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Venlafaxine

01 Mar 2018

Trade names: Effexor, Vipax, Velaxin, Velafax, Ephevelone, Venlaksor.

Venlafaxine - antidepressant from the group of selective inhibitors of the reuptake of serotonin and norepinephrine.

Venlafaxine is indicated for the treatment of major depression, as well as anxious neuroses of different etiologies.

The antidepressant effect of venlafaxine is associated with an increase in neurotransmitter activity in the CNS. Venlafaxine and its main metabolite O-desmethylvenlafaxine (EFA) are potent inhibitors of reuptake of serotonin and norepinephrine and poorly inhibit reuptake of dopamine by neurons. Venlafaxine and EFA equally effectively affect the reuptake of neurotransmitters. Venlafaxine and EFA reduce beta-adrenergic reactions.

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Venlafaxine does not have an affinity for muscarinic, cholinergic, histamine H1 and α1-adrenergic receptors in the brain. Venlafaxine does not suppress MAO activity. Has no affinity for opiate, benzodiazepine, phencyclidine or N-methyl-D-aspartate (NMDA) receptors.

Most studies have shown similar efficacy of venlafaxine and other antidepressants. In comparison with sertraline and escitalopram, venlafaxine demonstrates similar efficacy with these drugs in treating patients with severe depression and in improving their quality of life. One meta-analysis showed the advantage of venlafaxine over SSRIs, but only fluoxetine and paroxetine were included in the analysis, and the results can not be extrapolated to all SSRIs. A large meta-analysis combined the results of 33 RCTs with the participation of patients with deep depression who took venlafaxine, fluoxetine, paroxetine and fluvoxamine. The level of remission with venlafaxine was 45%, with the SSRI - 35%, and in the placebo-control group - 25%. Similar results (greater venlafaxine versus SSRIs) have been demonstrated in other large meta-analyzes.

The meta-analysis was criticized, because in it venlafaxine was compared with SSRI in low doses, which could not but affect the results. This circumstance caused the authors to conduct a new, more correct study, but the result was similar. The depth of effect and the frequency of remission were higher with venlafaxine. It was concluded that venlafaxine is actually a more effective antidepressant in comparison with SSRIs.

In a 2009 study (RCT that included 105 patients), a combination of venlafaxine with mirtazapine was particularly effective, with this combination of remission reaching 58% of patients - approximately twice that of using one antidepressant. These combinations are used in the treatment of resistant depressions. The combination of venlafaxine and mirtazapine in slang is called "California rocket fuel". There are different combinations of taking several antidepressants, if they belong to different groups. For example, a combination of venlafaxine with bupropion.

At the same time, there are studies that question the efficacy of venlafaxine. A comparative review of 42 clinical trials of 6 antidepressants (venlafaxine, sertraline, fluoxetine, paroxetine, citalopram and nefazodone), including those whose data was not previously published, showed that the results of the majority of these 42 trials are negative. The difference between placebo and drugs was on average only 1.8 points on the Hamilton scale - a number that is statistically significant but not clinically significant. According to another study (a meta-analysis of 35 clinical trials of 4 antidepressants, including venlafaxine), the difference between antidepressants and placebo reached clinical significance only with very severe depression.

The most typical side effect for venlafaxine is nausea (it depends on the dose and passes with time). A rare side effect is systemic hypertension, which also depends on the dose, occurs at the beginning of treatment, but tends to be stable. All venlafaxine-receiving patients need periodically in the first months of therapy and with an increase in the dose of the drug to measure blood pressure.

The withdrawal syndrome
Venlafaxine is characterized by one of the most powerful withdrawal syndromes among antidepressants. After a severe withdrawal of the drug or a significant reduction in its dose, general malaise, fatigue, drowsiness, unusual dreams / nightmares, headache, a feeling of faintness, dyspeptic phenomena (nausea, vomiting, diarrhea, anorexia), dry mouth, anxiety, anxiety, tremor limbs, convulsions, emotional instability, and so-called. "Brain zaps" - a phenomenon consisting in sensations of dizziness, a failure in an air hole, passage of an electric discharge through the body. To avoid these symptoms, it is very important to reduce the dose gradually, for a certain period: with a course of therapy lasting 6 weeks or more, the period of dose reduction should be at least 2 weeks and depend on the dose, duration of treatment and individual characteristics of the patient; During clinical trials of venlafaxine, the dose was reduced by 75 mg once a week.

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Sleeping Pills

28 Feb 2018

Sleeping Pills - a group of psychoactive drugs used to facilitate the onset of sleep and ensure its sufficient duration, as well as during anesthesia. At present, the classification of ATS does not distinguish such a separate pharmacological group.

The desire to provide a good sleep has long led people to try to use certain products and pure substances, like sleeping pills. Another Assyrians around 2000 BC. e. used preparations of belladonna for sleep improvement. The Egyptians used opium oil in 1550 BC. e.

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For a very long time, the inhibitory effect of ethanol and alcoholic beverages has been noticed, after a short period of excitation of the nervous system leading to its inhibition. High doses of alcoholic beverages Indian doctor Charaka used already for 1000 years BC. e. as a means for general anesthesia.

In Germany in the XIX century, inhalation anesthesia was invented with a mixture of opium, dope, cannabis, aconite, mandrake and other narcotic and toxic substances.

Today, for this purpose, medicinal preparations belonging to various pharmacological groups (tranquilizers, sedatives, many antihistamines, sodium oxybutyrate, clonidine, etc.) are used. Many medications (luminal, veranal, barbamil, nitrazepam, etc.) can reduce the level of excitation of the nervous system, providing a more or less satisfactory sleep.

Application
The modern requirements for safe and effective drugs bring to the fore the following properties of hypnotics:

● formation of normal physiological sleep;
● safety for different groups of people, absence of memory disorders and other side effects;
● Lack of addiction, psychological dependence.

Since "ideal" drugs have not been found, the use of some "traditional" hypnotics continues, including a number of barbiturates (barbituric acid derivatives, compounds formed by condensation of substituted malonic acid esters and urea). If condensation is used instead of urea to take thiourea, we get thiobarbiturates. The most famous barbiturates include phenobarbital, then amobarbital and thiopental, or pentotal (thiobarbiturate), used intravenously for anesthesia.

Modern hypnotic drugs benzodiazepine series (nitrazepam, etc.) have some advantages over barbiturates. However, by the nature of the sleep caused and by side effects, they do not fully meet the physiological requirements.

Recently, from the nomenclature of drugs, carbamal, barbamyl, cyclobarbital, barbital, barbital sodium, ethaminal sodium have been excluded, chloral hydrate and chlorobutanol hydrate have been stopped as a hypnotic.

Classification
Drugs that have a hypnotic activity are classified based on the principle of their action and chemical structure:

● GABA (benzodiazepine) receptor agonists: Benzodiazepines: Nitrazepam, Lorazepam, NosePam, Temazepam, Diazepam, Phenazepam, Flurozepam;
● Preparations of different chemical structure: Zolpidem, Zopiclone, Zaleplon.
Melatonin receptor agonists: Ramelteon, Tasimelteon.
Antagonists of orexin receptors: Suvorexant;
● Sleeping pills with a narcotic effect type: Heterocyclic compounds, barbiturates: Phenobarbital, Sodium ethanamine;
● Aliphatic compounds: chloral hydrate;
● Individual preparations of other groups: H1 blockers of histamine receptors: Dimedrol, Doxylamine;
● Means for anesthesia: sodium oxybutyrate;
● Preparations of the hormone epiphysis melatonin.

Sleeping pills are divided into three classes. Sleeping pills of the first class (generation) are barbiturates, antihistamines and drugs containing bromine (brominated, for example). Barbiturates interact with barbiturate receptors located on chemically-dependent ion channels for chloride ions, and the neurotransmitter for these channels is GABA. Barbiturates interact with these receptors, which leads to an increase in the sensitivity of chemically-dependent channels to GABA and leads to an increase in the opening of ion channels for chloride ions - the nerve cell polarizes and loses its activity. The action of barbiturates, however, is not selective, and they cause not only a sedative-hypnotic effect, but also muscle relaxation, anticonvulsant and anxiolytic action at the entire dose range. Barbiturates vary widely in duration of action. Sleep caused by barbiturates is different from the natural. Antihistamines block the histamine H1 receptors. Histamine is one of the key neurotransmitters of wakefulness, and the blockade of histamine receptors, respectively, leads to a sedative effect. Antihistamines, as well as barbiturates, break the architecture of sleep. Second-generation sleeping pills are represented by numerous benzodiazepine derivatives. If barbiturates cause an increase in the opening time of chemically-dependent channels, then benzodiazepines increase the frequency of opening.

Groups of sleeping pills
● Bromides
● Aldehydes
● Barbiturates (more than 2500 derivatives). Cyclobarbital is one of the active components of the preparation Reladorm (the second component is diazepam);
● Phenobarbital is part of combined sedatives (Corvalol, Valocordin).
● Piperidinodiones (glutethimide (noxidone, doridene)) Hinazolines (methaqualone, etc.)
● Benzodiazepines - a group of drugs with a pronounced hypnotic component in the spectrum of action.
● Chlordiazepoxide (Librium), brothisolam, midazolam, triazolam, nitrazepam, oxazepam, temazepam, flunitrazepam, flurazepam, phenazepamEthanolamines (Doxylamine). H1-histamine receptor antagonists cause M-cholinoblocking effect.
● Cyclopyrrolones (Zopiclone) Imidazopyridines. Selective GABA complex receptor blockers (Zolpidem) Pyrazolopyrimidines (Zaleplon) Alcohol (alcohol) in some countries is sometimes still recommended for use as a sleeping pill, but its effectiveness is low.

Modern preparations
The drugs of receptor action developed at the end of the 20th century differ somewhat, mainly by the frequency and spectrum of side effects, and also by their cost. The higher the selectivity of the drug, the closer its properties to the properties of the "ideal" hypnotic, and the less pronounced unwanted side effects.

Of the latest developments, we note new classes of hypnotics - cyclopyrrolone derivatives, for example, zopiclone (imovan), imidazopyridine derivatives (zolpidem), pyrazolopyrimidine derivatives (zaleplon).
● Bromisovaliun
● Gemineurinum (Hemineurinum)
● Piklodorm
● Zolpidem
● Zaleplon
● Methaqualonum
● Phenobarbitalum
● Flunitrazepam (Flunitrazepam)
● Nitrazepam (Eunoctinum, radedorm)

Other means of regulating sleep
● Electrosleep
● Suggestion and autosuggestion
● Magnesium preparations

The sleep caused by barbiturates is significantly different in structure from the natural. The main thing is changing the ratio of the phases of fast and slow sleep. Because of this, patients experience intermittent sleep, an abundance of dreams, sometimes nightmares. After sleep, there are drowsiness, weakness, nystagmus and other side effects. With the repeated use of barbiturates, it is possible to develop psychological and even physical dependence, similarly to narcotic "breaking".

The use of hypnotics should be performed only by a specialist, after he determines the cause of insomnia, will identify the presence of contraindications to these or other drugs and will make a conclusion about the general condition of the patient.

#psychiatry #psychopharmacology #sleeping pills #psychoactivedevices #hypnotics


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Topiramate

27 Feb 2018

Antiepileptic drug of unusual structure, is a derivative of fructose. It is not effective as an antimanic or antidepressant for bipolar disorder. Studies are also being conducted on its use in post-traumatic stress, alcoholism, overeating, headaches of various origins and neuropathy.

Trade names: Maxotopyr, Topamax, Topsaever, Toreal, Topaleptsin, Epimax, Epitope.

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It is included in the list of vital and essential medicines.

The Food and Drug Administration approved the use of topiramate for the prevention of migraine, and also for use in combination with phentermine for weight loss.

Antiepileptic drug. Refers to the class of sulfate-substituted monosaccharides. Antiepileptic activity of the drug is due to a number of its properties. Topiramate reduces the frequency of occurrence of action potentials that are characteristic of a neuron in a state of persistent depolarization, which indicates the dependence of the blocking action of the drug on the sodium channels on the state of the neuron. Topiramate potentiates GABA activity in some of the subtypes of GABA receptors (including GABAA receptors), and also modulates the activity of the GABAA receptors themselves, inhibits kainate activation of the sensitivity of kainate / AMPK receptors to glutamate, does not affect the activity of N-methyl-D- aspartate for NMDA receptors. These drug effects are dose-dependent with a plasma topiramate concentration of 1 μM to 200 μM, with minimal activity ranging from 1 μM to 10 μM. In addition, topiramate inhibits the activity of certain isoenzymes of carbonic anhydrase, but this effect in the topiramate is weaker than that of acetazolamide and, apparently, is not the main antiepileptic activity of topiramate.

Indications:

- partial or generalized tonic-clonic seizures in adults and children over 2 years of age, including those with newly diagnosed epilepsy (either as monotherapy or in combination with other anticonvulsants);
- Seizures associated with Lennox-Gastaut syndrome in adults and children older than 2 years (as part of complex therapy).
- Prevention of migraine attacks in adults. Ics

Side effect:

From the side of the central nervous system and peripheral nervous system: nervousness, dizziness, headache, speech and vision disorders, diplopia, nystagmus, anorexia, psychomotor retardation, ataxia, fatigue, impaired concentration, confusion, paresthesia, drowsiness, thinking disorder, depression; In addition, in children - personality disorders, increased salivation, hyperkinesia; rarely - perversion of taste, arousal, cognitive disorders, emotional lability, abnormal gait, apathy, psychotic symptoms, aggressive reactions; very rarely - suicidal thoughts, in addition to children - hallucinations.

The drug is approved for use in children older than 2 years. Influence on the ability to drive vehicles and manage mechanisms. Caution should be given to patients who are engaged in potentially dangerous activities that require increased attention and speed of psychomotor reactions, since the drug may cause drowsiness, dizziness.

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Catecholamines

26 Feb 2018

Catecholamines - physiologically active substances that serve as chemical intermediaries and "control" molecules (mediators and neurohormones) in intercellular interactions in animals and humans, including in their brains; derivatives of pyrocatechol. Catecholamines include, in particular, neurotransmitters such as epinephrine, norepinephrine, dopamine (dopamine). Adrenaline is often, especially in Western literature, called "epinephrine" (that is, the "substance of the adrenal glands"). Accordingly, norepinephrine is often called "norepinephrine".

Catecholamines adrenaline, norepinephrine and dopamine are synthesized in the adrenal medulla and brain. Since in various diseases catecholamines and their metabolites, for example, metanephrine and normetanephrine are secreted in elevated amounts, they can be used for diagnostic purposes. At a number of mental diseases in certain areas of the brain there is a lack of catecholamines.

Adrenaline is the final product of the biosynthesis of catecholamines. In general, the synthesis of catecholamines is a complex biochemical process. Schematically it looks like this: Tyrosine → DOPA → Dopamine → Noradrenaline → Adrenaline. A number of enzymes are required to catalyze this process.

Catecholamines directly or indirectly increase the activity of the endocrine glands, stimulate the hypothalamus and pituitary gland. At any hard work, especially physical, the blood content of catecholamines increases. This is an adaptive response of the body to a load of any kind. And the more pronounced the reaction, the better the organism adapts, the faster the state of fitness is achieved. With intensive physical work, increased body temperature, increased heart rate, etc. is caused by the release of a large number of catecholamines into the blood.

Adrenaline is called the "hormone of fear" due to the fact that when frightened the heart starts to beat more often. Emission of adrenaline occurs with any strong excitement or heavy physical exertion. Adrenaline increases the permeability of cell membranes for glucose, increases the breakdown of carbohydrates (glycogen) and fats, causes narrowing of the vessels of the abdominal cavity organs, skin and mucous membranes; dilates the vessels of skeletal muscles. Arterial pressure increases with adrenaline. If a person is frightened or agitated, then his stamina rises sharply.

Norepinephrine is called the "hormone of rage", because as a result of the release of norepinephrine into the blood, there is always a reaction of aggression, the muscular strength considerably increases. Its secretion and release into the blood increases with stress, bleeding, heavy physical work and other situations that require a quick rebuilding of the body. Since norepinephrine has a strong vasoconstrictor effect, its release into the blood plays a key role in regulating the rate and volume of blood flow.

Dopamine causes an increase in cardiac output, has a vasoconstrictive effect, improves blood flow, etc., stimulates the breakdown of glycogen and suppresses the utilization of glucose by tissues. Dopamine also causes a sense of pleasure, what influences the processes of motivation and learning. Dopamine causes an increase in the concentration of glucose in the blood. It is involved in the regulation of the formation of growth hormone, in inhibition of prolactin secretion. Inadequate synthesis of dopamine causes impaired motor function - Parkinson's syndrome. A sharp increase in the excretion of dopamine and its metabolites with urine is observed with hormone-active tumors. With gipovitaminozevitamin B6 in the brain tissues, the content of dopamine increases, its metabolites appear, which are absent in the norm.

Inactivation of catecholamines occurs with the participation of two enzymes: catechol-O-methyltransferase and monoamine oxidase, with the final formation of vanillylmandelic acid. The determination of vanillinmendal acid in urine is used for the diagnosis of pheochromocytoma (adrenal medulla tumor).

A number of pathological processes in the adrenal gland (usually a tumor etiology) is associated with the constant or paroxysmal discharge of catecholamines into the synaptic cleft. The most common is the so-called. pheochromocytoma, that is, the tumor of the adrenal medulla, where the synthesis of catecholamines occurs. In 10% of cases, pheochromocytomas show malignant tumor degeneration. In addition, an increase in the level of catecholamines and their metabolites of metanephrine and normetanephrine can be observed with carcinoid.

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Mildronate and trimetazidine: similarity and difference in their action

24 Feb 2018

What to do if any part of the body lacks oxygen, but a significant improvement in blood circulation is physically impossible (the blood vessels are clogged and sclerotized, the heart function is broken - heart attack, coronary heart disease, etc.)?

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It was this issue that was and remains relevant for everyone who has ever had to face hypoxia and ischemia in any form of its manifestation. Traditionally, for the treatment of coronary heart disease antianginal agents are used, which either reduce the work of the heart, or increase the coronary blood flow. These include nitrates, beta-adrenoblockers, calcium antagonists ("dipins"), angiotensin converting enzyme ("prilah") blockers or angiotensin receptor ("sartans"), vasopeptidase ("patrolate") inhibitors. These drugs are relatively effective in maintaining hemodynamic parameters of the heart (strength and heart rate, coronary blood flow, stress on the heart, etc.), but they can not change the efficiency of using oxygen by the heart muscle. That is why the above medicines often can not provide a sufficiently effective treatment of cardiovascular diseases and significantly inhibit their further development. In addition, the use of these agents to a large extent limits contraindications and the accumulation of unwanted side effects during treatment.

Today, it seems logical that in addition to this treatment, the use of oxygen should be optimized to generate energy in the myocardium. But how to do this? Scientists around the world for a long time searched for substances, so-called. cytoprotectors, which could prevent the harmful effect of oxygen starvation on the viability of cells. The use of antioxidants seemed to be promising, which, it was believed, could capture and neutralize the harmful radicals that arise in the body in conditions of oxygen deficiency, but especially when after prolonged ischemia the blood circulation is restored (at the stage of reperfusion).

trimetazidine

Whatever has been tested, nevertheless, none of the antioxidants has been effective enough in the treatment of diseases of the cardiovascular system. And only in 1961 the French company Servier (Servier) patented trimetazidine as the world's first antioxidant with clinically significant efficacy.

Ironically, the reason why this drug was effective in the treatment of coronary heart disease, the whole world and even the manufacturer itself learned only 27 years later, when the second generation of trimetazidine, Mildronate, was already developed, tested and tested in the clinic in Riga .

Although initially different drugs were postulated for both drugs, the attention of scientists was increasingly attracted by the striking similarity in the action of both drugs on the ischemic myocardium. This suggested that, perhaps, the mechanism of cytoprotective action of trimetazidine was not initially correctly understood, and its positive effects are not related to the properties of the antioxidant.

The fact that the use of trimetazidine, for example, as an antioxidant for the treatment of myocardial infarction (briefly, in the acute phase of myocardial infarction) does not make sense, was later confirmed by the EMIP-FR study (192325 patients with the European project for treatment of myocardial infarction: free radicals) acute myocardial infarction, of which 9,871 patients received a preductal as a 48-hour infusion. This study, conducted in 1996, showed that when applied in such a regime - as an antioxidant - trimetazidine is comparable in effectiveness to placebo.

At the same time, the effect on the oxidation of fatty acids in cells has already been clearly identified and proven for mildronate. Experiments conducted in the IOS, the Japanese firm Taiho, the US universities and the American concern Marion-Merell-Dow, as well as the company Servier confirmed the original hypothesis of the authors Mildronate: limiting the flow of fatty acids through the mitochondrial membranes protects the cell from death in conditions of oxygen starvation.

Intensive studies have shown that trimetazidine also inhibits beta oxidation of fatty acids in mitochondria. However, mildronate and trimetazidine affect different parts of the chain of fatty acid metabolism, which creates significant advantages for mildronate. As it was explained, trimetazidine blocks the last reaction of the four-stage oxidation of fatty acids (3-ketoacyl-CoA-thiolase). This, in turn, means that trimetazidine inhibits oxidation in the mitochondria of all fatty acids-both long-chain (number of carbon atoms greater than 8) and short-chain (number of carbon atoms less than 8), however, in no way interferes with the accumulation of activated fatty acids in mitochondria.

Mildronate acts differently. The drug limits the transport through the membranes of mitochondria to long-chain fatty acids only, while short-chain fatty acids can freely penetrate into the mitochondria and oxidize there.

What is the significance of these differences in protecting cells from changes in the cellular metabolism caused by oxygen starvation and, consequently, in treating pathological conditions associated with ischemia?

On the one hand, trimetazidine, which blocks the oxidation of all fatty acids, should be used in smaller doses than mildronate, the complete elimination of fatty acids from energy metabolism, at least theoretically, creates a potential threat to the functioning of the myocardium. At the same time, trimetazidine is not able to delay the flow of fatty acids into the mitochondria and, therefore, can not prevent the accumulation in the mitochondria of their activated forms, acyl-CoA and acylcarnitine, and the harmful effect of these metabolites on ATP transport and cell membranes. On the other hand, a decrease in the rate of oxidation of fatty acids in the case of a preductal undoubtedly has a positive effect on the metabolism of the ischemic myocardium, since an alternative energy production system is activated-glucose oxidation, which uses oxygen for the synthesis of ATP much more efficiently (by 12%). This circumstance, as well as the fact that glucose is not converted to lactate, determines, mainly, the cytoprotective effect of the reductase on ischemic cells.

And how does this happen in the case of Mildronate? Mildronate reversibly limits the rate of biosynthesis of carnitine from its predecessor, bilioutiboretaine. And since it is with carnitine that the transport of long chain fatty acids through the mitochondrial membranes is realized, it is clear that the mildronate, leading to a decrease in the carnitine concentration, reduces the intake of fatty acids and their accumulation in the mitochondria, but in no way inhibits the metabolism of short-chain fatty acids. This means that mildronate is practically unable to exert a toxic effect on the respiration of mitochondria, since it can not completely block the oxidation of all fatty acids.

It was suggested that, by inhibiting the transport of fatty acids and, consequently, their oxidation, it is possible to adapt (precondition) the cells of the heart muscle, brain and others to oxygen deficiency. This hypothesis was confirmed by experiments carried out in many countries of the world on isolated organs, as well as experiments aimed at reducing the size of myocardial infarction and the resulting heart failure. As was shown, Mildronate perfectly protects the ischemic zone of the myocardium from death, both in conditions of oxygen starvation and after restoration of blood circulation in the organ after a 10-day course. Mildronate has a cytoprotective effect in the case of adrenaline and noradrenaline-induced damage to the myocardium.

How is this possible? Many experimenters shrugged their shoulders in confusion. After all, coronary blood flow under the influence of mildronate rises only slightly! And the heart muscle uses mainly fatty acids to produce energy, but it's their transport of mildronate that limits it! And yet - it is known that carnitine definitely has a positive effect on the myocardium, but in fact mildronate inhibits the biosynthesis of this vitamin!

However, it turned out that these contradictions are only apparent. The explanation of the action of mildronate was found in a study of a widely known phenomenon, when people exposed to regular, not too strong stress, are less likely to have heart disease than those who survived stress one day, but in a large dose. This phenomenon was called the precondition effect, and its reason is simple: stress in small doses trains those enzyme systems of the cell that use sugar to generate energy. This is due to the fact that the oxidation of glucose, compared with the burning of fatty acids, allows you to save about 12% of oxygen! And so the cardiac muscle responds to adrenergic irritation (stress!) Not by the increase in the rate of oxidation of fatty acids, as thought so far, but receives all the additional energy from the oxidation of sugars, which requires less oxygen. Those who have these enzyme systems more trained, suffer, respectively, and higher loads. This is typical for athletes and other trained (adapted) people.

It turned out that it is here that the secret of the effectiveness of mildronate lies: the drug causes the preconditioning effect in cells, inducing the expression (biosynthesis) of enzymes necessary for the oxidation of sugars and increasing their activity. In other words, Mildronate acts as a pharmacological co-stimulant that helps cells maximize the oxygen consumption to obtain energy and prepare for ischemia.

But on this flow of surprises is not exhausted! It turned out that it is not enough to produce energy (this occurs in the mitochondria). It still needs to be delivered to the place of consumption - to the ion pumps of the organelles in the cytosol so that they can function and maintain the vital functions of the cell. But it is the activated fatty acids accumulating in the mitochondria that block this transport of ATP and simultaneously act as surface-active substances that mechanically injure the cell membranes and cause their destruction. Mildronate, reducing the penetration of fatty acids into the mitochondria, restores the transport of ATP and helps cells survive.

And what about antioxidant properties, the positive effect of which, at least at the postischemic stage of reperfusion, has been experimentally proven in many studies?

True, there are completely contradictory observations convincingly demonstrating that the advisability of using antioxidants to prevent reperfusion-induced damage is at least controversial. However, the preductal has the properties of an antioxidant, and Mildronate?

It has been revealed that mildronate itself, which does not possess the properties of an antioxidant, increases the concentration of gamma-butyrobetaine (GBB) in the body, since under the influence of mildronate it is slower than usual oxidizes to carnitine. In turn, GBB is able to induce the formation of NO, which acts as one of the most effective natural agents that bind free radicals in the body. It is the increase in the concentration of GBB under the influence of mildronate that explains the very unexpected effects of mildronate: a reduction in peripheral resistance of blood vessels, a decrease in nasal congestion caused by norepinephrine or angiotensin, inhibition of platelet aggregation, and an increase in the elasticity of erythrocyte membranes. Unexpected because it is well known that the preductal has no effect on hemodynamics. Mildronate, by increasing the concentration of gamma-butyrobetaine, is able to protect cells from free radicals), but the mechanism of its action is completely different from that for trimetazidine, because it is realized through the induction of NO biosynthesis.

Thus, Mildronate promotes biosynthesis of a physiologically regulated amount of NO, which allows the body to determine the necessary level of protection against radicals. As a result, the mildronate has a selective effect on the ischemic zone of various tissues, including the myocardium, practically without affecting the areas that are unaffected by ischemia (counteraction to the effect of stealing).

Perhaps this mechanism can explain the experimental observations obtained by the electron microscopic method, namely, that in the myocardium in the case of increased training loads under the influence of mildronate, the number of functioning capillaries (vascularization) increases 2-3 times, the number and size of mitochondria (hyperplasia and hypertrophy) and significantly (by 180%) the number of crises in them increases. The number of ribosomes and polysomes also increases, which indicates the ability of Mildronate to activate the synthesis of proteins (enzymes), as well as increase the respiratory capacity of the myocardium. Subsequent studies have shown that mildronate induces the biosynthesis and activity of Ca? + - ATPase, hexokinase and pyruvate dehydrogenase of the sarcoplasmic reticulum.

The ability to control the rate of oxidation of fatty acids in the ischemic myocardium, of course, has a positive effect on the antianginal action of both mildronate and trimetazidine. It has been experimentally proved that both these drugs are well combined with other antianginal agents, while the dose of other drugs in this case can be reduced. As clinical practice shows, metabolic cytoprotective therapy in the case of, for example, trimetazidine antianginal effect is equivalent to the action of propranolol or nifedipine, in addition, the drug can be combined with diltiazem. Both mildronate and trimetazidine in the case of stable angina reduce the frequency of angina attacks, increase the tolerance of patients to physical exertion and reduce the average daily intake of nitroglycerin.

Both drugs, but especially Mildronate, are low in toxicity and do not cause significant side effects. However, due to the blocking effect of trimetazidine on the oxidation of all fatty acids, it should be used in smaller doses, more often and more densely (3 tablets of 20 mg per day for at least 6 months) than mildronate, whose therapeutic effect, due to the higher allowable dose 2-4 capsules of 250 mg per day), manifests itself more quickly, and the course of treatment usually does not exceed six weeks. Of course, the curative courses of both drugs can be repeated if necessary. Thanks to the physiological, regulating and training effects of Mildronate on the body, the drug is approved for use by healthy people and athletes to enhance physical and mental performance. Since it is not a secret that overloads most often contribute to the occurrence of ischemic episodes in a healthy myocardium and muscle tissues, from which it is necessary to protect the body.

Does this mean that Mildronate is a panacea? In no case! Like any drug that affects the metabolism, the mildronate needs time to influence the viability of cells in conditions of oxygen deficiency through the mechanisms described above. train them. Therefore, as a result of the action of mildronate, there is no pronounced rapid effect, the drug acts gently, without sudden changes in pressure or other parameters of cardiac activity. However, the significance of its long-lasting effect on the body can not be overestimated. Mildronate optimizes oxygen consumption and increases the production of ATP not only in the myocardium, but also in muscle tissue and other cells. This means that the saturation of red blood cells with oxygen under the influence of mildronate increases, and oxygen enters the ischemic tissue more than usual.

Experiments of Japanese scientists have shown that mildronate significantly (by 30% or more) prolongs life expectancy in heart failure caused by severe myocardial infarction. Mildronate is perfectly combined with ACE inhibitors (captopril, lisinopril, etc.), and also enhances the effect of many other cardiac agents. But especially effective Mildronate on the so-called. a model of the pulmonary heart associated with general oxygen deficiency in the body and disorders in the small circulation.

These newly discovered properties of mildronate are an excellent addition to the widely known effects associated with inhibition of oxidation of fatty acids, which are well studied as a result of long-term use of trimetazidine.

Why can Mildronate be considered a second generation of trimetazidine?
Despite the fact that trimetazidine (preductal) in pharmacies appeared later than mildronate, it was established 15 years earlier. Trimetazidine and mildronate are undoubtedly preparations of one pharmacological group whose similar cytoprotective anti-ischemic action is based on the switching of energy supply of myocardium from fatty acids to aerobic glycolysis and restriction of acidosis - this also ensures the similarity of the clinical effects of drugs in the treatment of stable angina. However, mildronate is distinguished by the presence of additional positive effects, which are provided by induction of NO biosynthesis, as well as optimization in the cells of activity and the number of enzymes involved in energy and ion transport. These properties open up wider possibilities for the use of mildronate in the prevention of severe cases of heart disease (precondition), in the treatment of heart failure and in limiting hypertrophy of the heart (remodeling) in the post-infarction period.

If trimetazidine, as a cytoprotective anti-ischemic agent, is recommended for use by all patients with coronary heart disease, mildronate with good results is used for the treatment of other diseases associated with circulatory pathology, for example, disorders of cerebral and peripheral circulation and microcirculation. The cytoprotective effect of mildronate opens up wide possibilities for its use in the combination therapy of pulmonary diseases, especially asthma, for the relief of alcohol withdrawal syndrome, and in the treatment of many other pathological conditions, the pathophysiological mechanism of which is associated with the restriction of the supply of tissues and organs with oxygen.

To date, there are few clinical observations that directly compare the efficacy of mildronate and trimetazidine. Nevertheless, in one of the first clinical trials in which a comparative evaluation of the efficacy of 12 different antihypoxants was performed in intensive therapy of 620 patients with acute myocardial infarction, mildronate was found to be more effective than trimetazidine.

The next round of the spiral of searching for new anti-ischemic drugs is over!

In the treatment of coronary heart disease, cytoprotective anti-ischemic agents are not opposed to other antianginal drugs, they are considered to be medicines that provide a significant improvement in the quality of life of patients. It remains only to wish successes to our doctors: a deep understanding of the mechanism of the action of mildronate is the basis for the successful application of this promising drug for the treatment of patients suffering from blood supply disorders of any tissues. The use of Mildronate in combination with standard therapy is undoubtedly the key to achieving the maximum effect in the treatment of coronary heart disease, peripheral and cerebral circulatory disorders, and other ischemic conditions.


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Sertralinum

22 Feb 2018

Sertralinum - an antidepressant from the group of selective serotonin reuptake inhibitors (SSRIs).

Trade names are "Asentra", "Deprespolt", "Zoloft", "Emoton", "Seralin", "Serenata", "Sellyft", "Stimuloton", "Torin", "Adjuvin", "Misol".

zoloft

In a 2009 study comparing 12 new-generation antidepressants, sertraline along with mirtazapine, escitalopramome venlafaxine was found to be one of the best. It has a stimulating and sedative effect and is used to treat patients with depression, accompanied by both inhibition, hypersomnia, apathy and anguish, and with anxious depression, anxiety, bad sleep, irritability. He quickly suppresses both anxious and phobic component, and longing, although at the beginning of therapy can increase the manifestations of anxiety, which sometimes requires the appointment of tranquilizers.

In combination with cognitive-behavioral psychotherapy, sertraline gives excellent results in the treatment of obsessive-compulsive disorder (OCD).

Sometimes reduces the sensitivity of the sexual act, which can persist for some time after stopping the drug. During the entire period of use, some patients developed the idea of suicide and / or aggression to others. There have also been cases of committing suicides and murders during and after the end of the drug use period, for example shooting in American schools, as well as committed suicides. Despite the final decision of the international pharmaceutical commission on the high effectiveness of the drug, the question of its controversial effectiveness and the absence of side effects is now being raised again.

History of creation

The drug was developed by the pharmaceutical company Pfizer. Initially, the work was carried out on the drug "tametrolin", which was an inhibitor of the re-uptake of catecholamines. Tamerlagen has not proven itself as an effective antidepressant, since it demonstrated the undesirable effects of prohibited psychostimulants.

Many years later, studies of tametrolin resumed, resulting in the creation of sertraline. Sertraline differs from tametalin by the presence of two chlorine atoms in the molecule. However, studies have shown that this substance is an extremely selective inhibitor of serotonin reuptake. At the time of the research Pfizer considered other drugs as an antidepressant put forward on the broad market. However, scientists working on sertraline without any motivation persistently offered their invention. As a result of these actions, sertraline was sold under the trade name Zoloft and Lustral and for some time was the most prescribed remedy against depressive conditions in the USA.

pharmachologic effect

Antidepressant, a specific inhibitor of serotonin reuptake, enhances its effects, has little effect on the re-uptake of norepinephrine and dopamine; in therapeutic doses blocks the seizure of serotonin in human platelets. Suppression of serotonin reuptake activity increases serotonergic transmission, which leads to a subsequent inhibition of adrenergic activity in the blue nucleus (locus ceruleus). Sertraline also inhibits the excitation of serotonin neurons in the seam region (median line of the medulla oblongata); which leads to an initial increase in the activity of the blue core, followed by a decrease in the activity of postsynaptic beta-adrenergic receptors and presynaptic alpha-2-adrenergic receptors.

Does not cause drug dependence, does not have psychostimulating, sedative, m-holinoblokiruyuschego and cardiotoxic effect, does not change psychomotor activity. Due to selective inhibition of seizure of serotonin does not increase the activity of the sympathetic nervous system. Has no affinity for m-cholino-, serotonin (5-HT1A, 5-HT1B, 5-HT2), dopamine, adreno-histamine, GABA or benzodiazepine receptors; does not inhibit MAO. In contrast, tricyclic antidepressants in the treatment of depression or obsessive-compulsive disorder (obsessive-compulsive disorder) does not increase body weight. Unlike other representatives of SSRIs - to a lesser extent produces an inversion of phases from depression - in hypomaniacal and manic state. The initial effect develops by the end of the first week, to a greater extent after 2-4 weeks, the maximum therapeutic effect - after 3 months, from the beginning of the regular intake of the drug.

Indications for use

Depressive conditions (including those accompanied by a sense of anxiety); prevention of initial or chronic episodes of depression; obsessive-compulsive disorder; panic disorder, social phobia.

With poorly treatable depression, it is possible to use in combination with other drugs. Combine only drugs related to different groups of antidepressants. Sertraline can be combined, for example, with bupropion or mirtazapine.

Dosing and Administration

Inside, 50 mg, 1 time per day in the morning or evening, regardless of food intake. In the absence of effect, a gradual (for several weeks) increase in the dose to 200 mg / day (at 50 mg / week) is possible. Some clinicians recommend prescribing a dose of 25 mg / day for 1-2 days. Panic disorders: the initial dose is 25 mg / day, followed by an increase to 50 mg / day for 1 week. In the case of prolonged maintenance therapy, a minimum effective dose is prescribed, which is subsequently changed depending on the effect. Obsessive-compulsive disorders and social phobias: in children and adolescents 13-17 years, the initial dose is 50 mg / day, in children 6-12 years, the initial dose is 25 mg / day, followed by an increase in 1 week to 50 mg / day . If the effect is insufficient, the dose can be increased stepwise at 50 mg / day to 200 mg / day, with an interval of at least 1 week. In elderly patients, the initial dose is 25 mg / day (morning or evening) followed by a gradual increase.

Contraindications

Manic conditions, hypersensitivity, liver disease, alcohol poisoning, psychotropic drugs and other drugs, pregnancy, lactation, simultaneous administration of MAO inhibitors. C caution. Neurological disorders (including delayed mental development), epilepsy, hepatic and / or renal failure, weight loss, child age.

Treatment of obsessive-compulsive disorder with sertraline

Studies have shown that sertraline is slightly more effective in treating OCD than an antidepressant of the same class of SSRIs Fluoxetine (Prozac). With insufficient effect, increasing the dose above the recommended dose (50-200 mg) did not yield any results. Participants in the studies confirmed the positive effect of sertraline treatment and maintenance of this effect for a year or more of sertraline. The constant use of the drug is not required by everyone. However, when the drug was discontinued, OCD exacerbations were often observed, which were a consequence of side effects or withdrawal syndrome. 48% of patients who stopped using the drug felt the same as those who continued treatment. Sertralin is effective in the treatment of OCD in adults and children. It is known that setralin can be used in OCD with concomitant Tourette's syndrome, but it can cause an exacerbation of tics in the Tourette syndrome.

Side effects:

Anxiety, affect inversion (development of mania or hypomania), tremor, hyperhidrosis, allergic reactions, bleeding (including nasal), palpitations, dry mouth, decreased appetite. Rarely - increased appetite (possibly as a consequence of eliminating depression), nausea, vomiting, unstable stools, diarrhea, stomach or abdominal cramps, flatulence or pain, weight loss; headache, dizziness, insomnia, drowsiness, movement disorders (extrapyramidal symptoms, gait alteration), akathisia, convulsions, paresthesia, symptoms of depression, hallucinations, aggressiveness, agitation, anxiety, psychosis, skin hyperemia or "hot flushes" (including blurred vision), yawning, increased sweating, impaired sexual function (delayed ejaculation, priapism, decreased potency and / or libido, anorgasmia), dysmenorrhea, galactorrhea, hyponatremia (ADH inadequate secretion syndrome), hyperpres laktinemiya, withdrawal syndrome, erythema multiforme, skin rash and itching. In rare cases - serotonin syndrome.

Can lead to emotional and behavioral changes, including an increased risk of suicide.


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Neurotransmitter Acetylcholine

12 Feb 2018

The neurotransmitter acetylcholine improves memory and concentration of attention.

Acetylcholine can be considered the most important neurotransmitter involved in the process of remembering information. This highly chemically active substance is an ester of choline and acetic acid. It contributes to the fact that information is quickly and unhindered transmitted from the senses to the main control center - the brain.

Unfortunately, with age, less acetylcholine is synthesized in the human brain. As a result of this, scientists believe, forgetfulness, problems with concentration of attention, difficulties in the selection of necessary words.

Meclofenoxate and choline serve as a basis for good brain activity. In order to improve memory in a short time and keep it clear for a long time, the famous researcher of brain activity, professor of the University of Hyssin, Wilfried Dimpfel, recommends that the concentration of the main neurotransmitter, acetylcholine, be purposefully stabilized. This can be achieved by taking choline preparations. Choline is a natural building block for the synthesis of acetylcholine molecules.

It is even better to build your own food in such a way as to ensure sufficient natural intake of choline in the body with natural food. A large amount of choline contains cabbage (especially cauliflower and broccoli), eggs, peanuts, fish, meat, hard cheese varieties, liver, milk and wheat sprouts. In addition to choline for the synthesis of acetylcholine, vitamins such as pantothenic acid (vitamin B3), folic acid, vitamins B12 and B1 are needed. Just in the elderly, as well as in people suffering from bowel disease, there is a shortage of B vitamins.

The scientists also place great hopes on deanol (meclofenoxate) - in a scientific environment known as dimethylaminoethanol (Dimethylaminoethanol) or abbreviated DMAE. With a lack of acetylcholine in the body, it can be re-synthesized in the required amount from deanol. Some medical research has proved the positive effect of this substance on brain function.

In one experiment, conducted over a period of 3 months, a group of people with memory problems and concentration of attention took medications containing deanol and choline. At the end of the experiment, problems with concentration disappeared in 84% of the subjects, memory improved in 75% of the participants in the experiment.

In addition, supplying your body with all the necessary substances for building neurotransmitter molecules by substances, do not forget that the synthesis of acetylcholine (and hence memory improvement) will occur only if the brain is actively involved, receiving sufficient information for thought and memorization. Do not be lazy to load your memory, giving it food for thought.

And one more aspect of the problem of memorization. For intensive activity, brain cells require continuous intake of energy and nutrients, which is ensured by the flow of blood. Poor blood supply leads to rapid fatigue, headache and drowsiness. So do not be lazy at least 30 minutes a day to devote to intense physical training. Only all three factors - proper nutrition, physical and intellectual loads, - in aggregate will help to significantly improve memory and keep it to a very old age.


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TABLETS OR PSYCHOTHERAPY?

10 Feb 2018

At once it is necessary to make a reservation that it is possible to put so a question when it comes to mental disorders and psychological problems in which psychotherapy is shown. With problems related to the competence of psychiatry (psychotic states, schizophrenia, manic-depressive psychosis, etc.), without taking psychotropic drugs, alas, usually can not do.

xanax phenazepam

Psychotherapy in general and psychoanalysis, in particular - drug-free types of treatment of mental disorders, but sometimes the use of light antidepressants and tranquilizers can be combined with psychotherapy.

If we talk about the medical treatment of mental disorders, it should be noted that the use of psychotropic drugs can only alleviate the current mental state, to improve the condition in the long run, drugs are not invented. Self-administration is not recommended, as much depends on the dosage and frequent side effects; also psychotropic drugs cause dependence quickly enough, to obtain an effect, more and more dosage is required, and if they fail, the mental state is aggravated.

In general, there are the following groups of the most commonly used psychotropic drugs:

- tranquilizers (soothing, with anxiety and insomnia) - glycine, phenazepam, tazepam, elenium (librium), relanium (seduxen), nosepam,

- Neuroleptics (for the relief of psychotic disorders, in small doses for neurotic) - sonapaks, etaperazine, chloroprotexen, aminazine, haloperidol, respolept (the last three are for psychotic disorders only),

- antidepressants (increasing mood) - with all neurotic depressions and anxiety - Prozac (fluoxetine, portal, profluzak), tsipramil; at dreary and asthenic depressions - pyrazidol, eglonil; with anxious depression - ludiomil, coaxil, zoloft,

- nootropics (to improve memory and attention) - nootropil, pyracetam, coguitum, centedrine,

- Atarapticks (anti-anxiety preparations of selective action (before flight, examination) - Xanax.

The most common side effects of psychotropic drugs - drowsiness, decreased potency and sexual desire, decreased appetite, nootropics stimulate anxiety. All psychotropic drugs are incompatible with alcohol.

The use of psychotropic drugs can be recognized as justified when, for example, it is a question of quickly arresting severe emotional experiences, depressive episodes (antidepressants of the last generation), restoring the sleep regimen (tranquilizers) - that is, to help a person return to a workable state. The course should not exceed one to two months. Thus, it is necessary to understand that antidepressants relieve the condition, and do not treat. Although the availability of drugs in the treatment scheme is sometimes justified. But it is one thing - to conduct a course of antidepressant medication, to start to function normally, to fix the improved condition and to search for the causes of the emergence of psychic problems with the help of psychotherapy, it's another thing to see an antidepressant as a panacea for mental problems and come into dependence on it.


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Pyrithinol - Pyriditolum

06 Feb 2018

Pyrithinol (Pyriditolum)

Bis- (2-methyl-3-hydroxy-4-hydroxymethylpyridyl-5-methyl) -disulfide dihydrochloride.

Synonyms: Pyrithinol, Cerebol, Energol, Encephabol.

The structure of pyriditol differs from nootropic drugs GABAergicheskoy nature. It can be considered as a doubled pyridoxine molecule containing a disulfide "bridge" (pyridoxine polysulphide).

encephabol

Pharmacologically, the drug is characterized by nootropic activity with a complex spectrum of psychotropic activity. It enhances the effects of phenamine, but also reduces spontaneous motor activity, prolongs the hypnotic effect of barbiturates, enhances the anticonvulsant effect of phenobarbital. The drug activates metabolic processes in the central nervous system, promotes the acceleration of the penetration of glucose through the blood-brain barrier, reduces the excessive formation of lactic acid, increases the resistance of brain tissue to hypoxia. There is evidence of a decrease in the content of GABA in the nervous tissue under the influence of pyriditol. B6-vitamin activity does not.

According to clinical effects, pyriditol is similar to antidepressants, which have sedative properties, but in the aggregate, its action is classified as nootropic drugs.

Piriditol is used for complex therapy in shallow depressions with retardation phenomena in asthenic conditions, adynamia, neurosis-like disorders, traumatic and vascular encephalopathy, residual phenomena after neuroinfections and cerebral circulatory disorders, cerebral atherosclerosis, migraine. Children are used to delay mental development, cerebrosthenic syndrome, oligophrenia, encephalopathy.

Contraindicated in severe psychomotor agitation, epilepsy, increased convulsive readiness.


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Cogitum

01 Feb 2018

Continuing the topic of medicine, I want to say about Kogituma. Piracetam, encephabol, pantogam, ceraxon, glycine - give noticeable progress. But for many people it is Cogitum that becomes a real breakthrough.

Cogitum contains acetylamino-succinic acid, a biologically active substance, which:

  • stimulates the work of the central nervous system - all electrochemical processes in the brain are faster;
  • normalizes the processes of regulation - the tasks assigned to the brain are more clearly and harmoniously performed;
  • increases the plasticity of the nervous system - the child, like a sponge, absorbs the knowledge gained and easily applies them in practice;
  • Accelerates the child's mental and speech development;
  • has general toning properties, helps to cope more quickly with stress, increases stamina;
  • stimulates the production of interferon and antibodies, strengthens the immune system

Cogitumum to children is appointed at:

  • speech development delay
  • delay in psychomotor development
  • head injuries, including birth trauma
  • severe adaptation in school or kindergarten
  • asthenic syndrome, and also in the recovery period after a long protracted illness.

The drug does not interfere directly in the work of the brain, but only directs the development of the central nervous system in the right direction, helping the kid quickly catch up undeveloped skills and catch up with peers in development.

ALWAYS CONSULT THE DOCTOR WHICH YOU TRUST!


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