LONGECITY

Pramiracetam increases nitric oxide synthase (NOS) activity in the cerebral cortex of the rat [1]. NOS is the enzyme that catalyzes the formation of NO from oxygen and arginine is nitric oxide synthase [2]. NO has both positive and negative effects in the brain, as discussed in the following article [3]:

Scientists are finding evidence that NO participates in the brain cell damage that occurs in a variety of neurological ailments, such as stroke and Parkinson's disease. The new research is leading to:
• Targeted brain cell-protecting therapies that interfere with NO chemistry.
• Clearer insight into the complex behavior of NO.
• A better understanding of how gas compounds can impact biology.

For years, researchers were convinced that the tiny molecule consisting of a mere two atoms had no business in the body and brain. More complex compounds run many physiological processes so it made no sense that a gas could have an effect. Then in 1977 researchers determined that some of the drugs that are used to treat heart attacks by widening blood vessels, happen to release NO. Could NO naturally act to widen blood vessels in the body? Following a series of experiments, researchers concluded in 1986 that NO, indeed, regulates the widening of blood vessels. Research on NO snowballed. It turns out that NO influences a wide range of physiological functions. Among them, it appears to help the mechanisms that lead to memory and penile erection. Yes, NO mechanisms are behind the success of the well known impotence drug, Viagra.

Unfortunately you can get too much of a good thing.

Some researchers believe that many brain disorders can trigger an overproduction of NO. And the excess gas ends the life of brain cells known as neurons.

The first inkling of NO's sinister side came in 1991 when researchers found that they could block the neuron death that normally occurs in a cell model of stroke by inhibiting NO production. Specifically, they blocked the activity of an enzyme, known as nitric oxide synthase (NOS). This enzyme synthesizes the NO gas. Researchers have difficulty blocking NO directly because the gas has a very short lifespan in the neuron.

Additional research on animals also shows that NO is involved in neuron death. For example, studies determined that blocking NOS in the brain impedes the cell death that occurs from stroke as well as in other disorders such as Parkinson's disease.

Researchers now are actively investigating compounds that can derail NOS, in order to create new therapies that will control NO and protect human neurons in a range of brain ailments.

Scientists also are investigating other participants in NO's course of action in order to identify additional treatment targets. One participant that may hold promise is the enzyme called PARP. Some researchers believe that excess NO creates nicks and breaks in the DNA of neurons. The injuries in this important molecule activate PARP, which depletes energy sources in the cell, causing cell death. Scientists found that doses of small molecules that inhibit PARP reduce brain damage in a variety of animal stroke models. In addition, genetically-altered mice that do not produce PARP are protected from the damage of experimentally-induced stroke and Parkinson's disease.

Perhaps pramiracetam was taken off the market because it caused neuronal death, rather than protecting neurons.

References:

[1] Systemic administration of pramiracetam increases nitric oxide synthase activity in the cerebral cortex of the rat
by Corasaniti MT, Paoletti AM, Palma E, Granato T, Navarra M, Nistico G.
Faculty of Pharmacy, University of Reggio Calabria, Catanzaro, Italy.
Funct Neurol 1995 May-Jun;10(3):151-5

[2] http://www.aecom.yu....eau/nos/nos.htm

[3] http://www.sfn.org/c...tric.oxide.html

The question is whether this increase of NO caused by Pramiracetam is sufficient enough to induce neuronal death, or if it's only enough to offer the positive aformentioned effects.

I tend to think that Pramiracetam doesn't induce neuronal death, but if there is explicit evidence otherwise I'd like to see it.

"this nootropic produced an approximately 20% increase in NOS activity" [1]

20% is quite significant.

Since there are very few studies on pramiracetam, you cannot be sure that this drug does not cause neuronal death. Given that pramiracetam does increase NOS activity, which increases NO, it is therefore very likely that NO may rise high enough to cause neuronal death.

That is not assured, but it's a worrying possibliity.

Neither side of the argument is assured, but the evidence points towards neuronal death. Like you said, this is certainty "a worrying possibility" and should not be dismissed by even the most enthusiastic proponents of nootropics, e.g. Nootropi.
Edited by unipolar_mania, 23 November 2004 - 10:33 AM.

Pramiracetam is definetly not a very well researched nootropic. There are only about 3 studies involving human volunteers directly, two of which were pharmacokinetic studies. The remaining one shows that, in healthy volunteers, Pramiracetam partially reversed scopaline-induced amnesia (Arch Gerontol Geriatr. 1994 Mar-Apr;18(2):133-9).

One of the studies in rats showed that Pramiracetam increased high affinity choline uptake into the hippocampus (Act Nerv Super (Praha). 1987 Mar;29(1):62-5). Another study found that pramiracetam and aniracetam inhibit propyl endopeptidase indicating a possible interaction with neuropeptides such as vasopressin or thyrotropin-releasing hormone. Aniracetam, however, was shown to be more potent than pramiracetam in this regard (J Pharmacobiodyn. 1987 Dec;10(12):730-5).

So Pramiracetam is kind of in a grey area as far as safety and how it works (i.e. what differentiates it from the other structurally related racetams). The last study was published more than ten years ago, so it would seem that researchers find it of very little clinical usefulness in neurodegenerative pathologies.

Neither side of the argument is assured, but the evidence points towards neuronal death. Like you said, this is certainty "a worrying possibility" and should not be dismissed by even the most enthusiastic proponents of nootropics, e.g. Nootropi.

Of course....

Look I know that there hasn't been that much research into Pramiracetam, I wonder why that is the case, perhaps they couldn't find an applicable affliction which Pramiracetam could treat. Subjective reports are numerous and positive, but clearly that is far from enough, and subjective reports don't supply solid data about possible negative effects associated with Pram.

Click: For some discussion on NO

Pramiracetam increases nitric oxide synthase (NOS) activity in the cerebral cortex of the rat [1].  NOS is the enzyme that catalyzes the formation of NO from oxygen and arginine is nitric oxide synthase [2].  NO has both positive and negative effects in the brain, as discussed in the following article [3]: 

Scientists are finding evidence that NO participates in the brain cell damage that occurs in a variety of neurological ailments, such as stroke and Parkinson's disease.  ...

Some researchers believe that many brain disorders can trigger an overproduction of NO. And the excess gas ends the life of brain cells known as neurons.

The first inkling of NO's sinister side came in 1991 when researchers found that they could block the neuron death that normally occurs in a cell model of stroke by inhibiting NO production. Specifically, they blocked the activity of an enzyme, known as nitric oxide synthase (NOS). This enzyme synthesizes the NO gas. Researchers have difficulty blocking NO directly because the gas has a very short lifespan in the neuron. ...

Researchers now are actively investigating compounds that can derail NOS, in order to create new therapies that will control NO and protect human neurons in a range of brain ailments.

First, I would be careful in evaluating any articles or studies speaking generically of "nitric oxide synthase." There are at least 3 mammalian isoforms of the enzyme -- neuronal nNOS, inducible iNOS, and endothelial eNOS. eNOS and nNOS are the constitutive isoforms, while the iNOS isoformis induced in response to inflammatory cytokines (notably IFN-gamma and TNF). In fundamentally healthy people not suffering from very high oxidative stress brought on by neurodegenerative disease, the effects of NO derived from the constitutive enzymes are essentially benign. The abstract of the article showing increased "NOS" activity "in rat brain cortical homogenates but not in hippocampal homogenates" [1] does not specify the isoform, so this could just mean increased eNOS in the cerebral microcirculation, or neuronal nNOS.

More importantly, the abstract specifies that while "A dose of 300 mg/kg (i.p.) of this nootropic produced an approximately 20% increase in NOS activity in rat brain cortical homogenates ... A lower dose of pramiracetam (100 mg/kg i.p.) was ineffective on NOS mRNA expression and enzyme activity." [1] Even after adjusting for allometric scaling (assuming a mature (415 g) rat), this means respective doses in a 70 kg human of 5829 and 1943 mg, injected into the abdomen; typical human doses for this nootropic are 150-600 mg a day, orally. So there is plenty of room below the floor of (possible) neurotoxicity.

My own council, however, would in any case be to consider the original orthomolecule (pyroglutamic acid) instead of the various xenobiotic analogs.

Scientists also are investigating other participants in NO's course of action in order to identify additional treatment targets. One participant that may hold promise is the enzyme called PARP. Some researchers believe that excess NO creates nicks and breaks in the DNA of neurons. The injuries in this important molecule activate PARP, which depletes energy sources in the cell, causing cell death. Scientists found that doses of small molecules that inhibit PARP reduce brain damage in a variety of animal stroke models. In addition, genetically-altered mice that do not produce PARP are protected from the damage of experimentally-induced stroke and Parkinson's disease.

One more reason to take benfotiamine :

Here we studied whether benfotiamine inhibits the activation of PARP in vitro and in vivo. In endothelial cells placed in elevated glucose for 24h, benfotiamine dose-dependently reduced the activation of PARP. Benfotiamine was also effective against the activation of PARP in cultured cells challenged with oxidants with approx. 50% inhibition at 3-10 µM and near-complete inhibition at 200 µM. In a murine model of retinopathy, chronic benfotiamine treatment reduced the accumulation of poly(ADP-ribose), while it did not affect the expression of PARP protein itself. Inhibition of PARP may be a mode of action though which benfotiamine exerts its beneficial effects in diabetic complications. " [4]

To your health!

AOR

References:

[1] Systemic administration of pramiracetam increases nitric oxide synthase activity in the cerebral cortex of the rat
by Corasaniti MT, Paoletti AM, Palma E, Granato T, Navarra M, Nistico G.
Faculty of Pharmacy, University of Reggio Calabria, Catanzaro, Italy.
Funct Neurol 1995 May-Jun;10(3):151-5

[2] http://www.aecom.yu....eau/nos/nos.htm

[3] http://www.sfn.org/c...tric.oxide.html

[4] Mabley JG, Brownlee MG, Hammes HG, Szabo CG. The B1 vitamin analog benfotiamine inhibits poly(ADP-ribose) polymerase. Experimental Biology 2004. 2004 Apr 17-21; Abs 787.30

If you're scared of Nitric Oxide synthase, don't take Arginine or Garlic Supplements either! [tung]

FWIW
I have quite a bit of experience with all four of the commonly available 'racetams. I have used at least one form of 'racetam daily for over ten years. I find the subjective effects of pramiracetam (neupramir) to be the least desirable of the four. With the greater cost and greater uncertainty as to it's safety, I have avoided it for the last 4 years. I even have a couple of expired (& expensive) boxes of pram still around. Didn't think much of it after two trials from two different suppliers/lots.

It will be interesting to see the reaction of the forum if/when it becomes cheaply available in bulk. I personally have no interest in trying bulk Pram', but I have noticed that bulk piracetam and bulk oxiractam seem more effective than their pharm. tabbed alternatives.

obw

where did you get your bulk powders olderbutwiser?

Well, here's one

http://www.bulknutri...products_id=912

Could this apply to Oxiracetam too?

If you're scared of Nitric Oxide synthase, don't take Arginine or Garlic Supplements either! tung.gif

Bacopa, a cognitive supplement that have been been safely taken for thousand of years.

NOBEL PRIZE WINNER AND HEADS OF STATE
According to one report, Nobel Prize winner Dr. Robert Furchgott examined Bacopa and concluded that it worked similarly to nitric oxide (the subject of his prize-winning research). Quoting Dr Furchgott, "The compound [Bacopa] has been tested in our laboratory . . . . Based on our experiments . . . this compound appears to release nitric oxide . . . . The compound causes at least 75% relaxation of the [heart muscle] . . . ."13

If you're scared of Nitric Oxide synthase, don't take Arginine or Garlic Supplements either! tung.gif

Bacopa, a cognitive supplement that have been been safely taken for thousand of years.

NOBEL PRIZE WINNER AND HEADS OF STATE
According to one report, Nobel Prize winner Dr. Robert Furchgott examined Bacopa and concluded that it worked similarly to nitric oxide (the subject of his prize-winning research). Quoting Dr Furchgott, "The compound [Bacopa] has been tested in our laboratory . . . . Based on our experiments . . . this compound appears to release nitric oxide . . . . The compound causes at least 75% relaxation of the [heart muscle] . . . ."13

I realize this is an old post. Could you confirm if Bacopa increases NO and could you give me supportive evidence, please? It is not clear, because if it does, how to counteract this effect? Thanks
Edited by Beebs, 19 February 2010 - 03:25 PM.

Pramiracetam increases nitric oxide synthase (NOS) activity in the cerebral cortex of the rat [1]. NOS is the enzyme that catalyzes the formation of NO from oxygen and arginine is nitric oxide synthase [2]. NO has both positive and negative effects in the brain, as discussed in the following article [3]:

Scientists are finding evidence that NO participates in the brain cell damage that occurs in a variety of neurological ailments, such as stroke and Parkinson's disease. The new research is leading to:
• Targeted brain cell-protecting therapies that interfere with NO chemistry.
• Clearer insight into the complex behavior of NO.
• A better understanding of how gas compounds can impact biology.

For years, researchers were convinced that the tiny molecule consisting of a mere two atoms had no business in the body and brain. More complex compounds run many physiological processes so it made no sense that a gas could have an effect. Then in 1977 researchers determined that some of the drugs that are used to treat heart attacks by widening blood vessels, happen to release NO. Could NO naturally act to widen blood vessels in the body? Following a series of experiments, researchers concluded in 1986 that NO, indeed, regulates the widening of blood vessels. Research on NO snowballed. It turns out that NO influences a wide range of physiological functions. Among them, it appears to help the mechanisms that lead to memory and penile erection. Yes, NO mechanisms are behind the success of the well known impotence drug, Viagra.

Unfortunately you can get too much of a good thing.

Some researchers believe that many brain disorders can trigger an overproduction of NO. And the excess gas ends the life of brain cells known as neurons.

The first inkling of NO's sinister side came in 1991 when researchers found that they could block the neuron death that normally occurs in a cell model of stroke by inhibiting NO production. Specifically, they blocked the activity of an enzyme, known as nitric oxide synthase (NOS). This enzyme synthesizes the NO gas. Researchers have difficulty blocking NO directly because the gas has a very short lifespan in the neuron.

Additional research on animals also shows that NO is involved in neuron death. For example, studies determined that blocking NOS in the brain impedes the cell death that occurs from stroke as well as in other disorders such as Parkinson's disease.

Researchers now are actively investigating compounds that can derail NOS, in order to create new therapies that will control NO and protect human neurons in a range of brain ailments.

Scientists also are investigating other participants in NO's course of action in order to identify additional treatment targets. One participant that may hold promise is the enzyme called PARP. Some researchers believe that excess NO creates nicks and breaks in the DNA of neurons. The injuries in this important molecule activate PARP, which depletes energy sources in the cell, causing cell death. Scientists found that doses of small molecules that inhibit PARP reduce brain damage in a variety of animal stroke models. In addition, genetically-altered mice that do not produce PARP are protected from the damage of experimentally-induced stroke and Parkinson's disease.

Perhaps pramiracetam was taken off the market because it caused neuronal death, rather than protecting neurons.

References:

[1] Systemic administration of pramiracetam increases nitric oxide synthase activity in the cerebral cortex of the rat
by Corasaniti MT, Paoletti AM, Palma E, Granato T, Navarra M, Nistico G.
Faculty of Pharmacy, University of Reggio Calabria, Catanzaro, Italy.
Funct Neurol 1995 May-Jun;10(3):151-5

[2] http://www.aecom.yu....eau/nos/nos.htm

[3] http://www.sfn.org/c...tric.oxide.html

Does anyone have any current information on this?

Pramiracetam increases nitric oxide synthase (NOS) activity in the cerebral cortex of the rat [1]. NOS is the enzyme that catalyzes the formation of NO from oxygen and arginine is nitric oxide synthase [2]. NO has both positive and negative effects in the brain, as discussed in the following article [3]:

Scientists are finding evidence that NO participates in the brain cell damage that occurs in a variety of neurological ailments, such as stroke and Parkinson's disease. The new research is leading to:
• Targeted brain cell-protecting therapies that interfere with NO chemistry.
• Clearer insight into the complex behavior of NO.
• A better understanding of how gas compounds can impact biology.

For years, researchers were convinced that the tiny molecule consisting of a mere two atoms had no business in the body and brain. More complex compounds run many physiological processes so it made no sense that a gas could have an effect. Then in 1977 researchers determined that some of the drugs that are used to treat heart attacks by widening blood vessels, happen to release NO. Could NO naturally act to widen blood vessels in the body? Following a series of experiments, researchers concluded in 1986 that NO, indeed, regulates the widening of blood vessels. Research on NO snowballed. It turns out that NO influences a wide range of physiological functions. Among them, it appears to help the mechanisms that lead to memory and penile erection. Yes, NO mechanisms are behind the success of the well known impotence drug, Viagra.

Unfortunately you can get too much of a good thing.

Some researchers believe that many brain disorders can trigger an overproduction of NO. And the excess gas ends the life of brain cells known as neurons.

The first inkling of NO's sinister side came in 1991 when researchers found that they could block the neuron death that normally occurs in a cell model of stroke by inhibiting NO production. Specifically, they blocked the activity of an enzyme, known as nitric oxide synthase (NOS). This enzyme synthesizes the NO gas. Researchers have difficulty blocking NO directly because the gas has a very short lifespan in the neuron.

Additional research on animals also shows that NO is involved in neuron death. For example, studies determined that blocking NOS in the brain impedes the cell death that occurs from stroke as well as in other disorders such as Parkinson's disease.

Researchers now are actively investigating compounds that can derail NOS, in order to create new therapies that will control NO and protect human neurons in a range of brain ailments.

Scientists also are investigating other participants in NO's course of action in order to identify additional treatment targets. One participant that may hold promise is the enzyme called PARP. Some researchers believe that excess NO creates nicks and breaks in the DNA of neurons. The injuries in this important molecule activate PARP, which depletes energy sources in the cell, causing cell death. Scientists found that doses of small molecules that inhibit PARP reduce brain damage in a variety of animal stroke models. In addition, genetically-altered mice that do not produce PARP are protected from the damage of experimentally-induced stroke and Parkinson's disease.

Perhaps pramiracetam was taken off the market because it caused neuronal death, rather than protecting neurons.

References:

[1] Systemic administration of pramiracetam increases nitric oxide synthase activity in the cerebral cortex of the rat
by Corasaniti MT, Paoletti AM, Palma E, Granato T, Navarra M, Nistico G.
Faculty of Pharmacy, University of Reggio Calabria, Catanzaro, Italy.
Funct Neurol 1995 May-Jun;10(3):151-5

[2] http://www.aecom.yu....eau/nos/nos.htm

[3] http://www.sfn.org/c...tric.oxide.html

Does anyone have any current information on this?

You are going to love this. Get it while its hot and make sure you save it. Here is the good stuff.

From numerous animal studies over the last five years, we know that anything which inhibits nitric oxide synthase can stop this whole scenario. In a typical study, baboons were given the nitric oxide synthase inhibitor 7-nitroindazole. When subsequently given the poison MPTP, they were completely protected against cell death in the substantia nigra, and showed no physical symptoms of Parkinson’s.18 7-nitroindazole is not yet commercially available, and has some nasty side-effects. But simpler, non-toxic substances work equally well. Genistein, extracted from soybeans, specifically inhibits nitric oxide production.19 Genistein is also neuroprotective in mouse models of Lou Gehrig’s disease (amyotrophic lateral sclerosis), and stroke, and in protecting post-menopausal women from Alzhiemer’s.20,21
Another inexpensive, non-toxic chemical that strongly inhibits nitric oxide synthase is allicin, extracted from garlic. In the latest study, Schwartz and colleagues at Tel Aviv Sourasky Medical Center in Israel, show that allicin also inhibits the transport of arginine, from which nitric oxide is manufactured. So this simple herbal offers double-whammy brain protection.22
A third non-toxic herbal that regulates nitric oxide levels is ginkgo. In animal experiments, ginkgo effectively prevents the changes in nitric oxide levels caused by induced brain trauma, such as subarachnoid hemorrhage.23 In studies of Alzheimer’s patients, gingko stabilizes, and in less severe cases, improves cognitive performance.24
The final herbal I want to include in this chapter is the known liver protective agent Silymarin (milk thistle extract). It does not inhibit nitric oxide production, but can indirectly stop nitric oxide turning into peroxynitrite. Silymarin specifically inhibits production of the enzyme xanthine oxidase which, as a side-effect, produces the superoxide radical, the other half of peroxynitrite.25
One of the so-called smart drugs, aminoguanidine, is also an inhibitor of nitric oxide synthase. This chemical has low toxicity and is now being tried against multiple sclerosis. In the mouse model of multiple sclerosis called, encephalomyelitis, aminoguanidine suppresses nitric oxide production very effectively and reduces the disease.26
Then there is aspirin. For the last 18 years most clients of the Colgan Institute over age 35, have been taking a baby aspirin each day to inhibit platelet aggregation and clot formation, and prevent heart attacks. Little did they know that they are also protecting their brains. Recent animal studies show that small amounts of aspirin, the equivalent in humans of one adult aspirin per day (325 mg), effectively prevent the rise in nitric oxide which occurs in response to fear and anger caused by stressors such as immobilization.4
Another non-toxic substance that inhibits the excess nitric oxide scenario, is the omega-3 fat, docosohexaenoic acid (DHA) in fish oil. This nutrient works by inhibiting release of inflammatory cytokines that trigger nitric oxide production by brain glial cells.27
Thus we have an arsenal of substances with virtually no toxicity which can stop nitric oxide running amok in the brain, genistein, allicin, gingko, silymarin, aminoguanidine, aspirin, and docosohexaenoic acid. Make sure that you only take these in conjunction with a good multiple vitamin and mineral program.
You need to add to these supplements by fleeing the city and its stressors. You also need to program your mind, as detailed in a chapter ahead, to eliminate negative emotions. Follow these steps plus the strategies in previous chapters, and your brain will likely be good for more than a hundred years.

This is the abstract to the original incomplete one.

The effect of systemic administration of pramiracetam on neuronal type nitric oxide synthase (NOS) activity and NOS mRNA expression were studied in the hippocampus and cerebral cortex in rats. A dose of 300 mg/kg (i.p.) of this nootropic produced an approximately 20% increase in NOS activity in rat brain cortical homogenates but not in hippocampal homogenates; no significant changes were observed in NOS mRNA expression in the cortex and hippocampus. A lower dose of pramiracetam (100 mg/kg i.p.) was ineffective on NOS mRNA expression and enzyme activity. Interestingly, administration of pramiracetam (300 mg/kg i.p.) in rats pretreated (24 h before) with lithium chloride (LiCl) (3 mEq/kg i.p.) yielded a 40% increase in cortical NOS activity. However, in LiCl-pretreated rats this nootropic failed to affect cortical NOS mRNA expression; LiCl (3 mEq/kg i.p.) given alone produced no effect. In conclusion, the present data demonstrate that pramiracetam given alone or in combination with LiCl increases NOS activity in brain cortical homogenates of rats and this may contribute to the mechanisms underlying learning and memory improvement produced by this nootropic.

The conclusion is kind of strange seeing NOS is something we do not want.
Edited by valory5, 21 November 2010 - 11:44 PM.

This is the abstract to the original incomplete one.

The effect of systemic administration of pramiracetam on neuronal type nitric oxide synthase (NOS) activity and NOS mRNA expression were studied in the hippocampus and cerebral cortex in rats. A dose of 300 mg/kg (i.p.) of this nootropic produced an approximately 20% increase in NOS activity in rat brain cortical homogenates but not in hippocampal homogenates; no significant changes were observed in NOS mRNA expression in the cortex and hippocampus. A lower dose of pramiracetam (100 mg/kg i.p.) was ineffective on NOS mRNA expression and enzyme activity. Interestingly, administration of pramiracetam (300 mg/kg i.p.) in rats pretreated (24 h before) with lithium chloride (LiCl) (3 mEq/kg i.p.) yielded a 40% increase in cortical NOS activity. However, in LiCl-pretreated rats this nootropic failed to affect cortical NOS mRNA expression; LiCl (3 mEq/kg i.p.) given alone produced no effect. In conclusion, the present data demonstrate that pramiracetam given alone or in combination with LiCl increases NOS activity in brain cortical homogenates of rats and this may contribute to the mechanisms underlying learning and memory improvement produced by this nootropic.

The conclusion is kind of strange seeing NOS is something we do not want.

Heh, this sucks. I just purchased some Pram when I noticed this. So far Ive taken 1200mg in the span of two days. Is it likely that any noticeable effects resulting from NOS may linger or be potentiating as a result?

This is the abstract to the original incomplete one.

The effect of systemic administration of pramiracetam on neuronal type nitric oxide synthase (NOS) activity and NOS mRNA expression were studied in the hippocampus and cerebral cortex in rats. A dose of 300 mg/kg (i.p.) of this nootropic produced an approximately 20% increase in NOS activity in rat brain cortical homogenates but not in hippocampal homogenates; no significant changes were observed in NOS mRNA expression in the cortex and hippocampus. A lower dose of pramiracetam (100 mg/kg i.p.) was ineffective on NOS mRNA expression and enzyme activity. Interestingly, administration of pramiracetam (300 mg/kg i.p.) in rats pretreated (24 h before) with lithium chloride (LiCl) (3 mEq/kg i.p.) yielded a 40% increase in cortical NOS activity. However, in LiCl-pretreated rats this nootropic failed to affect cortical NOS mRNA expression; LiCl (3 mEq/kg i.p.) given alone produced no effect. In conclusion, the present data demonstrate that pramiracetam given alone or in combination with LiCl increases NOS activity in brain cortical homogenates of rats and this may contribute to the mechanisms underlying learning and memory improvement produced by this nootropic.

The conclusion is kind of strange seeing NOS is something we do not want.

Heh, this sucks. I just purchased some Pram when I noticed this. So far Ive taken 1200mg in the span of two days. Is it likely that any noticeable effects resulting from NOS may linger or be potentiating as a result?

Your guess is as good as mine. I wonder if a NOS inhibitor would be good to take with this? Curcumin is a NOS inhibitor. Here is an abstract:

Curcumin is a naturally occurring, dietary polyphenolic phytochemical that is under preclinical trial evaluation for cancer preventive drug development and whose working pharmacological actions include anti-inflammation. With respect to inflammation, in vitro, it inhibits the activation of free radical-activated transcription factors, such as nuclear factor κB (NFκB) and AP-1, and reduces the production of pro-inflammatory cytokines such as tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β), and interleukin-8. Inducible nitric oxide synthase (iNOS) is an inflammation-induced enzyme that catalyzes the production of nitric oxide (NO), a molecule that may lead to carcinogenesis. Here, we report that in ex vivo cultured BALB/c mouse peritoneal macrophages, 1–20 μM of curcumin reduced the production of iNOS mRNA in a concentration-dependent manner. Furthermore, we demonstrated that, in vivo, two oral treatments of 0.5 mL of a 10-μM solution of curcumin (92 ng/g of body weight) reduced iNOS mRNA expression in the livers of lipopolysaccharide(LPS)-injected mice by 50–70%. Although many hold that curcumin needs to be given at dosages that are unattainable through diet to produce an in vivo effect, we were able to obtain potency at nanomoles per gram of body weight. This efficacy is associated with two modifications in our preparation and feeding regimen: 1) an aqueous solution of curcumin was prepared by initially dissolving the compound in 0.5 N NaOH and then immediately diluting it in PBS; and 2) mice were fed curcumin at dusk after fasting. Inhibition was not observed in mice that were fed ad lib., suggesting that food intake may interfere with the absorption of curcumin.

I tried Prami a few times, seemed a little "speedier" than the other racetams, but only for a day or two of consistent use. I'd say consider reserving it for occasional use as a cognitive brightener, rather than as a daily nootropic. Personally, I like how I feel better on Oxiracetam. Oxiracatam actually tastes a bit sweet, so I take 400-800 mgs sublingually and within minutes I'm feeling a little more cheerful and my visual acuity is enhanced.

Is it relative to point out that the 20% increase in NO concentration was noticed at doses of 300mg/kg? That's well above any discussed human doses I've heard of. That's like me eating a full 25g canister at once. Is it possible that at lower doses your body is able to regulate the effect and naturally balance out the NO?

I've never tried prami and one of the reasons was because I was worried about the NO effects I read about. But I just realized the mg/kg level of the study. Those are the same levels they tested nefi at that caused testicular toxicity in dogs yet it is approved now for human use in post stroke apathy (hopefully that means that lower doses don't cause the same toxicity). I'm guessing the NO concerns are being exaggerated in comparison to the relatively low human nootropic dosage.

Is it relative to point out that the 20% increase in NO concentration was noticed at doses of 300mg/kg? That's well above any discussed human doses I've heard of. That's like me eating a full 25g canister at once. Is it possible that at lower doses your body is able to regulate the effect and naturally balance out the NO?

300mg/kg in a rat is equivalent to about 5g in a normal weight adult human. That is still quite a large dose for Prami, the ceiling of what I'd even recommend would be 800mg for a high bodyweight person (350+ pounds), I take 200mg/day because I'm taking other racetams with it, but taking 5g/day probably wouldn't offer any benefits, only increased risks over a more moderate dose of 400mg-600mg. I haven't heard about neuronal death as a side effect at a more conventional dose. (30mg/kg in rats one study indicates was optimal prami application [equivalent to about 4mg/kg in humans]).
http://www.ennassor.... in rats_II.pdf

This nootropic is wonderul!

THE POWER IS IN THE TASTE!

Is it relative to point out that the 20% increase in NO concentration was noticed at doses of 300mg/kg? That's well above any discussed human doses I've heard of. That's like me eating a full 25g canister at once.

Not quite. Nezxon already spoke to this, but 300mg/kg in a rat isn't the same as 300mg/kg in a human. Here's an article that explains why, as well as the best (currently known) method to figure out human dosages from animal studies. It takes less than two pages to make it's point; please read/spread it around:

http://www.fasebj.or...t/22/3/659.full

hopefully that means that lower doses don't cause the same toxicity

From the full abstract of that study, quoted on page one of this thread:
"A lower dose of pramiracetam (100 mg/kg i.p.) was ineffective on NOS mRNA expression and enzyme activity"
Meaning, yes, lower doses don't significantly increase NO and whatever negative effects it may have

Is it relative to point out that the 20% increase in NO concentration was noticed at doses of 300mg/kg? That's well above any discussed human doses I've heard of. That's like me eating a full 25g canister at once.

Not quite. Nezxon already spoke to this, but 300mg/kg in a rat isn't the same as 300mg/kg in a human. Here's an article that explains why, as well as the best (currently known) method to figure out human dosages from animal studies. It takes less than two pages to make it's point; please read/spread it around:

http://www.fasebj.or...t/22/3/659.full

hopefully that means that lower doses don't cause the same toxicity

From the full abstract of that study, quoted on page one of this thread:
"A lower dose of pramiracetam (100 mg/kg i.p.) was ineffective on NOS mRNA expression and enzyme activity"
Meaning, yes, lower doses don't significantly increase NO and whatever negative effects it may have

Thanks Duster... since learning this I found an allometric dosing calculator online ( ALLOMETRIC SCALING CALCULATOR). Thank goodness I found out this information before experimenting with higher doses of certain nootropics.

Is it relative to point out that the 20% increase in NO concentration was noticed at doses of 300mg/kg? That's well above any discussed human doses I've heard of. That's like me eating a full 25g canister at once.

Not quite. Nezxon already spoke to this, but 300mg/kg in a rat isn't the same as 300mg/kg in a human. Here's an article that explains why, as well as the best (currently known) method to figure out human dosages from animal studies. It takes less than two pages to make it's point; please read/spread it around:

http://www.fasebj.or...t/22/3/659.full

hopefully that means that lower doses don't cause the same toxicity

From the full abstract of that study, quoted on page one of this thread:
"A lower dose of pramiracetam (100 mg/kg i.p.) was ineffective on NOS mRNA expression and enzyme activity"
Meaning, yes, lower doses don't significantly increase NO and whatever negative effects it may have

Thanks Duster... since learning this I found an allometric dosing calculator online ( ALLOMETRIC SCALING CALCULATOR). Thank goodness I found out this information before experimenting with higher doses of certain nootropics.

Awesome! Bookmarked. So at a 0.75 exponent and a 0.15kg rat given 45mg (0.15*300mg), that makes 65kg human equivalent overdose (by injection?) to be 4274mg. Likewise, a 15mg (100mg/kg) for a rat would be a 1424mg dose for a human. The optimal 30mg/kg dose for rats gives 427mg for a 65kg human. Thus, 427mg/dose (an intake at less than 1/3 of the "safe" dose) is probably quite safe over time (as it won't reach 1424mg/day if taken 2-3x/day), especially if taken with ginkgo or garlic to clean up any extra NO.

I take 200mg 2-4x a day in my stack, so I feel pretty safe, especially since I eat garlic and omega3's regularly. I'm wondering if I should take more or find a more potent (per mg) racetam.

That's not too bad at all, especially considering B vitamins have lower upper limits. B6' upper limit is 100mg/day.

What's the oral bioavailability of pramiracetam?
Edited by devinthayer, 17 June 2011 - 05:51 PM.

Is it also suggested to use CDP-Choline or A-GPC? What kind of ratios? I just got 2 bottles of Pramiracetam before reading this. I've never tried it before.

BTW: I'm also very curious about whether Bacopa increases NOS activity.
Edited by exigentsky, 18 June 2011 - 01:41 AM.

What's the oral bioavailability of pramiracetam?

I wasn't able to track down the source, but I'm confident in saying pramiracetam's oral bioavailability is quite high, between 97% and 100%. I believe the same is true for the other core racetams as well.