidine alone (150 mg / day) for one week. After she established that she had no adverse reactions, she also began DM at 30 mg / day and increased to 120 mg / day after one month.

  During the second month after initiating DM / quinidine treatment, it was found that the patient had an almost complete cessation of itchiness with partial healing of her disorder. A follow-up experiment after several weeks showed that the patient's skin lesions were completely healed with little trace.

  After seeing the results, further studies were conducted by a skin specialist at a nearby university. The first expert trial was a white male with severe but intermittent dermatitis. The recurrence disappeared within 2 weeks of starting treatment. Due to the intermittent nature of the patient's dermatitis, this result cannot be attributed entirely to the DM-antioxidant combination; nevertheless, recurrence occurs immediately after DM-antioxidant treatment is initiated. The absence strongly suggests that the DM-antioxidant combination probably has a substantially effective effect.

  After the above initial success, further studies were conducted to determine the effect of DM / quinidine for the treatment of dermatitis as follows. Patients suffering from dermatitis were first assessed for general physical condition, and the severity of the dermatitis condition was assessed by a doctor using “standardized disease activity score” or “disability score” . Standardized disease activity score or disability score is a score of 1 to 5 severity given by a doctor who is testing for both erythema and surface disorders on a certain area of the patient's body (size 1 to 5). is there. The total score was then calculated. The patient showed the severity of itching and rash from dermatitis on a subjective visual scale. DM / quinidine was taken in the form of 30 mg DM and 75 mg quinidine capsules per capsule. Patients were usually re-examined for 2 weeks and then 6 weeks or more after the initial examination and DM / quinidine capsule inoculation.

  Patient # 1 was a 40-year-old woman suffering from atopic eczema that became intense with stress. Patients were first evaluated using standardized disease activity scoring and filled with a subjective itching / rash analysis form. The initial score was 42. The patient had an initial itch score severe and rash severe to moderate.

  The patient reported nausea and headache as side effects, and medication was stopped after 5 days. She was then given a reduced amount of 30 mg / 25 mg DM / quinidine / day. Subsequently, the patient reported that the rash and itching were almost completely gone within 5 days. At the second week assessment, the patient's standardized disease activity score dropped dramatically to 13. The patient's face actually improved significantly. At 2 weeks, the patient reported that itching had a moderate to slight decrease and the rash had a moderate to slight decrease. After 4 weeks, the patient reported that headache side effects persist, even at reduced doses. However, the overall standardized disease activity scoring was lower than the original with a total score of 24. She reported severe to moderate itch and moderate rash.

  Patient # 2 was a 55 year old male with 20 years of chronic eczema. The rash was mainly on the thigh. The initial total standardized disease activity score was 12. The patient took 30 mg / 75 mg of DM / quinidine once a day for 5 days and then every 12 hours for the time being. The patient first reported severe itching and moderate rash. After about a month, the disability score remained at 12, but the patient reported that itching had decreased to a moderate range with low itching and the rash had decreased from a moderate to a slight range. The medication was eventually discontinued due to side effects.

  Patient # 3 was a 54 year old man who began to suffer from eczema 7 or 8 years ago. Initial physical examination showed terrible, fairly universal exfoliative eczema dermatitis, especially in his lower leg. The rash tended to be secondary infection. The first obstacle score was 112. The patient initially had moderate itching and a moderate moderate rash. The patient took 30 mg / 75 mg of DM / quinidine once a day for 5 days and then every 12 hours for the time being.

  Two and a half months later, the patient was evaluated again with a disability score of 90. The overall appearance was reported as improved and the rash was less reddish. However, patients reported the same rate of itching and rash. Patients reported some side effects, most of which disappeared after a few days. However, the patient reported a delay in reaching orgasm, and the side effects persisted as long as he continued on medication.

  Due to the reports of side effects in some patients, DM / quinidine administration as a topical cream may be considered for the treatment of dermatitis.

Example 7: Pain Treatment Subsequent pain studies were performed to determine whether the dextromethorphan / quinidine composition alleviates or prevents chronic pain. The effect of treatment was determined by patient interview and clinical evaluation of the patient by the research physician.

  The patient's interview asks for his or her current pain level on a 0 to 10 linear visual analog scale, which scales from “probably the most painful” to 10 “no pain” ". After several weeks of medication, patients were asked to show their current level of pain and rate of pain reduction using a linear visual analog pain relief score from 10 without pain relief to 0 with complete pain relief. .

  The amount of DM administered to the patient varies from individual to individual, but the total daily dose is up to 120 mg DM, in the form of capsules combined with quinidine. Quinidine was administered in individual patients, but was administered from twice the daily dose of DM to a total daily dose of 150 mg.

  Patient # 1 was a 73 year old woman diagnosed with diabetes 10 years ago. She reported that her legs were aching and aching for two years, and that she suffered a lot of trouble last year. The patient reports that she feels especially when she walks or stands and also at night. The patient does not recognize the same sensation in the hand and has no obvious neck or back pain. Neurological examinations were normal, and examination of the sensory area only showed reduced needle stick, light exposure and vibration sensation perception in the lower terminal limb. Neurological assessment confirms the diagnosis of both sensory and motor polyneuropathy.

  Prior to dosing, patients entered a visual analog scale for pain levels on April 11 and April 25, just prior to dosing. The patient initially rated her pain score from 3 to 4 with 10 being the worst scale. The patient started taking the drug immediately and took dextromethorphan 30 mg and quinidine 70 mg once a day.

  A follow-up test was conducted on May 9th, about a month later. The patient reported that the pain was significantly reduced and she felt better. She said the pain in her feet and the pain in her right foot were gone. Her sleep pattern was the same. She reported no side effects after taking DM / quinidine 30 mg / 70 mg twice daily. From this point, her amount was increased to dextromethorphan 60 mg and quinidine 75 mg twice a day.

  Two weeks later, on 19 May, the patient entered a visual analog pain relief score, her pain level was substantially improved, 10 was the worst 1 to 2, and she was significant It showed that pain relief was obtained. The overall impression is that her pain has improved. She reported having no side effects and feeling good. When itching occurred 3-4 times per week, it was reduced compared to the past. On May 23, the patient reported her pain levels were 0 and 1 with 0 being painless. The patient then stopped taking DM / quinidine and reported again on May 27 that she was good without a clear recurrence of pain. On May 31, 1994, she reported that the pain in her feet and hands recurred and she could not sleep well. The patient asked for repeated medications.

  Patient # 2 has a painful sensation on his right side. A 53 year old man. This patient suffered a stroke in 1991. The CT scan at that time showed left posterior cerebral infarction. The patient also had vascular artery disease, underwent bypass surgery in 1991, and suffered from diabetes and hypertension. Neurologically, there was visual field and sensory damage and right hand weakness. In the past 4-5 months, the patient complained of a sensation on the right side and a cold or hot sensation, which spanned the right face, arms, elbows and feet. I did not feel the left side. This unpleasant sensation, particularly at night, lasts for about 5 minutes at a time and does not wake up all day. A sensation of sensation is generally always present. The sensation is unpleasant and does not always hurt, but it is a great cause of depression. In addition, the patient sometimes felt some pain in the lower leg when tapping the back of the head, with hot noise and lightheadness in the ear. In addition, the patient reported tinnitus.

  The patient was diagnosed by the investigating doctor as having symptoms of typical DeJerrine-Lucy syndrome, a pain derived from a secondary thalamic disorder of stroke.

  The patient first rated his pain on a visual analog scale, with 10 being the worst, 9 to 10 at the peak and 5 and 6 at other times. Six weeks after starting 30 mg DM / 75 mg quinidine twice daily, patients were rated 7 and 8 at peak and 3 and 4 at other times using the visual analog scale. At this time the patient showed a level of pain relief of 2 and 3 with 0 being complete pain relief and 10 being no pain relief. One week after stopping medication, the patient showed a recurrence of pain levels between 7 and 8.

  Patient # 3 was a 63 year old man who had been diagnosed with diabetes for 25 years. He also suffered from arthritis and hypertension. The patient has complained of hand paralysis for two years. In addition, the patient complained of his last 3 years of foot pain. The aching pain prevented sleep and required analgesics. He also had pain in the buttocks and intermittent pain in the neck. Neurological examination showed a significant decrease in the sense of needle stick to the foot and finger ends and normal position and slightly reduced shaking sensation. The clinical evaluation was that the patient had primarily sensory neuropathy secondary to his diabetes.

  Before starting DM-quinidine treatment with 12-hour intervals of dextromethorphan 30 mg and quinidine 75 mg, the patient completed his pain level with two visible analog scales on April 11 and on May 9 just before the start of medication. did. The patient said 10 was on the worst scale, first between 5 and 6, and 1 month later between 6 and 7. The patient dosed DM-quinidine twice daily, one tablet of dextromethorphan 30 mg and quinidine 75 mg daily.

  On May 16, the patient said on the phone that the lightheaded and stomach were a little uncomfortable, but the others were good and continue to take medication. The patient subsequently came to the clinic on May 23, at which time his pain was reduced from time to time to the pain that was happening at night, generally about 70-80% less than previously experienced. I said. He didn't take other types of painkillers and said that the pain only happened once at night since he started taking the medication. He reported that he still had some intermittent electric shock. As a side effect, I reported a little nausea but not every day. At this point, his pain relief reported 0 between 1 and 2 in complete pain relief and his current level of pain between 0 and 1 without pain. The doctors tested evaluated the patient's level of pain as quite good.

  On May 31, the patient reported foot pain last week. He continued to take one tablet of 30/70 DM / quinidine. Two more weeks later he stopped taking the medication. On July 19, the patient completed another visible analog scale that describes his current pain level. He reported pain levels between 2 and 3 below the initial assessment, despite not continuing medication.

Example 8: Treatment of tinnitus Patient # 2 described in Example 7 had been suffering from chronic ear reverberation, also known as tinnitus, for several years. As part of the pain study, this patient took DM 30 mg / quinidine 75 mg capsule twice a day to reduce the thalamic pain syndrome resulting from a stroke three years ago. Approximately 2 weeks after taking DM / kindin capsules to relieve pain, the patient reported unexpected and complete elimination of chronic tinnitus. This event, along with studies that discovered NMDA receptors in the coclear system, a probable site of tinnitus disease, indicates that the DM / antioxidant combination is a promising treatment for tinnitus.

  These examples demonstrate that a combination of dextromethorphan and an antioxidant such as quinidine is effective in treating incurable diseases including incurable cough, chronic pain, dermatitis, tinnitus and sexual dysfunction. Prove it. While these inventions have been described with reference to presently preferred embodiments, it will be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.

FIG. 1 shows the relationship between DM oral dose and DM plasma concentration in patients taking quinidine 150 mg / day orally.

Claims (12)

A composition for the manufacture of a medicament for the treatment of chronic pain due to stroke, cancer, trauma and neuralgia , comprising a medically effective amount of dextromethorphan or a pharmaceutically acceptable salt thereof, and a medically effective A composition comprising an amount of a debrisoquin hydroxylase inhibitor selected from the group consisting of quinidine, quinine sulfate, disulfiram , fluoxetine, propranolol , nortriptyline and pharmaceutically acceptable salts thereof. 2. The composition of claim 1, wherein the debrisoquin hydroxylase inhibitor is quinidine or a pharmaceutically acceptable salt thereof. The composition of claim 1 or 2, wherein the dose of dextromethorphan is 20 mg / day to 200 mg / day. The composition according to any one of claims 1 to 3, wherein the dose of dextromethorphan is 20 mg / day to 150 mg / day. The composition according to any one of claims 1 to 4, wherein the dose of quinidine is 300 mg / day or less. The composition according to any one of claims 1 to 5, wherein the dose of quinidine is 50 mg / day to 300 mg / day. The composition according to any one of claims 1 to 6, wherein the dose of quinidine is 50 mg / day to 150 mg / day. 8. A composition according to any of claims 1 to 7, wherein the dose of dextromethorphan is 60 mg / day and the dose of quinidine is 75 mg / day. 8. A composition according to any preceding claim, wherein the dose of dextromethorphan is 120 mg / day and the dose of quinidine is 150 mg / day. The composition according to any one of claims 1 to 9, wherein the pharmaceutically acceptable salt is selected from the group consisting of alkali metal salts, free acid salts and free base salts. The composition according to any one of claims 1 to 10, wherein the pharmaceutically acceptable salt is selected from the group consisting of sulfate salts, chloride salts, sodium salts, potassium acids, calcium salts and magnesium salts. 12. A composition according to any one of claims 1 to 11 in an oral dosage form.

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