HK1080716B - A use of desmethylselegiline in manufacture of medicine for preventing and treating peripheral neuropathy - Google Patents

Description

Application of desmethylselegiline in preparing medicine for preventing and treating peripheral neuropathy

Title:

[0001] application of desmethylselegiline in preparing medicine for preventing and treating peripheral neuropathy

Statement regarding federally sponsored research and development

[0002] Not applicable to

About "appendix to microform"

[0003] Not applicable to

Background

1. Field of the invention

[0004] The present invention relates to the use of the selegiline metabolite R (-) -desmethylselegiline (also referred to as "desmethylselegiline" or "R (-) DMS") alone; the enantiomer ent-desmethylselegiline (also known as "S (+) desmethylselegiline" or "S (+) DMS") was used alone; or methods and pharmaceutical compositions employing combinations of the two enantiomers, such as racemic mixtures. In particular, the invention provides compositions and methods for using these agents to prevent or treat peripheral neuropathy, and in particular to prevent or alleviate symptoms associated with peripheral neuropathy caused by the disease or the receipt of toxic agents such as chemotherapeutic drugs.

2. Description of the related Art

[0005] The causes of peripheral neuropathy are of a wide variety, including genetically acquired diseases, systemic diseases, and the acceptance of toxic agents. The manifestation of this disease is dysfunction of the motor, sensory, sensorimotor or autonomic nerves.

[0006] The most important toxic agents causing peripheral neuropathy are therapeutic drugs, particularly those used to treat neoplastic diseases. In some cases, peripheral neuropathy is a major complication of cancer therapy and a major factor limiting the dose of chemotherapeutic drugs that can be administered to patients (Macdonald, Neurologic Clinics 9: 955-. This is true for the commonly used drugs cisplatin, taxol and vincristine (Broun, et al., am. J. Clin. Oncol.16: 18-21 (1993); Macdonald, Neurologic Clinics 9: 955-. The efficacy of chemotherapy is typically dose dependent; thus, increasing the dose can increase patient survival (Macdonald, Neurologic Clinics 9: 955-. The discovery of methods to prevent and alleviate dose-limiting peripheral neuropathological side effects allows for higher, i.e., more therapeutically effective, doses of these chemotherapeutic agents to be administered to patients.

[0007] In addition to potentially increasing the effectiveness of cancer chemotherapy, the discovery of new methods of treating peripheral neuropathy is of significant value in alleviating the afflictions of patients who may have a wide range of systemic and genetic diseases. In many cases, progressive neuropathy of the peripheral nervous system can be debilitating or fatal.

[0008] Currently, a few drugs are available for the treatment of peripheral neuropathy. Examples of drugs that have been found to be useful in the treatment of peripheral neuropathy include prednisone and IVIg for the treatment of chronic inflammatory or immune-mediated polyneuropathy; cyclophosphamide for the treatment of vasculitic neuropathy; famciclovir, carbamazepine, tricyclic antidepressants, gabapentin, topical lidocaine, ribavirin and other immunomodulators for the treatment of viral infectious neuropathy; and dapsone, clofazimine, rifampin, nifurolimus, and benznidazole for the treatment of bacterial infectious neuropathy. Ganciclovir and foscarnet are also useful in the treatment of cytomegalovirus multifocal peripheral neuropathy in HIV infected patients. Selegiline can also be used to reduce, reduce or eliminate symptoms associated with peripheral neuropathy, as described in U.S. patent 6,239,181, which is incorporated herein by reference. Peripheral neuropathy may be caused by, for example, genetic diseases, systemic diseases, physical injury, or the receipt of toxic or chemotherapeutic drugs.

[0009] Two different monoamine oxidases are known in the art: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). The cDNAs encoding these enzymes have different promoter regions and different exon portions, indicating that they are independently encoded at different gene sites. In addition, analysis of these two proteins showed that their respective amino acid sequences were different.

[0010] The first compounds found to selectively inhibit MAO-B were (R) -N- α -dimethyl-N-2-propynyl benzacetamine, so-called L- (-) -N- α -N-2-propynyl phenethylamine, (-) -deprenil, L- (-) -benzethynylamine (deprenyl), R- (-) -benzethynylamine or selegiline. Selegiline has the following structural formula:

[0011] selegiline is known to be useful and can be applied to a subject by a wide variety of routes and dosage forms of administration. For example, U.S. patent 4,812,481(Degussa AG) discloses the use of concomitant selegiline-amantadine in oral, enteral, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intraarterial, intracardiac, intramuscular, intraperitoneal, intradermal, and subcutaneous formulations. U.S. patent 5,192,550(Alza Corporation) describes a dosage form comprising an outer wall that is impermeable to selegiline and permeable to external fluids. Such dosage forms are suitable for buccal, sublingual or buccal administration of selegiline. Similarly, U.S. patent 5,387,615 discloses various selegiline compositions, including tablets, pills, capsules, powders, aerosols, suppositories, skin patches, parenteral agents, and oral liquids, including oil-water suspensions, solutions, and emulsions. Sustained release (depot) formulations and devices containing selegiline are also disclosed.

[0012] Although selegiline is a highly potent and selective MAO-B inhibitor, its dose-dependent specificity for MAO-B limits its use. The selectivity of selegiline in inhibiting MAO-B is important for its safe profile after oral administration. Inhibition of MAO-A at peripheral sites (e.g., gastric epithelium, hepatic parenchymA, and sympathetic nerves) can cause toxic side effects by interfering with metabolism, e.g., interfering with the metabolism of dietary tyramine. Tyramine is normally metabolized by MAO-A in the gastrointestinal tract, but when MAO-A is inhibited, tyramine absorption increases with consumption of tyramine-containing foods, such as cheese, beer, herring, and the like. This results in the release of catecholamines, which can contribute to the hypertensive response, the so-called "cheesy". Goodman and Gilman describe this effect as the most severe toxic reaction associated with MAO-A inhibitors.

[0013] Selegiline is metabolized to its N-demethyl analog and other metabolites. Structurally, the N-demethylated metabolite is the R (-) enantiomer of R (-) DMS of a secondary amine of the formula:

[0014] to this end, it is not known that R (-) DMS has MAO-related pharmacological effects, i.e., potent and selective inhibition of MAO-B. For purposes of the present invention, the characteristics of the MAO-related effects of R (-) DMS are more fully described in determining the usefulness of R (-) DMS. This property confirms that desmethylselegiline has very weak inhibitory effect on MAO-B and that there is no advantage in selectivity for MAO-B compared to selegiline.

[0015]For example, current characterization determined IC of selegiline for MAO-B in human platelets₅₀Is 5 x 10^-9IC of M, and R (-) DMS₅₀Is 4 x 10^-7M, suggesting that the latter is about 80-fold less potent than the former as a MAO-B inhibitor. The following are datA on MAO-B and MAO-A inhibition measured in the mitochondriA-rich part of the rat cortex, where similar properties as described above can be found.

Table 1: inhibition of MAO by selegiline and desmethylselegiline

[0016] As is clear from the above table, selegiline is approximately 128-fold more potent as an inhibitor of MAO-B than it is as an inhibitor of MAO-A, while R (-) DMS is approximately 97-fold more potent as an inhibitor of MAO-B than it is as an inhibitor of MAO-A. Thus, the selectivity of R (-) DMS for MAO-B seems to be approximately comparable to that for MAO-A, which is similar to selegiline, although its efficacy is substantially reduced.

[0017]Similar results were obtained in rat brain tissue. IC of selegiline on MAO-B₅₀Is 0.11X 10^-7IC of M, and R (-) DMS₅₀Is 7.3X 10^-7M, indicating that R (-) DMS is about 70 times less potent than selegiline as a MAO-B inhibitor. The two compounds were of low potency in inhibiting MAO-A in rat brain tissue, 0.18X 10 for selegiline^-5R (-) DMS is 7.0X 10^-5. Thus, in vitro R (-) DMS is about 39-fold smaller than selegiline in inhibiting MAO-A.

[0018] According to its above pharmacological profile, R (-) DMS is not advantageous as MAO-B inhibitor, either in terms of potency or in terms of selectivity, compared to selegiline. Indeed, the above in vitro data suggest that R (-) DMS acts as an MAO-B inhibitor, requiring about 70 times the amount of selegiline.

[0019] Heinonen, E.H. et al report the efficacy of R (-) DMS as an MAO-B inhibitor in vivo ("R (-) Desmolysegiene, a methyl of Selegiline, is an irreversible inhibitor of MAO-B in human subjects", conducted in acquired analysis "Seletiline in the treatment of Parkinson's Disease", from Research Reports from the department of Neurology, University of Turku, Turku, Finland, No.33(1995), pp.59-61, as described by Heinonen, R DMS has an inhibitory effect only five times that of Segiline in vivo, i.e. 10mg of Segiline is required to have the same effect as 1.8mg of Segiline in vitro, R (-) is about 60 times that of Segiline in vitro (small rat, about 60 times that of Segiline B, about 60 times that of Bartamine, h.o., JNeural Trans. (Suppl.): 32: 131(1990)). Thus, previous data reported by all investigators suggest that R (-) DMS is a less preferred, less potent MAO inhibitor than selegiline and therefore a less desirable therapeutic compound.

Disclosure of Invention

[0020] The present invention is based on the surprising discovery that R (-) DMS and its enantiomer, S (+) DMS, have the following structures:

they are particularly useful for producing selegiline-like effects in a subject despite a significant reduction in MAO-B inhibitory activity and a significant lack of improvement in MAO-B selectivity compared to selegiline. Surprisingly, R (-) DMS, S (+) DMS, and combinations thereof, such as racemic mixtures of the two, all or part of the symptoms associated with peripheral neuropathy are reduced, or eliminated. The present disclosure provides, inter alia, a method for protecting a patient from or treating a peripheral neuropathy caused by a toxic agent in a patient using R (-) DMS, S (+) DMS, or a combination of the two, in an amount sufficient to prevent, treat, reduce, or eliminate one or more symptoms associated with the peripheral neuropathy. Typically, the patient will be a human and the toxic agent will be a chemotherapeutic agent, e.g. a drug for the treatment of cancer. Although this method is effective against any toxic chemotherapeutic drug that causes peripheral neuropathy, it is most effective against drugs that have particularly severe neurological side effects, such as cisplatin, taxol, vincristine, and vinblastine.

[0021] The present disclosure provides novel pharmaceutical compositions wherein R (-) DMS, S (+) DMS, or a combination of the two, such as a racemic mixture, is used as an active ingredient. Also provided are novel methods of treatment, including methods of using such compositions. More specifically, the present invention provides:

[0022] (1) a pharmaceutical composition comprising an amount of R (-) DMS, S (+) DMS, or a combination of the two, such that periodic administration of one or more unit doses of the composition is effective to treat or ameliorate, in whole or in part, peripheral neuropathy in a subject receiving the unit dose. Such compositions may be formulated for non-oral or oral administration.

[0023] (2) A method of treating a peripheral neuropathy in a subject, such as a mammal, comprising administering to the mammal R (-) DMS, S (+) DMS or a combination of the two in a dosage regimen effective to prevent, treat, reduce or eliminate the peripheral neuropathy in whole or in part, such as daily administration, in a single dose or in a multiple dose regimen, at least about 0.0015mg/kg of body weight of the mammal, calculated on the basis of free secondary amine.

[0024] (3) a transdermal delivery system for treating a peripheral neuropathy in a subject, comprising one or more layers of a layered composite, wherein at least one layer comprises an amount of R (-) DMS, S (+) DMS, or a combination of the two, sufficient to provide a daily transdermal dosage of at least about 0.0015mg of free secondary amine per kg of body weight of the mammal.

[0025] (4) a therapeutic package for administration of a drug to a subject suffering from peripheral neuropathy to be treated, or a therapeutic package for administration of a drug. The kit comprises one or more unit doses, each such unit dose comprising an amount of R (-) DMS, S (+) DMS, or a combination of the two, such that periodic administration is effective to treat the peripheral neuropathy in the subject. The kit further comprises a finished drug container containing a unit dose of R (-) DMS, S (+) DMS, or a combination thereof, and further contains or includes a label indicating the method of use of the kit in the treatment of peripheral neuropathy. The unit dose may be adapted for oral administration, for example as a tablet or capsule, or the unit dose may be adapted for non-oral administration.

[0026] (5) A method of distributing R (-) DMS, S (+) DMS or both to a patient receiving treatment for peripheral neuropathy. The method comprises providing to the patient a treatment package containing one or more unit doses of desmethylselegiline, ent-desmethylselegiline, or a mixture of the two in an amount that can be administered periodically to effectively treat the patient for peripheral neuropathy. The package also includes a finished pharmaceutical container containing desmethylselegiline, ent-desmethylselegiline, or a mixture of the two, and a label indicating the method of use of the package in the treatment of peripheral neuropathy. The unit doses in this package may be adapted for oral or non-oral use.

[0027] A preferred embodiment of the present disclosure is a method of preventing or treating a peripheral neuropathy, which may be caused by a toxic agent; a genetic disease; systemic diseases or caused by compression, trauma or entrapment are treated by applying R (-) -desmethylselegiline, S (+) -desmethylselegiline or a mixture of R (-) -desmethylselegiline, S (+) -desmethylselegiline to the subject. Preferably, the desmethylselegiline enantiomer or enantiomers are used in an amount sufficient to prevent, reduce or eliminate one or more symptoms associated with such peripheral neuropathy. In a preferred embodiment, the subject is a mammal, more preferably a human or a domestic animal.

[0028] In a preferred embodiment, the toxic agent causing the peripheral neuropathy is selected from the group consisting of drugs, industrial chemicals, and environmental toxins. Preferably, the drug is chloramphenicol, colchicine, dapsone, disulfiram, amiodarone, gold, isoniazid, misonidazole, nitrofurantoin, perhexiline, propafenone, vitamin B6, phenytoin, simvastatin, tacrolimus, thalidomide, or zalcitabine, and the peripheral neuropathy caused by the drug can be treated or prevented using R (-) -desmethylselegiline, S (+) -desmethylselegiline, or a mixture of R (-) -desmethylselegiline and S (+) -desmethylselegiline. In another preferred embodiment, the toxic agent is acrylamide, arsenic, carbon disulfide, hexacarbons, lead, mercury, platinum, organophosphates, thallium, or a chemotherapeutic agent. The chemotherapeutic agent is preferably cisplatin, taxol, vincristine or vinblastine, and the chemotherapeutic agent is for treating cancer in a subject.

[0029] In a preferred embodiment, the genetic disease causing the peripheral neuropathy is selected from the group consisting of progressive neurotic peroneal muscle atrophy, progressive hypertrophic interstitial neuropathy, Riley-Day syndrome, porphyria, giant axonal neuropathy and friedreich movement disorder. In another preferred embodiment, the peripheral neuropathy caused by the systemic disease is selected from the group consisting of acquired primary demyelinating neuropathy, peripheral symmetric sensory polyneuropathy, peripheral symmetric sensory-motor polyneuropathy, vasculitic neuropathy, infectious neuropathy, idiopathic neuropathy; immune-mediated neuropathy; trophic-related neuropathy and paraneoplastic neuropathy. In a preferred embodiment, the acquired primary demyelinating neuropathy is Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP), Acute Inflammatory Demyelinating Polyneuropathy (AIDP), or Guillain-Barre syndrome. In another preferred embodiment, the infectious neuropathy is caused by herpes simplex virus, herpes zoster virus, hepatitis b virus, hepatitis c virus, HIV, cytomegalovirus, diphtheria, leprosy or lyme disease. In a further preferred embodiment, the systemic disease is alcoholic polyneuropathy, diabetes mellitus, uremia, rheumatoid arthritis, sarcoidosis, pernicious anemia or hypothyroidism. In a preferred embodiment, the compression causing the peripheral neuropathy is selected from carpal tunnel syndrome, ulnar neuropathy at the elbow or wrist, common peroneal nerve at the knee, tibial nerve at the knee, and sciatic nerve.

[0030] Another preferred embodiment of the present disclosure is a method of treating a subject with cancer, comprising:

a) administering to the subject a chemotherapeutic agent known to have a toxic effect on peripheral nerves, wherein the chemotherapeutic agent is administered at a dose effective to delay the progression of the cancer; and

b) simultaneously administering to the patient R (-) -desmethylselegiline, S (+) -desmethylselegiline, or a mixture of R (-) -desmethylselegiline and S (+) -desmethylselegiline at a dose effective to reduce or eliminate peripheral neuropathy associated with the chemotherapeutic agent.

If appropriate, the dosage of the chemotherapeutic agent can be increased to optimize the therapeutic effect of the agent, while the use of R (-) -desmethylselegiline, S (+) -desmethylselegiline or a mixture of R (-) -desmethylselegiline and S (+) -desmethylselegiline minimizes the toxic effects of the agent on peripheral nerves. Thus, the subject can be administered this greater dose of chemotherapeutic agent while peripheral neuropathy, which is often associated with the greater dose, is reduced or eliminated.

[0031] A preferred embodiment of the present disclosure is a method of preventing or treating large-fiber peripheral neuropathy, small-fiber peripheral neuropathy, sensory peripheral neuropathy, motor peripheral neuropathy, sensorimotor peripheral neuropathy, or vegetative peripheral neuropathy in a subject in need of such prevention or treatment by applying R (-) -desmethylselegiline, S (+) -desmethylselegiline, or a mixture of R (-) -desmethylselegiline and S (+) -desmethylselegiline to the subject. Preferably, the desmethylselegiline enantiomer or enantiomers are employed in an amount sufficient to prevent, reduce or eliminate one or more symptoms associated with the particular peripheral neuropathy. In a preferred embodiment, the subject is a mammal, more preferably a human or a domestic animal.

[0032] In a preferred embodiment, the large-fiber peripheral neuropathy is large-fiber sensory neuropathy or large-fiber motor neuropathy, which is caused by dysfunction or pathological change in large myelinated axons. In another preferred embodiment, the small-fiber peripheral neuropathy is caused by a dysfunction or pathological change in small myelinated or small unmyelinated axons. In a further preferred embodiment, the autonomic peripheral neuropathy is caused by dysfunction of peripheral autonomic nerves, and the peripheral autonomic nerves preferably comprise small myelinated nerves.

[0033] A preferred embodiment of the present disclosure is a method of preventing or treating a motor neuron disorder in a subject in need of such prevention or treatment by applying to the subject R (-) -desmethylselegiline, S (+) -desmethylselegiline or a mixture of R (-) -desmethylselegiline and S (+) -desmethylselegiline. Preferably, the desmethylselegiline enantiomer or enantiomers are employed in an amount sufficient to prevent, reduce or eliminate one or more symptoms associated with such motor neuron diseases. In a preferred embodiment, the subject is a mammal, more preferably a human or a domestic animal. In another preferred embodiment, the motor neuron disease is caused by degeneration of an upper motor neuron, a lower motor neuron, or both an upper and a lower motor neuron. In a further preferred embodiment, the motor neuron disease is selected from the group consisting of progressive bulbar paralysis, spinal muscular atrophy, Kugelberg-Welander syndrome, Duchenne paralysis, Postpolio syndrome, Werwell-Hoodian disease, Kennedy's disease and benign focal muscular atrophy.

[0034] In a preferred embodiment, R (-) -desmethylselegiline or S (+) -desmethylselegiline is used in substantially enantiomerically pure form. In other preferred embodiments, R (-) -desmethylselegiline and/or S (+) -desmethylselegiline is used as a free base or as an acid addition salt. Such acid addition salts are preferably the hydrochloride salts. In another preferred embodiment, R (-) -desmethylselegiline, S (+) -desmethylselegiline, or a combination of both is administered orally or non-orally. These desmethylselegiline enantiomers are preferably employed by a route that avoids absorption of these desmethylselegiline enantiomers from the gastrointestinal tract. Preferred non-oral routes of administration are transdermal, buccal, sublingual and parenteral. In yet another preferred embodiment, R (-) -desmethylselegiline and/or S (+) -desmethylselegiline is used in a dose of 0.01 to 0.15 mg/kg/day, based on the weight of the free amine.

[0035] Another preferred embodiment of the present disclosure is a pharmaceutical composition comprising R (-) -desmethylselegiline, S (+) -desmethylselegiline, or a mixture of R (-) -desmethylselegiline and S (+) -desmethylselegiline, and a second therapeutic agent for the treatment of peripheral neuropathy. In a preferred embodiment, one or more therapeutic agents are included in the pharmaceutical composition. In another preferred embodiment, the pharmaceutical composition has an amount of R (-) -desmethylselegiline, S (+) -desmethylselegiline, or a combination of R (-) -desmethylselegiline and S (+) -desmethylselegiline in combination with a second therapeutic agent, such that one or more unit doses of the composition are effective to treat, prevent, reduce, or eliminate a peripheral neuropathy in a subject. In other preferred embodiments, the R (-) DMS and/or S (+) DMS used is a free base or an acid addition salt. The acid addition salt is preferably the hydrochloride salt. In another preferred embodiment of the present disclosure, the second therapeutic agent for treating peripheral neuropathy is selected from the group consisting of prednisone, IVIg, cyclophosphamide, famciclovir, carbamazepine, tricyclic antidepressants, dapsone, clofazimine, rifampin, nifurolimus, benznidazole, gabapentin, ganciclovir, foscarnet, cidofovir, acyclovir, topical lidocaine and ribavirin.

[0036] In other preferred embodiments, the R (-) DMS, S (+) DMS or combination of both enantiomers of the pharmaceutical composition is present in a unit dose of about 0.015 to about 5.0mg/kg, more preferably about 0.6 to about 0.8mg/kg, calculated as the free secondary amine. In another preferred embodiment, the R (-) DMS, S (+) DMS, or a combination of both enantiomers in a unit dose of the pharmaceutical composition is from about 1.0mg to about 100.0mg, more preferably from about 5.0mg to about 10.0 mg. In yet another preferred embodiment, the pharmaceutical composition is for oral administration, non-oral administration, or transdermal administration. In a preferred embodiment the pharmaceutical composition is a transdermal patch.

Brief Description of Drawings

[0037] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0038]FIG. 1: HPLC chromatogram of purified R (-) DMS (Microorb MV cyano column). The purity of the R (-) DMS formulation was determined by HPLC on a Microsorb MV cyano column and the results are shown in figure 1. The column had a volume of 4.6mm X15 cm and was expanded with a mobile phase at a flow rate of 1.0 ml/min90% of the total weight of the powder is 0.01M H₃PO₄(pH3.5) and 10% acetonitrile. The column was started at 40 ℃ and the effluent was monitored at a wavelength of 215 nm. The chromatogram showed that at 6.08 min a major peak appeared and that it contained 99.5% of all light absorbing species eluting from this column. No other peak was greater than 0.24%.

[0039] FIG. 2 is a drawing: HPLC elution profile of R (-) DMS (Zorbax Mac-Mod C18 column). The purity of the same formulation, identical to that analysed in the experiment of FIG. 1, was analysed by HPLC on a Zorbax Mac-Mod SB-C18 column (4.6 mm. times.75 mm). The effluent was monitored at 215nm and the results are shown in figure 2. More than 99.6% of the light absorbing species appeared in a single large peak, which eluted at a time of 2-3 minutes.

[0040]FIG. 3: r (-) DMS Mass Spectrometry. Mass spectra of purified R (-) DMS were obtained and are shown in FIG. 3. The mass spectrum and molecular weight are 209.72amu, and the molecular formula is C₁₂H₁₅The molecules of N-HCl are identical.

[0041]FIG. 4 is a drawing: infrared spectrum (KBr) of purified R (-) DMS. Infrared spectroscopy analysis of the R (-) DMS formulation is shown in FIG. 4. The solvent is CDCl₃。

[0042]FIG. 5: NMR spectrum of purified R (-) DMS. Dissolving the preparation of purified R (-) DMS in CDCl₃In the middle, at 300nm¹H NMR spectroscopic analysis. The results are shown in FIG. 5.

[0043] FIG. 6: HPLC chromatogram of S (+) DMS. The purity of the S (+) DMS preparation was checked by reverse phase HPLC on a 4.6min × 75min ZorbaxMac-Mod SB-C18 column. The elution profile was monitored at 215nm and is shown in FIG. 6. At about 3 minutes, a major peak appears in the profile, containing more than 99% of the total light absorbing species eluted from the column.

[0044] FIG. 7: mass spectrum of purified S (+) DMS. Mass spectrometry was performed on the same formulation detected in figure 6. The mass spectrum is shown in FIG. 7 and is consistent with the structure of S (+) DMS.

[0045] FIG. 8: infrared Spectrum (KBr) of purified S (+) DMS. The S (+) DMS formulation discussed in fig. 6 and 7 was examined by infrared spectroscopy.

[0046]FIG. 9: MAO-B inhibition in the hippocampus in guinea pigs. Guinea pigs were administered varying doses of selegiline, R (-) -desmethylselegiline and S (+) -desmethylselegiline daily for 5 days. The animals were then sacrificed and MAO-B activity was measured in hippocampal portions of the brain. Results are expressed as percent inhibition compared to control animals hippocampal MAO-B activity and are shown in FIG. 9. These maps are used to estimate the ID of each agent₅₀And (4) dosage. Selegiline ID₅₀About 0.008 mg/kg; about 0.2mg/kg of R (-) DMS; about 0.5mg/kg of S (+) DMS.

Detailed Description

[0047] In the following description, reference will be made to various methodologies well known to those skilled in the medical and pharmaceutical arts. These methodologies are described in standard reference books which set forth the principles of these guidelines.

[0048] The present disclosure relates to the use of R (-) DMS, S (+) DMS or a combination of R (-) DMS and S (+) DMS for the prevention or treatment of peripheral neuropathy. Peripheral neuropathy is a common manifestation of many genetic and systemic diseases. The nervous system is divided into two parts: the Central Nervous System (CNS) and the Peripheral Nervous System (PNS). The CNS consists of the brain and spinal cord, while the PNS consists of all other nerves. The CNS is located in the dorsal cavity of the body, which consists of the cranial cavity that houses the brain and the spinal canal that houses the spinal cord. As used herein, the term "peripheral neuropathy" refers to a dysfunction or pathological change in the peripheral nerve. Peripheral nerves located in the PNS include, but are not limited to, cranial nerves (except the second pair), spinal nerve roots, dorsal root ganglia, peripheral nerve trunks and their terminal branches, and the peripheral autonomic nervous system. The CNS uses the peripheral nervous system to communicate with the whole body. Any damage to the peripheral nervous system will impair this connection.

[0049] Peripheral neuropathy, the so-called peripheral neuritis, is a manifestation of many disorders that can cause damage to peripheral nerves. Many different symptoms are associated with peripheral neuropathy, which is a manifestation of this damage. The symptoms vary widely depending on the cause of the peripheral neuropathy and the particular type of nerve damaged. For example, these symptoms may depend on whether the condition affects sensory nerve fibers, which are nerve fibers that transmit sensory information from the affected area to the CNS, or motor nerve fibers, which are nerve fibers that transmit impulses from the CNS to muscles and coordinate motor activity, or both. Peripheral neuropathy was clinically diagnosed based on subject clinical history, physical examination, use of electromyography and Nerve Conduction Studies (NCS), autonomic nerve testing, cerebrospinal fluid analysis, and nerve biopsy. Because so many different disorders manifest as peripheral neuropathy by affecting a range of neurological types, clinical assessment and diagnosis of the causes of peripheral neuropathy can be difficult.

[0050] Peripheral neuropathy can be classified by the type of fiber that is primarily affected. Peripheral nerves consist of different types of axons. For example, large-fiber peripheral neuropathy typically affects large myelinated axons, including motor axons and sensory axons, which are responsible for transmitting vibrations, proprioception, and photo-touch. The somatosensory nerve is a myelinated fiber whose cell body is in the dorsal root ganglion (posterior horn). Somatic motor fibers are medullary fibers with their cell bodies in the anterior horn and brain stem of the spinal cord. Small-fiber peripheral neuropathy mainly includes the following fiber types: 1) small myelinated axons, including vegetative nerve fibers and sensory axons, responsible for transmitting sensations of photosensory, pain, and temperature; 2) small, unmyelinated axons, which are sensory fibers and contribute to the sensation of pain and temperature. Many visceral nerves are non-medullary fibers that include sensory and motor components. Any type of peripheral nerve dysfunction, such as sensory, motor, sensorimotor, autonomic or enteric nerves, may manifest as various symptoms as discussed herein.

[0051] Peripheral neuropathies include, but are not limited to, hereditary peripheral neuropathy; primary peripheral neuropathy; immune-mediated peripheral neuropathy; infectious peripheral neuropathy; paraneoplastic peripheral neuropathy; toxic, nutritional and drug-induced peripheral neuropathy; and traumatic and compressive peripheral neuropathy. The object of the present disclosure is to prevent, treat, reduce or eliminate symptoms associated with peripheral neuropathy using R (-) DMS, S (+) DMS or a racemic mixture of R (-) DMS and S (+) DMS.

[0052] The response patterns in which nerves in the PNS can respond to injury or damage are limited. In the periphery, the cell body is generally fasciculated, the so-called ganglion. One nerve is a bundle of axons, which together travel in this peripheral nerve. An axon is a single process of a nerve cell that normally conducts efferent (exiting) nerve impulses of the cell body and its remaining processes (dendrites) to the target cell. Axons can transmit nerve impulses (action potentials) to a distance. This efferent nerve controls voluntary and involuntary activity. Afferent parts of the PNS convey sensory information of the body to the CNS, while efferent parts of the PNS convey information of the CNS to the body. In PNS, myelinated axons are surrounded by myelin, which is provided by cells called schwann cells. Myelinated axons are surrounded by concentric layers of cell membranes derived from Schwann cells of the peripheral nervous system. The presence of myelin sheath around axons increases the speed at which it can conduct nerve impulses along its length. Along axons, open spaces that do not insulate axons appear between myelin sheaths. The conduction of nerve impulses is accelerated because nerve impulses effectively jump from one space to another between isolated cells.

[0053] Axonopathy is a lesion that occurs at the axonal level. This damage can cause a breakdown (e.g., trauma) of this axon, which can cause degeneration of the axon and myelin sheath distal to the site of injury, also known as Wallerian degeneration. In many toxic and metabolic injuries to PNS, the most distal part of the axon is denatured, which also leads to the destruction of the myelin sheath (also known as "reverse death," or length-dependent neuropathy). There are also many peripheral neuropathies involving mixed axonal degeneration and demyelination. Myelin disease, or acquired demyelinating neuropathy, causes myelination, while the remaining axons are relatively unaffected. By increasing the survival of schwann cells, R (-) DMS, S (+) DMS or a combination of R (-) DMS and S (+) DMS can also treat peripheral neuropathy, thereby reducing demyelination of axons. Neuronal disorders occur at the level of dorsal root ganglia or motor neurons, followed by degeneration of peripheral processes.

[0054] Peripheral neuropathy may include damage to a single nerve or group of nerves (mononeuropathy), or it may involve multiple nerves (polyneuropathy). Peripheral neuropathy can be focal, multifocal, symmetrical, or asymmetrical, and it can be caused by pressure injury, such as by direct injury, or by compression of nerves by other adjacent body structures. Trauma, compression and ligation (entreprent) are common causes of focal nerve injury. Compression may be caused by a peripheral nerve tumor, a tumor that presses against nerve tissue, abnormal bone growth, a cyst or other accumulated fluid or tissue that presses against a nerve, a model, a splint, a brace, a crutch, or other implement. Nerve damage can be caused by being in a narrow location or remaining in one location for an extended period of time. When a nerve passes through a narrow space, compression on the nerve can cause a peri-ligation neuropathy, and ischemia complicates the mechanical factors.

[0055] One class of peripheral neuropathies is focal neuropathy. Focal peripheral neuropathy includes, but is not limited to, common compression neuropathy, but also includes acute arterial occlusion, carpal tunnel syndrome, ulnar neuropathy at the elbow (chronic ulnar paralysis) or wrist, proximal median nerve at the elbow, median nerve at the wrist, anterior interosseous nerve, radial nerve of the upper arm, sciatic nerve, peroneal neuropathy at the head or knee, tibial nerve at the knee, lateral femoral cutaneous nerve (paresthesia femoral pain), lateral femoral cutaneous nerve at the thigh, or spinal accessory nerve at the cervical posterior triangle. In addition, ischemia is considered to be the basis of mild peripheral neuropathy of polycythemia.

[0056] Another type of peripheral neuropathy is sensory neuropathy. Sensory peripheral neuropathy typically includes dysfunction or damage to peripheral sensory neurons, which may manifest as loss of sensation, numbness, tingling, abnormal sensation (paresthesia), burning, pain (neuralgia), decreased sensation, and/or weakness defining an area of a joint location sensation, such as an extremity, or elsewhere. For example, the subject may feel numb fingers and/or toes. Sensation often starts in the foot or hand and progresses towards the center of the body. Sensory peripheral neuropathy may be caused by degeneration of the axonal portion of nerve cells or may be caused by loss of the myelin sheath surrounding nerve cell axons.

[0057] Motor neuropathy is another type of peripheral neuropathy. Motor peripheral neuropathy typically involves dysfunction or impairment of motor fibers, which can impair activity or function in the nerve support region because impulses to this region are blocked. The nervous excitation to the muscle group is impaired and can cause weakness, reduced activity, reduced or absent control of activity, difficulty or weakness in the movement of parts of the body (paralysis), loss of muscle function or sensation, muscle atrophy, foot pain, or muscle twitching (spontaneous contractions). Such dysfunction is typically manifested as clumsy, or muscle weakness, in accomplishing the physical task. For example, the patient may have difficulty in buttoning or combing. Muscle weakness can cause a patient to become exhausted after a relatively small amount of effort and in some cases can present difficulties in standing or walking.

[0058] Loss of nerve function, lack of nerve excitation, unused affected areas, inactivity, or lack of weight bearing can also cause structural changes in muscle, bone, skin, hair, nails, and body organs. Peripheral motor neuropathy manifests itself in subjects as muscle wasting or atrophy (loss of muscle mass).

[0059] Motor neuropathy often includes many acquired primary demyelinating neuropathies, such as Guillain-Barre syndrome. Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP); diabetes mellitus; porphyria; an osteosclerotic myeloma; waldenstrom's macroglobulinemia; castleman's disease; monoclonal gammopathy of unknown significance; acute arsenic polyneuropathy; lymphoma; diphtheria; HIV/AIDS; lyme disease; hypothyroidism; and vincristine toxicity can cause other proximal symmetrically-motile polyneuropathies. Demyelinating peripheral neuropathies include, but are not limited to, CIDP, osteoporotic myeloma, diphtheria, perhexiline toxicity, chloroquine toxicity, FK506(tacrolimus) toxicity, procainamide toxicity, zimelidine toxicity, monoclonal protein-associated peripheral neuropathy, hereditary motor and sensory peripheral neuropathies types 1 and 3, and genetic susceptibility to stress paralysis.

[0060] Motor neuropathy can also occur in Motor Neuron Disease (MND) as MND can include damage to peripheral motor neurons. MNDs comprise a group of serious neurological diseases characterized by progressive degeneration of motor neurons, without sensory abnormalities. MNDs may affect superior motor neurons, inferior motor neurons, or both superior and inferior motor neurons. Here, the superior motor neuron is a nerve leading from the brain to the spinal cord, and the inferior motor neuron is a nerve leading from the spinal cord to the muscle of the body. Damage to superior motor neurons is manifested by spasticity, hyperreflexia, and extensor plantar signs. Damage to inferior motor neurons is manifested by progressive wasting (atrophy) and weakness of muscles that lose neural support. The MND of a person is characterized by paralysis, as well as various other motor characteristics. MNDs include, but are not limited to, amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), progressive bulbar palsy, spinal muscular atrophy (all types), Kugelberg-Welander syndrome, Duchenne's palsy, post-polio syndrome, Wer-Hoodian's disease, Kennedy's disease, juvenile spinal muscular atrophy, benign focal muscular atrophy, and infantile spinal muscular atrophy.

[0061] In most MNDs, both superior and inferior motor neurons degenerate. For example, ALS is characterized by muscle weakness, rigidity, and spontaneous contractions (muscle twitches). In progressive bulbar paralysis, only the muscles involved in speech and swallowing are affected. A less common type of MND includes selective degeneration, either superior motor neuron degeneration (such as primary lateral sclerosis) or inferior motor neuron degeneration (progressive muscular atrophy). There is considerable overlap between these types of MNDs. R (-) DMS, S (+) DMS or a combination of R (-) DMS and S (+) DMS can be used to treat MND whether the disease involves superior motor neurons, inferior motor neurons, or both superior and inferior motor neurons.

[0062] Sensorimotor neuropathy is another type of peripheral neuropathy. Sensorimotor neuropathy involves both sensory and motor neurons, and typically appears as a mixed nerve with afferent and efferent fibers. Many toxic and metabolic peripheral neuropathies present as peripheral symmetric or reverse-dead lesions. Peripheral symmetric sensorimotor polyneuropathy is caused by the following factors: endocrine diseases such as diabetes, hypothyroidism and acromegaly; nutritional disorders such as alcoholism, vitamin B12 deficiency, folic acid deficiency, Whipple's disease, vitamin B1 deficiency, gastric restriction and post-gastrectomy; infectious diseases such as HIV and lyme disease; connective tissue diseases such as rheumatoid arthritis, polyarteritis nodosa, systemic lupus, erythroderma, Churg-Strauss nodular vasculitis, and cryopglobulinemia; toxic neuropathy caused by acrylamide, carbon disulfide, dichlorophenoxyacetic acid, ethylene oxide, six carbon, carbon monoxide, organophosphate, or gluesnifing; a drug therapy such as vincristine, taxol, nitric oxide, colchicine, isoniazid, amitriptyline, ethambutol, disulfiram, cimetidine, phenytoin, dapsone, alpha-interferon, lithium, didanosine, vitamin B6, metronidazole, hydralazine, cisplatin, thalidomide, vitamin B6, amiodarone, chloroquine, suramin or gold; hypophosphatemia; cancerous axonal sensorimotor polyneuropathy; lymphomatous axonal sensorimotor polyneuropathy; sarcoidosis; amyloidosis; gouty neuropathy; or metallic neuropathy caused by chronic arsenic poisoning, mercury, gold, or thallium.

[0063] The autonomic nervous system is the part of the peripheral nervous system that controls involuntary or semi-involuntary functions, such as the control of internal organs. The autonomic nervous system, also known as the visceromotor nervous system, includes neurons that relay efferents of the motor nerves to the heart muscle, smooth muscle and glands. The autonomic nervous system is generally divided into two parts: a parasympathetic portion and a sympathetic portion; the functional activities of these two parts are usually opposite to each other. For example, the parasympathetic portion controls the function of increasing heart rate, while the sympathetic portion generally acts to decrease heart rate.

[0064] Vegetative peripheral neuropathy typically includes dysfunction of peripheral vegetative nerves, which can cause changes in organ activity and can cause symptoms such as blurred vision, diplopia, reduced or anergy of sweating (anhidrosis), dizziness or fainting often associated with decreased blood pressure (orthostatic hypotension), decreased thermoregulatory capacity, intolerance, gastric or intestinal dysfunction such as nausea, vomiting, constipation or diarrhea, small amounts of post-prandial satiety (premature satiety), unintended weight loss (greater than 5% of body weight), abdominal swelling, bladder dysfunction (e.g., urinary incontinence or dysuria), sexual dysfunction (e.g., male impotence), arrhythmia, and other toxicities.

[0065] Diabetes (hereinafter also referred to as "diabetes") is a systemic disease that mainly affects the peripheral nervous system. Diabetes is also the most common cause of peripheral neuropathy. In fact, every individual with diabetes for more than 10 to 15 years has some signs of neuropathy. Complications of diabetes can affect virtually every aspect of the nervous system, including the central nervous system and its supporting structures. Abnormally high concentrations of glucose in the circulating blood (called hyperglycemia) can be found in diabetic patients. Diabetes is a very important risk factor for stroke, peripheral neuropathy, retinopathy and nephropathy. Other complications associated with diabetes are diabetic ketoacidosis and coma, hyperosmolar nonketotic coma, chronic diabetic encephalopathy, cataract formation and glaucoma.

[0066] Peripheral neuropathy is the most common complication of some diabetes. These diseases are known as diabetic neuropathy. About two-thirds of diabetic patients have one or more forms of diabetic peripheral neuropathy. Some symptoms of diabetic neuropathy are pain, which can be dull, burning, stabbing, tenderness or soreness and spastic pain; paresthesia, which can be manifested as a cold, numbing, tingling or burning sensation; and fibular tenderness. Peripheral neuropathies are generally classified into symmetric and asymmetric neuropathies. Most diabetic neuropathy affects primarily the lower extremity endings with symmetric sensorimotor polyneuropathy. Diabetic neuropathy can affect both sensory and motor peripheral nerves, as well as the autonomic nervous system.

[0067] Diabetic neuropathy can be small fiber sensory neuropathy, often accompanied by early painful paresthesia, or loss of pain and temperature sensations accompanied by peripheral reflex and proprioceptive deficits. Diabetic neuropathy cachexia, which usually occurs after the initiation of insulin injections, is a type of severe painful diabetic neuropathy that occurs in humans. Diabetic neuropathy can also manifest as large fiber sensory neuropathy; vegetative neuropathy (both sympathetic and parasympathetic nervous system are involved); motor neuropathy, also known as diabetic muscular atrophy; mixed polyneuropathy, such as mixed sensory-plant-motor polyneuropathy; focal compressive neuropathy; and dry neuropathy. R (-) DMS, S (+) DMS or a combination of R (-) DMS and S (+) DMS can be used to treat patients with any diabetic neuropathy manifestations.

[0068] Chronic alcoholics can suffer from peripheral neuropathy, which is often painful. The main symptoms of alcoholic peripheral neuropathy (or alcoholic toxic polyneuropathy) are burning, stinging and numbness of the feet and hands. Loss of sensation is often accompanied by painful hypersensitivity of the foot, loss of ankle reflex, and mild peripheral weakness. Alcoholism peripheral neuropathy may be caused by the toxic effects of ethanol, malnutrition, or both. Peripheral painful peripheral neuropathy is also common in the late stages of HIV infection. The main symptom of this peripheral neuropathy is persistent burning discomfort, usually on the foot, with some loss of sensation; motility is usually less affected. Acute and chronic inflammatory demyelinating peripheral neuropathy may also occur in asymptomatic populations with other HIV infections. R (-) DMS, S (+) DMS or a combination of R (-) DMS and S (+) DMS is useful for treating patients with alcoholism polyneuropathy, as well as patients infected with HIV and suffering from peripheral neuropathy.

[0069] Some subjects with systemic vasculitis also often suffer from peripheral neuropathy. Typically, vasculitic peripheral neuropathy is a consequence of ischemia, a neurotrophic vascular inflammation caused by inflammatory lesions. Normally nerves receive an adequate blood supply and are relatively resistant to ischemic injury. Thus, the occurrence of vasculitic peripheral neuropathy suggests the existence of a wide range of vascular diseases. Approximately 30% of patients with vasculitic peripheral neuropathy have symmetric polyneuropathy, approximately 30% have asymmetric polyneuropathy, and approximately 40% have mononeuropathy. Vasculitic peripheral neuropathy is found in large part in systemic vasculitis, polyarteritis nodosa, rheumatoid vasculitis, Sjogren's syndrome, Wegener's granulomatosis, and Churg-Strauss syndrome.

[0070] Inflammatory Sensory Polyneuropathies (ISPs) are a syndrome involving relatively simple sensory loss (particularly proprioception) and loss of reflexes. The sensory symptoms of ISPs can occur suddenly or can develop slowly, and sensory ataxia is often severe and debilitating. Early well described cases of ISPs are paraneoplastic and when diagnosing ISPs, the potential for underlying malignancies, particularly small cell lung cancer, should be considered. Other conditions associated with ISPs, such as those associated with sjogren's syndrome, are also reported, where T lymphocyte infiltration of the dorsal root ganglion is indicated. R (-) DMS, S (+) DMS or a combination of R (-) DMS and S (+) DMS are useful for treating patients with vasculitic peripheral neuropathy, as well as ISP patients.

[0071] It is estimated that about 5% of patients entering the intensive care unit may develop peripheral neuropathy, which may be severe. It is characterized by elongation of ICU, sepsis and organ system failure, which are common in many of the cited cases. R (-) DMS, S (+) DMS or a racemic mixture of the two can be used to treat patients in ICU to prevent or treat peripheral neuropathy.

[0072] There are many causes of peripheral neuropathy, which include, but are not limited to, toxic agents such as chemotherapeutic drugs, genetic diseases, systemic diseases, and nerve damage caused by trauma or compression. Axonal degeneration will slow or block impulse conduction through the nerve at the site of degeneration. Systemic causes of peripheral neuropathy include diseases that affect nerve connective tissue or affect the blood supply to nerves, as well as metabolic or chemical diseases, and also other diseases that damage peripheral nerve tissue.

[0073] The particular systemic disease, localized disease, genetic disease, toxic agent or trauma causing peripheral neuropathy is not critical to the present disclosure. Thus, R (-) DMS, S (+) DMS or a mixture of R (-) DMS and S (+) DMS is effective against peripheral neuropathy associated with systemic diseases including, but not limited to: acute inflammatory or immune-mediated peripheral neuropathy, such as Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP), Acute Inflammatory Demyelinating Polyneuropathy (AIDP), Guillain-Barre syndrome, Acute Motor Axonopathy (AMAN), Acute Motor and Sensory Axonopathy (AMSAN), Miller-Fisher syndrome, gangliitis, and autonomic neuropathy; inflammatory plexus diseases such as brachial plexus inflammation and lumbosacral plexus inflammation; infectious peripheral neuropathies, such as herpes simplex virus infection, herpes zoster virus infection (shingles), hepatitis b, hepatitis c, Acquired Immune Deficiency Syndrome (AIDS) -related neuropathy, HIV infection, cytomegalovirus infection, colorado tick fever, diphtheria, syphilis, leprosy, crohns trypanosomiasis (chagas disease), lyme disease, campylobacter jejuni infection, and poliomyelitis; uremia; botulism; cholestatic liver disease in children; chronic respiratory insufficiency; alcoholism neuropathy; multiple organ failure; sepsis; too little albumin; eosinophilia-myalgia syndrome; porphyria; hypoglycemia; chronic non-tropical sprue; vitamin deficiency; dietary deficiency (e.g., vitamin B12 deficiency; vitamin B1 deficiency (beriberi); vitamin E deficiency; folate deficiency); whipple's disease; postgastrectomy syndrome; iron deficiency; chronic liver disease; primary biliary cirrhosis; hypophosphatemia; hyperlipidemia; waldenstrom's macroglobulinemia; motor ataxia; crohn's disease; atherosclerosis; gouty neuropathy; sensory perineuritis; sjogren's syndrome; primary vasculitis (such as polyarteritis nodosa); Churg-Strauss vasculitis; allergic granulomatous vasculitis; allergic vasculitis; wegener's granulomatosis; rheumatoid arthritis; myxoedema; inflammatory Sensory Polyneuropathies (ISPs); systemic lupus erythematosus; mixed connective tissue disease; scleroderma; sarcoidosis; vasculitis; systemic vasculitis; acute tubular syndrome; sensorimotor polyneuropathy of cancerous axons; sensorimotor polyneuropathy of the axonal lymphoma; primary, secondary, localized or familial systemic amyloidosis; hypothyroidism; carpal tunnel syndrome; sciatica; chronic obstructive pulmonary disease; acromegaly; malabsorption (sprue, celiac disease); cancer (sensory, sensorimotor, advanced and demyelinating); lymphomas (including hodgkin's disease); polycythemia; multiple myeloma (lytic, sclerosing or solitary plasmacytoma); lymphomatoid granulomatosis; benign monoclonal immunoglobulin disease; lung cancer; leukemia; macroglobulinemia; cryopglobulinemia; tropical spinal neuropathy; diabetes mellitus; and diabetic muscular atrophy. Peripheral neuropathy is also associated with mitochondrial disease. Most peripheral neuropathies are idiopathic, and R (-) DMS, S (+) DMS, or a racemic mixture of the two may also be used to prevent or treat these peripheral neuropathies.

[0074] Gene acquired peripheral neuropathies suitable for treatment with R (-) DMS, S (+) DMS or combinations thereof include, but are not limited to: peroneal muscular atrophy (Charcot-Marie-Tooth disease), hereditary amyloid neuropathy, hereditary sensory neuropathy (type I and type II), porphyritic neuropathy, genetically induced compression palsy, congenital hypomyelinating neuropathy, familial brachial plexus neuropathy, porphyry, diffuse angiokeratoma, adrenomyelopolyneuropathy, Riley-Day syndrome, progressive hypertrophic interstitial neuropathy (hereditary motor-sensory neuropathy III), refsum's disease, ataxia-telangiectasia, hereditary hypertyrosinemia, anaphalipoproteemia, abetalipoproteinemia, giant axonal neuropathy, metachromatic leukodystrophy and adrenoleukodystrophy, globuloleukoencephalopathy, and Friedreich's dyskinesia.

[0075] R (-) DMS, S (+) DMS or a combination of R (-) DMS and S (+) DMS may also be used to treat peripheral neuropathy caused by toxic agents. Toxins causing peripheral neuropathy can generally be divided into three groups: drugs and pharmaceuticals; industrial chemicals and environmental toxins. When the term "toxic agent" is used herein, it is defined as any substance that, through its chemical action, impairs the normal function of one or more components of the peripheral nervous system. This definition includes agents that are airborne, ingested as contaminants in food or pharmaceuticals, or intentionally taken as part of a treatment regimen.

[0076] Toxic agents that can cause peripheral neuropathy include, but are not limited to: acetazolamide, acrylamide, doxorubicin, ethanol, allyl chloride, amitrazine, amitriptyline, amiodarone, amphotericin, arsenic, aurothioglucose, carbamate, carbon disulfide, carbon monoxide, carboplatin, chloramphenicol, chloroquine, cholestyramine, cimetidine, cisplatin, iodochloroquine, colestipol, colchicine, polymyxin E, cycloserine, arabinoside, dapsone, dichlorophenoxyacetic acid, dideoxyinosine, dideoxycytidine, dideoxyinosine, dideoxythymidine, dimethylaminopropionitrile, disulfiram, docetaxel, doxetaxel, doxorubicin, ethambutol, ethionamide, ethylene oxide, FK506(tacrolimus), phencyclinone, gold, hexacarbon, hexane, contraceptive hormones, hexamethylolmelamine, hydralazine, hydroxychloroquine, imipramine, indomethacin, inorganic lead, isoniazid, lithium, methyl mercury, lithium, methamphetamine, amitrazine, amphotericin, and the like, Metformin, methyl bromide, methyl hydrazine, metronidazole, misonidazole, methyl N-butyl ketone, nitrofurantoin, mechlorethamine, nitric oxide, organophosphate, oseltamide, taxol, penicillin, perhexiline maleate, phenytoin, platinum, polychlorinated biphenyl, primidone, procainamide, procarbazine, vitamin B6, simvastatin, sodium cyanate, streptomycin, sulfanilamide, suramin, tamoxifen, thalidomide, thallium, toluene, methotrexate, trimethyltin, tricresyl phosphate, L-tryptophan, fenaminous, vinblastine, vindesine, high dose vitamin A, high dose vitamin D, zalcitamine, zimelidine; industrial agents, especially solvents; heavy metals; and sniffing glue or other toxic compounds. Other peripheral neuropathies that may be treated with the present disclosure include those caused by ischemia or prolonged exposure to cold conditions.

[0077] Although the particular disease, toxic agent or trauma causing the peripheral neuropathy is not critical, the present disclosure would be particularly valuable in the treatment of peripheral neuropathy caused by the application of chemotherapeutic drugs to cancer patients. Chemotherapeutic agents known to cause peripheral neuropathy include vincristine, vinblastine, cisplatin, taxol, procarbazine, dideoxyinosine, arabinoside, interferon-alpha and 5-fluorouracil (see Macdonald, Neurologic Clinics 9: 955-967 (1991)).

[0078] As noted above, the present disclosure includes treatment of peripheral neuropathy comprising the use of DMS to prevent, alleviate, reduce or eliminate, in whole or in part, symptoms associated with peripheral neuropathy, the DMS being in the form of R (-) DMS, S (+) DMS or a mixture of R (-) DMS and S (+) DMS. As used herein, the term R (-) DMS refers to DMS in the form of the R (-) enantiomer, including the free base, and any acid addition salts thereof. These salts of R (-) DMS or S (+) DMS include those derived from organic and inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, pamoic acid, heptanoic acid, and the like. Thus, reference herein to the use of either or both of R (-) DMS and S (+) DMS includes the free base and acid addition salts. When R (-) DMS or S (+) DMS is used alone in the compositions and methods disclosed herein, it is used in a form that is substantially enantiomerically pure. The mixtures or combinations of R (-) DMS and S (+) DMS are contemplated to include both racemic and non-racemic mixtures of optical isomers.

[0079] The route of administration of R (-) DMS and/or S (+) DMS may be either oral (involving gastrointestinal absorption) or non-oral (independent of gastrointestinal absorption, i.e. avoiding absorption of R (-) DMS and/or S (+) DMS from the gastrointestinal tract). DMS is administered either as the free base or as a physiologically acceptable non-toxic acid addition salt as described above, depending on the particular route employed. When the route of administration is, for example, parenteral administration using aqueous solutions, salts, especially hydrochloride salts; the delivery of desmethylselegiline in its free base form is particularly useful for transdermal administration. While oral administration will generally be the most convenient route, R (-) DMS, S (+) DMS, or a mixture of the two, may be administered orally, enterally, pulmonarily, nasally, lingually, intravenously, intraarterially, intracardially, intramuscularly, intraperitoneally, intradermally, subcutaneously, parenterally, topically, transdermally, intraocularly, buccally, sublingually, intranasally, by inhalation, vaginally, rectally, or by other routes.

[0080] The optimal daily dose of the R (-) DMS, S (+) DMS, or a combination of both, such as a racemic mixture of R (-) DMS and S (+) DMS for use in the present invention, is determined by methods known in the art, e.g., depending on the severity of the peripheral neuropathy and the symptoms being treated, the condition of the subject being treated, the extent of the desired therapeutic response, and the concomitant therapy applied to the patient or animal. The total daily dose to be administered to a patient, typically a human patient, should be at least that required to prevent, reduce or eliminate one or more symptoms associated with peripheral neuropathy, where the symptom is typically one of the symptoms described above.

[0081] Typically, the non-oral daily starting dose applied by the attending physician will be at least about 0.01mg/kg body weight, calculated as free secondary amine, followed by a gradual increase in the dose in response to treatment. The final daily dose will be about 0.05mg/kg to 0.15mg/kg body weight (all these doses are also calculated on the basis of the free secondary amine). However, it is common that the initial dose to be administered by the attending physician or veterinarian will be at least about 0.015mg/kg, calculated as free secondary amine, with subsequent escalation of the dose depending on the route of administration and the therapeutic response. Typical daily doses will be in the range of about 0.02mg/kg or 0.05mg/kg to 0.10mg/kg or 0.15mg/kg to 0.175mg/kg or 0.20mg/kg or 0.5mg/kg and may range up to about 1.0mg/kg or even 1.5, 2.0, 3.0 or 5.0mg/kg body weight depending on the route of administration. Preferably, the daily dosage will be about 0.10mg/kg to 1.0 mg/kg. More preferably, the daily dose will be about 0.4mg/kg to about 0.9 mg/kg. Still more preferably, the daily dosage will be from about 0.6mg/kg to about 0.8 mg/kg. In addition, all of these dosages should be calculated based on the free secondary amine. In other preferred embodiments, the daily dose will be about 0.01mg to 1000mg per day. Preferred dosages will be about 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 mg/day.

[0082] These are merely instructive, as it must be the actual dosage that is carefully selected and determined by the attending physician according to the clinical conditions. The optimal daily dosage can be determined by methods known in the art and can be influenced by factors such as the age, weight, clinical condition of the patient, the peripheral neuropathy-related disorder or disease, the severity of the peripheral neuropathy and disease, disorder being treated in the patient, the extent of the response to treatment desired, concomitant therapy, and the observed response of the patient or individual animal. The daily dose employed may be a single dosing regimen or a multiple dosing regimen.

[0083] Either oral or non-oral dosage forms may be used, and for example, oral or non-oral dosage forms may provide for release of the active ingredient from a single dosage unit at once, such as an oral composition or sublingual or buccal administration, or for continuous release of a relatively small amount of the active ingredient from a single dosage unit over the course of one or more days, such as a transdermal patch. Alternatively, intravenous or inhalation routes may be preferred. The R (-) DMS, S (+) DMS or a combination of R (-) DMS and S (+) DMS may be applied in many different dosage forms including, but not limited to, tablets, pills, capsules, powders, aerosols, suppositories, skin patches, parenteral and oral liquids including oily and aqueous suspensions, solutions and emulsions. In addition, sustained release (depot) formulations and devices containing desmethylselegiline are contemplated.

[0084] Pharmaceutical compositions containing one or both of R (-) DMS and S (+) DMS can be prepared according to conventional techniques. For example, formulations for parenteral administration may employ sterile isotonic saline solutions, for example, by intramuscular, intravenous, intrathecal and intraarterial routes. Sterile buffered solutions may also be used for intraocular administration.

[0085] Transdermal dosage unit forms of R (-) DMS and/or S (+) DMS can be prepared using the various techniques described above (see, e.g., U.S. Pat. Nos. 4,861,800; 4,868,218; 5,128,145; 5,190,763 and 5,242,950; and EP-A404807, EP-A509761 and EP-A593807, which are incorporated herein by reference). For example, a one-piece patch construction may be employed wherein desmethylselegiline is added directly to the adhesive and the mixture is cast onto the liner. Alternatively, R (-) DMS and/or S (+) DMS may be incorporated into a multi-layer patch in the form of an acid addition salt which converts such salt to the free base, as described, for example, in EP-A593807 (incorporated herein by reference). Particularly contemplated by the present disclosure are transdermal patch compositions comprising about 5mg, 10mg, 20mg, 30mg, 50mg, or 100mg of R (-) DMS, S (+) DMS, or a combination of R (-) DMS and S (+) DMS.

[0086] One or both of R (-) DMS or S (+) DMS can also be applied by a device that applies a readily soluble liquid crystalline composition, where, for example, 5 to 15% desmethylselegiline is combined with a mixture of liquid and solid polyethylene glycols, polymers, and nonionic surfactants, optionally with the addition of propylene glycol and an emulsifier. For a more detailed description of the preparation of such transdermal formulations, reference is made to EP-A5509761 (incorporated herein by reference). Additionally, buccal and sublingual dosage forms of R (-) DMS, S (+) DMS, or a combination of R (-) DMS and S (+) DMS can be prepared using techniques described in, for example, U.S. Pat. Nos. 5,192,550; 5,221,536, respectively; 5,266,332, respectively; 5,057,321, respectively; 5,446,070, respectively; 4,826,875, respectively; 5,304,379 or 5,354,885 (incorporated herein by reference).

[0087] Subjects treatable by the present formulations and methods include both human and non-human subjects. Thus, the above compositions and methods provide, inter alia, treatment of mammals, including humans and livestock. Thus, the methods and compositions are useful for treating peripheral neuropathy in humans, primates, dogs, cats, cattle, horses, sheep, mice, goats, and pigs, among others.

[0088] Treatment with R (-) DMS, S (+) DMS or a combination of R (-) DMS and S (+) DMS should continue until the peripheral neuropathy related symptoms subside. The drug may be applied at regular intervals (e.g. twice a day) or may be administered in a substantially continuous manner, e.g. via a transdermal patch. The physician should evaluate the patient on a regular basis, e.g., once a week, once a month, twice a year, etc., to determine if the symptoms have improved and if the dosage of desmethylselegiline needs to be adjusted. Because progressive peripheral neuropathy has been shown to be delayed after discontinuation of cisplatin treatment (see, e.g., Gruber et al, Cancer Chemother. Pharmacol.25: 62-64(1989)), administration of R (-) DMS, S (+) DMS, or a combination of both, preferably will continue for a period of time (e.g., about 1 to 12 months) after chemotherapy is completed. In addition, R (-) DMS, S (+) DMS, or a combination of the two, can be used to prevent the development of peripheral neuropathy-related symptoms, particularly when the subject is at risk of developing peripheral neuropathy.

[0089] The disclosure also relates to methods of treating cancer patients receiving treatment with chemotherapeutic drugs in combination with R (-) DMS, S (+) DMS or a mixture of R (-) DMS and S (+) DMS, which are known to cause peripheral neuropathy. The same considerations discussed in the above section apply equally to this case, except as noted below, where R (-) DMS, S (+) DMS or a combination of both are used as part of the treatment regimen for these patients.

[0090] The R (-) DMS, S (+) DMS or racemic mixture of R (-) DMS and S (+) DMS can be used in combination with any chemotherapeutic agent that causes peripheral neuropathy as a side effect. Treatment is particularly preferred for chemotherapeutic agents which are so toxic that their dose is limited by the peripheral neuropathy they cause. This group includes taxol, cisplatin, vincristine and vinblastine. By preventing or reducing these drug-related peripheral neuropathies, R (-) DMS, S (+) DMS, or a combination of R (-) DMS and S (+) DMS, can allow for a higher single dose to be administered to a patient, thus increasing the overall efficacy of this treatment. In addition, the use of R (-) DMS, S (+) DMS, or a combination of both, allows patients to receive higher cumulative doses of chemotherapeutic drugs. Higher doses of chemotherapeutic agent applied in each treatment cycle, an increase in the number of treatment cycles, or a combination of higher doses and more cycles can increase the cumulative dose.

[0091]The most preferred chemotherapeutic agents for use in this disclosure are cisplatin and taxol, both of which have severe toxicity to peripheral nerves, which limits the safe dosages used (see Macdonald, Neurologic Clinics 9: 955-. Although the dose strength of these drugs is an important factor in achieving optimal therapeutic results, cisplatin essentially exceeds about 75-100mg/m²(Ozols, sensiars in Oncology 16: 22-30(1989)) and taxol in excess of about 175-225mg/m²(Giani, et al, J.nat' l Cancer Inst.87: 1169-75(1995)) is typically unusable.

[0092] Symptoms associated with peripheral neuropathy induced by cisplatin include sensory polyneuropathy with paresthesia, loss of vibration and proprioception, loss of pain and temperature sensation, and reduced deep tendon reflex (see Macdonald, neurological Clinics 9: 955-. Symptoms associated with other drugs such as vincristine and taxol include loss of the deep tendon reflex of the ankle joint, which may progress to complete reflex extinction, loss of peripheral symmetrical sensation, motor weakness, foot drop, muscle atrophy, constipation, ileus, urinary retention, impotence, and postural hypotension (id.; Casey, et al., Brain 96: 69-86 (1973)). For the present disclosure, the severity of these symptoms is considered unacceptable either when the patient judges that the symptoms are intolerable or when the patient's physician judges that they pose such a serious threat to the patient's health that the dosage of the chemotherapeutic drug must be reduced or its use discontinued.

[0093] Clinical considerations will dictate the particular route of administration of R (-) DMS, S (+) DMS, or a mixture of R (-) DMS and S (+) DMS, which is most preferred for patients receiving chemotherapeutic drug treatment, and which may include any of the above-described delivery or dosage forms. Administration routes that avoid gastrointestinal absorption may be preferred. Thus, preferred routes will typically include transdermal, parenteral, sublingual and buccal administration.

[0094] In certain instances, a patient administered R (-) DMS, S (+) DMS, or a combination of R (-) DMS and S (+) DMS in accordance with the present disclosure will have received chemotherapy at the same time that treatment with R (-) DMS, S (+) DMS, or a mixture of R (-) DMS and S (+) DMS is initiated. Thus, an upper limit on the dose of chemotherapeutic drugs may have been established beyond which patients will experience unacceptably severe peripheral neuropathy. In these cases, the application of the chemotherapeutic agent should be continued and treatment of R (-) DMS, S (+) DMS or a combination of R (-) DMS and S (+) DMS should be initiated. The precise timing of administration of the chemotherapeutic agent and R (-) DMS, S (+) DMS or a combination of R (-) DMS and S (+) DMS relative to each other is not critical as long as their therapeutic effects occur simultaneously. For example, it is not necessary that the chemotherapeutic agent be administered in a single dosage form with R (-) DMS, S (+) DMS, or a combination of both, or that each be administered within one or two hours of each other.

[0095] In the case where patients take multiple drugs or for some reason believe they are unusually sensitive to R (-) DMS, S (+) DMS or a combination of both, it will be desirable to start with a low initial dose (e.g., 0.01mg/kg) to ensure that the subject is tolerant to the drug. Once this starting dose is established, the dose can be adjusted upward. The effect of R (-) DMS, S (+) DMS, or a combination of both, on the symptoms of peripheral neuropathy should be assessed by the subject over a period of time or by the subject' S physician according to a rule. Once the concentration of R (-) DMS, S (+) DMS, or a combination of the two, which is effective to reduce symptoms, is determined, the dose of the chemotherapeutic agent can be increased until a new upper limit is established, i.e., until the established dose cannot be exceeded without causing unacceptable side effects. After the chemotherapy drug is discontinued, the application of R (-) DMS, S (+) DMS or a combination of R (-) DMS and S (+) DMS should continue for a period of time to prevent delayed and progressive peripheral neuropathy. For example, after chemotherapy is terminated, the subject may continue to receive R (-) DMS, S (+) DMS, or a combination of both for one month or more.

[0096] The same basic procedure described above can be used for subjects who begin chemotherapy. In these cases, it is necessary to establish the dose of the chemotherapeutic agent and the dose of R (-) DMS, S (+) DMS or a combination of both. Preferably, the step is pre-treating the subject with R (-) DMS, S (+) DMS or a combination of both prior to the initiation of the application of the chemotherapeutic agent. For example, 10mg of R (-) DMS, S (+) DMS, or a combination of both, per day will be administered to a subject for one week prior to the start of chemotherapy drug administration. The dose of this chemotherapeutic agent is then optimized with R (-) DMS, S (+) DMS, or a combination of both, as described above. In addition, application of R (-) DMS, S (+) DMS or a combination of R (-) DMS and S (+) DMS should continue after cessation of the application of the chemotherapeutic agent.

[0097] The present disclosure also includes a method of treating peripheral neuropathy by administering to a patient a pharmaceutical composition comprising R (-) DMS, S (+) DMS, or a combination of both, conveniently prepared according to methods known in the art, as described in example 1, and one or more additional therapeutic agents known to treat peripheral neuropathy. Therapeutic agents known to treat a variety of peripheral neuropathy symptoms include, but are not limited to, prednisone, IVIg, cyclophosphamide, famciclovir, carbamazepine, tricyclic antidepressants, dapsone, clofazimine, rifampin, nifurolimus, metronidazole, gabapentin, ganciclovir, foscarnet, cidofovir, acyclovir, topical lidocaine and ribavirin. The pharmaceutical composition can be used for preventing or treating peripheral neuropathy. These therapeutic agents, used in combination with R (-) DMS, S (+) DMS or a mixture of both, for treating peripheral neuropathy can also be applied to patients in separate formulations. Thus, the present disclosure contemplates the separate administration of the therapeutic agent, or the administration of the agent at spaced intervals, particularly when the agent and the DMS enantiomer or DMS enantiomer have a synergistic therapeutic effect.

[0098] Successful application of the above compositions and methods requires the use of a therapeutically effective amount of R (-) DMS or S (+) DMS or a combination of R (-) DMS and S (+) DMS. As mentioned above, and despite its clearly inferior MAO-B inhibitory properties, R (-) DMS and its enantiomer appear at least not inferior to selegiline in treating peripheral neuropathy.

[0099] The following examples are presented to illustrate preferred embodiments of the present invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its operation. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention. The following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example 1: preparation of R (-) DMS and S (+) DMS

[00100] A.R (-) -desmethylselegiline

[00101] R (-) DMS was prepared according to methods known in the art. For example, desmethylselegiline is a known chemical intermediate for the preparation of selegiline, as described in U.S. patent 4,925,878. R (-) -2-aminophenylpropane (L-amphetamine) in an inert organic solvent is treated with an equivalent molar mass of a reactive propargyl halide at a slightly elevated temperature (70-90 ℃):

the solution can be used for preparing norfloxacinLigolan, such as toluene, reactive propargyl halides such as propargyl bromide, Br-CH₂-C ≡ -CH. Alternatively, the reaction may be carried out under an acid acceptor, such as potassium carbonate. The reaction mixture is then extracted with an aqueous acid, for example using 5% hydrochloric acid, and the extract is added to a base. The non-aqueous layer formed is separated and extracted with, for example, benzene, distilled, and dried under reduced pressure.

[00102] Alternatively, the propargylation can be carried out in a two phase system of a water-immiscible solvent and an aqueous base using a salt of R (+) -2-aminophenylpropane and a weak acid such as tartaric acid, similar to the preparation of selegiline described in U.S. Pat. No. 4,564,706.

[00103] B.S (+) -desmethylselegiline

[00104] According to the above process for the preparation of desmethylselegiline, S (+) DMS is conveniently prepared from the enantiomer S (+) -2-aminophenylpropane (dextroamphetamine), i.e.:

[00105] Mixtures of optical antipodes

[00106] Mixtures of the R (-) and S (+) enantiomeric forms of desmethylselegiline, including racemic desmethylselegiline, can be conveniently prepared from mixtures of enantiomers, including racemic mixtures of the above mentioned aminophenylalane starting materials.

[00107] Conversion to acid addition salts

[00108] N- (prop-2-ynyl) -2-aminophenylalkanes, which may be in optically active or racemic form, may be converted into a physiologically acceptable non-toxic acid addition salt by conventional techniques, such as treatment with a mineral acid. For example, hydrogen chloride-containing isopropanol is used in the preparation of desmethylselegiline hydrochloride. The free base or salt may be further purified by conventional techniques, such as recrystallization or chromatography.

Example 2: characterization of substantially pure R (-) DMS

[00109]The substantially pure R (-) DMS formulation appears as a white crystalline solid with a melting point of 162-163 ℃ and an optical rotation of [ alpha.. alpha. ]]_D ^23c-15.2+/-2.0, determined at a concentration of 1.0M in water as solvent. The purity of R (-) DMS was 99.5% by HPLC analysis on a Microorb MV cyano column (see chromatogram in FIG. 1) and 99.6% by HPLC analysis on a Zorbax Mac-Mod SB-C18 column (see chromatogram in FIG. 2). The concentration of any individual impurity is not greater than or equal to 0.5%. The concentration of heavy metal is less than 10ppm, and the concentration of amphetamine hydrochloride is less than 0.03%. The final solvent used to dissolve the formulation, ethyl acetate and ethanol, were each less than 0.1%. The preparation was subjected to mass spectrometry (see FIG. 3), the mass spectrum and molecular weight were 209.72amu, and the formula C₁₂H₁₅The compounds of NHCl are identical. The infrared spectrum and the NMR spectrum are shown in figures 4 and 5, respectively. These are also in accordance with the known structure of R- (-) -DMS.

Example 3: characterization of substantially pure S (+) DMS

[00110]The substantially pure S (+) DMS formulation appeared as a white powder having a melting point of about 160.04 ℃ and a specific optical rotation of +15.1, as measured at a concentration of 1.0M in water at 22 ℃. The purity of this preparation was approximately 99.9% as analyzed by reverse phase HPLC on a Zorbax Mac-Mod SB-C18 column (see FIG. 6). The concentration of amphetamine hydrochloride is less than 0.13% (w/w). Subjecting the preparation to mass spectrometry, wherein the mass spectrum and molecular weight are 209.72, and the formula is C₁₂H₁₅The compound of NHC1 (see figure 7). Infrared spectroscopy was performed and the results were also consistent with the structure of S (+) DMS (see FIG. 8).

Example 4: effect of the R (-) and S (+) enantiomers of Desmethylselegiline (DMS) on the activity of human platelet MAO-B and ragmouse brain MAO-B and MAO-A

[00111] Human platelet MAO consists only of the B isomer of this enzyme. In this study, the inhibition of this enzyme by the two DMS enantiomers was determined in vitro and in vivo and compared to the inhibition caused by selegiline. The study also measured the inhibitory activity of these two DMS enantiomers against MAO-A and MAO-B in guineA pig hippocampal tissues. Ragweed brain tissue is an excellent animal model that can be used to study brain dopamine metabolism, the enzymatic kinetics of various forms of MAO, and the inhibitory properties of new agents that interact with these enzymes. The kinetic profile of the various forms of MAO in this animal was similar to that found in human brain tissue. Finally, the test agents were applied to guinea pigs and the extent to which they could act as brain MAO inhibitors in vivo was estimated.

[00112] Test method A

[00113]In vitro: the test system uses guineA pig hippocampus homogenate MAO-A (MAO-A)¹⁴C-5-hydroxytryptamine) or human platelet and guinea pig hippocampus homogenate MAO-B (¹⁴C-phenylethylamine) in vitro. The conversion of each substrate was determined in the presence of S (+) DMS, R (-) DMS or selegiline and compared to the activity of the isozyme in the absence of these agents. Percent inhibition was calculated from these values. Comparison results in 50% Inhibition (IC)₅₀Value) was evaluated for efficacy at each agent concentration.

[00114] In vivo: before sacrifice, R (-) DMS, S (+) DMS or selegiline was applied subcutaneously (sc) once a day for 5 days in vivo. Hippocampus homogenates containing the enzyme were prepared and tested for MAO-A and MAO-B activity in vitro. These experiments were performed to demonstrate that the DMS enantiomer is able to enter brain tissue and inhibit MAO activity.

[00115] Results B

[00116] In vitro MAO-B inhibitory Activity

[00117]The results of MAO-B inhibition are shown in tables 2 and 3. Table 4 is the IC of MAO-B inhibition compared to selegiline₅₀Value and potency.

Table 2: MAO-B inhibition of human platelet concentrations

Medicament	Concentration of	% inhibition 0. + -. SEM
			Selegiline	0.3nM5nM10nM30nM100nM300nM1μM	8.3±3.450.3±8.769.0±5.591.0±1.496.0±1.696.0±1.696.6±1.6
R(-)DMS	100nM300nM1μM3μM10μM3μM	14.3±3.642.1±4.076.9±1.4794.4±1.495.8±1.495.7±2.3
			S(+)DMS	300nM1μM3μM10μM30μM100μM1mM	6.4±2.811.1±1.026.6±1.942.3±2.368.2±2.3483.7±0.7794.2±1.36

Table 3: MAO-B inhibition of guinea pig hippocampus

Medicament	Concentration of	% inhibition 0. + -. SEM
			Selegiline	0.3μM5nM10nM30nM100nM300nM1μM	28.3±8.781.2±2.695.6±1.398.5±0.598.8±0.598.8±0.599.1±0.45
R(-)DMS	100nM300nM1μM3μM10μM30μM	59.4±9.686.2±4.798.2±0.798.4±0.9599.1±0.4599.3±0.40
			S(+)DMS	300nM1μM3μM10μM30μM100μM1μm	18.7±2.144.4±6.477.1±6.094.2±1.998.3±0.699.3±0.299.9±0.1

Table 4: guinea pig MAO-B inhibited IC ₅₀ Value of

Treatment of hippocampal cortex of human platelet guinea pig

Selegiline 5nM (1) 1nM (1)

R(-)DMS 400nM(80) 60nM(60)

S(+)DMS 1400nM(2800) 1200nM(1200)

() Reduction in potency compared to selegiline

[00118] As observed, R (-) DMS is 20-35 times more potent than S (+) DMS as a MAO-B inhibitor, and both enantiomers are less potent than selegiline.

[00119] In vitro MAO-A inhibitory Activity

[00120]Table 5 shows the results of the experiments to determine MAO-A inhibition in guineA pig hippocampus. Table 6 shows the IC of the two DMS enantiomers and selegiline₅₀The value is obtained.

Table 5: MAO-A inhibition of guineA pig hippocampus

Medicament	Concentration of	% inhibition 0. + -. SEM
			Selegiline	300nM1μM3μM10μM100μM1mM	11.95±2.422.1±1.253.5±2.791.2±1.1698.1±1.499.8±0.2
R(-)DMS	300nM1μM3μM10μM100μM1mM	4.8±2.14.2±1.510.5±2.019.0±1.364.2±1.596.5±1.2
			S(+)DMS	1μM3μM10μM100μM1nM10nm	3.3±1.54.3±1.010.5±1.4748.4±1.892.7±2.599.6±0.35

Table 6: IC for MAO-A inhibition ₅₀ Value of

IC for treatment of MAO-A in Hippocampus cortex of GuineA pigs₅₀

Selegiline 2.5 mu M (1)

R(-)DMS 50.0μM(20)

S(+)DMS 100.0μM(40)

() Reduction in potency compared to selegiline

[00121] As MAO-A inhibitors, R (-) DMS is twice as potent as S (+) DMS, and both are 20-40 times less potent than selegiline. In addition, these agents are 2-3 orders of magnitude less potent as MAO-A inhibitors than MAO-B inhibitors that are hippocampal brain tissue, i.e., 100 to 1000-fold. Thus, each enantiomer of DMS and selegiline can be classified as a selective MAO-B inhibitor in brain tissue.

[00122] Results of in vivo experiments

[00123]Each enantiomer of DMS was applied in vivo by subcutaneous injection once a day for 5 consecutive days, and then the inhibition of brain MAO-B activity was determined. In a previous study, the ID of selegiline was found₅₀0.03 mg/kg; and both R (-) DMS and S (+) DMS were determined to be about 10 times less potent than selegiline. In a recent study on large groups of animals, it was shown that as MAO-B inhibitors, in fact R (-) DMS is about 25-fold less potent than selegiline and S (+) DMS is about 50-fold less potent. The results are shown in FIG. 9, and Table 7 shows the IDs₅₀The value is obtained.

TABLE 7: brain MAO-B ID 5 days after dosing ₅₀ Value of

Treatment of MAO-B ID in Hippocampus cortex of Guinea pigs₅₀

Selegiline 0.008mg/kg (1)

R(-)DMS 0.20mg/kg(25)

S(+)DMS 0.50mg/kg(60)

() Reduction in potency compared to selegiline

[00124] This experiment shows that DMS enantiomer passes the blood brain barrier after in vivo administration and inhibits brain MAO-B. It has also been shown that, as MAO-B inhibitors, the difference in potency between each DMS enantiomer and selegiline observed in vitro is substantially reduced under in vivo conditions.

[00125] In an experiment to determine the effect of 5s.c. treatment on guineA pig cortical (hippocampal) MAO-A activity, selegiline was found to produce an inhibitory activity of 36.1% at A dose of 1.0 mg/kg. At a dose of 3.0mg/kg, R (-) DMS produced 29.8% inhibition. S (+) DMS did not produce any observable inhibition at the highest test dose (10mg/kg), suggesting it has a much smaller penetration response potential.

[00126] C. conclusion

[00127] In vitro, both R (-) DMS and S (+) DMS have activity as MAO-B and MAO-A inhibitors. Each enantiomer is selective for MAO-B. S (+) DMS is less potent than R (-) DMS, and both DMS enantiomers are less potent than selegiline in inhibiting MAO-A and MAO-B.

[00128] In vivo, both enantiomers were shown to be active in inhibiting MAO-B, suggesting that these enantiomers are able to cross the blood brain barrier. The ability of these agents to inhibit MAO-B suggests that these agents are valuable in the treatment of low dopamine disorders such as ADHD and dementia.

Example 5: neuroprotective effects of desmethylselegiline enantiomers in vivo

[00129] The DMS enantiomer was applied to a wobble mouse, an animal model of motor neuropathy, particularly Amyotrophic Lateral Sclerosis (ALS), to test the ability of these agents to prevent neurological degeneration. Rocking mice exhibit progressive worsening forelimb weakness, gait disturbances and forelimb muscle flexion contractures.

[00130] Test method A

[00131] In a randomized double-blind study, 0.1mg/kg of R (-) DMS, S (+) DMS or placebo was applied to the swing rats by intraperitoneal injection for 30 days. At the end of the test, the grip strength, running time, resting motor activity of these rats were measured and semi-quantitative scores were made for paw posture abnormalities and gait abnormalities. The investigators who prepared the test drugs and administered them to these animals differed from those who analyzed the behavioral changes.

[00132] Essentially according to Mitsumoto et al in ann.neurol.36: 142, 148(1994) were analyzed and scored. The grip of the animal's forepaws was determined by allowing the mouse to grasp a wire with both forepaws. The wire was connected to a dynamometer and the tail of the mouse was pulled until the animal was forced to release the wire. The reading of the muscle dynamometer when the lead is released is taken as the measurement of the grip strength.

[00133] The running time is defined as the minimum time necessary to travel a particular distance, e.g., 2.5 feet, and the optimal time for several trials is recorded.

[00134] The gait anomaly is scored according to a scale based on the degree of contracture, and the gait anomaly is scored according to a scale from normal gait to inability to support the body with the paw.

[00135] Locomotor activity was determined by transferring the animals to a test area covered with squares on the floor. Activity is measured by the number of squares the mouse moves over a set period of time, for example over a period of 9 minutes.

[00136] Results B

[00137] At the start of the study, all groups were not different in each variable, suggesting that 3 groups were comparable at baseline. The weight gain was the same in all 3 groups, suggesting that no serious side effects occurred in each animal. Table 8 shows the difference in average grip strength of the test animals.

Table 8: average grip Strength of Wobble mice treated with R (-) DMS or S (+) DMS

Treatment of	N	Grip strength (gm)
			Control (placebo)	10	9(0-15)
R(-)DMS	9	20(0-63)
			S(+)DMS	9	14(7-20)

N-number of animals analyzed

[00138] The grip strength of all animals decreased significantly at the end of the first week. At the end of the study, the animals in the control group had the least grip. Variability in grip strength among the treated animal groups made a statistical analysis of this data with no meaningful results, however, at a dose of 0.1mg/kg, the mean grip strength of DMS-treated animals was greater than that of the control group. These results suggest that it is possible that the dose is too low and that higher doses should be studied.

[00139] Running time, resting motor activity, semi-quantitative paw posture abnormality classification and semi-quantitative gait abnormality classification were also tested. However, none of these tests showed differences between these three groups.

Example 6: immune system recovery by R (-) DMS and S (+) DMS

[00140] There is an age-related decline in immunological function in animals and humans, which makes elderly individuals more susceptible to infectious diseases and cancer. Us patents 5,276,057 and 5,387,615 suggest that selegiline can be used to treat immune system dysfunction. This experiment was performed to determine if R (-) DMS and S (+) DMS could also be used to treat this dysfunction. It will be appreciated that the ability to support a patient's normal immunological defenses would be beneficial in the treatment of a variety of acute and chronic diseases, including cancer, AIDS, bacterial and viral infections, and certain types of peripheral neuropathy.

[00141] A. test procedure

[00142] A rat model was used in this experiment to determine the ability of R (-) DMS and S (+) DMS to restore immunological function. These rats were divided into the following experimental groups:

1) young rats (3 months old without any treatment);

2) aged rats (18-20 months old, no treatment);

3) aged rats injected with physiological saline;

4) selegiline treated geriatric rats at a dose of 0.25mg/kg body weight;

5) the dose of the selegiline-treated aged rats is 1.0mg/kg body weight;

6) r (-) DMS treated geriatric rats at a dose of 0.025mg/kg body weight;

7) r (-) DMS treated geriatric rats at a dose of 0.25mg/kg body weight;

8) r (-) DMS treated geriatric rats at a dose of 1.0mg/kg body weight;

9) s (+) DMS treated aged rats at a dose of 1.0mg/kg body weight.

[00143] The rats were given daily saline or test agent ip for 60 days. They were then subjected to an additional 10 days "wash period" during which no treatment was given. At the end of this period, the animals were sacrificed and their spleens removed. The spleen cells are then analyzed for various factors that may indicate immune system function. Specifically, standard tests were performed to determine the following:

1) concanavalin a stimulates the production of interferon-gamma in vitro by splenocytes;

2) in vitro concanavalin a-induced interleukin 2 production;

3) percentage of IgM positive splenocytes (IgM is a marker for B lymphocytes);

4) percentage of CD5 positive splenocytes (CD5 is a marker for T lymphocytes).

[00144] Results B

[00145] Tables 9 and 10 show the effect of selegiline, R (-) DMS and S (+) DMS on interferon production induced by concanavalin A in rat splenocytes. Table 9 shows that there is a significant decrease in the production of cytokinin, which occurs with age. Selegiline, R (-) DMS and S (+) DMS all caused gamma-interferon levels to recover, the most significant increase of which occurred at a dose of 1.0mg/kg body weight.

Table 9: effect of age on T cell function

T cell activity assay TH, cytokines, IL-2 and IFN-gamma after stimulation of rat splenocytes with concanavalin A. P is 0.0004 for young versus old age

Table 10: IL-2 and IFNg mean and% control

Aged rats without any treatment (22 months old)

[00146] Table 10 shows that R (-) DMS, S (+) DMS and selegiline are able to restore the degree of interferon-gamma production in splenocytes of aged rats. Interferon-gamma is a T cell-associated cytokine that inhibits viral replication and regulates various immunological functions. It affects the class of antibodies produced by B cells, upregulates class I and class II MHC complex antigens, and increases the efficiency of macrophage-mediated killing of intracellular parasites.

[00147] Histological immunofluorescence studies showed a significant loss of innervation in the spleen of rats with age. When mice were treated with R (-) DMS, innervation in the spleen of the animals was significantly elevated, and this elevation presented a dose-response pattern. S (+) DMS did not show any effect on histological examination, although there was a modest increase in interferon-gamma production. Treatment with either R (-) DMS or S (+) DMS did not increase IL-2 production, suggesting that the effects of these agents are limited to IFN- γ production.

[00148] C. conclusion

[00149] The results obtained from the histological examination, the production of interferon and the percentage of I gM positive splenocytes support the conclusion that the DMS enantiomer is able to restore, at least in part, the age-dependent loss of immune system function. The results obtained with IFN-y are particularly important. In humans and animals, the ability to successfully recover from infection by a virus or other pathogen correlates with IFN- γ production. In addition, for diseases or disorders caused by attenuated host immunity, R (-) DMS and S (+) DMS would appear to have beneficial therapeutic effects. This would include AIDS, response to vaccines, infectious diseases, cancer chemotherapy and adverse immunological effects caused by cancer, as well as certain types of peripheral neuropathy.

Example 7: examples of dosage forms

[00150] Desmethylselegiline patch

[00151]The two components are thoroughly mixed and cast onto a film backing (e.g., by casting9723 polyester) and dried. Cutting the backing into pieces and applying a fluoropolymer release liner (e.g.1022) And sealing the patches in a foil pouch. In the treatment of a condition caused by neuronal degeneration or neuronal trauma in humans, one patch is applied daily to provide 1-10mg desmethylselegiline every 24 hours.

[00152] Ophthalmic solution

[00153] Norselegiline hydrochloride (0.1g), 1.9g boric acid and 0.004g phenylmercuric nitrate were dissolved in an appropriate amount of 100ml sterile water. The mixture is sterilized and sealed. It can be used in ophthalmology for the treatment of neuronal degeneration or disorders caused by neuronal trauma, such as glaucomatous optic neuropathy and macular degeneration.

[00154] Intravenous solution

[00155] A1% solution was prepared by dissolving 1g of desmethylselegiline as the hydrochloride salt in enough 0.9% isotonic saline solution to give a final volume of 100 ml. The solution is buffered to a pH of 4 with citric acid, sealed and sterilized to produce a 1% solution suitable for intravenous administration for the treatment of conditions resulting from neuronal degeneration or neuronal trauma.

[00156] Oral dosage forms

[00157] Tablets and capsules containing desmethylselegiline (mg/unit dose) were prepared as follows:

desmethylselegiline 1-5

Microcrystalline cellulose 86

Lactose 41.6

Citric acid 0.5-2

0.1-2 parts of sodium citrate

Magnesium stearate 0.4

Wherein the ratio of citric acid to sodium citrate is about 1: 1.

Example 8: mouse model for treating cisplatin-induced neuropathy by using R (-) DMS

[00158] The ability of desmethylselegiline to treat peripheral neuropathy, neuropathy in a mouse model of cisplatin-induced neuropathy, was studied. Male CD1 mice were divided into 6 groups, 15 groups, these mice had a body weight of 15 to 20g at the start of the experiment and were dosed as follows:

group 1: control-saline plus buffer

And 2, group: cisplatin buffer solution

And 3, group: cisplatin plus selegiline

4 groups are as follows: selegiline alone

And 5, group: cisplatin plus R (-) -desmethylselegiline

6 groups are as follows: r (-) -desmethylselegiline alone

[00159] Cisplatin was administered to mice by intraperitoneal injection at a dose of 10mg/kg body weight 1 time a week for 8 consecutive weeks. Selegiline and R (-) -desmethylselegiline were applied to mice by subcutaneous administration at a dose of 1mg/kg body weight 5 times a week for 8 consecutive weeks. Additionally, mice were injected subcutaneously daily with normal saline to maintain hydration and normal kidney function.

[00160] The number of surviving mice per group after 8 weeks of cisplatin treatment is shown in table 11, with an initial number of 15:

table 11: surviving treated mice

Group 1: 14 (control)

And 2, group: 12 (cisplatin)

And 3, group: 11 (cisplatin and selegiline)

4 groups are as follows: 15 (selegiline)

And 5, group: 7 (cisplatin plus R (-) -desmethylselegiline)

6 groups are as follows: 13(R (-) -desmethylselegiline)

[00161] Except for the group receiving cisplatin and R (-) -desmethylselegiline, the other deaths were lower than those occurring in the cisplatin peripheral neuropathy study. This may be due to overhydration resulting from the saline injections during the daily experiment.

[00162] All behavioral tests were performed on surviving mice as described in this example on the day following the last dose of selegiline and R (-) -desmethylselegiline. Cisplatin typically produces large fiber sensory neuropathy. The tail flick test was used to examine the function of the mouse fibrous sensory neurons. This test measures the response of animals to heat noxious stimuli by spinal cord mediated reflexes. This flick tail test was performed by loosely restraining the mice and exposing their tails to a focused light beam at a distance. The latency of the mice to withdraw their tails from the light column was then determined. This has been a variable finding when significant changes in the tap tail threshold were observed in cisplatin-induced severe neuropathy, since small fiber neurons are not the main population sensitive to cisplatin. As shown in Table 12 below, the difference between the survival numbers of the different groups had no significant significance for the tap tail threshold

Table 12: tail survival threshold

Comparison: 7.0 + -0.3 seconds (mean + -SEM)

Cisplatin: 7.8. + -. 0.8 seconds (mean. + -. SEM)

Cisplatin + selegiline: 7.9. + -. 0.5 seconds (mean. + -. SEM)

Selegiline: 8.7. + -. 0.6 seconds (mean. + -. SEM)

Cisplatin + R (-) -desmethylselegiline: 7.4. + -. 0.8 seconds (mean. + -. SEM)

R (-) -desmethylselegiline: 6.9. + -. 0.4 seconds (mean. + -. SEM)

[00163] Proprioceptive assays were used to assess the effects of selegiline and R (-) -desmethylselegiline on peripheral nerve function in cisplatin-induced neuropathy mice. Proprioception is a large fiber sensory form that is typically abnormal in the presence of cisplatin-induced peripheral neuropathy. The proprioceptive test analyzes the function of the large fiber sensory neurons by placing the mouse on a rotating stake and removing the visible clues, and determining the ability of the mouse to maintain their equilibrium. This ability requires the mouse to feel where its limbs are in space and where the peg rotates, which is a proprioceptive function.

[00164] Mice were placed on rotating stakes in a completely dark room and timed until they fell off the stakes for a maximum of 20 seconds. The results of this experiment are shown in Table 13 to be of significant significance and suggest that selegiline and R (-) -desmethylselegiline can beneficially protect mice from cisplatin-induced peripheral neuropathy.

Table 13: proprioceptive test

Comparison: 18 ± 1.3 seconds (mean ± SEM)

Cisplatin: 8.3 + -2.6 seconds (mean + -SEM)

Cisplatin + selegiline: 14.8 ± 1.7 seconds (mean ± SEM)

Selegiline: 16.4 + -1.7 seconds (mean + -SEM)

Cisplatin + R (-) -desmethylselegiline: 20 + -0 seconds (mean + -SEM)

R (-) -desmethylselegiline: 17.1 ± 1.1 seconds (mean ± SEM)

[00165] All p values obtained by ANOVA analysis were 0.0004. The approximate p-value obtained using the Krukal-Wallis nonparametric AVOVA test was 0.0035. A Student-Newman-Keuls multiple comparison test was used to make the individual comparisons. Suggesting that there was a difference between this group and the cisplatin group, with a p-value < 0.05.

[00166] As can be seen from the above data, none of the other groups, except the cisplatin-treated group, had a significant difference from the control group. In addition, mice in the cisplatin plus R (-) -desmethylselegiline group were the most successful in the proprioceptive test because, unlike the cisplatin plus selegiline group, all mice in this group were able to remain intact on this stake for 20 seconds despite their cisplatin treatment.

[00167] Because cisplatin primarily affects large fiber sensory function, it will typically cause abnormalities in nerve conduction velocity in the sensory nerve. Large myelin sheaths wrap around good fibers contributing most of the conduction velocity; thus, this measurement was compromised in mice with cisplatin-induced neuropathy. Axonal integrity primarily determines the potential magnitude of activity, so it is unlikely to be affected. All groups of mice were subjected to electrophysiological testing 1 week after the last dose of selegiline or R (-) -desmethylselegiline. Measurements of conduction velocity and potential magnitude of activity of the compound were obtained in the tail nerve, which passes through the tail. As shown in Table 14 below, the data suggests that cisplatin significantly reduces nerve conduction velocity, and that the use of selegiline or R (-) -desmethylselegiline does not prevent this effect. For the potential amplitude of activity, the differences between cisplatin-treated groups did not have any statistical significance.

Table 14: electrophysiology study

[00168] For conduction velocity, all p values obtained by ANOVA analysis were 0.0001. Comparisons between groups were performed using Student-Newman-Keuls multiple comparison test. Indicates that there is a difference between this group and the control group, with p < 0.05.

[00169] Following electrophysiological testing, mice were sacrificed and the four spinal ganglia removed and the neuropeptide calcitonin gene-related peptide (CGRP) determined using the radioimmunoassay. CGRP is a ubiquitous neuropeptide that is primarily associated with small fiber sensory neurons, but it is also expressed in large fiber neurons. CGRP is thought to play a role in regulating pain perception, but it may also have a broader role in the spinal ganglia. The level of CGRP was determined because a significant reduction in CGRP was found in the spinal ganglia after receiving cisplatin treatment. As expected, a significant decrease in CGRP expression was found in cisplatin-treated mice. As shown in Table 15, selegiline or R (-) -desmethylselegiline treatment also did not improve the decrease in mouse CGRP expression.

Table 15: level of CGRP

Comparison: 424.8 + -27 fmol/ganglion (mean + -SEM)

Cisplatin: 163.2. + -. 30.6X fmol/ganglion (mean. + -. sEM)

Cisplatin + selegiline: 238.2 ± 27.6 fmol/ganglion (mean ± SEM)

Selegiline: 372.9 + -33.3 fmol/ganglion (mean + -SEM)

Cisplatin + R (-) -desmethylselegiline: 227.4 + -51.6 × fmol/ganglion (mean + -SEM)

R (-) -desmethylselegiline: 331.8 ± 18.3 fmol/ganglion (mean ± SEM)

[00170] All p values obtained by ANOVA analysis were 0.0001. A Student-Newman-Keuls multiple comparison test was used to make the individual comparisons. Indicates that the group is different from the control group, and the p is less than 0.05.

[00171] As shown by the above data, cisplatin causes sensory peripheral neuropathy in surviving mice. Indicating that there is a significant difference between cisplatin-treated mice and control mice in terms of proprioception, nerve conduction velocity, and CGRP expression in sensory ganglia. Animals also treated with selegiline or R (-) -desmethylselegiline were significantly better than mice treated with cisplatin alone in behavioral measures of proprioceptive function. However, neither selegiline nor R (-) -desmethylselegiline appears to prevent cisplatin-treated alterations in nerve conduction velocity and CGRP expression. One possible explanation is that functional proprioception depends on factors other than those of normal neural function, which are responsible for nerve conduction velocity and CGRP expression. It is not surprising that this dichotomy exists because CGRP is not known to be specifically expressed in large fiber neurons responsible for proprioception. In addition, the functional significance of CGRP expression, and its relationship to clinical neuropathy, remains unclear.

Example 9: treatment of vincristine-induced peripheral neuropathy

[00172]Intravenous bolus injection of vincristine at weekly dose of 1.4mg/m was given to endometrial patients². The toxic effects of vincristine cause loss of sensation in the fingers and toes, loss of the clonic reflex of the ankle, weakness and postural hypotension. 5mg of R (-) DMS and/or S (+) DMS were applied orally to the patient twice a day, once at breakfast and once at lunch. During this period, vincristine treatment was continued and tumor response and toxic side effects were evaluated by physicians on a weekly basis. After continued treatment, symptoms associated with peripheral neuropathy subside. At this point, the vincristine dose was increased to 1.8mg/m²And this process continues. If at the end of another round of chemotherapy, increase is madeDose until the upper limit is reached. Administration of R (-) DMS and/or S (+) DMS was maintained for one month after the final dose of vincristine was administered.

Example 10: combined application of desmethylselegiline enantiomer and cisplatin

[00173]Administering cisplatin weekly to a patient suffering from ovarian cancer at a dose of 120mg/m². Simultaneously, the patient is given oral R (-) DMS and/or S (+) DMS at a dose of 5mg twice a day. After one week, the patient was evaluated for peripheral neuropathy manifestations. If no symptoms are present, the dose of R (-) DMS and/or S (+) DMS is maintained and the cisplatin dose is increased to 140mg/m²This process was continued for/week until the cisplatin upper limit was determined. The effect of this treatment on tumor progression was evaluated to determine the efficacy of this treatment.

Example 11: treatment of paclitaxel-induced peripheral neuropathy

[00174]Breast cancer patients were treated with R (-) DMS and/or S (+) DMS orally (10 mg/day) for 1 week. At the end of this period, paclitaxel treatment was started by intravenous drip of this drug at a dose of 175mg/m²The period was 3 hours. The treatment is repeated every 3 weeks for 10 cycles, with each cycle increasing the paclitaxel dose by 25mg/m². During this period, treatment with R (-) DMS and/or S (+) DMS was continued and tumor response and toxic side effects were evaluated on a weekly basis by a physician. The paclitaxel dose is continued to be increased until the side effects are unacceptably severe. After the paclitaxel treatment is finished, the treatment with R (-) DMS and/or S (+) DMS is continued for 1 month.

Example 12: alternative treatment regimens employing paclitaxel and R (-) DMS and/or S (+) DMS

[00175]Breast cancer patients are treated with R (-) DMS and/or S (+) DMS via a transdermal patch at a dose of about 0.10 mg/kg/day for a period of 1 week. At the end of this period, paclitaxel treatment was started by intravenous drip of this drug at a dose of 175mg/m²The period was 3 hours. This treatment was repeated every 3 weeks. During this period, the treatment of R (-) DMS and/or S (+) DMS is continued and is followed by the physicianTumor response and toxic side effects were evaluated on a weekly basis. If the peripheral neuropathy is unacceptably severe, the dose of R (-) DMS and/or S (+) DMS is increased to about 0.15 mg/kg/day. If unacceptable side effects persist, the paclitaxel dose is reduced to 125mg/m². The treatment cycle will continue for an extended period as long as a beneficial effect on tumor progression is obtained, or until unacceptable side effects are not eliminated. After the paclitaxel treatment is finished, the treatment with R (-) DMS and/or S (+) DMS is continued for 1 month.

Example 13: treatment of peripheral neuropathy caused by diabetic neuropathy

[00176] The oral administration (10 mg/day) of R (-) DMS and/or S (+) DMS is used for treating diabetic patients who do not suffer from diabetic neuropathy. The early treatment of R (-) DMS and/or S (+) DMS is periodically evaluated by a physician to determine whether the patient is developing any diabetic neuropathy. The long term use of R (-) DMS and/or S (+) DMS is continued to reduce the likelihood of, or eliminate the occurrence of, diabetic neuropathy in a patient. Orally (20 mg/day) administration of R (-) DMS and/or S (+) DMS reduces and/or reverses the symptoms of diabetic neuropathy in diabetic patients with diabetic neuropathy. Treatment is continued until symptoms are reduced or resolved, and then 10mg of R (-) DMS and/or S (+) DMS is administered orally daily to reduce the likelihood of, or eliminate, the occurrence of subsequent diabetic neuropathy.

Example 14: treatment of peripheral neuropathy caused by alcoholic neuropathy

[00177] Patients suffering from alcoholic peripheral neuropathy were treated with R (-) DMS and/or S (+) DMS via transdermal patch at a dose of 0.05 mg/kg/day. The treatment with R (-) DMS and/or S (+) DMS is periodically evaluated by a physician to determine whether the patient continues to suffer from alcoholic neuropathy. Long-term application of R (-) DMS and/or S (+) DMS may be necessary until the patient eliminates the predisposition for alcoholic neuropathy.

[00178] All of the compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps and in the sequence of steps of the methods described herein without departing from the concept, spirit and scope of the invention. More particularly, it will be apparent that certain agents which are chemically or physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. It will be apparent to those skilled in the art that all such similar substitutes and modifications are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

Claims (10)

1. Use of desmethylselegiline for the manufacture of a medicament for preventing or treating large fiber motor neuropathy in a subject.

2. The use of claim 1, wherein the large fiber motor neuropathy is caused by a chemotherapeutic agent.

3. The use of claim 2, wherein the chemotherapeutic agent is used to treat cancer.

4. The use of claim 1, wherein desmethylselegiline is in the form of its R (-) enantiomer, substantially free of the S (+) enantiomer.

5. The use of claim 1, wherein desmethylselegiline is in the form of its S (+) enantiomer and is substantially free of the R (-) enantiomer.

6. The use of claim 1, wherein desmethylselegiline is administered by a route which avoids absorption of desmethylselegiline from the gastrointestinal tract.

7. The use of claim 6, wherein the desmethylselegiline is applied buccally, sublingually, or parenterally.

8. The use of claim 6, wherein the desmethylselegiline is applied transdermally.

9. The use of claim 1, wherein the subject is a human.

10. The use of claim 1, wherein the desmethylselegiline is used in an amount of 0.01 mg/kg/day to 0.15 mg/kg/day, based on the weight of the free amine.