Modafinil

Modafinil is a prescription drug for narcolepsy, increases concentration and eliminates sleepiness also increases the perception and memory abilities. Modafinil as a dietary supplement takes pride of place among nootropics. Modafinil is a drug to get rid of sleepiness during the day and for the treatment of narcolepsy. Perhaps the improvement of perception by stimulating neurotransmitters in the brain, used to improve mental abilities.

Pharmacological group: stimulants; psychostimulants; nootropics. Mode of action: the treatment of narcolepsy, sleep apnea and other sleep disorders. The impact on the receptors: α1-adrenergic receptors (agonist) is also known as: 2- (diphenylmethyl) sulfinyl acetamide, Provigil, Modalert, Modapro, Alertex.

Not to be confused with Adrafinil!

In the US and Canada, modafinil is issued strictly on the recipe and get it not so easy, its distribution is strictly controlled in the United States.
• Belongs to nootropics

Modafinil: instructions for use
The standard dose is 100-200mg, or 4 mg per kilogram of body weight, take in the event of deliberate suppression of sleep or after waking up in the morning to maintain a cheerful state and without any harm to sleep at night.

In clinical use for the treatment of excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea, the recommended dosage usually ranging from 200 to 400 mg per day. The dose may be taken once in the morning or in two divided doses (morning and noon). When used to enhance physical performance, typical effective dosage is in the range of 100-400 mg. The drug is often taken for 2-3 hours before sporting events. Note that the side effects are dose dependent. Often advised to start using modafinil at the minimum effective dose and increase it by 50-100 mg per reception to establish optimum level. Areas of application of the drug are enormous and, in fact, include all kinds of sports, focusing on aerobic exercise or stamina. It is also great for athletes, performing exercises for strength or speed in short intervals repetitions (anaerobic load), such as the shot put, pole vault and long jump. Modafinil drug is not popular among builders, since it does not directly affect an increase in muscle or fat reduction levels in the body. Some, however, believe that the drug is effective stimulant before a workout, especially during periods of fatigue or loss of physical activity after hard work or because of other reasons.

Description pf Modafinil
Modafinil or benzhydrylsulfinylcetamid - central stimulant (psychostimulant). The substance approved by the FDA for the treatment of narcolepsy (a disease characterized by sudden and uncontrollable episodes of deep sleep, fatigue or excessive sleepiness), sleep apnea, and sleep disturbances caused by changes in the operation. quality tests were performed medication, including, as an agent for treating Alzheimer's disease, depression, and attention deficit disorder. Modafinil belongs to a group of drugs known as evgeroiki (stimulators) that promote mental alertness and attention. One of the known mechanisms of action of these drugs is agonism alpha 1-adrenoceptor, resulting in drugs have an influence on the mood, increasing the power by increasing dopamine release in the central nervous system. This also leads to changes in the levels of glutamate and GABA. In studies of modafinil were as stimulant drug shows advantages compared to amphetamine. To begin with, that the substance is supposed to have a much lower potential for abuse due to the fact that the impact does not cause the same euphoria. Moreover, the drug has minimal effect on peripheral CNS stimulation (i.e., exhibit less side effects), it has a minimal effect on the blood pressure does not cause sleep interruptions (without hangover or needs "catch" sleep), and, according to clinical trials, It has a more robust safety profile. The drug is used by the US armed forces even as an energy stimulant for pilots and soldiers required to operate for long periods of time without sleep. This is not as strange as it may seem at first glance, since the last military pilots and soldiers is widely used Dexedrine (Amphetamine) during long periods of sleep deprivation. Soldiers who use modafinil, often report that the drug helps them to maintain excellent cognitive function for up to 40 hours without sleep, and has fewer side effects than Dexedrine. Modafinil has been tested the last combat situations, such as Afghanistan and Iraq, and possibly in the future will receive official recognition as a special preparation for the military. Recently, modafinil became known among competitive athletes. They use it not only as a preparation for the "courage", and as a stimulant that increases the performance and endurance. Such use is likely to be a surprise for this drug developers, as it was reported earlier that the "soft" drug enhancing the vigilance does not have strong stimulatory effects, and can not improve athletic performance. Recent studies contradict these statements. A study in Canada found that taking modafinil can provide a pronounced sporting advantage. In a double blind study 15 male volunteers took the drug at a dose of 4 mg per kg body weight (equivalent to 200 mg for a person weighing 220 pounds) or placebo. Three hours after the meal held aerobic exercise on a cycle ergometer at 85% of maximal aerobic capacity, up to exhaustion. Taking modafinil men could exercise over a much longer periods of time (up to 30% longer), and used more oxygen intake during exercise. Also reported a decrease in the perceived intensity, whereby there is an increase in exercise performance. Please pay attention to Ladasten.

History of Modafinil
Modafinil was developed by Lafon Laboratories in France. In 1998, the drug was approved by the FDA for sale in the United States, where it is sold under the brand name Provigil. Modafinil is also found on the international market for this and certain other trade names, including Modiodal, Vigil, Alertec and Modasomil. Although the drug has a favorable safety profile in the United States for some time, he was considered a drug capable of provoking possible abuse. Currently Modafinil is included in Schedule IV controlled substance, along with Valium and Xanax. For example, its use for non-medical purposes is limited by significant legal sanctions on the import and possession of the drug. The drug has a fairly broad medical use, including sleep disturbances associated with changes in the operation. The drug is often prescribed prescription. In 2000-2004 Modafinil has become popular among competitive athletes before athletic regulatory authorities have not begun to show concern about the use of the drug. In 2004 he broke out the doping scandal involving the company VALCO, when it became known that many of the athletes who gave a positive result in the use of tetragidrogestrinona also used and Modafinil. After that, the IOC prohibits the use of modafinil, and through a series of research methodology of detection of this chemical in the urine was developed. Now that testing is part of the standard survey of athletes before the Olympic competition. Most other international sporting bodies followed the example of the IOC and the ban on testing of modafinil. Since then, the drug has lost its appeal as an "invisible" in tests, although still used by many athletes, not passing urine sample testing.

How Modafinil supplied
Modafinil often supplied as tablets of 100 mg and 200 mg each.

Structural Features
Modafinil is a central nervous system stimulant, close to adrafinilu. It has the chemical name 2 [(diphenylmethyl) sulfinyl] acetamide.

Structure and Properties of Modafinil
Origin
Modafinil is a drug for the treatment of diseases associated with sleep disorders and also improves the mental state during the long wakefulness.

Modafinil forms
The term "modafinil" refers to a racemic mixture of two isomers, R-S-modafinil and modafinil. R-isomer is referred armodafinilom. Modafinil is a racemic mixture of S-R-modafinil and modafinil, armodafinil while is represented only R-modafinil.

Pharmacology
serum
The half-life of modafinil is 13-15 hours, and serum concentration at steady state up to 2 days after the start of the reception. Half-life of S-isomer of modafinil is 4-5 hours, while the R-isomer of modafinil is longer period (15 hours) and thereby receiving substantially equivalent armodafinil receiving modafinil. These experiments showed that the concentration in the blood armodafinila 18% percent greater than in the case of modafinil (5.44 +/- 1.64mg / ml versus 4.61 +/- 0.73mg / mL) and accumulate in a shorter period of time (1.8 hours versus 2.5 hours) and the total concentration in urine armodafinila up 32-40%. Although both options modafinil (modafinil and armodafinil) have the same half-life, the effect on the body armodafinila is stronger (according to the content in the urine and blood).

Localization
According immunocytochemistry gene c-Fos (the gene responsible for the response to stimulation and detected by neural stimulation, or sleep deprivation), administration of modafinil to cats caused a sharp activation of the gene c-Fos in the anterior hypothalamic nucleus and the surrounding areas and weak in the suprachiasmatic nucleus, and the minimum gene activation in other areas such as the cerebral cortex or striatum. This activation of the hypothalamic-point was visible everywhere, in the process was involved and the amygdala. Studies in humans have shown clear differences between human exposure to modafinil, and amphetamine. In contrast to the effects of amphetamine or methylphenidate - excessive cheerfulness (which indicates a widespread neuronal activation), modafinil is selectively affects: the hypothalamus and amygdala.

Neurology
dopaminergic effects
Modafinil can increase the extracellular levels of dopamine in the prefrontal cortex of rats and in the caudate nucleus in dogs. Modafinil worked on dopamine and noradrenaline receptors (in the striatum) and the absence of such effects in mice has been linked with the disappearance of the effects associated with sleep, which confirmed the fact that the mechanism of action of modafinil really affects sleep. Recent research has shown the lack of influence of modafinil on the dopaminergic system, which may be associated with lower dosage used previously.

andrenergic impact
The invigorating effect of modafinil significantly weakened adrenergic receptor antagonists (group alpha and beta), but inhibition of the synthesis of catecholamine alpha-methyl-paratirozin does not diminish the impact.

Orexin-ergic effects
People deficient orexin (narcoleptics) modafinil shows good results, directly affecting the orexin neurons. This effect has the greatest impact on deficient mice, the effect of modafinil on the orexin system of healthy animals and humans is unknown. 3.5. Sedative and stimulating effect negative results of some studies about the effects of modafinil during the intentional deprivation of sleep, because the effect of 300 mg of modafinil during sleep deprivation is equivalent to receiving 20mg D-amphetamine. However, it was noted that the deterioration of self-control (the ability to accurately assess themselves and their surroundings) changes in the overconfidence (incorrect assessment of what is really capable of). The studies lasted for 64 hours (two nights without sleep) with a single dose of modafinil every 15 hours. Admission modafinil before sleep can seriously alter the sleep cycle and lead to subsequent lethargy, and can also cause side effects (worsening of mood and mental abilities). Recurrent hypersomnia - a phenomenon in which after the expiry of drugs against sleepiness sleepy more than to receive them. In contrast, preparations based on amphetamine modafinil not causes the phenomenon in cats, rats and mice. People who do not sleep for 64 hours and taken modafinil, this phenomenon also seen, in contrast to results with D-amphetamine reception. Modafinil does not cause recurrent hypersomnia. Exacerbation of attention observed in sleep deprivation for 10-12 hours after a single dose of 300 mg of modafinil, which is equivalent to 20 mg of D-amphetamine. The dose of modafinil 300mg of sleepiness is equivalent to 20 mg of the second dose of D-amphetamine. Brain sleep cycle is a balance of "ascending activating system" consisting of activating neurotransmitters (catecholamines, acetylcholine, orehina and so on.) And neurotransmitters (GABA, galanin), which inhibit the stimulation and promote sleep. Changing levels of activation and suppression of neurotransmitter generates a unique series of "switch-breaker." In general, regulation loop of vivacity and rest depends on the one hand, the circadian biorhythm from caused suprahiazimatic core and on the other - on the homeostatic need for sleep, which occurs during wakefulness. Modafinil is able to communicate with various stimulatory systems including serotonergic, noradrenergic, dopaminergic, glyutaminergic, histaminergic, oreksinergic and GABAergic pathways. While some studies modafinil used in the treatment of several other diseases and found that the side effect of insomnia lasted longer than in the placebo group, and Modafinil, adopted before bedtime, sleep did not give the participants of the experiment. Admission modafinil promotes mental stress.

The memory and thought processes
In healthy people, when receiving 100-200 mg of modafinil for 2 hours before the test (arithmetic test) improved storage properties, visual-spatial scheduling and rate of reaction. Short-term memory and accuracy of information processing improved after taking 200 mg of modafinil. In addition to the above, improvements are observed in the performance of tasks in general - increased motivation, enjoyment of the work done. In methamphetamine-dependent cognitive impairment dose of modafinil in a 400 g split into 3 days, can improve the properties of the short-term memory, which previously was not possible, however, a single dose of 200 mg of modafinil is not able to cause such effects.

Effects on appetite
Researchers condemning drug abuse is sometimes reported as a side effect of appetite in 16% (164cheloveka). Some researchers believe that this fact cause weight loss within one week, but no statistically.

Addiction
Modafinil is not able to activate the neural pathway that occurs in dependence, and is therefore considered that the drug has a relatively low threshold addiction other similar drugs. It is unlikely that modafinil will be used as a drug among addicts. Modafinil can help ease the breaking in methamphetamine-dependent, alcoholics and addicted to gaming, but the impact of the effect varies. Modafinil also reduces impulsivity drug-addicted, but this effect has effect only with subjects whose threshold impulsivity before experiments was already at a low level.

The impact of the Modafinil drug on people with certain diseases
multiple sclerosis
Disposable reception armodafinil (250 mg), patients with multiple sclerosis showed improvement mnemonic play, this effect was comparable to the placebo effect, but the fatigue, the ability to focus and speed of information processing the drug had no effect.

Precautionary measures. Toxicology
Tests revealed the following adverse effects of the drug - headache, dizziness, urine output, heart palpitations, tachycardia, anxiety, nervousness, gastrointestinal problems such as nausea and dry mouth, and abdominal pain. Apart from the above, modafinil is considered to be well-tolerated drug. Common side effects of modafinil include insomnia and decreased appetite.

Modafinil side effects
Side effects of modafinil, usually associated with stimulation of the central nervous system and may include nervousness, insomnia, tremors, euphoria, excitement and personality changes. The drug can also cause gastrointestinal symptoms such as nausea, vomiting, abdominal pain, dry mouth, anorexia and headache. Also, there may be high blood pressure, heart palpitations or abnormal heart rhythm. In rare cases it may occur an allergic rash, increased alkaline phosphatase, or in violation of the voluntary movements.

Availability:

Modafinil is currently to be found in more than two dozen countries. The drug, however, are not particularly popular on the black market and is not profitable target for counterfeiting. Modafinil available on medical prescription.

Armodafinil

Armodafinil (trade name Nuvigil) is enantiomerically pure form of a substance that promotes wakefulness, or evgeroika, modafinil (Provigil). It consists only of (-) - (R) enantiomer of racemic modafinil. Armodafinil manufactured by the pharmaceutical company Cephalon Inc. and it has been approved by the Food Safety and Drug Administration USA (FDA) in June 2007. Despite the fact that the two substances have similar half-lives, armodafinil reaches its peak concentration in the blood later than modafinil that can make it more effective as a substance promoting wakefulness in patients with excessive daytime sleepiness.

Systematic (IUPAC) name: (-) - 2 - (the R) - (diphenylmethyl) sulfinyl) acetamide
Trade names: Nuvigil
Category drugs in pregnancy: C
Dependence: Low
Methods of application: oral
Legal status: US: List IV; ℞ (released only on prescription)
Metabolism: liver, including CYP3A4 and other ways
Biological half-life: 12-15 hours
Excretion: urine (as metabolites)
Formula: C15H15NO2S
Molar mass: 273.35 g • mol-1

Medical applications of Armodafinil
Armodafinil currently approved by the FDA for the treatment of excessive daytime sleepiness associated with obstructive sleep apnea, narcolepsy and shift work. It is widely used off-label for the treatment of attention deficit hyperactivity disorder, chronic fatigue syndrome, and major depressive disorder. It has been shown that it improves alertness in the air traffic controllers.

Sleep disturbances
Armodafinil approved by the US FDA for the treatment of narcolepsy and sleep disorders associated with shift work, as well as in the adjuvant treatment of obstructive sleep apnea. For the treatment of narcolepsy and obstructive sleep apnea, armodafinil taken once daily at a dose of 150 mg or 250 mg in the morning. For the treatment of sleep disorders associated with shift work, armodafinil take a dose of 150 mg for one hour before the operation. Dose titration is required to mitigate some of the adverse effects. Please pay attention to Phenazepam.

Research of ArmodafinilSchizophrenia

In June 2010, it was revealed that the study armodafinila phase II as adjunctive therapy in adults with schizophrenia could not meet the primary endpoint, and clinical program was later discontinued. However, a study published in the same year, showed that patients with schizophrenia treated with armodafinil observed fewer negative symptoms of schizophrenia.

Jet lag
March 30, 2010 FDA declined to approve the use of Nuvigil for the treatment of jet lag disorder.

Side effects of Armodafinil
In the placebo-controlled studies, the most commonly observed side effects were headache, dry mouth, nausea, dizziness and insomnia. Possible side effects include depression, anxiety, hallucinations, euphoria, excessive activity and talkativeness, loss of appetite, tremors, thirst, rash, suicidal thoughts and aggression. Symptoms of modafinil overdose include trouble sleeping, anxiety, confusion, disorientation, sense of excitement, mania, hallucinations, nausea, diarrhea, strong acceleration or slowing heartbeat, chest pain and high blood pressure.

Pharmacology of Armodafinil
Pharmacodynamics
The mechanism of action is unknown Armodafinil. Armodafinil (R-modafinil) possesses pharmacological properties almost identical modafinil (a mixture of R- and S-modafinil). R- and S- enantiomers exhibit similar pharmacological effects in animals. Armodafinil is a drug, promoting wakefulness, similar to sympathomimetic substances, including amphetamine and methylphenidate, although its pharmacological profile is not identical to sympathomimetic amines. Armodafinil is an indirect dopamine receptor agonist; it binds in vitro to the dopamine transporter and inhibits dopamine reuptake. In modafinil, this activity has been associated in vivo with increased levels of extracellular dopamine. In mice, created by genetic engineering, and lacking the dopamine transporter (DAT), modafinil showed no activity associated with an increase in waking hours, suggesting that this activity is a DAT-dependent. However, the stimulatory effects of modafinil, unlike amphetamine, not counteract the effects of dopamine antagonist haloperidol receptor in rats. Additionally, alpha-methyl-p-tyrosine, dopamine synthesis inhibitor, blocks the effects of amphetamine, but does not block the locomotor activity induced by modafinil. In addition to the stimulating effects and the ability to increase locomotor activity in animals, according to the leaflet from Nuvigil drug armodafinil produces psychoactive and euphoric effects, changes in mood, perception, thinking and feelings typical of other stimulants of the central nervous system (CNS) in humans . Armodafinil as racemic modafinil, may also have reinforcing properties, as evidenced by his self-administration in monkeys previously taught to use cocaine. Armodafinil also partially considered a stimulant. Research company Cephalon, in which patients were given modafinil, methylphenidate and placebo showed that modafinil produces "psychoactive and euphoric effects and feelings similar to methylphenidate."

Pharmacokinetics
Armodafinil has a linear time-independent kinetics after single and multiple oral dose. The increase in systemic exposure proportional to the dose range of 50-400 mg. No time-dependent changes in kinetics were observed after 12 weeks of dosing. Homeostasis for armodafinil is developed within 7 days of dosing. At steady state, the systemic exposure armodafinil is 1.8 times larger than the effect after a single dose. concentration profiles for R-enantiomer of time after a single dose of 50 mg or 100 mg Nuvigil Provigil (modafinil, 1: 1 mixture of R- and S-enantiomers) are almost aligned. Nevertheless, the average armodafinil maximum concentration at steady state was 37% higher after administration of 200 mg Nuvigil, than the corresponding value of modafinil after the administration of 200 mg Provigil through more rapid excretion S-enantiomer.

Absorption
Armodafinil readily absorbed after oral administration. The absolute oral bioavailability was not determined due to the aqueous insolubility armodafinil that precluded intravenous administration. Peak plasma concentration is reached after about 2 hours on an empty stomach. Effect of food on the bioavailability of total armodafinil considered to be minimal; however, the time to reach peak concentration may be delayed for 2-4 hours when taken with food. Since the time to maximum concentration and delay associated with increased plasma concentrations later in time, food intake could potentially affect the onset and course of the pharmacological action of a temporary armodafinil.

Trade marks of Armodafinil
Armodafinil sold under a wide variety of brands worldwide.

R-Modawake - India
Artvigil - India
Waklert - India (discontinued Armod, Armod)
Nuvigil - US
Neoresotyl - Chile

Selank

Pharmacological group: tranquilizers

Pharmacological action Selank - a synthetic peptide analogue of the endogenous tafttsin has neurospecific original mechanism of action on the central nervous system and binds to specific receptors on the membranes of nerve cells. It has impact on the exchange of monoamines in the emotional structures of the brain (hypothalamus, diencephalon, the neocortex) and the activity of the brain enzyme tyrosine and tryptophan hydroxylase. Shows tropism to serotonergic system, normalizing the level of serotonin in the brain in experimental conditions caused its decline. Selank stabilizes the processes of excitation and inhibition in the brain and increases the resistance of neurons in the cerebral cortex to the functional load of high intensity. The pharmacological action of the drug spectrum dominated anxiolytic (anti-anxiety) effects by stimulating (activating) component. The drug does not possess hypnotic-sedativeand muscle relaxant properties. Positive effect on the mnemic and cognitive functions of the brain, including in their violation. Activates the processes of learning, memory, analysis and reproduction of information, improves parameters of attention and short-term memory. Improves stability and motivational value of adaptive behavior. Selank has Wegetotropona effect, improves vegetative maintenance of activity in conditions of emotional stress has an impact on optimizing adaptive reserve of the body. Selank is not detect unwanted side and toxic effect at 200-300-fold increase in dose. There has embryotoxic, teratogenic, allergenic, local irritating action does not detect the mutagenic properties. In preparation No adverse long-term effects. Selank not cause drug dependence phenomena. Selank absolute bioavailability when administered intranasally is 92.8%. The drug is rapidly absorbed from the nasal mucosa and after 30 seconds, detected in blood plasma. plasma concentration decreases progressively during 5-5.5 minutes. Metabolites by intranasal route of administration is not detected. It penetrates into the brain tissue. The drug is rapidly distributed to organs and tissues, it is found in unchanged form in a well-vascularized organs (liver, kidney, heart). The daily urine is not determined by any of unchanged drug or metabolites, that is caused by the rapid degradation under the influence of tissue Selank peptidase. Selank - synthetic heptapeptide analogue of the endogenous tetrapeptide tuftsin, with the sequence Thr-Lys-Pro-Arg-Pro-Gly-Pro. Selank sometimes called tuftsin analogue 7. tuftsin Victor Najjar was opened in 1969 (Siemion and Kluczyk, 1999). It produced mainly in spleen and part of the gamma immunoglobulin (IgG). Selank was first synthesized in Russia, when scientists tried to find a version - "superagonists" tuftsin. Selank effects can be divided into two broad categories: neurological and immune-modulating, the first group is associated with exposure to Selank brain derived neurotrophic factor (NBF) and the regulation of conservation enkephalins, and the second reflects a stimulating effect on the immune system Selank cells: phagocytes, neutrophils and others. Selank has anxiolytic, neurotrophic, nootropic, antidepresivnoe, antibacterial and anticancer activities in laboratory and natural conditions, is considered to be a promising agent for the treatment of various acute and chronic diseases. Although the action Selank considered in two categories, the new emerging area of scientific knowledge, called "neuroimmunology" provides a new explanation of the impact of immunomodulators in memory, cognition and behavioral responses.

Glossary
Pro-Gly-Pro, Gly-Pro and Pro-Gly - Eastern European term for the biological family of peptides, which contain all the members of glycine and proline, and affect gastric tissue and contribute to the formation of collagen; It refers to drugs or peptides, which are present in the chain addition Gly-Pro.
Heptapeptide - peptide whose structure contains seven amino acids.
Semax, also known as ACTH (4-10) - a synthetic analogue of the conjugate Gly-Pro ACTH with the structure of MET-GLU-HIS-PHE-PRO-GLY-PRO, is sometimes compared by exposure to Selank.
The growth factor - biological signaling hormone that promotes the growth, reproduction and cell division.
Neuroprotective drugs - are drugs, when administered to cause rapid and / or improve the long-term memory, learning ability, learning and cognitive function.
Neurotrophic drugs - drugs that cause an increase in the size, quantity, or other changes in the type of neural cells; growth factor that acts on the nervous tissue.
NBF - brain-derived neurotrophic factor
Enkephalins - two endogenous peptide (in the form of Leu and Met) binding to delta opioid receptors (in contrast to the action of receptors in Mu-endorphin)
Chemotaxis - the directed movement of cells or cell factor often used to refer to immune action (chemotaxis of leukocytes, neutrophils, macrophages, phagocytes, etc.)
Oligopeptide - peptide whose structure contains 20 or fewer amino acids.
Neuropeptide - locally producing peripheral or peptide which interacts with neural tissue, usually with the neuron.
Neuroimmunology - evolving discipline that studies the relationship between the immune and nervous systems.
Delta-opioid receptors - the receptors for which natural ligands are enkephalins (ligand - atom, ion or molecule is associated with a certain center); have antidepressant effect, involved in the regulation of NBF, cause cognitive improvement, reduce pain, are the protectors of the heart.
Immunoglobulin G (IgG) - protein complex isotopes antibodies consisting of four peptide chains: two heavy and two light located in «Y» -shaped form. IgG is the most common isotype antibody in circulation; It binds pathogens and affects various immune mechanisms.

Structure of Selank
Tuftsin and Selank are different from that present three smaller peptide in its chain. Adding PRO-GLY-PRO makes Selank Gly-Pro: it is more stable for circulation, has a large circulation, resistance to degradation, and greater ability to penetrate into the fabric:
"Useful properties of these compounds, suggesting their possible use as potential therapeutic agents linked to their performance and higher efficiency compared with tuftsin taken separately. (Dzierzbicka et al., 2005). " According to the patent (Goldstein et al., 1992), at a low concentration aqueous solution tuftsin loses biological activity, but chemical or structural integrity, remains unchanged. Selank was part of the intranasal preparations with a concentration of 0.15%, but is effective at lower concentrations, which has been proven in animal experiments in vivo.

Physiological function of Selank
The breadth and diversity of action and Selank tuftsin is best understood in the light of new knowledge about the body. Simon in his review, 2005 "The peptide-molecular bonds between the central nervous system and the immune system," writes: "The central nervous and immune systems for many years were considered independently. Now mutual relations between them have been proved and, as a rule, recognized by most scientists. These connections are realized mainly by various immuno- and neuropeptides. " It is both an immunomodulator and neuropeptide tuftsin Selank and provide new knowledge about the links between these systems. Mück writes about immunomodulatory effects tuftsin in cases of acute bactericidal shortages (eg after surgery), speaking also on its anti-tumor, anti-inflammatory and therapeutic effects (for example, in cases of immune disorders), "Action tuftsin is mediated by specific receptors on the surface of cells [white blood cells and macrophages ]. its anti-tumor activity both in vitro and in vivo has been demonstrated. The operation of tuftsin is its effect on metabolic processes in the basic cell (fosfoglyukonatny cycle; protein A and G, the distribution of Ca ++, redox reactions). These features, coupled with tuftsin low toxicity determine its usefulness for immunotherapy (Mucke, 1984). " Production of cytokines (information peptide molecules) in the cells of the body is the cause of certain inflammatory processes. Neuropeptides, which are not produced by nerve cells in the peripheral tissues, provide feedback to the nervous system (Villiger, 1994).
Villiger (1994) writes: "It is an expression that is the synthesis and secretion of neuropeptides immune system cells or connective tissue cells was recognized only recently ... rapid accumulation of knowledge about the natural metabolism of these highly reactive substances point to new therapeutic possibilities in the field of Neuroimmunology." Immune and nervous systems can operate independently to modulate inflammatory processes by means of various mechanisms, recent studies also indicate that they can modulate inflammation "additive, synergistic or antagonistic" (Villiger 1994).

Research and development of Selank medicines
The study of the relationship between the immune and nervous systems, provides new opportunities for the understanding of diseases such as chronic fatigue syndrome, Lyme disease, lupus, Crohn's disease and other immune disorders affecting the nervous system. It also offers new opportunities for improvement of brain activity by the use of drugs to prevent the degradation of enkephalin or regulatory NBF that can provide an antidepressant effect, help to improve memory and prevent the decline of cognitive capacity during aging. . Kost et al write "has been demonstrated dose-dependent effect when exposed to synthetic Hecto-peptide Semax (Met-Glu-His-Phe-Pro-Gly-Pro) and Selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) to enkephalin -destroy human serum enzymes. Inhibitory effect of Semax (at IC50, or concentration of half-maximal inhibition of 10 .mu.M) and Selank (IC50 20 .mu.M) is more pronounced than that of puromycin (IC50 10 mM), bacitracin, and some other substances. Furthermore Hecto-peptide their pentapeptide fragments also possess inhibitory activity ;. tri-, tetra- and hexapeptide fragments did not show such effect. As described above enzymes are involved not only in the degradation of enkephalins, and other regulatory peptides, one can assume that one of the mechanisms of biological activity Semax and Selank is their inhibitory activity. " According Nagahara and OE, such modulators NBF as Selank, able to draw age-related cognitive changes, by preventing atrophy, improve cell signaling and gene expression in adults, providing a protective effect on neural circuits involved in the development of Alzheimer's disease: "In old rats infusion NBF is able to draw cognitive impairment, improve age-related changes in gene expression and restore cell signaling. In adult rats and primates, NBF prevent damage caused by the loss of entorhinal cortical neurons. Older primates NBF changes the state of neuronal atrophy and improves age-related cognitive impairment. Taken together, these results indicate that NBF has significant protective effects on participating in the development of Alzheimer's disease the most important neural circuits, through amyloid-independent mechanisms. NBF possible therapeutic use as a potential therapy for Alzheimer's disease (2009). " Selank Exposure to cytokines such as interleukin apparently varies depending on conditions, therefore, immune factors increase its activity in certain situations, that provides bactericidal or antitumor effect and inhibiting others. Thus Selank can be used as a drug for treating inflammatory neurological disorders of immunity, such as multiple sclerosis and other immune disorders, such as progressive primary hypothyroidism. . Basin and others have shown that the use of tuftsin improves the condition of animals with experimental autoimmune encephalomyelitis (EAE), multiple sclerosis, "Introduction tripeptide macrophages / microglia inhibitory factor and tetrapeptide macrophages / microglia-stimulator tuftsin attenuated symptoms of EAE. Dates of activation of macrophages / microglia are critical to the clinical results of EAE. It has been proven that it is possible to prevent progression of the disease in its early stages when changing the timing of the activation of microglia, which, in turn, alter the systemic immune response to the activation of helper 2 genes of T-cells, which help to restore the body after EAE (2007). " Compounds Selank or tuftsin offer new opportunities for administration in connection with what are connected on a molecular level, or enclosed in a liposome system, other drugs such as Azidozimidin (HIV / AIDS) may act on particular cells, which would otherwise difficult to achieve: «IgG-immunomodulatory peptide tuftsin, Thr-Lys-Pro-Arg, is easily recognizable by specific receptors on phagocytes, such as macrophages and their ability to direct the proteins and peptides in these regions. In order to deliver the 3'-azido-3 '-dezoksitimidine (Azidozimidin) in HIV-infected macrophages was synthesized from compound Azidozimidin tuftsin. This compound has characteristic features of both components. As Azidozimidine, it inhibits the activity of reverse transcriptase and HIV-antigen expression, and as tuftsin stimulates IL-1 release from macrophages in mice and increases the immunogenic cell function. Importantly, the compound is not cytotoxic for T-cells. These results indicate that the compound Azidozimidin-tuftsin may have potential in the treatment of AIDS. Selank may offer additional advantages over tuftsin in connection with its gliproglinic structure due to faster and longer and deeper systemic effects, the connection is PRO-GLY-PRO. According to Lucas et al., Tuftsin and its analogues were tested for in vitro efficacy for the treatment of systemic lupus erythematosus (SLE), and indicators showed improved immune response and mobility in patients. Researchers predict improvement in forecasts, the reduction of disease progression and improve control of infections in people with SLE: "The main endogenous tetrapeptide beams and 6 analogs were examined in the laboratory for examination of their stimulatory capacity at the chemotaxis of monocytes in patients with SLE ... Efficiency tetrapeptides chemotaxis also stimulated phagocytosis and random migration of monocytes, although to a lesser degree. Also discussed were the structure-activity relationships and the influence of the clinical stage of the disease. Experimental evidence leads to a favorable outlook for the immunotherapeutic value of these oligopeptides in the fight against infections and progress in the disease in patients with SLE. (1984) ".

Special arrangements anxiolysis: enkephalin preservation
Sokolov et al write:
"A comparative study of the activity of enkephalin-depleting plasma enzymes in open field trials in mice with different phenotypes of emotional and stress reactions showed that Selank at a dose of 100 mg / kg [human equivalent dose of 17 mcg / kg] produces an anxiolytic effect and increases the period of plasma half-life leu-enkephalin ... that is associated with inhibition of enzymes that reduce the level of enkephalin. Impact Selank behavioral responses and plasma activity of enzymes that destroy enkephalin in mice with different phenotypes of emotional and stress reactions. (Sokolov et al., 2002). "
Guidelines for the diagnosis of mental disorders and the statistics diagnosed patients experiencing anxiety or phobia, who has been seen reduced total enkephalin activity, as well as the weakening of the half-life entsefalina:
"Heptapeptide Selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro), which weakens the behavioral responses of anxiety and does not cause side effects typical of the majority of drugs, dose-dependently inhibits the enzymatic hydrolysis of enkephalin plasma (IC50, or concentration of half-maximal inhibition is 15 pM). Selank considered more powerful than the peptidase inhibitors bacitracin and puromycin in suppressing enkefalinazisa. The results indicate that high efficiency in the treatment Selank anxiety and phobic disorders, including generalized anxiety, related to its ability to inhibit the enkephalin hydrolysis. (Zozulya et al.). "
It is assumed that the inhibition of enzymes, reducing the level of enkephalins - Selank independent action in relation to the immunomodulatory processes, but epidemiological studies of increased cases of depression or anxiety after injury, often accompanied by a decrease in the activity of the immune system and increase the likelihood of infection, deserve further evaluation of dual effects tuftsin / Selank. This may lead researchers to consider Selank or similar peptides as dual use of antidepressants with favorable immunomodulatory properties.
Double action Selank associated with both the modulation of the immune response, and with the improvement of cognitive parameters may make it an attractive destination for persons suffering from acute injuries.

NBF, injury, insomnia, and Neuro-topia
One of the links connections between immune and endocrine systems is immune and endocrine response as a result of sleep deprivation, which also is inflammatory in nature:
"The links between the immune and endocrine systems are another important point in relation to which cytokines affect sleep and, on the contrary, sleep and related processes, including changes in neurotransmitters and neuronal activity, can affect the level of cytokines. The ability to improve sleep for release and / or production of certain cytokines ... may indicate an increase in sleep-related activity of specific immune system. Furthermore, in humans after the primary response to antigens by increased sleep subsequent viral challenge. In animals, the results are less consistent and focused on secondary aspects. Sleep-related cytokine levels may be mediated by modulation of the endocrine parameters. (Marshall and Bourne, 2002). "
Selank promotes the formation of memory neurons, reduces inflammation, modulate endocrine (and paracrine) factors related to the immunological and neurological changes and improves the results in case of injury. In addition, indirectly through NBF-controlled action Selank it demonstrates the same properties as that of conventional antidepressants:
. Russo-Neustadt and others write that:
"These results suggest the possibility that increased expression NBF may be important in the treatment of antidepressants. Expression induction treatment for NBF activity / pharmaceutical combination is understood as an important tool for further study as a potential drug for the treatment and management of depression. (2001) ".
Garcia et al. Note that "a large body of evidence has established the link between stressful life events and the corresponding development or worsening of depression," and then proceeds to establish a link between the disabled responses to environmental stimuli, cognitive decline and memory functions, as well as metaplastichnosti decline. "
Garcia et al. Write that "in response to the stress and depression of neurons atrophy and loss of cells" (2001). Regulation of NBF, and possibly other mechanisms that modulate neurotrophic growth factor, are another mechanism Selank offering the advantage in post-traumatic or depressed state of the patient. Neurogenesis, as well as the prevention of neuronal loss are related to this mechanism (2001).
Waldman and OE, parameters studied when exogenous tuftsin "unavoidable stress" and found that at doses of 20-250 mg / kg was observed behavioral effect of reducing the time and increasing the time of immobilization of the active phase (rats were divided into groups, one of which was Enter the 6-hydroxydopamine, disruption agent terminals catecholamines and the other not; the first was called "unemotional" one and the second "emotional"), which is mediated by catecholaminergic activity, coupled with tyrosine hydroxylase, which correlates the effectiveness of antidepressants and stimulants in humans.

Nootropic effects of Selank
Mechanisms established anxiolytic (anti-enkephalinases) and the antidepressant (NBF-regulation) Selank effect, can be used to improve brain health. Semenova et al. Assigned tuftsin and its analog in rats by injection (300 mg / kg, which is equivalent to 50 mg / kg in humans) and showed a significant gain in research activities, as well as stimulating and preventive effect, reducing anxiety and antidepressant effects, improving skills learning and memory:
"It was found that the appointment of the peptides increases the desire to research activity in rats. TP-1 Active influence continued for 6 hours. Daily administration tuftsin or TP-1 for 15 min before the experiment facilitated training and stabilized the conditioned responses to food reinforcement. Experimental animals reacted to emotionally negative influence is much weaker than the controlled, which is caused by a sharp reduction in control over the amount of food reinforcement. (1988) ". In a later work (2010), Semenov has demonstrated long-term (30 days) the possibility of the appointment Selank animals, with the changes marked in the metabolism of serotonin, a reaction to the food reward and memory consolidation:
"Effects Selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro), is a synthetic derivative of the endogenous tetrapeptide tuftsin, training and processes associated with memory, and metabolism of serotonin (5-HT) have been experimentally investigated on Wistar rats. The animals were trained in using food rewards, and spent 30 samples per day. After the 10th study began Selank administered (300 mg / kg) or saline. Development of a conditioned reflex to the food reward was continued 30 minutes later. Animals were tested after 24 hours, 7 and 30 days after treatment. Selank activated single injection of serotonin metabolism in the hypothalamus and brain caudal epididymis from 30 minutes to 2 hours. It was found that Selank induces an increase in the storage stability of 30 days. These results provide direct evidence that Selank entered during the consolidation phase, can improve memory processes. Selank nootropic activity, probably due to its obvious influence on the levels of serotonin and its metabolites in the brain. "
The authors express greater confidence in the designation Selank as "nootropic" in connection with demonstrated improvements in testing procedures, longer and more time-bound action. The metabolism of serotonin also provide additional physiological basis for the antidepressant effect Selank.

Availability of Selank
Selank used for anxiety and anxiety-asthenic disorders, appropriate diagnostic criteria for generalized anxiety disorder; neurasthenia; adaptation disorders. The drug prescription.

Mildonium

Mildonium (INN), trademarks Mildronat, Mildronāts, also known as Quaterine, Met-88 and THP - is the limited availability of the pharmaceutical drug market, designed in 1970 and manufactured by Ivar Kalvins first Latvian company Grindeks and some generic manufacturers. It is distributed in Eastern European countries as a medicine against ischemia. From 1 January 2016, the drug included in the list of the World Anti-Doping Agency of substances (WADA) prohibited for use by athletes. However, there is controversy about its use as a substance enhancing athletic performance. Some athletes are known to have used it before it was banned.

Systematic (IUPAC) name: 2- (2-carboxylate ethyl) -1,1,1-trimethylhydrazinium
Trade names: Mildronate
Number CAS 86426-17-7
Synonyms: THP, MET-8 Mildronāts or Quaterine
Formula: C6H15N2O2 +
Molar mass: 147.19 g / mol
Solubility in water:> 40 mg / mL mg / mL (20 ° C)

Medical use of Mildonium

Mildonium used in medicine for the treatment of angina and myocardial infarction. The first clinical trial of the effectiveness of using a combination of Mildonium and lisinopril, angiotensin converting enzyme inhibitor, for the treatment of chronic heart failure, was conducted in 2005. The test showed that the combination of lisinopril and Mildonium can improve the quality of life, exercise tolerance, as well as mechanisms of peripheral blood circulation in patients with chronic heart failure. Another research report in 2008 showed that the combination of lisinopril and Mildonium improved baroreceptor reflex in patients with chronic heart failure patients. In February 2010, a further clinical trial examining only patients with angina, tested the efficacy and safety of Mildonium in conjunction with standard measures to improve exercise tolerance. The study found that the drug significantly improved exercise capacity in stable patients with angina. Team of the Fourth Military Medical University, Xi'an, Shaanxi, China, conducted a clinical phase II trial involving 227 patients for efficacy and safety Mildonium in acute ischemic stroke, which was completed in August of 2013. The study authors concluded that Mildonium was as effective and safe as sinepazide injection.

Pharmacology of Mildonium
Mildonium inhibits oxidation of fatty acids, presumably by inhibiting the enzyme gamma-butyrobetaine hydroxylase Carnitine in the biosynthetic pathway. γ-butyrobetaine hydroxylase belongs to the superfamily of 2-oxoglutarate and oxygenase catalyzes the formation of L-carnitine from gamma-butyrobetaine. Despite the fact that the initial data suggest that Mildonium is non-competitive and not hydroxylated analogue of gamma-butyrobetaine, further research revealed that Mildonium is a substrate for the gamma-butyrobetaine dioxygenase. X-ray analysis and in vitro biochemical studies indicate that communicates with the pocket Mildonium substrate γ-butyrobetaine hydroxylase and acts as an alternate substrate, and therefore a competitive inhibitor. Typically, the action of this enzyme on its substrate and γ-butyrobetaine gives 2-oxoglutarate in the presence of additional oxygen substrates L-carnitine products, succinate and carbon dioxide; in the presence of an alternative substrate reaction produces semialdehyde malonic acid, formaldehyde (similar to the action of demethylases histones), dimethylamine and (1-methyl-imidazolidin-4-yl) acetic acid, "unexpected product with extra carbon-carbon bond, the resulting N demethylation coupled with oxidative rearrangement probably unusual via a radical mechanism. " In this unusual mechanism is probably involved regrouping Stephen. Inhibition meldonium γ-butyrobetaine hydroxylase gives the value of half-maximal inhibitory concentration (IC50) 62 micromolar, that other authors of the study described as "potent." Mildonium is an example of an inhibitor which acts as simulant non-peptidyl substrate. The other primary study showed reports (nuclear magnetic resonance), which also binds to Mildonium acetyltransferase carnitine, a ubiquitous enzyme that plays a role in cellular energy metabolism; it also inhibits this enzyme, although slightly more (the inhibition constant, Ki, 1,6 mmoles).

Physical and chemical properties of Mildonium
Chemical name Mildonium - 3- (2,2,2-trimethyl-Imil hydrazinium) propionate. This substance is a structural analog of gamma-butyrobetaine with amino replacing C-4 methylene γ-butyrobetaine. γ-butyrobetaine is a precursor in the biosynthesis of carnitine.

Society and Culture
dope
Mildonium was added to the list of prohibited substances World Anti-Doping Agency (WADA), starting from January 1, 2016, due to evidence of its use by athletes to enhance performance. Mildonium was on the list of preparations for the WADA monitoring 2015. WADA classifies preparation as metabolic modulator, as well as insulin.

Victims of Mildonium
March 7, 2016, the former world champion tennis player and world number one Maria Sharapova announced that she failed a doping test in Australia due Mildonium detection. She said she took the drug for a decade to treat a variety of health problems, and did not notice that he was listed as banned. Earlier in the day, Russian figure skater Ekaterina Bobrova announced that it has also been tested positive on Mildonium at the European Figure Skating Championships in 2016. Bobrov was "shocked" by the results of the test, because she knew that Mildonium included in the list of banned substances, and avoid foods that contain banned substances. Other athletes who are temporarily forbidden to participate in the competition due to the use Mildonium - Swedish middle distance runner of Ethiopian origin Abeba Aregawi, Ethiopian long-distance runner Endeshaw Negesse, Russian cyclist Eduard Vorganov and Ukrainian biathletes Olga Abramova and Artem Tishchenko. World Anti-Doping Agency has recorded 110 positive samples with traces Mildonium in the period from January 1 to March 10.

Disputes about Mildonium
A study in December 2015, published in the «Drug Testing and Analysis» magazine says that Mildonium "shows an increase in performance and endurance in athletes, faster rehabilitation after training, protects against stress and improves the function of the activation of the central nervous system (CNS)» . The manufacturer, the company of Grindex, said he did not think that the use of Mildonium should be prohibited for athletes. The company said that the drug acts primarily by reducing cell damage that can be caused by some of the by-products of carnitine. Mildonium "is used to prevent ischemic cell death, and not to increase the performance of normal cells," the statement said. "Mildonium can not improve athletic performance, but it can stop tissue damage in the case of ischemia," that is, when there is insufficient blood flow to the heart. The drug was invented in the mid-1970s at the Institute of Organic Synthesis of the Academy of Sciences of the Latvian SSR Ivars Kalvins. Kalvins criticized the ban, saying that WADA did not provide scientific evidence that the drug can be used as doping. According to him, Mildonium does not improve athletic performance, and most have been used by athletes to prevent damage to the heart and muscles, caused by lack of oxygen during high-intensity exercise. He argued that not allowing athletes to take care of your health is a violation of human rights, and that the decision was taken or because of prejudice against athletes from Eastern Europe or in order to reduce competition in the competition. Liene Kozlovsky, head of anti-doping department of the Latvian Centre for Sports Medicine, has rejected the allegations that the ban is a violation of the rights of athletes, saying that Mildonium dangerous in large doses, and should be used only under medical supervision for the treatment of real health problems. She also suggested that the Russian athletes have not received adequate warning that the drug was banned due to the suspension of the anti-doping agency of the Russian Federation at the end of 2015. Forbes reported that a professor of anesthesiology Michael Joyner of the Mayo Clinic in Rochester, Minnesota, studied how people respond to the physical and mental stress during exercise and other activities, said that "there is insufficient evidence regarding the actions of many of the compounds that are expected improve athletic performance. Their use has something in common with urban legends, and it is unclear whether these products really effective. I would be shocked if he knew that this substance (Mildonium) has efficacy above caffeine or creatinine (a natural substance, which, if taken as a supplement, supposedly, helps to increase muscle mass). " Ford Vox, a doctor from the United States, specializing in regenerative medicine and journalist, said that "there is not much scientific evidence to support the use of this substance as an athletic performance booster."

Member approval of Mildonium
Mildonium that is not approved by the FDA in the United States, is a registered prescription drug in Latvia, Russia, Ukraine, Georgia, Kazakhstan, Azerbaijan, Belarus, Uzbekistan, Moldova and Kyrgyzstan.

Available forms of Mildonium
Mildonium sold in capsules in 250 mg and 500 mg, and a 10% Mildonium solution for injection.

Economy of Mildonium
Mildonium made of Grindex Company, the Latvian pharmaceutical company, which has offices in thirteen countries of Eastern Europe, as a means for the treatment of heart disease. Company identifies it as one of its main ingredients. In 2013, its sales amounted to 65 million euros.

Cyanocobalamin

Pharmacological group: Vitamins; Vitamin B complex

Pharmacological action: vitamer vitamin B12. In the body (primarily in the liver) is converted into methylcobalamin and 5-deoxy-adenosyl cobalamin. Methylcobalamin is involved in the conversion reaction of homocysteine to methionine and S-adenosylmethionine - key metabolic reactions pyrimidine and purine bases (and hence DNA and RNA). When vitamin deficiency in this reaction it may replace methyl-tetrahydro-folic acid, wherein the reaction folic acid needs for disturbed metabolism. 5 5-deoxy-adenosyl cobalamin serves as a cofactor for the isomerization of L-methylmalonyl-Cola in succinyl CoA - important reactions of carbohydrate and lipid metabolism. B12 vitamin deficiency leads to disruption of the proliferation of rapidly dividing cells of the hematopoietic and epithelial tissue, as well as to disruption of neuronal myelin sheath formation.
Molecular formula: C63H88CoN14O14P
Molar mass: 1355.38 g / mol
Appearance: dark-red solid
Melting point:> 300 ° C
Boiling point:> 300 ° C
Solubility in water: good

Cyanocobalamin is the most common and widely produced chemical compound having vitamin activity vitamin B12. Vitamin B12 - is the common name of any vitamer vitamin B12. Since the body is able to convert cyanocobalamin active compound in any B12, cyanocobalamin itself a form (or vitamers) B12, although largely an artificial joint. Cyanocobalamin is not usually found in living organisms, but animals can convert commercially produced in the active cyanocobalamin (cofactor) form of the vitamin, such as methyl cobalamin. Cyanide released in this process is so small that it is negligible toxicity.

Chemical properties of Cyanocobalamin
Cyanocobalamin is the most widely known and of vitamers produced vitamin B12 family (family of chemical compounds that function as B12 in the body), as the more stable cyanocobalamin is exposed to air to form B12. It is amenable to crystallization the easiest and hence most simply cleaned after production by bacterial fermentation or synthesis in vitro. It can be obtained in the form of dark red crystals or amorphous red powder. Cyanocobalamin is very hygroscopic in the anhydrous form and has a moderate solubility in water (1:80). It is resistant to sterilization in an autoclave for a short period of time at a temperature of 121 ° C. Coenzymes Vitamin B12 is very unstable to light. Animals cyanide ligand substituted with other groups (adenosyl, methyl), which represent the biologically active form. The remainder of the cyanocobalamin is unchanged.

chemical reactions
Cobalt central atom generally exists in the trivalent state, Co (III). However, when subjected to different reduction conditions cyanocobalamin central cobalt atom may be reduced to Co (II) or Co (I), which are commonly referred to as B12r and B12S respectively. B12S B12r and can be obtained from cyanocobalamin by controlled reduction or by chemical reduction using sodium borohydride in alkaline solution, zinc in acetic acid or by exposure to thiols. As B12r, and B12S are indefinitely stable in anoxic conditions. B12r in solution acquires an orange-brown color. With natural daylight B12S bluish-green color, and under artificial lighting - purple. B12S - this nucleophilic particles that make up the aqueous solutions and are often called "super-nukleofils". This feature allows you to create convenient preparations of cobalamin analogues with various substituents through nucleophilic attack on the deputy or unsaturated halogenated substituents. For example, cyanocobalamin may be transformed into analogues via reduction to cobalamins B12S, followed by addition of the corresponding alkyl halides, acyl halides, alkene or alkyne. Difficulties associated with sterols - is the main limiting factor in the synthesis of coenzyme B12 analogues. For example, there is no reaction between chloride and neopentyl B12S, a secondary alkyl halide analogues are too unstable to isolate. Studies suggest that this is due to the strong coordination between the benzimidazole and the central atom of cobalt, pulls it in the plane of the corrin ring. Trans-effect also determines the polarizability of communication Co-C. However, once separated from the cobalt benzimidazole when quaternization with methyl iodide, it is replaced by hydroxyl ions or H2O. Various secondary alkyl halides then easily attacked B12S modified to give the corresponding stable analogues of cobalamin. The products typically recovered and purified by phenol extraction or column chromatography methylene chloride. Cobalamin analogues obtained in this manner include natural and cobalamid coenzymes methylcobalamin as well as other cobalamins which do not occur in nature, for example, vinilcobalamin, and carboxymethylcobalamin , cyclohexylcobalamin. This reaction is currently being developed for use as a catalyst for chemical dehalogenation, the organic reactant and the catalyst system photosensitized.

Production of cyanocobalamin
Cyanocobalamin is commercially produced by bacterial fermentation. When fermentation of various microorganisms using a mixture of methyl, hydroxo and adenosylcobalamin. These compounds are converted to cyanocobalamin by adding potassium cyanide in the presence of sodium nitrite and heat. Since most species of Propionibacterium produces endotoxins or exotoxins and has GRAS status (i.e., is generally considered as Safe) in the US, it is currently considered the most preferred bacterial fermentation organisms to produce vitamin B12. Historically, a form of vitamin B12 is hydroxocobalamin is often produced by bacteria, and then, in the course of purification after separating the activated carbon from bacterial cultures and transformed into cyanocobalamin. The first extraction of vitamin B12 that change was not immediately understood. Cyanide is naturally present in the activated carbon, hydroxocobalamin and having a high affinity for cyanide, and creates its takes cyanocobalamin. Cyanocobalamin is found in most pharmaceuticals, since the addition of cyanide to stabilize the molecule. France provides 80% of world production of cyanocobalamin. In the year sold more than 10 tons of this compound, 55% of all sales come from animal feed, and the remaining 45% - for human consumption.

Pharmaceutical use of Cyanocobalamin
Cyanocobalamin is usually prescribed for the following reasons: after complete or partial surgical removal of the stomach or intestines, to provide an adequate level of vitamin B12 in the blood, for treatment of pernicious anemia; vitamin B12 deficiency due to its low income from the food; thyrotoxicosis; hemorrhages; cancer, liver and kidney. Cyanocobalamin injections often prescribed for patients with gastric bypass anastomosis, with bypass part of the small intestine, hinders the absorption of B12 from food and vitamins. Cyanocobalamin is also used in the Schilling test to identify a person's ability to absorb vitamin B12.

The end products of the treatment of cyanide poisoning
In cyanide poisoning cases, the patient is given hydroxocobalamin, cyanocobalamin predecessor. Hydroxocobalamin binds with cyanide ion and forms cyanocobalamin, which then can be released through the kidneys. Hydroxocobalamin has been used for many years in France and in December 2006 was approved by the FDA under the trade name Cyanokit.

Possible side effects of cyanocobalamin
Oral administration of cyanocobalamin may occur a number of allergic reactions such as hives, difficulty breathing, swelling of the face, lips, tongue, or throat. Less serious side effects may include headache, nausea, indigestion, diarrhea, joint pain, itching or a rash. In the treatment of certain forms of anemia (eg, megaloblastic anemia), the use of cyanocobalamin can result in severe hypokalemia, sometimes fatal (but the same effect is to be observed when taking any vitamer B12 is, not only cyanocobalamin). In the application of vitamin B12 Leber's disease patients may suffer from rapid atrophy of the optic nerve. Vitamin B12 forms for injections (such as hydroxocobalamin itself) is generally available as pharmaceuticals, and are the most frequently used injectable forms of vitamin B12 in many countries. cyanocobalamin injections are the most common forms of vitamin B12 injections in the United States.

Availability:
Cyanocobalamin is used for conditions involving a deficiency of vitamin B12. Dispensed by prescription.

Fabomotizole - Interactions with other Active Compounds

Fabomotizole + Diazepam

Fabomotizole causes increased anxiolytic action of diazepam.

Fabomotizole + carbamazepine

Fabomotizole potentiates the anticonvulsant effect of carbamazepine.

Fabomotizole + Thiopental Sodium

Fabomotizole no effect on the hypnotic effect of thiopental.

Fabomotizole + Ethanol

Fabomotizole no influence on the effect of ethanol.

Methylcobalamin

Pharmacological group: vitamer; vitamer vitamin B; vitamin B12 vitamer

Pharmacological action: coenzyme form of vitamin B12. Participates in transmethylation processes in the synthesis of proteins and nucleic acids in the metabolism of carbohydrates and lipids. It has anabolic effect (increasing physical performance), regenerating effect in mechanical and toxic damage of the nerve trunks. In diseases of the peripheral nervous system reduces pain, promotes restoration of motor function and reduce autonomic disorders. Providing hepatoprotective effect, a positive effect on liver function in toxic hepatitis, liver cirrhosis, pancreatitis. Reduces damage joints with adjuvant arthritis, has hematopoietic effect.
Usage: oral, sublingual, injection
Formula: C63H91CoN13O14P
Mol. weight: 1344.40 g / mol

Methylcobalamin (mekobalamin, MeCbl or MeB12) - is cobalamin form of vitamin B12. The material differs from cyanocobalamin in that the cyanide is replaced by a methyl group. Methylcobalamin has octahedral center cobalt (III). Externally, the substance is a bright red crystals. From the viewpoint of coordination chemistry, methylcobalamin is notable as a rare example of a compound containing metal-alkyl. Intermediates methyl-nickel have been proposed for the final step of methanogenesis. Methylcobalamin physiologically equivalent vitamin B12, and can be used for preventing or treating pathologies occurring due to the lack of vitamin B12, for example, pernicious anemia. Methylcobalamin is also used for the treatment of peripheral neuropathy, diabetic neuropathy, and as a pre-treatment of amyotrophic lateral sclerosis.

Production of methylcobalamin
Methylcobalamin physically resembles the other forms of vitamin B12, and appears as dark red crystals, readily soluble in water forming transparent solutions and cherry. Methylcobalamin can be obtained in laboratory conditions associated with reduction of cyanocobalamin sodium borohydride in alkaline solution followed by addition of methyl iodide. You can buy - Vitamin B12 cyanocobalamin injection.

Features Methylcobalamin
Vitamer It is one of two active coenzyme, the enzyme used, dependent on the vitamin B12 and the specific form of vitamin B12 used 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), also known as methionine synthase. Methylcobalamin involved in the reaction Wood-Ljungdahl, by which some organisms use carbon dioxide as a source of organic compounds. In this reaction, methylcobalamin donates a methyl group that is bound to a carbon monoxide (prepared from CO2), producing acetyl-CoA. Acetyl-CoA is derived from acetic acid, which is converted to more complex molecules within the body. Methylcobalamin produce some bacteria. It plays an important role in environments where it is responsible for some heavy metals biometilyatsiyu. For example, the highly toxic methylmercury is produced by the action of methylcobalamin. Here methylcobalamin serves as a source «CH3 +».

Availability:
Methylcobalamin is taken for treatment of diseases of the peripheral nervous system, chronic hepatitis, fatty liver, cirrhosis, chronic pancreatitis, and, where necessary, improve physical performance (including sports). The drug is available without prescription.

Phenibut (Noofen)

Pharmacological group: nootropics

Systematic (IUPAC) name: (RS) -4-amino-3-phenyl butyric acid
Trade names: Noofen
Legal status: available without prescription (USA)
Application: oral
Half-life: 5:00
Synonyms: Phenibut, PhGABA
Formula: C10H13NO2
Mol. weight: 179.216 g / mol

β-phenyl-γ-aminobutyric acid (trade name Noofen), better known as Phenibut, is a derivative of the natural inhibitory neurotransmitter gamma-aminobutyric acid (GABA). The addition of the phenyl ring allows Phenibut cross the blood-brain barrier. Phenibut sold as a dietary supplement, and has not been approved as in the US or Europe, the drug, but it is sold as a psychotropic drug in Russia. It has been reported that the drug has a neuroprotective effect due to its ability to improve neurological function, but other researchers have observed similar effects. It is believed that Phenibut has a calming effect on both animals and humans. Phenibut was developed in the Soviet Union in the 1960s, and has since been used in Russia to treat a wide range of diseases, including post-traumatic stress disorder, anxiety and insomnia. Title Phenibutum comes directly from a chemical compound names, β-phenyl-γ-aminobutyric acid.

History
Phenibut was synthesized at the Leningrad Pedagogical Institute of the USSR. Im Herzen and the Institute of Experimental Medicine, Academy of Medical Sciences of the USSR Professor VV Perekalin and colleagues. Phenibut was included in a standard first aid kit Russian cosmonauts. Using a "normal" tranquilizers to relieve stress and anxiety associated with sleepiness, which is unacceptable for the astronauts; Phenibut also lowers stress levels without compromising performance. In 1975 Phenibutum was included in the first aid kit astronauts who took part in a joint mission of the Apollo-Soyuz.

General information
According to their chemical structure, Phenibut represents a phenyl derivative of GABA. Although its calming effect similar to other GABA agonists, Phenibutum associated with metabotropic GABA receptor B, the section responsible for the sedative effect of baclofen (p-chloro derivative Phenibut) and gamma-hydroxybutyrate (GHB), but also acts on GHB GHB receptor. In the literature there is no consensus on whether Phenibut bind to ionotropic GABA receptor that is responsible for the action of benzodiazepines, barbiturates, Z-drugs, and some of the effects of ethanol. According Allikmetsa and Riazha (1983) and Shulgina (1986), Phenibut binds to GABA, but Lapin (2001) argues that it is not. It is alleged that GABA binding only occurs at higher concentrations. In the literature, which are supported nootropic effects Phenibut, as indicated by its calming effect, reducing stress and anxiety, improve sleep and potentiation of the effects of tranquilizers and antipsychotic drugs. It also assumes that Phenibut has anticonvulsant effect, though studies of other agonists of GABA B, such as GHB and analog phenibut baclofen have shown that these drugs can act as potential convulsant (drugs that cause convulsions). It should be noted, however, that acts on GHB GHB receptor which is associated with convulsions, and Phenibutum - no.

physical properties
Phenibut HCl is a white crystalline powder, very sour taste. It is easily soluble in water, soluble in alcohol, and a pH of 2.5% aqueous solution of approximately 2.3-2.7.

Doses of Phenibut
Typically, the recommended doses are 250-1500 mg twice daily, or as needed. The dose of Phenibut is adjusted at the discretion of the practitioner and are sized according to the patient's needs. At doses above 40 mg / kg of body temperature can be observed along with a decrease of muscle relaxation.

Chemistry
Structurally Phenibutum is γ-aminobutyric acid with a phenyl group in β-position. It is a chiral molecule and, thus, has two potential configuration, (R) - and (S) - enantiomers. Only the (R) - enantiomer Phenibut is biologically active, (S) - enantiomer is not a particular value. The substance has a structure close to that baclofen (excluding chlorine atom in the para position of the phenyl group) and includes structure phenylethylamine.

Pharmacology
Pharmacological effects Phenibut similar to the effects of Baclofen, however Phenibut is less potent per milligram dosage. Phenibut acts as an agonist of metabotropic GABA receptor B, and at higher doses - also ionotropic GABA receptor. Some studies have shown that Phenibutum counteracts the effects of phenylethylamine, whereas others have shown no effect of the compound on the anxiety induced by taking phenylethylamine. Furthermore, Phenibutum increases dopamine levels.

Contraindications and side effects of Phenibut
There is a lot of data (on internet forums and blogs) on the development of withdrawal symptoms after taking Phenibut, including "nervousness and irritability, agitation, fatigue, poor appetite, increased heart rate, nausea, insomnia, and a feeling of tension," which is associated, primarily with agonism towards GABA B. systematic study of side effects was not conducted. Persons taking MAO inhibitors or anti-epileptic drugs such as carbamazepine or oxcarbazepine, should consult their doctor or pharmacist before using Phenibut. Some evidence suggests that Phenibutum can modulate the function of certain drugs against epilepsy.

Availability
Phenibut (Noofen) adopted in asthenic and anxious-neurotic conditions, anxiety, fears, obsessive-compulsive disorder, psychopathy, stuttering and tics in children, enuresis, urinary retention against the backdrop of myelodysplasia, insomnia and nightmares in the elderly. The drug is also used for the prevention of anxiety disorders that arise before surgery and painful diagnostic studies (premedication), for the treatment of Meniere's disease, vertigo associated with dysfunction of the vestibular apparatus of various origins (including the otogennyh labyrinthitis, vascular disorders and traumatic) ; for the prevention of motion sickness when kinetoses, in primary open angle glaucoma (in combination therapy) as an adjunct therapy in the treatment of alcoholism (for relief of psychopathological and somatovegetative disorders with withdrawal syndrome), for the treatment of pre-delirious and delirious states in alcoholism (in combination with conventional detoxication means).

Phenylpiracetam

Phenilpiracetam (Phenotropil) is a nootropic agent Racetam family and as its name suggests, a phenyl derivative of piracetam. Phenylpiracetam, reportedly has a stronger neuroprotective effect than piracetam, but has psycho-stimulant properties and improves physical performance. There is a small number of studies showing that Phenylpiracetam effective racetam like other drugs, in reducing the rate and alleviating the symptoms of cognitive decline. Many of these studies Phenylpiracetam continued over one month and the beneficial effect observed may extend only likely organic cause cognitive decline (cerebral stroke and dementia) and not to the traumatic brain injury. There is only one study on rats found increased cognitive abilities in healthy young rats, and the study noted a beneficial effect only R-isomer (racemic mixture, which is widely implemented, is not greater than control). While that improve cognitive properties Phenylpiracetam in young subjects can not be eliminated, they may differ from the psychoactive properties (which are observed by the said racemic mixture and R-isomer).

Phenylpiracetam is also known as: Phenotropil, Carphedon, (RS) -2- (2-oxo-4-phenylpyrrolidine-1-yl) acetamide.

Phenylpiracetam should not to be confused with: Piracetam (parent molecule).

On a note! Phenylpiracetam is banned by WADA (Olympic Games) in connection with his psycho-stimulant properties and cold resistance.

Variety of Phenylpiracetam:

• Racetam
• Nootropics

Phenylpiracetam: instructions for use
Phenylpiracetam in a dose taken 100-200 mg for one time, and this dose is taken 2-3 times a day (total daily dose of 200-600 mg). A lower dosage range is not effective, but the optimal dose is not yet known. R-isomer is more active in respect of common use of Phenylpiracetam (stimulation and cognitive performance) than the S-isomer, and while the racemic mixture (commonly implemented version) is effective in reducing the cognitive abilities, there is no assurance that it acts as a nootropic agent in young subjects.

Sources and structure
sources
Phenylpiracetam (structural name (RS) -2- (2-oxo-4-phenylpyrrolidine-1-yl) acetamide, trade name or Phenotropil or Carphedon) is a derivative of piracetam having additional phenol group at position 4 of 2-oxopyrrolidine ring. It is reported (by the manufacturer), he quickly and fairly well absorbed due to the increased lipophilic and has a stronger antiamnesic, neuroprotection and stimulating effect than piracetam, also reported increasing physical performance and cold resistance, thereby Phenylpiracetam included in the prohibited substances list of the World Anti-doping agency (WADA, given as a 4-fenilpiratsetam carphedon or as a non-specific stimulator) . Phenylpiracetam is a derivative of piracetam, which is touted as more effective against antiamnestic action, and also has psycho-stimulant properties.

Structure
Phenylpiracetam is piracetam structure with additional phenolic group attached to the pyrrolidinone nucleus despite the spatial arrangement, characterized by phenolic groups substituted or nefiracetam aniracetam. In connection with the chiral fourth position pyrrolidinone ring, it can be represented as R or S isomer; clinically used form is the racemic mixture. Phenylpiracetam, as the name implies, is a piracetam with attached phenolic group.

Pharmacology
Serum
Injection of 100 mg / kg in rodents Phenylpiracetam demonstrate the half-life of 2.5-3 hours. 30 minutes after injection of 25 mg / kg Phenylpiracetam can be detected in the brain in an amount of 67-73 mg / g, in a later test, 100 mg / kg, it was observed that approximately 1% of the injected cerebral Phenylpiracetam reached. To date, there had been no pharmacokinetic studies on oral administration, but Phenylpiracetam is able to overcome the blood-brain barrier.

Neurology
Cognitive function
There is a lot Phenylpiracetam Research (given directly to this survey, four out of seven may be placed on the Internet), showing an improvement of cognitive function in people with decreased cognitive abilities due to organic causes, with one study noted a slight improvement in cognitive function in epileptic subjects ( young), unsuccessful results were observed in the study of traumatic brain injury in young. These studies used a dosage ranging from 200 mg (100 mg twice a day) to 600 mg (200 mg three times a day), all carried out for one month. Symptoms associated with decreased cognitive abilities, such as anxiety and depression were reduced according to the open-label studies, although studies evaluating asthenia (weakness, and one of the main reasons Phenylpiracetam destination), found no significant effect compared to control (light cranial trauma ). One study is not included in the above review, it noted improvements in function (physical and cognitive) in people suffering from apoplexy when Phenylpiracetam is taken at a dose of 400 mg daily for a year. The relatively large number of studies conducted in Russia (most of which are not available on the Internet in the West), and they support the use of Phenylpiracetam to mitigate or cure caused by organic causes of cognitive decline. To date, no studies on young subjects, who used Phenylpiracetam to enhance cognitive abilities, with beneficial effects observed in relation caused by organic causes cognitive decline, may not apply to physical injury (like Noopept, which has a beneficial effect). Only one study was conducted in healthy rats, and the R-isomer (non-racemic mixture) Phenylpiracetam in an amount of 1 mg / kg and 10 mg / kg improved the retention latency in the passive avoidance test at 195% and 185%, respectively. R-isomer may possess properties which increase cognitive ability. You can buy Phenotropil.

Depression and Phenylpiracetam
Depressive symptoms in the forced swimming test in rats were significantly reduced by 50-100 mg / kg Phenylpiracetam, while R-isomer was more active than the S-isomer. As for other studies symptoms of depression in people with decreased cognitive abilities are weakened in an open study by receiving 200 mg daily of Phenylpiracetam (100 mg twice daily). Although it is not well understood, Phenylpiracetam has antidepressant effect, which occurs due to the racemic mixture, but stronger at the expense of R-isomer in particular.

Psycho-stimulation and Phenylpiracetam
Rats were administered Phenylpiracetam, 10-50 mg / kg increased locomotor activity (distance and speed) that is associated mostly with the R-isomer, with no apparent dose response. A dose of 50 mg / kg is valid for about four hours with R-isomer, and the racemic mixture is valid for two hours. One study noted sleep disorders as side effects Phenylpiracetam in relation to psychoactive properties. Other studies have found no such side effects, and the reason why it was found in one study is not known. Although it is not well understood, there is some evidence that psychostimulant properties Phenylpiracetam cause worsening of sleep.

Inflammation and Immunology
Interventions
Injection 25 mg / kg Phenylpiracetam daily for five days in rats, and later injected with LPS for the immune system stimulation, revealed that lipopolysaccharide induced changes DTHR and phagocytosis were normalized without a significant impact on the production of antibodies. Behavioral changes due to injection lipo-polysaccharides (anxiety and low mobility) have been completely eliminated. Although it is not well understood today, Phenylpiracetam may have immunopodderzhivayuschimi properties during periods of immunological stress.

Pramiracetam

Pramiracetam is derived from Racetam, is used to improve cognitive functions, and according to preliminary results helps in the formation of long-term memory. Although the mechanisms of its action is almost completely unknown, apparently Pramiracetam enhances acetylcholine synthesis.

Basic information about Pramiracetam

Pramiracetam (racetam molecule) is synthesized from piracetam and because their modifications has great potential in the fight against amnesia in rats. Compared to other racetam, pramiracetam not as well studied, but behaves relatively well with the people of the reception. In an animal study, such as healthy young and old rats, pramiracetam process was effective in long-term memory formation. These improvements were observed while taking the drug for 1-2 hours prior to testing, and improvements have been observed short-term memory. Tests on humans suggest a similar effect, but due to lack of data on the positive effects of the drug on cognitive abilities in healthy young people, this information does not have adequate statistical significance. Mechanisms of action Pramiracetam still not fully understood, but the drug is able to influence the EEG readings during studies in rats (both young and old) as well as to increase the capture of choline with high affinity. Pramiracetam similar to piracetam and other racetam, since the mechanisms of its action are based on the functioning of the adrenal glands and some external effects, but this is the only explanation pramiracetam mechanisms of action. Other Names: CI-879, diisopropyl-yl- (2-oxopyrrolidin-1-yl) acetamide, CI879.

Not to be confused with piracetam (also Racetam)!
Variety: 

• racetam
• nootropics

Pramiracetam: instructions for use
According to information obtained during the study of the drug in humans, Pramiracetam dosage should be 400 mg three times daily or 600 mg twice daily or 1200mg a day. Should I take pramiracetam with food, it is not clear, nor is it clear whether the optimal dosage of 1200mg, but it brings visible results.

Sources and structure
sources
Pramiracetam (full chemical name - diisopropyl-yl- (2-oxopyrrolidin-1-yl) acetamide and the code name - C-1 879)) is a synthetic molecule racetam and has similarity to the parent molecule, Piracetam is used as a nootropic agent. It was synthesized in 1984 by piracetam modification. Pramiracetam is a structural derivative of piracetam, which was synthesized as an anti-amnesia.

Structure
Pramiracetam is obtained by substitution of the piracetam group amidic group dipropan-2-ylamino-ethyl.
Pharmacology
Serum

Maximum plasma concentration (Cmax) was 2.71 +/- 0,54mkg / ml after administration of 400mg Pramiracetam, 1.34mkg +/- 5.40 / ml (800mg), 6.13 +/- 0.71mkg / ml (1,200mg) and 8.98 +/- 0.71mkg / ml (1,600mg) 3) after receiving 600mg figure was 5,80-6,80mkg / ml. The half-life in dogs is 2,3-3,9 hours, and in humans at a dosage of 400 to 1600mg Pramiracetam this figure is higher - from 4.5 to 6.5 hours, and at 600 mg and of longer - from 2 to 8 hours . Pramiracetam good digested in the human body and has a half-life of a considerable period of time, which depends on the dosage.
Neurology

After oral pramiracetam rats, the drug was detected in the brain, however, was negligible absorption of blood-brain barrier.

Neurology
Mechanics of Action
Effect of the drug (0,15-1,5mm) in the hippocampus had indicators -2.9 / -3.8% of the standard value, which is not significant. Moreover, at 10 microns and the IC50 was observed relationship with dopaminergic, adrenergic, serotonergic, GABAergic, muscarinic and adenosine receptors. In vitro, pramiracetam itself caused no significant effects in the hippocampal cells. Just as when receiving piracetam memory improving effects of reception may be terminated at Pramiracetam adrenektomia, 6) which indicates the importance of the adrenal mechanisms drug exposure. The results of further research revealed that aminoglutethimide (prevents the formation of pregnenolone from cholesterol) and epoximexeron (receptor antagonist of aldosterone) also reduced the effectiveness of the drug. Elevated levels of corticosteroid is generally also blocked the effect of the drug groups racetam. In Pramiracetam effects associated with improved cognitive processes involved metabolism of steroids, in fact aldosterone receptor. It is also noted that pramiracetam able to restore changes in the EEG functions in aged rats as well as young and in the range of 5 to 20 mg and the efficiency exceeding 200-400mg / kg of Piracetam. At the use of piracetam in healthy rats were marked changes in the function of brain waves, and changes in the magnitude of slow waves in the cerebral cortex and hippocampal theta waves contributed to the improvement of cognitive functions by passing water maze of rats. 8) In fact, pramiracetam affect the EEG and young adult rats. The mechanisms underlying these changes, are still unknown.

cholinergic neurotransmission
Intraperitoneal injection of Pramiracetam to the rats (44-88mg / kg) was able to increase high affinity choline levels increase in hippocampal sections of rats for 30 minutes. A similar effect is absent when using piracetam and aniracetam, as well as lower doses (8 mg / kg) or more (176mg / kg) were not effective. Pramiracetam (as do piracetam) normalized changes in the transfer of choline, which were caused by scopolamine. In in vitro tests, the direct application of pramiracetam on hippocampal sections of animals that were not previously used in the experiments did not lead to an increase in high affinity choline increase.

Memory and cognitive functions
The earliest studies of the impact Pramiracetam amnesia revealed that the potential ramiracetam pay amnesia with low efficiency (96% treatment) is shown at 5 mg / kg dose (effective within 12,5-80mg / kg, intraperitoneal injection). This study showed that the potential is greater than that of piracetam, which is the basis of Pramiracetam. In addition it was found that the amnesia caused by anticholinergic toxin hemiholinium-3 suppressed pre Pramicetam reception. With regard to the amnesia Studies in animals, data is not enough, however, we can say that pramiracetam behaves better than piracetam. Pramiracetam differentially affects the research activity, which increases with the dose of 15mg / kg and 60mg suppressed at / kg dose (a dose of 30mg / kg has no effect). In studies kynurenic acid effects pramiracetam was used as a comparative component, and 30 mg / kg of the drug improved the memory (better recognition of objects). Improvements in learning objects were observed at 30 mg / kg Pramiracetam (this dose was more effective than 15 mg / kg and 60 mg / kg) and is comparable to the effects of 400 mg / kg Piracetam. Avoiding collisions with objects in mice were also observed with the dosage Pramiracetam in 100mg / kg adopted for 1-2 hours prior to testing, which is comparable with the effect of oxiracetam (same dose), but superior to piracetam and aniracetam. Improvements were also observed with the passage of the water maze, a single dose was 10mg / kg, and more lower doses were less effective. Intraperitoneal administration of a dose pramiracetam 7,5-15mg / kg in rats for 7 weeks in a radial maze test improved the long-term memory, but has no effect on the short-term memory. And although the 15 mg / kg dose was more effective than the 7.5 mg / kg, there was little difference. It was confirmed influence of the drug on long-term memory, short-term memory but not exposed. Cognitive efficacy in animal studies appears when administered prior to testing. Older people with memory loss for the period of 12 weeks of taking the drug improved memory when recognizing objects, and the result was better than the simple memory training (90 minutes lessons with a teacher during the week). In young healthy people with cerebral injury after taking Pramiracetam (400 mg three times a day) have been observed to improve thought processes and memory that lasted for 18 months. In healthy volunteers, after which the 10-day course Pramiracetam (600 mg twice per day) was given scopolamine was marked decrease of amnesia caused by scopolamine. You can also like Piracetam.

Alzheimer's disease
In the course of a single experiment in the fight against this disease using pramiratsetama (dosage was chosen based on how the patient responded to the drug, from 1200 mg to 4000 mg daily) the drug's effectiveness has not been confirmed.

Interactions with other substances
Lithium
Since pramiracetam can increase the activity of nitric oxide synthase in rat cerebral cortex that occurs when administered intraperitoneally 300 mg / kg (up to 20% above the baseline value) but not 100 mg / kg, of lithium and 100 mg / kg pramiracetam increases the activity of nitric oxide synthase to 40 % of base.