WO1996022068A2 - Procedes et compositions pharmaceutiques utilisant de la desmethylselegiline - Google Patents

Procedes et compositions pharmaceutiques utilisant de la desmethylselegiline Download PDF

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Publication number
WO1996022068A2
WO1996022068A2 PCT/US1996/001561 US9601561W WO9622068A2 WO 1996022068 A2 WO1996022068 A2 WO 1996022068A2 US 9601561 W US9601561 W US 9601561W WO 9622068 A2 WO9622068 A2 WO 9622068A2
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WO
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Prior art keywords
desmethylselegiline
selegiline
dms
mao
ent
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PCT/US1996/001561
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English (en)
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WO1996022068A3 (fr
Inventor
Cheryl D. Blume
Anthony R. Disanto
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Somerset Pharmaceuticals, Inc.
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Application filed by Somerset Pharmaceuticals, Inc. filed Critical Somerset Pharmaceuticals, Inc.
Priority to EP96904573A priority Critical patent/EP0812188A2/fr
Priority to AU48644/96A priority patent/AU695359C/en
Priority to JP08522464A priority patent/JP3036847B2/ja
Priority to CA002209892A priority patent/CA2209892C/fr
Priority to US08/679,330 priority patent/US6348208B1/en
Priority to US08/679,328 priority patent/US6033682A/en
Publication of WO1996022068A2 publication Critical patent/WO1996022068A2/fr
Publication of WO1996022068A3 publication Critical patent/WO1996022068A3/fr
Priority to FI972988A priority patent/FI972988A/fi
Priority to NO19973261A priority patent/NO321830B1/no
Priority to HK98110118A priority patent/HK1009099A1/xx
Priority to US09/262,845 priority patent/US6299901B1/en
Priority to US09/315,840 priority patent/US6319954B1/en
Priority to US09/448,483 priority patent/US6210706B1/en
Priority to US09/800,022 priority patent/US6455060B2/en
Priority to US09/800,040 priority patent/US6375979B2/en
Priority to US09/805,281 priority patent/US6562364B2/en
Priority to US09/885,365 priority patent/US6420433B2/en
Priority to US09/895,718 priority patent/US6419948B2/en
Priority to US09/940,252 priority patent/US6528082B2/en
Priority to US09/960,277 priority patent/US6562365B2/en
Priority to US10/026,159 priority patent/US6699495B2/en
Priority to US10/251,727 priority patent/US6759053B2/en
Priority to US10/353,324 priority patent/US20030195260A1/en
Priority to US10/382,126 priority patent/US20030191191A1/en
Priority to US10/790,658 priority patent/US20040228907A1/en
Priority to US10/885,221 priority patent/US7144584B2/en
Priority to US11/290,772 priority patent/US20060167110A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention pertains to methods and pharmaceutical compositions for using the selegiline metabolite desmethylselegiline and its enantiomer, ent-desmethyl ⁇ selegiline.
  • the present invention provides compositions and methods for using these agents for selegiline-responsive diseases and conditions.
  • monoamine oxidase A MAO- A
  • monoamine oxidase B MAO-B
  • the cDNAs encoding these enzymes show different promoter regions and distinct exon portions, indicating they are encoded independently at different gene positions.
  • analysis of the two proteins has shown differences in their respective amino acid sequences.
  • the first compound found to selectively inhibit MAO-B was R-(-)-N-methyl-N- (prop-2-ynyl)-2-aminophenylpropane, also known as L-(-)-deprenyl, R-(-)-deprenyl, or selegiline. Selegiline has the following structural formula:
  • Tranylcypromine an MAO inhibitor introduced some thirty years ago but subsequently withdrawn due to its severe hypertensive side effects
  • selegiline is a non-selective inhibitor of MAO.
  • the acute toxicity of tranylcypromine arises from inhibition of MAO- A, which interferes with the metabolism of tyramine.
  • Tyramine is normally metabolized in the gastrointestinal tract by MAO- A but when MAO- A is inhibited, tyramine absorption is increased following consumption of tyra ⁇ -u e-cont ⁇ i ⁇ ing foods such as cheese, beer, herring, etc. This results in the release of catecholamines which can precipitate a hypertensive crisis, producing the "cheese effect. " This effect is characterized by Goodman and Gilman as the most serious toxic effect associated with MAO- A inhibitors.
  • the desmethylselegiline metabolite is the R (-) enantiomeric form of a secondary amine of the formula:
  • desmethylselegiline was not known to have pharmaceutically useful MAO-related effects, i.e. , potent and selective inhibitory effects on MAO-B.
  • MAO-related effects i.e. , potent and selective inhibitory effects on MAO-B.
  • the MAO-related effects of desmethylselegiline were more completely characterized. This characterization has established that desmethylselegiline has exceedingly weak MAO-B inhibitory effects and no advantages in selectivity with respect to MAO-B compared to selegiline.
  • the present characterization established that selegiline has an IC50 value against MAO-B in human platelets of 5 x 10 9 M whereas desmethylselegiline 's IC 50 value is 4 x 10 7 M, indicating the latter is approximately 80 times less potent as an MAO- B inhibitor than the former. Similar characteristics can be seen in the following data measuring inhibition of MAO-B and MAO-A in rat cortex mitochondrial-rich fractions: Table 1 : Inhibition of MAO by Selegiline and Desmethylselegiline
  • selegiline is approximately 128 times more potent as an inhibitor of MAO-B relative to MAO-A
  • desmethylselegiline is only 97 times more potent as an inhibitor of MAO-B relative to MAO-A. Accordingly, desmethylselegiline appears to have an approximately equal selectivity for MAO-B compared to MAO-A as selegiline, albeit with a substantially reduced potency.
  • MAO-B inhibitor provides no advantages in either potency or selectivity compared to selegiline. To the contrary, the above in vitro data suggest that use of desmethylselegiline as an MAO-B inhibitor requires on the order of 70 times the amount of selegiline.
  • the potency of desmethylselegiline as an MAO-B inhibitor in vivo has been reported by Heinonen, E. H., et al. ("Desmethylselegiline, a metabolite of selegiline, is an irreversible inhibitor of MAO-B in human subjects," referenced in Academic Dissertation "Selegiline in the Treatment of Parkinson's Disease," from Research Reports from the Department of Neurology, University of Turku, Turku, Finland, No. 33 (1995), pp.
  • desmethylselegiline in vivo has only about one-fifth the MAO-B inhibitory effect as selegiline, i.e., a dose of 10 mg of desmethylselegiline would be required for the same MAO-B effect as 1.8 mg of selegiline.
  • the various diseases and conditions for which selegiline is known to be useful include: depression (U.S. patent 4,861,800); Alzheimer's disease and Parkinson's disease, particularly through the use of transdermal dosage forms, including ointments, creams and patches; macular degeneration (U.S. patent 5,242,950); age-dependent degeneracies, including renal function and cognitive function as evidenced by spatial learning ability (U.S.
  • selegiline provides neuroprotection or neuronal rescue, possibly by reducing oxidative neuronal damage, increasing the amount of the enzyme superoxide dismutase, and/or reducing dopamine catabolism.
  • PCT Published Application WO 92/17169 reports that selegiline acts by directly maintaining, preventing loss of, and/or assisting in, the nerve function of animals.
  • Selegiline is known to be useful when administered to a subject through a wide variety of routes of administration and dosage forms.
  • U.S. patent 4,812,481 (Degussa AG) discloses the use of concomitant selegiline-amantadine in oral, peroral, enteral, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intraarterial, intracardial, intramuscular, intraperitoneal, intracutaneous, and subcutaneous formulations.
  • U.S. patent 5,192,550 (Alza Corporation) describes a dosage form comprising an outer wall impermeable to selegiline but permeable to external fluids. This dosage form may have applicability for the oral, sublingual or buccal administration of selegiline.
  • patent 5,387,615 discloses a variety of selegiline compositions, including tablets, pills, capsules, powders, aerosols, suppositories, skin patches, parenterals, and oral liquids, including oil-aqueous suspensions, solutions, and emulsions. Also disclosed are selegiline- containing sustained release (long acting) formulations and devices. In addition to desmethylselegiline, selegiline produces one other principal direct metabolite, memamphetamine. Both desmethylselegiline and methamphetamine are further metabolized to amphetamine. The last two metabolites, amphetamine and methamphetamine, are known to have the potential to exert neurotoxic effects on dopamine neurons, and are undesirable by-products. Unlike selegiline, desmethylselegiline does not produce methamphetamine as a metabolite, only amphetamine.
  • the present invention relates to the surprising discovery that both desmethyl ⁇ selegiline (“DMS” or “R(-)DMS”) and its enantiomer (ent-desmethylselegiline, abbreviated as “Ent-DMS” or “S(+)DMS”) are useful in providing selegiline-like effects in subjects, notwithstanding dramatically reduced MAO-B inhibitory activity and an apparent lack of enhanced selectivity for MAO-B compared to selegiline.
  • the present invention relates to the surprising discovery that desmethylselegiline, ent-desmethylselegiline and their isomeric mixtures provide a more advantageous way of obtaining selegiline-like therapeutic effects in selegiline -responsive diseases or conditions.
  • the present invention provides novel pharmaceutical compositions in which desmethylselegiline and/or ent-desmethylselegiline are employed as the active ingredients and novel therapeutic methods involving the administration of desmethylselegiline and ent-desmethylselegiline. Specifically, the present invention provides:
  • an improved method for obtaining selegiline-like therapeutic effects in a subject suffering from a selegiline-responsive disease or condition which comprises: administering to said subject desmethylselegiline, ent-desmethylselegiline, or a mixture thereof, in an amount sufficient to produce a selegiline-like therapeutic effect. ;
  • a pharmaceutical composition comprising, in addition to one or more optional pharmaceutically acceptable excipients or carriers, an amount of desmethylselegiline, ent- desmethylselegiline, or mixtures thereof, such that one or more unit doses of said composition administered on a periodic basis is effective to treat one or more selegiline- responsive diseases or conditions in a subject to whom said unit dose or unit doses are administered.
  • the term "selegiline-responsive disease or condition” refers to any of the various diseases or conditions in mammals, including humans, for which selegiline is known to be useful.
  • a "selegiline-responsive disease or condition” refers to the various diseases and conditions described above, e.g., Alzheimer's disease, cognitive dysfunction, neuronal rescue, and the like.
  • the term “selegiline-like therapeutic effect” refers to one or more of the salutary effects exerted by selegiline in a subject being treated for a selegiline-responsive disease or condition.
  • the selegiline-responsive diseases or conditions related to neuronal degeneration or trauma which respond to the present methods include Parkinson's disease, Alzheimer's disease, depression, glaucoma, macular degeneration, ischemia, diabetic neuropathy, attention deficit disorder, post polio syndrome, multiple sclerosis, impotence, narcolepsy, chronic fatigue syndrome, alopecia, senile dementia, hypoxia, cognitive dysfunction, negative symptomatology of schizophrenia, amyotrophic lateral sclerosis, Tourette's syndrome, tardive dyskinesia, and toxic neurodegeneration.
  • Parkinson's disease Alzheimer's disease, depression, glaucoma, macular degeneration, ischemia, diabetic neuropathy, attention deficit disorder, post polio syndrome, multiple sclerosis, impotence, narcolepsy, chronic fatigue syndrome, alopecia, senile dementia, hypoxia, cognitive dysfunction, negative symptomatology of schizophrenia, amyotrophic lateral sclerosis, Tourette's syndrome, tardive dyskinesi
  • the present invention also encompasses the restoration or improvement of immune system function by R(-)DMS, S(+)DMS or mixtures thereof. Such improvement or restoration has been reported to occur when selegiline is administered to animals.
  • the conditions or diseases treatable include age-dependent immune system dysfunction, AIDS, cancer and infectious diseases.
  • desmethyselegiline or ent- desmethylselegiline are administered in the form of a free base or as a physiologically acceptable non-toxic acid addition salt.
  • Such salts include those derived from organic and inorganic acids such as, without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulphonic 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, and the like.
  • the use of salts, especially the hydrochloride is particularly desirable when the route of administration employs aqueous solutions, as for example parenteral administration; use of delivered desmethylselegiline, or ent-desmethylselegiline, in the form of the free base is especially useful for transdermal administration. Accordingly, reference herein to the administration of DMS or ent-DMS or to mixtures thereof encompasses both the free base and acid addition salt forms.
  • the optimal daily dose of desmethylselegiline and/or ent-desmethylselegiline useful for the purposes of the present invention is determined by methods known in the art, e.g., based on the severity of the disease or condition being treated, the condition of the subject to whom treatment is being given, the desired degree of therapeutic response, and the concomitant therapies being administered to the patient or animal. Ordinarily, however, the attending physician or veterinarian will administer an initial dose of at least about 0.0015 mg/kg, calculated on the basis of the free secondary amine, with progressively higher doses being employed depending upon the response to the therapy.
  • the daily dose will be about 0.01 mg/kg and may extend to about 0.5 mg/kg of the patient's body weight (all such doses again being calculated on the basis of the free secondary amine). These guidelines further require that the actual dose be carefully titrated by the attending physician or veterinarian depending on the age, weight, clinical condition, and observed response of the individual patient or animal.
  • the daily dose can be administered in a single or multiple dosage regimen.
  • the dosage form and regimen may permit, for example, a continuous release of relatively small amounts of the active ingredient from a single dosage unit, such as a transdermal patch, over the course of one or more days. This is particularly desirable in the treatment of chronic conditions such as Parkinson's disease, Alzheimer's disease, and depression. Alternatively, it can be desirable in conditions such as ischemia or neural damage to administer one or more discrete doses by a more direct systemic route such as intravenously or by inhalation. In still other instances such as glaucoma and macular degeneration, localized administration, such as via the intraocular route, can be indicated.
  • the present invention encompasses the unexpected discovery that the oral use of desmethylselegiline, and/or ent-desmethylselegiline, is more effective than oral selegiline for use in a variety of conditions and diseases. Accordingly, desmethylselegiline and its enantiomer are employed orally in subjects where the use of selegiline itself would be contraindicated due to side effects.
  • compositions containing desmethylselegiline and/or ent- desmethylselegiline can be prepared according to conventional techniques.
  • preparations for parenteral routes of administration for desmethylselegiline e.g., intramuscular, intravenous and intraarterial routes, can employ sterile isotonic saline solutions.
  • Sterile isotonic solutions can also be employed for intraocular administration.
  • Transdermal dosage unit forms of desmethylselegiline and/or ent- desmethylselegiline can be prepared utilizing a variety of previously described techniques (see e.g. , U.S. Patent Nos.
  • a monolithic patch structure can be utilized in which desmethylselegiline is directly incorporated into the adhesive and this mixture is cast onto a backing sheet.
  • desmethylselegiline, and/or ent- desmethylselegiline can be incorporated as an acid addition salt into a multilayer patch which effects a conversion of the salt to the free base, as described for example in EP-A 593807.
  • Desmethylselegiline and/or ent-desmethylselegiline can also be administered by a device employing a lyotropic liquid crystalline composition in which, for example, 5 to 15% of desmethylselegiline is combined with a mixture of liquid and solid polyethylene glycols, a polymer, and a nonionic surfactant, optionally with the addition of propylene glycol and an emulsifying agent.
  • a lyotropic liquid crystalline composition in which, for example, 5 to 15% of desmethylselegiline is combined with a mixture of liquid and solid polyethylene glycols, a polymer, and a nonionic surfactant, optionally with the addition of propylene glycol and an emulsifying agent.
  • ent-desmethylselegiline refers to the S(+)-isomeric form of desmethylselegiline
  • reference above to mixtures of selegiline and ent-desmethylselegiline includes both racemic and non-racemic mixtures of optical isomers.
  • Subjects treatable by the present preparations and methods includes both human and non-human subjects for which selegiline-like therapeutic effects are known to be useful. Accordingly, the compositions and methods above provide especially useful therapies for mammals, especially domesticated mammals. Thus, the present methods and compositions are used in treating selegiline-responsive diseases or conditions in canine and feline species.
  • compositions and methods above require employment of an effective amount of desmethylselegiline, ent-desmethylselegiline or a mixture thereof.
  • desmethylselegiline and ent-desmethylselegiline are dramatically less potent than selegiline as inhibitors of MAO, employment of these agents, or a mixture of these agents, does not require a commensurately increased dosage to obtain a selegiline-like therapeutic response.
  • dosages necessary to attain a selegiline-like therapeutic effect are on the same order as the known doses of selegiline.
  • desmethylselegiline and ent-desmethylselegiline exhibit a much lower inhibition of MAO-A at such dosages
  • desmethylselegiline and ent-desmethylselegiline provide a substantially wider margin of safety with respect to MAO-A associated toxicity compared to selegiline.
  • the risk of the adverse effects of MAO-A inhibition e.g., hypertensive crisis, are minimized due to the 40-70 fold reduced potency for MAO-A inhibition.
  • desmethylselegiline and its enantiomer are signifi ⁇ cantly more effective than selegiline in treating selegiline-responsive conditions, e.g., conditions resulting from neuronal degeneration or neuronal trauma.
  • desmethylselegiline and/or its enantiomer like selegiline itself, are particularly useful when administered by a route which does not rely upon upper GI tract or other gastrointestinal absorption.
  • Preferred routes include the parenteral, topical, transdermal, intraocular, buccal, sublingual, intranasal, inhalation, vaginal, and rectal routes.
  • desmethylselegiline can be employed in both optically active forms and in racemic form, i.e., as mixtures of desmethylselegiline and ent-desmethylselegiline.
  • Desmethylselegiline, its enantiomer and mixtures thereof are conveniently prepared by methods known in the art, as described below in Example 1. Brief Description of the Figures
  • FIG. 1 Effect of Selegiline on Neuron Survival.
  • Mesencephalic cultures were prepared from embryonic 14 day rats. Cultures were used at about 1.5 million cells per plate and were maintained either in growth medium alone (control cultures) or in growth medium supplemented with selegiline. On day 1, 8 and 15, cells were immunostained for the presence of tyrosine hydroxylase ("TH"). Solid bars represent results obtained for cultures maintained in the presence of 50 ⁇ M selegiline and open bars represent results for control cultures. In all cases, results are expressed as a percentage of TH positive cells present in control cultures on day 1.
  • DIV refers to "days in vitro. " Asterisks or stars above bars both in Figure 1 and the figures discussed below indicates a result that differs from controls in an amount that is statistically significant, i.e. P ⁇ 0.05
  • FIG. 2 [ 3 H]-Dopamine Uptake in Mesencephalic Cells. Cells, cultured as described above for Figure 1 , were tested for their uptake of labeled dopamine and results are shown in Figure 2. Solid bars represent uptake in cells maintained in the presence of 50 ⁇ M selegiline and open bars represent uptake in control cultures
  • FIG. 3 Effect of Selegiline on Glutamate Receptor Dependent Neuronal Cell Death.
  • Rat embryonic mesencephalic cells were cultured as described above. After allowing cultures to stabilize, the culture medium was changed daily for a period of 4 days to induce glutamate receptor-dependent cell death. Depending on the culture, medium contained either 0.5, 5.0 or 50 ⁇ M selegiline. After the final medium change, cultured cells were immunostained for the presence of tyrosine hydroxylase. From left to right, bars represent results for controls, 0.5, 5.0 and 50 ⁇ M selegiline
  • Figure 4 Effect of Selegiline on Dopamine Uptake in Neuronal Cultures. Rat mesencephalic cells were cultured and medium was changed on a daily basis as discussed for Figure 3. Uptake of tritiated dopamine by cells was measured and results are shown in the figure. From left to right, bars are in the same order as for Figure 3.
  • FIG. 5 Effect of R(-)Desmethylselegiline on Glutamate Receptor Dependent Neuronal Cell Death. Rat embryonic mesencephalic cultures were prepared as described above except that R(-)DMS was used instead of selegiline. On day 9, the number of TH positive cells in cultures was determined. Results are expressed as a percentage of control. From left to right, bars show results for controls, 0.5, 5 and 50 ⁇ M R(-)DMS.
  • Figure 6 Effect of R(-)Desmethylselegiline on Dopamine Uptake in Neuronal Cultures. Cell cultures were prepared as described above for Figure 5 and then tested for uptake of tritiated dopamine.
  • Figure 8 Inhibition of Neuronal Dopamine Neuronal Re-Uptake by Deprenyl and the Enantiomers of Desmethylselegiline.
  • An in vitro nerve terminal preparation (synaptosome preparation) was prepared using fresh rat neostriatal tissue. This was examined for its ability to take up tritiated dopamine in buffer alone or in buffer supplemented with various concentrations of selegiline, R(-)desmethylselegiline or S(+)desmethylselegiline. Uptake in the presence of each of the MAO inhibitors was expressed as a percent inhibition relative to uptake in the presence of buffer alone and results are shown in Figure 8. As indicated in the figure, the plots were used to determine the ID 50 for each test agent. The ID 50 for S(+)DMS was 20 ⁇ M; for selegiline, 80 ⁇ M; and for R(-)DMS about 100 ⁇ M.
  • Figure 9 In Vivo MAO-B Inhibition in Guinea Pig Hippocampus.
  • Various doses of selegiline, R(-)desmethylselegiline, and S(+)desmethylselegiline were injected daily into guinea pigs for a period of 5 days. Animals were then sacrificed and the MAO-B activity in the hippocampus portion of the brain was determined. Results were expressed as a percent inhibition relative to hippocampus MAO-B activity in control animals and are shown in Figure 9. The plots were used to determine the ID 50 dosage for each agent.
  • the ID50 for selegiline was about 0.03 mg/kg; and for both enantiomers of DMS, about 0.3 mg/kg.
  • FIG. 10 In Vitro Interferon ("IFN") Production in Spleen Cells from Rats Injected with Selegiline, R(-)DMS or S(+)DMS.
  • F344 rats were injected ip, daily for 60 days with saline, selegiline, R(-)DMS or S(+)DMS. All injected rats were old, i.e., between 18 and 20 months of age. After allowing a 10 day “wash out” period in which no injections were made, rats were killed and their spleens removed.
  • the in vitro production of interferon- ⁇ by the stimulated spleen cells was determined and compared with production by spleen cells (lymphocytes) from non-injected old rats and from young rats (3 months old). From left to right, the bars reflect results for spleen cells from young rats; from old rats, from old rats injected with saline; from old rats injected with 0.25 mg/kg of selegiline; from old rats injected with 1.0 mg/kg of selegiline; from rats injected with 0.025 mg/kg of R(-)DMS; from rats injected with 0.25 mg/kg of R(-)DMS; from rats injected with 1.0 mg/kg of R(-)DMS; and from rats injected with 1.0 mg/kg of S(+)DMS.
  • the horizontal line indicates the point at which IFN levels differ significantly (P ⁇ .05) from the levels seen using young rat spleen cells. Results are expressed as units oer ml.
  • Figure 11 In Vitro IFN Production in Spleen Cells From Old Rats: The same results shown in Figure 10 are repeated 11 but without the inclusion of the results for young rat spleen cells. "#” indicates a result significantly different (P ⁇ 0.05) from that obtained for spleens from old rats injects with saline. "*” indicates a result significantly diferent from all groups except old rats injected with 1.0 mg/kg of deprenyl.
  • Figure 12 In Vitro Interleukin-2 Production by Spleen Cells from Old Rats. Rats were injected as described above (see Figure 10) and the production of interleukin-2 by stimulated spleen cells was determined. The order of bars from left to right is the same as for Figure 10.
  • Figure 13 Percentage of Rat Spleen Cells that are IgM Positive. Rats were injected with saline, selegiline, R(-)DMS or S(+)DMS as described above (see Figure 10). The spleens from the rats were assayed to determine the percentage of cells that were IgM positive and results are shown in the figure. The horizontal line in the figure corresponds to the decrease in IgM percentage that is statistically significant (P ⁇ 0.05) relative to the percentage seen in spleens obtained from young rats. The bars are in the same order from left to right as in Figures 10 and 12.
  • Figure 14 Percentage of Rat Spleen Cells that are CD5 Positive. The experiment of Figure 13 was repeated but instead of measuring the percentage of cells that are IgM positive, the percentage that are CD5 positive was determined. Detailed Description of the Invention
  • desmethylselegiline and ent-desmethylselegiline in treating selegiline-responsive diseases or conditions is attributable in part to their powerful action in preventing loss of dopaminergic neurons by promoting repair and recovery.
  • a reversal in neuronal damage and/or death can be observed.
  • desmethylselegiline and ent-desmethylselegiline prevent loss and facilitate recovery of nerve cell function, they are of value in a wide variety of neurodegenerative and neuromuscular diseases.
  • desmethylselegiline and ent-desmethylselegiline are substantially more potent than selegiline, as described more empirically in the examples below.
  • the Examples are for illustrative purposes only and are not intended to limit the scope of the invention.
  • Desmethylselegiline (designated below as "R (-) DMS") is prepared by methods known in the art.
  • desmethylselegiline is a known chemical intermediate for the preparation of selegiline as described in U.S. Patent No. 4,925,878.
  • Desmethyl ⁇ selegiline can be prepared by treating a solution of R(+)-2-aminophenylpropane (levoamphetamine) :
  • reaction inert organic solvent such as toluene with an equimolar amount of a reactive propargyl halide such as propargyl bromide, Br-CH 2 -C ⁇ CH, at slightly elevated tem ⁇ peratures (70°-90°C).
  • a reactive propargyl halide such as propargyl bromide, Br-CH 2 -C ⁇ CH
  • the reaction can be conducted in the presence of an acid acceptor such as potassium carbonate.
  • the reaction mixture is then extracted with aqueous acid, for example 5% hydrochloric acid, and the extracts are rendered alkaline.
  • the nonaqueous layer which forms is separated, for example by extraction with benzene, dried, and distilled under reduced pressure.
  • the propargylation can be conducted in a two-phase system of a water- immiscible solvent and aqueous alkali, utilizing a salt of R(+)-2-aminophenylpropane with a weak acid such as the tartrate, analogously to the preparation of selegiline as described in U.S. Patent No. 4,564,706.
  • Ent-desmethylselegiline (designated below as “S(+)DMS") is conveniently prepared from the enantiomeric S(-)-2-aminophenylpropane (dextroamphetamine), i.e.,
  • N-(prop-2-ynyl)-2-aminophenylpropane in either optically active or racemic form can be converted to a physiologically acceptable non-toxic acid addition salt by conventional techniques such as treatment with a mineral acid.
  • a mineral acid for example, hydrogen chloride in isopropanol is employed in the preparation of desmethylselegiline hydrochloride.
  • Either the free base or salt can be further purified, again by conventional techniques such as recrystallization or chromatography.
  • tyrosine hydroxylase the rate limiting enzyme in dopamine biosynthesis.
  • Assays are performed by determining the number of tyrosine hydroxylase positive cells in cultured E-14 embryonic mesencephalic cells over a period of 7 to 14 days. Protection in this system has been seen with a variety of trophic factors including BDNF, GDNF, EGF, and ⁇ -FGF.
  • Mesencephalon is dissected out without the membrane coverings and collected in Ca ++ and Mg ++ free balanced salt solution at 4°C. Tissue fragments are dissociated in chemically defined medium by mild trituration with a small bore pasteur pipette. Cell suspension is plated in polyornithine-coated 35 mm Falcon plastic dishes (0.1 mg/ml, Sigma) at a density of 1.5X10 * cells/dish.
  • Cultures are maintained at 37°C in an atmosphere of 10% CO 2 /90% air and 100% relative humidity, and fed twice weekly with chemically defined medium consisting of MEM/F12 (1 :1, Gibco), glucose (33 mM), HEPES (15 mM), NaHCO 3 (44.6 raM), transferrin (100 mg/ml), insulin (25 mg/ml), putrescine (60 nM), sodium selenite (30 nM), progesterone (20 nM), and glutamine (2 mM). Control cells receive no further additions.
  • the medium used for other cells also included test substance, e.g. selegiline, at one or more concentrations.
  • Cultures are fixed in 4% paraformaldehyde in 0.1 M phosphate buffer (pH 7.4) for 30 minutes at room temperature, permeabilized with 0.2% Triton X-100 for 30 minutes and incubated with an antibody against tyrosine hydroxylase (1 :1000; Eugene Tech) for 48 hours at 4°C in the presence of a blocking serum. They are then stained using a peroxidase-coupled avidin-biotin staining kit (Vectastain ABC kit; Vector Labs) with 3 ⁇ 3'- diaminobenzidine as a chromagen.
  • Vectastain ABC kit Vector Labs
  • the number of dopaminergic neurons in cultures is determined by counting the cells positively immunostained with TH antibodies. 100 fields (0.5 mm X 0.5 mm) in two transverse strips across the diameter of the dish, representing 2.5% of the total area, are counted using a Nikon inverted microscope at 200X magnification. B. Results
  • Example 3 Neuronal Survival as Measured Using Dopamine Uptake
  • the protective effect of desmethylselegiline on neuronal cells also can be determined by directly measuring dopamine uptake.
  • the amount of uptake by the cultured brain cells corresponds to axonal growth.
  • Example 4 Neuroprotective Action of Desmethylselegiline Enantiomers in Cultured Doparmne-Containing Mesencephalic Neurons In Vitro The survival of mesencephalic, dopamine-containing neuronal cultures of rat brain tissue was used in these experiments to examine neuroprotective properties of selegiline and R(-) desmethylselegiline. The number of TH positive neurons is directly proportional to the survival of dopaminergic neurons and 3 H-dopamine uptake is a measure of axonal growth in these neurons
  • the neuroprotective effect of selegiline was also examined using an experimental paradigm that causes neuronal cell death that can be blocked by inhibition of glutamate receptors.
  • cells were plated and allowed to stabilize for several days.
  • the growth medium of the cells was then changed on a daily basis to induce cell death that can be prevented by blocking glutamate receptors, e.g. using MK-801.
  • the results shown in Figures 3 and 4 further support the conclusion that selegiline promotes the survival of dopaminergic neurons.
  • Example 5 Desmethylselegiline and Ent-Desmethylselegiline as Inhibitors of Dopamine Re-Uptake
  • the biological actions of the brain neurotransmitter dopamine are terminated at the synapse by a high-affinity, sodium and energy -dependent transport system (neuronal re- uptake) present within the limiting membrane of the presynaptic dopamine - containing nerve terminal. Inhibition of this transport mechanism would extend the actions of dopamine at the synapse and therefore enhance dopamine synaptic transmission.
  • DMS desmethylselegiline
  • ADHD Attention Deficit Hyperactivity Disorder
  • the assay system used was essentially that described by Fang et al. (Neuro- pharmacology 55:763-768 (1994)). An in vitro nerce-temiinal preparation (synaptosome preparation) was obtained form fresh rat neostriatal brain tissue. Transport by dopamine nerve-terminals was estimated by measuring the uptake of tritiated dopamine.
  • Relative potency can be expressed in terms of the concentration required to inhibit dopamine re-uptake by 50% (ID 50 ).
  • ID 50 values were determined graphically (see Figure 8) and are shown below in Table 6.
  • Example 6 Actions of the R(-) and S(+) Enantiomers of Desmethylselegiline (DMS) on Human Platelet MAO-B and Guinea Pig Brain MAO-B and MAO-A Activity
  • Human platelet MAO is comprised exclusively of the type -B isoform of the enzyme.
  • the inhibition of this enzyme by the two enantiomers of DMS was determined and compared with inhibition due to selegiline.
  • the present study examined the two enantiomers of DMS for inhibitory activity with respect to the MAO-A and MAO-B in guinea pig hippocampal tissue.
  • Guinea pig brain tissue is the best animal model for studying brain dopamine metabolism, the enzyme kinetics of the multiple forms of MAO and the inhibitory properties of novel agents that interact with these enzymes.
  • the multiple forms of MAO in this animal species show identical kinetic properties to those found in human brain tissue.
  • agents were injected into guinea pigs to determine the extent to which they might act as inhibitors of brain MAO in vivo.
  • the test system utilized the in vitro conversion of specific substrates of MAO-A ( 14 C-serotonin) and MAO-B ( 14 C-phenylemylamine) by human platelets and/or guinea pig hippocampal homogenates.
  • the rate of conversion of each substrate was measured in the presence of S(-t-) DMS, R(-) DMS or selegiline and compared to the isozyme activity in the absence of these agents. A percent inhibition was calculated from these values. Potency was evaluated by comparing the concentration of each agent which caused a 50% inhibition (IC 50 value).
  • R(-) DMS, S(-f-) DMS or selegiline was administered in vivo subcutaneously (s.c), once a day for 5 days prior to sacrifice, preparation of enzyme hippocampal homogenates, and the in vitro assay of MAO-A and MAO-B activity.
  • R(-) DMS was twice as potent as S(+) DMS as an MAO-A inhibitor and both were 20-40 times less potent than selegiline. Moreover, each of these agents were 2-3 orders of magnitude, i.e., 100 to 1000 times, less potent as inhibitors of MAO-A than inhibitors of MAO-B in hippocampal brain tissue. Therefore, selegiline and each enantiomer of DMS can be classified as selective MAO-B inhibitors in brain tissue.
  • Table 12 IC 50 Values for Brain MAO-B When Agents are Injected Prior to Assay ICso for MAQ-B in Guinea Pig
  • R(-) DMS and S(+) DMS both demonstrate activity as an MAO-B and MAO-A inhibitors. Each enantiomer was selective for MAO-B. S(+) DMS was generally less potent than R(-) DMS and both enantiomers of DMS were less potent than selegiline in inhibiting both MAO-A and MAO-B. Both enantiomers demonstrated activity after in vivo administration, indicating that these enantiomers are able to enter brain tissue after parenteral administration. The ability of these agents to inhibit MAO-A or MAO-B suggests that these agents are of value as therapeutics for Parkinson's disease, Alzheimer's disease or depression.
  • Grip strength of the front paws of a mouse was determined by allowing the animal to grasp a wire with both paws. The wire was connected to a gram dynamometer and traction is applied to the tail of the mouse until the animal is forced to release the wire. The reading on the dynamometer at the point of release is taken as a measure of grip strength. Running time is defined as the shortest time necessary to traverse a specified distance, e.g. 2.5 feet and the best time of several trials is recorded.
  • Paw posture abnormalities are graded on a scale based upon the degree of contraction and walking abnormalities are graded on a scale ranging from normal walking to an inability to support the body using the paws.
  • Locomotive activity is determined by transferring animals to an examination area in which the floor is covered with a a square grid.
  • Activity is measured by the number of squares traversed by a mouse in a set time interval, e.g. 9 minutes.
  • C Results At the beginning of the study, none of the groups were different in any variables, indicating that the three groups were comparative at the baseline. Weight gain was identical in all three groups, suggesting that no major side effects occurred in any animals. Table 13 summarizes differences that were observed in the mean grip strength of the test animals:
  • Grip strength dropped markedly at the end of the first week in all animals. At the end of the study, grip strength was the least in control animals, ranging from 0 to 15 g, with a mean of 9 g.
  • the R(-) group had a mean grip strength of 20 g with values ranging from 0 to 63 g.
  • Rats were divided into the following experimental groups:
  • Rats were injected ip, daily for 60 days. They were then maintained for an additional "wash out” period of 10 days during which time no injections were given. At the end of this time, animals were sacrificed and their spleens were removed. The spleen cells were then assayed for a variety of factors which are indicative of immune system function. Specifically, standard tests were employed to determine the following: 1) in vitro production of ⁇ -interferon by spleen cells;
  • IgM is a marker of B lymphocytes
  • CD5 is a marker of T lymphocytes
  • the results support the conclusion that the enantiomers of DMS mimic the effects of selegiline on immune system function.
  • the results obtained with respect to the production of interferon, IL-2 and on the percentage of IgM positive spleen cells support the conclusion that the DMS enantiomers are capable of at least partially restoring the age-dependent loss of immune system function.
  • R(-) DMS and S(+ )DMS will have a therapeutically beneficial effect for diseases and conditions facilitated by weakened host immunity. This would include cancer, AIDS, and infectious diseases of all types.
  • the two ingredients are thoroughly mixed and cast on a Scotchpak ® 9723 polyester film backing sheet, and dried.
  • the backing sheet is cut into patches, a Scotchpak ® 1022 fluoropolymer release liner is applied, and the patch is hermetically sealed in foil envelopes.
  • One patch is applied daily to supply 1-5 mg of desmethylselegiline per 24 hours in the treatment of conditions in a human produced by neuronal degeneration or neuronal trauma, as for example Parkinson's disease.
  • Ophthalmic Solution Desmethylselegiline (0.1 g) as the hydrochloride, 1.9 g of boric acid, and .004 g of phenyl mercuric nitrate are dissolved in sterile water qs 100ml. The mixture is sterilized and sealed. It can be used ophthalmologically in the treatment of conditions produced by neuronal degeneration or neuronal trauma, as for example glaucomatous optic neuropathy and macular degeneration.
  • Example 3 Intravenous Solution.
  • a 1 % solution is prepared by dissolving 1 g of desmethylselegiline as the HC1 in sufficient 0.9% isotonic saline solution to provide a final volume of 100 ml.
  • the solution is buffered to pH 4 with citric acid, sealed, and sterilized to provide a 1 % solution suitable for intravenous administration in the treatment of conditions produced by neuronal degeneration or neuronal trauma.
  • a self-crosslinking acrylic based pressure sensitive adhesive is added to a solution of a copolymer of methacrylic acid and dimethylaminoethyl methacrylate in an organic solvent such as methyl ethyl ketone. This is cast onto a first removable foil, the solvents are evaporated, and the coated foil placed on a polyester backing layer, as set forth in EP- A 593807.
  • Desmethylselegiline hydrochloride is added to a solution of a non-crosslinking acrylic based pressure sensitive adhesive in a suitable organic solvent, as for example ethyl acetate. Additional solvent can be added and heat and stirring can be applied to facilitate formation of the dispersion. This is coated onto a second removable foil and the solvent evaporated. After removing the foil from the previously prepared polyester backed layer, it is laminated to the coated second removable foil. Additional self-crosslinking acrylic based pressure sensitive adhesive and copolymer of methacrylic acid and dimethylaminoethyl methacrylate in an organic solvent such as methyl ethyl ketone are cast onto a third removable foil and the solvent evaporated.
  • a suitable organic solvent as for example ethyl acetate.
  • Additional solvent can be added and heat and stirring can be applied to facilitate formation of the dispersion.
  • This is coated onto a second removable foil and the solvent evaporated. After removing the foil from the previously prepared polyester backed layer, it is laminated
  • the second and third foils are removed, the residual layers laminated, and the resulting laminate cut into patches and packaged.
  • the resulting patches will have a removable release liner, an adhesive layer initially free of desmethylselegiline, and a matrix layer containing desmethylselegiline as the hydrochloride (or other salt).
  • An impenetrable backing layer is adhered to the matrix layer through an intermediate adhesive layer similar to the adhesive layer contiguous to the removable release liner.
  • One patch is applied daily to supply desmethylselegiline as the free base in the treatment of conditions in a human produced by neuronal degeneration or neuronal trauma, as for example Parkinson's disease.
  • Tablets and capsules containing desmethylselegiline 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 with an approximately 1 : 1 ratio of citric acid and sodium citrate.

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Abstract

L'invention a pour objet des procédés et des compositions pharmaceutiques faisant appel à la desméthylsélégiline, un métabolite de la sélégiline, et à ses formes stéréoisomères. En particulier, la présente invention traite de nouvelles compositions et de procédés permettant d'utiliser la desméthylsélégiline et/ou l'ent-desméthylsélégiline, pour les maladies et les états réagissant à la sélégiline. Les maladies et les états réagissant à la sélégiline comprennent ceux entraînés par la dégénérescence des neurones ou par traumatisme nerveux ou ceux dûs à un dysfonctionnement du système immunitaire. La desméthylsélégiline, et/ou l'ent-desméthylsélégiline peut être administrée par voie orale ou selon un mode d'administration ne dépendant pas de l'absorption gastro-intestinale. La desméthylsélégiline est l'énantiomère R-(-) du N-méthyle-N(prop-2-ynyl)-2-aminophénylpropane et l'ent-destméthylsélégiline est l'énantiomère S(+). Les compositions décrites comprennent les isomères R-(-) et S-(+) ainsi que des mélanges de ces derniers. Des sels d'addition d'acide pharmaceutiquement acceptables peuvent être également utilisés. Des dosages efficaces comprennent une dose quotidienne d'au moins 0,0015 mg par kilogramme de poids corporel.
PCT/US1996/001561 1995-01-13 1996-01-11 Procedes et compositions pharmaceutiques utilisant de la desmethylselegiline WO1996022068A2 (fr)

Priority Applications (26)

Application Number Priority Date Filing Date Title
EP96904573A EP0812188A2 (fr) 1995-01-13 1996-01-11 Procedes et compositions pharmaceutiques utilisant de la desmethylselegiline
AU48644/96A AU695359C (en) 1995-01-13 1996-01-11 Methods and pharmaceutical compositions employing desmethylselegiline
JP08522464A JP3036847B2 (ja) 1995-01-13 1996-01-11 デスメチルセレギリンを用いる方法および医薬組成物
CA002209892A CA2209892C (fr) 1995-01-13 1996-01-11 Procedes et compositions pharmaceutiques utilisant de la desmethylselegiline
US08/679,328 US6033682A (en) 1995-01-13 1996-07-12 S(+) desmethylselegiline and its use in therapeutic methods and pharmaceutical compositions
US08/679,330 US6348208B1 (en) 1995-01-13 1996-07-12 Methods and pharmaceutical compositions employing desmethylselegiline
FI972988A FI972988A (fi) 1995-01-13 1997-07-14 Menetelmiä ja farmaseuttisia koostumuksia, joissa käytetään desmetyyliselegiliiniä
NO19973261A NO321830B1 (no) 1995-01-13 1997-07-14 Desmetylselegilin eller salt derav, medikament omfattende forbindelsen, samt anvendelser derav
HK98110118A HK1009099A1 (en) 1995-01-13 1998-08-24 Methods and pharmaceutical compositions employing desmethylselegiline
US09/262,845 US6299901B1 (en) 1995-01-13 1999-03-05 Methods and pharmaceutical compositions employing desmethylselegiline
US09/315,840 US6319954B1 (en) 1995-01-13 1999-05-21 S-(+)-desmethylselegiline and its use in the therapeutic methods and pharmaceutical compositions
US09/448,483 US6210706B1 (en) 1995-01-13 1999-11-24 S (+) Desmethylselegiline and its use in therapeutic methods and pharmaceutical compositions
US09/800,040 US6375979B2 (en) 1995-01-13 2001-03-05 S(+) desmethylselegiline and its use in transdermal delivery compositions
US09/800,022 US6455060B2 (en) 1995-01-13 2001-03-05 S(+) desmethylselegiline and its use to treat immune system dysfunction
US09/805,281 US6562364B2 (en) 1995-01-13 2001-03-13 Desmethylselegiline enantiomers and their use to treat drug withdrawal symptoms
US09/885,365 US6420433B2 (en) 1995-01-13 2001-06-20 S(+) desmethylselegiline and drug withdrawal
US09/895,718 US6419948B2 (en) 1995-01-13 2001-06-29 R(-)desmethylselegiline and its use in transdermal delivery compositions
US09/940,252 US6528082B2 (en) 1995-01-13 2001-08-27 Methods and pharmaceutical compositions employing desmethylselegiline to treat neoplastic diseases or conditions
US09/960,277 US6562365B2 (en) 1995-01-13 2001-09-21 Methods employing R(−)-desmethylselegiline
US10/026,159 US6699495B2 (en) 1995-01-13 2001-12-21 Methods for treating multiple sclerosis employing desmethylselegiline
US10/251,727 US6759053B2 (en) 1995-01-13 2002-09-20 S(+) Desmethylselegiline and its use to treat ADHD
US10/353,324 US20030195260A1 (en) 1995-01-13 2003-01-28 Methods and pharmaceutical compositions employing S(+)-desmethylselegiline to treat neoplastic diseases or conditions
US10/382,126 US20030191191A1 (en) 1995-07-31 2003-03-04 Methods for preventing and treating peripheral neuropathy by administering desmethylselegiline delivery compositions
US10/790,658 US20040228907A1 (en) 1995-01-13 2004-03-01 Methods and pharmaceutical compositions employing desmethylselegiline
US10/885,221 US7144584B2 (en) 1995-01-13 2004-07-06 S(+) desmethylselegiline and its use to treat narcolepsy
US11/290,772 US20060167110A1 (en) 1995-01-13 2005-11-30 Methods for treating cerebrovascular disease by administering desmethylselegiline

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US08/372,139 1995-01-13
US60/011,979 1995-07-31

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US08/679,330 Continuation-In-Part US6348208B1 (en) 1995-01-13 1996-07-12 Methods and pharmaceutical compositions employing desmethylselegiline
US08/679,328 Continuation-In-Part US6033682A (en) 1995-01-13 1996-07-12 S(+) desmethylselegiline and its use in therapeutic methods and pharmaceutical compositions
US09/940,252 Continuation-In-Part US6528082B2 (en) 1995-01-13 2001-08-27 Methods and pharmaceutical compositions employing desmethylselegiline to treat neoplastic diseases or conditions
US10/382,126 Continuation-In-Part US20030191191A1 (en) 1995-07-31 2003-03-04 Methods for preventing and treating peripheral neuropathy by administering desmethylselegiline delivery compositions

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WO1997028791A1 (fr) * 1996-02-09 1997-08-14 The University Of Toronto Innovations Foundation Utilisation de composes deprenyliques pour maintenir ou permettre de retrouver les fonctions des cellules nerveuses, ou pour eviter la perte de ces fonctions
EP0878191A2 (fr) * 1997-04-22 1998-11-18 IIP Institut für Industrielle Pharmazie Forschungs- und Entwicklungsgesellschaft mbH Solution aqueuse stable à base de sélegiline et dispositif pour son administration
WO1999047133A1 (fr) * 1998-03-16 1999-09-23 Somerset Pharmaceuticals, Inc. Utilisation de selegiline ou de desmethylselegiline pour traiter les plaies, les brulures et les lesions cutanees
US5981598A (en) * 1995-02-10 1999-11-09 The University Of Toronto Innovations Foundation Deprenyl compounds for treatment of glaucoma
WO2000021513A2 (fr) * 1998-10-09 2000-04-20 Shankar L Sai Latha Procedes pour traiter la sclerose en plaques
WO2000071109A2 (fr) * 1999-05-21 2000-11-30 Somerset Pharmaceuticals, Inc. S-(+)-desmethylselegiline et son utilisation therapeutique
WO2002019964A2 (fr) * 2000-08-28 2002-03-14 Somerset Pharmaceuticals, Inc. Procedes et compositions pharmaceutiques utilisant la desmethylselegiline pour traiter des maladies ou des etats neoplasiques
US6528082B2 (en) 1995-01-13 2003-03-04 Somerset Pharmaceuticals, Inc. Methods and pharmaceutical compositions employing desmethylselegiline to treat neoplastic diseases or conditions
EP1476147A1 (fr) * 2002-01-18 2004-11-17 Tatton Technologies, LLC. Methodes de traitement de troubles de la vue
EP1487427A1 (fr) * 2002-03-04 2004-12-22 Somerset Pharmaceuticals, Inc. Procedes de prevention et de traitement de la neuropathie peripherique par administration de desmethylselegiline
EP1621190A1 (fr) * 1998-10-09 2006-02-01 L. Sai Latha Shankar Analogues du deprenyle pour traiter la sclérose en plaques

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Cited By (25)

* Cited by examiner, † Cited by third party
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US5844003A (en) * 1991-04-04 1998-12-01 Innovations Foundation Use of deprenyl compounds to maintain, prevent loss, or recover nerve cell function
US6528082B2 (en) 1995-01-13 2003-03-04 Somerset Pharmaceuticals, Inc. Methods and pharmaceutical compositions employing desmethylselegiline to treat neoplastic diseases or conditions
US5981598A (en) * 1995-02-10 1999-11-09 The University Of Toronto Innovations Foundation Deprenyl compounds for treatment of glaucoma
US6455590B1 (en) 1995-02-10 2002-09-24 University Of Toronto Innovations.Foundation Deprenyl compounds for treatment of glaucoma
EP1621189A2 (fr) * 1996-02-09 2006-02-01 The University Of Toronto Innovations Foundation Utilisation de composés déprenyliques pour maintenir ou permettre de retrouver les fonctions des cellules nerveuses, ou pour éviter la perte de ces fonctions
WO1997028791A1 (fr) * 1996-02-09 1997-08-14 The University Of Toronto Innovations Foundation Utilisation de composes deprenyliques pour maintenir ou permettre de retrouver les fonctions des cellules nerveuses, ou pour eviter la perte de ces fonctions
EP1621189A3 (fr) * 1996-02-09 2006-02-08 The University Of Toronto Innovations Foundation Utilisation de composés déprenyliques pour maintenir ou permettre de retrouver les fonctions des cellules nerveuses, ou pour éviter la perte de ces fonctions
EP0878191A3 (fr) * 1997-04-22 1999-09-29 IIP Institut für Industrielle Pharmazie Forschungs- und Entwicklungsgesellschaft mbH Solution aqueuse stable à base de sélegiline et dispositif pour son administration
EP0878191A2 (fr) * 1997-04-22 1998-11-18 IIP Institut für Industrielle Pharmazie Forschungs- und Entwicklungsgesellschaft mbH Solution aqueuse stable à base de sélegiline et dispositif pour son administration
US7147864B2 (en) 1998-03-16 2006-12-12 Somerset Pharmaceuticals, Inc. Methods for preventing photodamaged skin by administering selegiline or desmethylselegiline
WO1999047133A1 (fr) * 1998-03-16 1999-09-23 Somerset Pharmaceuticals, Inc. Utilisation de selegiline ou de desmethylselegiline pour traiter les plaies, les brulures et les lesions cutanees
US6709664B2 (en) 1998-03-16 2004-03-23 Somerset Pharmaceuticals, Inc. Methods for treating photodamaged skin by administering selegiline or desmethylselegiline
US6461619B1 (en) 1998-03-16 2002-10-08 Somerset Pharmaceuticals, Inc. Method for treating wounds, burns and dermatological damage by administering selegiline or desmethylselegiline
WO2000021513A2 (fr) * 1998-10-09 2000-04-20 Shankar L Sai Latha Procedes pour traiter la sclerose en plaques
US6492427B2 (en) 1998-10-09 2002-12-10 L. Sai Latha Shankar Methods for treating multiple sclerosis
EP1621190A1 (fr) * 1998-10-09 2006-02-01 L. Sai Latha Shankar Analogues du deprenyle pour traiter la sclérose en plaques
WO2000021513A3 (fr) * 1998-10-09 2000-08-24 L Sai Latha Shankar Procedes pour traiter la sclerose en plaques
WO2000071109A3 (fr) * 1999-05-21 2001-03-01 Somerset Pharmaceuticals Inc S-(+)-desmethylselegiline et son utilisation therapeutique
WO2000071109A2 (fr) * 1999-05-21 2000-11-30 Somerset Pharmaceuticals, Inc. S-(+)-desmethylselegiline et son utilisation therapeutique
WO2002019964A3 (fr) * 2000-08-28 2003-02-27 Somerset Pharmaceuticals Inc Procedes et compositions pharmaceutiques utilisant la desmethylselegiline pour traiter des maladies ou des etats neoplasiques
WO2002019964A2 (fr) * 2000-08-28 2002-03-14 Somerset Pharmaceuticals, Inc. Procedes et compositions pharmaceutiques utilisant la desmethylselegiline pour traiter des maladies ou des etats neoplasiques
EP1476147A1 (fr) * 2002-01-18 2004-11-17 Tatton Technologies, LLC. Methodes de traitement de troubles de la vue
EP1476147A4 (fr) * 2002-01-18 2005-03-09 Tatton Technologies Llc Methodes de traitement de troubles de la vue
EP1487427A1 (fr) * 2002-03-04 2004-12-22 Somerset Pharmaceuticals, Inc. Procedes de prevention et de traitement de la neuropathie peripherique par administration de desmethylselegiline
EP1487427A4 (fr) * 2002-03-04 2006-01-18 Somerset Pharmaceuticals Inc Procedes de prevention et de traitement de la neuropathie peripherique par administration de desmethylselegiline

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