U.S. patent application number 11/361628 was filed with the patent office on 2006-06-29 for agents for treating neurodegenerative disorders.
Invention is credited to Andrei Z. Afanasiev, Svetlana V. Afanasieva, Sergei O. Bachurin, Elizaveta E. Bukatina, Valery P. Chetverikov, Vladimir V. Grigoriev, Irina V. Grigorieva, Marina A. Jurovskaya, Sergei E. Tkachenko, Nikolai S. Zefirov.
Application Number | 20060140866 11/361628 |
Document ID | / |
Family ID | 20173218 |
Filed Date | 2006-06-29 |
United States Patent
Application |
20060140866 |
Kind Code |
A1 |
Zefirov; Nikolai S. ; et
al. |
June 29, 2006 |
Agents for treating neurodegenerative disorders
Abstract
Compounds and methods of using these compounds to treat
neurodegenerative diseases, especially Alzheimer's disease, are
provided. The compounds that are provided for the treatment of
neurodegenerative diseases can be represented by a general formula
(I): ##STR1## wherein R.sub.1 is Me, Et or PhCH.sub.2; R.sub.2 is
H, PhCH.sub.2 or 6-Me-3-Py-(CH.sub.2).sub.2; and R.sub.3 is H, Me
or Br. The solid line accompanied by the dotted line i.e.
represents a single or double bond and salts thereof with
pharmacologically acceptable acids and quaternary derivatives.
Inventors: |
Zefirov; Nikolai S.;
(Moscow, RU) ; Afanasiev; Andrei Z.;
(Chernogolovka, RU) ; Afanasieva; Svetlana V.;
(Chernogolovka, RU) ; Bachurin; Sergei O.;
(Chernogolovka, RU) ; Tkachenko; Sergei E.;
(Chernogolovka, RU) ; Grigoriev; Vladimir V.;
(Chernogolovka, RU) ; Jurovskaya; Marina A.;
(Moscow, RU) ; Chetverikov; Valery P.;
(Novokuznetsk, RU) ; Bukatina; Elizaveta E.;
(Moscow, RU) ; Grigorieva; Irina V.; (Moscow,
RU) |
Correspondence
Address: |
MORRISON & FOERSTER LLP
755 PAGE MILL RD
PALO ALTO
CA
94304-1018
US
|
Family ID: |
20173218 |
Appl. No.: |
11/361628 |
Filed: |
February 24, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11004001 |
Dec 2, 2004 |
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11361628 |
Feb 24, 2006 |
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10652435 |
Aug 28, 2003 |
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11004001 |
Dec 2, 2004 |
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10057688 |
Jan 23, 2002 |
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10652435 |
Aug 28, 2003 |
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09778662 |
Feb 6, 2001 |
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10057688 |
Jan 23, 2002 |
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09269602 |
Mar 25, 1999 |
6187785 |
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PCT/RU96/00306 |
Oct 23, 1996 |
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09778662 |
Feb 6, 2001 |
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Current U.S.
Class: |
424/9.6 ;
514/291 |
Current CPC
Class: |
A61K 31/437 20130101;
A61P 25/28 20180101; A61K 49/006 20130101 |
Class at
Publication: |
424/009.6 ;
514/291 |
International
Class: |
A61K 49/00 20060101
A61K049/00 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 23, 1995 |
RU |
95118252 |
Claims
1. A method of measuring the accuracy of NMDA injection into a
mouse brain comprising co-injecting methylene blue and NMDA into
the mouse brain and monitoring the migration of methylene blue.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to the use of chemical
compounds in medicine, more specifically, to the use of the
compounds selected from hydrogenated pyrido[4,3-b]indoles for the
treatment of neurodegenerative diseases, and especially Alzheimer's
disease (AD), due to the discovery of new properties intrinsic to
these compounds.
[0003] 2. Description of the Related Art
[0004] Alzheimer's disease is currently one of the severest and
widely spread neurodegenerative diseases. The most traditional
approach to the treatment of this disease is compensatory therapy
based on the compensation of the cholinergic system functions which
are reduced in Alzheimer's disease. One of the therapeutic agents
used in the alleged method of treatment is tacrine hydrochloride
(hereinafter referred to as tacrine) which is
9-amino-1,2,3,4-tetrahydroacridine hydrochloride represented by the
formula (A): ##STR2##
[0005] The mechanism of action of the said agent involves
inhibiting choline esterase (Volger B. W. "Alternatives in the
treatment of memory loss in patient with Alzheimer's disease".
(Clinical Pharmacy, 1991 Jun. 10 (6): 447-56). As for the choline
esterase inhibiting activity, tacrine is an analogue of the world
famous physostigmine and is a traditional anticholine esterase
agent. However, the treatment with tacrine is not always effective.
Besides, tacrine tends to cause undesirable side-effects.
[0006] A wide range of neurological diseases such as Alzheimer's
disease. Huntington chorea: amiotrophic lateral sclerosis as well
as brain ischemia are known to be associated with an excitotoxic
effect of neuromediatory excitatory amino acids (EAA) such as
glutamate and aspartate (Excitatory Amino Acids and Drug Research,
Ed. by M. R. Szewczak N. I. Hrib Alan R. Liss, Inc., New York,
1989, p. 380; The NMDA Receptor, Eds. Watkins & Collingridge
G., 1989, IRL Press). In accordance with this mechanism,
hyperexcitation of neurones in prolonged activation of their
N-methyl-D-aspartate (NMDA) receptors with glutamate results in an
excessive entry of potassium ions into the cell which initiates a
number of pathological metabolic processes finally causing the
death of nerve cells (Mattson, Neurone, 1990, v. 2, p. 105, Mill S.
Kater, Neuron, 1990, v. 2, p. 149; Saitch et al., Lab Suvest, 1991,
v. 64, p. 596).
[0007] More specifically in Alzheimer's disease, death of numerous
neurones is believed to occur as follows. An endogenic
oligopeptide, such as .beta.-amyloid, is a neurotoxic factor
inducing neurodegenerative processes in the neurones.
.beta.-Amyloid is present in the neurotic plaques abundantly
located on the surface of the brain of the patients suffering from
Alzheimer's disease (Prelli et al.,--J. Neurochem., 1988, v. 51, p.
648; Yanuer et al.,--Science, 1990, v. 250, p. 279). As shown by
the investigations of recent years, .beta.-amyloid significantly
enhances the excitotoxic effect of glutamate which is effected
through the NMDA-receptor system (Koh et al., Brain Res., 1990, v.
533, p. 315; Mattson et al., J. Neurosci., 1992, v. 12, p. 376). As
a result, the glutamate mediator at concentrations that are
nontoxic under normal conditions becomes toxic for neurones under
conditions of the developing .beta.-amyloid dose and causes their
death.
[0008] In this connection, the search for effective antagonists of
the brain NMDA-receptors capable of preventing the realization of
the neurotoxic effect of EAA appears to be an original and
promising approach to creation of neuroprotectors of a wide
spectrum of activity including agents which can prevent the
development of Alzheimer's disease and be useful for treatment of
such diseases as Alzheimer's disease (Maragos W. F. et al., Trends
Neurosci., 1987, No. 10, p. 65).
[0009] A well known NMDA receptor antagonist is
2-amino-5-phosphonovaleric acid (AP5) (Evans et al.,--Brit. J.
Pharmacol., 1982 , v. 75, p. 65). The main disadvantage of AP5
compound a side neurotoxic effect (such as the disturbance of
coordination of movement and a sedative effect) which becomes
apparent when AP5 is used in the doses in which it produces
anti-NMDA effect (ED.sub.50=190 mg/kg) (Grigoriev et al., Chim.
Pharm. Journal, 1988, No. 3, p. 275-277). A intensive search for
and trials of the agents having the anti-NMDA properties but
without the neurotoxic effects is currently under way for treatment
of the neurodegenerative diseases. However, to date such agents
have not been available in clinics.
SUMMARY OF THE INVENTION
[0010] The present invention provides compounds and methods of
using these compounds to treat neurodegenerative diseases,
especially Alzheimer's disease.
[0011] According to the present invention, the compounds that are
provided for the treatment of neurodegenerative diseases can be
represented by a general formula (I): ##STR3## wherein R.sub.1 is
Me, Et or PhCH.sub.2; R.sub.2 is H, PhCH.sub.2 or
6-Me-3-Py-(CH.sub.2).sub.2; and R.sub.3 is H, Me or Br. The solid
line accompanied by the dotted line. i.e. represents a single or
double bond and salts thereof with pharmacologically acceptable
acids.
[0012] When represents a single bond, then R.sub.2=R.sub.3=Me;
R.sub.2=H; and the compound is in the form of a cis (.+-.)
isomer.
[0013] When represents a double bond, then [0014] (i) R.sub.1=Et or
PhCH.sub.2, R.sub.2=R.sub.3=H. [0015] (ii) R.sub.1=R.sub.3=Me,
R.sub.2=PhCH.sub.2. [0016] (iii) R.sub.1=Me,
R.sub.2=6-Me-3-Py-(CH.sub.2).sub.2, R.sub.3=H. [0017] (iv)
R.sub.1=R.sub.3=Me, R.sub.2=6-Me-3-Py-(CH.sub.2).sub.2, [0018] (v)
R.sub.1=Me, R.sub.2=H, R.sub.3=H or Me. [0019] (vi) R.sub.1=Me,
R.sub.2=H, R.sub.3=Br.
[0020] and salts thereof with pharmacologically acceptable acids
and quaternized derivatives.
[0021] Particular examples of the compound described above are:
[0022] 1. 2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;
[0023] 2. 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole
and its methyliodide; [0024] 3. cis(.+-.)
2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole and its
dihydrochloride; [0025] 4.
2-methyl-8-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and its
hydrochloride; [0026] 5.
2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; [0027] 6.
2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; [0028] 7.
2,8-dimethyl-5-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and
its hydrochloride; [0029] 8.
2-methyl-5-[2-(6-methyl-3-pyridyl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-
-b]indole and its sesquisulfate monohydrate; [0030] 9.
2,8-dimethyl-5-[2-(6-methyl-3-pyridyl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido-
[(4,3-b]indole and its dihydrochloride.
DETAILED DESCRIPTION OF THE INVENTION
[0031] The object of the invention is to provide compounds having a
high anti-NMDA activity and producing no side- and toxic
effects.
[0032] As one of the approaches is to search for such agents in the
known chemical compounds, from which the inventors have tried to
reveal new unexpected (in this case, anti-NMDA) properties which
are not due to the chemical structure of the compounds.
[0033] The inventors have carried out large-scale investigations of
some known compounds which are tetra- and
hexahydro-1H-pyrido[4,3-b]indole derivatives that manifest a broad
spectrum of biological activity. In the series of
2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles the following types of
activity were found: antihistamine activity (OS-DE NN 1.813 229,
Dec. 6, 1968; 1.952.80, Oct, 20, 1969), central depressive and
antiinflammatory activity (U.S. Pat. No. 3,718,657 Dec. 13, 1970),
neuroleptic activity (Herbert C. A., Plattner S. S., Wehch W.
N.--Mol. Pharm. 1980, v. 17, N 1, p. 38-42) and others.
2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole derivatives show
psychotropic (Welch W. H., Herbert C. A., Weissman A., Koe K. B. J.
Med. Chem., 1986, vol. 29, No. 10, p. 2093-2099), antiaggressive,
antiarrhythmic and other types of activity.
[0034] Several drugs such as diazoline (mebhydroline), dimebon,
dorastine, carbidine(dicarbine), stobadine, hevotroline based on
tetra- and hexahydro-1H-pyrido[4,3-b]indole derivatives are being
manufactured.
Diazoline(2-methyl-5-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole
dihydrochloride) (Klyuev M. A., Drugs, used in "Medical Pract.",
USSR, Moscow, "Meditzina" Publishers, 1991, p. 512) and dimebon
(2,8-dimethyl-5-(2-(6-methyl-3-pyridyl)ethyl-2,3,4,5-tetrahydro-1H-pyrido-
[4,3-b]indole dihydrochloride) (M. D. Mashkovsky, "Medicinal Drugs"
in 2 vol. Vol. 1--12th Edition, Moscow, "Meditzina" Publishers,
1993, p. 383) as well as its closest analogue
dorastine(2-methyl-8-chloro-5-[2-(6-methyl-3-pyridyl)ethyl]-2,3,4,5-tetra-
hydro-1H-pyrido[4,3-b]indole dihydrochloride) (USAN and USP
dictionary of drugs names (United States Adopted Names, 1961-1988,
current US Pharmacopeia and National Formular for Drugs and other
nonproprietary drug names), 1989, 26th Edition, p. 196) are known
as antihistamine drugs; carbidine (dicarbine)
(cis(.+-.)-2,S-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole
dihydrochloride) is a national neuroleptic agent having an
antidepressive effect (L. N. Yakhontov, R. G. Glushkov, Synthetic
Drugs, ed. by A. G. Natradze, Moscow, "Meditzina" Publishers, 1983,
p. 234-237), and its (-)isomer, stobadine, is known as an
antiarrythmic agent (Kitlova M., Gibela P., Drimal J., Bratisl.
Lek. Listy, 1985, vol. 84, No. 5, p. 542-549); hevotroline
(S-fluoro-2)(3-(3-pyridyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole
dihydrochloride) is an antipsychotic and anxiolytic agent
(Abou-Gharbi M., Patel U. R., Webb, M. B., Moyer J. A., Ardnee T.
H., J. Med. Chem., 1987, vol. 30, p. 1818-1823).
[0035] However no NMDA receptor antagonists have been found so far
among tetra- and hexahydro-1H-pyrido[4,3-b]indole derivatives.
[0036] The inventors have quite unexpectedly found that
hydrogenated pyrido[(4,3-b]indole derivatives are endowed with such
properties. It has been found in particular, that a number of known
hydrogenated pyrido[3,4-b]indole derivatives have NMDA antagonist
properties, which makes them useful for treating neurodegenerative
diseases, especially Alzheimer's disease.
[0037] According to the present invention, the compounds that are
provided for the treatment of neurodegenerative diseases can be
represented by a general formula (I): ##STR4## wherein R.sub.1 is
Me, Et or PhCH.sub.2; R.sub.2 is H, PhCH.sub.2 or
6-Me-3-Py-(CH.sub.2).sub.2; and R.sub.3 is H, Me or Br. The solid
line accompanied by the dotted line, i.e. represents a single or
double bond and salts thereof with pharmacologically acceptable
acids.
[0038] When represents a single bond, then R.sub.1=R.sub.2=Me;
R.sub.3=H; and the compound is in the form of a cis (.+-.)
isomer.
[0039] When represents a double bond, then [0040] (i) R.sub.1=Et or
PhCH.sub.2, R.sub.2=R.sub.3=H. [0041] (ii) R.sub.1=R.sub.3=Me,
R.sub.2=PhCH.sub.2. [0042] (iii) R.sub.1=Me,
R.sub.2=6-Me-3-Py-(CH.sub.2).sub.2, R.sub.3=H. [0043] (iv)
R.sub.1=R.sub.3=Me, R.sub.2=6-Me-3-Py-(CH.sub.2).sub.2, [0044] (v)
R.sub.1=Me, R.sub.2=H, R.sub.3=H or Me. [0045] (vi) R.sub.1=Me,
R.sub.2=H, R.sub.3=Br.
[0046] and salts thereof with pharmacologically acceptable acids
and quaternized derivatives.
[0047] Particular examples of the compound described above are:
[0048] 1. 2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;
[0049] 2. 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole
and its methyliodide; [0050] 3. cis(.+-.)
2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole and its
dihydrochloride; [0051] 4.
2-methyl-8-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and its
hydrochloride; [0052] 5.
2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; [0053] 6.
2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; [0054] 7.
2,8-dimethyl-5-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and
its hydrochloride; [0055] 8.
2-methyl-5-[2-(6-methyl-3-pyridyl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-
-b]indole and its sesquisulfate monohydrate; [0056] 9.
2,8-dimethyl-5-[2-(6-methyl-3-pyridyl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido-
[(4,3-b]indole and its dihydrochloride.
[0057] The information of the compounds listed above can be
obtained from the publications referred to below.
[0058] The synthesis of the compound No. 1 is described by U.
Horlein in Chem. Ber., 1954, Bd. 87, hft 4, p. 463-472. The
preparation of the compounds No. 2, 4 and 5 and the information
that the properties of serotonine antagonists are disclosed by C.
J. Cattanach, A. Cohen and B. H. Brown in J. Chem. Soc. (ser. C)
1968, 1235-1243. The preparation of methyliodide of the compound
No. 2 is described by M. A. Yurovskaya and I. L. Rodionov in Khim.
Geterots. Soed., 1981, No. 8, p. 1072-1078. The data on the
preparation and the neuroleptic properties of the compound No. 3
can be found in the publication by L. N. Yakhontov and R. G.
Glushkova Synthatic Drugs (edited by A. G. Natradze), Moscow,
"Meditsina Publishers", 1983, p. 234-237. The synthasis of the
compound No. 6 is described in the article by N. P. Buu-Hoi, O.
Roussel, P. Jacquignon, J. Chem. Soc., 1964, No. 2, p. 708-711. The
synthasis of the compound No. 7 is described by N. F. Kucherova and
N. K. Kochetkov in J. Obshch. Khim., 1956, v. 26, p. 3149-3154, and
the preparation of the compounds No. 8 and 9 is reported by A. N.
Kost, M. A. Yurovskaya and T. M. Mrlnikova in "Khim. Geterots.
Soed.", 1973, No. 2, p. 207-212.
[0059] The fact that the compounds of the formula (I) exhibit
anti-NMDA activity is confirmed by the following examples that show
the results of the biological experiments that were carried
out.
EXAMPLES
I. Anti-NMDA Activity of the Compounds Provided by the Present
Invention
[0060] The experiment was conducted in white non-inbred male mice
of 20-24 g of weight. A solution of the test agent in 0.2 ml of 5%
aqueous dimethylsulfoxide was injected intraperitoneally 40 minutes
before the injection of NMDA into the lateral vehicle of the brain.
For the mice that had been prepared beforehand for the experiment a
skin flap on the head of each mouse was removed under ether
anestesia and a hole was bored in the skull by a fine drill. NMDA
(0.1 .mu.g) in a volume of 1.4 .mu.l was injected with a
microsyringe. The microsyringe needle was immersed to a depth of
2.5 mm. After the operation, the wound was treated with a 2%
novocaine solution. After recovery from the anestesia, the mice
showed signs of pain disturbance. The accuracy of NMDA injection
was monitored by injection of methylene blue. Two to 4 hours after
the operation, the mice were used for a pharmacological
experiment.
[0061] The animals inoculated with a saline solution were used as
control. In the control group the injection of NMDA into the
lateral ventricle in a dose of 0.1 .mu.g per mouse caused run,
jumps, convulsions and then the death of the animals. In the
experimental groups the preinjection of the test substances
prevented the development of convulsions and death of the
animals.
[0062] Each dose of the agent was tested in a group of 6-8 animals.
The ED.sub.50 value (the dose of the agent preventing the
development of convulsions and the death of 50% of the animal) was
determined by a probit-analysis method (Litchfild J. T., Wicoxon F.
J.--Pharmacol. Exp. Therap., 1949, v. 96, p. 99-114).
[0063] The closest prior art agent tacrine characterized above and
the known compound AP-5 exhibiting the anti-NMDA activity were
tested for comparative purposes.
[0064] The test results are summarized in Table A.
[0065] It follows from Table A, that the compounds according to the
invention have an anti-NMDA activity expressed as ED.sub.50 in the
range of 16-45 mg/kg by intraperitoneal inoculation, i.e. in the
pharmacologically acceptable range, and do not show any appreciable
neurotoxic effect in the investigated doses.
[0066] Thus, the marked NMDA-antagonist properties found in the
compounds of formula (I) permit a conclusion on the potential
usefulness of the said compounds in the treatment of
neurodegenerative diseases, and in particular, Alzheimer's disease.
TABLE-US-00001 TABLE A ED.sub.50 (mg/kg, No. R.sub.1 R.sub.2
R.sub.3 Salt i.p.) 1 Me H H -- 30 .+-. 4 2 Me H Me -- 16 .+-. 4 3
Me H Me MeJ .about.40 4* Me H Me 2HCl 31 .+-. 7 5 Me H Br HCl 29
.+-. 5 6 Et H H -- 45 .+-. 6 7 PhCH.sub.2 H H -- 43 .+-. 5 8 Me
PhCH.sub.2 Me HCl 45 .+-. 5 9 ME 6-Me-3-Py- H
1.5H.sub.2SO.sub.4.H.sub.2O 22 .+-. 4 (CH.sub.2).sub.2-- 10** ME
6-Me-3-Py- Me 2HCl 42 .+-. 6 (CH.sub.2).sub.2-- 11 Tacrine not
active 12 AP-5 190 .+-. 20 i.p.--intraperitoneally *the "carbidine"
agent (hexahydro derivative. cis (.+-.)-isomer: the remaining
compounds are tertahydro derivatives) **the "dimebon" agent
II. Clinical Trials of the "Dimebon" Agent
[0067] The "dimebon" agent (compound No. 10, Table A) which is used
in medicine as an antiallergic agent (Inventor's Certificate No.
1138164, IP Class A61K 31/47.5, C07 D 209/52, published on Feb. 7,
1985) was also clinically tested as an agent for treatment of
Alzheimer's disease. The carbidine agent (compound No. 4) is less
suitable for preliminary clinical tests due to its obvious
psychotropic effect capable of masking some manifestations of
positive treatment results. Dimebon is non-toxic and does not show
any negative side-effects.
[0068] The test was carried out under the direct supervision by two
of the inventors, namely E. E. Bukatina and V. Grigorieva, in 14
patients who agreed to take part in the tests, 13 of whom lived in
a boarding house for senile persons and one patient lived with her
family.
[0069] The data on the patients (age, sex, place of observation and
duration of the disease) is presented in Table 1.
[0070] Alzheimer's disease was diagnosed on the basis of criteria
ICD-10 NINCDS ADRDA.
[0071] The information on the onset and the course of the disease
in 7 patients was given by their closest relatives. Six patients
(observations 1, 2, 3, 7, 9 and 12) living in the boarding house
had no relatives or other persons who could give any information on
the time of onset of the first symptoms and the pattern of the
course of the disease. However, it is apparent from the medical
charts of all the patients that the very first examinations by the
doctors revealed distinct disturbances of memory which increased
with time. No sharp changes in the condition of the patients during
their in the boarding house were found and recorded in the
available medical documents and in the doctor's conclusions in the
outpatient clinics where the patients had been examined before
admission to the boarding house.
[0072] From what has been stated above as well as the clinical
features of dementia suggested Alzheimer's disease which had
started before the admission to the boarding house. In one female
(observation 10) progressive decline of memory was noted in the
boarding house almost 2 years after her admission.
[0073] Dementia of different degree, from the initial to marked
manifestations, was found in all cases of the beginning of the
investigation. The clinical diagnosis was confirmed by computer
tomography (CT) of the brain.
[0074] Dimebon in the form of tablets (comprising 10 mg of dimebon,
30 mg of lactose, 5 mg of magnesium stearate was prescribed for
oral administration in a dose of 0.02 g three times a day. The
patients living in the boarding house received dimebon for 58 days.
A patient (observation 14) who was under outpatient observation
continued taking the agent for a month after the completion of the
tests.
[0075] Before the treatment with dimebon, and at 4 and 8 weeks
after treatment the patients were examined according to Hazegawa's
scale and the inventors' scale ("Social and Clinical Psychiatry",
1992, No. 4, pp. 29-37) which includes the following indexes:
[0076] (1) orientation in locality, time, immediate surroundings
and one's own personality; (2) orientation in space; (3) memory for
the past; (4) memory for the present; (5) "life in the past"; (6)
(a) articulation, (b) difficulty in finding words, and distortion
of words; (c) naming of objects; (d) following instructions; (7)
concentration (of attention); (8) anno affective sphere: (a) high
spirits, (b) low spirits; (9) delirium; (10) hearing
hallucinations; (11) visual hallucinations; (12) senile or
senile-like confusion (when motion anxiety is accompanied by the
revival of the past experience); (13) irritability; (14) anxiety;
(15) asthenia; (16) headaches; (17) dizziness; (18) tearfulness;
(19) spontaneous activity; (20) elementary self-service; and (21)
control of sphincters.
[0077] According to the Hazegawa's scale, the 0 score indicates the
poorest result; on the contrary, according to the inventors' scale,
the 0 score indicates the absence of a symptom 4 score indicates
the greatest manifestation thereof. At the examination according to
the inventors' scale, the decree of disturbance of some function
proved to be between the two evaluation indices, the value was of
intermediate type, e.g. 0.5, 1.5, or the like. Before the therapy
was started, the patients had been independently examined by two
doctors who used the inventors' scale. The examination during the
treatment was carried out by the doctors using both the scales. The
evaluation according to all the inventors' scale points during all
the tests and their variations during the treatment with dimebon
are given in the Appendix.
[0078] According to the inventors' scale, the degree of the
disturbance if the cognitive functions was determined by a sum of
evaluations according to the first 5 scale points reflecting the
condition of memory, orientation and relation with the reality. The
disturbance of speech was dealt with separately and was determined
by a sum of evaluations according to items 6b-6d. No disturbances
of articulation (item 6a) corresponding to peculiar disturbances of
speech functions in Alzheimer's disease were observed in any
cases.
[0079] Both absolute evaluations of the signs under investigation
(the evaluation prior to treatment is a mean evaluation of the two
examinations) and variations in them were analysed in the course of
therapy. In doing so, only those changes that were beyond the range
of evaluations obtained in two pre-treatment examinations were
taken into consideration.
[0080] The test results reflected the condition of the patients at
the time of the examination. Any changes in the metal state
observed in the interval between the tests and disappearing by the
moment of examination according to the scale there described in the
section "Clinical Observations".
[0081] The statistical data processing was carried out by means of
Student's t-test and Fisher's "Fi" criterion.
1. The Examination According to Hazegawa's Scale
[0082] The results obtained during the examination of the patients
according to Hazegawa's scale are shown in Table 2.
[0083] The test results of 7 patients with relatively mild dementia
are presented in Table 3. This group included the patients whose
evaluation for each of the inventor's 5-point scale did not exceed
2.5 scores. In fact, only one of the patients had such score
(observation 2) according to the 3rd scale point (memory for the
past). All the other patients had lower scores.
[0084] As can be seen from Table 2, against the background of
treatment with dimebon there is a trend for improvement which
becomes more marked with an increase in the duration of the
therapy.
[0085] Most close to the significant are the results obtained after
8-week course of treatment of the patients with mild dementia
(Table 3): for p<0.05, tst=2.2, td=2.1.
2. The Examination According to the Inventor's Scale
[0086] The results according to all the points of the investor's
scale are presented in Table 4.
2.1 Cognitive Functions.
[0087] The evaluations of the cognitive functions (the sum of
evaluations according to the first 5 points of the scale) are
presented in Table 5 and their variations in the course of the
therapy are shown in Table 6.
[0088] As in the case of examinations according to Hazegawa's
scale, there was a trend to some improvement in the cognitive
functions during the treatment with dimebon, which was more evident
when the agent was administered for a longer period (Table 5).
[0089] The data of Table 6 clearly shows that after 8 weeks of the
therapy there was significantly better improvement in the cognitive
functions than after 4 weeks.
[0090] Similar Tables (Tables 7 and 8) are provided for the
patients who had mild dementia. It follows from these Tables, that
in this group of patients there was not only significantly greater
improvement in the cognitive functions after the 8-week course of
treatment than after the 4-week course (like in the total group of
patients), but also significantly different absolute values of the
scores before treatment and after 8 weeks of dimebon
administration.
[0091] The pattern of distribution of the variations according to
the first 5 points of the scale reflecting the condition of the
cognitive functions (Table 9) reveals the lack of impairments both
after 4-week and 8-week treatment. There is also a trend for more
improvements with a longer treatment. Slight improvements were
significantly more frequent after 8 weeks of the treatment that
after 4 weeks.
[0092] It may be assumed that the 4-week treatment with dimebon
produces positive results at least for the patients suffering from
mild dementia. The inventors possess data on AD with a spontaneous
course in 8 patients with mild dementia. These patients were
observed in the Moscow Boarding House No. 20 in 1988 and given
placebo for a month. These patients had received no therapy that
could influence cognitive functions in AD.
[0093] By the degree of initial dementia (the mean sum of
evaluations of two examinations according to the first 5 items of
the scale prior to the test), both groups of the patients were
comparable: 5.72.+-.0.39 score for the patients in the control
group and 6.29.+-.0.7 score for those in the experimental
group.
[0094] The comparison of the changes of cognitive functions of this
and experimental group after 4 weeks showed the following: changes
in the cognitive functions in these groups of patients during one
month was 0.5.+-.0.14 in the experimental group and 0.12.+-.0.1 in
the control group, p<0.01.
[0095] 2.2 Speech Functions
[0096] The evaluation of speech functions (the sum of scores for
items bb-6d) during dimebon therapy are presented in Tables 10 and
11.
[0097] The data in Table 10 shows some trend for improvement of
speech functions during the period of dimebon administration, which
was slightly more evident in the prolonged treatment. The
distribution pattern of the variations in items 6b-6d reflecting
the condition of the speech functions is presented in Table 12.
2.3 Other Scale Values
[0098] During the test period none of the patients showed hearing
or visual hallucinations (items 10 and 11), senile confusion (item
12) or disturbances of sphincter control (item 21).
[0099] As mentioned above, the results of the examinations by all
the other items of the scale are presented in Table 4. The mean
values in this Table have been calculated for the whole group of
the patients examined. The dynamics of those pathological
manifestations which according to the data presented in Table 4
have a trend for marked variations during the course of treatment
with dimebon are dealt with in more detail below. Only those cases
are analysed where the appropriate manifestations occurred prior to
or during the treatment.
[0100] (a) Depression
[0101] Prior to the treatment, 11 patients had various depressive
symptoms. At 4 weeks after the treatment with demibon in 5 patients
(45%) the depression abated and there was not a single case of
deterioration or emergence of depression. After 8 weeks of
treatment, 6 patients showed an improvement (55%). One patient
showed signs of aggravation.
[0102] The mean values in 12 patients with depressive
manifestations prior to the treatment and after 4 and 8 weeks of
the treatment were 1.1.+-.0.2, 0.58.+-.0.18 and 0.58.+-.0.14 score,
respectively.
[0103] The dynamics of depressive manifestations in patients
suffering from evident depression prior to the treatment with
dimebon (the scores were not less than 1 in both examinations) are
presented in Table 13. As can be seen from the Table, abatement of
depression was significant after 8 weeks of the treatment. In this
case, after the course of the treatment with dimebon, there was a
close correlation between the improved cognitive functions and
abated depressive symptoms (Table 14): r=0.8, p<0.01.
[0104] The improvement in the values by Hazegawa's scale also
correlates with the abatement of depression after 8 weeks of
treatment. After 8 weeks r=0.63 and p<0.05, and after 4 weeks
r=0.3 and p>0.05.
[0105] (b) Delirium
[0106] During treatment with dimebon there was not a single case of
the first emergence of delirium.
[0107] It can be seen from Table 4, that there is a certain trend
for abatement of delirious symptoms during the course of treatment.
In the analysis of similar relationships among 10 patients who had
delirious symptoms prior to the treatment, no obvious differences
were found, either. The mean values of delirium manifestations
prior to the medical treatment and 4 and 8 weeks after the
treatment were 1.28.+-.0.21, 0.8.+-.0.33 and 0.7.+-.0.29,
respectively.
[0108] (c) Irritability
[0109] Not a single observation indicated the aggregation or
emergence of irritability during the treatment with dimebon.
[0110] Prior to the treatment 7 patients showed irritability (Table
15). As can be seen from the Table, an appreciable reduction in
irritability was noted after 8 weeks of the treatment.
[0111] (d) Headaches
[0112] 10 patients complained headaches during the observation
period. One of them (observation 14) had the first headaches in the
8th week of the treatment. The other 9 patients had headaches prior
to the treatment. The analysis of variations in these symptoms
after 4 and 8 weeks of the treatment in comparison with two
examinations carried out before the beginning of the treatment
showed no aggregation of headaches against the background of the
therapy in these cases.
[0113] Five patients (50%) showed abatement or complete cessation
of headaches after 4 weeks of treatment and 3 patients (30%) showed
the same improvement after 8 weeks. The data on the dynamics of the
intensity of headaches in the patients who suffered from them are
presented in Table 16. They show that the abatement of headaches
was observed 4 weeks after the treatment and some intensification
of these symptoms was observed after 8 weeks.
[0114] (e) Tearfulness
[0115] Prior to the treatment 5 patients suffered from tearfulness
(3 patients showed slight tearfulness). After four weeks 4 female
patients showed no signs of it and after 8 weeks not a single
female patient suffered from tearfulness.
[0116] Prior to the medical treatment and after 4 and 8 weeks of
the treatment the mean scores of tearfulness were 0.36.+-.0.18,
0.2.+-.0.18, and 0.+-.0.0, respectively. All the differences are
not significant.
3. Clinical Observations
[0117] The pattern of the dynamics of the mental states of the
patients during the treatment with dimebon registered in clinical
observations is presented in Table 17.
[0118] Psychopathic-like symptoms (lack of restraint, touchiness,
conflict making, evil-mindedness or aggressiveness) in all 7
patients who suffered from them decreased significantly during the
first 2 weeks or therapy. A distinct antidepressive effect of the
agent was also observed in 8 patients. One of them (observation 10)
showed no lower spirits during the test period, but, as the medical
stuff reported, she had frequent disphorias which ceased during
dimebon administration. Besides, the patient herself (dementia was
not profound in this case) constantly emphasized that her mood
improved during the treatment.
[0119] Only one female patient (observation 14) showed no signs of
abatement of depressive manifestations during the test period. This
patient continued to take dimebon after the termination of the
trial. On the 62nd day of the treatment she noted considerable
improvement in her mood which persisted during a month while she
was taking the medicinal preparation.
[0120] In most other cases normalization of the improvement of the
affection occurred soon after the beginning of the therapy: in one
patient (observation 7) on the 2nd day, in 2 patients (observations
4 and 10) on the 4th day, in 2 patients (observations 3 and 5) on
the 7th or 8th day, in 3 patients (observations 2, 1, 13) on the
11th or 12th day. In two of these patients (observations 1 and 13)
the spirits continued to improve and the effect attained after 8
weeks of the treatment was higher than that observed after 4
weeks.
[0121] 4 patients (observations 1, 2, 7 and 10) became more active
and noted themselves that they experienced a sense of cheerfulness
and freshness. 2 patients (observations 4 and 7) slept better. 4
patients (observations 1, 5, 6, and 7) complained of headaches much
less frequently during the treatment. 8 patients (observations 1,
2, 3, 4, 7, 8, 10, and 11) displayed a greater interest in what has
happening around.
[0122] On the whole, the patients became calmer and more sociable,
easier to deal with, they began acting and responding more
adequately. In some cases (observations 1, 2, 4, 7, and 13) the
entire appearance of the patients changed in the estimation of
those who were observing them.
4. EEG Investigations
[0123] No changes in the EEG during the course of treatment were
observed in any patients, except one (observation 12) who had
experienced increase of focal .DELTA.-waves and still greater
retardation of the rhythm.
[0124] Six patients showed the following slight changes in the EEG
during the treatment course: a tendency for a greater frequency of
the main rhythm (observations 4 and 5), some intensification of the
.beta.-rhythm (observations 5 and 14) (positive dynamics), a great
number of acute waves (observations 2 and 5) and paroxysmal
symptoms (observation 10), the latter considered to be the negative
dynamics. In observations 2, 11 and 14 the weakly positive dynamics
of the EEG was manifested in weaker outbursts during
hyperventilation and normalization of the zonal differences.
5. Blood and Urea Analysis
[0125] No pathologic changes in the hematological and biochemical
statutes were found during the course of the treatment. There was a
significant reduction in the amount of leukocytes (within normal
limits) after 4 weeks of the treatment, p<0.05. By the 8th week
of the treatment the amount of leukocytes was normal again.
6. Conclusion
[0126] A pilot research of the effectiveness of dimebon in 14
patients suffering from Alzheimer's disease revealed definite
positive effect of the agent on psychopatic-like and depressive
manifestations. The examinations carried out using Hazegawa's scale
and the inventor's scale revealed a significant improvement in
cognitive functions especially in patients with mild dementia.
[0127] The results obtained in the studies attest the therapeutic
activity of dimebon in the treatment of Alzheimer's disease.
TABLE-US-00002 TABLE 1 Distribution of Patients According to Age,
Sex, Observation Place and Duration of the Disease Observation
Residence time No Age Sex Place in boarding house Duration of the
disease 1 87 f boarding 2 years and 3 months more than 2 years and
house 3 months 2 83 f boarding 6 months more than 6 months house 3
74 m boarding 1 year and 4 months more than 1 year and 4 house
months 4 87 f boarding 1 year and 5 months 7 years house 5 87 f
boarding 2 years and 11 months 3 years house 6 88 f boarding 1 year
and 9 months 5 years house 7 85 f boarding 1 year and 4 months more
than 1 year and 4 house months 8 83 f boarding 1 year and 4 months
4 years house 9 83 f boarding 1 year and 5 months more that 1 year
and 5 house months 10 85 f boarding 3 years and 8 months 2 years
house 11 81 f boarding 1 year 1 year and a half house 12 81 f
boarding 1 year and 11 months more than 1 year and 11 house months
13 80 f boarding 2 years 9 years house 14 64 f out-patients -- 9
years clinic
[0128] TABLE-US-00003 TABLE 2 Evaluation according to Hazegawa's
Scale Prior to and after 4 and 8 Weeks of Treatment with Dimebon
Prior to med. Nos treatment After 4 weeks After 8 weeks 1 14 22 19
2 14 13.5 20 3 24.5 24 28.5 4 19 26.5 25.5 5 2.5 2.5 4.5 6 12.5
13.5 15 7 2 7.5 2 8 11.5 14.5 23.5 9 15.5 14.5 9 10 25.5 19 25.5 11
7 13 9.5 12 3.5 2 4.5q 13 7 7 7 14 24.5 26 25 M +/- m 12.35 +/-
1.95 14.68 +/- 1.87 15.68 +/- 2.39 P insignificant
insignificant
[0129] TABLE-US-00004 TABLE 3 Evaluation according to Hazegawa's
Scale Prior to and after 4 and 8 Weeks of Treatment with Dimebon in
Patients with Nonprofound Dementia Prior to med. Nos treatment
After 4 weeks After 8 weeks 1 14 22 19 2 14 13.5 20 3 24.5 24 28.5
4 19 26.5 25.5 8 11.5 14.5 23.5 10 25.5 19 25.5 14 24.5 26 25 M +/-
m 19 +/- 2.04 20.79 +/- 1.85 23 +/- 1.17 P insignificant t.sub.d =
2.1 p .apprxeq. 0.05 t.sub.st = 2.2
[0130] TABLE-US-00005 TABLE 4 Mean Values according to All Points
of the Inventor's Scale prior to and after 4 and 8 Weeks of the
Demibon Treatment and Their Variations during the Treatment in
Relation to Two Examinations prior to the Treatment Mean values:
scores Changes during the course of prior to med. the therapy,
scores No treatment after 4 weeks after 8 weeks after 4 weeks after
8 weeks 1 1.82 +/- 0.19 1.75 +/- 0.23 1.57 +/- 0.23 +0.11 +/- 0.07
+0.18 +/- 0.08 2 0.54 +/- 0.16 0.32 +/- 0.15 0.25 +/- 0.13 +0.11
+/- 0.07 +0.11 +/- 0.07 3 2.34 +/- 0.23 2.29 +/- 0.21 1.93 +/- 0.24
+0.07 +/- 0.07 +0.29 +/- 0.1 4 2.38 +/- 0.22 2.21 +/- 0.22 1.86 +/-
0.23 0 +/- 0 .+-.0.29 +/- 0.08 5 1.86 +/- 0.21 1.75 +/- 0.27 1.57
+/- 0.27 +0.14 +/- 0.08 .+-.0.29 +/- 0.1 6b 0.57 +/- 0.18 0.43 +/-
0.17 0.39 +/- 0.2 0 +/- 0 -0.04 +/- 0.03 6a 0.89 +/- 0.23 0.71 +/-
0.21 0.54 +/- 0.21 +0.11 +/- 0.07 +0.14 +/- 0.08 6g 0.64 +/- 0.17
0.46 +/- 0.16 0.54 +/- 0.19 -0.07 +/- 0.12 -0.07 +/- 0.18 7 1.9 +/-
0.27 1.75 +/- 0.26 1.75 +/- 0.3 0 +/- 0.5 -0.04 +/- 0.06 8b 0.95
+/- 0.22 0.5 +/- 0.16 0.46 +/- 0.14 +0.41 +/- 0.17 +0.43 +/- 0.2 9
0.91 +/- 0.2 0.57 +/- 0.29 0.5 +/- 0.19 +0.07 +/- 0.09 +0.25 +/-
0.17 13 0.57 +/- 0.19 0.21 +/- 0.15 0.14 +/- 0.09 +0.29 +/- 0.13
+0.36 +/- 0.16 14 0.38 +/- 0.09 0.29 +/- 0.12 0.18 +/- 0.1 -0.04
+/- 0.13 +0.07 +/- 0.09 15 0.13 +/- 0.06 0.18 +/- 0.1 0.04 +/- 0.03
-0.11 +/- 0.09 0 +/- 0 16 1.02 +/- 0.27 0.32 +/- 0.21 0.64 +/- 0.24
+0.54 +/- 0.21 +0.21 +/- 0.1 17 0.64 +/- 0.19 0.71 +/- 0.27 0.68
+/- 0.25 -0.14 +/- 0.17 -0.18 +/- 0.22 18 0.36 +/- 0.18 0.07 +/-
0.07 0.14 +/- 0.14 +0.14 +/- 0.14 +0.21 +/- 0.15 19 1.36 +/- 0.22
1.29 +/- 0.22 1.18 +/- 0.27 0 +/- 0 +0.04 +/- 0.11 20 0.13 +/- 0.08
0.07 +/- 0.07 0.14 +/- 0.4 +0.07 +/- 0.07 0 +/- 0.1 Notes to the
Table As can be seen from items 6a, 10, 11, 12, and 21, no
disorders were found in any case. Here and hereinafter "+" denotes
improvement. "-" denotes deterioration of function. No significant
differences were found in any of the scale points.
[0131] TABLE-US-00006 TABLE 5 Values of Cognitive Function (Sum of
Values according to First 5 Scale Points) Prior to and after 4 and
8 Weeks of Treatment with Demibon Mean values of 2 examinations
prior to Nos the treatment After 4 weeks After 8 weeks 1 8 5.5 3 2
8.5 8.5 5 3 4.25 3.5 2 4 7.5 6.5 5 5 12.5 12 12 6 8.5 9.5 7 7 13.25
10 12 8 7.5 8 6 9 12 12 11.5 10 4.25 3 3 11 9 8.5 8 12 15 15 13 13
12 11 10.5 14 4 3.5 3 M +/- m 9.02 +/- 0.9 8.32 +/- 0.93 7.21 +/-
0.82 P insignificant insignificant
[0132] TABLE-US-00007 TABLE 6 Variations of Cognitive Function with
Respect to Two Examinations Prior to and after 4 and 8 Weeks of
Treatment with Demibon Duration of the treatment Observation Nos 4
weeks 8 weeks 1 +1 +3 2 0 +2 3 +0.5 +2 4 +0.5 +3 5 +0.5 +0.5 6 0
+1.5 7 +2 +1 8 0 +0.5 9 0 0 10 +1 +1 11 0 0 12 0 +0.5 13 0 0 14
+0.5 +1 M +/- m +0.43 +/- 0.15 +1.14 +/- 0.26 P <0.05
[0133] TABLE-US-00008 TABLE 7 Values of Cognitive Functions Prior
to and after 4 and 8 Weeks of Treatment with Demibon in Patients
with Unprofound Dementia Mean values of 2 examinations prior to Nos
the treatment After 4 weeks After 8 weeks 1 8 5.5 3 2 8.5 8.5 5 3
4.25 3.5 2 4 7.5 6.5 5 8 7.5 8 6 10 4.25 3 3 14 4 3.5 3 M +/- m
6.29 +/- 0.795 5.5 +/- 0.79 3.93 +/- 0.5 P insignificant
<0.05
[0134] TABLE-US-00009 TABLE 8 Variations of Cognitive Function with
Respect to Two Examinations Prior to and after 4 and 8 Weeks of
Treatment with Demibon in Patients with Unprofound Dementia
Observation Duration of the treatment Nos 4 weeks 8 weeks 1 +1 +3 2
0 +2 3 +0.5 +2 4 +0.5 +3 8 0 +0.5 10 +1 +1 14 +0.5 +1 M +/- m +0.5
+/- 0.14 +1.79 +/- 0.35 P <0.05
[0135] TABLE-US-00010 TABLE 9 Distribution of Veriations accoding
to First 5 Scale Points which Indicate the State of Cognitive
Functions during 4 and 8 Weeks of Treatment with Demibon Duration
of the treatment 4 weeks 8 weeks Variations slight moderate marked
total slight moderate marked total Improvements abs. 4* 4 -- 8 18*
6 -- 24 % 5.7* 5.7 -- 11.4 25.7* 8.6 -- 34.3 Deteriorations abs. --
-- -- -- -- -- -- -- % -- -- -- -- -- -- -- -- No variations abs.
57 41 % 81.4 53.6 X abs. 5 5 % 7.1 7.1 Notes to the Table: Slight
variations by 0.5 score Moderarte variations by 1 score Marked
variations by more than 1 score X - No variations in the function
prior to and during the treatment *p < 0.05
[0136] TABLE-US-00011 TABLE 10 Evaluation of Speech Function (Sum
of Values according to Items 6b-bd) in scores prior to and after 4
and 8 Weeks of Treatment with Demibon Mean values of 2 examinations
prior to Nos the treatment After 4 weeks After 8 weeks 1 0.25 0 0 2
1.5 0 0 3 0 0 0 4 1 0 0 5 4 3 2 6 2 1 1 7 5 4.5 6 8 0.5 1 0 9 0.75
1.5 1 10 0 0 1 11 2 1.5 0 12 6.25 5 4.5 13 3 2 1 14 3.25 3 3 M +/-
m 2.11 +/- 0.5 1.61 +/- 0.44 1.39 +/- 0.47 P insignificant
insignificant
[0137] TABLE-US-00012 TABLE 11 Variations of Speech Function with
Respect to Two Examinations Prior to and after 4 and 8 Weeks of
Treatment with Demibon Observation Duration of the treatment Nos 4
weeks 8 weeks 1 0 0 2 0 0 3 0 0 4 +1 +1 5 +0.5 +0.5 6 0 0 7 0 -1.5
8 -1 0 9 0 -1 10 0 -1 11 0 +1.5 12 +1 +0.5 13 +1 +1 14 0 -0.5 M +/-
m +0.18 +/- 0.14 +0.04 +/- 0.22 P insignificant
[0138] TABLE-US-00013 TABLE 12 Distribution of Veriations accoding
to Items 6b, c, d of the Scale Points which Indicate the State of
Speech Functions during 4 and 8 Weeks of Treatment with Demibon
Duration of the treatment 4 weeks 8 weeks Variations slight
moderate marked total slight moderate marked total Improvements
abs. 1 3 -- 4 3 3 -- 6 % 2.4 7.14 -- 9.5 7.14 7.1 -- 14.3
Deteriorations abs. -- 1 -- 1 1 2 1 4 % -- 2.4 -- 2.4 2.4 4.8 2.4
9.6 No variations abs. 23 19 % 54.8 45.2 X abs. 14 13 % 33.3 30.95
Notes to the Table: Slight variations by 0.5 score Moderarte
variations by 1 score Marked variations by more than 1 score X - No
variations in the function prior to and during the treatment
[0139] TABLE-US-00014 TABLE 13 The Dynamics of Marked Depressive
Manifestation in Patients Having Depression Value of at least 1
Score for Two Examinations prior to and after 4 and 8 Weeks of
Treatment with Dimebon Values, scores Nos Prior to treatment After
4 weeks After 8 weeks 1 1.75 1 0.5 2 1.5 0 0.5 3 1 0.5 0 4 3 1 1 5
1 0 0 9 0 0 1 11 1 1 1 14 1.75 3 1.5 M +/- m 1.38 +/- 0.29 0.69 +/-
0.23 0.69 +/- 0.18 P insignificant <0.05
[0140] TABLE-US-00015 TABLE 14 Correlation between Variations in
Cognitive Functions and Variations in Depressive Manifestations
after 4 and 8 Weeks of Treatment with Demibon after 4 weeks after 8
weeks Variations in Variations in Variations in Variations in
cognitive depressive cognitive depressive Nos functions functions
functions functions 1 +1 +0.5 +3 +1.5 2 0 +1.5 +2 +1 3 +0.5 +0.5 +2
+1 4 +0.5 +2 +3 +2 5 +0.5 +1 +0.5 +1 6 0 0 +1.5 0 7 +2 0 +1 0 8 0 0
+0.5 0 9 0 0 0 -1 10 +1 0 +1 0 11 0 0 0 0 12 0 0 +0.5 +0.5 13 0 0 0
0 14 +0.5 0 +1 0 n -0.02 0.8 P insignificant <0.01
[0141] TABLE-US-00016 TABLE 15 Evaluation of the Degree of
Irritability in Scores prior to and after 4 and 8 Weeks of
Treatment with Dimebon Having these Symptoms in the Clinical
Picture Values. scores Nos Prior to treatment After 4 weeks After 8
weeks 2 0.5 0 0 3 1.5 0 0 4 1 0 0 5 1.75 2 0 7 0.5 0 0 10 0.75 0 1
13 2 1 1 M +/- m 1.14 +/- 0.21 0.43 +/- 0.28 0.29 +/- 5.17 P
insignificant <0.01
[0142] TABLE-US-00017 TABLE 16 Evaluation of Intensity of Headache
in Scores prior to and after 4 and 8 Weeks of Treatment with
Dimebon Having these Symptoms in the Clinical Picture Values.
scores Nos Prior to treatment After 4 weeks After 8 weeks 1 0.5 0.5
0 2 1 0 1 4 2 1 2 5 2.25 0 1.5 6 0.25 0 0.5 7 2.5 0 0 10 2.25 0 0
11 2.5 3 3 12 1 0 0 14 0 0 1 M +/- m 1.43 +/- 0.29 0.45 +/- 0.29
0.9 +/- 0.31 P <0.05 insignificant Notes to the Table:
Psychopatic-like manifestations: lack of restraint, touchiness,
conflict making, evil-mindedness, aggressiveness. During the test
period one female patient (observation 10) did not show low
spirits. but prior to the treatment she had frequent
disphorias.
[0143] TABLE-US-00018 TABLE 17 Test Results according to E. E.
Bukatina et al. Scale 1. Orientation in locality and time Patient
No. K1 K2 4 weeks Changes 8 weeks Changes 1 1.5 1.5 1.5 -- 1 +0.5 2
1.5 2 2 -- 1.5 -- 3 1 1 1 -- 0.5 +0.5 4 1.5 2 1 +0.5 1 +0.5 5 2 3
2.5 -- 2 -- 6 2 1.5 2 -- 2 -- 7 3.5 2 2 -- 3 -- 8 1.5 2 2 -- 1.5 --
9 2 2 2 -- 2 -- 10 1 1 0 +1 0 +1 11 2 1.5 2 -- 2 -- 12 3 3.5 3.5 --
3 -- 14 0.5 0.5 0.5 -- 0.5 -- 2. Orientation in space Patient No.
K1 K2 4 weeks Changes 8 weeks Changes 1 1 2 0 +1 0 +1 2 0.5 0 0 --
0 -- 3 0 0 0 -- 0 -- 4 0 0 0 -- 0 -- 5 1.5 1.5 1 +0.5 +1 +0.5 6 0 0
0 -- 0 -- 7 1 0 0 -- 0 -- 8 0 0.5 0 -- 0 -- 9 1.5 1.5 1.5 -- 1.5 --
10 0 0 0 -- 0 -- 11 0.5 0 0.5 -- 0 -- 12 1 1.5 1.5 -- 1 -- 13 1 0 0
-- 0 -- 14 0 0 0 -- 0 -- 4. Memory for the present Patient No. K1
K2 4 weeks Changes 8 weeks Changes 1 2.5 1.5 1.5 -- 1 +0.5 2 2.5 2
2 -- 1 +1 3 1 1 1 -- 0.5 +0.5 4 2 2.5 2 -- 1.5 +0.5 5 3 3.5 3 -- 3
-- 6 3 2.5 3 -- 2 +0.5 7 3.5 2.5 3 -- 3 -- 8 2 2 2 -- 1.5 +0.5 9
2.5 3 3 -- 2.5 -- 10 1.5 1 1 -- 1 -- 11 3 2 2 -- 2 -- 12 3.5 4 3.5
-- 3 +0.5 13 4 3 3 -- 3 -- 14 1 1 1 -- 1 -- 5. Life in the past
Patient No. K1 K2 4 weeks Changes 8 weeks Changes 1 1.5 1 1 -- 0.5
+0.5 2 1.5 2 1.5 -- 1 +0.5 3 1 1.5 0.5 +0.5 0.5 +0.5 4 1.5 1.5 1.5
-- 0.5 +1 5 2 3 2.5 -- 3 -- 6 2 2 2 -- 1 +1 7 3 3 2 +1 3 -- 8 1.5 2
2 -- 1.5 -- 9 3 2.5 2.5 -- 2.5 -- 10 0.5 1 1 -- 0.5 -- 11 2 2 2 --
2 -- 12 3 3 3 -- 3 -- 13 3 2 2.5 -- 2.5 -- 14 1 1 0.5 +0.5 0.5 +0.5
6b. Difficulty in finding words Patient No. K1 K2 4 weeks Changes 8
weeks Changes 1 0.5 0 0 -- 0 0 2 1 0 0 -- 0 -- 3 0 0 0 -- 0 -- 4 0
0 0 -- 0 -- 5 0 1.5 1 -- 0 -- 6 0.5 0 0 -- 0 -- 7 2.5 1 1.5 -- 1.5
-- 8 0 0 0 -- 0 -- 9 0 0.5 0.5 -- 0 -- 10 0 0 0 -- 0 -- 11 0.5 0 0
-- 0 -- 12 2 2.5 2 -- 2 -- 13 1 0 0 -- 0 -- 14 1 1.5 1 -- 2 -0.5
6c. Naming of objects Patient No. K1 K2 4 weeks Changes 8 weeks
Changes 1 0 0 0 -- 0 -- 2 0 0 0 -- 0 -- 3 0 0 0 -- 0 -- 4 0 0 0 --
0 -- 5 1.5 2 1 +0.5 1 +0.5 6 0 1.5 0 -- 0 -- 7 3 2 2 -- 2 -- 8 1 0
0 -- 0 -- 9 0 1 1 -- 0 -- 10 0 0 0 -- 0 -- 11 1 1 1 -- 0 +1 12 2 2
1 -1 1.5 +0.5 13 2 1 2 -- 1 -- 14 2 2 2 -- 2 +0.5 6d. Performing
instructions Patient No. K1 K2 4 weeks Changes 8 weeks Changes 1 0
0 0 -- 0 -- 2 0 2 0 -- 0 -- 3 0 0 0 -- 0 -- 4 1 1 0 +1 0 +1 5 1 2 1
-- 1 -- 6 1 1 1 -- 1 -- 7 1 0.5 1 -- 2.5 -1.5 8 0 0 1 -1 0 -- 9 0 0
0 -- 1 -1 10 0 0 0 -- 1 -1 11 1 0.5 0.5 -- 0 +0.5 12 1 3 2 -- 1 --
13 1 1 0 -1 0 +1 14 0 0 0 -- 0 0 7. Concentration Nos K1 K2 4 weeks
Changes 8 weeks Changes 1 1 2 1.5 -- 1 -- 2 2 1 1.5 -- 1 -- 3 0.5 0
0 -- 0 -- 4 2 0.5 1 -- 1 -- 5 * 3 3 -- 3 -- 6 1.5 2 2 -- 2 -- 7 3.5
4 3 +0.5 3.5 -- 8 1 1.5 2 -0.5 2 -0.5 9 1 1.5 1 -- 1 -- 10 1 1.5 1
-- 1 -- 11 3 3 3 -- 2.5 +0.5 12 3 3.5 3 -- 4 -0.5 13 1.5 3 2 -- 2
-- 14 0.5 0.5 0.5 -- 0.5 -- 8b. Lower spirits Patient No. K1 K2 4
weeks Changes 8 weeks Changes 1 1.5 2 1 +0.5 0.5 +1.5 2 1.5 1.5 0
+0.5 0.5 +1 3 1 1 0.5 +0.5 0 +1 4 3 3 1 +2 1 +2 5 1 1 0 +1 0 +1 6 0
1 0 -- 0 -- 7 0 1 0 -- 0 -- 8 0 0 0 -- 0 -- 9 0 0 0 -- 1 -1 10 0 0
0 -- 0 -- 11 1 1 1 -- 1 -- 12 1 0.5 0.5 -- 0 +0.5 13 1 0 1 -- 1 --
14 2 1.5 2 -- 1.5 -5 9. Delirium Patient No. K1 K2 4 weeks Changes
8 weeks Changes 1 0 0 0 -- 0 -- 2 0 0 0 -- 0 -- 3 0 0 0 -- 0 -- 4 2
1.5 1 +0.5 0 +1.5 5 1 1.5 0 +1 1.5 0 6 1 0 0 -- 0 0 7 2.5 1 1 -- 1
-- 8 2 2 2.5 -0.5 2 -- 9 1 2 1.5 -- 1.5 -- 10 0 1 0 -- 1 -- 11 1 0
0 -- 0 -- 12 2 0 0 -- 0 -- 13 2 2 2 -- 0 +2 14 0 0 0 -- 0 -- 13.
Irritability Patient No. K1 K2 4 weeks Changes 8 weeks Changes 1 0
0 0 -- 0 -- 2 0 0.5 0 -- 0 -- 3 1.5 1.5 0 +1.5 0 +1.5 4 1 1 0 +1 0
+1 5 2 1.5 2 -- 0 +1.5 6 0 0 0 -- 0 -- 7 0 1 0 -- 0 -- 8 0 0 0 -- 0
-- 9 0 0 0 -- 0 -- 10 1 0.5 0 +0.5 +1 -- 11 0 0 0 -- 0 -- 12 0 0 0
-- 0 -- 13 2 2 1 +1 1 +1 14 0 0 0 -- 0 0 14. Anxiety Patient No. K1
K2 4 weeks Changes 8 weeks Changes 1 0.5 0 0 -- 0 -- 2 1 0 0 -- 0
-- 3 1 0.5 0 +0.5 0 +0.5 4 1 1 0 +1 0 +1 5 0 1 1 -- 0 -- 6 0.5 0 0
-- 0 -- 7 0 0 0 -- 0 -- 8 0 1 1 -- 1 -- 9 0 0 1 -1 0 -- 10 0 1.5 0
-- 1 -- 11 0 0 1 -1 0.5 -0.5 12 0 0 0 -- 0 -- 13 0 0 0 -- 0 -- 14 0
0 0 -- 0 -- 15. Asthenia Patient No. K1 K2 4 weeks Changes 8 weeks
Changes 1 0.5 0 0 -- 0 -- 2 0.5 0 1 -0.5 0.5 -- 3 0 0 0.5 -- 0 -- 4
0 0 1 -1 0 -- 5 0 0 0 -- 0 -- 6 0.5 0 0 -- 0 -- 7 0 0 0 -- 0 -- 8 0
0 0 -- 0 -- 9 0 0 0 -- 0 -- 10 0 0 0 -- 0 -- 11 0 0 0 -- 0 -- 12
1.5 0 0 -- 0 -- 13 0 0 0 -- 0 -- 14 0 0 0 -- 0 -- 16. Headache
Patient No. K1 K2 4 weeks Changes 8 weeks Changes 1 1 0 0.5 -- 0 --
2 1 1 0 +1 1 -- 3 0 0 0 -- 0 -- 4 2 2 1 +1 2 -- 5 2.5 2 0 +2 1.5
+0.5 6 0 0.5 0 -- 0.5 -- 7 2 3 0 +2 0 +2 8 0 0 0 -- 0 --
9 0 0 0 -- 0 -- 10 3 1.5 0 +1.5 0 +1.5 11 3 2 3 -- 3 -- 12 2 0 0 --
0 -- 13 0 0 0 -- 0 -- 14 0 0 0 -- 1 -1 17. Dizziness Patient No. K1
K2 4 weeks Changes 8 weeks Changes 1 0 2 0.5 -- 0 -- 2 1 0 0 -- 0
-- 3 1.5 0.5 1 -- 1.5 1 4 1 1 1 -- 3 -2 5 0 0 0 -- 2 -2 6 0 0 0 --
0 -- 7 2 1 0 +1 0 +1 8 0 0 0 -- 0 -- 9 1 1 2 -1 1 -- 10 0 0 0 -- 0
-- 11 0 0.5 2.5 -2 1 -0.5 12 3 2 3 -- 1 +1 13 0 0 0 -- 0 -- 14 0 0
0 -- 0 -- 18. Tearfulness Patient No. K1 K2 4 weeks Changes 8 weeks
Changes 1 1 1 1 -- 0 +1 2 2 3 0 +2 0 +2 3 0 0 0 -- 0 -- 4 0 0 0 --
0 -- 5 1 0 0 0 0 -- 6 0 0 0 -- 0 -- 7 1 0 0 -- 0 -- 8 0 0 0 -- 0 --
9 0 0 0 -- 0 -- 10 0 1 0 -- 0 -- 11 0 0 0 -- 0 -- 12 0 0 0 -- 0 --
13 0 0 0 -- 0 -- 14 0 0 0 -- 0 -- 19. Spontaneous activity Patient
No. K1 K2 4 weeks Changes 8 weeks Changes 1 1 2.5 1.5 -- 1 -- 2 2 1
1 -- 1.5 -- 3 0.5 0.5 0.5 -- 0 -- 4 2 2 2 -- 1 +1 5 1 1 1 -- 1 -- 6
1 2 1 -- 1 0 7 2 1 1 -- 1 -- 8 1.5 0 1 -- 1 -- 9 2 2 2 -- 2 0 10 0
0 0 -- 0 -- 11 2 2 2 -- 2 -- 12 3 3 3 -- 4 -1 13 2 1 2 -- 1 0 14 0
0 0 -- 0 -- 20. Elementary self-service Patient No. K1 K2 4 weeks
Changes 8 weeks Changes 1 0 0 0 -- 0 -- 2 0 0 0 -- 0 -- 3 0 0 0 --
0 -- 4 0 0 0 -- 0 -- 5 0 0 0 -- 0 -- 6 0 0 0 -- 0 -- 7 0 0 0 -- 0
-- 8 0 0 0 -- 0 -- 9 1 1 0 +1 0 +1 10 0 0 0 -- 0 -- 11 0 0 0 -- 0
-- 12 1 0.5 1 -- 2 -1 13 0 0 0 -- 0 -- 14 0 0 0 -- 0 -- K1, K2 -
examination prior to the treatment: (--) - improvement
(deterioration) of function *The female patient refused to answer
questions Item 10. No hearing hallucinations were observed throught
the whole period of investigations. Item 11. Visual hallucinations
were observed for some days in one female patient (obsrvation 9) on
the 4th week of therapy. Item 12. Senile confusion was observed in
one female patient (observation 11) at the beginning of therapy as
the arterial pressure went up. Item 21. Sphincter control was not
terminated in a single observation throughout the medical treatment
period.
* * * * *