Phenylpiracetam
Several selected publications on phenylpiracetam that we cite here are from Russian journals, which are not in PubMed. We reviewed, without a selection bias, key and core articles that demonstrate evidence-based clinical investigations and other available information on marketed products, clinical findings, non-clinical biochemical and pharmacological data, and promising piracetam-like drugs with unknown benefit-risk profiles. 2.
Marketed Products There are six relevant medications on the market worldwide (table II). Piracetam and levetiracetam were developed by UCB Pharma, Belgium; oxiracetam by ISF, Italy; aniracetam by Roche Pharmaceuticals, Switzerland; pramiracetam by Warner-Lambert, USA;[6] and phenylpiracetam by the Medical-Biological Institute of the Russian Academy of Sciences (manufactured by Valenta Pharmaceuticals, Russia).
In 2003, the State Pharmacological Committee of Russia approved phenylpiracetam as a prescription drug for cerebrovascular deficiency, depression, apathy, attention and memory decline, and it is recommended for cosmonauts for increasing physical and mental/cognitive activities in space.[7]
The affinity of phenylpiracetam to the nicotinitic acetylcholine (nACh) receptor, but not the glutamate NMDA subtype, was demonstrated in ligandbinding experiments in vitro. However, injection of this drug (100 mg/kg, intraperitoneally) to rats increases the numbers of both nACh and NMDA receptors, but decreases serotonin and dopamine receptors in the brain tissue.[40]
Phenylpiracetam A phenyl derivative of piracetam, phenotropil or phenotropyl is absorbed fast and exhibits high oral bioavailability (Phenotropil?, product insert). Studies on rodents (100 mg/kg, intramuscular, oral) showed absorption time of <1 hour and half-life of 2.5–3 hours,[19,20] but its pharmacokinetic profiles in humans are unpublished. It ? 2010 Adis Data Information BV. All rights reserved.
Phenylpiracetam A phenyl derivative of piracetam, phenotropil or phenotropyl is absorbed fast and exhibits high oral bioavailability (Phenotropil?, product insert). Studies on rodents (100 mg/kg, intramuscular, oral) showed absorption time of <1 hour and half-life of 2.5–3 hours,[19,20] but its pharmacokinetic profiles in humans are unpublished. It ? 2010 Adis Data Information BV. All rights reserved.
Phenylpiracetam is reportedly beneficial to people who develop cognitive deficits and/or depression after encephalopathy and brain injures (table V). It increased quality of life in patients with encephalopathy after acute lesions (30 people), brain traumas (33 people) and gliomas surgery (36 people). The average minimental state examination (MMSE) scores (a standard 30-point questionnaire used to assess cognition) from baseline improved in all groups. In the end, anxiety improved and depression declined substantially, and that resulted in less discomfort and better ability to execute everyday activities.[85] Recovery of memory, attention and sensomotor disturbances were indistinguishable for similar treatments in mild cranial brain traumas. The differences noted favoured phenylpiracetam over piracetam because of faster alleviation of headaches and a general fatigue after 7 and 14 days.[86]
Phenylpiracetam was favoured in the treatment of chronic vascular encephalopathy as it improved the cognitive performance in all tests, whereas only two of the eight test scores increased in the piracetam arm.[87] It also improved both asthenia and depression scores, albeit to a lesser extent in MS patients.[88] In a comparative trial, asthenia and chronic fatigue syndrome (CFS) patients were treated with phenylpiracetam (68 people), piracetam (65 people) and placebo (47 people). The scores of the ten-word memory test and attention switching tests for the phenylpiracetam improved relative to those of piracetam and placebo. Overall, 83% of asthenic and 87% of CFS patients responded well to phenylpiracetam versus 48% and 55%, respectively, to piracetam.[89]
In agreement with this, phenylpiracetam markedly increased the problem-solving skills of adolescents with asthenia who were A-players, B-players and C-players (i.e. the number of individuals able to respond to the memory and attention tests after the first, second and third attempts) from 11%, 15%, 73% before to 23%, 40%, 37% after treatment, respectively. It was superior to piracetam Drugs 2010; 70 (3) Table V.
Piracetam-like compounds in clinical development Sponsor/study site Intent to treat Study design No. of pts (age in y) Dosage (mg/d, oral) (2)600 Trial duration Outcome measures Efficacy summary (% improvement rate) Tx 86 Cx 60 Adverse event References ? 2010 Adis Data Information BV. All rights reserved.
Drugs 2010; 70 (3) 300 Pramiracetam Army Central Hospital, Kiev, Ukraine Cognition/memory deficits (after TBI) Active (piracetam) controlled 65 (16–60, mean 31) 1 mo Amnesia and orientation NA 84 Phenylpiracetam Omsk State Medical Academy, Russia Encephalopathy (gliomas to acute lesions) Open-label 99 (40–60) 200 1 mo MMSE Anxiety Depression Tx 45 – 16 50 – 5 38 – 4 None 85 Navy Hospital, Vladivostok, Russia Encephalopathy (after TBI) Active controlled 56 (20–30) (2)100 1 mo Asthenia, headache ND None 86 Nizhny Novgorod State Medical Academy, Russia Encephalopathy (vascular) Active controlled 51 (mean 57.2) (2)200 1 mo Neurological and psychological Tx 32 – 11 Cx 25 – 11 None 87 Multiple Sclerosis Center of Novosibirsk, Russia Multiple sclerosis Open-label 39 200 1 mo Asthenia Anxiety Depression 11 20 21 Sleep disturbance 88 National Research Center for Social and Forensic Psychiatry, Moscow, Russia Asthenia/fatigue syndrome Active and placebo controlled 180 (21–40, mean 25 (3)100–200 1 mo Memory (10-word test) Tx 88 – 52 Cx 37 – 19 PL 16 – 13 None 89 Clinic No. 28, Volgograd, Russia Asthenia Active controlled 39 (14–19, mean 15) (2)100 1 mo Problem solving ND None 90 Malykh & Sadaie Ural State Medical Academy, Chelyabinsk, Russia Epilepsy rpc 61 (mean 29.7) (2)100 2 mo Seizure: Total no. Frequency Tx 46 – 1 46 – 3 None 91 Continued next page Table V. Contd Sponsor/study site Intent to treat Study design No. of pts (age in y) 40 (17–20) Dosage (mg/d, oral) (2)100 Trial duration 1 mo Outcome measures MMSE Efficacy summary (% improvement rate) 12 Adverse event None References ? 2010 Adis Data Information BV. All rights reserved. Drugs 2010; 70 (3) Piracetam and Related Drugs for CNS Disorders Gorbunov Hospital, Kemerovo, Russia Epilepsy rpc 92 Tver State Medical Academy, Russia Cerebral stroke Open-label 20 (31–67, mean 52) 100 1 mo Ab titres: MMP PHL Tx 34 – 4 7.5 – 0.6 None 93 Regional Neurologic Department, Moscow, Russia Cerebral stroke (ischaemic) Open-label 120 (3)100, 200 1 mo MMSE Barthel index Stroke scale Tx 10 – 0.4 6 – 0.4 9.1 Nausea (3%) 94 Orel State University, Russia Glaucoma Open-label 26 100 1 mo Vision acuity Tx 16 – 8 None 95 Nefiracetam Daiichi Sankyo, Tokyo, Japan; Prestwick Clinical, Washington, DC, USA Poststroke depression rdbpc 159 (mean 66.8) (3)600, 900 12 wk Depression Apathy None Tx 34 PL 5 None 96 97 NINDS Alzheimer’s disease Open-label 50 (50–90) NA 20 wk NA NA NA 98 Rolipram NIMH Major depressive disorder rdbpc 50 (18–65) NA 3y Depression, PDE4 test NA NA 99 NINDS Multiple sclerosis Open-label 6 (18–65) 7.5–9 8 mo MRI None Poor tolerability 100,101 Ab = antibody; Cx = control; MMP = main myelin protein; MMSE = Mini Mental State Examination; MRI = magnetic resonance imaging; NA = not available; ND = not done (test scores lacking); NINDS = National Institute of Neurological Disorders and Stroke; NIMH = National Institute of Mental Health; PDE4 = phosphodiesterase type 4; PHL = phospholipids; PL = placebo; rdbpc = randomized, double-blind, placebo-controlled; rpc = randomized, placebo controlled; TBI = traumatic brain injury; Tx = test agent; (2)-, (3)- indicates parallel fixed doses. 301 302 Malykh & Sadaie (400 mg/day) in combination with multivitamins and physiotherapy.[90] It is unclear whether any particular patient(s) was unresponsive to or relapsed after therapy. Convulsion/Epilepsy, Seizure Phenylpiracetam exhibited an antiepileptic action in rodents. Its effective dose (300 mg/kg) decreased the metrazol (a drug used as a circulatory and respiratory stimulant)-induced seizure by 50%.[106] Phenylpiracetam was administered to patients in addition to one standard AED (including valproyl amide, carbamazepine, lamotrigine, topiramate or a barbiturate, or structured polytherapy with more than one of these drugs). It substantially mitigated the number and frequency of seizures of patients receiving AED only and the number of individuals with a desynchronous EEG profile decreased from eight to three, while the number of individuals with seizure remissions increased modestly.[91] Consistent with this, cognitive functions in epileptic patients based on an MMSE test improved to only a small extent.[92] These trials favoured phenylpiracetam as add-on medication for epilepsy (table V). Cerebral Stroke/Ischaemia ganglial cell death was the rationale of a recent trial.
RUSSIAN FENOTROPIL INSTRUCTIONS TRANSLATION:
Instructions on Fenotropil TAB.100MG Fenotropil number 10 - a new nootropic drug with psychoactive effects. It is recommended for CNS pathological states of various origins: cerebrovascular insufficiency, neurotic state, asthenic depression vyaloapaticheskie state in schizophrenia, abstinence in alcoholism and drug addiction. Can also be used to increase resistance to stress, in order to prevent the development of fatigue, etc.
The composition and the form of: Fenotropil tablets of 10, 20 or 30 pieces. in the package. 1 tablet contains Fenotropil Phenotropil (N-carbamoyl-methyl-4-phenyl-2-pyrrolidone), 50 or 100 mg.
Pharmacological properties: Fenotropil - nootropic, cerebroprotector, neurometabolic stimulator. Effects similar to Piracetam therapeutic focus. Fenotropil has a marked neuroprotective effect of a psychoactive, anticonvulsant, anxiolytic, analgesic, antihypoxic, antitoxic, and antihypertensive effects. Fenotropil has a direct activating effect on the integrative activity of the brain, contributes to the consolidation of memory, improves concentration and mental performance, facilitates the learning process, increases the rate of information transfer between the hemispheres of the brain, regulates the activation and inhibition of the central nervous system and improves mood. Fenotropil has a positive effect on the exchange of blood and brain, stimulates the oxidation-reduction processes, increases the body's energy potential at the expense of glucose utilization, improves regional blood flow in the ischemic brain regions.
Increases the content of noradrenaline, dopamine and serotonin in the brain, does not affect the levels of GABA, is not associated with either GABA or the GAMKB receptors, has no appreciable effect on the spontaneous electrical activity of the brain. The stimulating effect of Fenotropil manifested in its ability to provide a moderately pronounced effect on motor responses, to improve physical performance, expressed antagonism to the cataleptic action of neuroleptics, as well as in reducing the severity of ethanol and the hypnotic action of hexenal. Stimulating effect Fenotropil ideatornoy prevalent in the field. Fenotropil stimulates antibody production in response to the antigen, indicating that its immune-boosting properties, but at the same time, it does not contribute to the development of immediate hypersensitivity and does not alter the allergic inflammation of the skin caused by the introduction of foreign protein.
Fenotropil has adaptogenic action in various models of stress, normalize circadian biorhythm indicator sympathoadrenal system. Adaptogenic effect Fenotropil manifested in excessive mental and physical fatigue while, hypokinesia and immobilization at low temperatures, with information overload. Phenotropil effect occurs during a single application, which is very important for use in hazardous environments requiring immediate effect. During the course of Fenotropil marked improvement in vision, which is manifested in the increasing severity, brightness and field of view. In exchange application Fenotropil not develop drug dependence and tolerance, "withdrawal syndrome". Fenotropil no effect on respiration and the cardiovascular system, showing unspoken diuretic effect, has anoreksigennoy activity in exchange application. Fenotropil improves blood flow to the lower extremities. Fenotropil has no teratogenic, mutagenic, carcinogenic and embryotoxic properties. Toxicity - low lethal dose in the acute experiment is 800 mg / kg.
Pharmacokinetics: Fenotropil is rapidly absorbed, penetrates into the various organs and tissues, easily passes the blood-brain barrier. The absolute bioavailability after oral administration of 100%. The maximum concentration achieved in blood after 1 hour, half-life is 3-5 hours. Fenotropil not metabolized in the body and is excreted unchanged. Approximately 40% of the drug is excreted in the urine and 60% of the drug is excreted in the bile and sweat.
Indications: Fenotropil recommended as a nootropic drug with psychoactive effects in pathological states of the central nervous system of various origins: post-traumatic conditions and phenomena of chronic cerebrovascular insufficiency sosuditoy accompanied by deterioration in intellectual-mental function, reduced motor activity, asthenic syndrome against cerebrovascular disease, neurotic condition manifested apathy , increased exhaustion, decreased activity, in violation of attention, memory impairment, disorders of learning processes, asthenic, apathetic, adynamic shallow (easy to moderate) depression, shallow psycho syndromes seen intellectual disabilities and mnesticheskimi apatiko-abulicheskimi phenomena vyaloapaticheskie state with schizophrenia, seizure disorder, alcohol abstinence, alcoholism and drug addiction (to reduce fatigue, depression, and intellectual-mental disorders), also recommended: hypertension stage I-II, obesity (alimentary-constitutional origins), for the prevention of hypoxia, increase resistance to stress, correction of the functional state of the body in extreme conditions, to prevent the development of fatigue and improve mental and physical performance, correction daily biorhythms, inversion of the cycle "sleep-wake" (the intersection of 4 or more time zones).
Dosage and Administration: inside. Dosage and set individually. Fenotropil taken orally immediately after meals. Do not take Fenotropil later than 15 hours. The average single dose of 150 mg (from 100 mg to 250 mg), the average daily dose is 250 mg (from 200 mg to 300 mg). The maximum permissible dose is - 750 mg per day. It is recommended to divide the daily dose into 2 doses. The daily dose is 100 mg taken once in the morning, and more than 100 mg daily dose is divided into two doses. Duration of treatment can vary from 2 weeks to 3 months. The average duration of treatment is 30 days. If necessary, the course may be repeated a month later. In order to increase efficiency - 100-200 mg once in the morning, within 2 weeks (for athletes - 3 days).
Recommended duration of treatment for patients with alimentary-constitutional obesity is 30-60 days at a dose of 100-200 mg once a day (morning). Overdose: No cases of overdose were reported. Treatment: symptomatic therapy.
Contraindications: Individual intolerance. Use during pregnancy and lactation: Fenotropil should not be administered during pregnancy and breastfeeding due to lack of data from clinical studies. Side Effects: Overstimulation, sleep disturbance (insomnia), autonomic dysfunction (flushing of the skin, a feeling of warmth), increased blood pressure. Cautions and precautions Fenotropil used with caution in patients with severe organic lesions of the liver and kidneys, severe hypertension, in patients with atherosclerosis, and patients who had undergone previous panic attacks, anxiety raptoidnye condition or acute psychotic states, especially with psychomotor agitation due to the possibility of worsening anxiety, panic, hallucinations and delusions, as well as in patients who are prone to allergic reactions to drugs of nootropic pyrrolidone. When excessive psycho-emotional exhaustion on the background of chronic stress and fatigue, chronic insomnia, a single dose Fenotropil the first day can cause a sharp need for sleep. Such patients on an outpatient basis should be advised to start taking the drug in exchange holidays. We do not recommend the appointment of Fenotropil children, due to lack of data of the drug in detey.Lekarstvennoe interaction: Fenotropil may exacerbate the effects of drugs that stimulate the central nervous system, antidepressants and nootropics. Fenotropil showing antagonism cataleptic action of neuroleptics, as well as reduces the severity of hypnotic action of ethanol and hexenal. Storage: List B. In dry place protected from light at temperatures above 30 ° C Shelf life 5 years. Do not use after expiry date. Conditions of supply from the pharmacy - a doctor's prescription