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).
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
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
Picamilon 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, xanthinol nicotinate, and
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 vinpocetine, 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.
hypoxic states, Picamilon 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 Picamilon 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 Picamilon
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
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
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
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
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
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, Picamilon can be used to abolish
withdrawal symptoms in chronic alcoholics.