Classifications

• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • 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

Definitions

• composition for the treatment of Alzheimer's disease and process for preparing the same
• the invention relates to a composition for the
• a further object of the invention is a method for treating Alzheimer's disease.
• Alzheimer's type of dementia has recently become of high professional interest as the disease is associated with elongation of average age and due to the great public interest thereto. Such an interest is obvious as dementia occurs in almost every family. This occurance, however, burdens the families both in .social (material) and emotional aspects. Contrary to the 10 billion in 1982 (Terry and Katzman) 34 billion dollars were spent for nursing patients suffering from any form of dementia in 1985. The number of people connected with the disease exceeded 2,5 million in 1985.
• Alzheimer's disease was described first by Alois Alzheimer, German neurologist, in 1906 as a presenile type of dementia. The patient, though only 51, showed the most serious symptoms of senile dementia. The deterioration of condition was very rapid and the patient died after a few days. After autopsy of brain Alzheimer described that the neurofibrils, which, under normal conditions, showed a coordinated, thread-like formation, appeared as an entangled bunch. These neurofibrillar bundles were described as
• Alzheimer's disease appears not. only in presenium but also in the late old age and generally comprises a greater part of senile dementiae.
• the morphological symptoms of the disease appear in the area of neurocortex as well as that of the temporal, parietal and occipital cortex, but symptoms can also be found in amygdalin and hippocampus.
• Tariska (1965) describes these as being situated diffusely in certain areas of the brain.
• the functional symptoms of the disease are as follows:
• a characteris.tic of the memory disturbance which is never functional, like in case of neuropaths and psychopaths, that it extends to all memory components. This disturbance can be interpreted by serious neurophysiological damages of organic origin.
• a characteristic symptom is presbiophrenia, the complete deterioration of memory: the patient does not remember the happenings of the previous day and even
• the loss of manual memory necessary for activity leads to apraxia; e.g., sewing on a button or tieing a necktie forms an insoluble problem.
• the early dementia is characterized by the disappearance of the EEG alpha rythm.
• the late dementia may be detected even by CT scanning.
• the emotional disturbances, fear and depression may also be attributed partly to frustrations caused by the forgetfulness.
• the patient mixes up the seasons and cannot use the calendar. Sometimes they even cannot recognize their own husband or wife and become totally impossible to social life.
• the disease is also called "double death" referring to the intellectual declining associated with a total physical decay.
• the Alzheimer ' s disease is very difficult to determine whether the Alzheimer ' s disease is very difficult to determine whether the Alzheimer ' s disease is very difficult to determine whether the Alzheimer ' s disease is very difficult to determine whether the Alzheimer ' s disease is very difficult to determine whether the Alzheimer ' s disease is very difficult to determine whether the Alzheimer ' s disease is very difficult to determine whether the Alzheimer ' s disease is very difficult to determine whether the Alzheimer ' s disease is very difficult to
• dementia may be caused by a number of diseases, like arteriosclerosis, apoplexy, tumors, dipsomania, anaemia, undernutrition, thyroid insufficiency, etc.
• diseases like arteriosclerosis, apoplexy, tumors, dipsomania, anaemia, undernutrition, thyroid insufficiency, etc.
• mental deterioration is a secondary process; it is formed on basis of an other illness, and accordingly, treatment is equal to curing the original disease.
• the situation is same with the dementation symptoms of Parkinson's disease, paralytic progressiva and senile psychosis.
• the Alzheimer's disease should be differentiated from the Kraepelin's disease and Pickatrophy occuring in the presenium, which, themselves are also primary dementiae. Differentiated diagnosis of both diseases is more or less possible by encephalography. If the presence of all the above diseases can be excluded, the diagnosis of Alzheimer's disease is probable. According to statistics, about 50% of the senile dementiae is of Alzheimer's type
• acetylcholin which is released from the cholinerg neurons.
• the abnormal function of cholinerg system results in innumerous disease entities.
• CAT cholinacetyl-transferase
• the cholinesterase (ChE) activity is also reduced. It has been established that there is a close correlation between the degree of dementia and the defective function of the cholinerg system (Perry et al, 1978) . It is thought that destruction of the Nissl-stained cells of the basal nucleus, as well as the number of plaques are in close correlation with the severity of the disease entity (Whitehouse et al, 1982). In histological experiments 70% of the nuclei showed degeneration. Though, Perry et al (1982) regarded the destruction of the cytosomes secondary only. The cholinerg feature of these cells was also proved immunocytochemically (Nagai et al, 1983).
• cortical cholinerg system about 50-60% of nucleus basalis, 20-40 % of interneuronal origin
• Alzheimer's disease is proved by the observation that in Huntington's disease associated with dementia
• the CAT activity does not decrease.
• the binding ability of the cerebral muscarine receptors does not change: there is no difference in 3 H-QNB (quinuclidyl benzylate) binding and affinity between brain tissues obtained from normal patients and those died in Alzheimer's disease.
• 3 H-QNB quinuclidyl benzylate
• DOPA-decarboxylase (DOPA-DC) activity is e.g. by 80% lower than on patients with
• the disease entity is also characterized, among other neurochemical modifications, by changes in the somatostatin and other neuropeptide content.
• chollne the precursor of ACh is added in high doses (16 g/day). Similarily, phosphatidyl choline is also
• Physostigmin was administered to patients suffering from Alzheimer's disease in a dosis of 1 to 1,5 mg/day (Davis et al , 1976, Goodnick and Gershon, 1984 ) and improvement of cognitive functions was observed. Accordingly, the reduced function of central noradrenerg, serotoninerg pathes was described. The formation of memory disturbances is likely promoted by other transmittance systems. Though physostigmin increases the ACh concentration in the synaptic space, the enhancing effect on the ACh release negative feedback
• Atropin inhibits the muscarine receptors also postsynaptically, and thus, though enhancing the cholinerg transmission by the presynaptic effect, this favourable effect is inhibited by the postsynaptic effect.
• This theory is supported by the literature describing chat administration of atropin damages learning ability and memory (Watts et al , 1981 ) , while the same are improved by the effect of physostigmin (Murray and Fibiger, 1985).
• THA tetrahydro-amino-acidine
• the present invention aims to provide an improved therapy to eliminate the disadvantegous effects of the above treatments and to provide a pharmaceutical composition which results in an effective therapy by using reasonably low drug concentrations.
• the present invention relates to a pharmaceutical composition which comprises the mixture of physostigmin and 4-aminopyridin as active ingredient.
• the composition does not possess the disadvantages caused by the negative feedback inhibition caused by the physostigmin and at the same time the total amount of the two components may be substantially lower than the effective amount of either the physostigmin or 4-aminopyridin when taken alone.
• Atropin also promotes ACh release as resulting in suspension of the negative feedback inhibition (see Table 1).
• atropin did not enhance ACh release to a higher level, i.e., the S2/S1 value did not raise. Accordingly, the negative feedback did not function in the presence of 4-AP.
• Oxotremorin is a compound stimulating the presynaptic muscarine receptors as well as inhibits ACh release.
• Fig 1 shows that 4-AP has a higher ACh release
• the physostigmin which was inactive due to the enhanced negative feedback inhibition, i.e. destroyed its own good effect by the function of its own negative feedback inhibition, results in enhanced ACh release and prolonged effect.
• a substantially lower concentration of physostigmin and 4-aminopyridin is sufficient to re-establish the normal cholinerg transmission, i.e. to improve cognitive disturbances. Accordingly, at least the most difficult problem caused by Alzheimer's disease, i.e. the social breakdown of the patient can be improved, at least partly, by the treatment according to the invention. Davidson et al (1988) administered to patients
• composition of the present invention comprises the synergistic mixture of physostigmin and 4-amino-pyridin as active ingredient.
• the ratio of the components within the mixture may vary within a broad range, preferably it is 1:1 to 1:20. Of course, the above preferred ratio may be exceeded in both directions.
• the suitable weight ratio is 1:2 to 1;10, most preferably 1:5.
• a preferred oral dosis unit contains e.g. 0,2 mg physostigmin and 1 mg 4-aminopyridin, the daily supply being suitably 3 dosis units.
• compositions can be prepared by methods well-known in the pharmaceutical industry, e.g. by mixing the two active components with usual formulation auxiliaries and forming the mixture into suitable dosis forms.
• the invention also relates to the process for the treatment of Alzheimer's disease, wherein physostigmin and 4-amino-pyridin are added to the patient. Clinical tests showed that the following components and preferred doses should be used:
• the 4-aminopyridin dosis may be raised to 2 mg.

Landscapes

• Health & Medical Sciences (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Pharmacology & Pharmacy (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Engineering & Computer Science (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Neurosurgery (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Hospice & Palliative Care (AREA)
• Psychiatry (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Epidemiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Steroid Compounds (AREA)

Applications Claiming Priority (3)

Publications (1)

Family

ID=10967276

Family Applications (1)

Country Status (8)

Families Citing this family (2)

Family Cites Families (2)

• 1990
  • 1990-07-12 HU HU904191A patent/HU207444B/hu unknown
• 1991
  • 1991-07-11 EP EP91912875A patent/EP0607125A1/de not_active Withdrawn
  • 1991-07-11 JP JP91512036A patent/JPH05508843A/ja active Pending
  • 1991-07-11 IE IE243191A patent/IE912431A1/en unknown
  • 1991-07-11 AU AU82053/91A patent/AU645826B2/en not_active Ceased
  • 1991-07-11 WO PCT/HU1991/000033 patent/WO1992000737A1/en not_active Application Discontinuation
  • 1991-07-12 ZA ZA915462A patent/ZA915462B/xx unknown
  • 1991-07-12 CZ CS912165A patent/CZ280474B6/cs unknown

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events