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Title:  Method for aiding cerebral recovery following neurodegeneration

United States Patent:  6,423,739

Inventors:  Otomo; Eiichi (Tokyo, JP); Takasu; Yoshiyuki (Tokyo, JP)

Assignee:  Daiichi Pharmaceutical Co., Ltd. (Tokyo, JP)

Appl. No.:  784048

Filed:  February 16, 2001

Abstract

A method for aiding cerebral recovery following neurodegeneration, particularly after a stroke, in a mammal, by administration of nefiracetam is disclosed. This method of treatment allows an improvement in the recovery from stroke.

DETAILED DESCRIPTION OF THE INVENTION

Thus, it is an object of the present invention to provide a method for improving the Activities of Daily Living (ADL) in a post-stroke patient which comprises administering to said patient an effective dose of nefiracetam, said administration being initiated within the first six months after the event.

In order to display the best activity, nefiracetam will be administered early or at least as soon as possible, advantageously within three month, preferably within one month after the stroke.

Nefiracetam can be administered in various manner to achieve the desired effect, for example for improving ADL in a post stroke patient or for the recovery of, or at least for improving the recovery of, a post-stroke patient. The compound can be administered alone or in the form of pharmaceutical compositions comprising a pharmacologically effective amount of nefiracetam as an active ingredient and a pharmaceutical acceptable carrier to the patient to be treated, preferably orally. The oral amount of nefiracetam administered will vary and can be any effective amount according to the physician's prescription. Normally, depending upon the patient and the mode of administration, the quantity of compound administered orally may vary over a wide range to provide from about 1 mg/kg to about 20 mg/kg, usually 1.5 mg/kg to 15 mg/kg of body weight of the patient per dose. Unit doses of nefiracetam in the oral pharmaceutical compositions may contain, for example, from about 50 mg to about 1200 mg, usually from 100 to 600 mg of the compound and may be administered 1 to 4 times daily.

The activity of nefiracetam to improve ADL in post-stroke patients has been discovered during a controlled clinical trial against placebo. The compound has been administered orally to 32 post-stroke patients within six months after the event whilst, concurrently, 27 patients received placebo. The two groups of patients were followed during at least 8 weeks and followed up at the end of week 4 and at the end of week 8 on a symptom scale measuring Activities of Daily Living. The nefiracetam-treated patients showed a moderate or remarkable improvement, whereas no patient in the group treated with placebo showed an improvement. Among the above 59 patients, 19 received nefiracetam and 10 received placebo within three months after stroke. Some 70% of the nefiracetam-treated patients showed a moderate or remarkable improvement whilst no improvement has be noted in the patients who received placebo. The difference was significant (p=0.035, .chi.2C test). Thus, unlike what the literature seemed to suggest, it has been discovered that nefiracetam has the surprising and unique property of showing a dramatically good activity when given early after stroke. According to the results of this study, the early treatment with nefiracetam after stroke objectively improves the recovery from stroke, as shown by the fact that, beside psychiatric symptoms such as emotional disturbance and reduced spontaneity, also intellectual dysfunction dramatically improved in a high percent of nefiracetam-treated patients whilst no improvement was noted in the placebo-treated patients. Moreover, nefiracetam surprisingly tends to improve neurological signs and incontinence. Thus nefiracetam, when administered early after the event, appears to be the first drug which is able to induce a recovery from stroke or, at least, to improve the recovery from stroke.

The mechanism of action of nefiracetam for this indication, which is not bound to the nootropic activity of the drug, is unknown, but it is believed that its surprising effect in improving ADL of a patient after a stroke or in the recovery of, or at least in improving the recovery of, a post-stroke patient, is due to a true brain repair. This assumption is confirmed by the effect of nefiracetam on spatial learning and retention in rats with cerebral embolism, treated for 9 days with nefiracetam or vehicle, starting within 24 hours of embolization. More particularly, a clear difference between nefiracetam and vehicle-treated animals was observed in the place-learning watermaze task 7 to 9 days after embolization. Moreover, the effect of nefiracetam is maintained even after washout (at day 17 after embolization). This result is predictive of a brain repair effect and shows that the administration of nefiracetam after a stroke provoked by an embolism induces a recovery of the cognition after the stroke.

Thus, it is a second object of the present invention to provide a method for recovering, or at least for improving the recovery of, a post-stroke patient which comprises administering to said patient an effective amount of nefiracetam, said administration being initiated within six months, advantageously within three months, preferably within one month, from the stroke. More particularly, the method comprises the administration to said patients of a pharmaceutical composition containing a pharmacologically effective amount of nefiracetam, as an active ingredient, and a pharmaceutically acceptable carrier. Said effective amount of nefiracetam is advantageously from 50 to 1200 mg, preferably from 100 to 600 mg per unit dose.

It is a third object of the present invention to provide a pharmaceutical composition for the improvement of ADL in post-stroke patients comprising a pharmacologically effective amount of nefiracetam, as an active ingredient, and a pharmaceutically acceptable carrier.

It is a fourth object of the present invention to provide a pharmaceutical composition for the recovery of, or at least for improving the recovery of, a post-stroke patient, comprising a pharmacologically effective amount of nefiracetam, as an active ingredient, and a pharmaceutically acceptable carrier.

It is a fifth object of the present invention to provide the use of nefiracetam for the preparation of a medicament for improving ADL in a post-stroke patient.

It is a sixth object of the present invention to provide the use of nefiracetam for the preparation of a medicament for the recovery, or at least for improving the recovery, of a post-stroke patient.

It is a seventh object of the present invention to provide the use of nefiracetam for the preparation of a medicament for the early treatment of stroke.

It is a eighth object of the present invention to provide a method for treating neurodegeneration in a mammal which comprises administering to said mammal in need of said treatment an effective amount of nefiracetam, more particularly a pharmaceutical composition comprising a pharmacological effective amount of nefiracetam, as an active ingredient, and a pharmaceutically acceptable carrier.

Biological in vitro studies carried out on primary cultures of hippocampal and cortical rat embryo neurons showed that nefiracetam, at concentrations of 0.1, 1, 10 and 100 micromoles/l, displays a neurotrophic effect on said neurons by significantly increasing neurite outgrowth. This effect is similar to that induced by basic Fibroblast Growth Factor (bFGF), for which a function as a neurotrophic factor in the brain has been suggested (R.S. Morrison et al., Proceedings of the National Academy of Sciences, 1986, 83, 7537-7541; K. Abe et al., 1990, 53, 221-227) and such an effect is surprisingly potentiated by bFGF in hippocampal neurons. This finding strongly suggests that nefiracetam, which is well absorbed and crosses the hematoencephalic barrier, should allow the regeneration of damaged brain neurons in mammals, for example after a stroke, thus favoring brain repair and can be used for combating neurodegeneration in mammals, particularly after a stroke.

The oral pharmaceutical compositions in which form nefiracetam will normally be utilized, are prepared in a manner well known per se in the pharmaceutical art and usually comprise nefiracetam, as an active ingredient, in admixture or otherwise in association with a pharmaceutically acceptable carrier or diluent thereof. For making those formulations said active ingredient will usually be mixed with a carrier, or diluted with a diluent, or enclosed or encapsulated in a capsule, sachet, cachet, paper or other suitable container. Suitable carriers and diluents are known per se.

The compositions may be administered to the post-stroke patient for example in the form of tablets, capsules, dragees, suppositories, syrups or suspensions.

Claim 1 of 16 Claims

What is claimed is:

1. A method for aiding cerebral recovery following neurodegeneration in a mammal comprising administering to said mammal in need of said treatment an effective dose of nefiracetam.

 


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