WO1992001455A1 - Medicament against degenerative brain performance diseases of the alzheimer type and cholinergic system disturbances - Google Patents

Abstract

Diseases of the Alzheimer type are characterized by various disturbances of brain functions and disturbances in the cholinergic system caused by deposits of aminoacid chains or aluminium. A link is established between boron and aluminium, by the cationic properties of acetylcholine and by considering Alzheimer diseases as a cation transport problem. This leads to the search for an anionic carrier substance. The therapeutic principle that consists in using a negatively-charged acetylcholine carrier substance is put into practice by means of organic boron compounds, the use of sodium tetraphenylborate representing an example of their application. This substance can increase two to eight times the flow of acetylcholine in the cell. Preliminary therapeutic tests give good reason to carry out systematic clinical tests. The principle of using an anionic acetylcholine carrier substance may however also be put into practice by means of other compounds.

Description

 A r z i m i t t e l g e n e r a t i v e H i r n l e i s t t u n g e n v o m A l h

The invention relates to pharmaceutical preparations or containers that ect for the treatment of degenerative brain disorders such as poor memory, increasing loss of previous intellectual skills, personality changes, word finding disorders, disorders of spatial and temporal orientation, dizziness, weakening of the control of body functions. as well as for the treatment of Alzheimer's disease, senile dementias of the Alzheimer's type (SDAT), degenerative encephalopathies and disorders in the cholinergic system.

The current state of therapy for this group of diseases is appropriately summarized in a presentation by A.Barocca, "Nootropica therapy" (progress in medicine, 108th year (1990) pp. 179-180). The presentation also refers to the report of the Federal Health Office "Brain disorders in old age" (see attachment). Nootropica are substances such as co-dergocrin melisate, pyritinol, piracetam and nicergoline, which increase the cerebral blood flow, oxygen and glucose sterilization. They have no special effect on the degenerative diseases of the Alzheimer's type. The fact that the treatment of dementia processes is unsatisfactory also results from the standard works. In H.G. Mertens and R. Rohkamm "Therapy of Neurological Diseases and Syndromes" (Stuttgart and New York 1990) p.589, both senile dementias of Alzheimer's type and Alzheimer's disease are counted among the causally non-treatable dementias. In the handbook "Psychiatry of the Present", published by

K.P. Kisker et al. (Berlin, Heidelberg, New York etc. 1989, 8th volume,

Geriatric psychiatry, edited by D.Cooper, p.192) states that there are no specific therapeutic measures available for this group of diseases.

In 1990 the assessment of nootropics is the same as that of the German Federal Health Office in 1986. According to leading German neurologists (S.Hoyer, Heidelberg; H.-J.Möller, Bonn; S.Kanowski, Berlin), the recommendations apply the commission commissioned by the Federal Health Office in 1986. (The New Medical Doctor No. 96 from May 22, 1990, p.7). The current state of scientific development in the therapy of brain disorders of the Alzheimer type is determined by the knowledge that there is a disorder in the cholinergic system in this group of diseases. Attempts are therefore being made to boost the production of acetylcholine by administering certain amino acids which are known as precursors of acetylcholine (the following patents are available: US patent no.495202 dated May 16, 1983 and on this basis European patent no.0125900A1, and a Another patent PCT, WO 85/03869 ("Method of treating memory of the eiderly") with amino acids and magnesium. Three years ago, the inventor also dealt with the problem of improving acetylcholine production by influencing the precursors of amino acids He noticed that pyridoxal phosphate (PALP = vitamin B6) plays an important role in the metabolism of numerous amino acids that are important for acetylcholine production However, the inventor has not been able to achieve any result in his clinical investigations of this group of diseases with either parenteral or oral administration can.

Another way to influence acetylcholine production is to delay or prevent the breakdown of the substance. This happens through anticholinesterases such as Physostigmine (eserine and derivatives) or tetrahydroaminoacridine = THA, suggested by the American neurophysiologist William Koopman Summers. A study on this drug was stopped by the American Food and Drug Administration (FDA) after just two months because 20% of those treated with THA had signs of liver damage. In the meantime, however, the drug can be tested further in a study led by the National Institute of Aging (NIA) (Science 239, page 969, 1988).

However, the model of Alzheimer's disease as a production disorder in acetylcholine metabolism also has a serious problem: it cannot explain some reliable results of Alzheimer's research. These results include:

1. The regular occurrence of considerable aluminum in narrow areas in Alzheimer's plaques (J. Edwardson, Medical Research Council Neuroendocrinology Unit, Newcastle; New Scientist 109: 23, 1986: Candy, JM, Lancet I, 3.354, 1986). Edwardson found in animal experiments that calcium deficiency means that more aluminum is taken up from food and stored in the brain. From this he concludes a compensatory mechanism between aluminum and calcium in the sense that aluminum is taken up more when calcium is absent.

Crapper also assumes such a compensatory mechanism between two elements, but between magnesium and aluminum (Crapper, DH.Quittcat S., Krishnan SS et al .: intranuclear aluminum content in Alzheimers disease, dialysis encephalopathy and experimental aluminum encephalopathy, Acta Neuropathologica 1980 , 50, pp. 19-24.

2. In the brain of Alzheimer's patients, increasing amounts of amyloid are found with increasing disease. The structure of this amyloid has only been elucidated by K.Beyreuther, Cologne (now Heidelberg) and C.Masters, Perth, since 1985. It is a 42-43 amino acid peptide called A4. This peptide is identical to the molecular part of a membrane receptor in the nerve cell (J.Kang: Nature 325; page 733-736, 1987). What does this receptor destruction of the nerve cell membrane have to do with a production disorder in acetylcholine metabolism?

3. Alzheimer's disease first damages short-term memory (STM). In contrast to long-term memory, which works with the construction of new protein structures in the nerve cells, it is believed that short-term memory has to do with the depolarization and hyperpolarization of the nerve cell membranes (G. Lynch, JLMcGaugh, NM Weinberger, Neurobiology of learning and memory, P.276, New York and London 1984; CDWoody, Memory, Learning and higher function, New York, Heidelberg, Berlin, 1982; M.Schwarz, physiological psychology, Weinheim and Basel 1980, page 399). 4. In the last book mentioned on page 380 ff. On "cholinergic processes". The numerous studies show that a general disturbance in the breakdown or build-up of acetylcholine cannot be held responsible for a short-term memory disturbance. In the case of a pathological memory disorder, there must be other factors besides the disturbance in the acetylcholine metabolism.

In summary, it can be stated that the previous attempts to bring about an improvement in demented syndromes solely on the basis of influencing the acetylcholine metabolism have not brought any noteworthy success. There is also no model that can combine the various undisputed research results. Accordingly, an attempt with a paradigm shift is required. The invention seeks to remedy this. The invention, as characterized in the claims, solves the problem of finding a medicament for the various dementia processes mentioned above, by an elecrophysiological consideration of the problem, as a result of which boron, boron compounds - in particular boron organic compounds - boron complexes and anionic carriers (= carriers) result.

 At the same time, the electrophysiological approach is able to provide a model which shows the increased aluminum content, the appearance of cell wall amino acids in the deposits, the disorders in the cholinergic system in dementia disorders of the Alzheimer's type with the "electrical"

Functioning of short-term memory (STM).

1. Two displacement or competitive hypotheses were referenced above for aluminum, one hypothesis relating to calcium and the other to magnesium. The underlying mechanism, namely the mutual displacement of substances or the competition of substances for a receptor, is very common in the body physiologically and pathologically (poisoning). However, magnesium and calcium are not particularly similar to aluminum in terms of e l e kt r o p hy s i o l o g i s c h e. This similarity depends on the electron configuration of the elements, especially in the outer shell;

 aluminum and bor are most similar in this respect.

 Precisely because of this similarity in the electron configuration of the

 These two elements also belong to a group of the outer shell

 Periodic table.

Boron and boron compounds currently play a completely subordinate role in medicine. Such compounds were previously known as disinfectants; however, after percutaneous poisoning was described, these substances were banned. Currently only borosotopes play a role in the treatment of gliomas (W.F. Harkness, Basic Life

 Science, Vol. 50, pp. 49-51, 1989).

Until recently, it was controversial whether boron is a trace element for the mammalian organism. This is also due to the fact that the technical possibilities of measuring trace elements were too imprecise until recently to achieve stable results. %. + Only with the newer mass spectrometric methods with the help of neutron radiation (W.B.Clarke, C.B. Webber, M.Koekebakker and R.D.

Barr, J.Lab.Clin.Med., Volume 109 (1987) pp. 155-158) have shown that the organism consistently tries to maintain a stable boron level of 80-100 ng per gram of wet weight in the blood. This is very different from aluminum, which the body tries to avoid consistently. After it was possible to produce a consistently boron-free diet, there were indications that boron is also an essential trace element for the mammal (C.Minoia;

 C.Gregotti; A. Di Nucci; S.M. Candura; M.Tonini; L.Manzo, in G.Ital.Med. Lav., 9 (3-4) 119-124 (1987). Measured in terms of daily urine excretion, the boron turnover is relatively high at 3.7 mg per day (scientific tables Geigy, Basel 1977, page 56).

2. The continuation of the electrophysiological approach shows that both choline and acetylcholine are positively charged, ie they are cations. This is known, but it has a problem with the approaches to the solution

 dementia problems have so far played no role. Since an essential mechanism of the CNS activity is the ion exchange through the cell membrane, the ionic property of the acetylcholine immediately suggests that this is not a product problem, but a problem.

 The acetylcholine is stored in the presynaptic vesicle, and is now not simply given off according to the concentration gradient, but rather to certain signals; the control can take place either by changing the electrical resistance in the cell membrane - that is to say by changing the potential difference between outside and inside - or by switching on carriers.

3. If it is correct that the deposits in Alzheimer's

 Part of the disease from the remains of cell wall components, we have another indication that Alzheimer's disease is at least partly a transport problem through the cell membrane.

4. We get a hint in the same direction by the above

 cited studies on how short-term memory works.

 It is demonstrated that the SMT works with depolarizations and hyperpolarizations of the cell membrane and that acetylcholine production cannot be the only limiting factor for the functioning of the memory.

These four considerations lead to the search for an ionic substance which can react with acetylcholine and which has a positive effect on its transport through the cell membrane. Because of the similarity of the electronic structure in the outer shell between aluminum and boron, we are looking for such a substance in the area of boron compounds. It shows that there are several relationships between acetylcholine and boron compounds. B-methyl-B- (3-trimethylammoniopropyl-) boric acid has the strongest competitive acetylcholinesterase inhibition known to date because of its bifunctionality, isosterie and structural similarity to acetylcholine. This acid is bound to the enzyme about 10 times more strongly than acetylcholine (KAKoehler,

G.P. Hess, Biochemistry 13 (1974) 5345-5350; C.A.82 (1975) No. 69733.

Furthermore, triarylcyanoborate and other tetraarylborates play an important role in choline and acetylcholine research as cation-binding and lipophilic anions. Sodium tetraphenylborate Na (B (C6H5) ₄ ) is an excellent precipitant for choline and choline esters (HWSpier, Biochem. Z.322 (1952) 467-470). With tetraphenylborate (= TPB), radioactively labeled acetylcholine can be used to determine choline acetyltransferase (F. Fonnum, J.Biochem 109 (1968) 389-398). PTCarroll and others have also carried out in vivo experiments to determine acetylcholine turnover in the brain (Biochem. Pharmakol. 26 (1977) 397-402). Sodium tetraphenylborate is also used by official pharmacopoeias as a reagent for qualitative and quantitative studies. In the US Pharmacopeia XVI of 1960, a 0.02 M volumetric sodium tetraphenylborate solution was included for the first time as a pharmaceutical reagent.

An acetylcholine-specific liquid membrane electrode based on tetraarylborate was specified by G. Baum (Anal.Letters 3.1970, p.105-111.

EALiberman and VPTopaly (Biophysica 14,1969, pp.452-461; Biophysics, USSR, 14, 1969, pp.477-487; CA71, 1969, Nr.56811) led the investigations on M e mb r to per me ab ilit eats under TPB. The membrane conductivity was found to be a function of the TPB concentration, but only between 10 ^-9 and 10 ^-3 (!). The increase in permeability of the cell membrane by TPB, namely through sports relief, is also confirmed by recent work (Gallo, RL; Wersto, RP; Notter, RH; Finkelstein, JN; Arch.Biochem. Biophys. (1984) B.235 , Pp.544-54). The change in electrical conductivity under tetraphenylborate was tested on bimolecular phosphoxlipid membranes made of brain substance. The conductivity of the membrane was increased in all cases (EALiberman, VPTopaly, LM Zofina,

Biofizika 15 (1970) pp.69-75). Tetraphenylborate ions are mainly adsorbed on the membrane surface and change the molecular organization there. The studies by DM Margulis (Biofizika 19 (1974) pp.155-160) suggest the "carrier" properties of the tetraphenylborate for quaternary ammonium bases. Breathing membrane vesicles from Escherichia coli accumulated a large amount of lipid-soluble quaternary ammonium cations under the influence of TPB (H.Hirata, K.Altendorf, SMHarold, Proz.Nat. Acad. Der Wissenschaften Sei.US 70 (1973) p.1804- 1808). TPB is also a suitable membrane-compatible anion for inducing translocations through the cell membrane (VPSkulachev, J.Bioenerg. 3 (1972)

P.25-38). TPB is also a very effective anion for inhibiting the

ATP synthesis and reverse electron transfer in mitochondria (H. Meisner, Biochem. Biophys. Acta 218 (1973) pp. 383-389).

The conductivity of cell plasma also changes in the presence of TPB (K.Asami, E.A. Liberman and others (Membr.Transp.Processes, Band 2, 1978, pp. 349-357).

The most important work for our problem on the influence of TPB on cholinergic receptors of the neuromuscular switching points has been published since 1968. A doubling of the important acetylcholine effects was found in a standard neuromuscular test preparation (J. Seifter, G. Guideri, E. Seifter, Eur. J. Pharmacol. Volume 3,

1968, p.263). However, neither a blocking of the cholinesterase was found nor an influence on the synthesis and degradation processes of the acetylcholine. Numerous animal experiments on frogs, chickens, rats, rabbits and dogs have shown the following mechanism of action: TPB triggers primarily nicotine-like and secondly the muscarinic acetylcholine effects on the muscles. The ganglia are hardly affected. The central nervous system (CNS) shows only nicotine-like effects after TPB.

TPB does not act directly like acetylcholine through depolarization of the postjunctional endplate membrane, but through an increased acetylcholine release from the motor nerve endings and weak anti-acetylcholinesterase activity (IGMarshall, Eur.J. Pharmacol. 13, 1970, pp. 51-54). TPB also attacks the postsynaptic membrane, where it reacts with cationic sites, and possibly causes the local change in membrane permeability. On the basis of the test results, activation of cholinergic receptors by a change in the occupation of cationic and anionic binding sites is also discussed (G. Guideri, E. Seifter, J. Seifter, Eur.J. Pharmakol. 17, 1972, pp. 253-258).

TPB also affects the autonomic nervous system. It was not the release of cholinergic transmitter substances or the prevention of their degradation that was responsible for the effect, but rather the change in the measure of activity and the in fl uence. The membrane or receptor effect of the TPB - instead of an indirect effect via acetylcholine release or acetylcholinesterase inhibition - corresponds to the results on the skeletal and cardiac muscle of the frog (G.Guideri, J.Seifter, Arch. Intern.Pharmaco.Dyn.

 Therap. 212 (1974) pp. 302-309).

Altogether, it can be said that there are so extensive experimental studies on the anionic effect of organic boron compounds on the cationic acetylcholine that one has to ask why no connection between organic boron compounds has so far been found

and disorders of acetylcholine turnover in diseases from

Alzheimer's type was produced. The answer is two

Considerations: 1. When the importance of acetylcholine metabolism for Alzheimer's disease was recognized and became the focus of a broader scientific public, the TPB studies on acetylcholine transport had been forgotten, 2. These studies were carried out by Russian pharmacologists, who are primarily concerned with the Relationships worked on the neuromuscular endplates. American neurochemists were primarily concerned with senile dementias of the Alzheimer's type, whose interest was directed to the acetylcholine metabolism in the brain and the conditions in the synaptic cleft. A

DIMDI research of July 12, 1990 showed that a connection between TPB and the disorders of the acetylcholine metabolism in Alzheimer's diseases has not been treated. Research on the

Cell membrane and on the neuromuscular end plate show that the acetylcholine effect with the help of TPB by improving transport can be increased by two to eight times through the cell membrane. These results justify the hypothesis that an improvement in disorders in the cholinergic CNS system can also be achieved in Alzheimer's disease with organoboron compounds.

A 0.1% sodium tetraphenylborate solution, which is isotized with NaCl in bidistilled water, is given as an example.

This solution is slowly infused intravenously until a total of 0.5 mg sodium tetraphenylborate per 1 kg body weight is reached. This dose should be increased to a maximum of 1 mg per kg body weight.

The example is based on the t o x i k o l o g i s c h e n information in the literature. In human experiments, side effects in healthy people after injection of a sodium tetraphenylborate solution that was less than 4.5% concentrated were not observed at all (H.W. Spier, G.Wagner, Klin.Wochenschrift 30 (1952) p.757-759). In dogs, the intravenous injection of 1 mg per kg body weight caused a temporary drop in blood pressure; 10 mg per kg body weight led to cardiac arrhythmias (A.H. Soloway in: Steinberg, A.L. McCloskey, Progr.in Boron Chemestry, Volume 1, Oxford 1964, pp.203-234). Intraperitoneal injection of 20 mg NaTPB / kg caused 70% mortality in mice and convulsions in 100% of the test animals. The lethality due to tetraphenylborate could be reduced to 20 or 30% by prophylactic administration of dipropylacetic acid or 1,2-bisaethanolamine (D.F. Ventura, J. Seifter, Pharmakologist 16 (1974) p.227). Chronic administration of subconvulsive doses of 10 mg per kg to mice led to liver swelling and a 70% decrease in the serotonin content in the brain of the animals (W.KLiegel, Bor, Berlin 1980, p.785). In the self-test, the intravenous administration of 1 mg NaTPB in 250 ml of physiological saline solution over an infusion of 60 minutes had no side effects.

According to the work by Liberman and Topaly cited above, an increase in membrane permeability can be expected at a TPB concentration between 10 ^-9 (!) And 10. A higher TPB concentration did not result in a further increase in membrane permeability. For use in humans, this would mean that a higher effect level than 1 mg per kg body weight is not sensible.

Attempts to heal according to the same dosage scheme resulted in the mini-mental status according to Folstein and others. (1975) Improvements that make a systematic clinical trial seem reasonable.

Claims

Claims 1.Drugs and containers that contain boron, boron compounds - especially organic boron compounds - and boron complexes and that are used to treat degenerative brain disorders such as memory impairment, increasing loss of previous intellectual skills, personality changes, word-finding disorders, disorders of spatial and temporal orientation, dizziness, relaxation the control of body functions ect. as well as for the treatment of Alzheimer's disease, senile dementias of the Alzheimer's type, degenerative encephalopathies and disorders in the cholinergic system, which are exemplified by sodium tetraphenylborate. 2. Medicinal preparations which contain carrier substances for acetylcholine and are intended for the treatment of the abovementioned diseases.