ANTIPARKINSON MAO REVERSIBLE INHIBITOR

Abstract: Use of caroxazone for the manufacture of a medicament having a new therapeutic use in the treatment of Parkinson's disease and other neurodegenerative conditions related to endogenous and/or exogenous toxins, alone or in association with other antiparkinson agents.

Description: "ANTIPARKENSON HAO REVERSIBLE INHIBITOR" The present invention refers to a new use of 2-oxo- 2H-l,3benzoxazine-3(4H) acetamide in the manufacture of a medicament having a new therapeutic use. This compound, having the generic name caroxazone, is described in US-A- 3,427,313 which discloses also its antidepressant activity. Experimental and clinical studies show that caroxazone is a reversible MAO (monoamine oxidase) inhibitor with some degree of specificity towards the form B, (Moretti A. et al., Biochem. Pharmac. , __&, 2728-2731, 1981, Moretti A. et al:, Br. J. Clin. Pharmac, __! ■ 511- 515, 1981; Moretti A., et al., in "Monoamine oxidase and disease", 537-546, published by Academic Press, London, 1984) . According to the present invention, it has been found that caroxazone may be used in the treatment of other diseases different from depression. More particularly, the present invention provides use of 2-oxo-2H-l,3benzoxazine-3(4H) acetamide (caroxazone) in the preparation of pharmaceutical composition for use in treating Parkinson's disease and/or another neurodegenerative condition related to an endogenous or exogenous toxin. The invention also provides an agent for use in treating Parkinson's disease and/or another neurodegenerative condition related to an endogenous or exogenous toxin, comprising caroxazone. As a third aspect the invention provides a method of treating Parkinson's disease and/or another neurodegenerative condition related to an endogenous or exogenous toxin, which method comprises administering to a patient in need of said treatment a therapeutically effective amount of caroxazone. Examples of other neurodegenerative conditions related to endogenous and/or exogenous toxins, include Alzheimer's disease and senile dementia. The caroxazone may be used alone or in association with other antiparkinson agents such as L-Dopa to improve control of side effects. Dopamine (DA) selective neurotoxine MPTP (1-methyl- 4-phenyl -1,2,3,6-tetrahydropyridine) selectively destroys dopa inergic neurons in the substantia nigra pars compacta, producing a Parkinson-like syndrome in man and animals. The compound of the present invention, caroxazone, was found to be active as a protective agent against striatal DA depletion induced by MPTP in C57B1 mice. Since similar neurotoxins are thought to be involved iτι the etiology of Parkinson's Disease, caroxazone may be employed for slowing down the neurodegenerative processes in this and similar diseases related to endogenous and/or exogenous toxins. The acute toxicity of caroxazone in rats is more than 2,000 mg/Kg p.p.. The full reversibility of caroxazone MAO-inhibitor activity makes it a suitable agent for the treatment of Parkinson's disease, without the unwanted side-effects associated with irreversible MAO-inhibitors. The compound is therefore indicated for use as an antiparkinson and anti neurodegenerative disease agent. The amount of active compound for this indication will, of course, be dependent on the subject being treated, the severity of the condition treated, the manner of administration and the judgement of the prescribing physician. However, an effective dosage is in the range of about 100 to about 1000 mg/day, preferably from 300 to 600, conveniently given in divided doses 1 to 5 times a day, preferably 1 to 3, in unit dosage form containing from about 100 to about 200 mg of the compound or in sustained release form. Administration of the active compound can be via any of the accepted modes of administration for antiparkinson agents. The routes of administration include parenteral, oral, buccal, peroral, transdermal, intranasal or other suitable routes. Depending on the intended route of administration, such compositions may be formulated in conventional manner or as other pharmaceutical systems for delivery of the drug at a rate and extent needed for the intended therapeutical use. The composition according to the invention may comprise a conventional pharmaceutically acceptable carrier or excipient and caroxazone and, in addition, may comprise other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc. For solid compositions, conventional non toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate and the like. Liquid pharmaceutically ad iniεtrable compositions can, for example, be prepared by dissolving, dispersing, etc. , an active compound as defined above and optional pharmaceutical adjuvant in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension. The following example further illustrates the invention without limiting it. EXAMPLE MPTP-INDUCED PARKINSONISM C57B1 mice were treated with MPTP (30 mg/Kg i.p., at 24 hours intervals for 3 days) . 1-6-9 hrs before each treatment with MPTP animals received caroxazone (100 mg/Kg orally) . The effects of pretreatment with caroxazone on striatal levels of dopamine in MPTP-treated C57B1 mice. TREATMENT DOPAMINE (ng/g tissue ± SEM) 13180 ± 412 MPTP 3579 ± 347 Caroxazone (1 h) + MPTP 11804 ± 503 Caroxazone (6 h) + MPTP 12660 ± 359 Caroxazone (9 h) + MPTP 5271 ± 525 P< 0.01 vs control (Dunnett's t test) The 70 % reduction in striatal DA levels after MPTP was completely prevented by prior administration of caroxazone at 1 and 6 hr. At 9 hr before MPTP no protective effect was displayed owing to the reversibility of caroxazone protection. The same was found in mesolimbic areas. The effects of pretreatment with caroxazone on mesolimbic levels of dopamine in MPTP-treated C57B1 mice. TREATMENT DOPAMINE (ng/g tissue ± SEM) 6872 ± 171 MPTP 3328 ± 232 Caroxazone (1 h) + MPTP 5929 ± 257 Caroxazone (6 h) + MPTP 5684 ± 278 Caroxazone (9 h) + MPTP 4119 ± 269 p< 0.01 vs. control (Dunnett's t test) In striatum the dose response curve for protective effect by caroxazone administered at 6 hr before MPTP provided an ED 5Q of 5.5 mg/kg orally showing an almost complete protection between 10-15 mg/kg.

Claims: CIAIM? 1. Use of 2-oxo-2H-l,3benzoxazine-3(4H) acetamide (caroxazone) in the preparation of a pharmaceutical composition for use in treating Parkinson's disease and/or another neurodegenerative condition related to an endogenous or exogenous toxin. 2. An agent for use in treating Parkinson's disease and/or another neurodegenerative condition related to an endogenous or exogenous toxin, comprising caroxazone. 3. A method of treating Parkinson's disease and/or another neurodegenerative condition related to an endogenous or exogenous toxin, which method comprises administering to a patient in need of said treatment a therapeutically effective amount of caroxazone.

Inventors: CACCIA CARLA, CARFAGNA NICOLA, FARIELLO RUGGERO, CACCIA, CARLA, CARFAGNA, NICOLA, FARIELLO, RUGGERO
Applicants: ERBA CARLO SPA, FARMITALIA CARLO ERBA S.R.L.
Application year: 1991
Main classification: A61K31
IPC codes: A61K31, A61P25, C07D265