JP2005525377A - Method for prevention and treatment of peripheral neuropathy by administration of desmethyl selegiline - Google Patents

Abstract

The present disclosure relates to methods for alleviating symptoms associated with peripheral neuropathy by administering R (−)-desmethylselegiline, S (+) desmethylselegiline, or a combination of the two. . This neuropathy can be the result of a common genetic condition, systemic disease, or exposure to a toxin. This disclosure also includes chemotherapeutic agents known to have toxic effects on peripheral nerves, together with R (−)-desmethylselegiline, S (+) desmethylselegiline, or combinations of the two It relates to a method for treating a patient having cancer by administering to a patient.

Description

(Declaration on federal-funded research or development)
Not applicable (see “Microfiche Appendix”)
Not applicable (Background of the invention)
(1. Technical field)
The present invention relates to the selegiline metabolite R (−)-desmethylselegilene (or simply referred to as “desmethylselegiline” or “R (−) DMS”) alone; its enantiomer ent -Desmethyl selegiline (or "S (+)-desmethyl selegiline" or "S (+) DMS") alone; or to use a combination of the two enantiomers (eg racemic mixture) To methods and pharmaceutical compositions. In particular, the present invention uses these agents to prevent or treat peripheral neuropathy, particularly symptoms associated with peripheral neuropathy caused by exposure to a disease or toxic agent (eg, a chemotherapeutic agent). Compositions and methods for preventing or alleviating are provided.

(2. Explanation of related technology)
Peripheral neuropathy is associated with a wide variety of causes, including genetic acquired conditions, systemic disease, and exposure to toxic drugs. It is clearly a motor, sensory, sensorimotor or autonomic dysfunction.

  One of the most important toxic agents that cause peripheral neuropathy is that used for the treatment of chemotherapeutic agents, especially neoplastic diseases. In certain cases, peripheral neuropathy is a major complication of cancer treatment and is a major factor limiting the dosage of chemotherapeutic agents that can be administered to patients (Macdonald, Neurologic Clinicals 9: 955-967 ( 1991)). This is true for the commonly administered drugs cisplatin, paclitaxel, and vincristine (Broon et al., Am. J. Clin. Oncol. 16: 18-21 (1993); Macdonald, Neurological Clinics 9: 955. -967 (1991); Casey et al., Brain 96: 69-86 (1073)). The therapeutic efficacy of chemotherapeutic drugs is typically a function of dose; therefore, increasing dosage provides increased patient survival (Macdonald, Neurologic Clinics 9: 955-967 (1991). ); Oxols, Seminars in Oncology 16, Addendum 6: 22-30 (1989)). The identification of methods to prevent or alleviate the side-effects of peripheral neuropathy that limit doses allows these higher and thus more therapeutically effective doses of chemotherapeutic drugs to be administered to patients.

  Beyond the potential to increase the effectiveness of cancer chemotherapy, the identification of new methods for treating peripheral neuropathy has obvious value in reducing patient damage from a wide variety of systemic diseases and genetic conditions. Have. In many cases, progressive neuropathy in the peripheral nervous system is debilitating or lethal.

  Currently, there are several types of drugs that are useful for treating peripheral neuropathy. Examples of drugs that have been shown to be useful in the treatment of peripheral neuropathy include prednisone and IVIg for the treatment of chronic inflammatory polyneuropathy or immune-mediated polyneuropathy; For the treatment of inflammatory neuropathies, cyclophosphamide; used to treat viral infectious neuropathies are famiciclovir, tegretol, tricyclic antidepressants, gevapentin, topical Sex lidocaine, ribavirin, and other immunomodulating agents; and dapsone, clofazamin, rifampin, niflutimox, and benznidaxol for the treatment of bacterial infectious neuropathies. Ganciclovir and foscanet can also be used to treat cytomegalovirus multiple peripheral neuropathy in patients infected with HIV. Selegiline can also be used to alleviate, reduce or eliminate symptoms associated with peripheral neuropathy, as described in US Pat. No. 6,239,181 (incorporated herein by reference). Peripheral neuropathy can be caused, for example, by genetic inheritance, systemic disease, physical injury, or exposure to toxic or chemotherapeutic agents.

  Two different monoamine oxidase enzymes 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 parts, indicating that they are independently encoded at different gene positions. In addition, analysis of the two proteins shows differences in their respective amino acid sequences.

  The first compounds found to selectively inhibit MAO-B are (R) -N-α-dimethyl-N-2-propynylbenzethanamine (also L-(−)-N-α). -N-2-propynylphenethylamine, (-)-deprenyl, also known as L-(-)-deprenyl, R-(-)-deprenyl, or selegiline). Seresillin has the following structural formula:

セレジリンは、広範な種類の投与経路および投薬形態を介して被験体ヘ投与される場合に有用であることが公知である。例えば、米国特許第４，８１２，４８１号（Ｄｅｇｕｓｓａ ＡＧ）は、経口的（ｏｒａｌ）処方、経口的（ｐｅｒｏｒａｌ）処方、経腸的処方、経肺的処方、経直腸的処方、経鼻処方、経腟処方、経舌処方、静脈内処方、動脈内処方、心臓内処方、筋肉内処方、腹腔内処方、皮内処方、および皮下処方でのセレジリン−アマンタジンの調合薬の使用を開示している。米国特許第５，１９２，５５０号（Ａｌｚａ Ｃｏｒｐｏｒａｔｉｏｎ）は、セレジリンに対しては不透過性であるが、外部の流体に対しては透過性である外壁を含む投薬形態を記載する。この投薬形態は、セレジリンの経口投与、舌下投与または粘膜投与に対する適用性を有し得る。同様に、米国特許第５，３８７，６１５号は、種々のセレジリン組成物（錠剤、丸剤、カプセル、粉末、エアロゾル、坐剤、皮膚パッチ、注射、ならびに経口性液体（油水サスペンジョン、溶液、およびエマルジョンを含む）が挙げられる）を開示する。また、セレジリン含有徐放性（長時間作用性）処方物およびデバイスも開示する。

Seresillin is known to be useful when administered to a subject via a wide variety of administration routes and dosage forms. For example, U.S. Pat. No. 4,812,481 (Degussa AG) includes oral formulations, oral formulations, enteral formulations, pulmonary formulations, rectal formulations, nasal formulations, Discloses the use of selegiline-amantadine formulations in vaginal, lingual, intravenous, intraarterial, intracardiac, intramuscular, intraperitoneal, intradermal, and subcutaneous formulations . US Pat. No. 5,192,550 (Alza Corporation) describes a dosage form that includes an outer wall that is impermeable to selegiline but permeable to external fluids. This dosage form may have applicability for oral, sublingual or mucosal administration of selegiline. Similarly, US Pat. No. 5,387,615 describes various selegiline compositions (tablets, pills, capsules, powders, aerosols, suppositories, skin patches, injections, and oral liquids (oil-water suspensions, solutions, and Including emulsions). Also disclosed are selegiline-containing sustained release (long-acting) formulations and devices.

  Although a MAO-B inhibitor with high potency and selectivity, the use of selegiline can be limited by dose-dependent selectivity to MAO-B. The selectivity of selegiline in the inhibition of MAO-B is important for the safety profile following oral administration. Inhibition of MAO-A at peripheral sites (eg, gastric epithelium, liver parenchyma, and sympathetic neurons) can interfere with, for example, dietary tyramine metabolism and cause toxic side effects. Tyramine is normally metabolized in the gastrointestinal tract by MAO-A, but when MAO-A is inhibited, tyramine absorption follows consumption of tyramine-containing foods (eg, cheese, beer, herring, etc.) Increase. This results in the release of catecholamines that can be involved in the hypertensive response referred to as the “cheese effect”. This effect has been characterized by Goodman and Gilman as the most serious toxic effect associated with MAO-A inhibitors.

  Seresillin is metabolized to N-desmethyl analogs and other metabolites. Structurally, this N-desmethyl metabolite has the formula:

の２級アミンであるＲ（−）エナンチオマー形態のＲ（−）ＤＭＳである。

R (-) DMS in the R (-) enantiomer form, which is a secondary amine.

  So far, R (−) DMS has not been known to have a pharmaceutically useful MAO-related effect, ie, a potent and selective inhibitory effect on MAO-B. In the course of determining the effectiveness of R (-) DMS for the purposes of the present invention, the MAO-related effects of R (-) DMS were more fully characterized. This characterization demonstrates that desmethyl selegiline has a very weak MAO-B inhibitory effect and has no advantage in selectivity for MAO-B compared to selegiline.

For example, by this characterization, selegiline has an IC ₅₀ value of 5 × 10 ⁻⁹ M against MAO-B of human platelets, while R (−) DMS has an IC ₅₀ of 4 × 10 ⁻⁷ M. It has been demonstrated that it has a value, indicating that the latter is about 1/80 weaker than the former as a MAO-B inhibitor. Similar characteristics can be seen in the following data measured for inhibition of MAO-B and MAO-A in the mitochondrial-rich fraction of rat cortex:

上記の表から明らかなように、セレジリンは、ＭＡＯ−Ａに対してよりも、ＭＡＯ−Ｂ阻害剤として約１２８倍強力であり、Ｒ（−）ＤＭＳはＭＡＯ−Ａに対してよりも、ＭＡＯ−Ｂ阻害剤として約９７倍強力である。従って、Ｒ（−）ＤＭＳは、実質的に効力が減少しているが、セレジリンとして、ＭＡＯ−Ａと比較して、ほぼ同等のＭＡＯ−Ｂに対する選択性を有するようである。

As is apparent from the table above, selegiline is about 128 times more potent as a MAO-B inhibitor than against MAO-A, and R (−) DMS is MAO more than against MAO-A. -97 times more potent as a B inhibitor. Thus, R (-) DMS appears to have substantially the same selectivity for MAO-B as selegiline compared to MAO-A, although it is substantially less potent.

Similar results are obtained with rat brain tissue. Selegiline has an IC ₅₀ value of 0.11 × 10 ⁻⁷ M against MAO-B, while R (−) DMS has an IC ₅₀ value of 7.3 × 10 ⁻⁷ M, This indicates that R (-) DMS is about 1/70 weaker as a MAO-B inhibitor compared to selegiline. Both compounds show low potency in inhibiting MAO-A in rat brain tissue (0.18 × 10 ^{−5 for} selegiline, 7.0 × 10 ⁻⁵ for R (−) DMS). Thus, in vitro R (-) DMS is about 39 times more potent than MA selegiline in inhibiting MAO-A.

  Based on the above pharmacological profile, R (-) DMS as a MAO-B inhibitor provides no advantage in either efficacy or selectivity compared to selegiline. Indeed, the above in vitro data suggests that the use of R (−) DMS as a MAO-B inhibitor requires an order of 70 times the amount of selegiline.

  The in vivo potency of R (-) DMS as a MAO-B inhibitor is described in Heinonen, E .; H. (In the academic paper “Selegilline in the Treatment of Parkinson's Dissease” (Research Reports from The Department of Neurology, University of Turk, 59. 59F. R (−) Desmethylelegileine, a metabolites of selegiline, is an irreversible inhibitor of MAO-B in human subjects ”). According to Heinonen, R (-) DMS in vivo has only about one-fifth the effect of selegiline's MAO-B inhibitory effect. That is, a dose of 10 mg desmethylselegiline is required for the same MAO-B effect as 1.8 mg selegiline. In rats, Borbe reports that R (-) DMS is an irreversible inhibitor of MAO-B that has about 1/60 the potency of selegiline in vitro and about 1/3 the potency ex vivo. (Barbe, HO, J Neural Trans. (Appendix): 32: 131 (1990)). Thus, all these previous studies have shown that R (-) DMS is a less preferred and less effective MAO inhibitor than selegiline and, therefore, is an undesirable therapeutic compound. Reporting.

(Simple Summary of Invention)
The present invention is based on the surprising discovery of R (-) DMS and its enantiomer S (+) DMS. S (+) DMS has the following structure:

を有する。Ｒ（−）ＤＭＳおよびＳ（＋）ＤＭＳは、セレジリンと比較してＭＡＯ−Ｂ阻害活性の劇的な減少および強いＭＡＯ−Ｂ選択性の明らかな欠失があるにもかかわらず、被験体にセレジリン様効果を提供する際に特に有用である。驚くべきことに、Ｒ（−）ＤＭＳ、Ｓ（＋）ＤＭＳおよびこの２つの組合せ（例えば、ラセミ混合物）は、末梢神経障害に関する症状の全体または一部を緩和、軽減、または除去し得る。特に、本開示は、末梢神経障害に関する症状の１つ以上を予防、処置、軽減、または除去するために十分な量で、Ｒ（−）ＤＭＳ、Ｓ（＋）ＤＭＳまたはその２つの組合せを投与することによって、毒性の薬剤によって引き起こされる末梢神経障害から患者を保護するか、またはその末梢神経障害の患者を処置する方法を提供する。代表的には、患者はヒトであり、毒性の薬剤は化学療法剤（例えば、癌の処置において投与される薬剤）である。本方法は、末梢神経障害を引き起こす任意の毒性の化学療法剤に対して効果的であるが、特に重篤な神経障害性の副作用を伴う薬剤（例えば、シスプラチン、パクリタキセル、ビンクリスチンおよびビンブラスチン）に対して、最も効果的である。

Have R (−) DMS and S (+) DMS have been found in subjects despite a dramatic decrease in MAO-B inhibitory activity and a clear lack of strong MAO-B selectivity compared to selegiline. It is particularly useful in providing a seresylline-like effect. Surprisingly, R (−) DMS, S (+) DMS and combinations of the two (eg, racemic mixtures) can alleviate, reduce or eliminate all or part of the symptoms associated with peripheral neuropathy. In particular, the present disclosure administers R (−) DMS, S (+) DMS or a combination of the two in an amount sufficient to prevent, treat, reduce or eliminate one or more of the symptoms associated with peripheral neuropathy. By providing a method for protecting a patient from peripheral neuropathy caused by a toxic agent or treating a patient with that peripheral neuropathy. Typically, the patient is a human and the toxic agent is a chemotherapeutic agent (eg, an agent administered in the treatment of cancer). This method is effective for any toxic chemotherapeutic agent that causes peripheral neuropathy, but especially for drugs with severe neuropathic side effects (eg cisplatin, paclitaxel, vincristine and vinblastine) Is the most effective.

The present disclosure provides novel pharmaceutical compositions that use R (-) DMS, S (+) DMS, or a combination of the two (eg, a racemic mixture) as the active ingredient. Also provided are novel methods of treatment involving administration of these compositions. More particularly, the present invention provides the following:
(1) A pharmaceutical composition comprising an amount of R (−) DMS, S (+) DMS, or a combination of the two, wherein one or more unit doses of the periodically administered composition is one or more A pharmaceutical composition that is effective to fully or partially treat or ameliorate peripheral neuropathy in a subject to whom a unit dose of is administered. The composition can be formulated for parenteral or oral administration.

  (2) A method for treating peripheral neuropathy in a subject (eg, a mammal), which is effective for completely or partially preventing, treating, reducing or eliminating the peripheral neuropathy A method comprising the step of administering to the mammal R (-) DMS, S (+) DMS or a combination of the two in a schedule. For example, a daily dose of at least about 0.0015 mg is administered on one or multiple dosing schedules. Here, the dose is calculated for 1 kg body weight of the mammal based on the free secondary amine.

  (3) A transdermal delivery system for use in treating a peripheral neuropathy in a subject comprising a layered structure consisting of one or more layers. This transdermal delivery system has a sufficient amount of R (−) DMS, S (+) to provide a daily transdermal dose of at least about 0.0015 mg of free secondary amine per kg body weight of the mammal. Having at least one layer comprising DMS or a combination of the two.

  (4) A therapeutic package for distribution to, or use in, distribution to a subject to be treated with peripheral neuropathy. The package includes one or more unit doses, each such unit dose comprising an amount of R (-) DMS such that periodic administration is effective in treating a subject's peripheral neuropathy, S (+) DMS or a combination of the two. The therapeutic package also includes a unit dose of R (−) DMS, S (+) DMS, or a combination of the two, and further includes a label indicating the use of the package in the treatment of peripheral neuropathy (contain) or Comprises the completed pharmaceutical container. This unit dose can be adapted for oral administration (eg, tablets or capsules) or can be adapted for parenteral administration.

  (5) A method of distributing R (−) DMS, S (+) DMS, or a combination of the two to subjects to be treated for peripheral neuropathy. The method has one or more dosage units of desmethyl selegiline, ent-desmethyl selegiline, or a combination of the two in an amount such that periodic administration to the patient is effective in the treatment of peripheral neuropathy Providing a therapeutic package to the patient. The package also includes a finished pharmaceutical container that includes desmethyl selegiline, ent-desmethyl selegiline, or a combination of the two, with a label that indicates use of the package in the treatment of peripheral neuropathy. This unit dose in the package can be adapted for either oral or parenteral use.

  Preferred embodiments of the present disclosure include in a subject in need of prophylaxis or treatment of a toxic agent; genetic inheritance; systemic disease; or peripheral neuropathy caused by compression, trauma, or entrapment. A method for such prevention or treatment, wherein the subject is treated with R (−)-desmethylselegiline, S (+)-desmethylselegiline, or R (−)-desmethylselegiline and S This is done by administering a mixture of (+)-desmethyl selegiline. Preferably, one or more enantiomers of desmethyl selegiline is administered in an amount sufficient to prevent, reduce or eliminate one or more symptoms associated with peripheral neuropathy. In preferred embodiments, the subject is a mammal, more preferably a human or livestock animal.

  In a preferred embodiment, the toxic agent that causes peripheral neuropathy is selected from the group consisting of drugs, industrial chemicals, and environmental toxins. Preferably, it is treated or prevented by R (−)-desmethyl selegiline, S (+)-desmethyl selegiline, or a mixture of R (−)-desmethyl selegiline and S (+)-desmethyl selegiline. Drugs that cause peripheral neuropathy are chloramphenicol, colchicine, dapsone, disulfiram, amiodarone, gold, isoniazid, misonidazole, nitrofurantoin, perhexiline, propaphenone, pyridoxine, phenytoin, simvastatin, tacrolimus , Thalidomide, or zalcitabine. In another preferred embodiment, the toxic agent is acrylamide, arsenic, carbon disulfide, hexacarbon, lead, mercury, platinum, organic phosphate, thallium, or a chemotherapeutic agent. Preferably, the chemotherapeutic agent is cisplatin, paclitaxel, vincristine, or vinblastine, and the chemotherapeutic agent is administered for the treatment of cancer in the subject.

  In preferred embodiments, the genetically inherited condition that causes peripheral neuropathy is Charcot-Marie-Tooth disease, Dujline-Sotta disease, Riley-Day syndrome, porphyria, giant axonal neuropathy, and Fleetrich ataxia It is selected from the group consisting of (Friedrich's taxia). In another preferred embodiment, the peripheral neuropathy caused by systemic disease is acquired primary demyelinating neuropathy, distal symmetric multiple sensory neuropathy, distal symmetric multiple sensorimotor neuropathy, vascular Selected from the group consisting of neuropathy, infectious neuropathy, idiopathic neuropathy; immune-mediated neuropathy; nutrition-related neuropathy, and paraneoplastic neuropathy. In preferred embodiments, the acquired primary demyelinating neuropathy is chronic inflammatory demyelinating polyradiant neuropathy (CIDP), acute inflammatory demyelinating polyneuropathy (AIDP), or Giant-Barre syndrome. In another preferred embodiment, the infectious neuropathy is caused by herpes simplex, herpes zoster, hepatitis B, hepatitis C, HIV, cytomegalovirus, diphtheria, Ley's disease, or Lyme disease. In yet another preferred embodiment, the systemic disease is alcoholic neuropathy, diabetes mellitus, uremia, rheumatoid arthritis, sarcoidosis, pernicious anemia, or thyroid failure. In preferred embodiments, compressions that cause peripheral neuropathy include carpal tunnel syndrome, ulnar neuropathy at the elbow or wrist, general peroneal ulnar neuropathy at the knee, ulnar neuropathy at the tibial nerve at the knee, and Selected from the group consisting of ulnar neuropathy with the sciatic nerve.

Another preferred embodiment of the present disclosure is a method of treating a subject having cancer, the method comprising:
a) administering to a 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) R (−)-desmethyl selegiline, S (+)-desmethyl selegiline, or a mixture of R (−)-desmethyl selegiline and S (+)-desmethyl selegiline, Co-administering to a patient at a dose effective to reduce or eliminate peripheral neuropathy associated with the therapeutic agent;
Is included. R (-)-desmethyl selegiline, S (+)-desmethyl selegiline, or a mixture of R (-)-desmethyl selegiline and S (+)-desmethyl selegiline, if appropriate, administered in combination While functioning to minimize the toxic effects of the drug on peripheral nerves, the dose of the chemotherapeutic agent can be increased to optimize the therapeutic benefit of the drug. Thus, high dose chemotherapeutic agents can be administered to patients while peripheral neuropathy often associated with high doses is reduced or eliminated.

  Preferred embodiments of the present disclosure include a subject in need of prophylaxis or treatment of large fiber peripheral neuropathy, small fiber peripheral neuropathy, peripheral sensory neuropathy, peripheral motor neuropathy, peripheral sensorimotor neuropathy, or peripheral autonomic neuropathy A method for performing such prevention or treatment in the body: R (−)-desmethylselegiline, S (+)-desmethylselegiline, or R (−)-desmethylselegiline and S ( +)-Desmethyl selegiline is administered to a subject. Preferably, one or more enantiomers of desmethyl selegiline is administered in an amount sufficient to prevent, reduce or eliminate one or more symptoms associated with a particular peripheral neuropathy. In preferred embodiments, the subject is a mammal, more preferably a human or livestock animal.

  In a preferred embodiment, the large-fiber peripheral neuropathy is a large fiber sensory neuropathy or a large fiber motor neuropathy resulting from dysfunction or pathological changes in large myelinated axons. In another preferred embodiment, the small-fiber peripheral neuropathy results from dysfunction or pathological changes of small or non-myelinated axons. In yet another preferred embodiment, the peripheral autonomic disorder results from peripheral autonomic dysfunction, preferably the peripheral autonomic nerve is associated with a small myelinated nerve.

  A preferred embodiment of the present disclosure is a method for preventing or treating motor neuron disease, and in a subject in need of such prevention or treatment, R (−)-desmethylselegiline, S (+) -Desmethyl selegiline or a mixture of R (-)-desmethyl selegiline and S (+)-desmethyl selegiline is administered to a subject. Preferably, one or more enantiomers of desmethyl selegiline is administered in an amount sufficient to prevent, reduce or eliminate one or more symptoms associated with motor neuron disease. In preferred embodiments, the subject is a mammal, more preferably a human or livestock animal. In another preferred embodiment, the motor neuron disease results from degeneration of upper motor neurons, lower motor neurons, or upper and lower motor neurons. In yet another preferred embodiment, the motor neuron disease is progressive bulbar palsy, spinal muscular atrophy, Kugelberg-Welander syndrome, Duchenne palsy, post-Polio syndrome, Verdwig-Hoffmann disease, Kennedy disease, and benign focal Selected from the group consisting of amyloidosis.

  In a preferred embodiment, R (−)-desmethylselegiline or S (+)-desmethylselegiline is administered in a substantially enantiomerically pure form. In other preferred embodiments, R (−)-desmethyl selegiline and / or S (+)-desmethyl selegiline are administered as the free base or acid addition salt. Preferably, the acid addition salt is a hydrochloride salt. In yet another preferred embodiment, R (−)-desmethyl selegiline, S (+)-desmethyl selegiline, or a combination of the two is administered orally or parenterally. Preferably, the enantiomer of desmethyl selegiline is administered by a route that avoids absorption of the enantiomer of this desmethyl selegiline from the gastrointestinal tract. Preferred routes of parenteral administration are the transdermal route, the buccal route, the sublingual route, and the parenteral route. In yet another preferred embodiment, R (−)-desmethyl selegiline and / or S (+)-desmethyl selegiline is 0.01 mg / kg to 0.15 mg / kg (weight of free amine) per day. At a dose between

  Another preferred embodiment of the present disclosure is R (−)-desmethyl selegiline, S (+)-desmethyl selegiline, or R (−)-desmethyl selegiline and S (+)-desmethyl selegiline. And a second therapeutic agent useful in the treatment of peripheral neuropathy. In preferred embodiments, one or more therapeutic agents are included in the pharmaceutical composition. In another preferred embodiment, R (−)-desmethyl selegiline, S (+)-desmethyl selegiline, or a combination of R (−)-desmethyl selegiline and S (+)-desmethyl selegiline, And the second therapeutic agent in an amount such that one or more unit dose compositions are effective to treat, prevent, reduce or eliminate peripheral nerve injury in a subject. It exists in things. In other preferred embodiments, R (−) DMS and / or S (+) DMS are administered as the free base or acid addition salt. Preferably, the acid addition salt is a hydrochloride salt. In another preferred embodiment of the present disclosure, a second therapeutic agent useful in the treatment of peripheral neuropathy is prednisone, IVIg, cyclophosphamide, famciclovir, tegretol, tricyclic system Antidepressant, dapsone, clofazimine, rifampin, nifurtimox, benznidaxole, gabapentin, ganciclovir, foscanet, cidofovir, acyclovir, selected from the group of lidocaine, topical lidocaine, and the topical lidavirin,

  In other preferred embodiments, R (−) DMS, S (+) DMS, or a combination of the two enantiomers in a unit dose pharmaceutical composition is about 0.015 to about 5.0 mg / kg. Between, and more preferably between about 0.6 and about 0.8 mg / kg (calculated for the base of the free secondary amine). In another preferred embodiment, R (−) DMS, S (+) DMS, or a combination of the two enantiomers in a unit dose pharmaceutical composition is between about 1.0 mg and about 100.0 mg. More preferably between about 5.0 mg and about 10.0 mg. In yet another preferred embodiment, the pharmaceutical composition is for oral administration, parenteral administration, or transdermal administration. In a preferred embodiment, the pharmaceutical composition is a transdermal patch.

(Detailed description of the invention)
In the following description, reference is made to various methodologies well known to those skilled in the fields of medicine and pharmacology. Such methodologies are described in standard references that describe the general principles of these fields.

  The present disclosure relates to the prevention or treatment of peripheral neuropathy using R (−) DMS, S (+) DMS, or a combination of R (−) DMS and S (+) DMS. Peripheral neuropathy is a common feature 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 is composed of the brain and spinal cord, and the PNS is composed of all other nerves. The CNS is housed in the spinal cavity in the body. This spinal cavity builds the cranial cavity and houses the brain and spinal canal. This spinal canal contains the spinal cord. As used herein, the term “peripheral neuropathy” refers to peripheral nerve dysfunction or pathological changes. Peripheral nerves located in the PNS include cranial nerves (except the second), spinal ganglia, spinal ganglia, peripheral nerve trunks and their terminal branches, and the peripheral autonomic nervous system. For example, but not limited to. The CNS communicates with the body using the peripheral nervous system. Any injury to the peripheral nervous system impairs this communication.

  Peripheral neuropathy (also known as peripheral neuritis) is a symptom of many disorders that can cause damage to peripheral nerves. Many different symptoms are associated with peripheral neuropathy, a symptom of injury. Symptoms vary widely depending on the cause of the peripheral neuropathy and the specific type of nerve affected. For example, the symptoms are sensory nerve fibers (fibers that transmit sensory information from the affected area to the CNS), motor nerve fibers (fibers that transmit impulses from the CNS to muscles and enhance movement). , Or both. Clinical diagnosis of peripheral neuropathy includes subject clinical history, physical examination, use of electromyography (EMG) and nerve conduction studies (NCS), autonomic nerve testing, cerebrospinal fluid analysis, and nerve biopsy Based. Because so many types of disorders develop as peripheral neuropathy by affecting a wide range of neuronal types, clinical assessment and diagnosis of the cause of peripheral neuropathy can be difficult.

  Peripheral neuropathy can be classified primarily by the type of fiber involved. The peripheral nerve is composed of various types of axons. For example, large fiber peripheral neuropathy typically involves large myelinated axons (including motor and sensory axons) that transmit vibrational sensations, proprioception, and light contact. Somatosensory nerves are myelinated fibers with cell bodies in the spinal ganglia (dorsal horn). Somatic motor nerve fibers are myelinated and have cell bodies in the anterior horn and brainstem of the spinal cord. Small fiber peripheral neuropathy mainly includes the following fiber types: 1) small myelinated axons that contain autonomous nerve fibers and sensory axons, and transmit sensory senses of light contact, pain, and temperature; and 2) A small unmyelinated axon that is a sensory nerve and that carries pain and temperature sensations. Many visceral nerves are nonmyelinated fibers that contain sensory and motor nerve elements. Dysfunction of any type of peripheral nerve (eg, sensory nerve, motor nerve, sensorimotor nerve, autonomic nerve, or enteric nerve) can develop any of the various symptoms discussed herein.

  Peripheral neuropathies include hereditary peripheral neuropathy; idiopathic peripheral neuropathy; immune-mediated peripheral neuropathy; infectious peripheral neuropathy; tumor-associated peripheral neuropathy; toxic, nutritional, and drug-induced peripheral neuropathy As well as, but not limited to, traumatic peripheral neuropathy and compressive peripheral neuropathy. The purpose of this disclosure is to use R (−) DMS, S (+) DMS, or R (−) DMS and S (+) DMS to prevent, treat, reduce or eliminate symptoms associated with peripheral neuropathy. Administration of a racemic mixture.

  There are a limited number of ways in which nerves in the PNS can respond to injury or injury. In the periphery, cell bodies are typically found as clusters known as ganglia. A nerve is a bundle of axons that extends along with the periphery. An axon is a process of nerve cells that transmits efferent (outward) nerve impulses out of the cell body under normal conditions, as well as the remaining processes (dendrites). Transmits impulses to target cells. Axons can transmit nerve impulses (action potentials) over some distance. The efferent nerve controls voluntary and involuntary movements. The centripetal part of the PNS sends sensory information from the body to the CNS, and the efferent part of the PNS sends information from the CNS to the body. In the PNS, myelinated axons are surrounded by a myelin sheath, which is provided by cells known as Schwann cells. Myelinated axons are enveloped by concentric cell membrane layers that originate from Schwann cells in the peripheral nervous system. The presence of the myelin sheath around the axon increases the speed at which the axon can transmit nerve impulses downstream. Along the axon, a non-insulating axon space is created between the myelin packages. Since nerve impulses effectively jump from one space to another between insulating cells, the transmission of nerve impulses increases.

  Axonal injury is injury that occurs at the level of axons. This injury can result in axonal destruction (eg, due to trauma), which can result in degeneration of axons and myelin sheaths (also called Wallerian degeneration) distal to the injury site. In many toxic and metabolic injuries to PNS, the most distal part of the axon degenerates, which also breaks down the myelin sheath ("dying back" or length-dependent nerves). Also known as an obstacle). There are also many peripheral neuropathies with a mixture of both axonal degeneration and demyelination. Myelinopathy, or acquired demyelinating neuropathy, results in degeneration of the myelin sheath and the axons remain relatively intact. R (−) DMS, S (+) DMS, or a combination of R (−) DMS and S (+) DMS can also treat peripheral neuropathy by increasing the survival of Schwann cells, thereby axonal Reduce demyelination. Neuropathy occurs at the level of spinal ganglia or motor neurons, followed by peripheral process degeneration.

  Peripheral neuropathy can involve injury to one nerve or group of nerves (mononeuropathy) or can involve multiple nerves (polyneuropathy). Peripheral nerve injury can be localized, multiple, symmetric, or asymmetric, and can be caused by pressure damage (eg, direct damage or compression of nerve cells by other adjacent body structures). Trauma, compression, and entrapment are common causes of localized nerve damage. Compression is caused by peripheral nerve tumors, tumors that push nerve tissue, abnormal bone growth, cysts or aggregates of other fluids or tissues that compress nerves, cast bandages, splints, braces, crutches, or other devices Can be. Nerve damage can also result from being placed in a clamped position or one position over a long period of time. Entrapment peripheral neuropathy can result from nerve compression when passing through confined spaces, and mechanical factors can be complicated by ischemia.

  One class of peripheral neuropathy is focal neuropathy. Localized neuropathies include general compression neuropathy (which can be accompanied by acute arterial occlusion), carpal tunnel syndrome, elbow (tardy unnar palsy) or ulnar neuropathy at the wrist, elbow Ulnar neuropathy in the proximal median nerve of the wrist, proximal medial neuropathy of the wrist, anterior interosseous neuropathy, peroneal neuropathy of the upper arm, sciatic neuropathy, peroneal neuropathy in the radial head or knee, tibial neuropathy of the knee , Lateral femoral neuropathy (sensory abnormal femoral neuralgia), lateral femoral cutaneous neuropathy, or accessory nerve in the posterior cervical triangle of the neck. In addition, ischemia is thought to be the basis of the mild distal neuropathy of erythrocytosis.

  Another class of peripheral nerve injury is sensory nerve injury. Sensory nerve injury typically involves dysfunction or injury of peripheral sensory neuronal neurons. This dysfunction or injury may include loss of sensation, numbness, stinging, abnormal sensation (dysthesia), burning sensation, pain (neuralgia), decreased sensation, and / or within an area (eg, extremity or elsewhere) Loss of function that determines joint sensation in For example, the subject may experience numbness in the fingers and / or toes. The sensation often begins with the legs or hands and progresses to the center of the body. Peripheral sensory nerve injury can result from degeneration of the axon portion of the nerve cell or loss of the myelin sheath that can surround the nerve cell axon.

  Motor nerve injury is another class of peripheral neuropathy. Peripheral motor nerve injury typically involves dysfunction or injury of the motor fiber, which can impair the movement or function of the area provided by the nerve (because impulses to this area are blocked). . Impaired nerve stimulation to muscle groups may result in weakness, decreased movement, reduced or lack of control of movement, difficulty or inability to move parts of the body (paralysis), loss of muscle function or sensation, Muscle atrophy, leg pain, or muscle spasm (bundle contraction) can occur. This dysfunction typically develops clumsiness when doing physical work, or muscle weakness. For example, a patient may experience difficulty in buttoning a shirt or putting hair together. Due to muscle weakness, after a relatively small exercise, the patient can become very tired and in some cases, difficulty in getting up or walking can occur.

  Structural changes in muscle, bone, skin, hair, nails, and body tissue can also result from loss of nerve function, lack of nerve stimulation, dysfunction of affected areas, immobility, or lack of weight support. Peripheral motor nerve injury can develop muscle sputum or muscle atrophy (loss of muscle mass) in a subject.

  Motor nerve injury often includes many acquired primary demyelinating neuropathies (eg, Guyan-Barre syndrome). Other proximal symmetric motor polyneuropathy is chronic inflammatory demyelinating multiple radiation neuropathy (CIDP); diabetes mellitus; porphyria; osteosclerotic myeloma; Waldenstrom macroglobulinemia Castleman's disease; monoclonal hypergammaglobulinemia of undefined severity; acute multiple neuropathy caused by arsenic; lymphoma; diphtheria; HIV / AIDS; Lyme disease; thyroid dysfunction; and vincristine toxicity obtain. Demyelinating peripheral neuropathies include CIDP, osteosclerotic myeloma, diphtheria, perhexiline toxicity, chloroquine toxicity, FK506 (tacrolimus) toxicity, procainamide toxicity, zimeldine toxicity, monoclonal protein-related peripheral Examples include, but are not limited to, neuropathy, types 1 and 3 of hereditary motor sensory peripheral nerve injury, and hereditary susceptibility to pressure palsy.

  Motor nerve injury can also occur in motor neuron disease (MND). This is because MND can involve injury to peripheral motor neurons. MNDs include a group of severe neurological injuries characterized by progressive motor neuron degeneration without sensory abnormalities. MNDs can affect upper motor neurons (the nerves that lead from the brain to the spinal cord); lower motor neurons (the nerves that lead from the spinal cord to the body muscles); or both upper and lower motor neurons. Injuries to upper motor neurons are indicated by signs of convulsions, exaggerated reflexes, and extensor planters. Injury to lower motor neurons is indicated by progressive itch (atrophy) and weakness of muscles that have lost their nerve supply. Human MND is characterized by signs of complete paralysis and various other movements. MNDs include amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), progressive bulbar paralysis, spinal muscular atrophy (all types), Kugelberg-Welander syndrome, Duchenne paralysis, post-Polio syndrome, Verdonich -Including but not limited to Hoffman disease, Kennedy disease, juvenile spinal muscular atrophy, benign focal muscular atrophy, and infantile spinal muscular atrophy.

  In most cases of MND, degeneration occurs in both upper and lower motor neurons. For example, ALS is characterized by muscle weakness, muscle stiffness, and muscle bundle contraction (muscle spasm). In progressive ball paralysis, only the muscles involved in speech and swallowing are affected. Uncommon forms of MND involve selective degeneration of either upper motor neurons (eg, primary lateral sclerosis) or lower motor neurons (progressive muscular atrophy). There are overlaps to consider between these forms of MND. R (−) DMS, S (+) DMS or a combination of R (−) DMS and S (+) DMS if the disease involves upper motor neurons, lower motor neurons, or upper and lower motor neuron force methods Can be used to treat MND.

  Sensorimotor nerve injury is another type of peripheral nerve injury. Sensorimotor neuropathy involves both sensory and motor neurons, and is typically referred to as a mixed nerve with afferent fibers and efferent nerves. Peripheral nerve injury due to many toxicants and metabolites appears as a distal symmetric process or a dieing back process. Distal symmetric multiple sensorimotor neuropathies are endocrine disorders (eg, diabetes mellitus, thyroid dysfunction, and acromegaly); nutritional disorders (eg, alcoholism, vitamin B12 deficiency, folate deficiency, Whipple disease) , Thiamine deficiency, gastric restraint, and gastrectomy); infectious diseases (eg, HIV and Lyme disease); joint tissue diseases (eg, rheumatoid arthritis, nodular polyarteritis, systemic lupus, erythema, Churg- Strauss syndrome, and cryoglobulinemia); neurotoxicity caused by poisons (due to acrylamide, carbon disulfide, dichlorophenoxyacetic acid, ethylene oxide, hexacarbon, carbon monoxide, organophosphates, or glu sniffing); Medicinal neuropathy (eg, vincristine, paclitaxel) Nitrous oxide, colchicine, isoniazid, amitriptyline, ethambutol, disulfiram, cimetidine, phenytoin, dapsone, α-interferon, lithium, didanosin, pyridoxine, metronidazole, hydralazine, cisplatin, thalidomide, pyridoxine, amiodarone, amiodarone, Hypophosphatemia; cancerous axonal polysensorymotor neuropathy; lymphomaous axonal polysensorymotor neuropathy; sarcoidosis; amyloidosis; gouty neuropathy; or chronic arsenic poisoning, copper, gold Or metallic neuropathy caused by lithium.

  The autonomic nervous system is a part of the peripheral nervous system that controls involuntary or semi-voluntary functions (eg, control of internal organs). The autonomic nervous system, also called the visceral motor system, includes neurons that convey motor outflow to the heart muscle, smooth muscle, and glands. The autonomic nervous system is generally divided into two parts: the parasympathetic part and the sympathetic part; the functional activities of the two divisions are almost opposite each other. For example, the parasympathetic department controls the function of increasing heart rate, while the sympathetic department generally functions to decrease heart rate.

  Peripheral autonomic neuropathy is typically accompanied by peripheral autonomic dysfunction, which can cause changes in organ function and symptoms (eg, blurred vision, double vision, reduced or disappearance of sweating ability (anhidrosis) ), Dizziness or fainting (postural hypotension), decreased thermoregulatory ability, heat intolerance, disruption of stomach or intestinal function (eg nausea, vomiting, constipation, or diarrhea), often associated with decreased blood pressure Satiety after a small meal (early satiety), unintentional weight loss (greater than 5% weight loss), abdominal bloating, impaired bladder function (eg, urinary incontinence or difficulty starting urination), sexual function Failure (eg, male inability), heart abnormalities, and other toxicities can occur.

  Diabetes mellitus (also referred to herein as “diabetes”) is a systemic disease that primarily affects the peripheral nervous system. Diabetes is also the most common cause of peripheral neuropathy. Almost all individuals who have been diabetic for longer than 10-15 years have some evidence of neurosis. Nearly every aspect of the nervous system, including the central nervous system and its supporting structures, can be affected by diabetic complications. Abnormally high concentrations of glucose in the circulating blood (hyperglycemia) can be seen in diabetic patients. Diabetes is an important risk factor for stroke, peripheral neuropathy, retinal disorders, and nephropathy. Other complications of diabetes are diabetic ketoacidosis and diabetic coma, hyperosmotic non-ketotic coma, chronic diabetic brain injury, cataract formation, and glaucoma.

  Peripheral neuropathy is the most common complication of diabetes among several. These disorders are referred to as diabetic neuropathy. About two-thirds of diabetic patients suffer from one or more forms of diabetic peripheral neuropathy. Some symptoms of diabetic neuropathy are pain (can be dull pain, burning pain, tingling or crunchy pain, or tingling and painful convulsions); sensory abnormalities (cold, numbness, tingling) Or can appear as a sensation of burning pain); and calf tenderness and pain. Peripheral neuropathies are generally divided into symmetric and asymmetric neuropathies. Many diabetic neuropathies present a dominant peripheral lower limb involvement with symmetric sensorimotor polyneuropathy. Diabetic neuropathy can affect both sensory and motor peripheral nerves, as well as the autonomic nervous system.

  Diabetic neuropathy can manifest as fibrillar sensory neuropathy (often with early sensory sensory abnormalities or loss of pain and warmth, with peripheral reflex and proprioceptive savings). Diabetic neurotic cachexia (which usually develops after initiating insulin injections) is a severe form of painful diabetic neuropathy that occurs in men. Diabetic neuropathy is also large fiber sensory neuropathy; autonomic neuropathy (including both sympathetic and parasympathetic); motor neuropathy (also called diabetic muscular atrophy); mixed polyneuropathy (E.g., mixed sensory-autonomic neuromotor polyneuropathy; local compression neuropathy; and neural trunk neuropathy. R (-) DMS, S (+) DMS, or R (- ) A combination of DMS and S (+) DMS can be used to treat patients who develop any symptoms of diabetic neuropathy.

  Patients with chronic alcoholism can often suffer from painful peripheral neuropathy. The main symptoms of alcoholic peripheral neuropathy (or alcoholic polyneuropathy) are burning pain in the limbs, stinging, and numbness. Sensory loss is often combined with painful hypersensitivity in the foot, loss of the Achilles tendon reflex and mild peripheral weakness. Alcoholic peripheral neuropathy can be caused by the toxic effects of ethanol, malnutrition, or both. Peripheral painful peripheral neuropathy is also common at the end of HIV infection. The main symptom of this peripheral neuropathy, with some degree of sensory loss in the normal foot, is the discomfort of continuous burning pain; motor complications are usually minor. Acute and chronic inflammatory demyelinating peripheral neuropathy can also occur in other asymptomatic people infected with HIV. R (-) DMS, S (+) DMS, or a combination of R (-) DMS and S (+) DMS is infected with patients with alcoholic polyneuropathy and HIV and suffers from peripheral neuropathy Can be used to treat patients.

  Subjects with certain systemic vasculitis also frequently suffer from peripheral neuropathy. Typically, the cause of vasculitic peripheral neuropathy is the result of ischemia, i.e. inflammation of the nerve's vegetative tract by an inflammatory process. Normally, nerves receive a robust supply of blood and are relatively resistant to ischemic damage. Thus, the occurrence of vasculitic peripheral neuropathy represents a wide range of vascular diseases. About 30% of patients with vasculitic peripheral neuropathy suffer from symmetric polyneuropathy, about 30% suffer from asymmetric polyneuropathy, and about 40% Suffers from multiple mononeuropathy. Vascular peripheral neuropathy is often found in systemic vasculitis nodular polyarthritis, rheumatoid vasculitis, Sjogren's syndrome, Wegner's granulomatosis and Churg-Strauss syndrome.

  Inflammatory sensory polyganglia (ISP) is a syndrome involving relatively pure sensory loss (especially self-acceptance) and loss of reflexes. The sensory symptoms of ISP can begin suddenly or progress slowly, and sensory ataxia is often severe and refractory. In the early well-documented cases of ISP, the possibility of an underlying malignancy (especially small cell lung cancer) should be considered with the tumor and when the ISP is diagnosed. Other associations with ISP have also been reported, for example showing association with Sjogren's syndrome (dorsal root ganglion infiltration by T lymphocytes). R (−) DMS, S (+) DMS, or a combination of R (−) DMS and S (+) DMS can be used to treat patients with vasculitic peripheral neuropathy as well as ISP.

  It is estimated that about 5% of patients in the intensive care unit can develop peripheral neuropathy (which can be severe). Long-term ICU hospitalization, sepsis and organ system failure are features that are common in many demonstrated 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.

  There are many causes of peripheral neuropathy, including but not limited to: toxic agents (eg, chemotherapeutic drugs), genetically inherited conditions, systemic diseases, and trauma or pressure Nerve destruction. Axonal degeneration slows down or blocks the transmission of impulses through the nerve just before degeneration. Systemic causes of peripheral neuropathy include disorders that affect nerve connective tissue, or blood supply to the nerve, as well as metabolic or chemical disorders, and other disorders that damage peripheral nerve tissue.

The particular systemic disease, local disease, hereditary condition, toxic agent, and trauma that cause 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 disease, These include, but are not limited to: acute inflammatory or immune-mediated peripheral neuropathies (eg, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), acute inflammatory demyelinating polyneuropathy Disorder (AIDP), Guillain-Barre syndrome, acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN), Miller-Fischer syndrome, ganglion neuritis, total autonomic nerve Failure, inflammatory plexus disorders (eg brachial plexitis and lumbosacral plexitis); infectious peripheral neuropathies (eg herpes simplex infection, herpes zoster virus (shingles)), Hepatitis C, hepatitis C, acquired immune deficiency syndrome (AIDS) related neuropathy, HIV infection, cytomegalovirus infection, Colorado tick fever, diphtheria, syphilis, leprosy, cruise trypanosoma (Chagas disease), Lyme disease, Campylobacter jejuni infection and leukomyelitis); Uremia; Botulism addiction; Childhood cholestatic liver disease; Chronic respiratory dysfunction; Alcohol neuropathy; Multiple organ failure; Sepsis; Hypoalbuminemia; Syndrome; porphyria; hypoglycemia; chronic glutenous enteropathy; vitamin deficiency; dietary deficiency (eg, vitamin B ₁₂ deficiency; thiamine deficiency (leg air) vitamin E deficiency; folic acid deficiency); Whipple disease; Iron deficiency; chronic liver disease; primary biliary cirrhosis; hypophosphatemia; hyperlipidemia; Stroke macroglobulinemia; spinal cord fistula; Crohn's disease; atherosclerosis; gout neuropathy; sensory peritonitis; Sjogren's syndrome; primary vasculitis (like nodular polyarteritis); Churg-Straus vasculitis; allergic granulomas vasculitis; hypersensitivity vasculitis; Wegener's granulomatosis; rheumatoid arthritis; myxedema; inflammatory sensory polygangliopathy (ISP); systemic lupus erythematosus; Connective tissue disease; scleroderma; sarcoidosis; vasculitis; systemic vasculitis; acute tunnel syndrome; multiple neuropathy of cancerous axon sensorimotor; multiple nerves of sensory movement of lymphoma axon Disorders: primary, secondary, topical, or familial systemic amyloidosis; thyroid dysfunction; carpal tunnel syndrome; sciatica; chronic obstructive pulmonary disease; Good (sprue, spondy's disease); carcinoma (sensory, sensorimotor, delayed, demyelination); lymphoma (including Hodgkin lymphoma); polycythemia vera; multiple myeloma (dissolved, osteosclerotic, or Lymphomatoid granulomatosis; benign monoclonal hypergammaglobulinemia; lung cancer; leukemia; macroglobulinemia; cold globulinemia; tropical bone marrow neuropathy; Diabetic muscle atrophy. Peripheral neuropathy is also associated with mitochondrial disease. A significant proportion of peripheral neuropathy is idiopathic, and R (-) DMS, S (+) DMS, or a mixture of the two racemics is also used to prevent or treat these peripheral neuropathies. obtain.

  Genetic acquired peripheral neuropathies suitable for treatment with R (−) DMS, S (+) DMS, or mixtures thereof include, but are not limited to: Peroneal muscle atrophy (Charcot-Marie) -Tooth disease), hereditary amyloid neuropathy, hereditary sensory neuropathy (type I and type II), porphyria neuropathy, hereditary tendency to pressure paralysis, congenital myelination-reducing neuropathy, family Brachial plexus neuropathy, porphyria, Fabry disease, adrenal spinal neuropathy, Riley-Day syndrome, Dujline-Sotta neuropathy (hereditary motor sensory neuropathy-IV), refsum disease, telangiectasia Ataxia, hereditary tyrosineemia, alpha lipoproteinemia, abeta-lipoproteinemia, giant axonal neuropathy, metachromatic leukodystrophy and adrenoleukodystrophy Trophy, spherical cell white atrophy and Friedrich ataxia.

  R (−) DMS, S (+) DMS, or a combination of R (−) DMS and S (+) DMS can also be used to treat peripheral neuropathy caused by a toxic agent. Toxins that produce peripheral neuropathy can generally be divided into three groups: drugs and drugs; chemicals; and environmental toxins. As used herein, the term “toxic agent” is defined as any substance that impairs the normal function of one or more components of the peripheral nervous system through its chemistry. This definition includes drugs that are airborne, ingested as food or drug contaminants, or intentionally ingested as part of a treatment regime.

  A list of toxic agents that can cause peripheral neuropathy includes, but is not limited to: acetazolamide, acrylamide, adriamycin, alcohol, allyl chloride, almitrine, amitriptyline, amiodarone, amphotericin, arsenic, aurothio Glucose, carbamate, carbon disulfide, carbon monoxide, carboplatin, chloramphenicol, chloroquine, cholestyramine, cimetidine, cisplatin, cisplatinin, coquinol, colestipol, colchicine, colistin, cycloserine, cytarabine, dapsone, dichlorophenoxyacetic acid, didanosine Dideoxycytidine, dideoxyinosine, dideoxythymidine, dimethylaminopropionitrile, disulfiram, docetaxe; , Doxorubicin, ethanebutle, etionamide, ethylene oxide, FK506 (tacrolimus), glutethimide, gold, hexacarbon, hexane, hormonal contraceptives, hexamethylolmelamine, hydralazine, hydroxychloroquine, imipramine, indomethacin, inorganic lead, inorganic mercury, isoniazid, lithium , Methylmercury, metformin, methylbromide, methylhydrazine, metronidazole, misonidazole, methyl N-butyl ketone, nitrofurantoin, nitrogen mustard, dinitrogen monoxide, organophosphate, osporot, paclitaxel, penicillin, par Perhexiline, perhexiline maleate, phenytoin, platinum, polychlorinated biphenyl, Midon, procainamide, procarbazine, pyridoxine, simvastatin, sodium cyanate, streptomycin, sulfonamide, suramin, tamoxifen, thalidomide, thallium, toluene, triamterene, trimethyltin, triorthocresyl phosphate, L-tryptophan, baker Vinca alkaloids, vindesine, overdose of vitamin A, overdose of vitamin D, zalcitamine, dimerzine; industrial drugs (especially solvents); heavy metals; and thinners or other toxic compounds. Other peripheral neuropathies that can be treated according to the present disclosure include neuropathies resulting from prolonged exposure to ischemia or cold.

  Although the specific diseases, toxic agents and trauma that cause peripheral neuropathy are not important, the present disclosure is particularly valuable in the treatment of peripheral neuropathy resulting from the administration of chemotherapeutic agents to cancer patients. Among chemotherapeutic agents, among others known to cause peripheral neuropathy are vincristine, vinblastine, cisplatin, paclitaxel, procarbazine, dideoxyinosine, cytarabine, alpha interferon and 5-fluorouracil (Macdonald, Neurologic Clinics 9: 955-967 (1991)).

  As noted above, the present disclosure relates to peripheral neuropathy through the use of DMS in the form of R (-) DMS, S (+) DMS, or a mixture of R (-) DMS and S (+) DMS. Includes treatment of peripheral neuropathy, including preventing, reducing, reducing or eliminating symptoms completely or partially. As used herein, the term “R (−) DMS” means the R (−) enantiomer of DMS, including the free base, as well as any acid addition salts thereof. Similarly, the term “S (+) DMS” encompasses the S (+) enantiomer of DMS, including the free base, as well as any acid addition salts thereof. Such salts of either R (−) DMS or S (+) DMS include salts derived from organic and inorganic acids, including but not limited to: hydrochloric acid, odor Hydrofluoric 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, embonic acid, enanthic acid Such. Thus, with reference to this specification, administration of either or both of R (−) DMS and S (+) DMS encompasses the therapy of the free base and acid addition salt forms. When either R (-) DMS or S (+) DMS is used alone in the compositions and methods of the present disclosure, it is used in substantially enantiomerically pure form. Reference to a mixture or combination of R (−) DMS and S (+) DMS includes both racemic and non-racemic mixtures of optical isomers.

  R (−) DMS and / or S (+) DMS can be administered by the oral route (including gastrointestinal absorption) or by the parenteral route (independent of gastrointestinal absorption, ie, R (−) DMS from the gastrointestinal tract). And / or routes that avoid absorption of S (+) DMS). Depending on the particular route used, DMS is administered in the form of the free base or as a physiologically acceptable non-toxic acid addition salt as described above. For example, for parenteral administration, the use of salts (especially hydrochloride) is particularly desirable when the route of administration employs an aqueous solution; the use of desmethyl selegiline delivered in a free base form is particularly useful for transdermal administration It is. The oral route of administration is generally the most convenient, but R (−) DMS, S (+) DMS, or a mixture of both can be administered orally, peroral, enteral, lung, nasal, tongue Intravenous, intraarterial, intracardiac, intramuscular, intraperitoneal, intradermal, subcutaneous, parenteral, topical, transdermal, intraocular, buccal, sublingual, intranasal, inhalation, vaginal, rectal, or It can also be administered by other routes.

  Optimal daily dose useful for the purposes of the present invention of two combinations, such as R (-) DMS, S (+) DMS, or a mixture of R (-) DMS and S (+) DMS racemates Based on, for example, the severity of the peripheral neuropathy and symptoms being treated, the condition of the subject being treated, the response to the desired degree of therapy, and the combination therapy administered to this patient or animal Determined by known methods. The total daily dose administered to a patient (typically a human) will at least prevent or reduce one or more of the symptoms associated with peripheral neuropathy (typically one of the above symptoms). Or should be the amount needed to eliminate.

  Usually, the attending physician will administer a starting parenteral daily dose of at least about 0.01 mg / kg body weight, calculated on the free secondary amines, which will gradually increase depending on the response to treatment. Is used. The final daily dose is between about 0.05 mg / kg and about 0.15 mg / kg of body weight (all such doses are again calculated based on free secondary amines) . Usually, however, the attending physician or veterinarian will administer a starting dose of at least about 0.015 mg / kg calculated based on the free secondary amine, and use progressively higher doses depending on the route of administration and response to subsequent treatment To do. Typically, the daily dose is about 0.02 mg / kg to about 0.10 mg / kg or 0.05 mg / kg to about 0.10 mg / kg, or about 0.15 mg / kg to 0.175 mg / kg. Or about 0.15 mg / kg to about 0.20 mg / kg, or about 0.15 mg / kg to about 0.5 mg / kg, and about 1.0 mg / kg of the patient depending on the route of administration Body weight can be reached, or 1.5 mg / kg, 2.0 mg / kg, 3.0 mg / kg, or even 5.0 mg / kg. A preferred daily dose is in the range of about 0.1 mg / kg to about 1.0 mg / kg. A more preferred daily dose is in the range of about 0.9 mg / kg to about 0.4 mg / kg. Even more preferred daily doses are in the range of about 0.6 mg / kg to about 0.8 mg / kg. All such doses should be calculated again based on the free secondary amine. In other preferred embodiments, the daily dose ranges from about 0.01 mg to about 1000 mg per day. Preferred doses are about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 1.0 mg, about 2.0 mg, about 3. 0 mg, about 4.0 mg, about 5.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg , About 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg.

  These are merely guidelines, as the exact dose must be carefully selected and titrated by the attending physician based on clinical status. The optimal daily dose is determined by methods known in the art, and the patient's age and weight, the patient's clinical condition, the condition or disease associated with peripheral neuropathy, the severity of both peripheral neuropathy and disease It is influenced by factors such as the degree to which the treatment is given, the desired degree of therapeutic response, the concomitant treatment being administered, and the observed response of the individual patient or animal. The daily dose can be administered by single or multiple dosage regimens.

  Either oral or parenteral dosage forms can be used and, for example, bursts of the active ingredient from a single dosage unit (eg, oral composition or sublingual or buccal) over one or more days Administration) or a sustained release (eg, transdermal patch) of a relatively small amount of the active ingredient from a single dosage unit. Alternatively, intravenous or inhalation routes may be preferred. Many different dosage forms can be used to administer R (-) DMS, S (+) DMS, or a combination of R (-) DMS and S (+) DMS, including the following: Is not limited to: tablets, pills, capsules, powders, aerosols, suppositories, dermal patches, parenteral drugs and oral liquids (including oily aqueous suspensions, solutions and emulsions). In addition, desmethylselegiline-containing sustained release (long acting) formulations and devices are contemplated.

  Pharmaceutical compositions containing one or both R (−) DMS or S (+) DMS can be prepared according to conventional techniques. For example, preparations for parenteral routes of administration (eg, intramuscular, intravenous, intrathecal and intraarterial routes) can use sterile isotonic saline solution. Sterile buffered solutions can also be used for intraocular administration.

  Transdermal unit dosage forms of R (−) DMS and / or S (+) DMS have been described using various techniques previously described (eg, US Pat. No. 4,861,800; US Pat. No. 4,868,218). 5,128,145, 5,190,763 and 5,242,950, and EP-A 404807, EP-A 509761 and EP-A 593807 (in this specification) Which is incorporated by reference in its entirety). For example, a monolithic patch structure can be utilized, desmethyl selegiline is incorporated directly into the adhesive, and the mixture is filled into the backing paper. Alternatively, R (−) DMS and / or S (+) DMS may act to convert the salt to the free base, as shown, for example, in EP-A 593807 (incorporated herein by reference). Can be incorporated as acid addition salts into the multilayer patch. Specifically contemplated by this disclosure are about 5 mg, 10 mg, 20 mg, 30 mg, 50 mg or 100 mg of R (−) DMS, S (+) DMS, or R (−) DMS and S (+). A transdermal patch composition having a combination of DMS.

  One or both R (−) DMS or S (+) DMS can also be administered by a device using a lyotropic liquid crystal composition, eg 5-15% desmethylselegiline is a polyethylene glycol, polymer and non- Combined with a liquid and solid mixture of ionic surfactants, propylene glycol and emulsifier are added as needed. Further details regarding the preparation of such transdermal drugs can be found in EP-A 5509761, which is incorporated herein by reference. In addition, the oral and sublingual dosage forms of R (−) DMS, S (+) DMS, or a combination of R (−) DMS and S (+) DMS are described, for example, in US Pat. No. 5,192,550. No. 5,221,536; No. 5,266,332; No. 5,057,321; No. 5,446,070; No. 4,826,875; No. 5 , 304,379; or 5,354,885 (incorporated herein by reference).

  Subjects that can be treated by the preparations and methods of the invention include both human and non-human subjects. Accordingly, the compositions and methods provide particularly useful treatment for mammals (including humans) and domestic mammals. Accordingly, the methods and compositions of the present invention are used in treating peripheral neuropathy in humans, primates, dogs, cats, cows, horses, sheep, mice, goats, pig species, and the like.

  Treatment with R (-) DMS, S (+) DMS, or a combination of R (-) DMS and S (+) DMS should be continued until symptoms associated with peripheral neuropathy subside. The drug can either be administered at regular intervals (eg, twice a day) or can be delivered in an essentially continuous manner (eg, via a transdermal patch). Patients are regularly (eg, once a week, once a month) by a physician to determine whether symptoms have improved and whether desmethylselegiline medication needs to be adjusted. (E.g. once a year, twice a year). Since delayed progressive peripheral neuropathy has been shown after cessation of cisplatin therapy (see, eg, Grunberg et al., Cancer Chemother. Pharmacol. 25: 62-64 (1989)), R (−) DMS, S ( +) Preferably, administration of DMS, or a combination of the two, is continued for a period of time (eg, about 1-12 months) after the end of chemotherapy. Further, because administration of R (−) DMS, S (+) DMS, or a combination of the two prevents the onset of symptoms associated with peripheral neuropathy (particularly, the subject is at risk of developing peripheral neuropathy). Can be used)

  The present disclosure may also cause peripheral neuropathy by using a combination of chemotherapeutic agents and R (−) DMS, S (+) DMS, or a mixture of R (−) DMS and S (+) DMS. It relates to methods for treating cancer patients treated with known chemotherapeutic agents. Except as indicated below, the same considerations as discussed in the previous section are that R (−) DMS, S (+) DMS, or a combination of the two is part of the treatment regimen for such patients. Applies equally to the terms used.

  R (−) DMS, S (+) DMS, or a 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 that are very toxic and their dosage is limited by the peripheral neuropathy they cause. This group includes paclitaxel, cisplatin, vincristine, and vinblastine. By preventing or reducing peripheral neuropathy associated with these agents, higher individual doses can be administered to patients by administration of R (−) DMS, S (+) DMS, or a combination of the two. , Thereby increasing the overall efficacy of the treatment. Further, by administration of R (−) DMS, S (+) DMS, or a combination of the two, patients can receive higher cumulative doses of chemotherapeutic agents. Increased cumulative doses can result from higher doses of chemotherapeutic agents administered in each treatment cycle, increased number of cycles, or a combination of higher doses and more cycles.

The most preferred chemotherapeutic agents for use in the present disclosure are cisplatin and paclitaxel, both of which are very toxic to peripheral nerves and limit the dosages that can be safely administered to patients (Macdonald, Neurologic Clinics). 9: 955-967 (1991)). The dose intensity of these drugs is an important factor in achieving optimal therapeutic results, but about 75-100 mg / m ² for cisplatin (Ozols, Seminars in Oncology 16: 22-30 (1989)). And doses substantially above about 175-225 mg / m ² (Gianni et al., J. Nat'l Cancer Inst. 87: 1169-75 (1995)) for paclitaxel typically cannot be given.

  Symptoms related to peripheral neuropathy caused by administration of cisplatin include sensory polyneuropathy with sensory abnormalities, loss of vibration and proprioception, loss of pain and temperature sensation, and reduced deep tendon reflexes (Macdonald, Neurologic Clinics 9: 955-967 (1991); see Ozols, Seminars in Oncology 16: 22-30 (1989)). Symptoms associated with other drugs such as vincristine and paclitaxel include loss of deep tendon reflexes at the ankle (which may progress to complete reflex loss), loss of distal symmetric sensation, motor weakness, foot loss (Foot drop), muscle atrophy, constipation, bowel obstruction, urinary retention, impotence, and postural hypotension (Id .; Casey et al., Brain 96: 69-86 (1973)). For the purposes of this disclosure, the severity of these symptoms may indicate that the patient cannot tolerate them, or that the patient's physician will present them as a significant threat to the patient's health and chemotherapy. An agent is considered unacceptable if it determines that the dosage of the agent must be reduced or stopped.

  The specific route of administration of R (−) DMS, S (+) DMS, or a mixture of R (−) DMS and S (+) DMS most preferred for patients treated with chemotherapeutic agents depends on clinical considerations. Any of the delivery or dosage form routes determined and discussed above may be included. A route of administration that avoids gastrointestinal absorption may be preferred. Thus, preferred routes typically include transdermal administration, parenteral administration, sublingual administration, and buccal administration.

  In some cases, patients who are administered R (−) DMS, S (+) DMS, or a combination of R (−) DMS and S (+) DMS according to the present disclosure may be R (−) DMS, S ( Chemotherapy has already been received when treatment of +) DMS, or a mixture of R (−) DMS and S (+) DMS begins. As a result, an upper limit on the dosage of chemotherapeutic agents may already be established. Beyond this, patients experience severe peripheral neuropathy that is unacceptable. In these cases, administration of the chemotherapeutic agent should be maintained and treatment with R (−) DMS, S (+) DMS, or a combination of R (−) DMS and S (+) DMS is initiated. It should be. The actual time that the chemotherapeutic agent and R (−) DMS, S (+) DMS, or a combination of the two are given to each other is not critical. However, their therapeutic effects overlap. For example, it is not essential that the chemotherapeutic agent and R (−) DMS, S (+) DMS, or a combination of the two be administered in a single dosage form or within 1 hour or 2 hours of each other.

  If there is a reason that the subject may receive multiple drugs or may be abnormally sensitive to R (−) DMS, S (+) DMS, or a combination of the two, the subject will tolerate the medication. It may be desirable to start with a low starting dose (eg, 0.01 mg / kg) to ensure that it is obtained. Once this is established, the dosage can be adjusted upward. The effect of R (−) DMS, S (+) DMS, or a combination of the two on the symptoms of peripheral neuropathy is assessed by the subject over a period of time and by the subject's physician against regular criteria. Should. Once a concentration of R (-) DMS, S (+) DMS, or a combination of the two is established that is effective in reducing symptoms, a new upper limit is established for the dosage of chemotherapeutic agents. (Ie, until a dosage is established that cannot be exceeded without causing unacceptable side effects). Administration of R (−) DMS, S (+) DMS, or a combination of R (−) DMS and S (+) DMS can be used to treat delayed and progressive peripheral neuropathy when chemotherapy is administered. Should be continued for a period of time after being stopped to block. For example, a subject may continue to receive R (−) DMS, S (+) DMS, or a combination of the two for more than a month after the end of chemotherapy.

  The same basic procedure as described above can be used for subjects initiating chemotherapy. In these cases, both chemotherapeutic agents and dosages of R (-) DMS, S (+) DMS, or a combination of the two must be established. A preferred procedure is to begin by pretreating the patient with R (−) DMS, S (+) DMS, or a combination of the two before administration of the chemotherapeutic agent begins. For example, a subject may be given 10 mg R (−) DMS, S (+) DMS, or a combination of the two for one week before treatment with a chemotherapeutic agent begins. The dosage of both the chemotherapeutic agent and R (−) DMS, S (+) DMS, or a combination of the two is then optimized as described above. Again, administration of R (-) DMS, S (+) DMS, or a combination of R (-) DMS and S (+) DMS should be continued after cessation of chemotherapeutic agents.

  The present disclosure further includes R (−) DMS, S (+) DMS, or a combination of the two (these are conveniently prepared by methods known to those skilled in the art as described in Example 1), And a method for treating peripheral neuropathy by administering to the patient a pharmaceutical composition comprising one or more additional therapeutic agents known to treat peripheral neuropathy. Therapeutic agents known to treat peripheral neuropathy symptoms in various disorders include, but are not limited to: prednisone, IVIg, cyclophosphamide, famciclovir, tegretol ( tegretol), tricyclic antidepressant, dapsone, clofazamine, nifurtimox, benznidazole, gabapentine, ganciclovir, focanet, cidofovir, cidofovir, cidofovir , And ribavirin. Such pharmaceutical compositions can be used to prevent or treat neurological disorders. The therapeutic agents used with R (−) DMS, S (+) DMS, or a mixture of the two to treat peripheral neuropathy can also be presented to the patient in separate formulations. Accordingly, another administration or timed administration of a therapeutic agent is contemplated by the present disclosure, particularly where the therapeutic agent and the DMS enantiomer have a synergistic therapeutic effect.

  Successful use of the above compositions and methods requires the use of a therapeutically effective amount of R (−) DMS, S (+) DMS, or a combination of R (−) DMS and S (+) DMS. As noted above, despite the apparently inferior inhibitory properties for MAO-B inhibition, R (−) DMS and its enantiomers are at least effective, if not more effective than selegiline for the treatment of peripheral neuropathy. There seems to be.

  The following examples are included to demonstrate preferred embodiments of the invention. The technology disclosed in the examples that follow represents the technology disclosed by the inventors to function well in the practice of the present invention, and therefore can be considered to constitute a preferred mode for its implementation. Should be understood by those skilled in the art. However, one of ordinary skill in the art, in view of this disclosure, may make many changes in the specific embodiments disclosed and still obtain similar or similar results without departing from the spirit and scope of the invention. Understand what you can do. The following working examples are illustrative only and are not intended to limit the scope of the invention.

Example 1: Preparation of R (-) DMS and S (+) DMS
(A.R (−)-desmethylselegiline)
R (−) DMS is prepared by methods known in the art. For example, desmethyl selegiline is a known chemical intermediate for the preparation of selegiline, as described in US Pat. No. 4,925,878. Desmethylselegiline is an inert organic solvent (eg, R (−)-2-aminophenylpropane (levoamphetamine) in toluene:

の溶液を等モル量の反応性プロパルギルハライド（例えば、臭化プロパルギル（Ｂｒ−ＣＨ_２−Ｃ≡−ＣＨ））と、少しの上昇温度（７０℃〜９０℃）で処理することによって調製し得る。必要に応じて、反応は、炭酸カリウムのような酸アクセプターの存在下で実行され得る。次いで、反応混合物を、水性の酸（例えば、５％塩酸）を用いて抽出し、そして抽出物は、アルカリを与える。形成された非水性層を分離し、そして例えば、ベンゼンで抽出し、蒸留し、そして減圧下で乾燥する。

Can be prepared by treating equimolar amounts of a reactive propargyl halide (eg, propargyl bromide (Br—CH ₂ —C≡—CH)) with a slight increase in temperature (70 ° C. to 90 ° C.). . If necessary, the reaction can be carried out in the presence of an acid acceptor such as potassium carbonate. The reaction mixture is then extracted with an aqueous acid (eg 5% hydrochloric acid) and the extract gives alkali. The formed non-aqueous layer is separated and extracted, for example, with benzene, distilled and dried under reduced pressure.

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

(B. S (+)-desmethylselegiline)
S (+) DMS is enantiomeric S (+)-2-aminophenylpropane (dextroamphetamine), ie, following the procedure described above for desmethylselegiline,

から簡便に調製される。

It is easily prepared from

(C. Mixture of enantiomers)
A mixture of the R (-) and S (+) enantiomer forms of desmethyl selegiline (including racemic desmethyl selegiline) is conveniently prepared from an enantiomeric mixture comprising a racemic mixture of the aminophenylpropane starting material.

(D. Conversion to acid addition salt)
N- (prop-2-ynyl) -2-aminophenylpropane in either optically active or racemic form is physiologically acceptable by conventional techniques such as treatment with mineral acids. Can be converted to non-toxic acid addition salts. For example, hydrogen chloride in isopropanol is used in the preparation of desmethyl selegiline hydrochloride. Either the free base or the salt can again be further purified by conventional techniques such as recrystallization or chromatography.

Example 2: Characteristics of substantially pure R (-) DMS
The preparation of substantially pure R (-) DMS had the appearance of a white crystalline solid, had a melting point of 162-163 ° C, and was measured at a concentration of 1.0M using water as the solvent. In the case of [α] _D ^{23 ° C.} = − 15.2 ± 2.0. R (−) DMS was 99.5% pure (see chromatogram in FIG. 1) when analyzed by HPLC on a Microsorb MV Cyano column and was analyzed by a Zorbax Mac-Mod SB-C 18 column. The case appears to be 99.6% pure (see chromatogram in FIG. 2). There is no single impurity with a concentration of 0.5% or more. Heavy metal is present at a concentration of less than 10 ppm and amphetamine hydrochloride is present at a concentration of less than 0.03%. The last solvents (ethyl acetate and ethanol) used to dissolve the preparation are both present at a concentration of less than 0.1%. The mass spectrum performed on the preparation (see FIG. 3) is consistent with a compound having a molecular weight of 209.72 amu and a formula of C ₁₂ H ₁₅ NHCl. Infrared spectra and NMR spectra are shown in FIGS. 4 and 5, respectively. These are also consistent with the known structure of R (-) DMS.

Example 3. Characteristics of substantially pure S (+) DMS
A substantially pure preparation of S (+) DMS has the appearance of a white powder, has a melting point of about 160.04 ° C., and when measured at 22 ° C. in water at a concentration of 1.0 M, It has a specific rotation of + 15.1 °. This preparation appears to be about 99.9% pure when tested by reverse phase HPLC on a Zorbax Mac-Mod SB-C 18 column (FIG. 6). Amphetamine hydrochloride is present at a concentration of less than 0.13% (w / w). A mass spectrum was performed on the preparation, which is consistent with a compound having a molecular weight of 209.72 and a molecular formula of C ₁₂ H ₁₅ NHCl (see FIG. 7). Infrared spectroscopy is performed, which also provides results consistent with the structure of S (+) DMS (see FIG. 8).

Example 4: Effects of R (-) and S (+) enantiomers of desmethylselegiline (DMS) on the activity of human platelet MAO-B and guinea pig brain MAO-B and MAO-A
Human platelet MAO is composed exclusively of the B-form isoform of the enzyme. In this study, in vitro and in vivo inhibition of this enzyme by the two enantiomers of DMS is determined and compared to the inhibition due to selegiline. This study also tested two enantiomers of DMS for inhibitory activity on MAO-A and MAO-B in guinea pig hippocampal tissue. Guinea pig brain tissue is an excellent animal model for studying brain dopamine metabolism, enzyme kinetics of multiple forms of MAO, and the inhibitory properties of novel drugs that interact with these enzymes. Multiple forms of MAO in this animal species show kinetic properties similar to those found in human brain tissue. Finally, the test agents were administered to guinea pigs and evaluated to the extent that they can act in vivo as inhibitors of brain MAO.

(A. Test method)
(In Vitro): The test system utilized in vitro conversion of MAO-B ( ¹⁴ C-phenylethylamine) by MAO-A ( ¹⁴ C-serotonin) or human platelets and guinea pig hippocampal homogenate in guinea pig hippocampal homogenate. The conversion rate of each substrate was measured in the presence of S (+) DMS, R (−) DMS, or selegiline and compared to isozyme activity in the absence of these agents. Percent inhibition was calculated from these values. Efficacy was assessed by comparing the concentration of each drug that caused 50% inhibition (IC ₅₀ value).

  (In vivo): R (−) DMS, S (+) DMS or selegiline was administered subcutaneously (sc) in vivo once a day 5 days before sacrifice. Hippocampal homogenates containing enzymes were prepared and MAO-A and MAO-B activities were assessed ex vivo. These experiments were performed to demonstrate that DMS enantiomers can enter brain tissue and inhibit MAO activity.

(B. Results)
(MAO-B inhibitory activity in vitro)
The results for MAO-B inhibition are shown in Tables 2 and 3. The IC ₅₀ values for MAO-B inhibition and potency compared to selegiline are shown in Table 4.

観察されるように、Ｒ（−）ＤＭＳは、Ｓ（＋）ＤＭＳより２０〜３５倍、ＭＡＯ−Ｂインヒビターとして効力があり、両方のエナンチオマーは、セレジリンよりも効力が小さかった。

As observed, R (−) DMS was 20-35 times more potent as a MAO-B inhibitor than S (+) DMS, and both enantiomers were less potent than selegiline.

(In vitro MAO-A inhibitory activity)
The results obtained from experiments testing MAO-A inhibition in the guinea pig hippocampus are summarized in Table 5. The IC ₅₀ values for the two enantiomers of DMS and selegiline are shown in Table 6.

  (Table 5: Inhibition of MAO-A in guinea pig hippocampus)

（表６：ＭＡＯ−Ａの阻害についてのＩＣ_５０値）
モルモット海馬皮質における
処置 ＭＡＯ−ＡのＩＣ _５０
セレジリン ２．５μＭ（１）
Ｒ（−）ＤＭＳ ５０．０μＭ（２０）
Ｓ（＋）ＤＭＳ １００．０μＭ（４０）
（ ）＝セレジリンと比較した効力の減少。

(Table 6: IC ₅₀ values for inhibition of MAO-A)
In the guinea pig hippocampal cortex
IC _{50 of} treatment MAO-A
Seresillin 2.5 μM (1)
R (−) DMS 50.0 μM (20)
S (+) DMS 100.0 μM (40)
() = Decreased potency compared to selegiline.

  R (−) DMS was twice as potent as MA (O) A inhibitor as S (+) DMS, both of which were 20-40 times less potent than selegiline. Furthermore, each of these agents was less potent as an inhibitor of MAO-A by 2-3 orders of magnitude (ie, 100-thousandth of a factor) than the inhibitor of MAO-B in hippocampal brain tissue. Thus, each enantiomer of selegiline and DMS can be classified as a selective MAO-B inhibitor in brain tissue.

(Results of in vivo experiments)
Each enantiomer of DMA was administered in vivo by subcutaneous injection once a day for 5 consecutive days, and then inhibition of brain MAO-B activity was determined. In preliminary studies, selegiline was found to have an ID _{50 of} 0.03 mg / kg; and both R (−) DMS and S (+) DMS were determined to be about 10 times less potent. It was done. More recent studies (performed in a larger group of animals) have shown that R (−) DMS is actually about 25 times more potent as MAO-B inhibitor than serigiline, and S (+) DMS is about 50 times more potent. It has been shown that fractional efficacy is small. The results are shown in FIG. 9 and the ID ₅₀ values are summarized in Table 7.

(Table 7: ID ₅₀ value of brain MAO-B 5 days after administration)
In the guinea pig hippocampal cortex
ID _{50 of} treatment MAO-A
Seresillin 0.008mg / kg (1)
R (−) DMS 0.20 mg / kg (25)
S (+) DMS 0.50 mg / kg (60)
() = Decreased potency compared to selegiline.

  This experiment demonstrates that DMS enantiomers cross the blood-brain barrier and inhibit brain MAO-B after in vivo administration. This experiment also demonstrates that the difference in potency as MAO-B observed in vitro between each of the DMS enantiomers and selegiline is substantially reduced under in vivo conditions.

  In an experiment examining the effect of five subcutaneous treatments on MAO-A activity in the guinea pig cerebral cortex (hippocampus), administration of selegiline at a dose of 1.0 mg / kg resulted in an inhibition of activity of 36.1%. Was found. R (−) DMS produced 29.8% inhibition when administered at a dose of 3.0 mg / kg. Administration of S (+) DMS does not produce any observable inhibition at the highest dose tested (10 mg / kg), indicating that it has very little cross-reactivity.

(C. Conclusion)
In vitro, both R (−) DMS and S (+) DMS exhibit activity as MAO-B and MAO-A inhibitors. Each enantiomer was selective for MAO-B. S (+) DMS was less potent than R (-) DMS, and both enantiomers of DMS were less potent than selegiline in inhibiting both MAO-A and MAO-B.

  In vivo, both enantiomers are active in inhibiting MAO-B, indicating that these enantiomers can cross the blood-brain barrier. The ability of these agents to inhibit MAO-B suggests that these agents may be valuable as therapeutic agents for hypodopaminergic diseases such as ADHD and dementia.

Example 5 In Vivo Neuroprotection by the Enantiomer of Desmethyl Selegiline
The ability of DMS enantiomers to prevent neuronal decline was tested by administering these agents to wobler mice, an animal model of motor neuropathy, particularly amyotrophic lateral sclerosis (ALS). The wobbler mice show progressively worsening forelimb weakness, gait disturbance, and flexion contraction of the forelimb muscles.

(A. Test method)
In randomized, double-blind, doses of 0.1 mg / kg R (−) DMS, S (+) DMS or placebo were administered to wobler mice by daily intraperitoneal injection for 30 days. At the end of this period, mice were tested for grip strength, running time, resting movement behavior, and ranked for semiquantitative leg posture abnormalities and deterministic gait abnormalities. Investigators who prepared these test drugs and administered them to animals were different from those who analyzed behavioral changes.

  Assays and ranking are basically described in Mitsumoto et al., Ann. Neurol. 36: 142-148 (1994). The grip strength of the mouse front leg was determined by having the animal grip the wire with both legs. The wire is connected to a gram dynamometer and a tow device is attached to the tail of the mouse until the animal releases the wire. Reading of the dynamometer at the time of release was performed as a measured value of grip strength.

  Running time is defined as the shortest time required to travel a specific distance (eg, 2.5 feet) and records the maximum time of several tests.

  Leg posture abnormalities are ranked on a scale based on the degree of contraction, and gait abnormalities are ranked on a scale ranging from normal walking to being unable to support the body using the legs.

  Migration behavior is determined by moving animals to a test area where the floor is covered with a square grid. Behavior is measured by the number of squares the mouse has traversed within a set period (eg, 9 minutes).

(B. Results)
At the start of the study, no group was different in any variable. This indicates that the 3 groups were comparable at baseline. Weight gain was the same in all three groups, suggesting that no major side effects occurred in any animal. Table 8 summarizes the differences observed in the average grip strength of these test animals.

(Table 8: Average grip strength of wobbled mice treated with R (−) DMS or S (+) DMS)
Treatment 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 tested.

  In all animals, grip strength decreased dramatically at the end of the first week. At the end of the study, the grip strength was lowest in the control animals. Although changes in grip strength in the treated animal group interfered with significant statistical analysis of this data, the average grip strength measured in animals treated with DMS was greater than the control at a dose of 0.1 mg / kg. These results suggest that this dose may have been too low and that higher dose studies should be performed.

  Running time, resting behavior, ranking of semiquantitative leg posture abnormalities, and ranking of semiquantitative gait abnormalities were also tested. However, none of these tests showed any difference between the three groups tested.

(Example 6: Recovery of immune system by R (-) DMS and S (+) DMS)
There is an age-related decline in immunological function that occurs in animals and humans, which makes older individuals more susceptible to infectious diseases and cancer. US Pat. Nos. 5,276,057 and 5,387,615 suggest that selegiline is useful in the treatment of immune system dysfunction. This study was conducted to determine whether R (−) DMS and S (+) DMS are also useful in the treatment of such dysfunction. The ability to improve a patient's normal immune defense is beneficial for the treatment of a wide variety of acute and chronic diseases, including cancer, AIDS, both bacterial and viral infections, and some forms of peripheral neuropathy It should be understood that.

(A. Test procedure)
This experiment tested the ability of R (−) DMS and S (+) DMS to restore immunological function using a rat model. Rats were divided into the following experimental groups:
1) Young rat (3 months old, no treatment).
2) Aged rats (18-20 months old, no treatment).
3) Aged rats injected with saline.
4) Aged rats treated with selegiline at a dosage of 0.25 mg / kg body weight.
5) Aged rats treated with selegiline at a dosage of 1.0 mg / kg body weight.
6) Aged rats treated with a dosage of 0.025 mg / kg body weight R (-) DMS.
7) Aged rats treated with R (-) DMS at a dosage of 0.25 mg / kg body weight.
8) Aged rats treated with a dosage of 1.0 mg / kg body weight of R (-) DMS.
9) Old rats treated with S (+) DMS at a dosage of 1.0 mg / kg body weight.

Rats received saline or test drug intraperitoneally daily for 60 days. The rats were then maintained for an additional “wash out” period of 10 days, during which no treatment was given. At the end of this period, the animals were sacrificed and their spleens were removed. The spleen cells were then assayed for various factors that exhibited immune passage function. Specifically, using standard tests, the following was determined:
1) In vitro production of γ interferon by concanavalin A stimulated spleen cells;
2) Concanavalin A-induced production of interleukin-2 in vitro;
3) Proportion of IgM positive spleen cells (IgM is a marker for B lymphocytes);
4) Proportion of CD5-positive spleen cells (CD5 is a marker for T lymphocytes).

(B. Results)
Tables 9 and 10 show the effects of selegiline, R (−) DMS and S (+) DMS administration on concanavalin A-induced interferon production by rat spleen cells. Table 9 shows that there is a sharp decline in cellular interferon production that occurs with aging. The administration of selegiline, R (−) DMS and S (+) DMS all resulted in recovery of γ-interferon levels, with the most dramatic increase occurring at a dosage of 1.0 mg / kg body weight.

(Table 9: Effect of age on T cell function ^* )

^＊ラット脾臓細胞をコンカナバリンＡで刺激した後にＴ細胞活性をアッセイした。
ＴＨ、サイトカイン、ＩＬ−２およびＩＦＮ−γを測定した。若年 対 老齢、ｐ＝０．０００４。

^* T cell activity was assayed after stimulation of rat spleen cells with concanavalin A.
TH, cytokines, IL-2 and IFN-γ were measured. Young versus old age, p = 0.0004.

  (Table 10: IL-2 and IFNγ mean and% control)

^＊ 処置なしの高齢のラット（２２ヶ月齢）。

^* Old rats (22 months old) without treatment.

  Table 10 shows the degree of ability of R (−) DMS, S (+) DMS and selegiline to restore γ-interferon production in spleen cells of aged rats. Interferon-γ is a T cell-related cytokine that inhibits viral replication and regulates various immunological functions. This 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.

  Histological immunofluorescence studies show a dramatic decrease in domination in the rat spleen with age. When rats are treated with R (−) DMS, there is a significant increase in dominance in the spleen of animals, and this increase occurs in a dose response manner. S (+) DMS did not show any effect on histological examination, but instead showed a gradual increase in interferon-γ production. IL-2 production was not increased by treatment with R (−) DMS or treatment with S (+) DMS. This suggests that the effects of these drugs may be limited to IFN-γ production.

(C. Conclusion)
These results observed with respect to histological examination, production of interferon and percentage of IgM positive spleen cells support the conclusion that the enantiomers of DMS can at least partially restore the age-dependent decline in immune system function . The results observed for IFN-γ are particularly important. In both humans and animals, IFN-y production is associated with the ability to successfully recover from infection with viruses and other pathogens. Furthermore, R (−) DMS and S (+) DMS appear to have therapeutically beneficial effects on diseases and conditions mediated by weak host immunity. The diseases and conditions include AIDS, response to vaccines, infectious diseases, immunological adverse effects and cancer caused by cancer chemotherapy, and some forms of peripheral neuropathy.

(Example 7: Example of dosage form)
(A. Desmethylselegiline patch)
Dry weight standard
Ingredient (mg / cm ² )
Durotak (R) 87-2194
Adhesive acrylic polymer 90 parts by weight desmethyl selegiline 10 parts by weight These two ingredients are thoroughly mixed, cast onto a film backing sheet (eg, Scotchpak® 9723 polyester) and dried. Cut the backing sheet into patches, apply a fluoropolymer release liner (eg, Scotchpak® 1022), and seal the patch in a foil pouch. In the treatment of conditions in humans caused by neurodegeneration or neurotrauma, one patch is applied daily to provide 1-10 mg desmethylselegiline per 24 hours.

(B. Ophthalmic solution)
Desmethylselegiline (0.1 g) as the hydrochloride salt, 1.9 g boric acid, and 0.004 g phenylmercuric nitrate are dissolved in physiological saline (appropriate amount to be 100 ml in total). The mixture is sterilized and sealed. This can be used ophthalmically to treat conditions caused by neurodegeneration or neurotrauma (eg, glaucomatous optic neuropathy and macular degeneration).

(C. Intravenous solution)
A 1% solution is prepared by dissolving desmethylselegiline (1 g) as HCl in 0.9% isotonic saline sufficient to provide a final volume of 100 gm. This solution is buffered to pH 4 with citric acid, sealed and sterilized to obtain a 1% solution suitable for intravenous administration in the treatment of conditions caused by neurodegeneration or nerve trauma.

(D. Oral dosage form)
Tablets and capsules containing desmethyl selegiline are prepared from the following ingredients (mg / unit dose):
Desmethylselegiline 1-5
Microcrystalline cellulose 86
Lactose 41.6
Citric acid 0.5-2
Sodium citrate 0.1-2
Magnesium stearate 0.4
(The ratio of citric acid to sodium citrate is about 1: 1).

Example 8: Treatment of a mouse model of cisplatin-induced neuropathy with R (-) DMS
The ability of desmethylselegiline to treat peripheral neuropathy in a mouse model of cisplatin-induced neurodegeneration was studied. Male CD1 mice (weighing between 15 and 20 g at the start of the experiment) were divided into 6 groups of 15 and the following were administered:
Group 1: Control-saline + buffer only.
Group 2: Cisplatin + buffer.
Group 3: Cisplatin + selegiline.
Group 4: selegiline only.
Group 5: Cisplatin + R (−)-desmethyl selegiline.
Group 6: R (−)-desmethyl selegiline only.

  Mice were administered cisplatin by intraperitoneal injection at a dose of 10 mg / kg body weight once a week for 8 consecutive weeks. Selegiline and R (−)-desmethylselegiline were administered subcutaneously to mice at a dose of 1 mg / kg body weight for 8 consecutive weeks, 5 times per week. In addition, these mice were subcutaneously administered daily with saline to maintain hydration and normal renal function.

  After a full 8 weeks of cisplatin treatment, the following number of mice shown in Table 11 survived in each group from the first number 15.

(Table 11: Surviving number of treated mice)
Group 1: 14 (control)
Group 2: 12 (cisplatin)
Group 3: 11 (cisplatin + selegiline)
Group 4: 15 (selegiline)
Group 5: 7 (cisplatin + R (−)-desmethylselegiline)
Group 6: 13 (R (-)-desmethyl selegiline).

  With the exception of the group receiving cisplatin and R-(−)-desmethyl selegiline, there was less mortality compared to those typically encountered in cisplatin peripheral neuropathy studies. This can be attributed to active hydration with saline infusion on each day during the experiment.

All behavioral studies of surviving mice described in this example were performed the next day after the last dose of selegiline and R (−)-desmethyl selegiline to mice. Cisplatin characteristically produces large fiber sensory neuropathies. A tail flick test was used to test the function of fibrillar sensory neurons in groups of mice. This test measures an animal's response to a noxious stimulus of heat via spinal cord mediated reflux. The tail flick test was performed by holding the mice loose and exposing their tails to a focused beam at a constant distance. The latency for the mice to pull their tails from the light was then measured. A significant change in the tail flick threshold was observed in severe cisplatin-induced neuropathy, a variable finding. This is because fibrillar neurons are not a major population sensitive to cisplatin. As shown below in Table 12, no significant differences were found between different groups of surviving members for the tail flick threshold:
Table 12: Tail flick threshold Control: 7.0 ± 0.3 seconds (mean ± SEM)
Cisplatin: 7.8 ± 0.8 seconds (mean ± SEM)
Cisplatin + selegiline: 7.9 ± 0.5 seconds (mean ± SEM)
Seresillin: 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)
A proprioceptive test was used to assess the effects of selegiline and R (−)-desmethylselegiline on peripheral nerve function in mice with cisplatin-induced neuropathy. Proper receptivity is a large fiber sensory modality that is typically abnormal in the presence of cisplatin-induced neuropathy. The proprioceptive test analyzes the function of large fiber sensory neurons by measuring their ability to maintain their balance against a rotating dwell with the visual cue removed. This ability needs to feel whether the limb is in place, as well as whether the dwell is rotating, these are proprioceptive functions.

These mice were placed on a rotating dwell in a complete dark room and the time it took for them to fall out of the dwell in a maximum of 20 seconds was measured. The results of this study shown in Table 13 are very significant, indicating that selegiline and R (−)-desmethyl selegiline beneficially protect mice against cisplatin-induced peripheral neuropathy. Suggest:
Table 13: Intrinsic acceptability test Control: 18 ± 1.3 ^* sec (mean ± SEM)
Cisplatin: 8.3 ± 2.6 seconds (mean ± SEM)
Cisplatin + selegiline: 14.8 ± 1.7 ^* sec (mean ± SE
M)
Selegiline: 16.4 ± 1.7 ^* sec (mean ± SE
M)
Cisplatin + R (−)-desmethyl selegiline: 20 ± 0 ^* second (mean ± SEM)
R (−)-desmethylselegiline: 17.1 ± 1.1 ^* sec (mean ± SE
M)
The overall p value was 0.0004 for ANOVA. The approximate p value using the Krukal-Wallis nonparametric ANOVA test was 0.0035. Individual comparisons were made using the Student-Newman-Keuls-multiple comparison test. ^{* Indicates} that this group is different from the cisplatin group at p <0.05.

  As shown in the data above, none of the other groups were significantly different from the control group, except for the group treated with cisplatin. Furthermore, the mice in the cisplatin and R (−)-desmethylselegiline group were the most successful group of mice in the proprioceptive test. This is because, unlike the cisplatin and selegiline groups, all mice in this group were able to stay on the dowels for a total period of 20 seconds despite being treated with cisplatin.

  Since cisplatin primarily affects large fiber sensory function, it typically causes abnormalities in neuronal transmission rates in sensory nerves. Large, fully myelinated fibers contribute primarily to the measured transmission rate; therefore, this measurement does not function well in mice with cisplatin-induced neuropathy. The operating potential amplitude is mainly determined by axon integrity. Because it may be less affected. All groups of mice underwent electrophysiological testing for 1 week after the last dose of selegiline or R (−)-desmethylselegiline. Measurements of transmission speed and action potential amplitude of the compound tail nerve running in the tail were taken. As shown in Table 14 below, these data indicate that cisplatin significantly reduced the rate of neurotransmission, and this effect was both administered by selegiline and by administration of R (−)-desmethylselegiline. Indicates that it was not prevented. There was no statistically significant difference between the groups treated with cisplatin for the operating potential amplitude.

伝達速度についての全体のｐ値は、ＡＮＯＶＡでは０．０００１であった。群間の比較をＳｔｕｄｅｎｔ−Ｎｅｗｍａｎ−Ｋｅｕｌｓ−多重比較検定を使用して行った。^＊は、この群がｐ＜０．０５でコントロール群とは異なることを示す。

The overall p value for transmission speed was 0.0001 for ANOVA. Comparisons between groups were performed using the Student-Newman-Keuls-multiple comparison test. ^{* Indicates} that this group is different from the control group at p <0.05.

  After electrophysiological testing, mice were sacrificed and the four dorsal root ganglion were removed and assayed for neuropeptide calcitonin gene related peptide (CGRP) using a radioimmunoassay. CGRP is a ubiquitin neuropeptide, which is primarily associated with small fiber sensory neurons, but is also expressed in large fiber neurons. CGRP is thought to play a role in pain sensation, but may also have a broader role in dorsal root ganglion. The level of CGRP was assayed. This is because it has been found that CGRP is significantly reduced in dorsal root ganglion after exposure to cisplatin. As expected, a significant decrease in CGRP expression was found in mice treated with cisplatin. This decrease in CGRP expression was not alleviated in mice treated with selegiline or R (−)-desmethylselegiline, as shown in Table 15.

Table 15: CGRP level Control: 424.8 ± 27 fmol / gang
Lion (mean ± SEM)
Cisplatin: 163.2 ± 30.6 ^* fmol / ganglion (mean ± SEM)
Cisplatin + selegiline: 238.2 ± 27.6 ^* fmol /
Ganglion (mean ± SEM)
Selegiline: 372.9 ± 33.3 fmol / g
Nglion (mean ± SEM)
Cisplatin + R (−)-desmethyl selegiline: 227.4 ± 51.6 ^* fmol /
Ganglion (mean ± SEM)
R (−)-desmethylselegiline: 331.8 ± 18.3 fmol / g
Nglion (mean ± SEM)
The overall p value for transmission speed was 0.0001 for ANOVA. Individual comparisons were made using the Student-Newman-Keuls-multiple comparison test. ^{* Indicates} that this group is different from the control group at p <0.05.

  As shown in the data above, cisplatin could reduce sensory peripheral neuropathy in surviving mice. Mice treated with cisplatin demonstrated significant differences from controls in proprioceptivity, nerve transmission rate and sensory ganglion expression of CGRP. Animals treated with selegiline or R (−)-desmethylselegiline also showed better differences in measuring the behavior of proprioceptive function compared to mice treated with cisplatin alone. However, neither selegiline nor R (−)-desmethyl selegiline appear to prevent changes in neurotransmission rate and CGRP expression resulting from treatment with cisplatin. One possible explanation is that functional proprioception depends on factors other than those of the aspect of normal neural function responsible for neurotransmission rate and CGRP expression. Since CGRP is not known to be specifically expressed in large fiber neurons responsible for proprioceptive sensation, it is not surprising that there are two groups in this way. Also, functionally important CGRP expression and its relevance to clinical neuropathy are unclear.

Example 9: Treatment of peripheral neuropathy caused by vincristine
Patients suffering from endometrial carcinoma are given a single intravenous injection of vincristine at a dose of 1.4 mg / m ² per week. The toxic effects of vincristine cause loss of finger, toe sensation, loss of ankle reflex relaxation, weakness, and postural hypotension. Patients receive 5 mg of R (−) DMS and / or S (+) DMS orally twice daily, at breakfast and lunch. During this time, treatment with vincristine continues and assessments of both tumor response and toxic side effects are performed by a physician on a weekly basis. After continued treatment, symptoms associated with peripheral neuropathy subside. At this point, the dose of vincristine is increased to 1.8 mg / m ² and the process continues. If peripheral neuropathy symptoms do not return in another cycle of chemotherapy, the dose is increased again until the upper limit is reached. Following the last dose of vincristine, R (−) DMS and / or S (+) DMS administration is maintained for 1 month.

Example 10: Administration of desmethyl selegiline enantiomer in combination with cisplatin
Patients suffering from ovarian cancer are given a weekly injection of cisplatin at a dose of 120 mg / m ² . At the same time, patients are orally dosed twice daily with 5 mg R (−) DMS and / or S (+) DMS. At the end of the week, patients are evaluated for signs of peripheral neuropathy. If symptoms do not appear, maintain a dose of R (−) DMS and / or S (+) DMS and increase the dose of cisplatin to 140 mg / m ² per week. This process continues until the upper limit of cisplatin is identified. Evaluate the effect of the treatment on tumor progression to determine the effectiveness of the treatment.

Example 11 Treatment of Peripheral Neuropathy Caused by Paclitaxel
Patients suffering from breast cancer are orally administered R (−) DMS and / or S (+) DMS (10 mg per day) for 1 week. At the end of this point, treatment with paclitaxel is initiated by injecting the drug intravenously at a dose of 175 mg / m ² over 3 hours. The treatment is repeated for a total of 10 cycles over a total of 10 cycles, and the paclitaxel dose is increased by 25 mg / m ^{2 in} each cycle. During this time, treatment with R (−) DMS and / or S (+) DMS is continued and assessment of both tumor response and toxic side effects is performed by the physician on a weekly basis. Paclitaxel medication continues to increase until the side effects become unacceptable. Administration of R (−) DMS and / or S (+) DMS is continued for 1 month after paclitaxel treatment is complete.

Example 12 Alternative Treatment Resume Using Paclitaxel and R (−) DMS and / or S (+) DMS
Patients suffering from breast cancer are orally administered via a transdermal patch at a dose of about 0.10 mg / kg per day with R (−) DMS and / or S (+) DMS for one week. At the end of this point, treatment with paclitaxel is initiated by injecting the drug intravenously at a dose of 175 mg / m ² over 3 hours. Repeat paclitaxel injection for a total of 3 weeks. During this time, treatment with R (−) DMS and / or S (+) DMS is continued and assessment of both tumor response and toxic side effects is performed by the physician on a weekly basis. If peripheral neuropathy becomes unacceptably severe, the dose of R (−) DMS and / or S (+) DMS is increased to about 0.15 mg / kg per day. If unacceptable side effects persist, the paclitaxel dose is reduced to 125 mg / m ² . The treatment cycle is continued as long as a beneficial effect on tumor progression is obtained, or until such time that unacceptable side effects can no longer be eliminated. Administration of R (−) DMS and / or S (+) DMS is continued for 1 month after paclitaxel treatment is complete.

Example 13 Treatment of Peripheral Neuropathy Caused by Diabetic Neuropathy
R (−) DMS and / or S (+) DMS is administered orally (10 mg per day) to a patient suffering from diabetes who has not yet suffered from diabetic neuropathy. This initial treatment with R (−) DMS and / or S (+) DMS is periodically evaluated by a physician to determine whether the patient has developed any diabetic neuropathy. In patients suffering from diabetes presenting with diabetic neuropathy, R (−) DMS and / or S (+) DMS is administered orally (20 mg per day) to reduce the symptoms of diabetic neuropathy and / or Or reverse. Treatment is continued until symptoms are reduced or eliminated, then 10 mg R (−) DMS and / or S (+) DMS is administered orally to the patient per day to develop subsequent diabetic neuropathy Reduce the possibility of or eliminate its onset.

Example 14 Treatment of Peripheral Neuropathy Caused by Alcoholic Neuropathy
Patients suffering from alcoholic peripheral neuropathy are administered R (−) DMS and / or S (+) DMS at a dose of about 0.05 mg / kg per day via a transdermal patch. This treatment with R (−) DMS and / or S (+) DMS is evaluated periodically by a physician to determine if the patient continues to suffer from alcoholic peripheral neuropathy. Long-term administration of R (−) DMS and / or S (+) DMS may be required until the cause of alcoholic peripheral neuropathy is eliminated from the patient.

  All of the compositions and methods disclosed herein and the claims can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of the present invention have been described in terms of preferred embodiments, the compositions and / or methods and methods disclosed herein are not deviated from the spirit, spirit and scope of the present invention. It will be apparent to those skilled in the art that changes may be applied to these steps or sequence of steps. More specifically, certain agents that are chemically or physiologically related can be substituted for the agents disclosed herein, while at the same time it is clear that the same or similar results are achieved. It is. All such substitutions and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

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.
FIG. 1 is an HPLC chromatogram of purified R (−) DMS (Microsorb MV Cyano Column). The purity of the preparation of R (−) DMS was determined by HPLC using a Microsorb MV Cyano Column. The result is shown in FIG. This column is 4.6 mm × 15 cm in size and uses a mobile phase containing 90% 0.01 MH ₃ PO ₄ (pH 3.5) and 10% acetonitrile at a flow rate of 1.0 ml / min. Expanded. The column was operated at a temperature of 40 ° C. and the eluate was monitored at a wavelength of 215 nm. The chromatogram shows one major peak at 6.08 minutes, which is 95.5% of the total light absorbing material eluted from the column. None of the other peaks exceeded 0.24%. FIG. 2 is an HPLC elution profile of R (−) DMS (Zorbax Mac-Mod C18 Column). The same preparation analyzed in the experiment discussed in FIG. 1 was also analyzed for purity by HPLC using a Zorbax Mac-Mod SB-C18 Column (4.6 mm × 75 mm). The eluate was monitored at 215 nm. The result can be seen in FIG. More than 99.6% of the light-absorbing material was seen in one large peak at a time between 2-3 minutes. FIG. 3 is a mass spectrum of R (−) DMS. Mass spectra were obtained for purified R (-) DMS. The result is shown in FIG. This spectrum is consistent with a molecule having a molecular weight 209.72 atomic mass units and the molecular formula _C 12 _H 15 N-HCl. FIG. 4 is an infrared spectrum (KBr) of purified R (−) DMS. Infrared spectra were performed on a preparation of R (-) DMS. The result is shown in FIG. The solvent used is was CDCl _3. FIG. 5 is an NMR spectrum of purified R (−) DMS. A purified preparation of R (−) DMS was dissolved in CDCl ₃ and ¹ H NMR spectroscopy was performed at 300 nm. The results are shown in FIG. FIG. 6 is an HPLC chromatogram of S (+) DMS. The purity of the preparation of S (+) DMS was tested by reverse phase HPLC on a Zorbax Mac-Mod SB-C18 Column (4.6 minm x 75 mm). The elution profile monitored at 215 nm is shown in FIG. One major peak is seen in the profile at about 3 minutes and contains more than 99% of the total light absorbing material eluted from the column. FIG. 7 is a mass spectrum of purified S (+) DMS. Mass spectra were performed on the same preparation tested in FIG. The spectrum is shown in FIG. This was consistent with the structure of S (+) DMS. FIG. 8 is an infrared spectrum (KBr) of purified S (+) DMS. The preparation of S (+) DMS discussed with respect to FIGS. 6 and 7 was tested by infrared spectroscopy and the results are shown in FIG. FIG. 9 shows in vivo MAO-B inhibition in the guinea pig hippocampus. Various doses of selegiline, R (−)-desmethyl selegiline, and S (+)-desmethyl selegiline were administered daily to guinea pigs for a period of 5 days. The animals were then sacrificed and MAO-B activity in the hippocampal part of the brain was determined. The results are expressed as% inhibition of MAO-B activity in the hippocampus of control animals and are shown in FIG. For each drug, a plot was used to estimate the ID ₅₀ dosage. The seredylline ID ₅₀ was about 0.008 mg / kg; about 0.2 mg / kg for R (−) DMS; and about 0.5 mg / kg for S (+) DMS.

Claims (26)

A method of preventing or treating large fiber peripheral neuropathy in a subject in need of prevention or treatment of large-fiber peripheral neuropathy, the method comprising:
Administering desmethyl selegiline to said subject in an amount sufficient to prevent, reduce or eliminate one or more of the symptoms associated with said large fiber peripheral neuropathy;
Including the method.   The method of claim 1, wherein the large fiber peripheral neuropathy is a large-fiber sensory neuropathy.   The method of claim 1, wherein the large fiber peripheral neuropathy is a large-fiber motor neuropathy.   The method of claim 1, wherein the large fiber peripheral neuropathy is manifestation of diabetic neuropathy.   2. The method of claim 1, wherein the large fiber peripheral neuropathy is caused by a chemotherapeutic agent.   6. The method of claim 5, wherein the chemotherapeutic agent is administered for cancer treatment. The method of claim 1, wherein the desmethyl selegiline is in the form of an R (−) enantiomer and is substantially free of an S (+) enantiomer.   The method of claim 1, wherein the desmethyl selegiline is in the form of an S (+) enantiomer and is substantially free of the R (−) enantiomer.   2. The method of claim 1, wherein the desmethyl selegiline is administered by a route that avoids desmethyl selegiline absorption from the gastrointestinal tract.   10. The method of claim 9, wherein the desmethyl selegiline is administered buccal, sublingual, or parenterally.   10. The method of claim 9, wherein the desmethyl selegiline is administered transdermally.   The method of claim 1, wherein the subject is a human.   The method of claim 1, wherein the desmethyl selegiline is administered at a dose of 0.01 mg / kg to 0.15 mg / kg per day based on the weight of free amine. A method of preventing or treating fibrillar peripheral neuropathy in a subject in need of prevention or treatment of small-fiber peripheral neuropathy, the method comprising:
Administering desmethylselegiline to the subject in an amount sufficient to prevent, reduce or eliminate one or more of the symptoms associated with the small fiber peripheral neuropathy;
Including the method.   15. The method of claim 14, wherein the small fiber peripheral neuropathy results from abnormal function or pathological changes in small myelinated axons.   15. The method of claim 14, wherein the small fiber peripheral neuropathy results from abnormal function or pathological changes in small unmyelinated axons.   15. The method of claim 14, wherein the small fiber peripheral neuropathy is the development of diabetic neuropathy.   15. The method of claim 14, wherein the large fiber peripheral neuropathy is caused by a chemotherapeutic agent.   19. The method of claim 18, wherein the chemotherapeutic agent is administered for cancer treatment.   15. The method of claim 14, wherein the desmethyl selegiline is in the form of the R (-) enantiomer and is substantially free of the S (+) enantiomer.   15. The method of claim 14, wherein the desmethyl selegiline is in the form of an S (+) enantiomer and is substantially free of the R (-) enantiomer.   15. The method of claim 14, wherein the desmethyl selegiline is administered by a route that avoids desmethyl selegiline absorption from the gastrointestinal tract.   24. The method of claim 22, wherein the desmethyl selegiline is administered buccal, sublingual, or parenterally.   24. The method of claim 22, wherein the desmethyl selegiline is administered transdermally.   15. The method of claim 14, wherein the subject is a human.   15. The method of claim 14, wherein the desmethyl selegiline is administered at a dose of 0.01 mg / kg to 0.15 mg / kg per day based on the weight of free amine.

Images