Piracetam – an overview | ScienceDirect Topics

Piracetam is a first-generation prototype nootropic drug found by serendipity to be antimyoclonic only in cortical myoclonus (Brown et al., 1993; Gouliaev and Senning, 1994).

From: Animal Models of Movement Disorders, 2005

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Pharmacological Interventions to Enhance Stroke Recovery

Steven R. Flanagan MD, Heidi Fusco MD, in Stroke Rehabilitation, 2019

Piracetam

Piracetam belongs to a class of drugs known as nootropics. It is a derivative of gamma aminobutyric acid that has been used for decades in Europe as an enhancer of various cognitive stills. The precise actions of piracetam are not well delineated, although it is thought to enhance acetylcholine and glutamate transmission with evidence suggesting it facilitates memory and learning in humans.126 Other reported physiological actions include increasing cerebral blood flow and glucose metabolism in infarcted cerebral tissue and its penumbra and neuroprotective effects in an animal stroke model.127 Thus, it is a seemingly attractive agent to potentially ameliorate or limit functional loss from stroke. However, a Cochrane review of its use in acute ischemic stroke failed to reveal a significant difference between active drug and control groups on functional outcome and dependence, but did detect a nonsignificant trend for early death in the piracetam group, possibly related to an imbalance in one study with more severe stroke receiving the drug.128 An earlier Cochrane review examining the effectiveness of several pharmacologic agents in poststroke aphasia found weak evidence supporting piracetam, noting the strength of the findings were hindered by a large number of drop outs from the trials included in the analysis. However, similar to the latter Cochrane review, there was a nonsignificant trend of increased mortality associated with piracetam use.129 The most recent trial examining its effectiveness in poststroke aphasia failed to demonstrate a benefit in subjects with large left hemisphere strokes.130

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The Pharmacological Treatment of Aphasia

ANDREW W. LEE, ARGYE E. HILLIS, in Handbook of the Neuroscience of Language, 2008

40.3.2. Piracetam

Piracetam belongs to the pyrrolidone family of chemicals and first came to prominence in the 1970s in France as a nootropic agent, a term meaning to “enhance learning and memory.” Interest in this group of drugs has been renewed in their use in mild cognitive impairment and epilepsy. The pyrrolidone group of compounds are unique in that subtle changes in their chemical structure can result in very different effects on the central nervous system. An example of this group is levetiracetam, which is related to piracetam but has a profound antiepileptic effect. However, all have a common mechanism of action of potentiating acetylcholine by either increasing its production or decreasing its breakdown. In addition piracetam may potentiate neuron function with added neuroprotective functions such as enhancing cellular metabolism and oxidative glycolysis, as well as optimizing cerebral blood flow and reducing the risk of thrombosis by improving erythrocyte function and decreasing platelet aggregation. For a comprehensive dissertation on the pyrrolidone family of agents, the reader is directed to the review of Shorvon (2001).

An additional pilot study by Kessler et al. (2000) showed that in 12 patients assigned to piracetam for 6 weeks, that there was an increase in blood flow in eloquent cortex in the treatment versus the placebo group. Specifically, there was an increase in perfusion to Heschl’s gyrus and both Wernicke’s and Broca’s areas. In contrast, the placebo group showed an increased perfusion, but only to the inferior part of the left precentral gyrus. Improvement in cortical perfusion was also associated with an improvement of neuropsychological functions. However, it is unclear whether the improvement of neuropsychological functions was the result of improved blood flow, or whether piracetam resulted in the potentiation of neural plasticity, followed by improved function, reflected in increased blood flow. Either way, the changes in blood flow to language cortex shown by Kessler et al. (2000) provides a biologically plausible mechanism for the effect of piracetam on the language improvement found by Huber et al. (1997).

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Pharmacotherapy for Aphasia

Daniel A. Llano, Steven L. Small, in Neurobiology of Language, 2016

85.4.4 Human Studies: Piracetam

Piracetam is a derivative of GABA and has a range of effects on the CNS. Piracetam facilitates cholinergic and excitatory amine neurotransmission (Giurgea, Greindl, & Preat, 1983; Vernon & Sorkin, 1991), increases regional cerebral blood flow (Jordaan, Oliver, Dormehl, & Hugo, 1996), and alters neuronal membrane properties (Müller, Eckert, & Eckert, 1999). It has been claimed that this agent improves learning and memory, but it is not clear which of its biological effects (e.g., neuroprotective, circulatory, or others) are responsible for the purported cognitive benefit (Malykh & Sadaie, 2010). Piracetam is currently available as a nutritional supplement in the United States and is approved for the treatment of myoclonus in Europe.

The data on piracetam for aphasia are mixed. One large multicenter trial (n=927) aimed to treat all stroke patients within 12 h and used a variety of outcome measures, including assessment of aphasia. This study showed no effect on the primary outcome measure of neurological status (Barthel Index and Orgogozo scale) at 4 weeks (De Deyn, Reuck, Deberdt, Vlietinck, & Orgogozo, 1997). A post hoc analysis of an “early treatment subgroup” (defined prospectively as within 6 h, but retrospectively as within 7 h) showed some benefit of piracetam. This was particularly true in the moderate to severe subgroup (De Deyn et al., 1997; Orgogozo, 1999). Of these patients, approximately one-third (n=373) were aphasic, and aphasia recovery at 12 weeks was better in the piracetam group than in the control group, particularly for the early treatment subgroup (Huber, 1999; Orgogozo, 1999).

In postacute and chronic aphasia, several randomized controlled trials have been performed. Enderby et al. observed significant improvements on a multivariate analysis of Aachen Aphasia subtest scores relative to baseline in favor of piracetam (P=0.02) at 12 weeks. This effect was no longer present at 24 weeks (Enderby, Broeckx, Hospers, Schildermans, & Deberdt, 1994). A later double-blind, placebo-controlled study involving chronic aphasia showed trends for improvements across all subsets of the Aachen Aphasia Test, which only reached statistical significance written language (Huber, Willmes, Poeck, Van Vleymen, & Deberdt, 1997). Integrating functional imaging measures into a treatment trial, another study showed an increase in task-related blood flow in several left hemisphere regions generally associated with language over the course of the treatment period; more increase in blood flow in the treatment group than the placebo group. The piracetam group improved on six language measures and the placebo group improved on three (Kessler, Thiel, Karbe, & Heiss, 2000). Most recently, Güngör, Terzi, and Onar (2011), in a single-blind design, examined the impact of 6 months of piracetam given after ischemic stroke causing aphasia and found no benefit across any of the primary language or disability outcome measures, although subjects receiving piracetam showed improvement in auditory comprehension (P=0.023). Thus, there were signals for efficacy in three out of four trials, three of which were relatively small (less than 25 active subjects each) and were thus likely underpowered to see small differences between groups.

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Balance, Gait, and Falls

Jonathan F. Marsden, in Handbook of Clinical Neurology, 2018

Piracetam

Piracetam is a GABA derivative used for the treatment of cortical myoclonus where it may act on 3H-glutamate sites (Ince Gunal et al., 2008). Case reports and open-label case series (n = 8) of moderate to high doses (30–60 grams/day) have found improvements in posture and walking in people with autosomal-dominant cerebellar ataxias (Vural et al., 2003; Ince Gunal et al., 2008). The high dose required may indicate that the effects are mediated by a possible metabolite of the drug (Vural et al., 2003).

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Pathophysiology, Neurophysiology, and Pharmacology of Human Myoclonus

MICHAEL R. PRANZATELLI, in Animal Models of Movement Disorders, 2005

b. Racetams.

Piracetam is a first-generation prototype nootropic drug found by serendipity to be antimyoclonic only in cortical myoclonus (Brown et al., 1993; Gouliaev and Senning, 1994). Despite the high doses required (Ikeda et al., 1996), the safety index is excellent in children (Pranzatelli et al., 2001). Compared to levetiracetam, it has more antimyoclonic effect but little antiepileptic activity (Genton and Van Vleymen, 2000). Both have a place in the treatment of PME (Fedi et al., 2001) and post-hypoxic myoclonus (Krauss et al., 2001).

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Paroxysmal Disorders

Gerald M. Fenichel MD, in Clinical Pediatric Neurology (Sixth Edition), 2009

Management

Piracetam, 40 mg/kg/day, showed a 92% reduction in spells compared with 30% for placebo. The drug is not available in the United States, but levetiracetam is very similar and equally effective. I believe that picking up the child, which is the natural act of the mother or other observer, prolongs the spell. Placing a child who has lost consciousness because of decreased cerebral perfusion in an upright position seems wrong. I always caution parents to hold the child with the head in a dependent position.

Most important is to identify the nature of the spell and explain that it is harmless. Children do not die during breath-holding spells, and the episodes always cease spontaneously. Does anyone know an adult who has breath-holding spells?

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Paroxysmal Disorders

Gerald M. Fenichel MD, in Clinical Pediatric Neurology, 2005

Management.

Piracetam, 40 mg/kg/day, showed a 92% reduction in spells compared with 30% for placebo (Donma, 1998). The drug is not available in the United States, but levetiracetam is similar and equally effective. I believe that picking up the child, which is the natural act of the mother or other observer, prolongs the spell. Placing a child who has lost consciousness because of decreased cerebral perfusion in an upright position seems wrong. I always caution parents to hold the child with the head in a dependent position.

Most important is to identify the nature of the spell and explain that it is harmless. Children do not die during breath-holding spells, and the episodes always cease spontaneously. Does anyone know an adult who has breath-holding spells?

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Epilepsy

Roger J. Porter, … Michael A. Rogawski, in Handbook of Clinical Neurology, 2012

Levetiracetam

Levetiracetam is a piracetam derivative whose antiseizure effect was discovered by its protective activity against audiogenic seizures in susceptible mice and other nonstandard models, as opposed to the conventional maximal electroshock and chemoconvulsant screening tests (Gower et al., 1992). Levetiracetam is used to treat partial seizures and is also probably effective against myoclonic and primary generalized seizures and also absence seizures.

SV2A is the molecular target in brain of levetiracetam (Rogawski and Bazil, 2008; Kaminski et al., 2012). It has been known for some time that the drug binds to a specific saturable and stereoselective site in brain membranes (Noyer et al., 1995). More recently, this binding site was identified as SV2A, which is a 12-transmembrane segment integral membrane glycoprotein that is ubiquitous in synaptic vesicles (Lynch et al., 2004). SV2A is a member of a family of related proteins that exist in three isoforms. SV2A is the most widely distributed, being nearly ubiquitous in the central nervous system; SV2B is also brain specific, with a widespread but not ubiquitous distribution; SV2C is a minor isoform in brain (Buckley and Kelly, 1985; Bajjalieh et al., 1994). Levetiracetam has affinity only for the SV2A isoform. The physiological role of SV2A in epilepsy has not been defined. However, it is interesting that homozygous SV2A knockout mice experience severe seizures and die between postnatal period P12 and P23; heterozygous animals are also susceptible to seizures but have nearly normal survival (Kaminski et al., 2009). SV2A appears to play a role in vesicle dynamics: an absence of SV2A results in a decrease of the readily releasable pool of vesicles (Xu and Bajjalieh, 2001). SV2 may prime vesicles in quiescent neurons; it may also play a role in low-frequency neurotransmission (Custer et al., 2006). Indeed, SV2 proteins are also known to modulate the formation of soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) complexes that are essential for vesicle fusion (Lezzi et al., 2005). In sum, SV2A almost certainly plays a role in regulating neurotransmitter release but how levetiracetam interacts with this protein and how it exerts its antiseizure action is, at present, obscure.

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Anticonvulsant-Related Bone Disease

Alison M. Pack, in Osteoporosis (Fourth Edition), 2013

Levetiracetam

Levetiracetam is a heterocyclic amide related to piracetam (a nootropic or a cognitive enhancer) [92]. It was approved as an anticonvulsant in the US in 1999 and is now available worldwide. It is a broad-spectrum anticonvulsant treating both partial and generalized seizures. It has multiple anticonvulsant mechanisms of action. It is not a cytochrome P450 enzyme-inducing anticonvulsant (Table 50.1).

Levetiracetam has received extremely limited study. There are currently no peer-reviewed publications evaluating its effect on bone health in humans. Results from an animal study found that levetiracetam therapy may affect bone quality [58]. Rats treated with low-dose levetiracetam had reduced bone strength and bone formation and no changes in bone mass.

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Therapeutic Areas I: Central Nervous System, Pain, Metabolic Syndrome, Urology, Gastrointestinal and Cardiovascular

L.J.S. Knutsen, M. Williams, in Comprehensive Medicinal Chemistry II, 2007

6.11.6.2.13 Levetiracetam

Levetiracetam is an analog of the nootropic, piracetam, and is thus structurally dissimilar to other AEDs (Figure 2). It is used as an adjunct in the treatment of partial drug-resistant epilepsy and refractory patients and can be used as monotherapy. The synaptic vesicle protein SV2A, a protein that modulates vesicle exocytosis, is a target for levetiracetam, although how this contributes to its anticonvulsant profile is unknown. Seletracetam (UCB-44212) (Figure 2) and brivaracetam (UCB-34714) (Figure 2) are second-generation AEDs, the latter being approximately 10 times more potent than levetiracetam as an anticonvulsant in audiogenic seizure-prone mice. Levetiracetam is well tolerated, the most common reported side effects being asthenia, somnolence, headache, and dizziness. It does not impair cognitive function.

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