Phenotropil Spectrum of Pharmacological Effects

Phenotropil refers to the group of nootropics of pyrrolidone derivatives family, which includes such a drug as Piracetam. Unlike their predecessors, Phenotropil is characterized by an extremely wide range of pharmacological and therapeutic effects. Phenotropil improves cognitive function, learning and memory processes,Phenylpiracetam has anti-hypoxic, anxiolytic, psychoactive, anticonvulsant, analgesic effect, increases efficiency and resistance to extreme influences, surpassing Piracetam in many respects. All these qualities allow us to recommend Phenotropil as a treatment for patients with lesions of the central nervous system, and to enhance the stability and level of healthy life of people in extreme situations

Phenotropil (N-carbamoyl-methyl-4-phenyl-2-pyrrolidone) in its main pharmacological action relates to the neuroprotective drug is registered and permitted to the Russian Ministry of Health of industrial production in 2003.

Basics nootropics concept formed in the 1980s, when, after a successful introduction into clinical practice of the first of this class of drug - Piracetam (2-oxo-1-pyrrolidone-acetamide; nootropil, firm «UCB», Belgium, 1977) began to appear other drugs of Pyrrolidone series. Currently, a family of Nootropics, Pyrrolidone includes more than 10 original drugs, the most famous is Piracetam, Oxiracetam, Aniracetam, and Etiracetam, Pramiracetam. Based on the chemical structure, these nootropics is often called Racetam. There were other family of nootrop drugs. After them, including cholinergic, GABA-ergic, Glutamatergic, Peptidergic and other substances. In addition, the neuroprotective action of the components have many medicinal plants - ginseng, Siberian Ginseng, Schisandra, etc.

However, the most popular is a Nootropic Piracetam, which is produced by many companies under different brand names and is the reference drug for the entire group of these drugs. On the extreme importance of drugs with neuroprotective effect suggests a wide range of application data: according to the WHO statistics, one third of the adult population in Europe and Japan takes nootropics, and with good reason can be attributed to a group of essential drugs.

Phenotropil as piracetam, a pyrrolidone derivative, i.e. its base is closed in a loop γ-aminobutyric acid (GABA), which is the major inhibitory neurotransmitter, and control the actions of other mediators. Unlike Piracetam, Phenotropil has a phenyl radical, which determines a significant difference in the spectra of the pharmacological activity of these drugs. So Phenotropil, like most other nootropics, is similar in chemical structure to endogenous mediators.

Common Principles of Nootropics action

For Pyrrolidone group nootropics, and in particular Phenotropil and Piracetam are characterized by low toxicity and the absence of pronounced side effects even in sub-toxic doses. Mechanisms for implementation of nootropics the effects are similar to the natural and reflect their neurometabolic action. Thus, the electrophysiological mechanisms of action of nootropics expressed in facilitating the flow of information between brain structures, strengthening of synaptic transmission, increasing the level of consciousness, strengthening the absolute and relative EEG power spectrum of the cortex and subcortical structures such as the hippocampus.

The mechanism of the neurochemical effects of Pyrrolidone nootropics determined by the metabolic stimulation, bio-energy and plastic processes in the brain, including increased protein synthesis, and phospholipids, increased turnover rate information molecules. While there is no evidence of the existence of its own receptors for nootropics pyrrolidone, and it is shown that they do not have a high affinity for the majority of known receptors. However pyrrolidone nootropics have synaptic affect the basic system - cholinergic, adrenergic, dopaminergic, GABAergic and glutamatergic, and in the direction in which these systems are related to the memory and adaptation to extreme stress.

Experimantal Research of Phenotropil

Phenotropil has the most extensive, compared to other nootropics, spectrum of actually neuroprotective effects, and much greater in activity than Piracetam. As Piracetam, Phenotropil has expressed antiamnesic effect in different types of amnesia.

Antiamnestic effects of Phenotropil were studied in rats using the technique of passive avoidance (CRPA) in a special installation. The installation consists of a dark ( "dangerous") with the electrode chamber floor, the connection is closed the opening with a brightly lit platform. To develop CRPA (learning) rat is placed on the platform of the tail to the opening of the chamber with electrode floor. During 180 seconds to record the time of the first entry of the animal into the chamber. At the moment when the animal enters into the dark chamber, the hole is closed and is applied through the floor electrical pain stimulation. Thereafter, the rat was removed from the chamber. Preservation checked CRPA in 24 hours after its production by placing the animal on the platform installation in the same way as in training. Within 180 seconds was recorded during the first call to the camera. If the rat did not go into it, it is not considered equal to 180 seconds. Amnesia (CRPA fading) caused by maximal electroshock (MES), applied through corneal electrodes immediately after training, or the introduction of anticholinergic scopolamine 60 minutes before training.

Control (intact) animals not subjected to amnesial effects when playing CRPA in 24 hours after training be preferred despite the disadvantage of, on illuminated platform. In contrast, rats that received MES or scopolamine, forget training and in a short time entry into the dark chamber where they had previously received pain stimulation. This behavior indicates forgetting the acquired skills.

Phenotropil in over a wide dose range (12.5 to 600 mg / kg) completely restored the memory, impaired MES. In addition, rats that received Phenotropil, superior control animals CRPA reproduction. Influenced of Phenotropil significantly increased time to call in a dark cell, indicating that it antiamnestic activity and ability to eliminate amnesial action MES. Antiamnestic effect of Phenotropil is intensified with increasing dose. According antiamnestic action of Phenotropil is significantly superior to Piracetam. Thus, Piracetam provided antiamnesic effect at a dose of 300 mg / kg, and Phenotropil - 12.5 mg / kg. Identical depth Phenotropil effects were caused by a dose of 25 mg / kg and Piracetam at a dose of 600 mg / kg. Thus, Phenotropil was in 25 times more active than Piracetam. At a dose of 1200 mg / kg Piracetam provides no antiamnestic effect which causes Phenotropil in a dose of 50 mg / kg. At this dose increases the Phenotropil prior to entry into the dark compartment 7.5 times as compared with 0,9% NaCl, and Piracetam at a dose of 1200 mg / kg increases this time only 3.9 times.

The Phenotropil far effect on impaired memory exceeds Piracetam and other types of amnesia, for example after administration of scopolamine. At a dose of 100 mg / kg significantly weakened Phenotropil amnesiac effect of scopolamine is more than 2 times increasing the time before entering the dark compartment. When using this model, even Piracetam 1000 mg / kg had no effect so pronounced antiamnestic.

Thus, Phenotropil has significant advantages over Piracetam in both doses, and quality antiamnestic effect. Antiamnestic action of Phenotropil is stronger threshold dose below, and the range of effective doses is wider than that of Piracetam.

Anti-hypoxic effect Phenotropil is studied on different models of hypoxia, including hypobaric and normobaric with hypercapnia.

Influence of Phenotropil for resistance to hypobaric hypoxia was investigated in mice. Animals were placed in a glass pressure chamber connected to a vacuum pump, and the vacuum created in the chamber corresponding to 11 thousand. M above sea level. "Lifting" speed was 100 m / s. The protective effect of the drugs was evaluated by the duration of animal life. Phenotropil, piracetam or 0,9% NaCl were injected 30-60 minutes prior to "rise".

Phenotropil significantly increased the life span of mice in the pressure chamber is already at a dose of 100 mg / kg and piracetam - only at a dose of 2000 mg / kg (figure 3.). Thus, when comparing the minimum effective dose Phenotropil exceeded Piracetam 20 times. With increasing doses of Phenotropil 300 mg / kg increased lifespan by 10 times compared with the control. Life expectancy in the chamber after the introduction of Piracetam 2000 mg / kg increased only 2 times.

To study the effect of Phenotropil on resistance to normobaric hypoxia mice were placed individually in room without absorber of CO2. Phenotropil, Piracetam, or 0,9% NaCl was administered 30-60 minutes prior to the experiment. Phenotropil significantly increased the lifespan of mice in room. Piracetam under these conditions did not show antihypoxic properties or 600 mg / kg or at a dose of 1200 mg / kg. Thus, Phenotropil has a pronounced anti-hypoxic action than piracetam.

Influence of Phenotropil on locomotor activity of mice was investigated using a multichannel analyzer motor activity. The analyzer chamber 10 mice were placed, and observation was carried out in the open field for individual animals. Locomotor activity was recorded for 20 minutes. Phenotropil, piracetam or 0,9% NaCl was injected intraperitoneally 5 minutes prior to registration.

Phenotropil increased spontaneous motor activity due to increased frequency of horizontal and vertical movements. When using Phenotropil in doses of 50 and 100 mg / kg increased locomotor activity an average of 17 and 18%. Piracetam, in contrast, caused a reduction in motor activity. Increased physical activity was observed under the influence of Phenotropil in test rats in the open field. A moderate increase in locomotor activity influenced phenotropil indicates its stimulating effect.

Anti-drug effects of Phenotropil. Influence of Phenotropil the duration of drug action of ethanol was studied in mice. Phenotropil in a dose of 50 mg / kg, piracetam in the dosage of 300 mg / kg or 0,9% NaCl was administered 30 minutes before administration of ethanol. The duration of narcotic sleep (immobility) was evaluated by the disappearance and recovery reflex turning.

Phenotropil weakened the narcotic effect of ethanol. Among the animals that received only NaCl, 91% went to sleep after the introduction of the ethanol, the dream lasted more than 10 minutes. Among the animals that received Phenotropil, covered 56%, and sleep was significantly shorter. Against the background of the introduction of piracetam share of conscious animals in the control and experimental groups did not differ significantly (Fig. 4). Thus, Phenotropil has a strong wake-up action and the ability to attenuate the toxic effects of ethanol.

Anticonvulsant effects of Phenotropil and Piracetam are compared in experiments on mice. It was used to induce seizures blocker of the GABA-A receptor bikukuline (40 minutes after administration of test drug) corazol GABA antagonist (30 minutes after Phenotropil or piracetam) or MES. It was recorded clonic, tonic and clonic-tonic convulsions and lethality.

Phenotropil at doses of 100 and 300 mg / kg completely blocked the convulsive effect bikukuline and warned the death of animals in 100% of cases. Conversely, Piracetam at doses of 300 and 600 mg / kg did not block the effect a convulsive bikukuline.

At a dose of 100 mg / kg Phenotropil partially eliminated seizures and 25% reduced mortality when administered Corazol, and 600 mg / kg completely prevented the development of convulsions and death of the mice. Piracetam in doses of 300 and 600 mg / kg anticonvulsive possessed action against Corazol.

Phenotropil exerted a pronounced protective action with respect to convulsions induced by MES. At a dose of 100 mg / kg, it warned convulsions and death in 75% of mice in a dose of 300 and 450 mg / kg - 100% of animals. Piracetam in this test showed no anticonvulsant actions. The findings suggest that Phenotropil unlike piracetam has a pronounced anticonvulsant effect.

Thus, pharmacological studies show that Phenotropil has the unique ability to increase the overall level of life and resistance to extreme influences. This has a rejuvenating effect of Phenotropil under emotional stress, mental and physical overload, hypoxia, trauma, intoxication, fatigue, hypomotility, immobilization, sleep disorders, colds and cramps.

Influence of Phenotropil on the cardiovascular system was studied in experiments on rats and rabbits of both sexes. Phenotropil was administered intravenously or by gavage in gastric.

Intravenous administration to rats of Phenotropil in doses of 50, 100 and 300 mg / kg provided a three-phase influence on blood pressure (BP). During the first three minutes of blood pressure during treatment with Phenotropil decreased by an average of 12, 13 and 18%, respectively, and then increases slightly (by an average of 7% compared to the control) and 9 minutes, returned to baseline values.

In rabbits at 60 minutes after in gastric administration of Phenotropil in doses of 50 and 100 mg / kg blood pressure decrease was noted in the average by 13.4% compared to baseline values. At a dose of 300 mg / kg Phenotropil had no significant effect on blood pressure. After 90 minutes, blood pressure corresponded to baseline values within an arithmetic error.

Phenotropil in doses studied had no effect on ECG rabbits after 15, 30 and 60 minutes after in gastric administration.

The results indicate that when administered intravenously Phenotropil has a three-phase effect on blood pressure, while in gastric – 2 phase effect. The effect of the drug on blood pressure and cardiac function was not pronounced.

Electroencephalographic studies of Phenotropil in doses of 50, 100 and 300 mg / kg when administered intravenously to rabbits of both sexes were performed on every third day for 30 days with 9 stereotaxically implanted with unipolar electrodes. Registration of bioelectrical activity of the brain was performed 8-10 days after implantation of electrodes in free behavior of the rabbits in the experimental chamber with a transparent front wall.

Adaptation period when the animals in the chamber prior to the study was 30 minutes. EEG recording was performed using a 4-channel electroencephalograph. After 3-fold background activity registration test substances were administered to rabbits. Recording biopotentials conducted at 5, 15, 30, 45, 60, 90 and 120 minutes. During the entire study period record changes in the behavior of animals. Every 4th study on the same animal was a control with administration of physiological saline.

Analyzed EEG effects of Phenotropil with Physostigmine (0.2-0.3 mg / kg), Amphetamine (3 mg / kg) and Amizil (0.2-0.3 mg / kg). Studied changes physostigmine and fenamic desynchronization and synchronization amizilic influenced of Phenotropil. Phenotropil administered 5 minutes after injection of test substance. After the research was carried out histological examination of the brain.

Phenotropil in doses of 50 and 100 mg / kg had no effect on spontaneous EEG in rabbits, and in a dose of 300 mg / kg increased the number and the amplitude held cortex rhythm EEG activity, hippocampus and reticular formation. Under the influence of Phenotropil were no significant changes in the EEG effects analyzers substances only in a dose of 300 mg / kg drug provided a antagonistic effect on activation caused by phenamine and desynchronization caused by physostigmine.

The results obtained show that Phenotropil in doses of 50 and 100 mg / kg had no effect on spontaneous EEG and EEG effects analyzers compounds (amphetamine, amizil, physostigmine) and 300 mg / kg has a specific synchronizing effect and antagonizes against the action of amphetamine and physostigmine.

Pharmacokinetics and toxicity of Phenotropil

Phenotropil is rapidly absorbed from the gastrointestinal tract and readily penetrates the blood-brain barrier. The bioavailability of the drug when administered orally is 100%, the maximum blood concentration reached after one hour. Phenotropil is completely eliminated from the body within 3 days; clearance is 6.2 ml / min / kg. Eliminated of Phenotropil slower piracetam - T1 / 2 is 3-5 and 1.8 hours, respectively. As Piracetam, Phenotropil is not metabolized in the body and is excreted unchanged. Piracetam is completely excreted by the kidneys, while 40% Phenotropil excreted in urine and 60% - in the bile and then.

Phenotropil acute toxicity was assessed in mice. Death registration was performed 24 hours. LD50 of product, calculated by the method of Litchfield and Wilcoxon, amounted to 800 (0,796 ÷ 0,803) mg / kg. Comparing the dose that Phenotropil exhibits a nootropic properties (25-100 mg / kg), with its LD50, we can conclude that the formulation has a sufficiently wide therapeutic range and low toxicity. The therapeutic index, calculated as the ratio of therapeutic and toxic doses, is 32 units.

CONCLUSION

Phenotropil has a wide spectrum of pharmacological effects, and on a number of parameters favorably with piracetam. Experimental and clinical studies show that Phenotropil improves cognitive function, learning and memory, psychostimulant has anti-hypoxic, anxiolytic, antiaggressive, antispasmodic, analgesic, antidepressant, vegetative stabilization, anorectic effect, improves cerebral blood flow, increases efficiency and sustainability to extreme stress.

Phenotropil has significantly less antihypoxic effects in comparison with Piracetam. It has a delicate and light vegetative stabilization action and anxiolytic effect, increases resistance to a certain extreme factors, does not have anti-asthenic, psychoactive, antidepressant, anticonvulsant, antiaggressive, analgesic and anorexigenic effects, does not increase physical performance.

Phenotropil has significant advantages to Piracetam evidence revealed in the experiment and clinic performance speed of onset of effect and magnitude of the current dose. Phenotropil has been operating under a single administration, and its application rate is from 2 weeks to 2 months, whereas piracetam effect occurs only after a treatment duration of 2-6 months. The daily dose is 0.1-0.3 g phenotropil and piracetam - 1,2-12 g.

Mechanisms for implementation of Phenotropil effects are determined primarily by its neuro-metabolite profile. As a derivative of Pyrrolidone, Phenotropil resembles Pyrrolidone nootropic mechanism of action. The most striking effects of Pyrrolidones are increasing ATP levels, the activation of adenylate cyclase, a decrease in activity of Na, K-ATPase, increased activity sinopsomalnoy phospholipase A activation of adenylate kinase, inhibition of the cortical release of proline, increased synthesis of nuclear RNA in the brain, enhancing glucose utilization, and others.

A wide range of pharmacological activity and mechanism of phenotropil action are prerequisites for its clinical application. Phenotropil is shown in violation of memory of various origins (aging, the initial stages of dementia, ischemia, and brain trauma, hypoxia, stress, intoxication, fatigue, sleep disorders), cerebral dysfunction in children with learning, acute and chronic cerebral circulatory disorders, in including in subacute and rehabilitative period of ischemic stroke. The indications for use are as Phenotropil: encephalopathy and dystonia, trauma, including craniocerebral, intoxication, convulsive state, dizziness, hyperactivity syndrome with impaired attention, neuroses and neurosis-like states, fatigue, depression, alcoholism (relief of withdrawal symptoms, sober action), obesity.

Phenotropil can use and healthy people to support mental and physical activity, improve the stability and level of life under extreme conditions (stress, hypoxia, intoxication, sleep disorders, injuries, physical and mental overload, overwork, constant cooling, immobility, pain syndromes).

Thus, Phenotropil is a new-generation nootropic neuropsychotropic with unique spectrum of effects and mechanisms of action. Application of Phenotropil in medical practice can significantly improve treatment efficiency and deliver a new level of quality of life in patients with CNS disorders.