Nefiracetam

Pharmacological group: nootropics

Systematic (IUPAC) name: N- (2,6-dimethylphenyl) -2 - (2-oxo-pyrrolidin-1-yl) acetamide
Legal status: unregulated (USA)
Application: oral
Half-life: 3-5 hours
Formula: C14H18N2O2
Mol. weight: 246.305 g / mol

Nefiracetam - a neuroprotective drugs against dementia of drugs Racetam family. The cytoprotective action of Nefiracetam mediated increase GABA, choline and monoaminergic neural systems. The drug is indicated for the effective treatment of apathy and increase motivation among stroke patients. Nefiracetam anti-amnesic takes effect in dementia such as Alzheimer's disease and cerebrovascular dementia. Furthermore, it was also shown that Nefiracetam anti-amnesic exhibit activity against a wide spectrum of substances that cause memory loss including ethanol, hlorodaz-epokside (Librium), scopolamine, bicuculline, picrotoxin and cycloheximide.

general information
Nefiracetam is a cognitive enhancer (nootropic drug) of Racetam family, originally derived from the parent molecule Piracetam, but structurally it is most similar to Aniracetam. As Nefiracetam and aniracetam are fat-soluble drugs Racetamic type. They are used to improve the treatment of memory and cognitive disorders. With a single use, Nefiracetam no significant impact on the quality of memory. Nefiracetam may influence the formation of the memory used at daily for at least 7 days, it was repeatedly demonstrated that in animal studies, in humans the same effect is manifested. Long-term use has also been associated with a higher degree of neurogenesis, which does not occur at a single reception. The mechanism of action is associated Nefiracetam two so-called ways. The first way is to extend the opening of calcium channels (tied to PKA and Gi / o proteins) that enhances receptor response, regardless of the synapse; a second path associated with PKC and CAMKII, which then complete the reaction due to the cholinergic receptors (which are then the most excitatory neurotransmitter release at the presynaptic level, as is the case with nicotine). The previous path (calcium channel) is important in the long term, while the latter path (PKC / CAMKII) has an impact on the strengthening of neural signals and their transmission. Some other minor ways can be partial agonists at the glycine binding NDMA receptor (may enhance interaction at certain levels of glycine, thus weakening the interaction), as well as increase communication muskanic acetylcholine receptors to their ligand acetylcholine. Nefiracetam is a cognitive enhancer that improves the functioning of the memory by increasing the exposure of acetylcholine and glutamate in the synapse, prolonging the action of calcium in the activated neuron. This process does not occur at a single reception, this requires daily use of supplements. Regarding the potential toxicity Nefiracetam, it is quite toxic to dogs at doses higher than the recommended; lower dosages do not have a toxic effect, and these low dosages barely fit in the recommended dosage interval. There is also reason to believe that the drug is only toxic to dogs, since experiments on rats and monkeys did not reflect such properties. To date, there is not enough information on the issue concerning the people, however limited testing using the recommended dosage Nefiracetam is showed no complications. Nefiracetam is highly toxic to dogs, but this does not apply to the monkeys and rodents. While it is still not fully confirmed harmful or harmless effect Nefiracetam per person, standard recommended doses of the drug is not associated with overt toxicity in preliminary studies.

Nefiracetam is also known as: DM-9384, N- (2,6-dimethylphenyl) -2- (2-oxopyrrolidin-1-yl) acetamide

Nefiracetam Represents:

• Racetam
• Nootropics

Nefiracetam is not compatible with:

Glycine and other ligands involved in binding of glycine NDMA (including D-serine).

Nefiracetam: instructions for use
Standard dosage Nefiracetam, apparently, should be included in the range 150-450 mg daily (when divided into Three-reception). Animal studies using single-dose demonstrated efficacy using dosages in the range of 3-10 mg per kg of body weight, these data correlate with human dosage 0,48-1,6 mg per kg body weight (corresponding to 70 kg person, the dosage is 33 -110 mg), which is approximately agrees with the above values. Although a single use Nefiracetam does not improve the cognitive functions of the body, it can affect the brain activity after only 30-60 minutes after oral administration. While that is not exactly clear whether you need to take Nefiracetam directly to the upcoming mental stress.

Sources and structure
sources
Nefiracetam (N- (2,6-dimethylphenyl) -2- (2-oxopyrrolidin-1-yl) acetamide or its code name DM-93841)) is a hydrophobic derivative of piracetam and all Racetam compound Piracetam synthesized synthetically. Nefiracetam is mainly produced by Daiichi Sankyo (Japanese pharmaceutical company) for the treatment of Alzheimer's disease. Along with all the mechanisms attributed to Nefiracetam, it is usually considered a substance that is the discoverer of calcium channels in the body, as well as the indirect transfer of excitation signal substance, being a partial agonist of the glycine binding site of NDMA receptors. Niferacetam - is pyrrolidone nootropic drug, whose structure resembles Racetamic substance classes, namely Piracetam. Structurally, it is more different from Aniracetam or Oxiracetam (very similar to piracetam), but retains some common features with them.

Structure
Nefiracetam structure is generally similar to the structure of piracetam, although piracetam amine added to phenyl and two methyl groups.

Neurology
machinery
Nefiracetam can dose-dependently inhibit neuronal toxicity opening of the sodium channel (veratridine) at a concentration of 50 nm and 500 nm, providing equally save about 75% of cells in comparison to the baseline measurements. Nefiracetam can protect drugs from contributing opening sodium channels (neurotoxic substances).

G-proteins and calcium
G-proteins - are small intracellular binding molecules that are accompanied by G-protein receptors, two of which (GS holere4 sensitive), and Gi / Go pertussinu5 sensitive)) involved in the interaction with Nefiracetam. In particular, the effect is to prevent GS activation of neurotransmitter release and activation of presynaptic receptors atsetilholina.6) G-proteins involved in the interaction with the above receptors, many of which are neurological purposes. They mediate the effects Nefiracetam. Stimulation of receptors presynaptically acetylcholine (causing neurotransmitter release) depend from GS protein. The influx of calcium into the neuron is of vital importance in the development of long-term potentiation (LTP), and when the calcium channels are less involved in this process than glutamine retseptory7), they still continue to have a significant impact. Since calcium is involved in the processes of interaction at the expense of stimulating receptors (acetylcholine and glutamate), modulators of ion receptors can affect the cognitive features, while providing a new mechanism vozdeystviya.8) Nefiracetam effect on long-term calcium channel L-type (active mostly at the level of 1 micron to 204.8 +/- 12.9% of the reference measurement in the range of 0.1-10 microns at 123,7-136,2%) without affecting the transit components. This is similar to aniracetam reaction, which is more powerful (up to 10 microns Aniracetam level and 160.8 +/- 14.1%), having similar properties to the manifestations dibutyryl AMP; they complement each other, but do not increase the intensity. This increase in long-term cooperation is accompanied by calcium G0 / Gi protein that inhibits the abolition of the intensified interaction. Inhibition of calcium channels also prevents enhancement of learning capacity and antiamnesic effect Nefiracetam. Protein kinase C alpha is the main isoform protein in hippocampal LTP10), and Nefiracetam auto-phosphor enhances protein kinase C in a concentration that correlates with influx of calcium (with a maximum of 10 nm). This increase in protein kinase C alpha due target proteins (MARCKS and the NR1) is inhibited by inhibitors of protein kinase C, which has already been mentioned in previous studies. Protein kinase A and its target proteins (GluR112) and DARPP-3213)) is not affected at the same concentration Nefiracetam (10 nm). Activation of protein kinase C alpha was confirmed by oral Nefiracetam is used in a dosage of 1 mg per kg mouse body weight (approximately 125% of the control measurements), with activation occurred in mice with cognitive disorders and without them. Activation of protein kinase C dependent on the interaction glutamine (metabotropic receptors or blocking NMDA receptors cancel this effect). Activation of protein kinase C-alpha is a vital base of how Nefiracetam induces the formation of memory and cognitive enhancement properties, it all depends on the activation of the glutamate receptor. CaM kinase II autophosphorylation is increased depending on the concentration in the range of 10-1000 nm without changes in the protein content, while dependent on phosphorylation of synapsin I (synaptic mark¸r14)). Inhibition CAMKII, similar to protein kinase C and increase neuronal abolishes interaction (in this case, glutamine) and long-term potentiation in hippocampal neurons. Activation CAMKII interaction depends on glutamine as a blocker metabotropic receptors or activation of NMDA receptors. CAMKII also undergoes activation by oral Nefiracetam mice used in a concentration of 1 mg per kg body weight (150% as compared to control measurements), with confirmed efficacy in mice with cognitive disorders and healthy. CAMKII also a critical intermediary in the process of memory formation is similar to protein kinase C in the sense that both of them depend on the interaction of glutamine. You can also like Piracetam.

cholinergic neurotransmission
Nefiracetam antiamnesic effect on the protein synthesis inhibition may be canceled by means of scopolamine, which reflects the important role of muscarinic acetylcholine receptors; Acetylcholine itself has a protective effect against amnesia (caused by protein synthesis inhibitors) and can save nefiracetam acetylcholine concentration during the formation of toxins in amnesia. Effects of acetylcholine is a prerequisite for antiamnesic nefiracetam effect. Older rabbits improvements in the blink delay were associated with the use of Nefiracetam. So this property (delay blinking) is strongly associated with cholinergic emissions septogippokamic area and Nefiracetam can affect the hippocampus in this case, it suggests that the improvement in the use of cognitive properties Nefiracetam is directly related to the cholinergic neurotransmission. It is noted that Nefiracetam 5 mg per kg body weight can increase the concentration of QNB (3-Hinuklidil benzilate, a ligand), binding to muscarinic receptors; All this leads to an increase in Bmax parameter (by 138.7% compared to the control measurements). QNB may participate in binding to the acetylcholine. Oral use of Nefiracetam can increase the ability of the ligand binding to muscarinic acetylcholine receptors. Presynaptic acetylcholine receptors tend to the potential interaction with Nefiracetam (1-10 microns) in hippocampal cells, which promotes the release of glutamate and the LTP (this effect is not observed with piracetam and aniracetam). This increase in neurotransmitter release is secondary to the activation of the receptor and the α4β2 10nm and is ineffective without the acetylcholine neurone thus not react to the presence of acetylcholine. Increased activity of acetylcholine in the presynaptic protein kinase C dependent, but not inhibited due to the inhibition of G-protein. Increased release of acetylcholine (by 200-211% as compared to control measurements for 10-30 minutes with a duration of 60 minutes) has confirmed the effectiveness of Nefiracetam a concentration of 1 mg per kg body weight of the rats (dosage in humans is 0.16 mg per kg of body weight body) function on the prefrontal cortex. Release tetradotoksin is sensitive to, but is not caused by the action of scopolamine, longitudinal studies based nefiracetam 10 mg per kg body weight showed no change basal concentrations of acetylcholine (both normal rats and rats with brain damage). Nefiracetam may increase the effects of acetylcholine at the presynaptic level, increasing the release of acetylcholine (along with other neurotransmitters, including glutamate and). This was confirmed in a real study with oral use of Nefiracetam, which also revealed its effect on memory formation and protein kinase C. drawing attention to the study, which is not allocated a particular receptor interaction can be suppressed due to normal Nefiracetam (0 concentrations, 1-10 .mu.m) in a reversible manner over 30 minutes (a-sensitive protein kinase); This effect is enhanced at high concentrations (100-1000 m) due to the sensitive Gi / Go mechanism.) It is believed that the identified effects can manifest itself in two different ways, their inhibition is terminated after 70 minutes. Due to the interaction with the protein GS (no Gi / Go) protein kinases and independent A / C nefiracetam can stimulate acetylcholine α4β2 effects in a reversible form, which typically occurs at a concentration of 1 nm (in case of aniracetam - 0.1 nm), showing some efficacy at concentrations ranging from 10 nm to 10 microns. Potentiation occurs when acetylcholine receptor saturation of, and may occur more at values of 200-300% of baseline measurements. Other studies examining the effect of this receptor have noted that it is sensitive to protein kinase C as α7.25 receptor) This stimulation does not show enhancement effect of protein kinase C as well as a receptor for α4β2 will not prevent activation of protein kinase C; potentiation retseptorovα4β2 not manifested in HEK cells, which demonstrates a lack of incentive effect (other studies used cortisol neurons or PC12). Regarding speed α7 nicotinic acetylcholine receptor Nefiracetam demonstrated irreversible inhibition at a concentration of 1-100 microns, although it is weakly expressed (at 2,8-20,1% inhibition). This effect increased the EC50 value of acetylcholine on the receptor without activating the maximum. α7 receptor sensitive to protein kinase C (although it is not responsible for the activation of protein kinase C), in studies using all receptors and inhibit their function it has not shown any effect. Effects of nicotinic acetylcholine receptor is subject to change due to the incubation Nefiracetam, while marked as excitation and inhibition. Inhibitory way seem to be more dependent on the Gi / Go and protein kinase A (and increase the impact of calcium), while the increase in more ways tied to the GS and protein kinase C.

Glutamic neurotransmission
Nefiracetam (1-10 microns) can activate presinaptic acetylcholine receptors in hippocampal neurons, which are known to stimulate the release of neurotransmitters, including glutamate (among many others). It is possible that presinaptic Nefiracetam activity on acetylcholine release can cause increase glumata, and thus lead to greater activity at postsynaptic level. This is probably proglutaminic effect, which does not depend on the interaction of receptors. Inducible NDMA streams may increase in cortisol in rat neurons (due to binding of glycine). This also leads to an increase in NMDA exposure due to protein kinase C at 10 nm in the range 160-180% of baseline values, while not depending on the concentration of NDMA. This is due to the fact that the protein kinase C reduces the effect of blocking magnesium NMDA receptors (labeled when used Nefiracetam and in general what is the case with glycine found not; incubation Niferacetam may reduce potent effect of glycine at a concentration of 3 microns that comparable concentrations Nefiracetam 10 nm, although the combination of the effect is slightly lower. Surprisingly, unlike acetylcholine, increased exposure of the hippocampus induced Nefiracetam is independent of NMDA receptors because their blocking not abolished the effect. These interactions with receptor glycine are similar to those which involved a partial agonist (high affinity, but glycine appears lower activity), it is quite probably lead to that Gi / o protein is not inhibited due to the cancellation NMDA effects. glycine Binding considered active process and it does not include the reactions mentioned earlier, but the NMDA binding excluded from this process by blocking the direct effects on the inhibition Nefiracetam NDMA receptors, while retaining the activity of protein kinase C. Nefiracetam, apparently due to the interaction modulates binding to NMDA receptor glycine , being a partial agonist (more than allosteric modulator), since it does not work with other ligands, such as glycine. However, this fact does not play a vital importance for long-term potentiation. AMPA and kainate Nefiracetam is not exposed to a concentration of 10 nm, but little effect on the AMPA can be significant, if the concentration is increased to 100 nm. AMPA effect is dependent on the activation of CaMKII, but so far it is unclear how AMPA receptors influence the formation of memory in the use Nefiracetam as Nefiracetam 1000 nm (corresponding to the high activation of AMPA receptors) is not associated with long-term potentiation (the LTP) as at 10-100 nm. While kainate receptors are completely amazed, AMPA receptors are less exposed to concentrations under standard Nefiracetam. With higher concentrations, the AMPA receptors are beginning to get more glutamic load, which may be reduced at the expense of NDMA (marked downward trend). 200-500 nm Nefiracetam may seem to weaken the glutamate-induced toxicity in vitro by reducing glutamate-induced cell death by 26%; ischemic experiment in vitro (mediated by excessive activation of NDMA) showed that 10 nm could reduce Nefiracetam NDMA flow by 30% as compared to control measurements and also reduce the influx calcium. High concentrations of 1 micron are also effective, however, in comparison with 10 nm, they do not prove much more significant. At higher levels of neuronal activation (where excitotoxicity is a problem), NMDA exposure Nefiracetam weakens and thus prevents excessive levels of glutamate.

GABA neurotransmission
Nefiracetam has no similarities with GABA and benzodiazepine binding central receptors in the active range; This dissimilarity is also observed in the case of aniracetam and oksiratsetamom.31) It should be noted that Nefiracetam showed no change in binding with muscimol, a GABA receptor in the normal concentrations, but promoted displacement at a high concentration in 8.07 m.32) Although unexpressed binding in the central receptors of GABA Nefiracetam effect enhances GABAA receptors, whereas GABA itself in high concentration suppresses this effect. This interaction with receptors associated with Gi / o protein kinase and protein A.33) GABA apparently has no similarities with the GABA receptors directly by the appropriate range of concentrations, but due to the interaction with the Gi / o protein, it can modulate the effect (enhanced at low concentrations inhibited at high concentrations). In vitro, Nefiracetam (10-100 nm) may increase the release of GABA with potassium participation of neurons without affecting basal secretion of GABA; aniracetam showed their effectiveness in this regard. No change in the basal outflow of GABA, GABA release with the participation of potassium can be increased at the expense of reception Nefiracetam. Nefiracetam 10 mg per kg body weight can increase the uptake of GABA synaptic neurons by 36% one hour after oral administration rats, with the dosage of 1-3 mg per kg of body weight, which seems to be effective in in vitro experiment showed no effect. Uptake of GABA neurons can be enhanced at the expense of reception Nefiracetama. This effect is not manifested in the experiment in vitro, but it is associated with metabolism Nefiracetam. The antiamnesic effect in Nefiracetam memory impairment due to protein synthesis inhibitors canceled using GABA receptor inhibitors and agonists of these receptors previously showed protective effects against amnesia induced protein synthesis inhibitors. In rats with lesions of the brain (cerebral ischemia) it was prevented reduction of GABA in the brain cortex and hippocampus in Nefiracetam 10 mg per kg body weight. 10 mg Nefiracetam kg body weight daily for days contributes glutamate decarboxylase activity without changes in concentrations of GABA (in the hippocampus and cerebral cortex) 34), reducing the activity of these enzymes on the background of cerebral lesions may also be terminated at the same dose, though subsequent studies They did not confirm these findings. GABA concentrations in the brain may vary when receiving Nefiracetam, an increase was observed in rats (no change in basal concentrations) in relatively healthy rodents also observed in GABA amnesic preservation periods when GABA must, in fact, decrease. With respect to the peripheral-type benzodiazepine receptor (which activation may cause spasms) Nefiracetam oral use capable of inhibiting seizure activity by agonists of these receptors with EC50 values of 17.2 mg per kg (potentially higher than aniracetam) for 75% inhibition (dose 50 mg kg36)) that is caused by inhibition of ligand binding at a concentration (IC50) 150-200 microns. In this case, piracetam and oxiracetam poorly effective or even ineffective. Nefiracetam apparently can inhibit the binding of ligand and its effect due to the peripheral-type benzodiazepine receptors, which may underlie some properties of antiepileptic drug. Nefiracetam is more powerful nootropic of the total number of racetam, but weaker than Vinpocetine.

Dopaminergic neurotransmission
Nefiracetam at a concentration of 10-30 mg per kg body weight did not affect the change in concentrations of dopamine in the brain of gerbil following ischemia. Reducing the concentration of dopamine and HVA (homovanillic acid) in the hippocampus was observed at a dose of 30 mg per kg body weight by 63% from baseline measurements, and at a dosage of 10 mg per kg body weight was observed in the brain of the gerbil effect. This fact is accompanied by an increase DOPAC concentrations. In addition, there is a slight increase in dopamine in the striatum in rats, in vivo microdialysis but showed no change in rats. Dopamine in synaptosomes is not affected nefiracetam when receiving a dose of 1-10 nm. While the interaction with dopaminergic neurotransmission can not be ruled out (due to the fact that the activation of the nicotinic acetylcholine receptor can release dopamine), dopamine is not the primary target for Nefiracetam and neuroprotective effects, apparently not much depend on dopamine.

Serotonin neurotransmission
Nefiracetam (10-30 mg per kg, but not 1.3 mg per kg) can counteract the ischemia-induced loss of serotonin in the striatum (not shown effect in other areas of the brain). Nefiracetam 3-10 mg per kg of body weight, as used for 30 minutes before injection of 8-OH-DPAT (an agonist of 5-HT1A) weakened some anomalies noted in the course of the experiment (% correct and incorrect choices, reaction time, motor activity); the same effect can be achieved by use of aniracetam 10-100 mg per kg body weight. These receptors (5-HT1A) can inhibit the activity of neurons. The absorption of serotonin in synaptosomes is not changed by the use of 1-10 nm Nefiracetam. Just as in the case of dopamine when serotonergic Nefiracetam interaction can not be excluded, these interactions are not the main target of these nootropic agents.

Memory and Learning
Nefiracetam may affect learning processes due to the increase of long-term potentiation (LTP) through protein kinase C, increasing NMDA-dependent LTP at low concentrations and AMPA-dependent LTP at higher concentrations. Moreover, the increased release of acetylcholine was observed in vivo, and learning ability is directly related to the influence of acetylcholine in the hippocampus, which suggests the occurrence of stimulating paths (cholinergic and glutamine). Furthermore, immunohistological analysis of said increased number of gear polysialylated cells after long-term use in Nefiracetam concentration 1.9 mg per kg of body weight (such as shown and identified with the use of other cognitive stimulators) that is marked with cognitive training. This may be due to the observed increase in growth factor selected in vitro with maximum efficiency at 100 nm (lower dosages have not been tested for efficacy), and it was confirmed, with 9 mg Niferacetam per kg body weight (and not 3 mg per kg of body weight) in rats during a 40-day course. Due to the increase in glutamine and cholinergic pathways Nefiracetam, apparently, it has a reinforcing effect cognitive properties. In relatively healthy rats eating Nefiracetam (3-30 mg per kg of body weight) did not change significantly reduced latency, and one-time use of 1-10 mg per kg of body weight showed no facilitate the avoidance reaction. In other words, the use of single doses of 10 mg per kg of body weight could not change the latency parameters in rats (a test healthy rats were used, which are also involved in the experiment with cerebral ischemia); dose of 10-30 mg per kg body weight did not cause changes in performance in a water maze test, after a single oral administration. Nefiracetam can increase the speed of developing new tastes with a dosage of 3-10 mg per kg of body weight, although the follow-up study showed the immutability of new indicators to control; The authors suggest that Nefiracetam helps in the assimilation of new information. In the experiment with mice in the use of 1 mg per kg body weight did not show effect on these parameters. Nefiracetam single use to improve cognitive functions, unlike Pramiracetam rarely causes an improvement in memory formation in animal studies. In studies lasting longer period Nefiracetam 15 mg per kg body weight for 38 days (from day 41 after birth and up to 79 days) caused improvement in spatial memory formation. With this long-term use, nootropic potential Nefiracetam was previously noted in rabbits, and in another study, which showed no effects after a single use of 3-10 mg per kg of body weight, the results became evident after seven days of reception. Nefiracetam apparently contributes to improve cognitive function in healthy people and a relatively young animals with long courses Hour (minimum of seven days), although one study did not show any effect on cognition Nefiracetam during training. The use of rats with cerebral ischemia Nefiracetam 10 mg per kg of body weight per day (preliminary studies suggest a greater effectiveness of the dosage than 3 mg per kg of body weight) can partially reverse the deterioration of spatial memory, caused by trauma. In rats with cerebral injury, nefiracetam is a neuroprotectant, restoring memory function. Amnesia induced protein synthesis inhibitors may be impaired when used before Nefiracetam loads (3-30 mg per kg of body weight) or after stress (5-15 mg per kg of body weight), with a stronger effect is achieved when used to load; Nefiracetam efficient in this case than Aniracetam. Antiamnesic effect, reveal after drinking Nefiracetam may also occur when taking drugs that affect cholinergic, GABA and dopamine neyrotransmissiyu46), including alcohol, 47) which also applies to some of the endogenous compounds, such as beta-amyloid protein, 48) including carbon monoxide .49) if scopolamine (cholinergic amnesia), reduction effects noted amnesic Nefiracetam when used at a dosage of 1-30 mg per kg of body weight with a maximum effect (67% protection) at a dose of 10 mg per kg body weight, which is ahead of aniracetam performance (33% protection at a dosage of 1-30 mg per kg of body weight). It has been noted in other studies, and for example, can be observed in rabbits high impact on calcium channels. In response to electric shocks can reduce manifestations Nefiracetam amnesia in a dosage of 1-3 mg per kg of body weight, with the higher dosage will not have a protective effect. The same mechanisms may underlie the ability to attenuate seizures Nefiracetam under various stress faktorah50) (less efficiently than levetiracetam) are also possible inhibitory effect on the sodium channels (activity manifests itself in the range 5-50 nm). Nefiracetam apparently has antiamnesic properties, showing greater effectiveness than aniracetam; This is according to tests on animals. Antiamnesic effects of diversity can be quite large, affecting most causes amnesia and acting on the calcium channels (opening them).

Apathy and depression
Nefiracetam showed antidepressant effect in rats CAMKII associated with activation at a dosage of 1 mg per kg body weight. In people with angina who are suffering from depression, receiving 600-900 mg nefiracetam had no effect on the values of HAM-D at 4 weeks (duplicated in Medline study). In stroke patients and those suffering from depression and severe apathy within four weeks (on a rating scale of apathy, apathy is a common consequence of stroke), receiving 600-900 mg Nefiracetam twice daily (300-450 mg each) helped reduce apathy in a dose-dependent form, but this effect is not associated with depression or with cognitive functions. Apathy may be reduced in patients who have suffered a stroke, with no apparent effect on depressive symptoms. While it is unclear what effect is achieved in relatively healthy individuals suffering from apathy.

Alzheimer's and dementia
In Alzheimer's disease both glutamine and cholinergic neurons are depressed, leading to the use of cholinergic and proglutamin molecules (which are usually acetylcholinesterase inhibitors). It is believed that nefiracetam can affect the process of these diseases as glutamic and cholinergic effects are associated with the intracellular calcium influx. In patients with dementia associated with cerebrovascular disorders, reception nefiracetam at dosages of 150, 300 and 450 mg (divided into three equal doses) helped alleviate the condition by 24.5%, 28.4%, 41.7% (study has not been published, but it referred to the Internet), which shows the effectiveness comparable to that of idebenone (an analogue of coenzyme Q10). The substance may have a therapeutic role in Alzheimer's disease and dementia, however these claims are not well understood. Preliminary results are promising.

Interaction with hormones

Testosterone
180-300 mg per kg Nefiracetam males breed of body weight in beagle lowered blood testosterone levels during week course without effect, reducing the level of testosterone occurs after use of the drug for four hours.

Estrogen
300mg Nefiracetam per kg body weight in male beagle apparently increases the circulating concentration of estrogen in the blood serum within weeks of treatment (the effect is retained for four weeks) when used 180 mg per kg body weight exerts its effects via four weeks and to a lesser extent.

Safety and Toxicology
general information
Nefiracetam single toxic dose (LD50 value) of 1940-2005 mg per kg body weight in mice, 1182-1408 mg per kg of body weight in rats of more than 500 mg per kg body weight in beagle dogs. In the held tests on human studies on toxicity and identify side effects Nefiracetam 600-900 mg for four weeks did not show in this parameter no difference to placebo. In general, limited studies in humans have shown no toxicity when consuming the recommended dosages Nefiracetam.

Studies in dogs
In male beagle dogs treated with 180 mg Nefiracetam per kg of body weight or 300 mg per kg body weight for four weeks, histological examination of the testes revealed a decrease in germ cell quality (degeneration and fewer), including spermatids and seminiferous tubules, but changes in the Leydig cells, Sertoli and weight of testes were found. These adverse effects were dependent on the dose, while increasing subjected sperm changes dependent on the use duration and dosage (there is a slight inhibition of sperm), other changes in sperm occurred at a dose of 60 mg per kg body weight, at 20 mg per kg body weight they have already been identified, 58) 52 week studies confirmed the safety of the dosage of 30 mg per kg body weight. 60-90 mg per kg of body weight or higher in dogs (of both sexes) can cause renal necrosis at the first week of the course. These lesions arise due Nefiracetam metabolic products, which is the reaction of 3-hydroxylation and subsequent sulfation by-product, which then inhibits the renal synthesis of prostaglandins. It is reported that this effect is only in dogs, but not in rats or monkeys, which implies the absence of symptoms and in humans. Studies conducted on dogs, demonstrate that a dose of more than 60 mg per kg body weight can rather quickly lead to renal necrosis, renal tissue hitting, thus reducing the production of sperm and testosterone concentrations. It is believed that this effect is only seen in dogs and humans refers to (also relates to rats and monkeys). If the above information to convert to human dosage of 30 mg per kg body weight will be equivalent to a human dose at a concentration of 16.2 mg per kg of body weight, the marked minimum toxic dose (60 mg per kg body weight) will be 32.4 mg per kg of body weight body. Previous dosage for humans with a body weight of 70 kg is about 1100 mg per day. If the parameters are projected toxicity on humans, the highest safe dosage is the recommended dosage. However, the therapeutic index (toxic buffer between security and safe dosage) is very small.

Fears
Studies Nefiracetam term consumption in humans and primates showed that the drug is toxic. Animals that metabolize Nefiracetam differently than humans and primates are threatened by the development of kidney and testicular toxicity. Dogs show special sensitivity caused by a particular metabolite, M-18. Rats testicular toxicity manifested at higher doses than in dogs, and monkeys was observed no toxicity at all.