GABA

In a concentration-dependent manner, piracetam (UCB-6215) can greatly reduce the fusogenic and destabilizing effect of Abeta 29–42. Piracetam preincubation, at a piracetam/peptide ratio of 960, for 20 minutes prior to Abeta 29-42 addition virtually eliminates the mixture of the two fluorescent probes. Piracetam/lipid preincubation virtually eliminates the peptide-induced calcein release in a dose-dependent manner (piracetam/peptide ratios ranging from 9.6 to 960)[1].

Age-related changes in membrane fluidity in mice, rats, and humans are demonstrated by decreased anisotropy of the membrane-bound fluorescence probe 1,6-diphenyl-1,3,5-hexatriene (DPH) in the presence of piracetam (UCB-6215) at concentrations less than 1.0 mM prior to preincubation. In some brain regions of both young and old rats, piracetam (UCB-6215) (300 mg/kg once daily) dramatically enhances membrane fluidity; however, in young rats, it has no discernible effect[2]. (UCB-6215) (300 mg/kg daily for 6 weeks) increases membrane fluidity in all brain regions except the cerebellum in old rats and only enhances active avoidance learning in these rats. Additionally, NMDA receptor density in the hippocampus and muscarinic cholinergic receptor densities in the frontal cortex, striatum, and to a lesser extent in the hippocampus of rats are improved by piracetam (UCB-6215) (300 mg/kg daily for 6 weeks)[3].

In vitro preincubation of brain membranes of aged mice with piracetam (0.1-1.0 mmol/L) enhanced membrane fluidity, as indicated by decreased anisotropy of the membrane-bound fluorescence probe 1,6-diphenyl-1,3,5-hexatriene (DPH). Piracetam had similar in vitro effects on brain membranes of aged rats and humans, but it did not alter brain membrane fluidity in young mice. Chronic treatment of young and aged rats with piracetam (300 mg/kg once daily) significantly increased membrane fluidity in some brain regions of the aged animals, but had no measurable effect on membrane fluidity in the young rats. The same treatment significantly improved active avoidance learning in the aged rats only. It is suggested that some of the pharmacological properties of piracetam can be explained by its effects on membrane fluidity [2].

Amyloid peptide (Abeta) is a 40/42-residue proteolytic fragment of a precursor protein (APP), implicated in the pathogenesis of Alzheimer's disease. The hypothesis that interactions between Abeta aggregates and neuronal membranes play an important role in toxicity has gained some acceptance. Previously, we showed that the C-terminal domain (e.g. amino acids 29-42) of Abeta induces membrane permeabilisation and fusion, an effect which is related to the appearance of non-bilayer structures. Conformational studies showed that this peptide has properties similar to those of the fusion peptide of viral proteins i.e. a tilted penetration into membranes. Since Piracetam interacts with lipids and has beneficial effects on several symptoms of Alzheimer's disease, we investigated in model membranes the ability of Piracetam to hinder the destabilising effect of the Abeta 29-42 peptide. Using fluorescence studies and 31P and 2H NMR spectroscopy, we have shown that Piracetam was able to significantly decrease the fusogenic and destabilising effect of Abeta 29-42, in a concentration-dependent manner. While the peptide induced lipid disorganisation and subsequent negative curvature at the membrane-water interface, the conformational analysis showed that piracetam, when preincubated with lipids, coats the phospholipid headgroups. Calculations suggest that this prevents appearance of the peptide-induced curvature. In addition, insertion of molecules with an inverted cone shape, like piracetam, into the outer membrane leaflet should make the formation of such structures energetically less favourable and therefore decrease the likelihood of membrane fusion [1].

In order to test the hypothesis that piracetam improves cognitive functions by restoring biochemical deficits of the aging brain, we investigated the effects of piracetam treatment (300 mg/kg daily for 6 weeks) on the active avoidance performance of young and aged rats. After testing, the rats were killed and membrane fluidity and NMDA as well muscarinic cholinergic receptor densities were determined in the frontal cortex, the hippocampus, the striatum, as well as the cerebellum. Piracetam treatment improved active avoidance learning in the aged rats only and elevated membrane fluidity in all brain regions except the cerebellum in the aged animals. Moreover, we observed a positive effect of piracetam treatment on NMDA receptor density in the hippocampus and on muscarinic cholinergic receptor densities in the frontal cortex and the striatum and to a lesser extent in the hippocampus. Again, these effects were only observed in aged animals. Discrimination analysis indicated that piracetam effects on membrane fluidity in the frontal cortex, the hippocampus, and the striatum and its effects on NMDA densities in the hippocampus might be involved in its positive effects on cognitive performance. [3]

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Dissolved in saline; 300 mg/kg; oral gavage

Male Wistar rats

Absorption, Distribution and Excretion
Piracetam displays a linear and time-dependent pharmacokinetic properties with low intersubject variability over a large range of doses. Piracetam is rapidly and extensively absorbed following oral administration with the peak plasma concentration is reached within 1 hour after dosing in fasted subjects. Following a single oral dose of 3.2 g piracetam, the peak plasma concentration (Cmax) was 84 µg/mL. Intake of food may decrease the Cmax by 17% and increase the time to reach Cmax (Tmax) from 1 to 1.5 hours. Tmax in the cerebrospinal fluid is achieved approximately 5 hours post-administration. The absolute bioavailability of piracetam oral formulations is close to 100% and the steady state plasma concentrations are achieved within 3 days of dosing.
Piracetam is predominantly excreted via renal elimination, where about 80-100% of the total dose is recovered in the urine. Approximately 90% of the dose of piracetam is excreted in the urine as unchanged drug.
Vd is approximately 0.6L/kg. Piracetam may cross the blood-brain barrier as it was measured in the cerebrospinal fluid following intravenous administration. Piracetam diffuses to all tissues except adipose tissues, crosses placental barrier and penetrates the membranes of isolated red blood cells.
The apparent total body clearance is 80-90 mL/min.
Piracetam is rapidly and almost completely absorbed. Peak plasma levels are reached within 1.5 hours after administration. The extent of oral bioavailability, assessed from the Area Under Curve (AUC), is close to 100% for capsules, tablets and solution.
Peak levels and AUC are proportional to the dose given. The volume of distribution of piracetam is 0.7 L/kg, and ... Clearance of the compound is dependent on the renal creatinine clearance and would be expected to diminish with renal insufficiency.
Piracetam is excreted in human breast milk.
Piracetam crosses the blood-brain and the placental barrier and diffuses across membranes used in renal dialysis.
Piracetam is excreted almost completely in urine and the fraction of the dose excreted in urine is independent of the dose given.

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Metabolism / Metabolites
As large proportion of total piracetam administered is excreted as unchanged drug, there is no known major metabolism of piracetam.
... No metabolite of piracetam has been found.

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Biological Half-Life
The plasma half life of piracetam is approximately 5 hours following oral or intravenous administration. The half life in the cerebrospinal fluid was 8.5 hours.
... The plasma half-life is 5.0 hours, in young adult men.

Protein Binding
Piracetam is not reported to be bound to plasma proteins.

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Interactions
... Confusion, irritability and sleep disorders /have been/ reported with concomitant use /of/ thyroid extract (T3 + T4) /and piracetam/.
At present although based on a small number of patients, no interaction has been found with the following anti-epileptic medications: clonazepam, carbamazepine, phenytoin, phenobarbitone and sodium valproate.
In a single-blind study on patients with severe recurrent venous thrombosis, piracetam 9.6 g/d did not modify the doses of acenocoumarol necessary to reach INR (international normalized ratio) 2.5 to 3.5, but compared with the effects of acenocoumarol alone, the addition of piracetam 9.6 g/d significantly decreased platelet aggregation, beta-thromboglobulin release, levels of fibrinogen and von Willebrand's factors (VIII : C; VIII : vW : Ag; VIII : vW : RCo) and whole blood and plasma viscosity.

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Non-Human Toxicity Values
LD50 Mouse oral 26 g/kg

[1]. Piracetam inhibits the lipid-destabilising effect of the amyloid peptide Abeta C-terminal fragment. Biochim Biophys Acta, 2003. 1609(1): p. 28-38.

[2]. Effects of piracetam on membrane fluidity in the aged mouse, rat, and human brain. Biochem Pharmacol, 1997. 53(2): p. 135-40.

[3]. Piracetam improves cognitive performance by restoring neurochemical deficits of the aged rat brain. Pharmacopsychiatry, 1999. 32 Suppl 1: p. 10-6.

Therapeutic Uses
/Investigators/ report on a 30-year-old patient with advanced cerebellar degeneration due to sickle cell amemia 2. He presented with severe myoclonus, which was resistant to conventional therapy and dramatically improved after administration of 12-18 g/day piracetam. Piracetam may be considered in the treatment of refractory myoclonus in spinocerebellar degenerations.
/Piracetam/ is indicated for patients suffering from myoclonus of cortical origin, irrespective of etiology, and should be used in combination with other anti-myoclonic therapies.

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Drug Warnings
Piracetam is contraindicated in patients with severe renal impairment (renal creatinine clearance of less than 20 mL per minute), hepatic impairment and to those under 16 years of age.
Piracetam is contraindicated in patients with cerebral hemorrhage and in those with hypersensitivity to piracetam, other pyrrolidone derivatives or any of the excipients.
Due to the effect of piracetam on platelet aggregation, caution is recommended in patients with underlying disorders of hemostasis, major surgery or severe hemorrhage.
Abrupt discontinuation of treatment should be avoided as this may induce myoclonic or generalised seizures in some myoclonic patients.
For more Drug Warnings (Complete) data for PIRACETAM (9 total), please visit the HSDB record page.

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Pharmacodynamics
Piracetam is known to mediate various pharmacodynamic actions: **Neuronal effects**: Piracetam modulates the cholinergic, serotonergic, noradrenergic, and glutamatergic neurotransmission although the drug does not display high affinity to any of the associated receptors (Ki >10μM). Instead, piracetam increases the density of postsynaptic receptors and/or restore the function of these receptors through stabilizing the membrane fluidity. In the forebrain of aging mice, the density of NMDA receptors was increased by approximately 20% following 14 days of piracetam treatment. Based on the findings of various animal and human studies, the cognitive processses including learning, memory, attention and consciousness were enhanced from piracetam therapy without inducing sedation and psychostimulant effects. Piracetam mediate neuroprotective effects against hypoxia-induced damage, intoxication, and electroconvulsive therapy. In two studies involving alcohol-treated rats with evidences of withdrawal-related neuronal loss, piracetam was shown to reduce the extent of neuronal loss and increase the numbers of synapses in the hippocampus by up to 20% relative to alcohol-treated or alcohol-withdrawn rats. This suggests that piracetam is capable in promoting neuroplasticity when recoverable neural circuits are present. Although the mechanism of action is not fully understood, administration of piracetam prior to a convulsant stimulus reduces the seizure severity and enhances the anticonvulsant effectiveness of conventional antiepileptics such as carbamazepine and diazepam. **Vascular effects**: Piracetam is shown to increase the deformability of erythrocytes, reduce platelet aggregation in a dose-dependent manner, reduce the adhesion of erythrocytes to vascular endothelium and capillary vasospasm. In healthy volunteers, piracetam mediated a direct stimulant effect on prostacycline synthesis and reduced the plasma levels of fibrinogen and von Willebrand’s factors (VIII: C; VIII R: AG; VIII R: vW) by 30 to 40%. Potentiated microcirculation is thought to arise from a combination of effects on erythrocytes, blood vessels and blood coagulation.

C6H10N2O2

142.16

142.074

C, 50.69; H, 7.09; N, 19.71; O, 22.51

7491-74-9

Piracetam-d8;1329799-64-5;Piracetam-d6

4843

White to off-white solid powder

1.4±0.1 g/cm3

337.3±44.0 °C at 760 mmHg

151-152ºC

157.8±28.4 °C

0.0±1.7 mmHg at 25°C

1.603

-1.39

1

2

2

10

167

0

SIXPSGNZQPKXTG-UHFFFAOYSA-N

InChI=1S/C6H10N2O2/c1-5(9)7-8-4-2-3-6(8)10/h2-4H2,1H3,(H,7,9)

1-Acetamido-2-pyrrolidinone

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (17.59 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (17.59 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: 100 mg/mL (703.43 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)