Method for treating affected amnestic functions

FIELD: medicine, psychiatry, neurology.

SUBSTANCE: the present innovation deals with treating affected amnestic functions in women after uterine and adnexal extirpation. For this purpose, after a 7-d-long introduction of estradiol as suppositories at curative dosage of 8-20 mcg/kg body weight patients should be additionally injected with galanthamine intramuscularly once daily for 7-10 d at the dosage 5 mg, moreover, decreasing the number of estradiol injections up to once/3 d. The innovation suggested provides high antiamnestic effect at decreased dosage of preparations due to their agonistic action.

EFFECT: higher efficiency of therapy.

 

The invention relates to medicine, namely is used for the treatment of patients with amnesia, which is inherent in, for example, Alzheimer's disease and which can clearly be seen with dementia, is caused by hormonal disorders.

Dementia is acquired due to organic brain disease impaired memory and other higher mental functions (speech, thought, gnosis, praxis). Dementia leads the patient to disadaptation in professional and domestic activities to the reduction of mental activity, loss of orientation, a change in behavior of the person.

Alzheimer's disease is the most common dementia in the elderly. The basis of Alzheimer's disease is a process of progressive senile brain atrophy in combination with toxic and genetic factors. On the occurrence of senile psychosis significantly affected by intoxication and infectious factors.

Autopsy study notes General atrophy of the brain, particularly the cortex. In the cortex, see medical literature rebirth of intracellular neurofibril, degeneration and loss of nerve cells of the cortex, which is growing glia. In the result no longer be new conditional connection and lost the old, long retained the ability of the simple education is conditional reflexes with the first signal system when a sudden disorder of the second signal system.

There cholinergic theory of Alzheimer's disease [Lancet 2 (1976) 1403-1405; Brit. Med. J. 2 (1978) 1457-1459], which is confirmed by histological studies. According to this theory, a progressive degeneration of cholinergic neurons is non-random factor. Experimental animal studies have demonstrated that anticholinergic drugs cause the animal severe oppression of cognitive functions and behavior. Therefore, M-holinoblokatora used as experimental models of Alzheimer's disease.

In the process of studying Alzheimer's disease has also been found that patients is a violation of various neurotransmitter systems, especially, noradrenergic and serotonergic [Clin. Neuropathol. 3 (1984) 199-205].

Treatment of Alzheimer's disease and other diseases involving rough mnestic intellectual disabilities, in connection with the trend of aging population in developed countries is a very important problem, though far from being resolved ["the Use of Cerebrolysin in neurological and psychological practice". 1998. Unterach. P.36-45].

It is known that in the process of treatment improvement (increase) of cholinergic transmission reach by applying a precursor for the synthesis of acetyl-choline: choline and lecithin, or anticholinesterase drugs: physostigmine, tetrahedr what aminoacridine and other [Acta Psychiat. Scand. 366 (1991) 47-51].

Their disadvantage is a slight effect on the disease, a few only improve cognitive function.

It is known that for the treatment of Alzheimer's disease apply cholinergic tools that cause an increase in cholinergic nanoperiodic by suppressing the activity of cholinesterase. Such drugs are physostigmine [Human Psychopharmacology 1995. 10. 89-96], token [Jqbal K., Winblad Century, Nishimura T., Takeda M., Wisnewski H.M. (Eds.) Alzheimer's: Biology, diagnosis and therapeutics., 1997. pp.659-669], tetrahydroaminoacridine [Chung Kuo Yao Li Hsueh Pao 1997. Vol.18 No. 1. P.6-10] and others. The drugs of this series inhibit the action of acetylcholinesterase, the enzyme that inactivates acetylcholine. But these drugs are aimed at improving cognitive functions, not fixing the achieved effect. They do not provide the long-term impact on the dynamics of decline of cognitive functions. To stop the process of degeneration of neurons, these drugs can not.

The prototype of our invention is a method of treatment with galantamine is an acetylcholinesterase inhibitor. Most often galantamine used in the treatment of Alzheimer's disease [VIDAL. On The Main Page. Drugs in Russia. Edition of 5. M. Attraversare. 1999, E-100]. This therapeutic drug facilitates cholinergic transmission, strengthening and extension is irue the effect of endogenous acetylcholine. Its disadvantage in the treatment of mental disorders is that he does not have long-term effects on the system.

The purpose of this invention is complete correction process play trace memory, restore the optimal level of activity of Central cholinergic receptors, which restores the acquisition and subsequent playback is received from the outside world information.

The objective of this invention is the combination in the treatment of neurotropic and endocrinolo drugs, which eliminated violations of mnestic functions. The essence of this invention is the simultaneous effect on the body affected by dementia, a drug that inhibits the action of acetylcholinesterase, and hormonal drug that affects the hypothalamic-pituitary-ovarian system of the brain and exhibiting estrogenic effect.

In the process of studying Alzheimer's disease since, as it is identified as a separate disease, it was found that among patients is dominated by women that violations occur in the cholinergic system with a lack of estrogen. In the treatment of such disorders was used estradiol [VIDAL. On The Main Page. Drugs in Russia. Edition of 5. M Attraversare. 1999, E-84]. The authors do not know that at the same time ispolzovaniem, the inhibitory activity of acetylcholinesterase (galantamine), and the drug estrogenic activity type (estradiol). Conducting experiments on animals, authors in the experiment reached a conclusive positive results confirming the effectiveness of this approach to the treatment of mental disorders. The combined introduction of the inhibitor of acetylcholinesterase and drug estrogenic effect of causing antiamnesic effect, i.e. in animals experience returns to the normal playback of the memory trace.

The application of the proposed method for the treatment of patients confirmed the data obtained in animal experiments.

Research methods (experiments on animals)

The work was done at 120 white mongrel rats-females weighing 280-320 g, obtained from the kennel "Rapolano". The animals were kept in a vivarium with natural light and maximum standardization of temperature and food regimes with free access to food and water. The study was conducted in the morning (9.00-12.00). For all behavioral tests, rats were divided into several groups of 10-20 animals each: group 1 - intact females (intact control), treated with saline; group 2 - intact rats receiving scopolamine hydrobromide (1.0 mg/kg, subcutaneously 30 minutes before the start of the training session) - pharmacological the hotel amnesia; group 3 - ovariectomised females; group 4 - ovariectomized females after 21 days after surgery, treated with estradiol (20,0 mg/kg in 0.5 ml of the oil solvent intramuscularly, daily for 7 days); group 5 - ovariectomized females after 21 days after surgery, treated with galantamine hydrobromide (1.0 mg/kg, intraperitoneally, daily for 7 days); group 6 - ovariectomized females after 21 days after surgery, treated with a combination of galantamine hydrobromide (1.0 mg/kg, intraperitoneally, daily for 7 days) and estradiol (20,0 µg/kg in 0.5 ml of the oil solvent, intramuscularly, daily for 7 days). 30 minutes before the start of the training session, half of the animals (10 animals out of 20) of the 3rd, 4th, 5th and 6th groups received scopolamine hydrobromide (1.0 mg/kg, subcutaneously) to simulate amnesia. The remaining half of the rats of these groups was determined by the conservation of the trace memory model of conditional reactions passive avoidance (passive avoidance reaction) in the absence of injection of scopolamine hydrobromide.

Removal of the ovaries was performed according to the standard technique. The effectiveness of exogenous input estradiol at ovariectomized females was assessed by vaginal strokes.

The preservation of the memory trace in terms scopolamine amnesia was assessed by conditioned reflex of passive avoidance.

The statistical the AE processing of the obtained results was performed using non-parametric ANOVA test using the software package STATISTICA for Windows NT 4.0. Measurement error P<0,05.

The results of studying the action of drugs in the experiment presented in figure 1 and 2.

Figure 1. The influence of chronic administration of galantamine one or in combination with estradiol to save reflex of passive avoidance response in ovariectomized female rats.

Note: this and the following drawing on the y-axis of the bars shows the latent period was calling the animal in a dark chamber (s) when testing the reflex of passive avoidance in 24 hours. On the x - axis groups of animals: 1 - intact females (15 months); 2 - ovariectomy; 3 - ovariectomy + galantamine; 4 - ovariectomy + estradiol; 5 - ovariectomy + estradiol + galantamine.

Figure 2. The influence of chronic administration of galantamine one or in combination with estradiol to save reflex of passive avoidance in terms scopolamine amnesia in ovariectomised female rats.

On the y - axis is time, s; x-axis - groups of animals:

1 - intact females (15 months). + scopolamine; 2 - ovariectomy + scopolamine; 3 - ovariectomy + galantamine + scopolamine; 4 - ovariectomy + estradiol + scopolamine; 5 - ovariectomy + estradiol + galantamine + scopolamine.

The results of the study

On the model of passive avoidance reaction 24 hours after the session is complete prior learning in the intact female rats was observed preservation of exp is spent skill passive avoidance that was characterised by an animal stay in the lighted chamber within 180 seconds of observation (figure 1). Ovariectomy caused the amnesia of passive avoidance response, which was reflected in significantly less time animal in the illuminated chamber (94,9±4,9 sec, P<0.05) in subsequent testing as compared with intact rats. While chronic introduction galantamine ovariectomised females Mature age did not improve the process of playing passive avoidance reaction (106,3±8,6 sec) compared with the control ovariectomized females. Introduction estradiol one or in combination with galantamine similarly restored preserving reflex of passive avoidance response in ovariectomized female rats, i.e. experienced females were lit chamber within 180 seconds of observation, like rats intact group.

Model scopolamine amnesia in the determination within 24 hours after the preliminary study it was found that the introduction of scopolamine intact animals several times reduces the time spent by rats in the bright chamber (13,5±1,68 sec, P<0.05) as compared with intact females treated with saline solution, which was lit in the chamber during the test 180 seconds (figure 2). Ovariectomised females of middle age after administration of scopolamine 30 minutes on the start of the training session was also observed complete amnesia of the memory trace (10,2± 0.4 sec, P<0,05 - the time spent by rats in the bright chamber) compared with the control ovariectomized rats. When using estradiol as standard replacement therapy in ovariectomized female rats 15 months of age playback of the conditioned reflex was observed only in 30% of cases (figure 2, group 4, high bar). In 70% of animals conditioned reflex was not reproduced (figure 2,group 4, low bar). Introduction galantamine ovariectomised rats the average age was slightly improved playback of the memory trace in terms scopolamine amnesia, though not sufficient (98,0±6,4 sec, P<0,05 - the time spent by rats in the bright chamber) compared to ovariectomised animals not treated with the drug. At the same time, the combined introduction of galantamine and estradiol ovariectomised females Mature fully restored and adjusting the process play passive avoidance in terms scopolamine amnesia (180 sec - stay rats in light camera).

Analysis of the results of the present work shows that the combined introduction of galantamine is an inhibitor of acetylcholinesterase and estradiol drug estrogenic action has antiamnesic effect, i.e. normalize the playback process of the memory trace the conditions of the pharmacological amnesia in ovariectomised female rats adulthood.

The results of these experiments indicate that the introduction of a single estradiol as a substitution therapy ovariectomised rats midlife is not sufficient for full recovery of the playback process of the memory trace. It is known that with age in females decreases the sensitivity of estrogen receptors for estradiol; a long period of estrogen deficiency in older females due ovariectomies, in the absence of timely substitution treatment also inhibits the ability of estrogen receptors to bind estradiol [Brain Res. - 1997. - V.757. - R.10-16; Brain Res. - 1997. - V.749. - R-146]. Therefore, the use of only one estradiol as a substitution therapy for normalization mnestic processes in Mature ovariectomized female rats does not restore the optimal level of activity of Central cholinergic receptors for adequate understanding and evaluation of incoming information from the outside world. Treatment one inhibitor of acetylcholinesterase does not give the desired result.

Thus, only the repeated introduction of galantamine in combination with estradiol has expressed antiamnesic activity in the conditions of scopolamine amnesia in ovariectomised rats-females of middle age, i.e. it is necessary concomitant action is e acetylcholinesterase inhibitor and drug estrogenic actions to achieve sustained therapeutic effect.

The proposed method of treatment of three women in menopause after removal of the uterus and appendages. In patients after treatment, a survey of their cognitive functions.

Assessment of cognitive abilities was conducted on the test Munsterberg, in which the number of words made by the patient from a number of suggested letters and memorized within 2 minutes, should be equal to 23. The test is designed to assess the selectivity of attention, concentration, and immunity.

As a substitution therapy used containing estrogen drug avestin (dosage form estriol) according to the traditional scheme in the form of vaginal suppositories containing 500 micrograms of estradiol (i.e., about 8 μg/kg body weight). Inhibitor of acetylcholinesterase, nivalin (galantamine) was administered in the dose of 5 mg of 1 times a day intramuscularly for 10 days in combination with vestina (one candle 1 time in three days).

Before treatment concomitant introduction acetylcholinesterase inhibitor and estrogen patients were subjected to therapy for gynecologic indications (complaints of dryness in the vagina) with candles of ovestin (1 candle 1 time a day for 1 week).

Testing of cognitive functions: 1) before treatment, 2) after 7 days of daily administration of ovestin and 3) within 10 days after co-injection oats is in (1 every three days) with daily intramuscular injection nivalin (galantamine).

The normal time allotted for the test is 2 minutes and the number of correctly remembered words is equal to 23.

Example 1. Patient A., 1949 birth. 12.02.2003 was held panhysterectomy (removed a uterus with appendages). Complaints of hot flashes, insomnia, anxiety, agitation, impaired memory, inability to concentrate.

Example 2. Patient B., B. 1954. 05.02.2002, underwent hysterectomy with appendages. Complaints, anxiety and fatigue, experiencing difficulties, poor memory, poor sleep, incontinence and dryness in the vagina.

Example 3. Patient C., 1947 birth. 21.08.2001, underwent hysterectomy with appendages. Complaints of hot flashes, sweating, fatigue, bad intelligence, incontinence and dryness in the vagina.

The results of testing the cognitive functions of the patients are shown in the table, which shows a distinct improvement in their ability to analyze and memorize the proposed task.

At the end of the course of treatment with galantamine in combination with estradiol in all patients improved overall health, disappeared anxiety, normalized sleep, decreased discomfort in the vagina.

ExamplesTestingTest time (min)Number of wordsWord 1 is in
Patient A.1 (before treatment)b152,5
2 (1 week)4194,75
3 (in 2.5 weeks).3227,33
Patient B.1 (before treatment)5204,0
2 (1 week)423of 5.75
3 (in 2.5 weeks).22311,5
Patient C.1 (before treatment)6193,2
2(1 week)5204,0
3 (in 2.5 weeks).3227,33

Such results could not be achieved using one of ovestin. The mechanism of action of this combination therapy requires a deeper study. We can assume that galantamine supports a higher level of estrogen in the blood and helps him in finding and interacting with their receptors.

A method of treatment of disorders of mental function in women who underwent hysterectomy the appendages, includes introduction to the sick estradiol, characterized in that after seven days of administration of estradiol therapeutic dose in the form of vaginal suppositories patients additionally injected intramuscularly galantamine daily once a day for 7-10 days at a dose of 5 mg, thus reducing the number of injections of estradiol to once in 3 days in therapeutic doses 8-20 mcg/kg of body weight.



 

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4 cl, 3 sch, 1 tbl, 8 ex

FIELD: medicine, gynecology.

SUBSTANCE: the present innovation deals with carrying out hormone-substitution therapy in women during menopause period or in sterilized women. For this purpose the above-mentioned therapy consists of the phase of relative dominant estrogen activity including three daytime dosages of a substance inducing estrogen activity being equivalent to approximately to 1 mg 17beta-estradiol daily, and the phase of relative dominant progestogen activity including combination of a substance inducing estrogen activity being equivalent to approximately 1 mg 17beta-estradiol daily and a substance that demonstrates progestogen activity being equivalent to approximately 90 mcg norgestimate daily. To fulfill such a therapy a pharmaceutical preparation is, also, suggested and a set of mentioned preparations. The innovation provides maximal weakening the symptoms of the disease, in particular, congestions along the safety of application due to decreased risk of known complications of estrogen therapy.

EFFECT: higher efficiency of therapy.

31 cl, 1 dwg, 1 ex, 2 tbl

FIELD: organic chemistry, steroids, pharmacy.

SUBSTANCE: invention describes unsaturated 14,15-cyclopropanoandrostanes of the general formula (I):

wherein R1 means hydrogen atom (H), hydroxy-group (OH); R2 means hydroxy-group (OH), hydrogen atom (H); R3 means hydrogen atom (H), (C1-C10)-alkyl at α- or β-position; R4 means halogen atom (F, Cl, Br) or pseudohalogen group (azide, rhodanide), hydroxy-group (OH), perfluoroalkyl; R5 means (C1-C4)-alkyl; if double bond is at 1,2-position then R4 can mean hydrogen atom (H). Also, invention relates to a method for preparing these compounds and pharmaceutical compositions containing these compounds. Compounds of the formula (I) are compounds eliciting gestagenic and/or androgenic effect.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

11 cl, 1 tbl, 9 ex

The invention relates to steroids of General formula I

where R1- Oh, (H,H), (H,OR), NOR, where R is H1-6alkyl, C1-6acyl; R2- H or C1-6alkyl, R3- H, or R3- C1-6alkyl, C2-6alkenyl,2-6quinil, possibly substituted with halogen, R4- H, C1-6alkyl or C2-6alkenyl; R5- C1-6alkyl, R5- H, R7- H, C1-6alkyl, R8Is H, OH, halogen;

R9and R10independently H, or R9and R10independently C1-6alkyl, possibly substituted C1-4alkoxy or halogen;

R11- H, SO3H1-15acyl, dashed line indicates a possible link from4,5(10)or4,9-diene system

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a combination comprising mirtazapine or its pharmaceutically acceptable salt or solvate and hepiron, or its pharmaceutically acceptable salt or solvate but optionally in combination with one or some pharmaceutically acceptable carriers. The combination of amounts of hepiron and mirtazapine provide the more favorable effect of this combination as compared with additional effects of each preparation taken separately. Proposed combination can be used in treatment of depression and associated disorders. Also, the invention represents a new method for treatment of depression and associated disorders. The combination of mirtazapine and hepiron shows the better effects in more number of patients as compared with effect of each separate preparation that involve less amounts of adverse effects.

EFFECT: improved and valuable medicinal properties of combination.

5 cl, 5 tbl, 2 ex

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