GABA

以浓度依赖性方式，吡拉西坦 (UCB-6215) 可以极大地降低 Abeta 29-42 的融合和不稳定作用。在添加 Abeta 29-42 之前，以吡拉西坦/肽比例为 960 预孵育 20 分钟，实际上消除了两种荧光探针的混合物。吡拉西坦/脂质预孵育实际上以剂量依赖性方式消除了肽诱导的钙黄绿素释放（吡拉西坦/肽比率范围为 9.6 至 960）[1]。

小鼠、大鼠和人类的膜流动性与年龄相关的变化通过膜结合荧光探针 1,6-二苯基-1,3,5-己三烯 (DPH) 在吡拉西坦 (UCB- 6215），预孵育前浓度低于 1.0 mM。在年轻和年老大鼠的某些大脑区域中，吡拉西坦 (UCB-6215)（300 毫克/千克，每天一次）可显着增强细胞膜的流动性；然而，在幼年大鼠中，它没有明显的效果[2]。 (UCB-6215)（每日 300 mg/kg，持续 6 周）可增加老年大鼠除小脑外所有脑区的膜流动性，并且仅增强这些大鼠的主动回避学习。此外，吡拉西坦 (UCB-6215)（每日 300 mg/kg，持续 6 周）可改善大鼠海马中的 NMDA 受体密度以及额叶皮层、纹状体以及较小程度上海马中的毒蕈碱胆碱能受体密度。 3]。

用吡拉西坦（0.1-1.0 mmol/L）对老年小鼠的脑膜进行体外预孵育可增强膜流动性，如膜结合荧光探针1,6-二苯基-1,3,5-己三烯（DPH）的各向异性降低所示。吡拉西坦对老年大鼠和人类的脑膜具有相似的体外作用，但它不会改变年轻小鼠的脑膜流动性。用吡拉西坦（300mg/kg，每日一次）对年轻和老年大鼠进行慢性治疗，显著增加了老年动物某些脑区的膜流动性，但对年轻大鼠的膜流动率没有可测量的影响。同样的治疗仅显著改善了老年大鼠的主动回避学习。有人认为，吡拉西坦的一些药理特性可以通过其对膜流动性的影响来解释[2]。

淀粉样肽（Abeta）是前体蛋白（APP）的40/42残基蛋白水解片段，与阿尔茨海默病的发病机制有关。Abeta聚集体和神经元膜之间的相互作用在毒性中起着重要作用的假设已经得到了一些认可。此前，我们已经证明，Abeta的C末端结构域（如氨基酸29-42）诱导膜通透性和融合，这一作用与非双层结构的出现有关。构象研究表明，这种肽具有与病毒蛋白融合肽相似的特性，即倾斜渗透到膜中。由于吡拉西坦与脂质相互作用，并对阿尔茨海默病的几种症状具有有益作用，我们在模型膜中研究了Piracetam阻碍Abeta 29-42肽不稳定作用的能力。通过荧光研究和31P和2H NMR光谱，我们发现吡拉西坦能够以浓度依赖的方式显著降低Abeta 29-42的融合和失稳作用。虽然肽诱导脂质紊乱，随后在膜-水界面出现负曲率，但构象分析表明，吡拉西坦与脂质预孵育时，会包裹磷脂头基。计算表明，这可以防止肽诱导的弯曲的出现。此外，将倒锥形分子（如吡拉西坦）插入外膜小叶中，会使这种结构的形成在能量上不太有利，从而降低膜融合的可能性[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

63.4

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (17.59 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (17.59 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: 100 mg/mL (703.43 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。