How And Why Picamilon Works
   by R. P. Kruglikova

Drugs that normalize the gamma aminobutyric acid (GABA) system consist mainly of substances that activate GABA receptors, inhibit GABA utilization or increase the permeability of the blood-brain barrier to GABA. One way of creating preparations of this kind is to use substances that are carriers of the GABA molecule, including vitamins or their derivatives and, in particular, nicotinic acid (niacin).
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Niacin has been chosen as the carrier because of its valuable pharmacological properties, its low toxicity, and its high biological availability.  It has therefore been suggested that a combination of niacin and GABA in the same molecule would increase the potency of each component.
Picamilon (nicotinyl-y-aminobutyric acid) was first synthesized at the All-Union Vitamin Research Institute in 1970.  It is a white crystalline powder that is odorless, highly hygroscopic (takes up moisture readily), and readily soluble in water.

In studies in animals Picamilon has been shown to have positive action on the cerebral circulation, and also exhibits the properties of a tranquilizer with a stimulating component.  Unlike tranquilizer drugs, Picamilon does not induce muscle relaxation, drowsiness or lethargy.

The action of the compound on cerebral circulation and on neural regulation was studied in anesthetized cats; conscious, unrestrained cats; and on unanesthetized rabbits.  Picamilon stimulated cerebral circulation and lowered vascular tone in both arterial systems of the brain. The increase in the blood supply to the brain in conscious animals took place to a more marked degree than in cats under general anesthesia. The drug also lowered blood pressure.  It must be emphasized that these effects manifested themselves after both intravenous and oral administration of the compound. In all the animals, Picamilon increased blood flow.

In the strength and duration of its cerebrovascular effect, Picamilon is much superior both to GABA and to niacin.  Under the same experimental conditions, GABA in a dose of 10 mg/kg (intravenously) caused no change in cerebral blood flow, and only when given in a dose of 300 mg/kg did it increase blood flow, with the effect lasting three to five minutes. Niacin in large doses (50 to 100 mg/kg) increased cerebral blood flow by 5 to 10 percent.

Brain Blood Flow
In its effect on cerebral circulation, Picamilon was shown to be more effective than papaverine, nialamide, complamin (xantinol nicotinate), and dihydroergotoxin (redergin).

An essential role in the mechanism of action of Picamilon is its effect on nervous control of the cerebral circulation.  It weakens changes in cerebral blood flow during the vasomotor reflex, considerably inhibits constrictor responses of vessels in the carotid and vertebrobasilar basins due to stimulation of afferent fibers of somatic nerves, and causes gradually developing inhibition of tonic and reflex activity in sympathetic nerves.
Neuropharmacological screening tests on Picamilon have demonstrated its tranquilizing properties in small doses.  For instance, at a dose of l mg/kg, Picamilon prevents the negative consequences of emotional stress (in cats it normalizes the orienting reaction when disturbed by the response to rage and fear).  Like diazepam, it has an inhibitory effect on motivated aggression, associated with fighting for territory in rats.

Investigation of Picamilon's effect on the threshold of "self-stimulation" showed that in higher doses (80 and 160 mg/kg), in contrast with small doses, which have a tranquilizing effect, Picamilon lowered the "self-stimulation" threshold (like amphetamine), but at the same time reduced the number of self-stimulation.  The stimulating action of the drug also has been shown in general anesthesia.  For instance, at a dose of 100 mg/kg, Picamilon reduced by 1.7 times the duration of the sedative effect of hexobarbital sodium and reduced by half the duration of thiopental anesthesia.
Unlike tranquilizer drugs (chlorodiazepoxide, diazepam, relanium, phenazepam), Picamilon does not induce muscle relaxation, drowsiness or lethargy.  Clinicians have stated that the drug closely resembles cavinton (the ethyl ester of apovincamic acid), but comparison of the properties of the two compounds showed that Picamilon is superior.

After the administration of Picamilon at a dose of 5 mg/kg, defense-conditioned reflexes (jumping onto a rod) were restored after their disappearance due to fatigue (by 130 percent, compared with 12 percent in the control). Given to rats at a dose of 50 mg/kg it restored physical working capacity during a rest period of one hour by 76 percent, compared with 38 percent in the controls.

In a model of shock-induced amnesia of the conditioned passive avoidance reaction, like other GABA-ergic drugs (sodium hydroxy butyrate, fenibut, pantogam), Picamilon exhibited anti-amnesiac properties.  In hypoxic states, the compound was found to have anti-hypoxic activity. The presence of anti-amnesiac and anti-hypoxic properties in the spectrum of action of Picamilon places it in the group of nootropic agents.

There is evidence that activation of the GABA-ergic system in various kinds of stress can prevent damage to the body when exposed to various stimuli. In confirmation of this hypothesis, scientists who studied the effect of GABA derivatives on the development of toxic (nicotinic) cerebral edema (fluid on the brain), showed that Picamilon in a dose of 500 mg/kg, injected 30 minutes before nicotine (40 mcg/kg), prevented the development of edema. If the compound was given at a dose of 200 to 300 mg/kg, the density of the brain tissue was increased, but not up to the control level, and the total water content had no significant change. They suggested that the mechanism of the anti-edematous action of Picamilon is linked with a change in energy metabolism in neurologic tissue.

Quickly through The Blood Barrier
Thirty minutes after injections of Picamilon into rats at a dose of 100 mg/kg (intraperitoneally) the concentration of the oxidized form of nicotinamide adenine dinucleotide (NAD) in the brain rises by 67 percent above the control level, and that serum lactate dehydrogenase activity falls by 23 percent, with glutamateoxalate transaminase activity showing no significant change.  A more prolonged action of the compound led to normalization of the NAD level in the rats' brains.
The study of the effect of Picamilon on active GABA uptake by synaptosomes in the rat cerebral cortex showed that it moderately inhibits GABA uptake by synaptosomes, whereas niacin has no appreciable inhibitory action on this process.
Scientists at the Department of Biochemistry, Odessa University, found that Picamilon passes quickly through the blood-brain barrier.  As early as 30 minutes after subcutaneous injection, the compound was found in the brain, penetrating it by an order of magnitude more rapidly than GABA. The time course of accumulation of Picamilon in the brain correlated with its blood level.  Accumulation of the compound in muscle tissue one to two hours after injection was greater (10 times) than that of GABA. Picamilon is retained in the body longer than GABA.

A six-month toxicity study showed that Picamilon does not change the behavior or condition of rats when administered in doses of three to 75 mg/kg, and causes no significant changes in the blood, urine and internal organs of the animals. Some morphological changes were found in the kidneys of rats receiving Picamilon in a dose of 75 mg/kg (15 times higher than the therapeutic dose).  A microscopic study of the kidneys indicated manifestations of glomerulonephritis and nephrosclerosis, which led to the consideration of renal pathology as a contraindication to Picamilon. However, during clinical studies with Picamilon- even when administered over a long period or in repeated courses-no disturbances were found in the kidneys or the urinary system.

Adverse Effects Few
Picamilon produces no allergenic, teratogenic, embryotoxic or carcinogenic effects. On this basis, the pharmacological committee of the Ministry of the Health (Russia) recommended clinical trials of Picamilon for cerebrovascular disturbances, as a daytime tranquilizer, as a stimulant in depressive and asthenic (weakening) states, and to improve physical and mental working capacity. Picamilon was studied in a large number of scientific facilities within Russia.  The total number of patients under observation was 984. Picamilon tablets were prescribed two to three times a day at a dose of 0.02 to 0.05 grams, and in a daily dose of 0.04 to 0.3 grams.  Courses of treatment lasted from two weeks to one-and-a-half months. The effectiveness of treatment was assessed by clinical and laboratory tests.  Cerebral blood movements were evaluated by objective methods, including echopulsography, echoencephalography, rheo- encephalography, ultrasonic scanning, biomicroscopy of the conjuctiva, and electroencephalography.

In patients with acute cerebrovascular disturbances, improvement occurred on the fourth or fifth day, when the severity of neurologic symptoms was reduced.  Later, headache, dizziness, noise in the head and memory disorders were reduced, motor and speech disorders began to regress rapidly, sleep improved, and irritability, emotional stress and anxiety were reduced. The velocity of cerebral blood flow was increased.
Administration of Picamilon to patients suffering from the results of cerebrovascular disturbances (more than a month later) proved effective after the second or third day of treatment.  The patients' emotional background, speech and memory were improved, and levels of enzyme activity (AST, ALT, LDH) and lactate concentration were restored to normal. Scientists who studied the effects of GABA derivatives on the development of toxic cerebral edema (fluid on the brain) showed that Picamilon in specific doses prevented the development of edema.
In chronic cerebral insufficiency, Picamilon improved the mood and memory of the patients, reduced irritability and tearfulness, abolished autonomic vascular manifestations, and reduced metabolic disturbances. In patients with memory disorders (global amnesia), considerable improvement in memorization and recall was observed on the fifth to seventh day of treatment, and the patients were able to return to work.
In patients with astheno-neurotic anxiety and depression, activation of mental functions and motor activity was observed, including improved speed and quality of operative activity, concentration of attention and mood, relief of anxiety, improved working capacity, and so on.  The use of Picamilon in depression, along with moderate doses of tricyclic antidepressants, enabled the doses of the latter to be reduced. In patients with alcoholism, Picamilon abolished many withdrawal symptoms, especially apathy, weariness and lethargy. The patients later become more tranquil, less fussy and anxious, and their working capacity improved.

Lowers Blood Pressure
The effect of Picamilon on cerebral blood flow was compared with that of papaverine and xanthinol nicotinate.  The scientists found that Picamilon had a stronger blood pressure-lowering effect than papaverine; xanthinol nicotinate mainly affects the peripheral circulation, and it exhibits neither tranquilizing nor stimulating properties.
Picamilon is an approved drug in Russia. It is intended for use in adults as a vasoactive (effecting the caliber of blood vessels) and nootropic (benefiting cognition and nerves) agent for acute cerebrovascular disturbances of mild severity, chronic cerebrovascular insufficiency, and vegetovascular dystonia (an imbalance between sympathetic and parasympathetic influences on vascular tone). The drug is indicated as a tranquilizer for states of anxiety, fear, increased irritability and emotional stress.  Picamilon is recommended for depressive disorders in the elderly and for senile psychoses.  In management of drug addictions, the compound can be used to abolish withdrawal symptoms in chronic alcoholics.  

Picamilon is a very effective vasodilator (it improves brain blood flow), in fact Russian experiments suggest that picamilon is better than Hydergine and even better than vinpocetine in this regard.  For while vasodilatation is occurring, more likely the result of the niacin it is also displaying a mild tranquilizing effect, which helps prevent the negative effects of emotional stress.  This second trait is the likely affect of GABA, as it is with the basis of the diazepam tranquilizing drugs (such as Valium) which inhibits the reuptake of GABA, the presence of GABA appears to have a calming effect.  But what makes picamilon unique is that while it counteracts stress and anxiety, it doesn't have a sedative action. Picamilon can have a mild stimulatory action.  Picamilon may be the first anti-anxiety drug that doesn't make you drowsy.  Again Russian studies have compared picamilon with other psycho-stimulant drugs including piracetam, phenazepam, diazepam, vinpocetine, xanthinol nicotinate, and papaverine.  It was noted that the stimulant properties of picamilon were greater than that of piracetam.  After taking picamilon the patients felt better and giddiness and tremor disappeared.  Further benefits of picamilon over the standard tranquillizing drugs are that it does not display any signs of inducing muscle relaxation, lethargy, or drowsiness.  Picamilon has a number of positive benefits for the patient; it can reduce anxiety, lower stress and yet at the same time display a non-sleepy action or indeed even a stimulatory property.  Many patients claim that they have a 'good feeling' while using picamilon.

The good news is that in over 10 years of use in the former Russian states, picamilon can be considered to be a very safe drug.  It has not been shown to produce any allergenic, teratogenic, embryotoxic or carcinogenic effects. Most side effects have been noted as headache, dizziness and nausea.  It has been stated that at higher dosages picamilon can lower blood pressure, and while this may be advantageous in some cases those persons with already low blood pressure should be monitored. 

The effects of picamilon are fast acting, often within an hour and the half-life usually ensures that these effects continue for a period of approximately 6 hours.  Accordingly dosages have been applied twice or three times daily, but late evening use should be avoided otherwise insomnia may ensue.  Dosages for anti-anxiety are approximately 50mg 2 or 3 times daily.  If a stimulatory property is also required dosage can be increased to 100mg 2 or 3 times daily.

To list a few of the known clinical results, picamilon has shown promise in memory, mood, anxiety, stress, motor and speech disturbances, sleep, irritability, alcohol withdrawal, and visual acuity.

WHAT IS PICAMILON?
Picamilon is a combination of GABA and Niacin.  By chemically bonding these two nutrients into one compound, new and unique spectrums of beneficial nootropic (cognitive enhancing) effects are achieved.

WHAT THE STUDIES SAY:
Studies show that Picamilon dramatically increases blood flow and circulation within the brain, and achieves results far superior to other nootropic agents such as Hydergine, Ginkgo Biloba etc. In small doses, Picamilon has a tranquilizing action, which prevents the negative physiological effects of emotional stress. This tranquilizing influence is also helpful for moderate states of anxiety and depressed negative emotions. Unlike most tranquilizing agents, Picamilon doesn’t have any sedative qualities, making it much more suitable for daily activities. Picamilon provides a tranquilized yet energized state of being.

EFFECTS:
The effects of Picamilon are usually felt quickly, with most people noticing impact within an hour. The effects of each dose last for about 4-6 hours. In small doses of 50mg three times per day, Picamilon provides a mild tranquilizing and mood stabilizing effect without sedation. In higher doses of 100mg three times per day, Picamilon provides a stimulating influence that is experienced as an increase in energy and endurance. The cognitive enhancing effects of Picamilon are cumulative and become more evident after several weeks of daily usage. Picamilon has extremely low toxicity, and shows no allergenic or carcinogenic properties. With its unique spectrum of effects, Picamilon may very well be the most amazing dietary supplement discovery of the century!

WARNING:
Not for use by children, pregnant or lactating women. If you are under medical supervision, or if you are taking MAO inhibitor medications or any other drugs then consult with your physician before using this product.

DIRECTIONS:
1 to 2 tablets daily up to three times daily.  For maximum absorption take between meals, on an empty stomach.  For best results use consistently for a period of several weeks as the cognitive enhancing effects are cumulative.

Picamilon Draws Attention
   by A.L. Karayev

The chemical modification of widely used vitamins is one of the fundamental trends in the search for new pharmaceutical agents. The main advantages of vitamin-like drugs are the broad spectrums of action, the easy penetration through cellular membranes, the low toxicity, and the rare side effects. The broad spectrum of action of these agents is connected not only with their influence on unspecific metabolic processes, but also on various neurotransmitter systems.

In experiments, Picamilon decreases cerebral blood-vessel tone and increases intracranial circulation rate.  The drug exceeds in force and duration the effects of GABA and niacin alone.  In small doses, Picamilon shows tranquilizing action to prevent the negative effects of emotional stress.  As with diazepam, it depresses motivative aggression.  The tranquilizing influence of the drug on negative emotions expressed through the hypothalamic system has been proved.  Picamilon is characterized by a tranquilizing effect, without a sedative component but with elements of stimulant action.
The drug effectively counteracts stress and lowers the depressing influence of ethanol on the behavior of animals.  It rapidly penetrates through the blood-brain barrier and improves the functional state of the brain by producing a beneficial effect on its metabolism.

Picamilon has been found to have low toxicity during experiments on animals.  The median lethal dose is more than 10 gram per kilogram of body weight and more than 6 g/kg intravenously.  The low toxicity was demonstrated during six months of chronic toxicity testing when the drug displayed no allergenic, carcinogenic, teratogenic or embryotoxic action.

Independent researchers in 16 medical centers in Russia carried out a clinical trial with Picamilon in a great number of patients.  Picamilon was prescribed two or three times a day in doses of 20 to 50 mg. The course of therapy ranged from two weeks to three months.

Significant Neurologic Improvement
Picamilon proved to be quite effective in patients with acute brain syndrome.  On the second or third day after taking the medicine, the patients showed significant neurologic improvement.  The positive dynamics of the cerebral signs were noted.  The effect increased when taking the drug, especially during the second and third week of treatment. In this case, objective methods of examination were used to document the increase of cerebral circulation, and the normalization of cerebrovascular resistance.
Picamilon was effective in patients with mild-to-moderate impairment during subacute and early convalescent periods.  It improved emotional conditions, speech and memory.  Patients showed increased general activity, and better work and social adaptation.

Picamilon stimulated physical and psychic rehabilitation from various asthenic (weakening) disorders due to mental and somatic pathology. Picamilon was effective in patients with neurotic disorders in which the leading signs were asthenic-astheno-depression, and astheno-hypochondriac disturbances that accompany fear, anxiety, fatigue, emotional and vegetative instability, and sleep disturbances.

Picamilon reduced anxiety and hyperesthesia (whereby normal touch creates pain) without sedative effects, which improved sleep.
According to the majority of researchers, usage of Picamilon employed as a means of correcting neuroses, manic-depressive syndrome, involutional depression and schizophrenia enabled doctors to decrease doses of psychotropic drugs used in the treatment of these conditions. The combining of Picamilon with conventional treatments accelerated reduction of the psychopathological signs when compared to conventional treatments alone.

Improvement in A Week
Picamilon also was effective in patients with psycho-organic syndromes including cerebral atherosclerosis, brain injury from physical trauma, and toxic lesions of the brain.  The condition of these patients took a turn for the better by the end of the first week.

The effectiveness of Picamilon in patients with migraine headache was studied.  It has been established that the drug has a pronounced effect on painful hemicrania-pain or headache in one side of the head-by decreasing its intensity and mitigating or stopping any accompanying symptoms.  In persons suffering from chronic alcoholism, Picamilon alleviated withdrawal symptoms.

Alcohol Withdrawal Aided
The effectiveness of Picamilon was compared with other similar drugs, including piracetam, phenazepam, diazepam, vinpocetine, xanthinol nicotainate and papaverin.  It was noted that the psycho-stimulant effect of Picamilon was greater than piracetam. After taking Picamilon the patients felt significantly better. Giddiness and tremor disappeared quicker.
Most patients preferred Picamilon to piracetam.  It normalized the behavior of patients faster and more completely than piracetam. In another study, Picamilon acted faster than vinpocetine in treating withdrawal symptoms in patients suffering from chronic alcoholism.

According to clinical studies, Picamilon is recommended for the treatment of cerebrovascular diseases in subacute and early convalescent periods, as well as for transient brain damage, neurocirculatory dystonia, and chronic cerebral circulatory insufficiency. The drug is recommended as a tranquilizer possessing no sedative action.  Picamilon can be prescribed in cases of asthenic (weakening) syndrome and disorders due to various psychotic and somatic pathology.  It is used in the treatment of depressive disorders in the elderly and as therapy for senile psychoses.  It also is recommended for the prevention and treatment of anxiety and stress.  Picamilon may be used to relieve the symptoms of alcoholism withdrawal.

Picamilon 
  translated from Russian

Pharmacological properties
Picamilon increases blood supply and functional state of the brain, increases microcirculation and hemodynamics of the eyes, and enables improved arterial blood supply to internal organs.  It possesses nootropic, anti-hypoxic and antioxidant properties; is retained for a long time in body tissues; it is mildly toxic.  In addition, Picamilon renders tranquilizing (not causing myorelaxation, sleepiness or apathy), and psychostimulating effects, restores physical and mental working ability after overwork, and lessens the suppressing influence of ethanol on the central nervous system.

Indications for use
Picamilon is used in the capacity of a nootropic and vasoactive agent for acute ischemic disturbances of the cerebral blood circulation of mild to moderate severity; and also during various stages of the restorative period, for discirculatory encephalopathy, vegetative dystonia, craniocerebral traumas and neuroinfections.  It is recommended for prevention and stopping assaults of the simple form of migraine.

Preparation is indicated by conditions accompanied by anxiety, fear, and elevated irritability; by the asthenic states caused by various neuro-psychological illnesses or connected with increased physical and mental stress, depressive disorders of the elderly, or senile psychosis.

It is used in complex therapy for stopping acute alcoholic intoxication. With chronic alcoholism—for decreasing asthenic and asthenoneurotic, post-psychotic, pre-relapse states, and also for alcoholic encephalopathy.

In opthalmological practice, for primary open-angle glaucoma with normalized intraocular pressure, and for diseases of the retina and the optic nerve.

In urological practice Picamilon is used in children and adults with urinary disorders for the purpose of an improvement in the adaptive function of the urinary bladder.

Methods of treatment and dosage
Picamilon is taken internally (independent of food intake).

For discirculative encephalopathy, 0.02-0.05g 3 times per day. A course of treatment lasts from 1-2 months, and may be repeated after 5-6 months.

For prevention of migraine, tablets of 0.05g 3 times per day; for treating an attack use 0.1g in a single dose.

For asthenic states, 0.04-0.08g per diem, in unusual cases up to 0.2-0.3g per day, for the duration of 1 to 1.5 months.

For depressive states in the elderly, 0.04-0.2g per day in 2-3 doses, for the duration of 1.5 to 3 months.

For restoration of working ability and with increased workload, 0.06-0.2g per day for 1 to 1.5 months; for athletes the same dose for 2 weeks of the training period.

For alcoholism in a period of abstinence, 0.1-0.15g per day for the duration of 6-7 days; for more prolonged breakdowns or relapses a daily dose of 0.04-0.06g.

For treatment of primary open-angle glaucoma, 0.05g 3 times per day for the duration of 1 month.  In opthalmological practice after intramuscular or parabulbar introduction, depending on conditions, from 0.02-0.05g 3 times per day, or 0.06-0.15g per day for duration of 1 month.

For functional disorders of urination in children, 0.02g 2 times per day for children 3-10 years; 0.02g 3 times per day for children over 10 years. For organic disorders of urination caused by myelodysplasia, 0.02g 3 times per day for children under 10 years; 0.05g 2 times per day for children 11-15 years; and 0.05g 3 times per day for children over 15 years. A course of treatment is 30 days.

For disorders of urination in adults, 0.05g 3 times per day. A course of treatment is 4-6 weeks.

Contraindications
Use of Picamilon is contraindicated in cases of acute sensitivity to the preparation, or acute severe illnesses of the kidneys.

Picamilon 
A Unique Domestic Preparation With a Wide Spectrum of Action
  Translated from Russian

The beginning of the 1970s and subsequent years is characterized by the appearance of a new class of medicinal preparations, called nootropics, which are finding increasingly wider applications in various areas of medicine.  Nootropic preparations are applied successfully for breakdowns of memory, attention, learning, and for treatment of loss of brain blood circulation, brain trauma, chronic alcoholism and other disorders. Among the medicinal properties of this group a notable place is occupied by the domestic preparation Picamilon, synthesized in 1969 by the All-Union Scientific Research Institute and studied in the NII pharmacological RAN . By chemical structure Picamilon is a derivative of the gamma-amino-butyric acid (GABA) and nicotinic acid. The preparation was introduced in medical practice in 1986, and to the present time has achieved sufficiently large experience in its application.

The great interest of clinicians in Picamilon may be attributed to the unique combination of its pharmacological properties.  It possesses high cerebrovascular activity, which exceeds the effect of cinnarizine, papaverine, xanthinol niacinate and piracetam.  One of the most important components in the spectrum of psychotropic activity is its nootropic effect, which determines its clinical use to a significant degree. The preparation has a unique tranquilizing effect (the manifestation of action is inferior to diazepam); in this case the preparation does not cause a myorelaxation effect. The important property of Picamilon is the ability to quickly restore mental and physical fitness for work, which was lost through overstress. Clinical experience with application of Picamilon shows that it is effective for ischemic disturbances of cerebral blood circulation, discirculatory encephalopathy, vegetative dystonia, and for prevention and treatment of the simple form of migraine. Picamilon has proven an effective medicinal treatment for patients with disorders of a neurotic level, with accompanying manifestations of anxiety, fear, emotional and vegetative instability. Picamilon finds a use in the complex treatment of alcoholism and acute alcoholic intoxication.  At this time the list of indications for prescription of Picamilon is constantly growing.  Clinical studies have shown that Picamilon possesses favorable properties in opthalmological practice in the treatment of primary open glaucoma, diseases of the retina and the optic nerve of vascular genesis.  It has been adapted also in urological practice for treatment of neurological disorders of urination in children and adults. It is important to note that the use of this preparation does not cause habituation, but its safety is proven for 10 years in wide and intensive clinical application. Picamilon is prescribed both in mono-preparation and in combination with other medicinal agents.

The fact of the varied spectrum of therapeutic action, noted by many clinicians, testifies to the possibility of a wider application of Picamilon in the capacity of a medicinal and preventative agent.