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Semax: general properties
22 Dec 2016
SEMAX (Semax)
H-Met-Glu-His-Phe-Pro-Gly-Pro-OH
Synthetic peptide designed on the basis of ACTH (4-7). Efficient memory stimulant, protected from hydrolysis by peptidase action; after clinical testing is recommended for clinical and physiological application.
Semax - NEW nootropics
Neuroprotective drugs Semax is developed at the Institute of Molecular Genetics, Russian Academy of Sciences, where he established the industrial production (License N64 / 570/98 from 06/04/98).
Registered name: Semax.
Chemical name: heptapeptide (Met-Glu-His-Phe-Pro-Gly-Pro).
Manufacturer: Institute of Molecular Genetics, Russian Academy of Sciences.
Structure:
Monocomponent: one drop (0,05 ml) 0,1% Semax aqueous solution containing 50 micrograms of synthetic polypeptide methionine-glutamine-phenylalanine-histidine-prolyl-glycine-proline (Met-Glu-His-Phe-Pro-Gly-Pro) . The general formula S39N55N9O12S. The molecular weight of 873.97.
Properties and preparation method:
Semax - is a white hygroscopic amorphous powder with a characteristic odor, soluble in water. Semax colorless aqueous solution, its pH is from 4.0 to 5.5. Semax are synthetic method. The peptide sequence is patented. The patent belongs to the Institute of Molecular Genetics, Russian Academy of Sciences.
Semax - synthetic analogue of ACTH 4-10 has several important advantages compared to other similar products: the complete absence of toxicity and side effects, hormonal activity, increased duration of action of more than 24-fold as compared to native analogue, intranasal application possibility with real penetration into the brain. Intranasal application of Semax 4 minutes penetrates the blood-brain barrier; its half-life in the body after a single dose lasts 20-24 hours. Semax prolonged action is due to its sequential degradation, in which most of the neuropeptide is stored in fragments EHFPGP (Glu-His-Phe-Pro-Gly-Pro) and HFPGP (His -Phe-Pro-Gly-Pro), which are also stable neuropeptides independently modulate cholinergic neurotransmission and generation of nitrogen oxide.
In tissue culture experiments to demonstrate the powerful effect of the drug on trophotropic cholinergic neurons in both groups complete medium and adverse conditions caused by glucose and oxygen deprivation. When adding Semax at 100 nM and 10 mol neuronal survival was significantly increased by about a factor of 2, which is comparable to the same effect NGF.
The specificity of action of Semax on the population of cholinergic neurons in the forebrain basal ganglia confirmed by the results of experiments in which shows the absence of a positive effect of the peptide on the survival of GABAergic neurons and granule cells of the cerebellum. Directional effects of neuropeptide in the cholinergic neurons is accompanied by a significant increase in activity of the enzyme acetylcholinesterase specific brain structures that generally correlates with the improvement of the processes of learning and memory formation.
It is found that the effect on acetylcholinesterase activity of Semax made by transcription of the gene encoding one enzyme isoform.
When studying the effect of conductivity on Semax electrotonic identified synapse between two neurons it is shown that after 14-30 min after administration of neuropeptide at 200 nM indicated a doubling rate of nerve impulse transmission. Improved conductivity persists for 5-6 hours.
In animal experiments found that even very small doses (3-30 mg / kg) Semax has a pronounced neuroprotective effect, increases the adaptive capacity of the brain, increasing its resistance to the stress damage, hypoxia and ischemia. Higher doses of Semax (150-300 mg / kg), not being toxic and preserving nootropic properties of small doses, in addition, have a pronounced anti-oxidant, anti-hypoxic, angioprotective and neurotrophic effect.
Clinical trials confirmed the safety of the neuropeptide drug Semax (ACTH 4-10), its lack of toxicity, and hormonal activity.
Semax has a strong comprehensive neuroprotection, whose main components are immunomodulation, inflammation inhibition of glial responses, improving maintenance of the trophic brain, inhibition of the synthesis of nitric oxide and oxidative stress reactions. Induced neuropeptide chain of metabolic transformations reinforce and support each other, leading to inhibition of most important mechanisms of delayed cell death.
Semax Treatment is most effective when the carotid ischemic stroke, although the positive effects of the drug occur and vertebrobasilar localization of vascular lesion. Intranasal application of a daily dose of 12-18 mg drug reduces the 30-day mortality and improves the clinical outcome of stroke and increases the degree of functional recovery, especially in cases of early treatment in the first 6 hours of the disease.
Positive clinical effect of Semax correlates with its normalizing effect on the functional activity of the brain, which according to data multimodal neurophysiological monitoring.
Tact semax way, a representative group of regulatory neuropeptides, is an effective means of protecting the brain that allows us to recommend it as a secondary neuroprotectant for inclusion in complex intensive therapy of ischemic stroke.
Semax acts quickly and efficiently:
- 1. Semax improves intelligence and memory of healthy people, especially in those engaged in hard physical labor and responsible work requiring high concentration;
- 2.Semax for the rehabilitation of patients with memory disorders, motor skills, and as a result of stroke, as a result of head injuries, Parkinson's disease, Huntington's.
When brain stroke Semax significantly limits brain damage, if it is applied immediately after the stroke. Semax restores strength, ability to communicate and stroke patients, and returns them to normal life. Semax accelerates the rehabilitation process of patients in the aftermath of the disease, when they are transferred to everyday life.
Semax promotes restoration:
- Self-help skills;
- Motor skills;
- Interpersonal skills and speech;
- Cognitive abilities;
- The ability of a normal social life.
In Parkinson's disease Semax slows progression of the disease at an early stage.
Semax promotes:
- A decrease in muscle immobility;
- The removal of loss of balance;
- Removal of involuntary muscle movements;
- The improvement of speech activity;
- Restoration of chewing and swallowing skills.
As a rule, Semax significantly improves all the parameters of the patient's functioning in daily life activities, behavior, self-service. Furthermore, Semax has no hormonal side effects and activity does not affect the immune system, has no allergic or immunotoxic effects and is not addictive.
GENERAL INFORMATION ABOUT SEMAX
Semax - white hygroscopic amorphous powder, readily soluble in water. Spreads in the form of ready-to-use solution 0.1%. 3 ml vial contains Semax 0.1%, 0.1% nipagin as a preservative and distilled water.
Semax - a peptide with the amino acid sequence of the original protected state patent. Semax - a heptapeptide (Met-Glu-His-Phe-Pro-Gly-Pro), synthetically produced analogue 4-7 fragment of adrenocorticotropic hormone (ACTH), lacking hormonal activity. It belongs to a group of neuropeptides, and having an adaptive neuroprotective effect. Semax containing seven natural amino acids (methionine, glutamine, histidine, phenylalanine, shed, glycine and proline), are not included in the list of banned substances.
Semax - an original non-hormonal medication without contraindications and side effects; non-toxic, non-addictive. Semax is used in the form of nose drops. Patients administered 2-3 drops into each nostril (left and right) several times a day. To maximize the absorption of the drug should take a break of 2 minutes between the instillation into the nostrils.
Semax after administration into the body by nasal instillation of drug absorbed through the mucosa and enters a few minutes to the brain. Very quickly Semax is cleaved in the body into amino acids. Eliminated via the kidneys as well as other amino acids. Small amounts Semax remain in the brain for 20 h, and triple intake per day Semax maximizes prolonged therapeutic effect.
Driving Semax therapeutic purpose in a clinical setting:
Thrombophlebitis brain 3 drops 4 times per day in each nostril for four weeks; break 21 day after dosing interval as follows: 2 drops, 3 times a day in each nostril for four weeks under the supervision of a neurologist.
Cerebral ischemic stroke: 2 drops, 3 times a day in each nostril for four weeks; a break of 14 days; dosage is repeated according to the scheme 2 drops 3 times a day in both nostrils for four weeks under the supervision of a neurologist.
Organic degenerative cerebral vascular pathology: 3 drops 4 times per day in each nostril for four weeks; 28-day break; Dosage is then assigned according to the scheme 2 drops, 3 times a day for four weeks under the supervision of a neurologist.
Parkinson's Disease: 3 drops 4 times per day in each nostril for six weeks; then the 21-day break; Dosage is then assigned as follows: 2 drops, 3 times a day in both nostrils within six weeks under the supervision of a neurologist.
CLINICAL RESEARCHES of SEMAX
Semax drug study were conducted in accordance with the principles of modern clinical pharmacology, whereby in the test included not only patients suffering from diseases which are designed for the study drug, but also healthy people. Selection of animal and human testing was carried out at random.
Clinical trials Semax carried out as follows:
1982-1990 GG - Preclinical tests on laboratory animals. Tests were conducted for 8 years and have shown that Semax has no hormonal effects or narcotic, non-toxic, does not cause addiction syndrome, meets the standards and requirements of the Russian Federation Ministry of Health
1990-1994 GG - The first phase of clinical trials. The study was conducted on 303 patients. 200 patients received the drug Semax. 103 patients received standard treatment. 59 patients were treated with double placebo.
Semax tested in the following hospitals:
Center of autonomic pathology of the RF Ministry of Health
Moscow Medical Academy. THEM. Sechenov
Military-Medical Academy. CM. Kirov
Research Institute of Neurology
Institute of Neuropathology them. Spondylitis (Saint-Petersburg).
1994-1996 GG - The second phase of clinical trials. The study lasted 2 years in the Russian Federation and includes thousands of hospital patients. Studies have shown that drug Semax meets all the requirements of the Russian Ministry of Health. It is proved that Semax can prescribe healthy people with the aim to raise the adaptive ability of the body to work in conditions of emotional, mental and physical overload.
1996 - the drug has received approval from the Ministry of Health of the Russian Federation and from 28 March 1996 to the Institute of Molecular Genetics, Russian Academy of Sciences issued a license for manufacturing and medical applications. Semax approved for sale in the territory of the Russian Federation and for export to other countries.
1.Pharmacological data.
1.1. Studies in vitro.
To study the mechanism of action of Semax conducted two types of research.
Studied corticosteroid synthesis stimulation in isolated rat adrenal cells under the influence of ACTH fragments (1-24 ACTH and of ACTH 5-10) compared to SEMAX. Stimulation of melanocytes was determined by frog skin darkening her skin by the action of the same substances. It was found that both ACTH polypeptide fractions (1-24 and 5-10) significantly stimulated the synthesis of adrenal corticosteroids isolated cells and darkening of the frog skin, whereas Semax had no such effects. This proves that no Semax hormonal activity, which is important for its therapeutic use to treat humans.
1.2. Studies in vivo.
In experiments in vivo from animals in the early '60s, it was shown that the regulation of ACTH restores behavioral disturbances in animals with pituitary gland removed, and it was confirmed later. In addition, it was found that the ACTH fragments (4-10) affect the learning process and behavior (De Wield et al, 1975;. De Wield and Jolles, 1982). As for Semax, this speeds up the process hecto -peptid memory in rats, increased the number of active responses, improved long-term consolidation of skills and adaptation processes (documents semax, 1996). Semax has no effect on the emotional function, motor skills, body temperature, respiratory and cardiac function (Ponomarev-Steppe and al. 1984). It was also established that Semax strengthens the resistance of the organism during hypoxia (Kaplan et al, 1992).
Tests performed on a sufficiently large number of mice, and guinea pigs confirmed that Semaks does not cause allergic reactions. Semax not affect the immune system, induction of interleukins, adhesion and leukocyte lysis. It also does not affect the activity of phagocytes, granulocytes and gemotaksic antibodies to erythrocytes (SEMAX Papers, 1996).
The dosages used in these studies, 50 times higher than used for the treatment of humans. The drug was first tested in the form of droplets, and then intravenously.
Analyzing the results of studies in vivo and in vitro, should two important facts:
1) Semax has hormonal effects on the body:
2) does not allergic and immunotoxicity effect.
1.3. Therapeutic doses. Five drops (750 mcg) three times a day for five days. Burying produced in a supine position, one drop alternately in one direction and then in the other nostril. If necessary, the treatment can be continued up to 28 days. The maximum daily dose - up to 5000 micrograms (9.0 ml).
2.Pharma-kinesis.
2.1. Suction.
After burying his nose in 60-70% of Semax rapidly absorbed from naso-pharyngeal mucosa into the systemic circulation, so that within 1-5 minutes of the drug to the liver, adrenal glands, brain, heart, kidney and skeletal muscle (Potoman, 1991; documents Semax , 1996).
2.2. Distribution of the drug in the organs.
Semax maximum concentration of rats following intranasal administration of a detectable after 60 minutes and concentrations were highest in the liver, adrenals, kidneys, heart and brain cells. For intravenous drug administration rats highest concentrations were found in 1-5 minutes in the heart, kidney adrenal gland, and after 60 minutes - in the heart and kidneys (Potoman et al, 1991; for Semaks Documents, 1996). The half Semax distribution in different organs and tissues of rats after intravenous injection is 20 seconds (Potoman et al., 1992). Semax crosses the placenta, but we have no evidence that it is excreted in breast milk.
2.3.Biotransformation.
Semax dissolves in serum of rats under the action of aminopeptidases and angiotensin-converting enzyme (Potoman et al., 1991b and 1993). The first methionine is cleaved at position 1, leaving hexapeptide then glutamine at position 2. A further decay continues until the individual amino acids (Potoman et al., 1992).
2.4. Removal from the body.
Semax quickly removed from the plasma in two steps with half-lives t 1/2 and equal to 0.4 for about 5 minutes. Since Semax disintegrates into individual amino acids, their fate in the body is not different from other origins such as amino acids.
2.5. of the preparation time.
Quick disintegration of Semax, perhaps indicative of its short-term exposure. However, the results obtained in experiments with rats, demonstrate that after instillation in nose quickly comes to organs and tissues, and is the maximum concentrations in the organs (brain, heart, skeletal muscle) are achieved after 60 min, and the effect of the drug after administration of single dose lasts up to 20 hours (SEMAX Papers, 1996).
From the above data it can be concluded that when resuming reception Semax three times a day, therapeutic concentration of drug in the body are constantly maintained and generated good correlation between pharmacokinetic parameters and its pharmacodynamic effect.
3. The pharmaceutical formulas and their implications for pharmacokinetics.
Semax is available only in the form of a solution for administration through the nose, with a very good biological absorption (60-70%).
3.Toxicological test on animals.
4.1. Adverse pharmacodynamic effects on the body.
Studies were conducted in rats, administered with Semax doses of 1.5 and 3 mg / kg intravenously or intranasally for 30 days, and in dogs, which at the same time give a dose of 10-30 mg / kg. It was found that, compared with placebo Semax not alter blood counts (the number of erythrocytes, leukocytes and hemoglobin level), the activity of liver enzymes, creatine, albumin, globulins, total albumin, urea, total bilirubin, body weight, respiration rate, heart rate (Documents by Semax, 1996). Thus the drug is practically not cause any unwanted pharmacodynamic effects when administered intranasally to rats and dogs and dogs when administered intravenously.
4.2. Local toxicity.
There were no adverse effects of the drug when administered intranasally to mice, rats and dogs. However, the appointment of the drug to people observed - but only in some cases - pale nasal mucosa (documents semax, 1996).
4.3. Acute general toxicity.
Semax practically non-toxic to mice and rats; when administered intravenously maximum doses of 100 mg / kg in rats and 1000 mg / kg to mice intramuscularly and 100 mg / kg in rats. There were no cases of intoxication and animals coloring sheets, although the dose of 1000 mg / kg in 14 thousand times higher than the therapeutic dose for humans based on body weight (documents semax, 1996).
4.4. The toxicity of long-term use.
Investigations in rats treated i.p. Semax (1.5 mg / kg and 3 mg / kg) and intranasally in doses of 30-80 mg / kg daily for 30 days. The control group received distilled water. All the animals survived, and in comparison with the control group in the experimental animals had no clinical, laboratory or histopathological violations (documents Semax, 1996).
4.5. Toxicity during pregnancy.
Study teratogenic effects and embryotoxicity carried out on female rats treated Semax through the gastrointestinal tract from the first to the eighteenth day of pregnancy at doses of 30 mg / kg, 150 mg / kg and 3 mg / kg. Control animals received 0.5 ml of saline. The data on all parameters (conception, fetal development, the number of babies and survival) were the same as those in the control group, ie Semax does not have any embryotoxic or tetragennogo effects (documents semax, 1996).
4.6. The mutagenic and carcinogenic effects.
Studying in vivo mutagenesis treatment was carried out using test Imes parallel with the positive control (azide-Na, 9-aminoacridine) and in vitro by determining chromosomal aberrations mice spinal cord cell. 10-100-fold relative to dose therapeutic dose for humans showed that Semax has no mutagenic effect on the body. This is confirmed by research on fruit flies and rats (documents semax, 1996). Testing for drug carcinogenic effect was not carried out, since Semax consists solely of natural amino acids and peptides such as the use of ACTH 4-10, ACTH 1-24 and 1-39 ACTH in humans for several decades never caused carcinogenesis.
4.Clinical experience abroad.
5.1. The product is registered in Yugoslavia. Additional studies conducted in the country, contributed to the registration of the drug. In these clinical studies involved 30 patients with mild to moderate symptoms and signs of disorders of attention, concentration, memory and motor skills caused by ischemic cerebrovascular disorders (one month after the stroke), head injuries without complications (one year after the injury) and Parkinson's disease in phase with no signs of dementia. Semax patients received 750 micrograms per day (5 drops 3 times a day) for five days, then after an interval of 10 days, the cycle was repeated. The results of treatment were checked by clinical and laboratory parameters on the basis of a comparison of the initial indicators of the patient with the control group and the performance after treatment.
The data showed that the result of the application of Semax has been a significant improvement in cognitive, motor and visual motor skills of the patient, a significant improvement of attention and the electrical activity of the brain. As mentioned by some authors, "it showed a significant improvement of all types of patient activity, from everyday behavior and ending with the ability to fully serve yourself." It was pointed out that the product is well tolerated and does not affect any of the known biochemical parameters.
The results of Kaplan et al. (1992) correspond to the above-mentioned reports and argue that Semax increases a person's resistance to hypoxia.
Additional clinical studies in Yugoslavia conducted on 303 patients of both sexes suffering from cerebrovascular disorders; Huntington's chorea; those who underwent surgery after a traumatic brain injury as a result of discogenic radiculopathy. Patients were divided into two groups. One group of 200 people received Semax (1500-2000 mg daily for 5-14 days), and the other, the control group received traditional drugs.
It was established that after the application of Semax, 80% of patients with acute cerebrovascular disorders there have been major improvements, such as those described in the document on Semax (1996), - increasing efficiency, improving cognitive functions and audio-verbal memory, better sleep and mood, shorter reaction to stimuli ethers and esters. In 87.5% of patients with Huntington's chorea in the form of hyperactivity observed decrease in headaches, sleep recovery to normal, reducing the number raandom movements, improvements in the audio-verbal memory, concentration, mood and performance; at the same time improved ECG parameters. In those patients who underwent neurosurgical intervention after a traumatic brain injury, some improved memory performance, rose statistical level memorization of the material; improve the process of learning and memorizing letters and long-term storage of the written and educational material. In patients undergoing surgery over discogenic sciatica without brain disorders, for the prevention and treatment of post-anesthetic complications Semax helped quickly restore the memory, improve short-term and distraction, enhance verbal memory and concentration level of memory and attention.
To compare the impact of the application of Semax it is tested on healthy people held adaptation to increased physical stress. Here, the results also proved successful. It is proved that Semax affects the intellectual-mental performance, improves mental performance, reduces mental stress index, has no negative effect on the respiratory and cardiovascular systems. Concomitant use of Semax and increase physical stress on the body leads to significant savings in the cardiorespiratory system in the studied group of patients compared with the group that was limited to athletic activities.
5.2. Evaluation of pre-clinical studies.
5.2.1. Evaluation documentation.
There is a large literature on preclinical studies Semax. These studies were conducted in accordance with modern principles of pharmacology and toxicology. Also systems in vitro, were used four types of experimental animals (mice, dogs, guinea pigs, rats). The drug was administered in several ways to receive (intravenous, intramuscular, intranasal). In human nasal drops applied research. Checked a large number of doses of various volumes and duration of action. The control group received a placebo.
5.2.2. The therapeutic range.
Semax has an excellent therapeutic range. Neither assigns lethal doses had no effects even if it was in 14 thousand times greater than the dosage, designed for people.
5.Accidents when using the drug.
6.1. Side effects.
Drops Semax well tolerated and if side effects occur, they manifest themselves in the form of passing headache and blanching of the nasal mucosa.
6.2. Contraindications.
Acute mental status, pregnancy, lactation, hypersensitivity to individual ingredients.
6.3. Poisoning, treatment, antidotes.
Cases of excessive reception Semax in the literature are not described, and if that happens, the treatment should be symptomatic.
6.4. Causes of treatment interruption.
Individual hypersensitivity to the components of the preparation.
6.5. The interaction with other substances.
Since Semax assigned locally, it should not be instilled into the nose along with other drops. This will help eliminate possible chemical or pharmacodynamic response.
7. Therapeutic indications.
- Memory and thinking disorders in patients with ischemic stroke, head trauma; in patients suffering from neurological disorders; In these cases, the drug is prescribed to improve the quality of life and work; drug improves concentration and memory, functional abilities and motor skills;
- Healthy persons drug is given at high psycho-physical fatigue to improve attention span, motor activity, performance.
8. Data on the history of the drug.
In 1982, De Veld and Dzholles published in "Physical Review" a detailed article about the pharmacology of ACTH fragments and noted their positive impact on many of the central nervous system. For fifteen years, the Institute of Molecular Genetics, Russian Academy of Sciences in cooperation with Moscow State University. MV Lomonosov developed and clinically tested on patients drug Semax (Kaplan et al., 1992). The drug was incorporated into the Russian Pharmacopoeia where semax separate article (WSF 1994 a), especially the 0.1% solution nose drops (WSF 1994 b). The product is registered for use in Russia (RS, 1995). Continuously published reports of its therapeutic effect (Koroleva et al, 1996; Gusev EI et al., 1998).
At the same time, a number of modern pharmacology of drugs that stimulate the central nervous system. They are called nootropics and listed in the old (Haynes, 1990) and the new edition of the classic List farmakopreparatov Goodman-Gilman (Baldessarini, 1996). Of this group, the most known piracetam (Reynolds, 1996).
9. The latest news about Semax.
February 27, 1997 the State Pharmacological Committee allowed Semax clinical trials for diseases of the optic nerve in adults, which were conducted in the Department of Ophthalmology and therapeutic Opthalmo-Pharmacology Research Institute of Eye Diseases RAMS. The study included 74 patients aged 16 to 84 years (31 women and 43 men) with optic nerve vascular disease, toxic-allergic and inflammatory etiology (resp. 25.5, 16.3 and 24.5%), as well as partial optic atrophy (33.7%). The study showed that:
a) The inclusion Semax in the complex treatment of diseases of the optic nerve has a beneficial effect on the severity and pace of the recovery processes, contributing to the improvement of visual functions.
b) The drug Semax can be used intranasally in the form of instillation and administered by intranasal electrophoresis, thereby increasing the impact on the pathological focus.
c) achieved through the use of the drug in the treatment of Semax positive dynamics of the state of the optic nerve provides improved visual function. Semax preparation used in the method and endonasal electrophoresis enhances visual acuity 83.9 and 92.1%, expansion of the field boundaries in 76.9 and 84.3% of the sensitivity and increase the electrical conductivity of the optic nerve and retina 67 7 and 76.3% of the examined eye, respectively. These findings are consistent with a number of experimental studies, where it was found that the mechanisms of neuronal cell death has an important place not only the absolute amount of neurotoxic substances, and neurotrophic effects of deficits.
d) Use of the drug Semax, especially in the acute stage of the disease of the optic nerve effectively protects nervous tissue from the effects of damage, significantly increases the positive clinical dynamics, estimated in the growth of visual acuity, the total field of view, the increase in electrical sensitivity and conduction of the optic nerve, improve the color vision.
d) Preparation Semax can be used for clinical use in intranasal form by intranasal instillation or electrophoresis as nootropic agents for treating diseases of the optic nerve vascular, inflammatory, toxic-allergic etiology and treatment of partial optic nerve atrophy.
e) The optimal dose is 600-900 mg / day for instillation or 400-600 mg / day for the electrophoretic method of administration, the ten-day course of treatment leads to more stable results compared to the five-day course of application Semax.
g) The drug Semax well tolerated by all patients, adverse events were noted.
As a result, food and drug administration solution for N 4 on May 27, 1999 authorized the use of Semax as a 0.1% solution for the treatment of diseases of the optic nerve.
After further research on the toxicity of Semax immature animals (acute and chronic toxicity, local irritating effect) food and drug administration authorized clinical trials 0.1% Semax solution for intranasal administration to children.
10. Conclusions.
Semaks new drug, a synthetic heptapeptide based on natural amino acids, belongs to a group of neuropeptides nootropic action, no hormonal effect. Therapeutic indications Semax - a violation of motor and cognitive function after an ischemic stroke, closed head trauma, and neurodegenerative diseases such as Parkinson's disease, Huntington's chorea. Semax improves concentration, functional abilities, motor skills, stimulates brain functions and slows down their weakening. The clinical use of the drug in the Russian Federation and abroad indicates that the drug is rapid and effective action and well tolerated. The drug received written advice from many experts with a worldwide reputation in the field of neurology.
Neurotropic and nootropic action
Investigation of the effect of Semax animal training showed that intraperitoneal administration of this peptide accelerates the production of food skills in the T-maze. The positive effect of Semax animal training is also shown in the test generation CRPA. Intraperitoneal administration of the peptide in a dose of 0.015 mg / kg 1 hour before the start of the experiment significantly increased latency of entering the dark section on the second day of training. A similar effect is observed with administration of the peptide for 6 hours before the start of the experiment [Ashmarin et al, 1995]. It has been shown that Semax stimulates mnemonic processes not only in intact animals, but also in terms of pathology: the introduction of a peptide significantly attenuated amnesia induced by electric shock. It is proved also that the analogue does not change the level and orientation reaction emotional status of the animals in the test "open field." In addition, there was no impact Semax at a dose of 0.05 mg / kg, heart rate, respiratory rate and body temperature of animals fixed.
Investigation of stability to the action of proteases Semax serum showed that the first step is the elimination of the degradation of the molecule N- terminal methionine. This forms sufficiently stable intermediate Glu-His-Phe-Pro-Gly-Pro.
Study neuroprotective effects of Semax was conducted on people volunteers. The experiments showed that intranasal administration of peptide at a dose of 0.016 mg / kg significantly increased the attention and short-term memory test when tested at the beginning and at the end of the working day. EEG data showed that intranasal administration of the peptide in an amount of 0.25-1.0 mg causes a change in the parameters encephalographic similar changes occurring with the introduction of typical nootropics.
To compare the effects of Semax with the effects of other studies have been conducted nootrop antihypoxic his actions. The experiments were conducted on rats showed that the peptide in 2.5 animals increases the life extreme "high" (12,000 m), and positively affects the body's adaptation to hypoxia. In studies on human volunteers found the ability to stop drug post-hyper-ventilation EEG effects caused by a compensatory reduction in cerebral blood flow.
It conducts research on the effect of Semax effects of acute hypobaric hypoxia in rats of different ages. It was shown that pre semax single administration at a dose of 0.05 mg / kg increases the stability of individual animals to hypoxia, a positive effect on the parameters of cardiac activity during hypoxia and behavior change of delayed weakens animals caused by oxygen deficiency
Semax is able to exert a neuroprotective effect. Large doses of Semax (0.15-0.3 mg / kg) increased animal survival and reduce the severity of neurologic defect in experimental ischemic stroke. Moreover, experiments carried out on cultures of embryonic rat brain cells, showed that at a dose of 0.1-10 semaks uM increases the number of surviving neurons in 1.5-3 times compared with the control and thus does not affect the proliferation of glial cells. The authors suggest that semaks exerts its neurotrophic effect through regulation of the level of expression of neurotrophic factors.
Neurotrophic properties Semax confirmed during studies of the drug for diseases of the optic nerve of various etiologies. Introduction semax intranasally or as endonasal electrophoresis, especially in the acute stage of the disease, effectively protects nervous tissue from the effects of injury. This significantly increased the severity of growth, expanding the total field of vision, increased sensitivity, and electric conductivity of the optic nerve, improved color vision.
It was found a positive effect of Semax with acute hemispheric ischemic stroke. Semax intranasally administered in a daily dose of 12, 18 and 24 mg for 5 days. The first administration was carried out in 3-4 hours after admission to the hospital, that is, in the early hours of the disease. Together with the introduction of Semax, all patients were subjected to a comprehensive basic therapy. Clinical trials have shown that intranasal administration of Semax conjunction with intensive therapy of acute hemispheric ischemic stroke has a beneficial effect on the severity and pace of the recovery processes, helping to accelerate the regression of brain disorders and focal.
To determine the possibility of using Semax correction postresuscitation neurological disorders have been conducted studies of the drug on the model of clinical death. total circulation is stopped by clamping the vascular bundle of the heart in rats. After 10 minutes, the animals revived with the help of closed cardiac massage and artificial respiration. Further, in rats evaluated the degree of storing the experimental conditions during the second test in the "open field". Daily intranasal administration of Semax at a dose of 0.05 mg / kg for two weeks normalized parameters orienting-investigative reaction of rats, bringing their values to intact control.
Data on positive action to restore semax mnemonic brain functions postresuscitation were obtained in clinical trials. The effect of the drug on the restoration of the central nervous system function in patients with severe pathology postresuscitational (intellectual and mental disorders). In 89% of patients receiving Semax, there was a significant improvement. Neuropsychological examination revealed improvement in attention, memory, cognitive abilities, mobility of muscles, verbal memory. These encephalopathy-graphic survey also confirmed the effectiveness of the drug Semax It noted improvement in the functional state of the brain.
In the literature, there is evidence that Semax may have anti-stress effect. It is known that the emotional stress has been increasing the expression of the gene c-Fos in the different structures of the brain. The most pronounced expression of this gene was detected in the brain predisposed to emotional stress animals. Preliminary intraperitoneal administration Semax causes a decrease in stress-induced expression of c-Fos gene in paraventricular hypothalamus and the medial septum in predisposed to emotional stress in rats.
The mechanism of action has not been elucidated Semax to date. The most important aspect for understanding the central effects of the peptide is the assessment of its ability to penetrate the blood-brain barrier. A series of experiments using tritiated Semax was performed. Studies have shown that after intravenous injection into the brain of experimental animals penetrates 0.01% of the injected peptide. These data are comparable to those described for the other analog AKTG4-10 - Org 2766 (0.004%).
Further attempts were made to identify the receptor binding Semax with preparations of plasma membranes of neurons and glial cells in the brain of rats and intact neurons. Hitherto detect specific peptide receptors failed. However, there is evidence that semax able to bind to the membranes of nerve cells of the basal forebrain nuclei of rat, and this binding is specific and reversible. It is possible that the receptors which bind Semax, is presented in very limited quantities and few brain structures.
It has been suggested that the effects of Semax related to the change in the activity of acetyl-cholinergic system. Introduction of the peptide in a dose of 0.150 mg / kg causes an increase in acetylcholinesterase activity in the hippocampus and cerebral white matter is more than 2 times. Effect of the drug is observed within 2-3 hours after injection. In other parts of the brain activation was not observed.
We also show the effect of Semax on exchange of monoamines in the brain. For a single intraperitoneal injection at doses of 0.15 and 0.6 mg / kg Semax increases dopamine, serotonin and its metabolite 5-hydroxyindoleacetic acid. The effect was observed during 24 hours after administration of the peptide. Chronic daily administration Semax at a dose of 0.6 mg / kg (1 per day) for 7 days, there was a tendency to a decrease in dopamine levels and a significant decrease in the concentration of serotonin in the hypothalamus.
Currently Semax drug is widely used in the clinic for the treatment of various CNS diseases. However, the creators of the drug believe that the therapeutic potential of Semax not been exhausted, and new indications for its use can be identified in the future. In recent years, appeared in the press about the work Semax action research on pathological conditions not associated with damage to the nervous system. For example, experiments conducted on laboratory animals have shown that Semax able to positively influence the course of acute pancreatitis in rats. A single intraperitoneal injection of the drug at a dose of 0.1 mg / kg reduced the mortality rate of animals, reduced hyper-fermentatio, activation of lipid peroxidation, vascular permeability, improves and accelerates the healing of areas of destruction in the pancreas. Study of the effect on hemostasis semax shown Semax that can interact with a macromolecular heparin to form a complex compound having anticoagulant and fibrinolytic properties both under in vitro, and in vivo when administered intravenously. The authors suggest that Semax, especially in combination with heparin may be a promising anti-thrombotic agent.
There is evidence of a possible anti-inflammatory effect of Semax. It was shown that has the ability to change semax activity of human neutrophils influencing the exchange of calcium ions.
Based on the above we can conclude that Semax has a whole range of positive effects on the CNS. The drug stimulates the function of the forebrain: enhances selective focus at the moment of perception, improves memory consolidation, increases the ability to learn. Thus, unlike most nootropics nonpeptide, Semax not cause depletion of the corresponding functions. The drug increases the adaptive capacity of the brain, increasing its resistance to the stress damage, and vascular hypobaric hypoxia reduces the severity of experimental ischemic stroke in animals. Clinical trials have shown high efficacy in the treatment of Semax intellectual-mental disorders, asthenic conditions of various origins, as well as the prevention and treatment postanesthesia amnestic disorders.
However, despite the fact that Semax more than a decade in clinical practice has not yet been sufficiently explored its neurotrophic and neuroprotective properties, not to study the effect of the peptide on the developing brain.
