Chemical formula: C₆H₁₀N₂O₂ Molecular mass: 142.156 g/mol
Piracetam is a pyrrolidone (2-oxo-1-pyrrolidine-acetamide), a cyclic derivative of gamma-aminobutyric acid (GABA).
Available data suggest that piracetam basic mechanism of action is neither cell- nor organ-specific. Piracetam binds physically in a dose-dependent manner to the polar head of phospholipids membrane models, inducing the restoration of the membrane lamellar structure characterised by the formation of mobile drug-phospholipid complexes. This probably accounts for an improved membrane stability, allowing the membrane and transmembrane proteins to maintain or recover the three-dimensional structure or folding essential to exert their function.
Piracetam has neuronal and vascular effects.
At the neuronal level, piracetam exerts its membrane activity in various ways.
In animals, piracetam enhances a variety of types of neurotransmission, primarily through postsynaptic modulation of receptor density and activity.
In both animals and man, the functions involved in cognitive processes such as learning, memory, attention and consciousness were enhanced, in the normal subject as well as in deficiency states, without the development of sedative or psychostimulant effects.
Piracetam protects and restores cognitive abilities in animals and man after various cerebal insults such as hypoxia, intoxications and electroconvulsive therapy.
It protects against hypoxia-induced changes in brain function and performance as assessed by electroencephalograph (EEG) and psychometric evaluations.
Piracetam exerts its haemorrheological effects on the platelets, red blood cells, and vessel walls by increasing erythrocyte deformability and by decreasing platelet aggregation, erythrocyte adhesion to vessel walls and capillary vasospasm.
In patients with sickle cell anemia, piracetam improves the deformability of the erythrocyte membrane, decreases blood viscosity, and prevents rouleaux formation.
In open studies in healthy volunteers and in patients with Raynaud.s phenomenon, increasing doses of piracetam up to 12 g was associated with a dose-dependent reduction in platelet functions compared with pre-treatment values (tests of aggregation induced by ADP, collagen, epinephrine and βTG release), without significant change in platelet count. In these studies, piracetam prolonged bleeding time.
In animal studies, piracetam inhibited vasospasm and counteracted the effects of various spasmogenic agents. It lacked any vasodilatory action and did not induce “steal” phenomenon, nor low or no reflow, nor hypotensive effects.
In healthy volunteers, piracetam reduced the adhesion of RBCs to vascular endothelium and possessed also a direct stimulant effect on prostacycline synthesis in healthy endothelium.
In healthy volunteers, compared with pre-treatment values, piracetam up to 9.6 g reduced plasma levels of fibrinogen and von Willebrand’s factors (VIII : C; VIII R : AG; VIII R : vW) by 30 to 40%, and increased bleeding time.
In patients with both primary and secondary Raynaud phenomenon, compared with pre-treatment values, piracetam 8 g/d during 6 months reduced plasma levels of fibrinogen and von Willebrand’s factors (VIII : C; VIII R : AG; VIII R : vW (RCF)) by 30 to 40%, reduced plasma viscosity, and increased bleeding time.
In patients with both primary and secondary Reynaud phenomenon, compared with pre-treatment values, piracetam 8 g/d during 6 months reduced plasma levels of fibrinogen and von Willebrand’s factors (VIII: C; VIII R: AG; VIII R: vW (CF)) by 30 to 40%, reduced plasma viscosity and increased bleeding time.
Another study in healthy volunteers did not show any statistically significant difference between piracetam (up to 12 g b.i.d.) and placebo regarding effects on hemostasis parameters and bleeding time.
The pharmacokinetic profile of piracetam is linear and time-independent with low inter-subject variability over a large range of doses. This is consistent with the high permeability, high solubility, and minimal metabolism of piracetam. Plasma half-life of piracetam is 5 hours. It is similar in adult volunteers and in patients. It is increased in the elderly (primarily due to impaired renal clearance) and in subjects with renal impairment. Steady state plasma concentrations are achieved within 3 days of dosing.
Piracetam is rapidly and extensively absorbed following oral administration. In fasted subjects, the peak plasma concentrations are achieved 1 hour after dosing. The absolute bioavailability of piracetam oral formulations is close to 100%. Food does not affect the extent of absorption of piracetam but it decreases Cmax by 17% and increases tmax from 1 to 1.5 hours. Peak concentrations are typically 84 µg/ml and 115 µg/ml following a single oral dose of 3.2 g and repeat dose of 3.2 g t.i.d., respectively.
Piracetam is not bound to plasma proteins and its volume of distribution is approximately 0.6 l/kg. Piracetam crosses the blood brain barrier as it has been measured in cerebrospinal fluid following intravenous administration. In cerebrospinal fluid, the tmax was achieved about 5 hours post-dose and the half-life was about 8.5 hours. In animals, piracetam highest concentrations in the brain were in the cerebral cortex (frontal, parietal and occipital lobes), in the cerebellar cortex and in the basal ganglia. Piracetam diffuses to all tissues except adipose tissues, crosses placental barrier, and penetrates the membranes of isolated red blood cells.
Piracetam is not known to be metabolized in the human body. This lack of metabolism is supported by the lengthy plasma half-life in anuric patients and the high recovery of parent compound in urine.
The plasma half-life of piracetam in adults is about 5 hours following either intravenous or oral administration. The apparent total body clearance is 80-90 ml/min. The major route of excretion is via urine, accounting for 80 to 100 % of the dose. Piracetam is excreted by glomerular filtration.
The pharmacokinetics of piracetam are linear over the dose range of 0.8 to 12 g. Pharmacokinetic variables like half-life and clearance are not changed with respect to the dose and the duration of treatment.
In a bioequivalence study comparing formulations at a dose of 2.4 g, Cmax and AUC were approximately 30% higher in women (N=6) compared to men (N=6). However, clearances adjusted for body weight were comparable.
Formal pharmacokinetic studies of the effects of race have not been conducted. Cross study comparisons involving Caucasians and Asians, however, show that pharmacokinetics of piracetam were comparable between the two races. Because piracetam is primarily renally excreted and there are no important racial differences in creatinine clearance, pharmacokinetic differences due to race are not expected.
In the elderly, the half-life of piracetam is increased and the increase is related to the decrease in renal function in this population.
No formal pharmacokinetic study has been conducted in children.
Piracetam clearance is correlated to creatinine clearance. It is therefore recommended to adjust the daily dose of piracetam based on creatinine clearance in patients with renal impairment.
In anuric End Stage Renal Disease subjects, the half-life of piracetam is increased up to 59 hours. The fractional removal of piracetam was 50 to 60% during a typical 4-hour dialysis session.
The influence of hepatic impairment on the pharmacokinetics of piracetam has not been evaluated. Because 80 to 100% of the dose is excreted in the urine as unchanged drug, hepatic impairment solely would not be expected to have a significant effect on piracetam elimination.
The preclinical data indicate that piracetam has a low toxicity potential. Single dose studies showed no irreversible toxicity after oral doses of 10 g/kg in mice, rats and dogs.
No target organ for toxicity was observed in repeated dose, chronic toxicity studies in mice (up to 4.8 g/kg/day) and in rats (up to 2.4 g/kg/day). Mild gastrointestinal effects (emesis, change in stool consistency, increased water consumption) were observed in dogs when piracetam was administered orally for one year at a dose increasing from 1 to 10 g/kg/day. Similarly, i.v. administration of up to 1 g/kg/day for 4-5 weeks in rats and dogs did not produce toxicity.
In vitro and in vivo studies have shown no potential for genotoxicity and carcinogenicity.
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