Pyrrolidone derivatives family of chemicals has been the subject of research for more than three decades. Experimental and clinical work first focused on their so-called nootropic effects; later came the possibilities for neuroprotection after stroke and use as antiepileptic agents. Piracetam, the first of the class, was developed by pioneering research by C Glurgea in the late 1960s, and it was he who coined the term "nootropic", to mean enhancement of learning and memory. The term is sometimes extended to include other actions such as neuroprotection. These properties, together with the lack of other generally adverse psychopharmacological actions (eg, sedation, analgesia, or motor or behavioural changes), distinguish the pyrrolidones from other psychoactive drug classes. The mechanisms of action of these drugs are still not fully established; indeed, different compounds In this class may have different modes of action. Interest in this drug class has recently been reawakened by the licensing of levetiracetam as a potentially major new antiepileptic drug and of piracetam for Its antimyoclonic action and effects after stroke and in mild cognitive impairment. Other drugs In this class are currently at an advanced stage of development, and the renewal of interest in this therapeutic area is likely to mean not only that more pyrrolidones will enter clinical practice in the next few years but also that the clinical indications of drugs already licensed will widen.


1-Piracetam

Piracetam was the first nootropic drug to reach clinical practice (in France in 1971). However, the many clinical studies of this drug have yielded conflicting results.52 For this reason, piracetam has not gained a licence for this indication in the USA, UK, or in several other parts of Europe, although it is licensed and widely used as a nootropic agent in many countries, particularly in the lessdeveloped world. Piracetam was followed by a number of other so-called nootropics, and the whole area became fogged by uncontrolled trials and excessive claims. A new wave of studies has been initiated to assess piracetam's value in MCI, and even potentially to prevent disease progression (although the experimental evidence on this application is thin). Recent interest has also focused on the neuroprotective effects of piracetam, for instance in the aftermath of acute stroke,53,54 and on its antimyoclonic action.55 A range of other indications have been studied (eg, Alzheimer's disease"), and piracetam's licensing status reflects its long and idiosyncratic history (panel 2).

Experimental evidence

How piracetam produces these effects is not entirely clear. Its main actions seem to be an enhancement of oxidative glycolysis, anticholinergic effects, positive effects of the cerebral circulation, effects on membrane physics,"', and also reduction of platelet aggregation and improvement in erythrocyte function. Such properties could underpin a cognition-enhancing effect and a neuroprotective effect in stroke. Improvements in cognitive function have been shown experimentally, even in goldfish,","-" but these positive findings have not always been replicated clinically. The "goldfish-to-man" problem bedevils many drugs in this field.

Pharmacokinetics

Studies of the pharmacokinetics of piracetam indicate that the drug has favourable properties for both acute and chronic oral use.9.6. Absorption is rapid and complete, and blood concentrations peak 30-50 min after dosing. The Cm_ values are 15-37 mg/L after a single dose of 800 mg, and 30-54 mg/L after 1600 mg. The volume of distribution is 0-5-075 L/kg, and there is no significant protein binding. Piracetam crosses the blood-brain barrier with a peak concentration achieved later than that in blood. The mean half-life in cerebrospinal fluid is 7'7 h after intravenous injection in healthy volunteers. After oral administration of single doses between 800 mg and 1200 mg, an elimination half-life of 4-5 h is reported, and similar findings have been recorded in elderly people. There are no known metabolites and the drug is excreted via the kidneys. There are no known pharmacokinetic interactions, and the lack of protein binding and of hepatic metabolism are reassuring in this respect.

Side-effects

Piracetam is well tolerated. In clinical trials in patients with myoclonus, ischaemic stroke, or cognitive dysfunction, side-effects were seldom reported and those that were tended not to be serious. For example, in placebo-controlled trials, reported side-effects were often no more common than they were with placebo, and consisted (all at a frequency of less than 10%) of dizziness, insomnia, nausea, gastrointestinal discomfort, hyperkinesis, weight gain, and agitation." Rash occurs in less than 1% of patients, and there have been no serious idiosyncratic reactions. Even at the very high doses sometimes used in the treatment of myoclonus, few patients report side-effects but formal studies of safety at these very high doses have yet to be done.

2-Levetiracetam

Levetiracetam is structurally close to piracetam but its pharmacological properties and clinical effects are different (panel 3).67 It is an S-enantiomer, and the early laboratory and clinical studies were on cognitive function. However, the clinical results with cognition enhancement were inconclusive, and this line of investigation has not been pursued. The focus is now on epilepsy.

Experimental and early clinical studies

The antiepileptic effect of this drug was revealed during studies of audiogenic seizures in the sound-sensitive mouse and was confirmed by the suppression of spike-- and-wave discharges in a genetic rat model of absence epilepsy (GAERS model) and by marked effects on kindling in rats and mice.28,31,47,68 The antiepileptic profile of this drug experimentally differs from that of almost all antiepileptic drugs, old and new.28-"-'3,46-49,68 Interestingly, it has no effect on the maximal electroshock or pentylenetetrazol models, which are the classic screening tests for antiepileptic drugs.21 Indeed, had the traditional laboratory screening methods been relied upon, the drug's activity against epilepsy might not have been revealed.

An early clinical study, published in 1996, showed that levetiracetam, at single oral doses of 250-500 mg, resulted in a long-lasting (up to 30 h) reduction in the photoparoxysmal response in some patients," and at 1000 mg the photoparoxysmal response was abolished or much reduced in all patients. Not many antiepileptic drugs have this effect, and this is of interest because of the close association between photosensitivity and idiopathic generalised epilepsy. Interestingly, levetiracetam also abolished myoclonus in those patients in this study who exhibited myoclonus as well as photosensitivity, and this and subsequent anecdotal evidence suggests that levetiracetam, like piracetam, has antimyoclonic action. These findings prompted a programme to assess the effect of the drug in intractable partial epilepsy. This is the usual course for licensing a drug in epilepsy. It is nevertheless a pity that the potential of the drug in idiopathic generalised epilepsy or indeed other forms of epilepsy has not yet been fully studied. Experimental studies, and the clinical effect on photosensitivity, suggest a potential for levetiracetam in these conditions.

Pharmacokinetics

Pharmacokinetic studies in healthy volunteers70 72 show that levetiracetam is rapidly and completely absorbed after oral doses ranging between 250 mg and 5000 mg. Peak concentrations are reached at a mean of 1'3 h after dosing, and oral bioavailability approaches 100%. Food affects the speed but not the extent of absorption. There is no protein binding, and the volume of distribution is 0-5-0-7 L/kg, a value close to that of body water. 66% of the oral dose is excreted unchanged, and an inactive metabolite produced by hydrolysis of the acetamide moiety accounts for a further 24%. There is no hepatic metabolism. The terminal half-life is 7-6 h and the apparent total body clearance is 0-9 mL min-' kg-'. The drug is metabolised in a variety of tissues including blood (but not plasma). The pharmacokinetic properties of the drug are comparable between the ages of 18-39 years and 40-60 years, and are similar in whites and Asians. 95% of excretion is via the kidneys and the renal clearance of levetiracetam is 0'6 mL min-' kg '.

The pharmacokinetic profile in adult patients receiving 500-3000 mg daily is similar to that in healthy volunteers. Single-dose studies in children show increased metabolism and excretion, and Cm_ and area-under-curve values have been found to be 30-40% lower than in adults, with an the apparent body clearance of 143 mL min-' kg-' and half-life of 6 h. Conversely, in a small study in elderly people, the half-life was recorded as 10-11 h, partly because of a reduction in renal function. The renal clearance of both levetiracetam and its main metabolite is proportional to creatinine clearance, and dose reductions are recommended in those with renal impairment. In isolated hepatic failure, there is no marked effect on pharmacokinetics.

The drug's pharmacokinetic properties indicate that drug interactions are unlikely. Levetiracetam is highly soluble, and permeable, and has a high pH-independent intrinsic dissolution rate. In vitro, there is no interaction with or inhibition of the major liver CYP450 enzymes by the drug or its metabolite." One study suggested a possible interaction with phenytoin," but this was not confirmed in a specific interaction study.'" Nonetheless patients with high baseline phenytoin levels could be at risk of further increases if levetiracetam is added so caution is indicated in this situation. No other interactions have been shown with any other commonly used antiepileptic drug or with warfarin, digoxin, or the contraceptive pill."

Side-effects

A striking finding in clinical trials is the low frequency of side-effects. The overall frequency in randomised studies reported to the European Medicines Evaluation Agency"" was: somnolence 14%, asthenia 11'5%, dizziness 6-7% (compared with 8%, 8'8% and 3.1%, respectively, on placebo). Similar effects were found in the US studies" though infection was reported more commonly with levetiracetam than placebo. Less common reported side-effects are emotional lability, agitation, hostility, and nervousness (<3%). Although these side-effects are not frequent, post-marketing experience has shown that it is wise to monitor carefully patients prone to psychiatric disorder. There are no marked changes in laboratory tests or physical or neurological examinations. In controlled studies, the proportion of patients discontinuing treatment prematurely or who required a dose reduction because of adverse events was not significantly different between levetiracetam and placebo groups (150% vs 116%). Adverse events that led to withdrawal in patients treated with levetiracetam included somnolence (4'4%), convulsion (3'0%), dizziness (1.4%), asthenia (1.3%), and headache (1'0%). These rates are lower than in the randomised trials for most other antiepileptic drugs.


3-Aniracetam

This drug was first investigated in the 1980s for cognition enhancement." It is still licensed in Italy and Switzerland but was withdrawn last year in Japan as a result of a negative study. There is no binding to the usual receptor sites, although a cerebral binding site has been reported.4 There is no GABAergic action and no effect on cerebral blood flow.''24,20,81 However, it does have cholinergic effects.15,16 It is a positive allosteric modulator of AMPA receptors (ampakine effect).," It also protects against glutaminergic toxicity, as do piracetam and nefiracetam, and inhibits N-type calcium-channel conductance. However, the drug has only slight antiepileptic action. In experimental studies, cognitive impairment due to cholinergic-induced and electroshock-induced deficits in rodents, in senescent animals, and in monkeys did show improvement,""," but for deficits produced by hypoxia or ischaemia the findings have been less consistent. The drug has little effect on behaviour, cognition, or learning in healthy adult animals. The safety profile in animal studies has been excellent, and the pharmacokinetic profile has been defined.ez-85

Clinical studies have been disappointing. Some controlled studies showed slight but significant effects in a variety of cognitive tasks" but others, including a recent large randomised trial, did not." There have also been uncontrolled case reports of the use of aniracetam in improving cerebral blood flow in Alzheimer's disease" and in improving insomnia in neurological conditions.ee


4-Fasoracetam

This nootropic agent is not yet licensed. Its pharmacological profile differs from that of other pyrrolidones.' It up-regulates the GABA-B receptor, stimulates cAMP formation, and shows striking positive effects in spatial memory tests in rats with induced forebrain ischaemia, and in passive and active avoidance tasks in rats with lesions in nucleus basalis magnocellularis. Its nootropism in lesioned rats is stronger than that of aniracetam. Improved performance in forced swimming and learned helplessness tasks in rats point to possible antidepressant activity also.

Early clinical studies suggest benefit, and fasoracetam is currently in phase III trials in Alzheimer's disease and in cerebrovascular disease.

5-Nebracetam

This pyrrolidone is awaiting marketing approval in Japan for cognitive enhancement but its development in Germany was abandoned. Nebracetam enhances cholinergic neurotransmission','," and acts as a partial agonist presynaptically at muscarinic receptors. It also reduces dopaminergic and serotonergic uptake'," and inhibits intracellular calcium flux in response to glutaminergic stimulation.' Substantial neuroprotection has been shown in animals with hypoxia and hypoglycaemia.,5'," In animals with dementia, nebracetam improves performance in the working memory of rats dose-dependently. Given orally the drug decreases the latency of passive avoidance in rats treated with a neurotoxic choline analogue. Nebracetam shows cognition-enhancing effects in mice, and animal experimentation also indicates possible antidepressant properties. A few clinical studies have been carried out in dementia but the benefit has not been impressive and the findings have not been consistent. Clinical studies of its nootropic and neuroprotective potential are underway in Japan.

6-Nefiracetam

Nefiracetam is not yet licensed. Preclinical studies suggested promise in the areas of cognition enhancement and neuroprotection. There are strong effects on cholinergic function,2z,zb.", GABA function, N/L-type calcium-channel action, and protective activity against ischaemic brain damage." 27,44,45 The drug also improves learning in rats with memory defects induced by beta-amyloid infusion,24 with obvious implications for Alzheimer's disease, and induces neuritogenesis.21 It shows long-term potentiation-like facilitation of hippocampal synaptic transmission.23 Nefiracetam has also been shown to have antiepileptic actions in kainic-acid-induced limbic seizures." The pharmacokinetic profile is less satisfactory than that of piracetam or levetiracetam. The drug is well absorbed, though absorption is impeded by food, and is extensively metabolised.89 The kinetics are linear. The Tmax of the metabolites is 4-9 h (twice that of the parent drug). Metabolism is via the hepatic P450 system.89 There are suggestions of teratogenicity and toxicity to bladder and to testicular function,98 92 and these problems will need clarification before clinical use. There is one interesting study showing that nefiracetam prevents the anterograde and retrograde amnesia induced by propofol anaesthesia in rodents without affecting the quality of anaesthesia.27 Despite promising animal data and limited phase I clinical data, no phase II or III clinical studies have been published although these are underway.

7-Oxiracetam

This drug is licensed in Italy and Portugal as a cognitive enhancer, and is under development in other countries. Experimental studies have demonstrated improved learning and memory in rodents" but there are few recent clinical studies. A significant improvement of short-term memory, anxiety, and emotional lability has been shown in one short-term randomised controlled trial in 40 elderly patients.93 Anticonvulsant properties have been demonstrated in mice with convulsions produced by a benzodiazepine-receptor agonist," but no data on patients with epilepsy have

8-Pramiracetam

Pramiracetam is licensed in Italy as a cognitive enhancer but development in the USA has been discontinued. Its mode of action is unclear, but there is some evidence of cholinergic action and that it increases nitric oxide synthase activity.94 It reverses memory defects in rats with induced cholinergic deficits, and increases choline uptake and acetylcholine release, but has no affinity for muscarinic receptors. Despite its structural similarity to GABA, it has no GABAergic, serotonergic, or adrenergic actions. There is strong experimental evidence of positive effects on electroshock-induced amnesia and other experimental rodent and monkey models of memory. Pramiracetam is also a strong amphetamine potentiator. It penetrates the central nervous system poorly in human beings, however,95 and clinical results in dementia have been disappointing. Although more recent studies in dementia and post-trauma have shown some promise.

I thank Michelle Lian for her help in assembling the reference list and Betty Van Vleymen and Henrik Klitgaard for advice and for their useful comments on the paper. The author wrote the clinical expert report for the European licensing agency for levetiracetam, and has also received hospitality and lecturing honoraria at UCB-sponsored symposia.



refference:
Pyrrolidone derivatives
Simon Shorvon. The Lancet. London: Dec 1, 2001.Vol.358, Iss. 9296; pg. 1885, 8 pgs


Subjects: Chemicals, Pharmaceuticals, Pharmacology
Author(s): Simon Shorvon
Document types: Feature
Publication title: The Lancet. London: Dec 1, 2001. Vol. 358, Iss. 9296; pg. 1885, 8 pgs
Source type: Periodical
ISSN/ISBN: 01406736

Text Word Count 7003

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thanksfor the info .....anir. pir, nefir, and pram all soon to be used and abused

Aye... yet another post that I must bookmark to my favorites file

I think it would be nice for referencing if members listed the subjective experiences they've had with the cetams in this post as well.

In my experience...

Piracetam: up to 2.5 grams daily for two weeks, I found it hard to distinquish if it was really having any effect. I think this is definitely something that needs to be taken chronically. I had to stop all things I was taking after experiencing some vision problems. However I can't directly relate that to just the Piracetam.

Aniracetam: 600 - 900 mg produced effects that I noticed rather quickly. I found myself seeing things in a somewhat more novel way and interesting way. However I felt a little mentally foggier than usual, and seemed to have even worse multi-tasking abilities than usual (which are naturally fairly bad). The effect I was hoping for was more mental clarity, and a better ability to multi-task; so I stopped after a few days use.

Levetiracetam: Goes by the name of Keppra, and I read that it was being put through a trial for social anxiety. I'm itching to see if my doctor will give me a script for this.... to update later

the fog is usually from lack of choline or just a natural adjustment that the body is trying to make. I have never gotten through it, but with aniracetam by itself with @-GPC i am fine but iwth piracetam and ANir i have lost hope that i can use them lol. I only use 100mg anir with 1600mg pir.

I took Choline Bitartrate with it. Perhaps a different Choline source would be better... sooner or later I'll give Pir and Anir another go.

I did try A-GPC on its own at 500mg, and my head felt oddly refreshed like I dunked it in some cold water.... this was more of a physical sensation than an increase in mental clarity. I don't know what to make out of that Other than that I didn't notice much else for the short amount of time that I took it.

I have been doing some reading lately and I'm thinking that CDP-Choline might be the route to go. Seems to have a dopamine like effect. Here is an interesting study I found.

Methods Find Exp Clin Pharmacol. 1995 Oct;17 Suppl B:1-54.


CDP-choline: pharmacological and clinical review.

Secades JJ, Frontera G.

F.I.S.A. Medical Department, Barcelona.

Cytidine 5'-diphosphocholine, CDP-choline or citicoline, is an essential intermediate in the biosynthetic pathway of the structural phospholipids of cell membranes, especially in that of phosphatidylcholine. Upon oral or parenteral administration, CDP-choline releases its two principle components, cytidine and choline. When administered orally, it is absorbed almost completely, and its bioavailability is approximately the same as when administered intravenously. Once absorbed, the cytidine and choline disperse widely throughout the organism, cross the blood-brain barrier and reach the central nervous system (CNS), where they are incorporated into the phospholipid fraction of the membrane and microsomes. CDP-choline activates the biosynthesis of structural phospholipids in the neuronal membranes, increases cerebral metabolism and acts on the levels of various neurotransmitters. Thus, it has been experimentally proven that CDP-choline increases noradrenaline and dopamine levels in the CNS. Due to these pharmacological activities, CDP-choline has a neuroprotective effect in situations of hypoxia and ischemia, as well as improved learning and memory performance in animal models of brain aging. Furthermore, it has been demonstrated that CDP-choline restores the activity of mitochondrial ATPase and of membranal Na+/K+ ATPase, inhibits the activation of phospholipase A2 and accelerates the reabsorption of cerebral edema in various experimental models. CDP-choline is a safe drug, as toxicological tests have shown; it has no serious effects on the cholinergic system and it is perfectly tolerated. These pharmacological characteristics, combined with CDP-choline's mechanisms of action, suggest that this drug may be suitable for the treatment of cerebral vascular disease, head trauma of varying severity and cognitive disorders of diverse etiology. In studies carried out on the treatment of patients with head trauma, CDP-choline accelerated the recovery from post-traumatic coma and the recuperation of walking ability, achieved a better final functional result and reduced the hospital stay of these patients, in addition to improving the cognitive and memory disturbances which are observed after a head trauma of lesser severity and which constitute the disorder known as postconcussion syndrome. In the treatment of patients with acute cerebral vascular disease of the ischemic type, CDP-choline accelerated the recovery of consciousness and motor deficit, attaining a better final result and facilitating the rehabilitation of these patients. The other important use for CDP-choline is in the treatment of senile cognitive impairment, which is secondary to degenerative diseases (e.g., Alzheimer's disease) and to chronic cerebral vascular disease. In patients with chronic cerebral ischemia, CDP-choline improves scores on cognitive evaluation scales, while in patients with senile dementia of the Alzheimer's type, it slows the disease's evolution. Beneficial neuroendocrine, neuroimmunomodulatory and neurophysiological effects have been described. CDP-choline has also been shown to be effective as co-therapy for Parkinson's disease. No serious side effects have been found in any of the groups of patients treated with CDP-choline, which demonstrates the safety of the treatment.

since every one is posting his experience with practeam, here is my experience.

i have used pireacteam (3-4g ed) stack with cholin, Inositol, Huperzine A, Vinpocetine, and Gingko Biloba. i used stack for 2 months last semester.

after taking this for a while, i noticed that i became confused, it was hard for me to but my thoughts together. concentrating on small details was very difficult. i was unable focus on something on long periods of time. My GPA was lowest last semester, but of course i cant just blame that on piracteam, my courses were very hard. however the stack had wired audio effects on me, i was able to listen to voices, and music more clearly. i remember that voices had an echo in my head. for example when beside the fountain in my college i was able to hear the echo of water drops from a distance, its almost like magnifier, or listing to sound effects of a movie in theater. i was also using some stimulates at same time like EC.

im going to try same stack again after couple of weeks, and i will add some alcar, green tea extract, and i will see what happens. i hope i dong get dumper though

Are you sure you should take Huperzine/Vinpocetine AND Ginko? Those are both vasodialators, I've read somewhere it's best just to use one.

Ginko is a very weak vasodilator, i doubt it has a pronounce effect.

nice info, i too like see the info in post rather than a link

but.. if i posted in that manner i would get hammered