[Design of the novel dipeptide neuropsychotropic drug preparations].

PubMed

Gudasheva, T A; Skoldinov, A P

2003-01-01

The paper considers a new strategy in the field of neuropsychotropic dipeptide drug design, the main points being as follows: (i) determination of the structural elements of dipeptides, such as fragments of amino acid side radicals and peptide bonds, in nonpeptide drugs; (ii) design of peptide analogs topologically close to the drug; (iii) synthesis and activity testing of these analogs; (iv) determination of the corresponding endogenous neuropeptide among the known neuropeptides or identification of the new neuropeptides in the brain of experimental animals. Using this approach, new pyroglutamyl- and prolyl-containing dipeptides were obtained based on the structure of the well-known classical nootropic drug piracetam. The new drugs exhibit nootropic activity in doses 100-10,000 times lower than those of piracetam. The structure of most active pyroglutamyl dipeptide pGlu-Asn-NH2 coincides with that of the N-end fragment of the endogenous memory peptide AVP(4-9). Noopept (N-phenylacetylprolylglycine ethyl ester), patented in Russia and USA as a new nootropic drug, is currently under stage 2 of successful clinical trials. The main metabolite of noopept, cyclo-Pro-Gly, is identical to the endogenous dipeptide designed in this work and is most close analog of piracetam with respect to pharmacological activity. The universal character of the proposed strategy is demonstrated by the design of active dipeptide analogs of an atypical neuroleptic drug sulpiride. As a result, a potential dipeptide neuroleptic dilept was obtained, which has been patented in Russia and now passes broad preclinical trials.

Nootropic dipeptide noopept enhances inhibitory synaptic transmission in the hippocampus.

PubMed

Povarov, I S; Kondratenko, R V; Derevyagin, V I; Ostrovskaya, R U; Skrebitskii, V G

2015-01-01

Application of nootropic agent Noopept on hippocampal slices from Wistar rats enhanced the inhibitory component of total current induced by stimulation of Shaffer collaterals in CA1 pyramidal neurons, but did not affect the excitatory component. A direct correlation between the increase in the amplitude of inhibitory current and agent concentration was found. The substance did not affect the release of inhibitory transmitters from terminals in the pyramidal neurons, which indicated changes in GABAergic interneurons.

Effects of nootropics on the EEG in conscious rats and their modification by glutamatergic inhibitors.

PubMed

Vorobyov, Vasily; Kaptsov, Vladimir; Kovalev, Georgy; Sengpiel, Frank

2011-05-30

To study the effects of acute and repeated injections of nootropics and to learn how glutamate receptors might be involved in their mediation, the frequency spectra of cortical and hippocampal electroencephalogram (EEG) were analyzed in non-narcotized rats subcutaneously injected repeatedly with Piracetam (400mg/kg) or its analogue, Noopept (0.2mg/kg), after intracerebroventricular infusions of saline (5 μl) or the antagonists of NMDA and quisqualate/AMPA receptors: CPP (0.1 nmol) and GDEE (1 μmol), respectively. Piracetam increased alpha/beta1 EEG activity in the left frontal cortex, and alpha activity in both the right cortex and hippocampus, with a 10-min latency and 40-min duration. Noopept increased alpha/beta1 activity, with 30-min latency and 40-min duration in all brain areas. CPP pretreatment eliminated Piracetam EEG effects; reduced Noopept effects in the cortex and completely suppressed them in the hippocampus. After four injections of Piracetam, EEG effects were very small in the cortex, and completely lacking in the hippocampus, while GDEE pretreatment partially recovered them. The effect of Noopept in the alpha/beta1 ranges was replaced by increased beta2 activity after the eighth injection, while no effects were observed after the ninth one. GDEE pretreatment restored the effect of Noopept in the beta2 frequency range. These results demonstrate similarities in EEG effects and their mediatory mechanisms for Piracetam and its much more effective analogue, Noopept. Activation of NMDA receptors is involved in the effects of a single injection of the nootropics, whereas activation of quisqualate/AMPA receptors is associated with the decrease in their efficacy after repeated use. Copyright © 2011 Elsevier Inc. All rights reserved.

[The role of non-NMDA glutamate receptors in the EEG effects of chronic administration of noopept GVS-111 in awake rats].

PubMed

Kovalev, G I; Vorob'ev, V V

2002-01-01

Participation of the non-NMDA glutamate receptor subtype in the formation of the EEG frequency spectrum was studied in wakeful rats upon a long-term (10 x 0.2 mg/kg, s.c.) administration of the nootropic dipeptide GVS-111 (noopept or N-phenylacetyl-L-prolyglycine ethylate). The EEGs were measured with electrodes implanted into somatosensor cortex regions, hippocampus, and a cannula in the lateral ventricle. The acute reactions (characteristic of nootropes) in the alpha and beta ranges of EEG exhibited inversion after the 6th injection of noopept and almost completely vanished after the 9th injection. Preliminary introduction of the non-NMDA antagonist GDEE (glutamic acid diethyl ester) in a dose of 1 mumole into the lateral ventricle restored the EEG pattern observed upon the 6th dose of GVS-111. The role of glutamate receptors in the course of a prolonged administration of nootropes, as well as the possible mechanisms accounting for a difference in the action of GVS-111 and piracetam are discussed.

[On the mechanism of noopept action: decrease in activity of stress-induced kinases and increase in expression of neutrophines].

PubMed

Ostrovskaia, R U; Vakhitova, Iu V; Salimgareeva, M Kh; Iamidanov, R S; Sadovnikov, S V; Kapitsa, I G; Seredenin, S B

2010-12-01

The influence of noopept (N-phenylacetyl-L-prolylglycine ethyl ester, GVS-111)--a drug combining the nootrope and neuroprotector properties--on the activity of mitogen-activated protein kinases (MAPKs) and the level of NGF and BDNF gene and protein expression in the frontal cortex, hippocampus, and hypothalamus has been studied in rats. Under conditions of chronic administration (28 days, 0.5 mg/day, i.p.), noopept decreased the activity of stress-induced kinases (SAPK/JNK 46/54 and pERK1/2) in rat hippocampus and increases the level of mRNA of the BDNF gene in both hypothalamus and hippocampus. The content of BDNF protein in the hypothalamus was also somewhat increased. In the context of notions about the activation of stress-induced kinases, as an important factor of amyloidogenesis and tau-protein deposition in brain tissue, and the role of deficiency of the neurotrophic factors in the development of neurodegenerative processes, the observed decrease in the activity of stress-activated MAPKs and increased expression of BDNF as a result of noopept administration suggest thatthis drug hasaspecific activity withrespect to some pathogenetic mechanisms involved in the Alzheimer disease.

Noopept efficiency in experimental Alzheimer disease (cognitive deficiency caused by beta-amyloid25-35 injection into Meynert basal nuclei of rats).

PubMed

Ostrovskaya, R U; Belnik, A P; Storozheva, Z I

2008-07-01

Experiments on adult Wistar rats showed that injection of beta-amyloid25-35 (2 microg) into Meynert basal nuclei caused long-term memory deficiency which was detected 24 days after this injection by the memory trace retrieval in conditioned passive avoidance reflex (CPAR). The effects of noopept, an original nootropic and neuroprotective dipeptide, on the severity of this cognitive deficiency were studied. Preventive (for 7 days before the injury) intraperitoneal injections of noopept in a dose of 0.5 mg/kg completely prevented mnestic disorders under conditions of this model. Noopept exhibited a significant normalizing effect, if the treatment was started 15 days after the injury, when neurodegenerative changes in the basal nuclei, cortex, and hippocampus were still acutely pronounced. The mechanisms of this effect of the drug are studied, including, in addition to the choline-positive effect, its multicomponent neuroprotective effect and stimulation of production of antibodies to beta-amyloid25-35. Noopept efficiency in many models of Alzheimer disease, its high bioavailability and low toxicity suggest this dipeptide for further studies as a potential agent for the treatment of this condition (initial and moderate phases).

[Anti-inflammatory properties of noopept (dipeptide nootropic agent GVS-111)].

PubMed

Kovalenko, L P; Miramedova, M G; Alekseeva, S V; Gudasheva, T A; Ostrovskaia, R U; Seredenin, S B

2002-01-01

It is established that single intravenous (0.5 and 5 mg/kg, p.o.) or single peroral (10, 50, 100 mg/kg) and prolonged peroral (5 mg/kg, over 10 days) administration of noopept produces a dose-dependent inhibition of the model inflammatory response to concanavaline A in CBA mice. Intravenously injected (5 mg/kg) noopept suppressed the acute nonimmune carrageenan-induced foot inflammation in rats by 62.2% within 3 h. The most pronounced antiinflammatory effect of dipeptide was observed on the model of adjuvant arthritis in rats, where the drug administered over 25 days in a daily dose of 0.5 mg/kg (i.m.) or 5 mg/kg (p.o.) significantly reduced the chronic immune inflammation (on the 12th day, by 94.0 and 74.1%, respectively). The in vitro experiments with neutrophilic leukocytes of F1(CBA.C57BL/6) mice treated with noopept in a single dose of 5 mg/kg (i.v.) showed a 5- to 6-fold suppression of the hemiluminescence stimulated by opsoinized zymosan or phorbolmyristate acetate. It is suggested that the antiinflammatory activity of noopept is probably related to its antioxidant properties.

[The dynamics of behavioral and neuroreceptor effects after acute and long-term noopept administration in C57BL/6 and BALB/c mice].

PubMed

Kovalev, G I; Kondrakhin, E A; Salimov, R M; Neznamov, G G

2014-01-01

The effect of acute, 7-fold and 14-fold noopept (1 mg/kg/day) administration on the dynamics of anxiolitic and nootropic behavioral effects in cross-maze, as well as their correlations with NMDA- and BDZ-receptor density was studied in inbred mice strains, differing in exploratory and emotional status--C57BL/6 and BALB/c. The dipeptide failed to affect the anxiety and exploration activity in C57BL/6 mice at each of 3 steps of experimental session. In this strain the B(max) values of [3H]-MK-801 and [3H]-Flunitrazepam binding changed only after single administration. In respect to BALB/c mice noopept induced both the anxiolitic and nootropic effects reaching their maximum on 7th day. In BALB/c strain the dynamics of hippocampal NMDA-receptor binding corresponds to the dynamics of exploratory efficacy whereas the dynamics of BDZ-receptors in prefrontal cortex was reciprocally to dynamics of anxiety level.

[Noopept in the treatment of mild cognitive impairment in patients with stroke].

PubMed

Amelin, A V; Iliukhina, A Iu; Shmonin, A A

2011-01-01

Noopept is a neuroprotector and nootropics. Literature data revealed the treatment effect of noopept on mild cognitive impairment in patients with discirculatory encephalopathy. The present open prospective study included 60 patients with stroke treated with noopept during 12 months. Cognitive functions were assessed before and after treatment using neuropsychological tests. An analysis of MMSE scores and lateral and categorical associations revealed the significant improvement of cognitive functions after 2 months in patients of the main group compared to the controls. The global assessment of efficacy revealed the mild improvement in the main group while no changes were found in the control group. The results have demonstrated that noopept, used in dose 20 mg daily during 2 months, improves cognitive functions in stroke patients and has a high level of safety.

The nootropic and neuroprotective proline-containing dipeptide noopept restores spatial memory and increases immunoreactivity to amyloid in an Alzheimer's disease model.

PubMed

Ostrovskaya, Rita U; Gruden, Marina A; Bobkova, Natalya A; Sewell, Robert D E; Gudasheva, Tatyana A; Samokhin, Alexander N; Seredinin, Sergey B; Noppe, Wim; Sherstnev, Vladimir V; Morozova-Roche, Ludmilla A

2007-08-01

The effects of the novel proline-containing nootropic and neuroprotective dipeptide, noopept (GVS-111, N-phenylacetyl-L-prolylglycine ethyl ester) were investigated in NMRI mice following olfactory bulbectomy. We have shown previously that these animals developed Alzheimer's disease (AD)-like behaviour, morphology and biochemistry including impairment of spatial memory, regional neuronal degeneration and elevated Abeta peptide brain levels. In the current investigation, spatial memory was assessed using the Morris water maze and serum antibodies to in vitro morphologically characterized amyloid structures of both Abeta((25-35)) peptide and equine lysozyme, as well as to neurotrophic glial factor S100b, were analyzed by enzyme-linked immunosorbent assay (ELISA). Noopept (administered at a dose of 0.01 mg/kg for a period of 21 days and during a further 5 days training) restored spatial memory and increased serum antibody levels to oligomers of Abeta((25-35)) peptide but not to equine lysozyme amyloid or S100b protein in bulbectomized animals. The positive immunotropic effect of noopept to Abeta((25-35)) peptide prefibrillar aggregates was more marked in sham-operated compared to the bulbectomized subjects which were characterized by an overall suppression of immunoreactivity. Enhancement of the immune response to Abeta((25-35)) peptide prefibrils caused by noopept may attenuate the neurotoxic consequences of amyloid fibrillization and also be associated with an improvement in spatial memory in bulbectomized mice. These actions of noopept, combined with its previously reported neuroprotective and cholinomimetic properties, suggests that this dipeptide may well be useful for improving cognitive deficits induced by neurodegenerative diseases.

[Genotype-dependent mice behavior in cognitive tasks. Effect of noopept].

PubMed

Bel'nik, A P; Ostrovskaia, R U; Poletaeva, I I

2007-01-01

The interstrain differences in performance of C57BL/6J, BALB/c and DBA/2J male mice in two cognitive tasks were found. Mice C57BL/6J showed good learning ability and preservation of memory traces tested 10 days after performance in a simplified version of Morris water maze. Mice BALB/c learned the task but, virtually, no long-term memory traces were revealed, whereas DBA/2J demonstrated poor learning. The effect of nootropic drug Noopept (GVS-111, N-phenil-acetyl-L-prolylglycin ethyl ether) was shown to be genotype-dependent. Its administration (0.5 mg/kg i.p., 15 min before learning) improved the long-term memory in Morris test in BALB/c mice but failed to produce any improvement in C57BL/6J. The ability of mice for extrapolation of the direction of stimulus movement differently changed after Noopept injections: the proportion of correct task solutions increased in C57BL/6J and BALB/c mice, whereas the performance of DBA/2J did not change.

[Noopept improves the spatial memory and stimulates prefibrillar beta-amyloid(25-35) antibody production in mice].

PubMed

Bobkova, N V; Gruden', M A; Samokhin, A N; Medvinskaia, N I; Morozova-Roch, L; Uudasheva, T A; Ostrovskaia, R U; Seredinin, S B

2005-01-01

The effects of the novel proline-containing nootropic and neuroprotective dipeptide noopept (GVS-111, N-phenylacetyl-L-prolylglycine ethyl ester) were studied on NMRI mice upon olfactory bulbectomy, which had been previously shown to imitate the main morphological and biochemical signs of Alzheimer's disease (AD). The spatial memory was assessed using the Morris (water maze) test; the immunological status was characterized by ELISA with antibodies to prefibrillar beta-amyloid(25-35), S100b protein, and protofilaments of equine lysozyme, which are the molecular factors involved in the pathogenesis of AD. The control (sham-operated) animals during the Morris test preferred a sector where the safety platform was placed during the learning session. Bulbectomized animals treated with saline failed to recognize this sector, while bulbectomized animals treated with noopept (0.01 mg/kg for 21 days) restored this predominance, thus demonstrating the improvement of the spatial memory. These animals also demonstrated an increase in the level of antibodies to beta-amyloid(25-35)--the effect, which was more pronounced in the sham-operated than in bulbectomized mice. The latter demonstrated a profound decrease of immunological reactivity in a large number of tests. Noopept, stimulating the production of antibodies to beta-amyloid(25-35), can attenuate the well-known neurotoxic effects of beta-amyloid. The obtained data on the mnemotropic and immunostimulant effects noopept are indicative of good prospects for the clinical usage of this drug in the therapy of patients with neurodegenerative diseases.

Neuroprotective effect of novel cognitive enhancer noopept on AD-related cellular model involves the attenuation of apoptosis and tau hyperphosphorylation.

PubMed

Ostrovskaya, Rita U; Vakhitova, Yulia V; Kuzmina, Uliyana Sh; Salimgareeva, Milyausha Kh; Zainullina, Liana F; Gudasheva, Tatiana A; Vakhitov, Vener A; Seredenin, Sergey B

2014-08-06

Noopept (N-phenyl-acetyl-L-prolylglycine ethyl ester) was constructed as a dipeptide analog of the standard cognition enhancer, piracetam. Our previous experiments have demonstrated the cognition restoring effect of noopept in several animal models of Alzheimer disease (AD). Noopept was also shown to prevent ionic disbalance, excitotoxicity, free radicals and pro-inflammatory cytokines accumulation, and neurotrophine deficit typical for different kinds of brain damages, including AD. In this study, we investigated the neuroprotective action of noopept on cellular model of AD, Aβ 25-35-induced toxicity in PC12 cells and revealed the underlying mechanisms. The neuroprotective effect of noopept (added to the medium at 10 μM concentration, 72 hours before Аβ 25-35) was studied on Аβ 25-35-induced injury (5 μM for 24 h) in PC12 cells. The ability of drug to protect the impairments of cell viability, calcium homeostasis, ROS level, mitochondrial function, tau phosphorylation and neurite outgrowth caused by Аβ 25-35 were evaluated. Following the exposure of PC12 cells to Аβ 25-35 an increase of the level of ROS, intracellular calcium, and tau phosphorylation at Ser396 were observed; these changes were accompanied by a decrease in cell viability and an increase of apoptosis. Noopept treatment before the amyloid-beta exposure improved PC12 cells viability, reduced the number of early and late apoptotic cells, the levels of intracellular reactive oxygen species and calcium and enhanced the mitochondrial membrane potential. In addition, pretreatment of PC12 cell with noopept significantly attenuated tau hyperphosphorylation at Ser396 and ameliorated the alterations of neurite outgrowth evoked by Аβ25-35. Taken together, these data provide evidence that novel cognitive enhancer noopept protects PC12 cell against deleterious actions of Aβ through inhibiting the oxidative damage and calcium overload as well as suppressing the mitochondrial apoptotic pathway. Moreover, neuroprotective properties of noopept likely include its ability to decrease tau phosphorylation and to restore the altered morphology of PC12 cells. Therefore, this nootropic dipeptide is able to positively affect not only common pathogenic pathways but also disease-specific mechanisms underlying Aβ-related pathology.

Neuroprotective effect of novel cognitive enhancer noopept on AD-related cellular model involves the attenuation of apoptosis and tau hyperphosphorylation

PubMed Central

2014-01-01

Background Noopept (N-phenyl-acetyl-L-prolylglycine ethyl ester) was constructed as a dipeptide analog of the standard cognition enhancer, piracetam. Our previous experiments have demonstrated the cognition restoring effect of noopept in several animal models of Alzheimer disease (AD). Noopept was also shown to prevent ionic disbalance, excitotoxicity, free radicals and pro-inflammatory cytokines accumulation, and neurotrophine deficit typical for different kinds of brain damages, including AD. In this study, we investigated the neuroprotective action of noopept on cellular model of AD, Aβ25–35-induced toxicity in PC12 cells and revealed the underlying mechanisms. Results The neuroprotective effect of noopept (added to the medium at 10 μM concentration, 72 hours before Аβ25–35) was studied on Аβ25–35-induced injury (5 μM for 24 h) in PC12 cells. The ability of drug to protect the impairments of cell viability, calcium homeostasis, ROS level, mitochondrial function, tau phosphorylation and neurite outgrowth caused by Аβ25–35 were evaluated. Following the exposure of PC12 cells to Аβ25–35 an increase of the level of ROS, intracellular calcium, and tau phosphorylation at Ser396 were observed; these changes were accompanied by a decrease in cell viability and an increase of apoptosis. Noopept treatment before the amyloid-beta exposure improved PC12 cells viability, reduced the number of early and late apoptotic cells, the levels of intracellular reactive oxygen species and calcium and enhanced the mitochondrial membrane potential. In addition, pretreatment of PC12 cell with noopept significantly attenuated tau hyperphosphorylation at Ser396 and ameliorated the alterations of neurite outgrowth evoked by Аβ25–35. Conclusions Taken together, these data provide evidence that novel cognitive enhancer noopept protects PC12 cell against deleterious actions of Aβ through inhibiting the oxidative damage and calcium overload as well as suppressing the mitochondrial apoptotic pathway. Moreover, neuroprotective properties of noopept likely include its ability to decrease tau phosphorylation and to restore the altered morphology of PC12 cells. Therefore, this nootropic dipeptide is able to positively affect not only common pathogenic pathways but also disease-specific mechanisms underlying Aβ-related pathology. PMID:25096780

[Peptidergic modulation of the hippocampus synaptic activity].

PubMed

Skrebitskiĭ, V G; Kondratenko, R V; Povarov, I S; Dereviagin, V I

2011-11-01

Effects of two newly synthesized nootropic and anxiolytic dipeptides: Noopept and Selank on inhibitory synaptic transmission in hippocampal CA1 pyramidal cells were investigated using patch-clamp technique in whole-cell configuration. Bath application of Noopept (1 microM) or Selank (2 microM) significantly increased the frequency of spike-dependent spontaneous m1PSCs, whereas spike-independent mlPSCs remained unchanged. It was suggested that both peptides mediated their effect sue to activation of inhibitory interneurons terminating on CA1 pyramidal cells. Results of current clamp recording of inhibitory interneurons residing in stratum radiatum confirmed this suggestion, at least for Noonent.

Cyclopropyl glycine and proline-containing preparation noopept evoke two types of membrane potential responses in synaptoneurosomes.

PubMed

Lutsenko, V K; Vukolova, M N; Gudasheva, T A

2003-06-01

Proline, cyclo(Pro-Gly), and acyl-prolyl-containing dipeptide GVS-111 decreased synaptoneurosome membrane potential in a Ca2+-free medium. The efficiency of these preparations decreased in the following order: GVS>cyclo(Pro-Gly)>proline. Depolarization responses induced by endogenous nootropic agent cyclo(Pro-Gly) was dose-dependent and saturable; the threshold concentration of cyclo(Pro-Gly) was 10(-9) M. In a Ca2+-containing medium GVS and cyclo(Pro-Gly) induced both hyperpolarizing and depolarizing membrane responses of synaptoneurosomes. Possible mechanisms underlying changes in the membrane potential of synaptoneurosomes induced by nootropic agents are discussed. It was interesting whether modulation of electrogenesis can improve memory and potentiate the neuroprotective effect of the test nootropic agents.

[The role of synaptic transmission in memory and neurodegeneration processes and effects of neurotropic preparations].

PubMed

Voronina, T A

2003-01-01

Academician Zakusov, in his book Pharmacology of Central Synapses (Moscow, 1973), emphasized the central role of synaptic processes in regulation of various forms of behavior, memory, and psychotropic drug action. The paper considers most promising directions in the search for substances possessing nootropic and neuroprotector properties, many of which were developed at the Institute of Pharmacology based on the notion about synaptic processes. These investigations led to the creation of well-known drugs such as mexidole, noopept, nooglutyl, beglimin, etc. Special attention is devoted to the implementation and modern development of the ideas of Academician Zakusov. Recent data are presented on the role of neuropeptides, neurotrophins, and intracellular signaling mechanisms in synaptic plasticity, memory processes, and development of neurodegenerative states.

[A method for reproducing amnesia in mice by the complex extremal exposure].

PubMed

Iasnetsov, V V; Provornova, N A

2003-01-01

It is suggested to reproduce a retrograde amnesia in mice by means of a complex extremal action: emaciating swim in cold water with simultaneous wheel rotation. It was found that nootropes such as pyracetam, mexidol, semax, nooglutil, acephen, and noopept fully or completely prevent from the amnesia development.

[Strategy for the development of dipeptide drugs].

PubMed

Gudasheva, T A

2011-01-01

The author describes an original approach to the development of dipeptide drugs based on the concept of the leading role of the beta-bend in the interaction of biologically active endogenous peptides with their receptors. The approach called "peptide-based drug design" includes both developments from the structure of a known psychotropic agent toward its topological peptide analog and developments from the active dipeptide site of a neuropeptide toward its mimetic. This strategy has been worked out at the V.V. Zakusov Research Institute of Pharmacology for 25 years. Results of investigations that discovered endogenous peptide prototypes of the known non-peptidic drugs (piracetam and sulpiride) are presented. They provided a basis for the creation of highly active non-toxic oral dipeptide preparations, such as nootrop Noopept, potential anti psychotic Dilept, and potential selective anxiolytic GB-115.

[Evolution of the neuroprotection concept].

PubMed

Ostrovskaia, R U

2003-01-01

Although the modern concept of neuroprotection has been formulated quite recently, the basis of this approach was laid about four decades ago when Zakusov initiated the study of mechanisms involved in the neuroprotector action of GABA shunt metabolites (in particular, alpha-hydroxybutyric acid and succinic semialdehyde) during hypoxia. It was suggested to consider these agents as a system of endogenous neuroprotectors. The interest of Zakusov in endogenous regulators (including oligopeptides) had stimulated research in this direction and gave impact to the investigations of A. P. Skoldinov and T. A. Gudasheva initiated in the early 1980s. Proceeding from the original concept of the possibility of imitation of the action of neurotropic agents by their structural-conformational oligopeptide analogs, a number of biologically active stable dipeptides were obtained, based on pyroglutamate and proline, and high specific bioaccessibility of these dipeptides for the brain was established. Our investigations showed that these compounds not only possess nootropic activity (in a dose 1000 times lower than that of piracetam), but produce a pronounced neuroprotector action as well. Most thoroughly studied in this respect were substituted acyl-prolyl dipeptides, in particular, the drug noopept exhibiting a combined neuroprotector effect both in vitro and in vivo. Noopept decreases the extent of necrotic damage caused by photoinduced thrombosis of cortical blood vessels. It was established that the neuroprotector effect of noopept is related to its action upon the well-known "triad", whereby the drug reduces neurotoxic effects of excess extracellular calcium, glutamate, and free radicals. Two additional components of the neuroprotector action of noopept are related to the antiinflammatory and antithrombotic activity. The prospects of using direct and indirect action upon neurotrophin system for neuroprotection purposes are considered. Taking into account common secondary mechanisms of the neuronal damage, it is possible to provide for pleotrophic brain protection with dipeptides in a broad spectrum of pathological states, including strokes, cerebral traumas, neurodegenerative processes, epilepsy, and schizophrenia.

Proline-containing dipeptide GVS-111 retains nootropic activity after oral administration.

PubMed

Ostrovskaya, R U; Mirsoev, T K; Romanova, G A; Gudasheva, T A; Kravchenko, E V; Trofimov, C C; Voronina, T A; Seredenin, S B

2001-10-01

Experiments on rats trained passive avoidance task showed that N-phenyl-acetyl-L-prolyl-glycyl ethyl ester, peptide analog of piracetam (GVS-111, Noopept) after oral administration retained antiamnesic activity previously observed after its parenteral administration. Effective doses were 0.5-10 mg/kg. Experiments on a specially-developed model of active avoidance (massive one-session learning schedule) showed that GVS-111 stimulated one-session learning after single administration, while after repeated administration it increased the number of successful learners among those animals who failed after initial training. In this respect, GVS-111 principally differs from its main metabolite cycloprolylglycine and standard nootropic piracetam.

[The antiamnestic effect of nootropic substances in rats].

PubMed

Iasnetsov, Vik V; Krylova, I N

2013-01-01

It has been established in experiments in rats that some nootropic substances (oxyracetam, aniracetam, nooglutil, mexidol, new 3-hydroxypyridine derivative SK-170, piracetam and noopept) produce marked antiamnestic effect on various models of amnesia (induced by microwave irradiation, acute hypoxia, and motion sickness). At the same time, meclophenoxate exhibited antiamnestic effect in the first and second models of amnesia, while 9-aminoacridine derivative HTOS-404 was only effective in the model of amnesia caused by microwave irradiation. The antiamnestic effect of nooglutil and SK-170 was caused to a significant degree by activation of non-NMDA receptors of excitatory amino acids (generally AMPA receptors), while the effect of mexidol was related to GABA(A) receptors.

Genotype-dependent characteristics of behavior in mice in cognitive tests. The effects of Noopept.

PubMed

Bel'nik, A P; Ostrovskaya, R U; Poletaeva, I I

2009-01-01

Male C57BL/6J, BALB/c, and DBA/2J mice showed differences in their abilities to perform two cognitive tests. C57BL/6J mice had good learning ability and memory trace retention (at 10 days) in a simplified Morris maze, while BALB/c mice had low levels of memory trace retention and DBA/2J mice had low learning ability in this test. I.p. administration of the nootropic agent Noopept (GVS-111, N-phenylacetyl-L-prolylglycine ethyl ester) at a dose of 0.5 mg/kg 15 min before the start of the test induced significant improvements in long-term memory in this test in BALB/c mice but no further improvement in C57BL/6J mice, and had no effect in DBA/2J mice. On testing the ability to extrapolate the direction of movement of a stimulus, administration of Noopept increased the proportion of correct responses in C57BL/6J and BALB/c mice, but had no effect in DBA/2J mice.

[Interspecies differences of noopept pharmacokinetics].

PubMed

Boĭko, S S; Korotkov, S A; Zherdev, V P; Gudasheva, T A; Ostrovskaia, R U; Voronina, T A

2004-01-01

Significant interspecific differences in the pharmacokinetics of noopept are manifested by a decrease in the drug elimination rate on the passage from rats to rabbits and humans. Very intensive metabolism of noopept was observed upon intravenous administration in rats. In these animals, presystemic elimination mechanisms lead to the formation of a specific metabolite representing a product of drug biotransformation hydroxylated at the phenyl ring. In rabbits, unchanged noopept circulates in the blood for a longer time upon both intravenous and peroral introduction, biotransformation proceeds at a much slower rate, and no metabolites analogous to that found in rats are detected. The noopept pharmacokinetics in humans differs from that in animals by still slower elimination and considerable individual variability. No drug metabolites are found in the human blood plasma, probably because of a relatively small dose and low concentration.

Comparative activity of proline-containing dipeptide noopept and inhibitor of dipeptidyl peptidase-4 sitagliptin in a rat model of developing diabetes.

PubMed

Ostrovskaya, R U; Ozerova, I V; Gudascheva, T A; Kapitsa, I G; Ivanova, E A; Voronina, T A; Seredenin, S B

2014-01-01

Developing diabetes was modeled on adult male Wistar rats by repeated intraperitoneal injections of streptozotocin in a subdiabetogenic dose of 30 mg/kg for 3 days. Proline-containing dipeptide drug Noopept or a standard diabetic drug dipeptidyl peptidase-4 inhibitor sitagliptin was administered per os in a dose of 5 mg/kg before each injection of the toxin and then for 16 days after streptozotocin course. In active control group, spontaneously increase glucose level and reduced tolerance to glucose load (1000 mg/kg intraperitoneally) were observed on the next day after the third administration of toxin. Basal glucose level decreased by day 16, but glucose tolerance remained impaired. Noopept normalized the basal blood glucose level and tolerance to glucose load on the next day after administration of streptozotocin. The effect of Noopept persisted to the end of the experiment. At early terms of the experiment, sitagliptin was somewhat superior to Noopept by the effect on baseline glucose level, but was inferior by the influence on glucose tolerance.. By the end of the experiment, Noopept significantly (by 2 times) surpassed sitagliptin by its effect on glucose tolerance.

[Effect of the novel nootropic and neuroprotective dipeptide noopept on the streptozotocin-induced model of sporadic Alzheimer disease in rats].

PubMed

Ostrovskaia, R U; Tsaplina, A P; Vakhitova, Iu V; Salimgareeva, M Kh; Iamidanov, R S

2010-01-01

Streptozotocin-intracerebroventricularly treated rats are proposed as an experimental model of sporadic Alzheimer disease (AD). Diabetogenic toxin streptozotocin (STZ) administered in both cerebral ventricles in a dose of 3 mg/kg decreases the expression of NGF and BDNF mainly in the hippocampus and increases the content of malonic dialdehyde (MDA)--a product of lipid peroxidation--in the brain tissues. These metabolic changes are accompanied by a pronounced cognitive deficiency, which is manifested by long-term memory deterioration in the passive avoidance test. These manifestations of pathology are not accompanied by hyperglycemia in the case of intraventricular STZ administration, in contrast to the systemic (in particular, intraperitoneal) route of introduction that causes a pronounced increase in the blood glucose level. These results are consistent with the existing notions that (i) STZ administered intraventricularly provokes a complex of changes imitating the sporadic AD and (ii) this disease can be considered as a manifestation of type-III diabetes. The new original cognition enhancing and neuroprotective dipeptide noopept decreases the aforementioned metabolic changes and the accompanying long-term deterioration of the memory. Previously, this systemically active dipeptide was shown to be capable of increasing expression of NGF and BDNF in the hippocampus, stimulating the antibody production to beta-amyloid, inhibiting the lipid peroxidation, activating the endogenous antioxidant systems, and decreasing the rate of glutamate release (cholinopositive effect). Taken together, these data indicate that noopept can be considered as a multipotent substance acting upon several important pathogenic chainsof the sporadic AD.

[Prevention of neuro- and cardiotoxic side effects of tuberculosis chemotherapy with noopept].

PubMed

Mordyk, A V; Lysov, A V; Kondria, A V; Gol'dzon, M A; Khlebova, N V

2009-01-01

The study evaluated clinical efficiency of noopept used to prevent adverse side effects of antituberculous agents. It included 60 patients with newly diagnosed respiratory tuberculosis. Those in group 1 (n = 30) received 10 mg of noopept twice daily during the first month. The treatment promoted functional normalization of vegetative nervous system and antioxidative systems, reduced manifestations of anxiety, decreased frequency of adverse neuro- and cardiotoxic responses to antituberculous drugs.

[Meteoadaptogenic properties of peptide drugs in healthy volunteers].

PubMed

Shabanov, P D; Ganapol'skiĭ, V P; Aleksandrov, P V

2007-01-01

The meteoadaptogenic properties of a series of drugs with peptide (cortexin, noopept, dilept) and nonpeptide (vinpotropil) structure were investigated in a climate thermobarocomplex (Tabay, Japan) on a group of healthy volunteers aged 20-24. All the studied drugs produced a meteoadaptogenic action, the extent of which depended on the environmental test conditions (overcooling, overheating, hypobaric hypoxia). Vinpotropil, optimizing a physiological component of the functional state, can be recommended as a meteoadaptogen for both cold and hot climate as well as for hypobaric hypoxia, where it improved the psychological component of the functional state. Cortexin is qualified as an adaptogen and actoprotector only for hypobaric hypoxia conditions (uplands). Noopept, affecting positively a psychological component of the functional state, can be used for rapid adaptation to both cold and hot climate. In the hot climate, noopept also enhanced the physical work capacity. Dilept mostly elevated the psychological component of the functional state and can be considered as a psychomotor enhancer and adaptogen. Therefore, all the drugs studied (vinpotropil, cortexin, noopept and dilept) can be recommended as the agents producing activation, support and recovery of the physical and psychological efficiency under rapidly changing environment conditions.

Studies of long-term noopept and afobazol treatment in rats with learned helplessness neurosis.

PubMed

Uyanaev, A A; Fisenko, V P

2006-08-01

Long-lasting effects of new Russian psychotropic drugs Noopept and Afobazol on active avoidance conditioning and formation of learned helplessness neurosis were studied on an original experimental model in rats. Noopept eliminated the manifestations of learned helplessness after long-term (21-day) treatment by increasing the percent of trained animals. Afobazol was low effective in preventing manifestations of learned helplessness, but if used for a long time, it reduced the incidence of learned helplessness development by increasing the percent of untrained animals.

[An experimental study of the anti-inflammatory action of noopept and its effect on the level of cytokines].

PubMed

Alekseeva, S V; Kovalenko, L P; Tallerova, A V; Gudasheva, T A; Durnev, A D

2012-01-01

The anti-inflammatory effects of noopept (dipeptide analog of piracetam) upon a single intraperitoneal (i.p.) administration at doses of 1, 5, and 10 mg/kg in comparison to the reference drug diclofenac (10 mg/kg, i.p.) have been studied on a model of acute exudative inflammation induced by carrageenan in outbred rats and concanavalin A (Con A) in CBA mice. The level of cytokines was studied on the lipopolysaccharide (LPS) model (single administration, 100 mg/kg, i.p.) with 5-day administration of noopept at a dose of 5 mg/kg (i.p., before endotoxin injection) in C57BL/6 mice. The administration of noopept led to a significant suppression of the inflammatory response to both carrageenan and Con A. The administration of Con A caused a 16-fold increase in the level of IL-6 interleukin in the blood serum of mice as compared to control. Noopept (5 mg/kg) reduced the level of IL-6 by a factor of 1.8 in the inflammatory response to Con A. The administration of LPS led to pronounced increase in the levels ofpro-inflammatory IL-6 and TNF-alpha in the blood serum of test mice as compared to intact animals. The course administration of noopept (5 mg/kg) significantly decreased the level of IL-6 and reduced by half the level of TNF-alpha.

Smart drugs for cognitive enhancement: ethical and pragmatic considerations in the era of cosmetic neurology.

PubMed

Cakic, V

2009-10-01

Reports in the popular press suggest that smart drugs or "nootropics" such as methylphenidate, modafinil and piracetam are increasingly being used by the healthy to augment cognitive ability. Although current nootropics offer only modest improvements in cognitive performance, it appears likely that more effective compounds will be developed in the future and that their off-label use will increase. One sphere in which the use of these drugs may be commonplace is by healthy students within academia. This article reviews the ethical and pragmatic implications of nootropic use in academia by drawing parallels with issues relevant to the drugs in sport debate. It is often argued that performance-enhancing drugs should be prohibited because they create an uneven playing field. However, this appears dubious given that "unfair" advantages are already ubiquitous and generally tolerated by society. There are concerns that widespread use will indirectly coerce non-users also to employ nootropics in order to remain competitive. However, to restrict the autonomy of all people for fear that it may influence the actions of some is untenable. The use of potentially harmful drugs for the purposes of enhancement rather than treatment is often seen as unjustified, and libertarian approaches generally champion the rights of the individual in deciding if these risks are acceptable. Finally, whether the prohibition of nootropics can be effectively enforced is doubtful. As nootropics use becomes widespread among students in the future, discussion of this issue will become more pressing in the years to come.

Piracetam and TRH analogues antagonise inhibition by barbiturates, diazepam, melatonin and galanin of human erythrocyte D-glucose transport

PubMed Central

Naftalin, Richard J; Cunningham, Philip; Afzal-Ahmed, Iram

2004-01-01

Nootropic drugs increase glucose uptake into anaesthetised brain and into Alzheimer's diseased brain. Thyrotropin-releasing hormone, TRH, which has a chemical structure similar to nootropics increases cerebellar uptake of glucose in murine rolling ataxia. This paper shows that nootropic drugs like piracetam (2-oxo 1 pyrrolidine acetamide) and levetiracetam and neuropeptides like TRH antagonise the inhibition of glucose transport by barbiturates, diazepam, melatonin and endogenous neuropeptide galanin in human erythrocytes in vitro. The potencies of nootropic drugs in opposing scopolamine-induced memory loss correlate with their potencies in antagonising pentobarbital inhibition of erythrocyte glucose transport in vitro (P<0.01). Less potent nootropics, D-levetiracetam and D-pyroglutamate, have higher antagonist Ki's against pentobarbital inhibition of glucose transport than more potent L-stereoisomers (P<0.001). Piracetam and TRH have no direct effects on net glucose transport, but competitively antagonise hypnotic drug inhibition of glucose transport. Other nootropics, like aniracetam and levetiracetam, while antagonising pentobarbital action, also inhibit glucose transport. Analeptics like bemigride and methamphetamine are more potent inhibitors of glucose transport than antagonists of hypnotic action on glucose transport. There are similarities between amino-acid sequences in human glucose transport protein isoform 1 (GLUT1) and the benzodiazepine-binding domains of GABAA (gamma amino butyric acid) receptor subunits. Mapped on a 3D template of GLUT1, these homologies suggest that the site of diazepam and piracetam interaction is a pocket outside the central hydrophilic pore region. Nootropic pyrrolidone antagonism of hypnotic drug inhibition of glucose transport in vitro may be an analogue of TRH antagonism of galanin-induced narcosis. PMID:15148255

Effectiveness of nootropic drugs with cholinergic activity in treatment of cognitive deficit: a review

PubMed Central

Colucci, Luisa; Bosco, Massimiliano; Ziello, Antonio Rosario; Rea, Raffaele; Amenta, Francesco; Fasanaro, Angiola Maria

2012-01-01

Nootropics represent probably the first “smart drugs” used for the treatment of cognitive deficits. The aim of this paper is to verify, by a systematic analysis of the literature, the effectiveness of nootropics in this indication. The analysis was limited to nootropics with cholinergic activity, in view of the role played by acetylcholine in learning and memory. Acetylcholine was the first neurotransmitter identified in the history of neuroscience and is the main neurotransmitter of the peripheral, autonomic, and enteric nervous systems. We conducted a systematic review of the literature for the 5-year period 2006–2011. From the data reported in the literature, it emerges that nootropics may be an effective alternative for strengthening and enhancing cognitive performance in patients with a range of pathologies. Although nootropics, and specifically the cholinergic precursors, already have a long history behind them, according to recent renewal of interest, they still seem to have a significant therapeutic role. Drugs with regulatory indications for symptomatic treatment of Alzheimer’s disease, such as cholinesterase inhibitors and memantine, often have transient effects in dementia disorders. Nootropics with a cholinergic profile and documented clinical effectiveness in combination with cognate drugs such as cholinesterase inhibitors or alone in patients who are not suitable for these inhibitors should be taken into account and evaluated further. PMID:27186129

Establishing Natural Nootropics: Recent Molecular Enhancement Influenced by Natural Nootropic.

PubMed

Suliman, Noor Azuin; Mat Taib, Che Norma; Mohd Moklas, Mohamad Aris; Adenan, Mohd Ilham; Hidayat Baharuldin, Mohamad Taufik; Basir, Rusliza

2016-01-01

Nootropics or smart drugs are well-known compounds or supplements that enhance the cognitive performance. They work by increasing the mental function such as memory, creativity, motivation, and attention. Recent researches were focused on establishing a new potential nootropic derived from synthetic and natural products. The influence of nootropic in the brain has been studied widely. The nootropic affects the brain performances through number of mechanisms or pathways, for example, dopaminergic pathway. Previous researches have reported the influence of nootropics on treating memory disorders, such as Alzheimer's, Parkinson's, and Huntington's diseases. Those disorders are observed to impair the same pathways of the nootropics. Thus, recent established nootropics are designed sensitively and effectively towards the pathways. Natural nootropics such as Ginkgo biloba have been widely studied to support the beneficial effects of the compounds. Present review is concentrated on the main pathways, namely, dopaminergic and cholinergic system, and the involvement of amyloid precursor protein and secondary messenger in improving the cognitive performance.

Establishing Natural Nootropics: Recent Molecular Enhancement Influenced by Natural Nootropic

PubMed Central

Adenan, Mohd Ilham; Hidayat Baharuldin, Mohamad Taufik

2016-01-01

Nootropics or smart drugs are well-known compounds or supplements that enhance the cognitive performance. They work by increasing the mental function such as memory, creativity, motivation, and attention. Recent researches were focused on establishing a new potential nootropic derived from synthetic and natural products. The influence of nootropic in the brain has been studied widely. The nootropic affects the brain performances through number of mechanisms or pathways, for example, dopaminergic pathway. Previous researches have reported the influence of nootropics on treating memory disorders, such as Alzheimer's, Parkinson's, and Huntington's diseases. Those disorders are observed to impair the same pathways of the nootropics. Thus, recent established nootropics are designed sensitively and effectively towards the pathways. Natural nootropics such as Ginkgo biloba have been widely studied to support the beneficial effects of the compounds. Present review is concentrated on the main pathways, namely, dopaminergic and cholinergic system, and the involvement of amyloid precursor protein and secondary messenger in improving the cognitive performance. PMID:27656235

[Neuroprotective activity of the proline-containing dipeptide noopept on the model of brain ischemia induced by the middle cerebral artery occlusion].

PubMed

Gavrilova, S A; Us, K S; Ostrovskaia, R U; Koshelev, V B

2006-01-01

The influence of noopept (N-phenylacetyl-L-prolylglycine ethyl ester, GVS-111) on the extent of ischemic cortical stroke was investigated in experiments on white mongrel male rats with ischemia induced by a combination of the middle cerebral artery occlusion with ipsilateral common carotid artery ligation. Animals were treated with noopept (0.5 mg/kg, i.p.) according to the following schedule: 15 min and 2, 24, and 48 h after the occlusion. Test rats were decapitated 72 h after occlusion, brains were extracted and frozen, and thin brain slices were stained with 2,3,5-triphenyltetrazolium chloride. The slices were scanned and processed using Auc 1 computer program, which estimates the percentage of damaged area relative to that of the whole ipsilateral hemisphere. The conditions of coagulation the distal segment of middle cerebral artery were selected, which caused necrosis localized in the fronto-parietal and dorso-lateral regions of the brain cortex without any damage of subcortical structures. The extent of the brain damage in control group (treated by saline) was 18.6%, while that in the group treated with noopept was 12.2%, thus demonstrating a decrease in the infarction area by 34.5% (p < 05). The data on noopept efficacy on the model of the extensive ischemic injury of brain cortex show that this drug has good prospects for use in the neuroprotective treatment of stroke.

Presynaptic Modulation of the Hippocampal Mossy Fiber Synapse

DTIC Science & Technology

1991-10-07

al., 1987). In addition, the nootropic (cognitive enhancing) drug bifemaline has been shown to increase the magnitude of MF LTP (Satoh et al., 1988...Different susceptibilities of long-term potentiations in CA3 and CAl regions of guinea pig hippocampal slices to nootropic drugs. Neurosci. Lett., 1988; 93

Swedish Defence Research Abstracts 82/83-2 (Froe Foersvars Forsknings Referat 82/83-2).

DTIC Science & Technology

1983-08-01

alarm (78) Carbon dioxide retention inside motorcycle helmets (79) Vibration and decompression gas bubbles (80) No effects of nootropic drugs on memory... nootropic drugs on memory and psychomotor performance during reduced air pressure (in English) S. Levander and others Report I from the Roche Clinical Unit

Synaptic Plasticity and Memory Formation

DTIC Science & Technology

1991-06-14

past year defined the cellular changes likely to be responsible for expression. The nootropic ("cognitive enhancing") drug aniracetam prolongs the open...modified glutamate receptors are responsible for LTP expression was obtained in the past year. Aniracetam , a drug that reversibly modulates the AMPA...as the substrate of LTP. Tests of this became possible with the discovery by Ito and co-workers Q’. Ph, si , 1990) that the nootropic drug aniracetam

GVS-111 prevents oxidative damage and apoptosis in normal and Down's syndrome human cortical neurons.

PubMed

Pelsman, Alejandra; Hoyo-Vadillo, Carlos; Gudasheva, Tatiana A; Seredenin, Sergei B; Ostrovskaya, Rita U; Busciglio, Jorge

2003-05-01

The neuroprotective activity of a novel N-acylprolyl-containing dipeptide analog of the nootropic 2-oxo-1-pyrrolidine acetamide (Piracetam) designated as GVS-111 (DVD-111/Noopept) was tested in two in vitro models of neuronal degeneration mediated by oxidative stress: normal human cortical neurons treated with H(2)O(2), and Down's syndrome (DS) cortical neurons. Incubation of normal cortical neurons with 50 microM H(2)O(2) for 1h resulted in morphological and structural changes consistent with neuronal apoptosis and in the degeneration of more than 60% of the neurons present in the culture. GVS-111 significantly increased neuronal survival after H(2)O(2)-treatment displaying a dose-dependent neuroprotective activity from 10nM to 100 microM, and an IC(50) value of 1.21+/-0.07 microM. GVS-111 inhibited the accumulation of intracellular free radicals and lipid peroxidation damage in neurons treated with H(2)O(2) or FeSO(4), suggesting an antioxidant mechanism of action. GVS-111 exhibited significantly higher neuroprotection compared to the standard cognition enhancer Piracetam, or to the antioxidants Vitamin E, propyl gallate and N-tert-butyl-2-sulpho-phenylnitrone (s-PBN). In DS cortical cultures, chronic treatment with GVS-111 significantly reduced the appearance of degenerative changes and enhanced neuronal survival. The results suggest that the neuroprotective effect of GVS-111 against oxidative damage and its potential nootropic activity may present a valuable therapeutic combination for the treatment of mental retardation and chronic neurodegenerative disorders.

Dipeptide Piracetam Analogue Noopept Improves Viability of Hippocampal HT-22 Neurons in the Glutamate Toxicity Model.

PubMed

Antipova, T A; Nikolaev, S V; Ostrovskaya, P U; Gudasheva, T A; Seredenin, S B

2016-05-01

Effect of noopept (N-phenylacetyl-prolylglycine ethyl ester) on viability of neurons exposed to neurotoxic action of glutamic acid (5 mM) was studied in vitro in immortalized mouse hippocampal HT-22 neurons. Noopept added to the medium before or after glutamic acid improved neuronal survival in a concentration range of 10-11-10-5 M. Comparison of the effective noopept concentrations determined in previous studies on cultured cortical and cerebellar neurons showed that hippocampal neurons are more sensitive to the protective effect of noopept.

Cognitive enhancers (nootropics). Part 3: drugs interacting with targets other than receptors or enzymes. disease-modifying drugs.

PubMed

Froestl, Wolfgang; Pfeifer, Andrea; Muhs, Andreas

2013-01-01

Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from Alzheimer's disease, schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition refers to a capacity for information processing, applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, and psychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed in clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. To classify the compounds, a concept is proposed assigning drugs to 19 categories according to their mechanism(s) of action, in particular drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re-uptake transporters, antioxidants, metal chelators, and disease modifying drugs, meaning small molecules, vaccines, and monoclonal antibodies interacting with amyloid-β and tau. For drugs, whose mechanism of action is not known, they are either classified according to structure, e.g., peptides, or their origin, e.g., natural products. The review covers the evolution of research in this field over the last 25 years.

Cognitive enhancers (nootropics). Part 2: drugs interacting with enzymes.

PubMed

Froestl, Wolfgang; Muhs, Andreas; Pfeifer, Andrea

2013-01-01

Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from Alzheimer's disease, schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition refers to a capacity for information processing, applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, and psychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed in clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. To classify the compounds, a concept is proposed assigning drugs to 19 categories according to their mechanism(s) of action, in particular drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re-uptake transporters, antioxidants, metal chelators, and disease modifying drugs meaning small molecules, vaccines, and monoclonal antibodies interacting with amyloid-β and tau. For drugs whose mechanism of action is not known, they are either classified according to structure, e.g., peptides, or their origin, e.g., natural products. This review covers the evolution of research in this field over the last 25 years.

Cognitive enhancers (nootropics). Part 1: drugs interacting with receptors.

PubMed

Froestl, Wolfgang; Muhs, Andreas; Pfeifer, Andrea

2012-01-01

Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from Alzheimer's disease, schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition refers to a capacity for information processing, applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, and psychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed in clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. To classify the compounds, a concept is proposed assigning drugs to 18 categories according to their mechanism(s) of action, in particular drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re-uptake transporters, antioxidants, metal chelators, and disease-modifying drugs meaning small molecules, vaccines, and monoclonal antibodies interacting with amyloid-β and tau. For drugs, whose mechanism of action is not known, they are either classified according to structure, e.g., peptides, or their origin, e.g., natural products. The review covers the evolution of research in this field over the last 25 years.

Immunopharmacological properties of noopept.

PubMed

Kovalenko, L P; Shipaeva, E V; Alekseeva, S V; Pronin, A V; Durnev, A D; Gudasheva, T A; Ostrovskaja, R U; Seredenin, S B

2007-07-01

Noopept, a peptide analog of piracetam, enhanced phagocytic activity of mouse peritoneal macrophages, stimulated humoral and cellular immune response to various antigens, and markedly increased spontaneous proliferative activity of splenocytes. In animals with secondary immune deficiency caused by cyclophosphamide, noopept exhibited immunocorrector properties.

In Vitro Effects of Cognitives and Nootropics on Mitochondrial Respiration and Monoamine Oxidase Activity.

PubMed

Singh, Namrata; Hroudová, Jana; Fišar, Zdeněk

2017-10-01

Impairment of mitochondrial metabolism, particularly the electron transport chain (ETC), as well as increased oxidative stress might play a significant role in pathogenesis of Alzheimer's disease (AD). Some effects of drugs used for symptomatic AD treatment may be related to their direct action on mitochondrial function. In vitro effects of pharmacologically different cognitives (galantamine, donepezil, rivastigmine, 7-MEOTA, memantine) and nootropic drugs (latrepirdine, piracetam) were investigated on selected mitochondrial parameters: activities of ETC complexes I, II + III, and IV, citrate synthase, monoamine oxidase (MAO), oxygen consumption rate, and hydrogen peroxide production of pig brain mitochondria. Complex I activity was decreased by galantamine, donepezil, and memantine; complex II + III activity was increased by galantamine. None of the tested drugs caused significant changes in the rate of mitochondrial oxygen consumption, even at high concentrations. Except galantamine, all tested drugs were selective MAO-A inhibitors. Latrepirdine, donepezil, and 7-MEOTA were found to be the most potent MAO-A inhibitors. Succinate-induced mitochondrial hydrogen peroxide production was not significantly affected by the drugs tested. The direct effect of cognitives and nootropics used in the treatment of AD on mitochondrial respiration is relatively small. The safest drugs in terms of disturbing mitochondrial function appear to be piracetam and rivastigmine. The MAO-A inhibition by cognitives and nootropics may also participate in mitochondrial neuroprotection. The results support the future research aimed at measuring the effects of currently used drugs or newly synthesized drugs on mitochondrial functioning in order to understand their mechanism of action.

The Nootropic Concept and Dyslexia.

ERIC Educational Resources Information Center

Wilsher, Colin R.

1986-01-01

Studies with Nootropic psychoactive drugs (such as Piracetam) suggest that Piracetam lacks significant side effects; promotes memory and learning; and improves the reading ability of dyslexics, possibly by directly affecting the left-brain hemisphere. Results are contrasted with studies showing the lack of effectiveness of intensive teaching.…

[Comparative efficiency of nootropic drugs in complex treatment of patients with remote consequences of closed craniocereberal trauma].

PubMed

Hliebova, O S; Tkachenko, O V

2008-01-01

Main data of the research were data obtained after a complex treatment of 120 persons with late consequences of closed craniocereberal trauma (CCRCT). The treatment included administration of one of nootropic agents (noophen, aminolon or entropil), magnesium sulfate, group B vitamins. All patients have passed a complex examination: specially developed questionnaire, anamnesis gathering, neurologic status, neuropsychological status with the use of multiple-aspect scales and questionnaires, examination of fundus of eye, rheoencephalography, echoencephalography, brain MRT. Results of a complex examination proved positive effect of the use of nootropic agents, in particular noophen, entropil and aminolon in complex treatment of late consequences of closed craniocereberal trauma. For optimisation of the use of nootropic agents in the treatment of late consequences of closed craniocereberal trauma it is recommended to consider features of influence of nootropic agents on certain clinical aspects of the disease.

Cognitive enhancers (Nootropics). Part 1: drugs interacting with receptors. Update 2014.

PubMed

Froestl, Wolfgang; Muhs, Andreas; Pfeifer, Andrea

2014-01-01

Scientists working in the fields of Alzheimer's disease and, in particular, cognitive enhancers are very productive. The review "Cognitive enhancers (nootropics): drugs interacting with receptors" was accepted for publication in July 2012. Since then, new targets for the potential treatment of Alzheimer's disease were identified. This update describes drugs interacting with 42 receptors versus 32 receptors in the first paper. Some compounds progressed in their development, while many others were discontinued. The present review covers the evolution of research in this field through March 2014.

PASS assisted prediction and pharmacological evaluation of novel nicotinic analogs for nootropic activity in mice.

PubMed

Khurana, Navneet; Ishar, Mohan Pal Singh; Gajbhiye, Asmita; Goel, Rajesh Kumar

2011-07-15

The aim of present study is to predict the probable nootropic activity of novel nicotine analogues with the help of computer program, PASS (prediction of activity spectra for substances) and evaluate the same. Two compounds from differently substituted pyridines were selected for synthesis and evaluation of nootropic activity based on their high probable activity (Pa) value predicted by PASS computer program. Evaluation of nootropic activity of compounds after acute and chronic treatment was done with transfer latency (TL) and step down latency (SDL) methods which showed significant nootropic activity. The effect on scopolamine induced amnesia was also observed along with their acetylcholine esterase inhibitory activity which also showed positive results which strengthened their efficacy as nootropic agents through involvement of cholinergic system. This nootropic effect was similar to the effect of nicotine and donepezil used as standard drugs. Muscle coordination and locomotor activity along with their addiction liability, safety and tolerability studies were also evaluated. These studies showed that these compounds are well tolerable and safe over a wide range of doses tested along with the absence of withdrawal effect which is present in nicotine due to its addiction liability. The study showed that these compounds are true nicotine analogs with desirable efficacy and safety profile for their use as effective nootropic agents. Copyright © 2011 Elsevier B.V. All rights reserved.

Molecular Mechanism Underlying the Action of Substituted Pro-Gly Dipeptide Noopept.

PubMed

Vakhitova, Y V; Sadovnikov, S V; Borisevich, S S; Ostrovskaya, R U; A Gudasheva, T; Seredenin, S B

2016-01-01

This study was performed in order to reveal the effect of Noopept (ethyl ester of N-phenylacetyl-Lprolylglycine, GVS-111) on the DNA-binding activity of transcriptional factors (TF) in HEK293 cells transiently transfected with luciferase reporter constructs containing sequences for CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, HSF1, and HIF-1. Noopept (10 μM) was shown to increase the DNA-binding activity of HIF-1 only, while lacking the ability to affect that of CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, and HSF1. Noopept provoked an additional increase in the DNA-binding activity of HIF-1 when applied in conditions of CoCl2-induced HIF- 1 stabilization. The degree of this HIF-positive effect of Noopept was shown to be concentration-dependent. Piracetam (1 mM) failed to affect significantly any of the TF under study. The results of molecular docking showed that Noopept (L-isomer), as well as its metabolite, L-isomer of N-phenyl-acetylprolyl, unlike its pharmacologically ineffective D-isomer, is able to bind to the active site of prolyl hydroxylase 2. Taking into account the important role of the genes activated by HIF-1 in the formation of an adaptive response to hypoxia, data on the ability of Noopept to provoke a selective increase in the DNA-binding activity of HIF-1 explain the wide spectrum of neurochemical and pharmacological effects of Noopept revealed before. The obtained data allow one to propose the HIF-positive effect as the primary mechanism of the activity of this Pro-Gly-containing dipeptide.

Impairment of learning and memory after photothrombosis of the prefrontal cortex in rat brain: effects of Noopept.

PubMed

Romanova, G A; Shakova, F M; Gudasheva, T A; Ostrovskaya, R U

2002-12-01

Experiments were performed on rats trained conditioned passive avoidance response. Acquisition and retention of memory traces were impaired after photothrombosis of the prefrontal cortex. The acyl-prolyl-containing dipeptide Noopept facilitated retention and retrieval of a conditioned passive avoidance response, normalized learning capacity in animals with ischemic damage to the cerebral cortex, and promoted finish training in rats with hereditary learning deficit. These results show that Noopept improves all three stages of memory. It should be emphasized that the effect of Noopept was most pronounced in animals with impaired mnesic function.

Molecular Mechanism Underlying the Action of Substituted Pro-Gly Dipeptide Noopept

PubMed Central

Vakhitova, Y. V.; Sadovnikov, S. V.; Borisevich, S. S.; Ostrovskaya, R. U.; A.Gudasheva, T.; Seredenin, S. B.

2016-01-01

This study was performed in order to reveal the effect of Noopept (ethyl ester of N-phenylacetyl-Lprolylglycine, GVS-111) on the DNA-binding activity of transcriptional factors (TF) in HEK293 cells transiently transfected with luciferase reporter constructs containing sequences for CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, HSF1, and HIF-1. Noopept (10 μM) was shown to increase the DNA-binding activity of HIF-1 only, while lacking the ability to affect that of CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, and HSF1. Noopept provoked an additional increase in the DNA-binding activity of HIF-1 when applied in conditions of CoCl2-induced HIF- 1 stabilization. The degree of this HIF-positive effect of Noopept was shown to be concentration-dependent. Piracetam (1 mM) failed to affect significantly any of the TF under study. The results of molecular docking showed that Noopept (L-isomer), as well as its metabolite, L-isomer of N-phenyl-acetylprolyl, unlike its pharmacologically ineffective D-isomer, is able to bind to the active site of prolyl hydroxylase 2. Taking into account the important role of the genes activated by HIF-1 in the formation of an adaptive response to hypoxia, data on the ability of Noopept to provoke a selective increase in the DNA-binding activity of HIF-1 explain the wide spectrum of neurochemical and pharmacological effects of Noopept revealed before. The obtained data allow one to propose the HIF-positive effect as the primary mechanism of the activity of this Pro-Gly-containing dipeptide. PMID:27099787

Varsity Medical Ethics Debate 2015: should nootropic drugs be available under prescription on the NHS?

PubMed

Thorley, Emma; Kang, Isaac; D'Costa, Stephanie; Vlazaki, Myrto; Ayeko, Olaoluwa; Arbe-Barnes, Edward H; Swerner, Casey B

2016-09-13

The 2015 Varsity Medical Ethics debate convened upon the motion: "This house believes nootropic drugs should be available under prescription". This annual debate between students from the Universities of Oxford and Cambridge, now in its seventh year, provided the starting point for arguments on the subject. The present article brings together and extends many of the arguments put forward during the debate. We explore the current usage of nootropic drugs, their safety and whether it would be beneficial to individuals and society as a whole for them to be available under prescription. The Varsity Medical Debate was first held in 2008 with the aim of allowing students to engage in discussion about ethics and policy within healthcare. The event is held annually and it is hoped that this will allow future leaders to voice a perspective on the arguments behind topics that will feature heavily in future healthcare and science policy. This year the Oxford University Medical Society at the Oxford Union hosted the debate.

[Nootropics and antioxidants in the complex therapy of symptomatic posttraumatic epilepsy].

PubMed

Savenkov, A A; Badalian, O L; Avakian, G N

2013-01-01

To study the possibility of application of nootropics and antioxidants in the complex antiepileptic therapy, we examined 75 patients with symptomatic focal posttraumatic epilepsy. A statistically significant reduction in the number of epileptic seizures, improvement of cognitive function and quality of life of the patients as well as a decrease in the severity of depression and epileptic changes in the EEG were identified. The potentiation of antiepileptic activity of basic drugs, normalization of brain's electrical activity and reduction in EEG epileptiform activity, in particular coherent indicators of slow-wave activity, were noted after treatment with the antioxidant mexidol. A trend towards the improvement of neuropsychological performance and quality of life was observed. There was a lack of seizure aggravation typical of many nootropic drugs. Thus, phenotropil and mexidol can be recommended for complex treatment of symptomatic posttraumatic epilepsy.

Design, synthesis, and preliminary pharmacological evaluation of 1, 4-diazabicyclo[4.3.0]nonan-9-ones as a new class of highly potent nootropic agents.

PubMed

Manetti, D; Ghelardini, C; Bartolini, A; Bellucci, C; Dei, S; Galeotti, N; Gualtieri, F; Romanelli, M N; Scapecchi, S; Teodori, E

2000-05-18

Several 4-substituted 1,4-diazabicyclo[4.3.0]nonan-9-ones have been synthesized and tested in vivo on mouse passive avoidance test, to evaluate their nootropic activity. The results show that they represent a new class of nootropic drugs with a pharmacological profile very similar to that of piracetam, showing much higher potency with respect to the reference. Among the compounds studied, 7 (DM 232) shows outstanding potency, being active at the dose of 0. 001 mg kg(-1) sc.

[Hypoxia and memory. Specific features of nootropic agents effects and their use].

PubMed

Voronina, T A

2000-01-01

Hypoxia and hypoxic adaptation are powerful factors of controlling memory and behavior processes. Acute hypoxia exerts a differential impact on different deficits of mnestic and cognitive functions. Instrumental reflexes of active and passive avoidance, negative learning, behavior with a change in the stereotype of learning are more greatly damaged. Memory with spatial and visual differentiation and their rearrangement change to a lesser extent and conditional reflexes are not deranged. In this contract, altitude hypoxic adaptation enhances information fixation and increases the degree and duration of retention of temporary relations. Nootropic agents with an antihypoxic action exert a marked effect on hypoxia-induced cognitive and memory disorders and the magnitude of this effect depends on the ration of proper nootropic to antihypoxic components in the spectrum of the drugs' pharmacological activity. The agents that combine a prevailing antiamnestic effect and a marked and moderate antihypoxic action (mexidole, nooglutil, pyracetam, beglymin, etc.) are most effective in eliminating different hypoxia-induced cognitive and memory disorders, nootropic drugs that have a pronounced antiamnestic activity (centrophenoxine, etc.) and no antihypoxic component also restore the main types of mnestic disorders after hypoxia, but to a lesser extent.

Piperazines as nootropic agents: New derivatives of the potent cognition-enhancer DM235 carrying hydrophilic substituents.

PubMed

Martino, Maria Vittoria; Guandalini, Luca; Di Cesare Mannelli, Lorenzo; Menicatti, Marta; Bartolucci, Gianluca; Dei, Silvia; Manetti, Dina; Teodori, Elisabetta; Ghelardini, Carla; Romanelli, Maria Novella

2017-03-15

The piperazine ring of the potent nootropic drug DM235 has been decorated with H-bond donor and acceptor groups (CH 2 OH, CH 2 OMe, CH 2 OCOMe, COOEt); the aim was to insert new functional groups, suitable for further chemical manipulation. The influence of these modifications on nootropic activity was assessed by means of the mouse passive avoidance test; some of the newly synthesized molecules (alcohol 7b, acetate 8b and ester 10d) showed interesting in vivo potency. This makes it possible to use these functional groups for adding other residues, in order to increase molecular diversity, or for anchoring a biotin group, to obtain compounds useful to capture the biological target. Moreover, the new compounds will improve our knowledge of structure activity relationships of this family of drugs. Copyright © 2017 Elsevier Ltd. All rights reserved.

Noopept reduces the postischemic functional and metabolic disorders in the brain of rats with different sensitivity to hypoxia.

PubMed

Zarubina, I V; Shabanov, P D

2009-03-01

Chronic cerebral ischemia was induced by ligation of both common carotid arteries in Wistar rats, divided by sensitivity to hypoxia into highly sensitive and low-sensitive. Noopept (peptide preparation), injected (0.5 mg/kg) during 7 days after occlusion of the carotid arteries, reduced the neurological disorders in rats with high and low sensitivity to hypoxia and improved their survival during the postischemic period. Noopept normalized behavior disordered by cerebral ischemia (according to the open field and elevated plus maze tests), prevented accumulation of LPO products and inhibition of antioxidant systems in the brain of rats with high and low sensitivity to hypoxia. Hence, noopept exhibited a neuroprotective effect in cerebral ischemia.

Design and study of piracetam-like nootropics, controversial members of the problematic class of cognition-enhancing drugs.

PubMed

Gualtieri, Fulvio; Manetti, Dina; Romanelli, Maria Novella; Ghelardini, Carla

2002-01-01

Cognition enhancers are drugs able to facilitate attentional abilities and acquisition, storage and retrieval of information, and to attenuate the impairment of cognitive functions associated with head traumas, stroke, age and age-related pathologies. Development of cognition enhancers is still a difficult task because of complexity of the brain functions, poor predictivity of animal tests and lengthy and expensive clinical trials. After the early serendipitous discovery of first generation cognition enhancers, current research is based on a variety of working hypotheses, derived from the progress of knowledge in the neurobiopathology of cognitive processes. Among other classes of drugs, piracetam-like cognition enhancers (nootropics) have never reached general acceptance, in spite of their excellent tolerability and safety. In the present review, after a general discussion of the problems connected with the design and development of cognition enhancers, the class is examined in more detail. Reasons for the problems encountered by nootropics, compounds therapeutically available and those in development, their structure activity relationships and mechanisms of action are discussed. Recent developments which hopefully will lead to a revival of the class are reviewed.

Effect of noopept and afobazole on the development of neurosis of learned helplessness in rats.

PubMed

Uyanaev, A A; Fisenko, V P; Khitrov, N K

2003-08-01

We studied the effects of new psychotropic preparations noopept and afobazole on acquisition of the conditioned active avoidance response and development of neurosis of learned helplessness in rats. Noopept in doses of 0.05-0.10 mg/kg accelerated acquisition of conditioned active avoidance response and reduced the incidence of learned helplessness in rats. Afobazole in a dose of 5 mg/kg produced an opposite effect, which is probably related to high selective anxiolytic activity of this preparation.

Nootropic activity of tuber extract of Pueraria tuberosa (Roxb).

PubMed

Rao, N Venkata; Pujar, Basavaraj; Nimbal, S K; Shantakumar, S M; Satyanarayana, S

2008-08-01

Nootropic effect of alcoholic (ALE; 50, 75, 100 mg/kg) and aqueous (AQE; 100, 200, 400 mg/kg) extracts of P. tuberosa was evaluated by using Elevated Plus Maze (EPM), scopolamine-induced amnesia (SIA), diazepam-induced amnesia (DIA), clonidine-induced (NA-mediated) hypothermia (CIH), lithium-induced (5-HT mediated) head twitches (LIH) and haloperidol-induced (DA- mediated) catalepsy (HIC) models. Piracetam was used as the standard drug. A significant increase in inflexion ratio (IR) was recorded in EPM, SIA and DIA models. A significant reversal effect was observed on rectal temperature in CIH model, reduction of head twitches in LIH models. However no significant reduction in catalepsy scores in HIC models were observed with test extracts and standard piracetam. The results indicate that nootropic activity observed with ALE and AQE of tuber extracts of P. tuberosa could be through improved learning and memory either by augmenting the noradrenaline (NA) transmission or by interfering with 5-hydroxytryptamine (5-HT) release. Further, the extracts neither facilitated nor blocked release of the dopamine (DA). Thus ALE and AQE elicited significant nootropic effect in mice and rats by interacting with cholinergic, GABAnergic, adrenergic and serotonergic systems. Phytoconstituents like flavonoids have been reported for their nootropic effect and these are present in both ALE and AQE extracts of tubers of P. tuberosa (Roxb) and these active principles may be responsible for nootropic activity.

Evaluation of nootropic potential of Ocimum sanctum Linn. in mice.

PubMed

Joshi, Hanumanthachar; Parle, Milind

2006-02-01

Dementia is one of the age related mental problems and a characteristic symptom of various neurodegenerative disorders including Alzheimer's disease. Certain drugs like diazepam, barbiturates and alcohol disrupt learning and memory in animals and man. However, a new class of drugs known as nootropic agents is now used in situations where there is organic disorder in learning abilities. The present work was undertaken to assess the potential of O. sanctum extract as a nootropic and anti-amnesic agent in mice. Aqueous extract of dried whole plant of O. sanctum ameliorated the amnesic effect of scopolamine (0.4 mg/kg), diazepam (1 mg/kg) and aging induced memory deficits in mice. Elevated plus maze and passive avoidance paradigm served as the exteroceptive behavioral models. O. sanctum extract decreased transfer latency and increased step down latency, when compared to control (piracetam treated), scopolamine and aged groups of mice significantly. O. sanctum preparations could of beneficial in the treatment of cognitive disorders such as dementia and Alzheimer's disease.

[Role of functional state of neuronal mitochondria of cerebral cortex in mechanisms of nootropic activity of neuroprotectors in rats with alloxan hyperglycemia].

PubMed

Zhiliuk, V I; Mamchur, V I; Pavlov, S V

2015-01-01

The influence of citicoline, phenylpiracetam, pentoxifylline and N-phenylacetyl-L-prolylglycine on cognitive processes and functional state of mitochondria in the neocortex of alloxan-diabetic rats has been studied. The drug effects on cognitive processes were assessed using passive avoidance tests in the dark-light camera. Latent period and the number of animals with amnesia skill on 6th and 20th days of drug administration were recorded. Functional status of mitochondria was assessed by mitochondrial pore opening and mitochondrial transmembrane potential (Y) on 20th day. It has been established that course administration of phenylpiracetam, citicoline and to a lesser extent N-phenylacetyl-L-prolylglycine, but not pentoxifylline, improves the processes of learning and storing conditional skill. At the same time, the nootropic activity of studied drugs was comparable to their effect on the functional state of mitochondria in neocortical neurons in rats with chronic hyperglycemia. According to mitoprotective activity (prevention of opening of mitochondrial cyclosporin-A-sensitive pores and restoration of mitochondrial transmembrane potential), the maximum potential was observed for citicoline and phenylpiracetam, and the minimum--for pentoxifylline. The results point out the importance of mitoprotective properties in nootropic effects of studied drugs.

The Brain Tourniquet: Physiological Isolation of Brain Regions Damaged by Traumatic Head Injury

DTIC Science & Technology

2008-06-19

brain slices were treated after injury with either a nootropic agent ( aniracetam , cyclothiazide, IDRA 21, or 1-BCP) or the antiepileptic drug...tourniquet approach. Four well-known nootropic agents were evaluated: aniracetam , a pyrrolidione analog that slows non-NMDA (AMPA/kainate) receptor...to improve cognition in rats [Stdubli et al., 1994], and has more potent effects than aniracetam in rat brain slices [Arai et al., 1994]. In

Synthesis and nootropic activity of some 2,3-dihydro-1H-isoindol-1-one derivatives structurally related with piracetam.

PubMed

Reyes, Adelfo; Huerta, Leticia; Alfaro, Marisol; Navarrete, Andrés

2010-11-01

Three 2,3-dihydro-1H-isoindol-1-ones structurally related with piracetam (=2-oxopyrrolidine-1-acetamide) have been synthesized and tested for their nootropic effects in the passive avoidance test in mice. Compounds (RS)-2, (R,R)-3, and (R,S)-3 were obtained in good yields in only two steps starting from methyl DL-phthaloylalanine. Compound (RS)-2 exhibited nootropic activity at lower doses than piracetam, used as reference drug, but it showed lower efficacy. Whereas diastereoisomers (R,R)-3 and (R,S)-3 were as potent as piracetam to revert amnesia induced by scopolamine, (R,S)-3 showed lower efficacy than (R,R)-3. Only (R,R)-3 showed myorelaxant effect at doses of 10 and 30 mg/kg; other compounds did not exhibit any anticonvulsant, sedative, myorelaxant, or impaired motor-coordination effect in mice. These synthesized 2,3-dihydro-1H-isoindol-1-one derivatives constitute a new kind of nootropic compounds.

[Effects of nootropic drugs on hippocampal and cortical BDNF levels in mice with different exploratory behavior efficacy].

PubMed

Firstova, Iu Iu; Dolotov, O V; Kondrakhin, e A; Dubynina, E V; Grivennikov, I A; Kovalev, G I

2009-01-01

The influence of subchronic administration of nootropic drugs (piracetam, phenotropil, meclophenoxate, pantocalcine, semax, nooglutil) on the brain-derived neurotrophic factor (BDNF) content in hippocampal and cortical tissues in mice with different exploratory behavior--high efficacy (HE) against low efficacy (LE)--in cross-maze test has been studied. The initial BDNF concentration in hippocamp (but not in cortex) of control HE mice was higher than that in LE mice (LE, 0.091 +/- 0.005 pg/microg; HE, 0.177 +/- 0.005 pg/microg; p < 0.0005). After drug administration, changes in the BDNF level were only observed in the hippocamp of LE mice, where it reached (pg/microg) 0.115 +/- 0.004 (for piracetam); 0.119 +/- 0.006 (for phenotropil); 0.123 +/- 0.007 (for semax); and 0.122 +/- 0.009 (for meclophenoxate). In the LE mice cortex, the BDNF content increased only after piracetam and semax injections (to 0.083 +/- 0.003 and 0.093 +/- 0.008, respectively, vs. 0.071 +/- 0.003 pg/microg in the control group; p < 0.0005). No changes were observed in the cortex of HE mice. Thus, the obtained results demonstrate that clinically used drugs piracetam, phenotropil, meclophenoxate, and semax realize their nootrope effects, at least partially, via increase in hippocampal BDNF level, which is achieved only under conditions of cognitive deficiency.

Effect of piracetam, a nootropic agent, on rat brain monoamines and prostaglandins.

PubMed

Bhattacharya, S K; Upadhyay, S N; Jaiswal, A K; Bhattacharya, S

1989-03-01

Piracetam is the prototype of a new class of psychotropic drugs, the nootropic agents, which are claimed to selectively improve the higher telencephalic integrative activities. The effect of piracetam on rat brain monoamines and prostaglandins (PGs) was assessed so as to garner information on its mode of action. Two doses of the drug were used, a lower dose (20 mg/kg ip) and a higher dose (100 mg/kg, ip), the latter being known to exert a facilitatory effect on learning and memory. Piracetam produced a dose-related effect on rat brain serotonin (5HT) and noradrenaline (NA), with the lower dose inducing a decrease in 5HT levels and an increase in NA concentrations. The higher dose of piracetam produced the opposite effect. Dopamine (DA) levels were not significantly affected. The lower dose of the drug attenuated 5HT turnover and augmented that of NA, whereas the higher dose of piracetam produced the reverse effects, in clorgyline treated rats. The lower dose of piracetam produced a slight and statistically insignificant increase in rat brain PGE2 and PGF2 alpha. However, the higher dose of the drug produced marked increase in the levels of both the PGs. The observed biochemical effects may provide a basis for the nootropic effect of piracetam. However, they may also be due to the GA-BA-mimetic action of the drug, particularly those observed with the lower dose of piracetam.

Anti-stress and nootropic activity of drugs affecting the renin-angiotensin system in rats based on indirect biochemical evidence.

PubMed

Anil Kumar, K V; Nagwar, Shrasti; Thyloor, Rama; Satyanarayana, Sreemantula

2015-12-01

Various stress hormones are responsible for bringing out stress-related changes and are implicated in learning and memory processes. The extensive clinical experience of angiotensin receptor blockers (ARBs) and direct renin inhibitor as antihypertensive agents provides anecdotal evidence of improvements in cognition. The neurochemical basis underlying the anti-stress and nootropic effects are unclear. This study was aimed to determine the effects of aliskiren, valsartan and their combination on the neuromediators of the central nervous system (CNS) and periphery as well as on cognitive function. Groups of rats were subjected to a forced swim stress for one hour after daily treatment with aliskiren, valsartan and their combination. The 24 h urinary excretion of vanillylmandellic acid (VMA), 5-hydroxyindoleacetic acid (5-HIAA), 6-β-hydroxycortisol (6-β-OH) cortisol and homovanillic acid (HVA) was determined in all groups under normal and stressed conditions. Nootropic activity was studied using cook's pole climbing apparatus and acetylcholinesterase (AChE) inhibitory activity by Ellman's method. Administration of aliskiren (10 mg/kg), valsartan (20 mg/kg) and their combination at a dose of 5 and 10 mg/kg respectively reduced the urinary metabolite levels. Further, all drugs showed significant improvement in scopolamine-impaired performance and produced inhibition of the AChE enzyme. The present study provides scientific support for the anti-stress and nootropic activities of aliskiren, valsartan and their combination. © The Author(s) 2014.

Preparation of silica nanoparticles loaded with nootropics and their in vivo permeation through blood-brain barrier.

PubMed

Jampilek, Josef; Zaruba, Kamil; Oravec, Michal; Kunes, Martin; Babula, Petr; Ulbrich, Pavel; Brezaniova, Ingrid; Opatrilova, Radka; Triska, Jan; Suchy, Pavel

2015-01-01

The blood-brain barrier prevents the passage of many drugs that target the central nervous system. This paper presents the preparation and characterization of silica-based nanocarriers loaded with piracetam, pentoxifylline, and pyridoxine (drugs from the class of nootropics), which are designed to enhance the permeation of the drugs from the circulatory system through the blood-brain barrier. Their permeation was compared with non-nanoparticle drug substances (bulk materials) by means of an in vivo model of rat brain perfusion. The size and morphology of the nanoparticles were characterized by transmission electron microscopy. The content of the drug substances in silica-based nanocarriers was analysed by elemental analysis and UV spectrometry. Microscopic analysis of visualized silica nanocarriers in the perfused brain tissue was performed. The concentration of the drug substances in the tissue was determined by means of UHPLC-DAD/HRMS LTQ Orbitrap XL. It was found that the drug substances in silica-based nanocarriers permeated through the blood brain barrier to the brain tissue, whereas bulk materials were not detected in the brain.

Preparation of Silica Nanoparticles Loaded with Nootropics and Their In Vivo Permeation through Blood-Brain Barrier

PubMed Central

Zaruba, Kamil; Kunes, Martin; Ulbrich, Pavel; Brezaniova, Ingrid; Triska, Jan; Suchy, Pavel

2015-01-01

The blood-brain barrier prevents the passage of many drugs that target the central nervous system. This paper presents the preparation and characterization of silica-based nanocarriers loaded with piracetam, pentoxifylline, and pyridoxine (drugs from the class of nootropics), which are designed to enhance the permeation of the drugs from the circulatory system through the blood-brain barrier. Their permeation was compared with non-nanoparticle drug substances (bulk materials) by means of an in vivo model of rat brain perfusion. The size and morphology of the nanoparticles were characterized by transmission electron microscopy. The content of the drug substances in silica-based nanocarriers was analysed by elemental analysis and UV spectrometry. Microscopic analysis of visualized silica nanocarriers in the perfused brain tissue was performed. The concentration of the drug substances in the tissue was determined by means of UHPLC-DAD/HRMS LTQ Orbitrap XL. It was found that the drug substances in silica-based nanocarriers permeated through the blood brain barrier to the brain tissue, whereas bulk materials were not detected in the brain. PMID:26075264

[Antihypoxic effect of 3-hydroxypyridine and succinic acid derivatives and their nootropic action in alloxan diabetes].

PubMed

Volchegorskiĭ, I A; Rassokhina, L M; Miroshnichenko, I Iu

2011-01-01

Relationship between the antihypoxic effect of 3-hydroxypyridine and succinic acid derivatives (emoxipine, reamberin and mexidol) and their effect on conditional learning, glycemia, and lipidemia was studied in rats with alloxan-induced diabetes. In parallel, the analogous relationship was investigated for alpha-lipoic acid that is regarded as a "gold standard" in treatment of diabetic neuropathy. It was established that single administration of emoxipine and mexidol in mice in doses equivalent to therapeutic-range doses in humans produces antihypoxic effect manifested by increased resistance to acute hypoxic hypoxia in test animals. Alpha-lipoic acid is inferior to emoxipin and mexidol in the degree of antihypoxic action. Reamberin does not exhibit this effect. The introduction of emoxipin, reamberin, mexidol, and alpha-lipoic acid in rats with alloxan diabetes during 7 or 14 days in doses equivalent to therapeutic-range doses in humans corrects conditional learning disorders in direct relationship with the antihypoxic activity of these drugs. The development of the nootropic effect of emoxipin, mexidol, and alpha-lipoic acid is related to a decrease in hyperglycemia and hyperlipidemia in rats with alloxan diabetes. The nootropic action of reamberin is accompanied by a transient hypoglycemizing effect and aggravation of dyslipidemic disorders. The antihypoxic activity of investigated drugs determines the direction and expression of their lipidemic effect, but is not correlated with the hypoglycemizing action these drugs on test animals with alloxan diabetes.

Molecular simplification of 1,4-diazabicyclo[4.3.0]nonan-9-ones gives piperazine derivatives that maintain high nootropic activity.

PubMed

Manetti, D; Ghelardini, C; Bartolini, A; Dei, S; Galeotti, N; Gualtieri, F; Romanelli, M N; Teodori, E

2000-11-16

Several 4-substituted 1-acylpiperazines, obtained by molecular simplification of 4-substituted 1,4-diazabicyclo[4.3.0]nonan-9-ones, have been synthesized and tested in vivo on the mouse passive avoidance test, to evaluate their nootropic activity. The results show that, apparently, an N-acylpiperazine group can mimic the 2-pyrrolidinone ring of 1,4-diazabicyclo[4.3.0]nonan-9-one, as the compounds of the new series maintain high nootropic activity. Moreover molecular simplification produces more clear-cut structure-activity relationships with respect to the parent series. The mechanism of action also appears to be similar in the two series. In fact, although the molecular mechanism remains to be elucidated, the most potent compound of each class (DM232 and 13, DM235) is able to increase acetylcholine release in rat brain. Piperazine derivatives represent a new class of nootropic drugs with an in vivo pharmacological profile very similar to that of piracetam, showing much higher potency with respect to the reference compound. Among the compounds studied, 13 (DM235) shows outstanding potency, being active at a dose of 0.001 mg kg(-1) sc.

Synthesis and biological evaluation of 3,7-diazabicyclo[4.3.0]nonan-8-ones as potential nootropic and analgesic drugs.

PubMed

Martini, Elisabetta; Di Cesare Mannelli, Lorenzo; Bartolucci, Gianluca; Bertucci, Carlo; Dei, Silvia; Ghelardini, Carla; Guandalini, Luca; Manetti, Dina; Scapecchi, Serena; Teodori, Elisabetta; Romanelli, Maria Novella

2011-04-14

A series of cis and trans 3,7-diazabicyclo[4.3.0]nonan-8-ones has been synthesized and tested for their ability to revert scopolamine-induced amnesia in the mouse passive-avoidance test. The racemates of the most potent compounds 4 and 7 were separated and tested, but no enantioselectivity was found for the nootropic activity. Compounds 4 and 7 and their enantiomers displayed interesting antihyperalgesic activity in two models of neuropathic pain (streptozotocin-induced and oxalilplatin-induced neuropathy) in comparison with pregabalin.

Influence of ring size on the cognition-enhancing activity of DM235 and MN19, two potent nootropic drugs.

PubMed

Guandalini, L; Martini, E; Di Cesare Mannelli, L; Dei, S; Manetti, D; Scapecchi, S; Teodori, E; Ghelardini, C; Romanelli, M N

2012-03-01

A series of analogs of DM235 and MN19, characterized by rings with different size, have been prepared and evaluated for their nootropic activity in the mouse passive-avoidance test. It was found that the optimal ring size for the analogs of DM235, showing endocyclic both amidic groups, is 6 or 7 atoms. For the compounds structurally related to MN19, carrying an exocyclic amide group, the piperidine ring is the moiety which gives the most interesting compounds. Copyright © 2012 Elsevier Ltd. All rights reserved.

Unifi nootropics from the lab to the web: a story of academic (and industrial) shortcomings.

PubMed

Gualtieri, Fulvio

2016-01-01

This paper is a review of the work of my former academic group of research in the past 15 years, in the field of cognition enhancers (also called nootropics) that identified two very potent molecules: Unifiram and Sunifiram that for a variety of reasons were not protected by a patent. Some 12 years after their disclosure (2000) I casually found that on the web, there were dozens of sites offering Unifiram and Sunifiram as drugs that improve cognition in healthy individuals even if only few preclinical studies were done and their long-term toxicity was unknown.

[Plant metabolites as nootropics and cognitives].

PubMed

Cervenka, F; Jahodár, L

2006-09-01

Nowadays several millions of people suffer from Alzheimer's disease and other types of dementia. Etiology of these diseases is not known very well. There occur different levels of neurotransmitters, the level of acetylcholine in the brain is decreased and pathological changes affect the brain tissue. Organic and toxic damage of the brain, free radicals, and other changes participate in the development of these diseases. Drugs as nootropics, cognitives, and neuroprotectives are commonly used to treat these diseases. Some of these drugs have often side and undesirable effects. In recent years some natural substances (galanthamine, huperzine A, vinpocetine), and standardized plant extracts (Ginkgo biloba L., Centella asiatica L.) Urban, Bacopa monniera L., Evolvulus alsinoides L.) are often used. These plant preparations produce fewer undesirable effects and the same effectiveness as the classic therapy, or these preparations are used as a supplement to the classic therapy.

Study of the protective effects of nootropic agents against neuronal damage induced by amyloid-beta (fragment 25-35) in cultured hippocampal neurons.

PubMed

Sendrowski, Krzysztof; Sobaniec, Wojciech; Stasiak-Barmuta, Anna; Sobaniec, Piotr; Popko, Janusz

2015-04-01

Alzheimer's disease (AD) is a common neurodegenerative disorder, in which progressive neuron loss, mainly in the hippocampus, is observed. The critical events in the pathogenesis of AD are associated with accumulation of β-amyloid (Aβ) peptides in the brain. Deposits of Aβ initiate a neurotoxic "cascade" leading to apoptotic death of neurons. Aim of this study was to assess a putative neuroprotective effects of two nootropic drugs: piracetam (PIR) and levetiracetam (LEV) on Aβ-injured hippocampal neurons in culture. Primary cultures of rat's hippocampal neurons at 7 day in vitro were exposed to Aβ(25-35) in the presence or absence of nootropics in varied concentrations. Flow cytometry with Annexin V/PI staining was used for counting and establishing neurons as viable, necrotic or apoptotic. Additionally, release of lactate dehydrogenase (LDH) to the culture medium, as a marker of cell death, was evaluated. Aβ(25-35) caused concentration-dependent death of about one third number of hippocampal neurons, mainly through an apoptotic pathway. In drugs-containing cultures, number of neurons injured with 20 μM Aβ(25-35) was about one-third lesser for PIR and almost two-fold lesser for LEV. When 40 μM Aβ(25-35) was used, only LEV exerted beneficial neuroprotective action, while PIR was ineffective. Our results suggest the protective potential of both studied nootropics against Aβ-induced death of cultured hippocampal neurons with more powerful neuroprotective effects of LEV. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Nootropic nefiracetam inhibits proconvulsant action of peripheral-type benzodiazepines in epileptic mutant EL mice.

PubMed

Nakamoto, Yurie; Shiotani, Tadashi; Watabe, Shigeo; Nabeshima, Toshitaka; Yoshii, Mitsunobu

2004-10-01

Piracetam and structurally related nootropics are known to potentiate the anticonvulsant effects of antiepileptic drugs. It remains to be seen, however, whether these nootropics inhibit proconvulsant actions of many toxic agents including Ro 5-4864, a specific agonist for peripheral-type benzodiazepine receptors (PBR). The present study was designed to address this issue using EL mice, an animal model of epilepsy. In behavioral pharmacological experiments, EL mice were highly susceptible to convulsions induced by Ro 5-4864 (i.p.) in comparison with nonepileptic DDY mice. Nefiracetam administered orally to EL mice inhibited spontaneous seizures. In DDY mice, convulsions induced by Ro 5-4864 were prevented by nefiracetam when administered by i.v. injection. Aniracetam (i.v.) was partially effective, but piracetam and oxiracetam were ineffective as anticonvulsants. Binding assay for brain tissues revealed a higher density of mitochondrial PBR in EL mice compared with DDY mice. Binding of the PBR ligands Ro 5-4864 to either EL or DDY mouse brain was inhibited by micromolar concentrations of these nootropic agents in the sequence of nefiracetam > aniracetam > oxiracetam, piracetam. This rank order is identical to potency as anticonvulsants. These data suggest that nefiracetam may prevent toxic effects of PBR agonists through interacting with PBR.

[Effect of centrophenoxine, piracetam and aniracetam on the monoamine oxidase activity in different brain structures of rats].

PubMed

Stancheva, S L; Alova, L G

1988-01-01

In vitro studies of effects of some nootropic drugs (centrophenoxine, piracetam and aniracetam) on monoamine oxidase (MAO) activity in the rat striatum and hypothalamus, using tyramine, serotonin and beta-phenylethylamine as substrates, were carried out. At all concentrations used (5.10(-5)-1.10(-3) M) centrophenoxine inhibited total MAO, MAO A and MAO B in both brain structures. Piracetam activated striatal and hypothalamic total MAO, hypothalamic MAO A and MAO B but exerted a pronounced inhibitory effect on MAO A and MAO B activity in the striatum. Aniracetam inhibited total MAO and MAO A in both brain structures but activated striatal and hypothalamic MAO B. The different effects of centrophenoxine, piracetam and aniracetam on MAO activity in the brain structures support the view for the independent mode of action of nootropic drugs in spite of their similar molecular and metabolic activity.

[The influence of piracetam on behavior and brain receptors in C57BL/6 and BALB/c mice: nootropic and anxiolytic effects].

PubMed

Kovalev, G I; Kondrakhin, E A; Salimov, R M; Neznamov, G G

2013-01-01

The influence of acute and long-term piracetam administration on the dynamics of rapid (non-specific, anxiolytic) and slow (specific, nootropic) behavioral drug effects, as well as on their interrelation with NMDA- and BDZ-receptors was studied in inbred mice strains differing in cognitive and emotional status--C57BL/6 and BALB/c. The BALB/c strain contained 17% less [3H]-flunitrazepam binding sites in frontal cortex and 22% less [3H]-MK801 binding sites in hippocampus as compared to those in C57BL/6 mice. Based on these data, BALB/c strain was used as a model of psychopathology, combining increased anxiety and cognitive deficit. Under the action of single, 7-fold, and 14-fold piracetam i.p. injections (200 mg/kg body weight, daily), a fast increase in NMDA-receptor density and slow escalation of the specific nootropic effect was observed in BALB/c mice. Non-specific anxiolytic effects in these mice increased for the first 1 - 7 days without any changes in BDZ-binding and then decreased to initial values accompanied by decrement of brain receptor concentration. Thus, in BALB/c mice, a slowly manifested specific nootropic action of piracetam develops, following an increase in NMDA receptor density, whereas the non-specific anxiolytic effect precedes the fast-paced changes in BDZ-binding site density.

Approaches to Measuring the Effects of Wake-Promoting Drugs: A Focus on Cognitive Function

PubMed Central

Edgar, Christopher J.; Pace-Schott, Edward F.; Wesnes, Keith A.

2009-01-01

Objectives In clinical drug development, wakefulness and wake-promotion maybe assessed by a large number of scales and questionnaires. Objective assessment of wakefulness is most commonly made using sleep latency/maintenance of wakefulness tests, polysomnography and/or behavioral measures. The purpose of the present review is to highlight the degree of overlap in the assessment of wakefulness and cognition, with consideration of assessment techniques and the underlying neurobiology of both concepts. Design Reviews of four key areas were conducted: commonly used techniques in the assessment of wakefulness; neurobiology of sleep/wake and cognition; targets of wake promoting and/or cognition enhancing drugs; and ongoing clinical trials investigating wake promoting effects. Results There is clear overlap between the assessment of wakefulness and cognition. There are common techniques which may be used to assess both concepts; aspects of the neurobiology of both concepts may be closely related; and wake promoting drugs may have nootropic properties (and vice-versa). Clinical trials of wake promoting drugs often, though not routinely, assess aspects of cognition. Conclusions Routine and broad assessment of cognition in the development of wake promoting drugs may reveal important nootropic effects, which are not secondary to alertness/wakefulness, whilst existing cognitive enhancers may have under explored or unknown wake promoting properties. PMID:19565524

Molecular determinants for drug-receptor interactions. Part 2. An ab initio molecular orbital and dipole moment study of the novel nootropic agent piracetam (2-oxopyrrolidin-1-ylacetamide)

NASA Astrophysics Data System (ADS)

Lumbroso, H.; Liégeois, C.; Pappalardo, G. C.; Grassi, A.

From the ab initio molecular energies of the possible conformers and from a classical dipole moment analysis of 2-oxopyrrolidin-l-ylacetamide (μ = 4.02 D in dioxan at 30.0°C), the preferred conformation in solution of this novel nootropic agent has been determined. The exocyclic N-CH 2 bond is rotated in one sense by 90° and the exocyclic CH 2-C bond rotated in the same sense by 120° from the "planar" ( OO)- cis conformation. The structures of the two enantiomers in solution differ from that of the crystalline molecule.

The fluorescence and resonance Rayleigh scattering spectra study on the interactions of palladium (II)-Nootropic chelate with Congo red and their analytical applications

NASA Astrophysics Data System (ADS)

Chen, Fang; Peng, Jingdong; Liu, Shaopu; Peng, Huanjun; Pan, Ziyu; Bu, Lingli; Xiao, Huan; Zhang, Ruiwen

2017-04-01

A highly sensitive detection approach of resonance Rayleigh scattering spectra (RRS) is firstly applied to analyzing nootropic drugs including piracetam (PIR) and oxiracetam (OXI). In HCl-NaAc buffer solution (pH = 3.0), the OXI chelated with palladium (II) to form the chelate cation [Pd2·OXI]2 +, and then reacted with Congo red (CGR) by virtue of electrostatic attraction and hydrophobic force to form binary complex [Pd2·OXI]. CGR2, which could result in the great enhancement of RRS. The resonance Rayleigh scattering signal was recorded at λex = λem = 375 nm. This mixture complex not only has higher RRS, but also makes contribution to significant increase of fluorescence, and the same phenomena also were discovered in PIR. The enhanced RRS intensity is in proportion to the PIR and OXI concentration in the range of 0.03-3.0 μg mL- 1, and the detection limit (DL) of RRS method for PIR and OXI is 2.3 ng mL- 1 and 9.7 ng mL- 1. In addition, the DL of fluorescence method for PIR and OXI is 8.4 μg mL- 1 and 19.5 μg mL- 1. Obviously, the RRS is the highly sensitive method, and the recoveries of the two kinds of nootropic drugs were range from 100.4% to 101.8.0% with RSD (n = 5) from 1.1% to 3.1% by RRS method. This paper not only investigated the optimum conditions for detecting nootropics with using RRS method, but also focused on the reasons for enhancing RRS intensity and the reaction mechanism, which in order to firm and contract the resultant. Finally, The RRS method has been applied to detect nootropic drugs in human urine samples with satisfactory results. Fig. S2. The effect of ionic strength: Pd (II)-CGR system (curve a); Pd (II)-OXI-CGR system (curve b); Pd (II)-PIR- CGR system (curve c). Pd (II): 2.0 × 10- 4 mol L- 1; CGR: 1.0 × 10- 5 mol L- 1; OXI: 1.5 μg mL- 1; PIR: 2 μg mL- 1; NaCl: 1 mol L- 1. Fig. S3. The effect of time: Pd (II)-OXI-CGR system (curve a); Pd (II)-PIR-CGR system (curve b). Pd (II): 2.0 × 10- 4 mol L- 1; CGR: 1.0 × 10- 5 mol L- 1; OXI: 1.5 μg mL- 1. Fig. S4 Absorption spectra for Pd (II)-Nootropic-CGR system. Measured using a water blank: (1) OXI; (2) GIR; (3) OXI-CGR; (4) Pd (II); (5) Pd(II)-OXI; (6) PIR-OXI-CGR, OXI: 1.0 μg mL- 1; Pd (II) concentration: 3.0 × 10- 4 mol L- 1; CGR concentration: 1.0 × 10- 5 mol L- 1; HCl-NaAc: pH 3.0.

Nootropic, anxiolytic and CNS-depressant studies on different plant sources of shankhpushpi.

PubMed

Malik, Jai; Karan, Maninder; Vasisht, Karan

2011-12-01

Shankhpushpi, a well-known drug in Ayurveda, is extensively used for different central nervous system (CNS) effects especially memory enhancement. Different plants are used under the name shankhpushpi in different regions of India, leading to an uncertainty regarding its true source. Plants commonly used under the name shankhpushpi are: Convolvulus pluricaulis Chois., Evolvulus alsinoides Linn., both from Convolvulaceae, and Clitoria ternatea Linn. (Leguminosae). To find out the true source of shankhpushpi by evaluating and comparing memory-enhancing activity of the three above mentioned plants. Anxiolytic, antidepressant and CNS-depressant activities of these three plants were also compared and evaluated. The nootropic activity of the aqueous methanol extract of each plant was tested using elevated plus-maze (EPM) and step-down models. Anxiolytic, antidepressant and CNS-depressant studies were evaluated using EPM, Porsolt?s swim despair and actophotometer models, respectively. C. pluricaulis extract (CPE) at a dose of 100 mg/kg, p.o. showed maximum nootropic and anxiolytic activity (p < 0.001). E. alsinoides extract (EAE) and C. ternatea extract (CTE) showed maximum memory-enhancing and anxiolytic activity (p < 0.001) at 200 and 100?mg/kg, respectively. Amongst the three plants, EAE and CTE showed significant (p < 0.05), while CPE did not exhibit any antidepressant activity. All the three plants showed CNS-depressant action at higher dose levels. The above results showed all the three plants possess nootropic, anxiolytic and CNS-depressant activity. The results of memory-enhancing activity suggest C. pluricaulis to be used as true source of shankhpushpi.

Cognitive enhancers (Nootropics). Part 3: drugs interacting with targets other than receptors or enzymes. Disease-modifying drugs. Update 2014.

PubMed

Froestl, Wolfgang; Pfeifer, Andrea; Muhs, Andreas

2014-01-01

Scientists working in the field of Alzheimer's disease and, in particular, cognitive enhancers, are very productive. The review "Drugs interacting with Targets other than Receptors or Enzymes. Disease-modifying Drugs" was accepted in October 2012. In the last 20 months, new targets for the potential treatment of Alzheimer's disease were identified. Enormous progress was realized in the pharmacological characterization of natural products with cognitive enhancing properties. This review covers the evolution of research in this field through May 2014.

Pharmacological validation of in-silico guided novel nootropic potential of Achyranthes aspera L.

PubMed

Gawande, Dinesh Yugraj; Goel, Rajesh Kumar

2015-12-04

Achyranthes aspera (A. aspera) has been used as a brain tonic in folk medicine. Although, ethnic use of medicinal plant has been basis for drug discovery from medicinal plants, but the available in-silico tools can be useful to find novel pharmacological uses of medicinal plants beyond their ethnic use. To validate in-silico prediction for novel nootropic effect of A. aspera by employing battery of tests in mice. Phytoconstituents of A. aspera reported in Dictionary of Natural Product were subjected to in-silico prediction using PASS and Pharmaexpert. The nootropic activity predicted for A. aspera was assessed using radial arm maze, passive shock avoidance and novel object recognition tests in mice. After behavioral evaluation animals were decapitated and their brains were collected and stored for estimation of glutamate levels and acetylcholinesterase activity. In-silico activity spectrum for majority of A. aspera phytoconstituents exhibited excellent prediction score for nootropic activity of this plant. A. aspera extract treatment significantly improved the learning and memory as evident by decreased working memory errors, reference memory errors and latency time in radial arm maze, step through latency in passive shock avoidance and increased recognition index in novel object recognition were observed, moreover significantly enhanced glutamate levels and reduced acetylcholinesterase activity in hippocampus and cortex were observed as compared to the saline treated group. In-silico and in-vivo results suggest that A. aspera plant may improve the learning and memory by modulating the brain glutamatergic and cholinergic neurotransmission. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

The nootropic properties of ginseng saponin Rb1 are linked to effects on anxiety.

PubMed

Churchill, James D; Gerson, Jennifer L; Hinton, Kendra A; Mifek, Jennifer L; Walter, Michael J; Winslow, Cynthia L; Deyo, Richard A

2002-01-01

Previous studies have shown that crude ginseng extracts enhance performance on shock-motivated tasks. Whether such performance enhancements are due to memory-enhancing (nootropic) properties of ginseng, or to other non-specific effects such as an influence on anxiety has not been determined. In the present study, we evaluated both the nootropic and anxiolytic effects of the ginseng saponin Rb1. In the first experiment, 80 five-day-old male chicks received intraperitoneal injections of 0, 0.25, 2.5 or 5.0 mg/kg Rb1. Performance on a visual discrimination task was evaluated 15 minutes, 24 and 72 hours later. Acquisition of a visual discrimination task was unaffected by drug treatment, but the number of errors was significantly reduced in the 0.25 mg/kg group during retention trials completed 24 and 72 hours after injection. Animals receiving higher dosages showed trends towards enhancement initially, but demonstrated impaired performance when tested 72 hours later. Rb1 had no effect on response rates or body weight. In the second experiment, 64 five-day-old male chicks received similar injections of Rb1 (0, 0.25, 2.5 or 5.0 mg/kg) and separation distress was evaluated 15 minutes, 24 and 72 hours later. Rb1 produced a change in separation distress that depended on the dose and environmental condition under which distress was recorded. These data suggest that Rb1 can improve memory for a visual discrimination task and that the nootropic effect may be related to changes in anxiety.

Chromatographic behaviour predicts the ability of potential nootropics to permeate the blood-brain barrier.

PubMed

Farsa, Oldřich

2013-01-01

The log BB parameter is the logarithm of the ratio of a compound's equilibrium concentrations in the brain tissue versus the blood plasma. This parameter is a useful descriptor in assessing the ability of a compound to permeate the blood-brain barrier. The aim of this study was to develop a Hansch-type linear regression QSAR model that correlates the parameter log BB and the retention time of drugs and other organic compounds on a reversed-phase HPLC containing an embedded amide moiety. The retention time was expressed by the capacity factor log k'. The second aim was to estimate the brain's absorption of 2-(azacycloalkyl)acetamidophenoxyacetic acids, which are analogues of piracetam, nefiracetam, and meclofenoxate. Notably, these acids may be novel nootropics. Two simple regression models that relate log BB and log k' were developed from an assay performed using a reversed-phase HPLC that contained an embedded amide moiety. Both the quadratic and linear models yielded statistical parameters comparable to previously published models of log BB dependence on various structural characteristics. The models predict that four members of the substituted phenoxyacetic acid series have a strong chance of permeating the barrier and being absorbed in the brain. The results of this study show that a reversed-phase HPLC system containing an embedded amide moiety is a functional in vitro surrogate of the blood-brain barrier. These results suggest that racetam-type nootropic drugs containing a carboxylic moiety could be more poorly absorbed than analogues devoid of the carboxyl group, especially if the compounds penetrate the barrier by a simple diffusion mechanism.

Nootropic agents stimulate neurogenesis. Brain Cells, Inc.: WO2007104035.

PubMed

Taupin, Philippe

2009-05-01

The application is in the field of adult neurogenesis, neural stem cells and cellular therapy. It aims to characterize the activity of nootropic agents on adult neurogenesis in vitro. Nootropic agents are substances improving cognitive and mental abilities. AMPA (alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate) and nootropic agents were assessed for the potential to differentiate human neural progenitor and stem cells into neuronal cells in vitro. They were also tested for their behavioural activity on the novel object recognition task. AMPA, piracetam, FK-960 and SGS-111 induce and stimulate neuronal differentiation of human-derived neural progenitor and stem cells. SGS-111 increases the number of visits to the novel object. The neurogenic activity of piracetam and SGS-111 is mediated through AMPA receptor. The neurogenic activity of SGS-111 may contribute and play a role in its nootropic activity. These results suggest that nootropic agents may elicit some of their effects through their neurogenic activity. The application claims the use of nootropic agents for their neurogenic activity and for the treatment of neurological diseases, disorders and injuries, by stimulating or increasing the generation of neuronal cells in the adult brain.

Cognitive enhancers (nootropics). Part 2: drugs interacting with enzymes. Update 2014.

PubMed

Froestl, Wolfgang; Muhs, Andreas; Pfeifer, Andrea

2014-01-01

Scientists working in the field of Alzheimer's disease and, in particular, cognitive enhancers are very productive. The review on Drugs interacting with Enzymes was accepted in August 2012. However, this field is very dynamic. New potential targets for the treatment of Alzheimer's disease were identified. This update describes drugs interacting with 60 enzymes versus 43 enzymes in the first paper. Some compounds progressed in their development, while many others were discontinued. The present review covers the evolution of research in this field through April 2014.

[Preclinical prognosis of pyracetam and picamilon safety based on acute toxicity data].

PubMed

Bugaeva, L I; Spasov, A A; Verovskiĭ, V E; Iezhitsa, I N

2003-01-01

A comparative acute toxicity test of the nootropic drugs piracetam and picamilon was performed on rats. The study was based on the principles of integral evaluation of the drug effect upon the functional and behavioral state of animals. It was found that the conventional therapeutic index does not coincide with the actual therapeutic activity range. Piracetam and picamilon, while exhibiting significantly different toxicity, are characterized by approximately equal ranges of the therapeutic activity.

Nootropic activity of Crataeva nurvala Buch-Ham against scopolamine induced cognitive impairment

PubMed Central

Bhattacharjee, Atanu; Shashidhara, Shastry Chakrakodi; Saha, Santanu

2015-01-01

Loss of cognition is one of the age related mental problems and a characteristic symptom of neurodegenerative disorders like Alzheimer’s. Crataeva nurvala Buch-Ham, a well explored traditional Indian medicinal plant of Westernghats, is routinely used as folkloric medicine to treat various ailments in particular urolithiasis and neurological disorders associated with cognitive dysfunction. The objective of the study was to evaluate the nootropic activity of Crataeva nurvala Buch-Ham stem bark in different learning and memory paradigm viz. Elevated plus maze and Y-maze against scopolamine induced cognitive impairment. Moreover, to elucidate possible mechanism, we studied the influence of Crataeva nurvala ethanolic extract on central cholinergic activity via estimating the whole brain acetyl cholinesterase enzyme. Ethanolic extracts of Crataeva nurvala (100, 200 and 400 mg/kg body weight) were administered to adult Wistar rats for successive seven days and the acquisition, retention and retrieval of spatial recognition memory was determined against scopolamine (1 mg/kg, i.p.) induced amnesia through exteroceptive behavioral models viz. Elevated plus maze and Y-maze models. Further, whole brain acetyl cholinesterase enzyme was estimated through Ellman’s method. Pretreatment with Crataeva nurvala ethanolic extract significantly improved spatial learning and memory against scopolamine induced amnesia. Moreover, Crataeva nurvala extract decreased rat brain acetyl cholinesterase activity in a dose dependent manner and comparable to the standard drug Piracetam. The results indicate that ethanolic extract of Crataeva nurvala might be a useful as nootropic agent to delay the onset and reduce the severity of symptoms associated with dementia and Alzheimer’s disease. The underlying mechanism of action of its nootropic potentiality might be attributed to its anticholinesterase property. PMID:27065767

A novel CaV2.2 channel inhibition by piracetam in peripheral and central neurons.

PubMed

Bravo-Martínez, Jorge; Arenas, Isabel; Vivas, Oscar; Rebolledo-Antúnez, Santiago; Vázquez-García, Mario; Larrazolo, Arturo; García, David E

2012-10-01

No mechanistic actions for piracetam have been documented to support its nootropic effects. Voltage-gated calcium channels have been proposed as a promising pharmacological target of nootropic drugs. In this study, we investigated the effect of piracetam on Ca(V)2.2 channels in peripheral neurons, using patch-clamp recordings from cultured superior cervical ganglion neurons. In addition, we tested if Ca(V)2.2 channel inhibition could be related with the effects of piracetam on central neurons. We found that piracetam inhibited native Ca(V)2.2 channels in superior cervical ganglion neurons in a dose-dependent manner, with an IC(50) of 3.4 μmol/L and a Hill coefficient of 1.1. GDPβS dialysis did not prevent piracetam-induced inhibition of Ca(V)2.2 channels and G-protein-coupled receptor activation by noradrenaline did not occlude the piracetam effect. Piracetam altered the biophysical characteristics of Ca(V)2.2 channel such as facilitation ratio. In hippocampal slices, piracetam and ω-conotoxin GVIA diminished the frequency of excitatory postsynaptic potentials and action potentials. Our results provide evidence of piracetam's actions on Ca(V)2.2 channels in peripheral neurons, which might explain some of its nootropic effects in central neurons.

Chromatographic Behaviour Predicts the Ability of Potential Nootropics to Permeate the Blood-Brain Barrier

PubMed Central

Farsa, Oldřich

2013-01-01

The log BB parameter is the logarithm of the ratio of a compound’s equilibrium concentrations in the brain tissue versus the blood plasma. This parameter is a useful descriptor in assessing the ability of a compound to permeate the blood-brain barrier. The aim of this study was to develop a Hansch-type linear regression QSAR model that correlates the parameter log BB and the retention time of drugs and other organic compounds on a reversed-phase HPLC containing an embedded amide moiety. The retention time was expressed by the capacity factor log k′. The second aim was to estimate the brain’s absorption of 2-(azacycloalkyl)acetamidophenoxyacetic acids, which are analogues of piracetam, nefiracetam, and meclofenoxate. Notably, these acids may be novel nootropics. Two simple regression models that relate log BB and log k′ were developed from an assay performed using a reversed-phase HPLC that contained an embedded amide moiety. Both the quadratic and linear models yielded statistical parameters comparable to previously published models of log BB dependence on various structural characteristics. The models predict that four members of the substituted phenoxyacetic acid series have a strong chance of permeating the barrier and being absorbed in the brain. The results of this study show that a reversed-phase HPLC system containing an embedded amide moiety is a functional in vitro surrogate of the blood-brain barrier. These results suggest that racetam-type nootropic drugs containing a carboxylic moiety could be more poorly absorbed than analogues devoid of the carboxyl group, especially if the compounds penetrate the barrier by a simple diffusion mechanism. PMID:23641330

[Electrophysiological correlates of efficacy of nootropic drugs in the treatment of consequences of traumatic brain injury in adolescents].

PubMed

Iznak, E V; Iznak, A F; Pankratova, E A; Zavadenko, N N; Guzilova, L S; Guzilova, Iu I

2010-01-01

To assess objectively a dynamics of brain functional state, EEG spectral power and peak latency of the P300 component of cognitive auditory evoked potentials have been analyzed in adolescents during the course of nootropic therapy of residual asthenic consequences of traumatic brain injury (ICD-10 F07.2). The study included 76 adolescents, aged 12-18 years, who have undergone severe closed head trauma with brain commotion 1/2--5 years ago. Patients have been divided into 3 groups treated during one month with cerebrolysin, piracetam or magne-B6, respectively. After the end of the nootropic therapy, 77% of patients treated with cerebrolysin as well as 50% of patients treated with piracetam and magne-B6 have demonstrated the positive dynamics of their brain functional state that manifested itself in the appearance of occipital EEG alpha rhythm or in the increase of its spectral power; in the normalization of alpha rhythm frequency; in the decrease in the spectral power of slow wave (theta and delta) EEG activity, in the amount (up to the disappearance) of paroxysmal EEG activity, in the EEG response to hyperventilation and in the shortening of the P300 peak latency. Such positive changes of neurophysiological parameters have been associated with the improvement of clinical conditions of patients and correlated significantly with the dynamics of psychometric scores of attention and memory.

The Effects of Anti-Dementia and Nootropic Treatments on the Mortality of Patients with Dementia: A Population-Based Cohort Study in Taiwan.

PubMed

Wu, Chen-Yi; Hu, Hsiao-Yun; Chow, Lok-Hi; Chou, Yiing-Jenq; Huang, Nicole; Wang, Pei-Ning; Li, Chung-Pin

2015-01-01

Few studies have examined the contribution of treatment on the mortality of dementia based on a population-based study. To investigate the effects of anti-dementia and nootropic treatments on the mortality of dementia using a population-based cohort study. 12,193 incident dementia patients were found from 2000 to 2010. Their data were compared with 12,193 age- and sex-matched non-dementia controls that were randomly selected from the same database. Dementia was classified into vascular (VaD) and degenerative dementia. Mortality incidence and hazard ratios (HRs) were calculated. The median survival time was 3.39 years (95% confidence interval [CI]: 2.88-3.79) for VaD without medication, 6.62 years (95% CI: 6.24-7.21) for VaD with nootropics, 3.01 years (95% CI: 2.85-3.21) for degenerative dementia without medication, 8.11 years (95% CI: 6.30-8.55) for degenerative dementia with anti-dementia medication, 6.00 years (95% CI: 5.73-6.17) for degenerative dementia with nootropics, and 9.03 years (95% CI: 8.02-9.87) for degenerative dementia with both anti-dementia and nootropic medications. Compared to the non-dementia group, the HRs among individuals with degenerative dementia were 2.69 (95% CI: 2.55-2.83) without medication, 1.46 (95% CI: 1.39-1.54) with nootropics, 1.05 (95% CI: 0.82-1.34) with anti-dementia medication, and 0.92 (95% CI: 0.80-1.05) with both nootropic and anti-dementia medications. VaD with nootropics had a lower mortality (HR: 1.25, 95% CI: 1.15-1.37) than VaD without medication (HR: 2.46, 95% CI: 2.22-2.72). Pharmacological treatments have beneficial effects for patients with dementia in prolonging their survival.

The Effects of Anti-Dementia and Nootropic Treatments on the Mortality of Patients with Dementia: A Population-Based Cohort Study in Taiwan

PubMed Central

Wu, Chen-Yi; Hu, Hsiao-Yun; Chow, Lok-Hi; Chou, Yiing-Jenq; Huang, Nicole; Wang, Pei-Ning; Li, Chung-Pin

2015-01-01

Background Few studies have examined the contribution of treatment on the mortality of dementia based on a population-based study. Objective To investigate the effects of anti-dementia and nootropic treatments on the mortality of dementia using a population-based cohort study. Methods 12,193 incident dementia patients were found from 2000 to 2010. Their data were compared with 12,193 age- and sex-matched non-dementia controls that were randomly selected from the same database. Dementia was classified into vascular (VaD) and degenerative dementia. Mortality incidence and hazard ratios (HRs) were calculated. Results The median survival time was 3.39 years (95% confidence interval [CI]: 2.88–3.79) for VaD without medication, 6.62 years (95% CI: 6.24–7.21) for VaD with nootropics, 3.01 years (95% CI: 2.85–3.21) for degenerative dementia without medication, 8.11 years (95% CI: 6.30–8.55) for degenerative dementia with anti-dementia medication, 6.00 years (95% CI: 5.73–6.17) for degenerative dementia with nootropics, and 9.03 years (95% CI: 8.02–9.87) for degenerative dementia with both anti-dementia and nootropic medications. Compared to the non-dementia group, the HRs among individuals with degenerative dementia were 2.69 (95% CI: 2.55–2.83) without medication, 1.46 (95% CI: 1.39–1.54) with nootropics, 1.05 (95% CI: 0.82–1.34) with anti-dementia medication, and 0.92 (95% CI: 0.80–1.05) with both nootropic and anti-dementia medications. VaD with nootropics had a lower mortality (HR: 1.25, 95% CI: 1.15–1.37) than VaD without medication (HR: 2.46, 95% CI: 2.22–2.72). Conclusion Pharmacological treatments have beneficial effects for patients with dementia in prolonging their survival. PMID:26098910

[Analysis of the binding capacity of the benzodiazepine site of gabaa receptor in mice C57BL/6 and BALB/C pretreated with anxiolytics].

PubMed

Iarkova, M A

2011-01-01

The level of specific 3H-flunitrazepam binding in synaptosomal membranes of C57BL/6 and BALB/c mice brain underwent to the stress of different types has been studied. Mild stress (Elevated Plus Maze) was shown to induce the decrease of benzodiazepine binding in BALB/c mice only, while the strong one (Exposure to a predator) was revealed to cause this decrease in both strains. Behavioral effects of different non-benzodiazepine drugs possessing anxiolytic properties (Afobazol, Ladasten and Noopept) was accompanied with the normalization of the level of benzodiazepine reception, reduced by the stress of both modalities.

PASS-predicted design, synthesis and biological evaluation of cyclic nitrones as nootropics.

PubMed

Marwaha, Alka; Goel, R K; Mahajan, Mohinder P

2007-09-15

Out of 400 virtually designed imidazoline N-oxides, five cyclic nitrones were selected on the basis of PASS prediction as potent nootropics and were evaluated for their biological activities in albino mice. The selected N-alkyl and aryl-substituted nitrones were found to be excellent nootropics. A series of lead compounds acting as cognition enhancers have been provided, which can be further exploited in search of such New Chemical Entities (NCEs).

Delayed nootropic effects of arginine vasopressin after early postnatal chronic administration to albino rat pups.

PubMed

Kim, P A; Voskresenskaya, O G; Kamensky, A A

2009-06-01

Intranasal administration of arginine vasopressin (10 microg/kg) to albino rat pups had a strong nootropic effect during training with positive and negative reinforcement. This effect was different in animals of various age groups: training with positive reinforcement was improved in "adolescent" rats and pubertal animals, while during training with negative reinforcement, the nootropic effect of the peptide was more prolonged and persisted also in adult animals.

Efficacy of acetylcholinesterase inhibitors versus nootropics in Alzheimer's disease: a retrospective, longitudinal study.

PubMed

Tsolaki, M; Pantazi, T; Kazis, A

2001-01-01

The aim of this study was to investigate the efficacy of nootropics (piracetam, aniracetam, nimodopine and dihydroergicristine) versus acetylcholinesterase inhibitors (AChE-Is) (tacrine and donepezil) in the treatment of Alzheimer's disease. This is a retrospective study of 510 patients with Alzheimer's disease. To determine clinical efficacy of treatment, we used the mean change over time in scores for the following tests: the Mini-Mental State Examination (MMSE); the Cambridge Cognitive Examination for the Elderly; and the Functional Rating Scale for Symptoms of Dementia. In all patients and in patients with severe Alzheimer's disease (baseline MMSE < 11), no significant differences were seen in the neuropsychological test scores between the two treatment groups. In patients with moderate dementia (baseline MMSE between 11 and 20), however, there was a significantly greater deterioration, as shown on the CAMCOG scale, after 12 months' treatment for patients receiving AChE-Is compared with those receiving nootropics (-4.38 for AChE-Is group versus 1.48 for nootropics group). For patients with mild dementia (baseline MMSE score between 21 and 26), there was a significantly greater deterioration on the MMSE scale for each time-point in the nootropics group compared with the AChE-Is group. In conclusion, we did not find any strong evidence that a difference in efficacy exists between AChE-Is and nootropics in the treatment of Alzheimer's disease.

Allosteric potentiation of quisqualate receptors by a nootropic drug aniracetam.

PubMed

Ito, I; Tanabe, S; Kohda, A; Sugiyama, H

1990-05-01

1. Allosteric potentiation of the ionotropic quisqualate (iQA) receptor by a nootropic drug aniracetam (1-p-anisoyl-2-pyrrolidinone) was investigated using Xenopus oocytes injected with rat brain mRNA and rat hippocampal slices. 2. Aniracetam potentiates the iQA responses induced in Xenopus oocytes by rat brain mRNA in a reversible manner. This effect was observed above the concentrations of 0.1 mM. Kainate. N-methyl-D-aspartate and gamma-aminobutyric acid responses induced in the same oocytes were not affected. 3. The specific potentiation of iQA responses was accompanied by an increase in the conductance change of iQA and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) responses, but the affinity of receptors for agonist and the ion-selectivity of the channels (reversal potentials) were not changed. 4. Aniracetam reversibly potentiated the iQA responses recorded intracellularly from the pyramidal cells in the CA1 region of rat hippocampal slices. The excitatory postsynaptic potentials (EPSPs) in Schaffer collateral-commissural-CA1 synapses were also potentiated by aniracetam. 5. Population EPSPs recorded in the mossy fibre-CA3 synapses as well as Schaffer-commissural synapses were also potentiated by aniracetam. The amplitudes of the potentiation were not changed by the formation of long-term potentiation.

Allosteric potentiation of quisqualate receptors by a nootropic drug aniracetam.

PubMed Central

Ito, I; Tanabe, S; Kohda, A; Sugiyama, H

1990-01-01

1. Allosteric potentiation of the ionotropic quisqualate (iQA) receptor by a nootropic drug aniracetam (1-p-anisoyl-2-pyrrolidinone) was investigated using Xenopus oocytes injected with rat brain mRNA and rat hippocampal slices. 2. Aniracetam potentiates the iQA responses induced in Xenopus oocytes by rat brain mRNA in a reversible manner. This effect was observed above the concentrations of 0.1 mM. Kainate. N-methyl-D-aspartate and gamma-aminobutyric acid responses induced in the same oocytes were not affected. 3. The specific potentiation of iQA responses was accompanied by an increase in the conductance change of iQA and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) responses, but the affinity of receptors for agonist and the ion-selectivity of the channels (reversal potentials) were not changed. 4. Aniracetam reversibly potentiated the iQA responses recorded intracellularly from the pyramidal cells in the CA1 region of rat hippocampal slices. The excitatory postsynaptic potentials (EPSPs) in Schaffer collateral-commissural-CA1 synapses were also potentiated by aniracetam. 5. Population EPSPs recorded in the mossy fibre-CA3 synapses as well as Schaffer-commissural synapses were also potentiated by aniracetam. The amplitudes of the potentiation were not changed by the formation of long-term potentiation. PMID:1975272

Pharmacological and neurophysiological aspects of space/motion sickness

NASA Technical Reports Server (NTRS)

Lucot, James B.; Crampton, George H.

1991-01-01

A motorized motion testing device modeled after a Ferris wheel was constructed to perform motion sickness tests on cats. Details of the testing are presented, and some of the topics covered include the following: xylazine-induced emesis; analysis of the constituents of the cerebrospinal fluid (CSF) during motion sickness; evaluation of serotonin-1A (5-HT sub 1A) agonists; other 5HT receptors; antimuscarinic mechanisms; and antihistaminergic mechanisms. The ability of the following drugs to reduce motion sickness in the cats was examined: amphetamines, adenosinergic drugs, opioid antagonists, peptides, cannabinoids, cognitive enhancers (nootropics), dextromethorphan/sigma ligands, scopolamine, and diphenhydramine.

[Functional-behavioral profile of new cyclic GABA analogs in acute toxicity tests].

PubMed

Bugaeva, L I; Spasov, A A; Verovskiĭ, V E

2004-01-01

The properties of karphedone and phepyrone--new phenyl derivatives of pyrrolidone possessing nootropic activity--were studied in the course of the acute toxicity tests on rats. The drug effects were evaluated in terms of their integral influence on the state and behavior of test animals. The real therapeutic range and the profit/risk ratio of karphedone were comparable with those of the reference drug pyracetam and exceeded by a factor of 1.3 the corresponding values for phepyrone (irrespective of the LD50 values). The results give grounds for the further preclinical investigation of karphedone.

[Nootropic and analgesic effects of Semax following different routes of administration].

PubMed

Manchenko, D M; Glazova, N Iu; Levitskaia, N G; Andreeva, L A; Kamenskiĭ, A A; Miasoedov, N F

2010-10-01

Heptapeptide Semax (MEHFPGP) is the fragment of ACTH(4-10) analogue with prolonged neurotropic activity. The aim of the present work was to study the Semax effects on learning capability and pain sensitivity in white rats following intraperitoneal and intranasal administration in different doses. Semax nootropic effects were studied in the test of acquisition of passive avoidance task. Pain sensitivity was estimated in Randall-Selitto paw-withdrawal test. It was shown that Semax exerts nootropic and analgesic activities following intraperitoneal administration. Analysis of dependence of these effects on dose resulted in different dose-response curves. Following intranasal administration, Semax was more potent in learning improvement compared to intraperitoneal administration. The peptide failed to affect the animal pain sensitivity following intranasal administration as opposed to intraperitoneal administration. The data obtained suggest different mechanisms and brain structures involved in realization of the nootropic and analgesic effects of Semax.

Neurocognitive Effect of Nootropic Drug Brahmi (Bacopa monnieri) in Alzheimer's Disease

PubMed Central

Chaudhari, Kaustubh S.; Tiwari, Nishant R.; Tiwari, Rakesh R.; Sharma, Rohan S.

2017-01-01

Alzheimer's disease (AD) is a progressive neurodegenerative disease of the elderly. The rapid increase in its incidence has necessitated development of newer drugs. Ayurvedic herbal medications are increasingly researched due to their biosafety profile and usefulness in cognitive impairment. In this article, we critically reviewed one such Medhya Rasayana (nootropic drug) Brahmi-derived from extract of Bacopa monnieri (EBm). Studies have shown that EBm promotes free radical scavenger mechanisms and protects cells in prefrontal cortex, hippocampus, and striatum against cytotoxicity and DNA damage implicated in AD. It also reduces lipoxygenase activity reducing lipid peroxidation, increases glutathione peroxidase and chelates iron. Administration of EBm was seen to protect the cholinergic neurons and reduce anticholinesterase activity comparable to donepezil, rivastigmine, and galantamine. It also reduces hippocampal β-amyloid deposition and stress-induced hippocampal damage. The neuroprotective effect of EBm is also due to nitric oxide-mediated cerebral vasodilation. EBm improved the total memory score and maximum improvement was seen in logical memory and paired associate learning in humans and reversed phenytoin-induced memory impairment in experimental model. EBm has not shown any serious clinical, neurological, hematological complications, or vital organs damage in experimental studies. Rats showed marked reduction in fertility; however, libido was unaffected. There is no experimental evidence of genotoxicity or teratogenesis by use of EBm. Mild nausea and gastrointestinal upset are seen in humans. Brahmi promises to be a novel agent in AD; however, further human trials are recommended to verify the efficacy and rule out any side effects as evidenced by the experimental models. PMID:28588366

S-52, a novel nootropic compound, protects against β-amyloid induced neuronal injury by attenuating mitochondrial dysfunction.

PubMed

Gao, Xin; Zheng, Chun Yan; Qin, Guo Wei; Tang, Xi Can; Zhang, Hai Yan

2012-10-01

Accumulating evidence suggests that β-amyloid (Aβ)-induced oxidative DNA damage and mitochondrial dysfunction may initiate and contribute to the progression of Alzheimer's disease (AD). This study evaluated the neuroprotective effects of S-52, a novel nootropic compound, on Aβ-induced mitochondrial failure. In an established paradigm of moderate cellular injury induced by Aβ, S-52 was observed to attenuate the toxicity of Aβ to energy metabolism, mitochondrial membrane structure, and key enzymes in the electron transport chain and tricarboxylic acid cycle. In addition, S-52 also effectively inhibited reactive oxygen species accumulation dose dependently not only in Aβ-harmed cells but also in unharmed, normal cells. The role of S-52 as a scavenger of free radicals is involved in the antioxidative effect of this compound. The beneficial effects on mitochondria and oxidative stress extend the neuroprotective effects of S-52. The present study provides crucial information for better understanding the beneficial profiles of this compound and discovering novel potential drug candidates for AD therapy. Copyright © 2012 Wiley Periodicals, Inc.

Nootropic and anxiolytic activity of saponins of Albizzia lebbeck leaves.

PubMed

Une, H D; Sarveiya, V P; Pal, S C; Kasture, V S; Kasture, S B

2001-01-01

The effect of saponin containing, n-butanolic fraction (BF), extracted from dried leaves of Albizzia lebbeck, was studied on cognitive behavior and anxiety in albino mice. The elevated plus maze was used for assessment of both nootropic and anxiolytic activity. The nootropic activity was evaluated by recording the effect of BF (0, 10, 25, and 50 mg/kg) on the transfer latency, whereas anxiolytic activity was assessed by studying its effect on the duration of occupancy in the closed arm. Results showed significant improvement in the retention ability of the normal and amnesic mice as compared to their respective controls. Animals treated with BF (25 mg/kg) spent more time in the open arm in a dose-dependent manner. The BF was without any significant effect on motor coordination. However, it significantly inhibited passivity and hypothermia induced by baclofen (10 mg/kg), a GABA(B) agonist. The data emanated in the present study suggests involvement of gamma-aminobutyric acid (GABA) in the nootropic and anxiolytic activity of saponins obtained from A. lebbeck.

Effect of donepezil in patients with Alzheimer's disease previously untreated or treated with memantine or nootropic agents in Germany: an observational study.

PubMed

Klinger, Tatjana; Ibach, Bernd; Schoenknecht, Peter; Kamleiter, Martin; Silver, Gabrielle; Schroeder, Johannes; Mielke, Ruediger

2005-05-01

This open-label, prospective, observational, Post-Marketing Surveillance (PMS) study assessed the efficacy and safety of donepezil in patients who had been switched from therapies currently used in Germany to treat Alzheimer's disease (AD), such as memantine and nootropics, due to insufficient efficacy or poor tolerability. A treatment-naive population was included as a comparator. Patients with AD were treated with donepezil and observed for a period of approximately 3 months. A cognitive assessment was made using the Mini-Mental State Examination (MMSE). Quality of life (QoL) was assessed by the investigators who answered the question 'How did therapy with donepezil influence the QoL of the patient and/or his family over the observation period?' and was graded using three ratings: improved/unchanged/worsened. Adverse events (AEs) were also monitored. A total of 913 patients entered the study (mean +/- SD MMSE score 18.03 +/- 5.34). Efficacy assessments were analyzed for three groups: an overall group of patients who had received any form of prior AD drug therapy (N+ group; n = 709); a subgroup of patients from the N+ group who had received prior memantine therapy only (M+ group; n = 111) and patients who were drug treatment naive (N- group; n = 204). In the evaluable population donepezil improved MMSE scores by 2.21 +/- 3.47 points on average, with similar improvements observed in all three groups. QoL was judged to be improved in at least 70% of patients, again with similar results obtained for all three groups. Donepezil was well tolerated, with 85 of 913 (9.3%) patients reporting AEs. The most common AEs were those typically seen with cholinergic therapies (i.e., diarrhoea, vomiting and nausea). In this observational PMS study, donepezil was shown to be efficacious and well tolerated in patients who were being insufficiently treated with memantine or nootropic therapy. The magnitude of response was similar to that observed in patients who were previously treatment naive, suggesting prior medication does not effect donepezil's efficacy.

Nootropic activity of extracts from wild and cultivated Alfredia cernua.

PubMed

Mustafin, R N; Shilova, I V; Suslov, N I; Kuvacheva, N V; Amelchenko, V P

2011-01-01

Antihypoxic and nootropic activities of extracts from aerial parts of wild and cultivated Alfredia cernua (L.) Cass. were studied on the models of pressure chamber hypoxia, open field test, and passive avoidance conditioning. The extracts of Alfredia cernua promoted retention of the orientation reflex and passive avoidance conditioned response and normalized orientation and exploratory activities disordered as a result of hypoxic injury. The efficiency of the extracts was superior to that of piracetam by the effect on retention of passive avoidance response throughout the greater part of the experiment. Nootropic activity of cultivated Alfredia cernua was not inferior to that of the wild plant.

[The effect of the new nootropic dipeptide GVS-111 in different functional disorders of the escape reaction].

PubMed

Inozemtsev, A N; Trofimov, S S; Borlikova, G G; Firova, F A; Pragina, L L; Gudasheva, T A; Ostrovskaia, R U; Tushmalova, N A; Voronina, T A

1998-01-01

The authors studied the effect of a new nootropic agent with anxiolytic properties GVS-111 (ethyl ether N-phenylacetyl-L-prolylglycine) on formation of the avoidance reaction (AR) in rats and its functional disorders which were induced by two methods. In one case the stereotype of the relations between the stimulus, reaction and its consequence which developed during the experiment were urgently disturbed: the change of the animal to the other half of the chamber in response to a conditioned stimulus did not lead to its cutting off and prevention of the electropain stimulation for three successive combinations (AR error). In another case the spatial stereotype of the experiment was altered by changing the place of the opening through which the animal avoided the stimulus (spatial remodeling). Intraperitoneal injection of GVS-111 (0.1 mg/kg/day) improved the learning, but the effect differed from experiment to experiment. Along with this, the dipeptide prevented AR disturbance during the error and quickened restoration of the habit in spatial remodeling. It was shown earlier that AR disorders during an error are prevented by anxiolytics and nootropic agents but during spatial remodeling only by nootropic agents. It may be assumed that the positive effect of GSV-111 on AR in functional disorders is due to its nootropic effect.

Antidepressant, psychostimulant, and nootropic effects of major and trace element composition.

PubMed

Afanasieva, O G; Suslov, N I; Shilova, I V

2013-06-01

The antidepressant, psychostimulant, and nootropic effects of a composition of major and trace elements including KCl, RbNO3, magnesium sulfate, and zinc sulfate were studied on the models of behavioural despair (Porsolt test) and conditioned passive avoidance test. The preparation was found to shorten the immobilization time in the Porsolt test and promote retention of the conditioned passive avoidance. The most pronounced psychostimulant effect of the substance was observed at a dose of 4.68 mg/kg and the most pronounced antidepressant effect was found at a dose of 18.72 mg/kg. Maximum nootropic activity of the preparation was found at a dose of 93.6 mg/kg.

Nootropic Effects of Filipendula Vulgaris Moench Water Extract Fractions.

PubMed

Shilova, I V; Suslov, N I; Amelchenko, V P

2015-07-01

Nootropic activity of water extract fractions from aerial parts of Filipendula vulgaris Moench was demonstrated on the models of hermetic volume hypoxia, conditioned passive avoidance response, open field test, and forced swimming with a load. The fractions stimulated hypoxic resistance, normalized orientation and exploratory behavior, improved conditioned response reproduction during testing after hypoxic injury, and increased exercise tolerance. Fractionation of the extract led to dissociation of the effect components, which suggests that individual constituents have specific characteristics. Ethylacetate fraction exhibited most pronounced nootropic activity and was superior to plant extract by some characteristics. The detected effects seemed to be caused by modulation of the hippocampus activity the under the effects of phenol and triterpene compounds.

Evaluation of antibacterial, antioxidant and nootropic activities of Tiliacora racemosa Colebr. leaves: In vitro and in vivo approach.

PubMed

T, Vivek Kumar; M, Vishalakshi; M, Gangaraju; Das, Parijat; Roy, Pratiti; Banerjee, Anindita; Dutta Gupta, Sayan

2017-02-01

The antibacterial and antioxidant potential of Tiliacora racemosa leaf extracts in various solvents (methanolic, hexane, chloroform and ethyl acetate) was determined. Additionally, the presence of bisbenzylisoquinoline alkaloids in the plant prompted us to evaluate the nootropic activity of the methanolic extract in mice. Further, we seek to verify the nootropic effect by examining the anticholinesterase inhibition potential of the methanolic extract. The leaf extracts in various solvents were evaluated for their antibacterial and antioxidant activity by agar diffusion technique and α, α-diphenyl-β-picrylhydrazyl (DPPH) free radical scavenging method, respectively. The ex vivo acetylcholine esterase inhibitory activity of the methanolic extract was carried out by Ellman's method in male Wistar rats. The nootropic capacity of the methanolic extract was examined in Swiss albino mice by utilizing the diazepam induced acute amnesic model. The chloroform/n-hexane and ethyl acetate fraction showed promising antioxidant and antibacterial (Gram positive and Gram negative bacteria) property, respectively. The methanolic extract was able to diminish the amnesic effect induced by diazepam (1mg/kg i.p.) in mice. The extract also showed significant acetyl cholinesterase inhibition in rats. The findings prove that the memory enhancing capability is due to increased acetyl choline level at the nerve endings. The strong antioxidant nature and potential nootropic activity shown by the extract suggests its future usage in the treatment of neurodegenerative disorders such as dementia and Alzheimer. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Acetylcholinesterase inhibitory activity of Thai traditional nootropic remedy and its herbal ingredients.

PubMed

Tappayuthpijarn, Pimolvan; Itharat, Arunporn; Makchuchit, Sunita

2011-12-01

The incidence of Alzheimer disease (AD) is increasing every year in accordance with the increasing of elderly population and could pose significant health problems in the future. The use of medicinal plants as an alternative prevention or even for a possible treatment of the AD is, therefore, becoming an interesting research issue. Acetylcholinesterase (AChE) inhibitors are well-known drugs commonly used in the treatment of AD. The aim of the present study was to screen for AChE inhibitory activity of the Thai traditional nootropic recipe and its herbal ingredients. The results showed that ethanolic extracts of four out of twenty-five herbs i.e. Stephania pierrei Diels. Kaempfera parviflora Wall. ex Baker, Stephania venosa (Blume) Spreng, Piper nigrum L at 0.1 mg/mL showed % AChE inhibition of 89, 64, 59, 50; the IC50 were 6, 21, 29, 30 microg/mL respectively. The other herbs as well as combination of the whole recipe had no synergistic inhibitory effect on AChE activity. However some plants revealed antioxidant activity. More research should have be performed on this local wisdom remedy to verify the uses in scientific term.

[Peptidergic nootropic therapy in cerebral palsy associated with epilepsy].

PubMed

Kholin, A A; Zavadenko, N N; Il Ina, E S; Kolpakchi, L M; Fedonyuk, I D; Bembeeva, R C; Esipova, E S

To assess the efficacy and safety of сortexin in the treatment of children with cerebral palsy (CP) combined with epilepsy. Eighty-four patients (55 boys and 29 girls), aged from 1 to 11 years, with CP combined with epilepsy received cortexin together with antiepileptic drugs (AEDs). Cortexin was administered in doses of 5-10 mg depending on the patient's age and body weight intramuscularly during hospitalization. Cortexin as add-on to AEDs reduced for more than two times the number of seizures, along with improvement of motor function, in 31 (36.9%) patients. The improvement of motor function, but without a significant decrease in epileptic seizures, was achieved in 15 (17.8%) of the patients. Reduction of epileptic seizures frequency (>2 times), but without a significant effect on motor function, was observed in 14 cases (16.7%). Twenty-three patients (27.4%) did not respond the therapy. The aggravation of epileptic seizures during cortexin therapy was observed in only 1 girl with West syndrome (1.2%), and this was significantly lower than the probability of seizures aggravation on AED. Polypeptide nootropic medication cortexin demonstrated efficacy and safety as adjunctive therapy in children with CP combined with epilepsy.

Pharmacokinetics of new nootropic acylprolyldipeptide and its penetration across the blood-brain barrier after oral administration.

PubMed

Boiko, S S; Ostrovskaya, R U; Zherdev, V P; Korotkov, S A; Gudasheva, T A; Voronina, T A; Seredenin, S B

2000-04-01

Pharmacokinetics of GVS-111, a new acylprolyldipeptide with nootropic properties and its penetration across the blood-brain barrier were studied in rats using HPLC. It was found that the dipeptide is absorbed in the gastrointestinal tract, enters the circulation, and penetrates through the blood-brain barrier in an unmodified state.

[The effect of bemitil on conditioned-reflex memory in normal rats and under stress exposures].

PubMed

Pragina, L L; Tushmalova, N A; Inozemtsev, A N; Smirnov, A V

1999-01-01

The authors studied the effect of the actoprotector bemitil on the conditional-reflex memory of rats and its functional disorder by disturbance of the cause-effect (abatement of the avoidance reaction) or space relations. Intraperitoneal injections of 1.8 mg/kg of bemitil were given daily 30 min before the experiment. The training of animals improved authentically from experiment to experiment. Thus, the drug, possesses the nootropic properties. Exposure to stressogenic factors of various depth demonstrated the stress-protective effect of bemitil.

Towards better brain management: nootropics.

PubMed

Malik, Ruchi; Sangwan, Abhijeet; Saihgal, Ruchika; Jindal, Dharam Paul; Piplani, Poonam

2007-01-01

The learning and memory deficits have been recognized as severe and consistent neurological disorders associated with numerous neurodegenerative states. Research in this area has gained momentum only in the recent past after the biochemical and physiological basis of these processes have been understood. A considerable alteration in the neurotransmission is a consistent finding in cognitive disorders. Therefore, many therapeutic strategies to augment the concentration of neurotransmitters in brain such as cholinergic agents, biogenic amines and neuropeptides etc. have been evaluated in cognitive deficits. CNS modulators are the type of antiamnesics that act via modulation of the neurological processes underlying memory storage. These include psychostimulants, excitatory amino acids and most important of all "nootropics". Nootropics are a heterogeneous group of compounds of diverse chemical composition and biological function that allegedly facilitate learning and memory or overcome natural or induced cognitive impairments. The literature survey incorporated in this article hallmarks the success achieved in the design and development of potential nootropic agents. Additionally, this review is an attempt towards discussing various approaches available to enhance memory, along with the classification of the known memory enhancers, authors research work towards various structural modifications carried out and the biological screening.

[Effects of nootropic agents on visual functions and lacrimal antioxidative activity in patients with primary open-angle glaucoma].

PubMed

Davydova, N G; Kuznetsova, T P; Borisova, S A; Abdulkadyrova, M Zh

2006-01-01

The paper presents the results of an investigation of the effect of the nootropic agents pantogam and nooclerine on visual functions in patients with primary open-angle glaucoma. These agents have been found to have a beneficial effect on the functional activity of the retina and optic nerve, light sensitivity, hemo- and hydrodynamics of the eye.

Evaluation of anticonvulsant and nootropic effect of ondansetron in mice.

PubMed

Jain, S; Agarwal, N B; Mediratta, P K; Sharma, K K

2012-09-01

The role of serotonin receptors have been implicated in various types of experimentally induced seizures. Ondansetron is a highly selective 5-hydroxytryptamine 3 (5-HT(3)) receptor antagonist used as antiemetic agent for chemotherapy-, and radiotherapy-induced nausea and vomiting. The present study was carried out to examine the effect of ondansetron on electroshock, pentylenetetrazole (PTZ)-induced seizures and cognitive functions in mice. Ondansetron was administered intraperitoneally (i.p.) at doses of 0.5, 1.0 and 2.0 mg/kg (single dose) to observe its effect on the increasing current electroshock seizure (ICES) test and PTZ-induced seizure test. In addition, a chronic study (21 days) was also performed to assess the effects of ondansetron on electroshock-induced convulsions and cognitive functions. The effect on cognition was assessed by elevated plus maze and passive avoidance paradigms. Phenytoin (25 mg/kg, i.p.) was used as a standard anticonvulsant drug and piracetam (200 mg/kg) was administered as a standard nootropic drug. The results were compared with an acute study, wherein it was found that the administration of ondansetron (1.0 and 2.0 mg/kg) significantly raised the seizure-threshold current as compared to control group in the ICES test. Similar results were observed after chronic administration of ondansetron. In PTZ test, ondansetron in all the three tested doses failed to show protective effect against PTZ-induced seizure test. Administration of ondansetron for 21 days significantly decreased the transfer latency (TL) and prolonged the step-down latency (SDL). The results of present study suggest the anticonvulsant and memory-enhancing effect of ondansetron in mice.

Nootropic and antiamnestic effects of tenoten (pediatric formulation) in immature rat pups.

PubMed

Voronina, T A; Molodavkin, G M; Borodavkina, M V; Kheyfets, I A; Dugina, Yu L; Sergeeva, S A

2009-09-01

The antiamnestic effects of tenoten (pediatric formulation) was demonstrated on the model of scopolamine-induced amnesia of passive avoidance reflex and the nootropic effect of this preparation was demonstrated on the model of incomplete conditioning and in rat pups with experimental attention deficit syndrome. The efficiency of the preparation was comparable to that of piracetam and phenibut and even surpassed it by some parameters.

Nefiracetam facilitates hippocampal neurotransmission by a mechanism independent of the piracetam and aniracetam action.

PubMed

Nomura, T; Nishizaki, T

2000-07-07

Nefiracetam, a nootropic (cognition-enhancing) agent, facilitated neurotransmission in the dentate gyrus of rat hippocampal slices in a dose-dependent manner at concentrations ranged from 1 nM to 1 microM, being evident at 60-min washing-out of the drug. The facilitatory action was blocked by the nicotinic acetylcholine (ACh) receptor antagonists, alpha-bungarotoxin and mecamylamine. A similar facilitation was induced by the other nootropic agents, piracetam and aniracetam, but the facilitation was not inhibited by nicotinic ACh receptor antagonists and it did not occlude the potentiation induced by nefiracetam. In the Xenopus oocyte expression systems, nefiracetam potentiated currents through a variety of neuronal nicotinic ACh receptors (alpha 3beta 2, alpha 3beta 4, alpha 4 beta 2, alpha 4 beta 4, and alpha 7) to a different extent. In contrast, neither piracetam nor aniracetam had any potentiating action on alpha 7 receptor currents. While aniracetam delayed the decay time of currents through the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, GluR1, -2, -3, expressed in oocytes, nefiracetam or piracetam had no effect on the currents. Nefiracetam, thus, appears to facilitate hippocampal neurotransmission by functionally targeting nicotinic ACh receptors, independently of the action of piracetam and aniracetam.

Quantitative Determination of Vinpocetine in Dietary Supplements.

PubMed

French, John M T; King, Matthew D; McDougal, Owen M

2016-05-01

Current United States regulatory policies allow for the addition of pharmacologically active substances in dietary supplements if derived from a botanical source. The inclusion of certain nootropic drugs, such as vinpocetine, in dietary supplements has recently come under scrutiny due to the lack of defined dosage parameters and yet unproven short- and long-term benefits and risks to human health. This study quantified the concentration of vinpocetine in several commercially available dietary supplements and found that a highly variable range of 0.6-5.1 mg/serving was present across the tested products, with most products providing no specification of vinpocetine concentrations.

Cognition enhancers between treating and doping the mind.

PubMed

Lanni, Cristina; Lenzken, Silvia C; Pascale, Alessia; Del Vecchio, Igor; Racchi, Marco; Pistoia, Francesca; Govoni, Stefano

2008-03-01

Memory, attention and creativity represent three different cognitive domains, which are interconnected and contribute the "mental performance" of an individual. Modern neuroscience has investigated some of the neuronal circuits and of the neurotransmitters and molecular events underlying the above-mentioned cognitive functions. Within this renewed reference context, some of the properties of the components of the remedies to increase mental performance have been studied and validated in experimental models and, to date, these substances are named "smart drugs", "memory enhancing drugs" or "nootropic drugs" (from the Greek root noos for mind and tropein for toward). Recently pharmaceutical industries are increasingly focusing on the research for potential substances in this field: several "smart drugs" are in clinical trials and could be on the market in few years. Furthermore, a quick survey from Internet highlights the presence of a great variety of both approved and non-approved drugs, with some of them addressing to only medical and others to performance-oriented use, opening room to some reflections or speculations from scientific and ethical points of view. In order to point out the effect of nootropic drugs on cognition of healthy people, we reviewed the literature on drug enhancement of various cognitive functions, including memory, attention and creativity. As their simplest, memory is regarded as the ability to remember events or learned material, attention is the cognitive process of selectively concentrating on one aspect while ignoring distracters and creativity could be described as the ability to create products or ideas which are original and which possess a social usefulness. Reports from literature reveal that some medications currently available to patients with memory disorders may also increase performances in healthy people and that drugs designed for psychiatric disorders can also be used to enhance certain mental functions. However, the long-term effects of these drugs are unknown, but their apparent effectiveness allows room to their use and misuse. At variance with these literature data showing scientific, even if poor, evidence of the effect of smart drugs in the field of memory and attention, only indirect information on creativity can be obtained by studies of the effects of diseases and drugs on the artistic productivity of classic painters and famous authors, offering a link to understand the neuronal basis of this cognitive function and a cue to understand how drugs (used to correct the illness) may affect the function. On the basis of these cues, in this review we will discuss some critical aspects of the different cerebral circuits and molecular events regulating memory, attention and creativity in order to outline the neurobiological bases of the effects of "smart drugs" on cognitive functions, and to evaluate their putative pharmaceutical development.

Modulating effect of the nootropic drug, piracetam on stress- and subsequent morphine-induced prolactin secretion in male rats.

PubMed Central

Matton, A.; Engelborghs, S.; Bollengier, F.; Finné, E.; Vanhaeist, L.

1996-01-01

1. The effect of the nootropic drug, piracetam on stress- and subsequent morphine-induced prolactin (PRL) secretion was investigated in vivo in male rats, by use of a stress-free blood sampling and drug administration method by means of a permanent indwelling catheter in the right jugular vein. 2. Four doses of piracetam were tested (20, 100, 200 and 400 mg kg-1), being given intraperitoneally 1 h before blood sampling; control rats received saline instead. After a first blood sample, rats were subjected to immobilization stress and received morphine, 6 mg kg-1, 90 min later. 3. Piracetam had no effect on basal plasma PRL concentration. 4. While in the non-piracetam-treated rats, stress produced a significant rise in plasma PRL concentration, in the piracetam-pretreated rats PRL peaks were attenuated, especially in the group given 100 mg kg-1 piracetam, where plasma PRL concentration was not significantly different from basal values. The dose-response relationship showed a U-shaped curve; the smallest dose had a minor inhibitory effect and the highest dose had no further effect on the PRL rise. 5. In unrestrained rats, morphine led to a significant elevation of plasma PRL concentration. After the application of immobilization stress it lost its ability to raise plasma PRL concentration in the control rats, but not in the piracetam-treated rats. This tolerance was overcome by piracetam in a significant manner but with a reversed dose-response curve; i.e. the smaller the dose of piracetam, the higher the subsequent morphine-induced PRL peak. 6. There is no simple explanation for the mechanism by which piracetam induces these contradictory effects. Interference with the excitatory amino acid system, which is also involved in opiate action, is proposed speculatively as a possible mediator of the effects of piracetam. PMID:8821540

A study to evaluate the effect of nootropic drug-piracetam on DNA damage in leukocytes and macrophages.

PubMed

Singh, Sarika; Goswami, Poonam; Swarnkar, Supriya; Singh, Sheelendra Pratap; Wahajuddin; Nath, Chandishwar; Sharma, Sharad

2011-11-27

Piracetam is a nootropic drug that protects neurons in neuropathological and age-related diseases and the activation and modulation of peripheral blood cells in patients with neuropathological conditions is well known. Therefore, in the present study, in vivo, ex vivo, and in vitro tests were conducted to investigate the effect of piracetam on leukocytes and macrophages. Lipopolysaccharide (LPS) causes oxidative DNA damage; thus, in the present study, LPS was used as a tool to induce DNA damage. In vivo experiments were conducted on Sprague Dawley rats, and piracetam (600mg/kg, oral) was provided for five consecutive days. On the fifth day, a single injection of LPS (10mg/kg, i.p.) was administered. Three hours after LPS injection, blood leukocytes and peritoneal macrophages were collected and processed, and a variety of different assays were conducted. Ex vivo treatments were performed on isolated rat blood leukocytes, and in vitro experiments were conducted on rat macrophage cell line J774A.1. Cell viability and the level of reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and DNA damage were estimated in untreated (control) and piracetam-, LPS- and LPS+piracetam-treated leukocytes and macrophages. In vivo experiments revealed that rats pretreated with piracetam were significantly protected against LPS-induced increases in ROS levels and DNA damage. Ex vivo isolated leukocytes and J774A.1 cells treated with LPS exhibited augmented ROS levels and DNA damage, which were attenuated with piracetam treatment. Thus, the present study revealed the salutary effect of piracetam against LPS-induced oxidative stress and DNA damage in leukocytes and macrophages. Copyright © 2011 Elsevier B.V. All rights reserved.

Cannabis-induced impairment of learning and memory: effect of different nootropic drugs.

PubMed

Abdel-Salam, Omar M E; Salem, Neveen A; El-Sayed El-Shamarka, Marwa; Al-Said Ahmed, Noha; Seid Hussein, Jihan; El-Khyat, Zakaria A

2013-01-01

Cannabis sativa preparations are the most commonly used illicit drugs worldwide. The present study aimed to investigate the effect of Cannabis sativa extract in the working memory version of the Morris water maze (MWM; Morris, 1984[43]) test and determine the effect of standard memory enhancing drugs. Cannabis sativa was given at doses of 5, 10 or 20 mg/kg (expressed as Δ(9)-tetrahydrocannabinol) alone or co-administered with donepezil (1 mg/kg), piracetam (150 mg/ kg), vinpocetine (1.5 mg/kg) or ginkgo biloba (25 mg/kg) once daily subcutaneously (s.c.) for one month. Mice were examined three times weekly for their ability to locate a submerged platform. Mice were euthanized 30 days after starting cannabis injection when biochemical assays were carried out. Malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide, glucose and brain monoamines were determined. Cannabis resulted in a significant increase in the time taken to locate the platform and enhanced the memory impairment produced by scopolamine. This effect of cannabis decreased by memory enhancing drugs with piracetam resulting in the most-shorter latency compared with the cannabis. Biochemically, cannabis altered the oxidative status of the brain with decreased MDA, increased GSH, but decreased nitric oxide and glucose. In cannabis-treated rats, the level of GSH in brain was increased after vinpocetine and donepezil and was markedly elevated after Ginkgo biloba. Piracetam restored the decrease in glucose and nitric oxide by cannabis. Cannabis caused dose-dependent increases of brain serotonin, noradrenaline and dopamine. After cannabis treatment, noradrenaline is restored to its normal value by donepezil, vinpocetine or Ginkgo biloba, but increased by piracetam. The level of dopamine was significantly reduced by piracetam, vinpocetine or Ginkgo biloba. These data indicate that cannabis administration is associated with impaired memory performance which is likely to involve decreased brain glucose availability as well as alterations in brain monoamine neurotransmitter levels. Piracetam is more effective in ameliorating the cognitive impairments than other nootropics by alleviating the alterations in glucose, nitric oxide and dopamine in brain.

Cannabis-induced impairment of learning and memory: effect of different nootropic drugs

PubMed Central

Abdel-Salam, Omar M.E.; Salem, Neveen A.; El-Sayed El-Shamarka, Marwa; Al-Said Ahmed, Noha; Seid Hussein, Jihan; El-Khyat, Zakaria A.

2013-01-01

Cannabis sativa preparations are the most commonly used illicit drugs worldwide. The present study aimed to investigate the effect of Cannabis sativa extract in the working memory version of the Morris water maze (MWM; Morris, 1984[43]) test and determine the effect of standard memory enhancing drugs. Cannabis sativa was given at doses of 5, 10 or 20 mg/kg (expressed as Δ9-tetrahydrocannabinol) alone or co-administered with donepezil (1 mg/kg), piracetam (150 mg/ kg), vinpocetine (1.5 mg/kg) or ginkgo biloba (25 mg/kg) once daily subcutaneously (s.c.) for one month. Mice were examined three times weekly for their ability to locate a submerged platform. Mice were euthanized 30 days after starting cannabis injection when biochemical assays were carried out. Malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide, glucose and brain monoamines were determined. Cannabis resulted in a significant increase in the time taken to locate the platform and enhanced the memory impairment produced by scopolamine. This effect of cannabis decreased by memory enhancing drugs with piracetam resulting in the most-shorter latency compared with the cannabis. Biochemically, cannabis altered the oxidative status of the brain with decreased MDA, increased GSH, but decreased nitric oxide and glucose. In cannabis-treated rats, the level of GSH in brain was increased after vinpocetine and donepezil and was markedly elevated after Ginkgo biloba. Piracetam restored the decrease in glucose and nitric oxide by cannabis. Cannabis caused dose-dependent increases of brain serotonin, noradrenaline and dopamine. After cannabis treatment, noradrenaline is restored to its normal value by donepezil, vinpocetine or Ginkgo biloba, but increased by piracetam. The level of dopamine was significantly reduced by piracetam, vinpocetine or Ginkgo biloba. These data indicate that cannabis administration is associated with impaired memory performance which is likely to involve decreased brain glucose availability as well as alterations in brain monoamine neurotransmitter levels. Piracetam is more effective in ameliorating the cognitive impairments than other nootropics by alleviating the alterations in glucose, nitric oxide and dopamine in brain. PMID:26417227

Nootropic agents enhance the recruitment of fast GABAA inhibition in rat neocortex.

PubMed

Ling, Douglas S F; Benardo, Larry S

2005-07-01

It is widely believed that nootropic (cognition-enhancing) agents produce their therapeutic effects by augmenting excitatory synaptic transmission in cortical circuits, primarily through positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptors (AMPARs). However, GABA-mediated inhibition is also critical for cognition, and enhanced GABA function may be likewise therapeutic for cognitive disorders. Could nootropics act through such a mechanism as well? To address this question, we examined the effects of nootropic agents on excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) recorded from layer V pyramidal cells in acute slices of somatosensory cortex. Aniracetam, a positive modulator of AMPA/kainate receptors, increased the peak amplitude of evoked EPSCs and the amplitude and duration of polysynaptic fast IPSCs, manifested as a greater total charge carried by IPSCs. As a result, the EPSC/IPSC ratio of total charge was decreased, representing a shift in the excitation-inhibition balance that favors inhibition. Aniracetam did not affect the magnitude of either monosynaptic IPSCs (mono-IPSCs) recorded in the presence of excitatory amino acid receptor antagonists, or miniature IPSCs (mIPSCs) recorded in the presence of tetrodotoxin. However, the duration of both mono-IPSCs and mIPSCs was prolonged, suggesting that aniracetam also directly modulates GABAergic transmission. Cyclothiazide, a preferential modulator of AMPAR function, enhanced the magnitude and duration of polysynaptic IPSCs, similar to aniracetam, but did not affect mono-IPSCs. Concanavalin A, a kainate receptor modulator, had little effect on EPSCs or IPSCs, suggesting there was no contribution from kainate receptor activity. These findings indicate that AMPAR modulators strengthen inhibition in neocortical pyramidal cells, most likely by altering the kinetics of AMPARs on synaptically connected interneurons and possibly by modulating GABA(A) receptor responses in pyramidal cells. This suggests that the therapeutic actions of nootropic agents may be partly mediated through enhanced cortical GABAergic inhibition, and not solely through the direct modification of excitation, as previously thought.

[Use of the new psychotropic preparation bemitil in treating asthenic disorders (clinico-pharmacological research)].

PubMed

Aleksandrovskiĭ, Iu A; Bobkov, Iu G; Neznamov, G G; Serebriakova, T V; Boĭko, S S

1988-01-01

In a series of 130 patients with asthenic conditions related to borderline forms of neuro-mental disturbances the authors compared clinico-pharmacological action of the actoprotector bemitil with that of nootropic drugs (piracetam and piridotol). The treatment with bemitil was either continuous or intermittent, being conducted according to the scheme elaborated in the course of the study. Bemitil proved to be more effective than piracetam and piriditol in relation to its influence on the manifestations of the asthenic symptom complex in general. Its application was characterized by a faster onset of the therapeutic effect and a peculiar mild psychostimulating action, primarily manifested in the impact on obligate manifestations of the asthenic disorders. The degree of the psychotropic action of the drug was found to be subject to changes depending on the scheme of its use.

Nootropic effect of meadowsweet (Filipendula vulgaris) extracts.

PubMed

Shilova, I V; Suslov, N I

2015-03-01

The effects of the extracts of the aboveground parts of Filipendula vulgaris Moench on the behavior and memory of mice after hypoxic injury and their physical performance in the open-field test were studied using the models of hypoxia in a sealed volume, conditioned passive avoidance response (CPAR), and forced swimming with a load. The extracts improved animal resistance to hypoxia, normalized orientation and exploration activities, promoted CPAR retention after hypoxic injury, and increased physical performance. Aqueous extract of meadowsweet had the most pronounced effect that corresponded to the effect of the reference drug piracetam. These effects were probably caused by modulation of hippocampal activity.

Quantitative determination of vinpocetine in dietary supplements

PubMed Central

French, John M. T.; King, Matthew D.

2017-01-01

Current United States regulatory policies allow for the addition of pharmacologically active substances in dietary supplements if derived from a botanical source. The inclusion of certain nootropic drugs, such as vinpocetine, in dietary supplements has recently come under scrutiny due to the lack of defined dosage parameters and yet unproven short- and long-term benefits and risks to human health. This study quantified the concentration of vinpocetine in several commercially available dietary supplements and found that a highly variable range of 0.6–5.1 mg/serving was present across the tested products, with most products providing no specification of vinpocetine concentrations. PMID:27319129

Probable Nootropicinduced Psychiatric Adverse Effects: A Series of Four Cases

PubMed Central

Ajaltouni, Jean

2015-01-01

The misuse of nootropics—any substance that may alter, improve, or augment cognitive performance, mainly through the stimulation or inhibition of certain neurotransmitters—may potentially be dangerous and deleterious to the human brain, and certain individuals with a history of mental or substance use disorders might be particularly vulnerable to their adverse effects. We describe four cases of probable nootropic-induced psychiatric adverse effects to illustrate this theory. To the best of our knowledge this has not been previously reported in the formal medical literature. We briefly describe the most common classes of nootropics, including their postulated or proven methods of actions, their desired effects, and their adverse side effects, and provide a brief discussion of the cases. Our objective is to raise awareness among physicians in general and psychiatrists and addiction specialists in particular of the potentially dangerous phenomenon of unsupervised nootropic use among young adults who may be especially vulnerable to nootropics’ negative effects. PMID:27222762

The effect of Bacopa monnieri on gene expression levels in SH-SY5Y human neuroblastoma cells.

PubMed

Leung, How-Wing; Foo, Gabriel; Banumurthy, Gokulakrishna; Chai, Xiaoran; Ghosh, Sujoy; Mitra-Ganguli, Tora; VanDongen, Antonius M J

2017-01-01

Bacopa monnieri is a plant used as a nootropic in Ayurveda, a 5000-year-old system of traditional Indian medicine. Although both animal and clinical studies supported its role as a memory enhancer, the molecular and cellular mechanism underlying Bacopa's nootropic action are not understood. In this study, we used deep sequencing (RNA-Seq) to identify the transcriptome changes upon Bacopa treatment on SH-SY5Y human neuroblastoma cells. We identified several genes whose expression levels were regulated by Bacopa. Biostatistical analysis of the RNA-Seq data identified biological pathways and molecular functions that were regulated by Bacopa, including regulation of mRNA translation and transmembrane transport, responses to oxidative stress and protein misfolding. Pathway analysis using the Ingenuity platform suggested that Bacopa may protect against brain damage and improve brain development. These newly identified molecular and cellular determinants may contribute to the nootropic action of Bacopa and open up a new direction of investigation into its mechanism of action.

The effect of Bacopa monnieri on gene expression levels in SH-SY5Y human neuroblastoma cells

PubMed Central

Foo, Gabriel; Banumurthy, Gokulakrishna; Chai, Xiaoran; Ghosh, Sujoy

2017-01-01

Bacopa monnieri is a plant used as a nootropic in Ayurveda, a 5000-year-old system of traditional Indian medicine. Although both animal and clinical studies supported its role as a memory enhancer, the molecular and cellular mechanism underlying Bacopa’s nootropic action are not understood. In this study, we used deep sequencing (RNA-Seq) to identify the transcriptome changes upon Bacopa treatment on SH-SY5Y human neuroblastoma cells. We identified several genes whose expression levels were regulated by Bacopa. Biostatistical analysis of the RNA-Seq data identified biological pathways and molecular functions that were regulated by Bacopa, including regulation of mRNA translation and transmembrane transport, responses to oxidative stress and protein misfolding. Pathway analysis using the Ingenuity platform suggested that Bacopa may protect against brain damage and improve brain development. These newly identified molecular and cellular determinants may contribute to the nootropic action of Bacopa and open up a new direction of investigation into its mechanism of action. PMID:28832626

Aniracetam does not alter cognitive and affective behavior in adult C57BL/6J mice.

PubMed

Elston, Thomas W; Pandian, Ashvini; Smith, Gregory D; Holley, Andrew J; Gao, Nanjing; Lugo, Joaquin N

2014-01-01

There is a growing community of individuals who self-administer the nootropic aniracetam for its purported cognitive enhancing effects. Aniracetam is believed to be therapeutically useful for enhancing cognition, alleviating anxiety, and treating various neurodegenerative conditions. Physiologically, aniracetam enhances both glutamatergic neurotransmission and long-term potentiation. Previous studies of aniracetam have demonstrated the cognition-restoring effects of acute administration in different models of disease. No previous studies have explored the effects of aniracetam in healthy subjects. We investigated whether daily 50 mg/kg oral administration improves cognitive performance in naïve C57BL/6J mice in a variety of aspects of cognitive behavior. We measured spatial learning in the Morris water maze test; associative learning in the fear conditioning test; motor learning in the accelerating rotarod test; and odor discrimination. We also measured locomotion in the open field test, anxiety through the elevated plus maze test and by measuring time in the center of the open field test. We measured repetitive behavior through the marble burying test. We detected no significant differences between the naive, placebo, and experimental groups across all measures. Despite several studies demonstrating efficacy in impaired subjects, our findings suggest that aniracetam does not alter behavior in normal healthy mice. This study is timely in light of the growing community of healthy humans self-administering nootropic drugs.

Aniracetam Does Not Alter Cognitive and Affective Behavior in Adult C57BL/6J Mice

PubMed Central

Elston, Thomas W.; Pandian, Ashvini; Smith, Gregory D.; Holley, Andrew J.; Gao, Nanjing; Lugo, Joaquin N.

2014-01-01

There is a growing community of individuals who self-administer the nootropic aniracetam for its purported cognitive enhancing effects. Aniracetam is believed to be therapeutically useful for enhancing cognition, alleviating anxiety, and treating various neurodegenerative conditions. Physiologically, aniracetam enhances both glutamatergic neurotransmission and long-term potentiation. Previous studies of aniracetam have demonstrated the cognition-restoring effects of acute administration in different models of disease. No previous studies have explored the effects of aniracetam in healthy subjects. We investigated whether daily 50 mg/kg oral administration improves cognitive performance in naïve C57BL/6J mice in a variety of aspects of cognitive behavior. We measured spatial learning in the Morris water maze test; associative learning in the fear conditioning test; motor learning in the accelerating rotarod test; and odor discrimination. We also measured locomotion in the open field test, anxiety through the elevated plus maze test and by measuring time in the center of the open field test. We measured repetitive behavior through the marble burying test. We detected no significant differences between the naive, placebo, and experimental groups across all measures. Despite several studies demonstrating efficacy in impaired subjects, our findings suggest that aniracetam does not alter behavior in normal healthy mice. This study is timely in light of the growing community of healthy humans self-administering nootropic drugs. PMID:25099639

Selective suppression of the slow-inactivating potassium currents by nootropics in molluscan neurons.

PubMed

Bukanova, Julia V; Solntseva, Elena I; Skrebitsky, Vladimir G

2002-09-01

The role of the voltage-gated K+ channels in the effect of some nootropics was investigated. Earlier, the multiple effect of high concentrations of two nootropics, piracetam and its peptide analogue GVS-111 [Seredenin et al. (1995), US Patent No. 5,439,930], on Ca2+ and K+ currents of molluscan neurons was shown [Solntseva et al. (1997), General Pharmacology 29, 85-89]. In the present work, we describe the selective effect of low concentrations of these nootropics as well as vinpocetine on certain types of K+ current. The experiments were performed on isolated neurons of the land snail Helix pomatia using a two-microelectrode voltage-clamp method. The inward voltage-gated Ca2+ current (ICa) and three subtypes of the outward voltage-gated K+ current were recorded: Ca2+-dependent K+ current (IK(Ca)), delayed rectifying current (IKD), and fast-inactivating K+ current (IA). It has been found that I Ca was not changed in the presence of 30 microM vinpocetine, 100 microM piracetam or 10 nM GVS-111, while slow-inactivating, TEA-sensitive IK(Ca) and IKD were inhibited (IK(Ca) more strongly than IKD). In contrast, the fast-inactivating, 4-AP-sensitive K+ current (IA) was not diminished by low concentrations of piracetam and GVS-111, while vinpocetine even augmented it. A possible role of slow-inactivating subtypes of the K+ channels in the development of different forms of dementia is discussed.

[Effect of nootropic agents on impulse activity of cerebral cortex neurons].

PubMed

Iasnetsov, V V; Pravdivtsev, V A; Krylova, I N; Kozlov, S B; Provornova, N A; Ivanov, Iu V; Iasnetsov, V V

2001-01-01

The effect of nootropes (semax, mexidol, and GVS-111) on the activity of individual neurons in various cerebral cortex regions was studied by microelectrode and microionophoresis techniques in cats immobilized by myorelaxants. It was established that the inhibiting effect of mexidol upon neurons in more than half of cases is prevented or significantly decreased by the GABA antagonists bicuculline and picrotoxin. The inhibiting effect of semax and GVS-111 upon neurons in more than half of cases is related to stimulation of the M-choline and NMDA receptors, respectively.

[The pharmacokinetics of the dipeptide analog of piracetam with nootropic activity GVS-111 and of its basic metabolites].

PubMed

Boĭko, S S; Zherdev, V P; Dvorianinov, A A; Gudasheva, T A; Ostrovskaia, R U; Voronina, T A; Rozantsev, G G; Seredenin, S B

1997-01-01

The pharmacokinetics of a new nootropic dipeptide analog of piracetam-N-phenylacetyl-L-prolylglycine (GWS-111) and its main metabolites were studied in rats by means of high performance liquid chromatography and gas-liquid chromatography. The compound under study showed a greater resistance to an enzymatic effect than natural neuropeptides. In addition to an unchanged compound three of its metabolites were found in the blood plasma of the rats. One of them, cyclo-Pro-Gly was an active metabolite of GWS-111.

[STUDYING SOME PHARMACOLOGICAL EFFECTS OF NEW 3-HYDROXYPYRIDINE DERIVATIVE].

PubMed

Yasnetsov, V V; Tsublova, E G; Yasnetsov, Vic V; Skachilova, S Ya; Karsanova, S K; Ivanov, Yu V

2016-01-01

It was established that a new 3-hydroxypyridine (3-HP) derivative, 2-ethyl-6-methyl-3-hydroxypyridine L-aspartate (3-HP), in small doses (1 and 5 mg/kg) increased physical performance in treadmill and swimming tests on rats. The new substance showed greater or equal effects compared to the reference actoprotector drugs metaprot and ladasten in much higher doses. The gluconeogenesis inhibitor tryptophan significantly (74 ± 5%, p < 0.01) prevented this stimulatory effect of 3-HPA in the treadmill test on rats. 3-HPA at a higher dose (30 mg/kg) had marked antiamnesic effect on various models of amnesia in mice. It was more effective than reference drugs mexidol (another 3-HP derivative) in a dose of 30 mg/kg and nootropic drug piracetam in a dose of 200 mg/kg, but had equal effect with these drugs in doses of 50 and 800 mg/kg, respectively. 3-HPA (30 mg/kg per day) had neuroprotective effect in rats with brain ischemia and decreased the neurologic deficiency more effectively than mexidol (50 mg/kg per day).

Neurite outgrowth of murine cerebellar granule cells can be enhanced by aniracetam with or without alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA).

PubMed

Fushiki, S; Matsumoto, K; Nagata, A

1995-10-27

To assess the neurotrophic effects of a nootropic drug, aniracetam, we studied neurite extension of mouse cerebellar granule cells in culture with low or with high K+ under different combinations of drugs and then immunohistochemically stained the cells with an antibody against L1, a neural cell adhesion molecule on cerebellar granule cells. Quantitative analyses using parameters of the total neurite length, maximal neurite length and number of branches disclosed that aniracetam, in the presence of high K+ and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), significantly enhanced neurite extension of cultured granule neurons. Aniracetam alone also stimulated neurite extension of cerebellar granule cells at a longer period of culture with low K+ showing a bell-shaped dose response curve with maximal effects at 10 microM. Aniracetam may influence remodeling of the neural network after injury.

X-ray and 1H-NMR spectroscopic studies of the structures and conformations of the new nootropic agents RU-35929, RU-47010 and RU-35965

NASA Astrophysics Data System (ADS)

Amato, Maria E.; Bandoli, Giuliano; Casellato, Umberto; Pappalardo, Giuseppe C.; Toja, Emilio

1990-10-01

The crystal and molecular structures of the nootropics (±)1-benzenesulphonyl-2-oxo-5-ethoxypyrrolidine ( 1), (±)1-(3-pyridinylsulphonyl)-2-oxo-5-ethoxypyrrolidine ( 2) and (±)1-benzenesulphonyl-2-oxo-5-isopropyloxypyrrolidine ( 3) have been determined by X-ray analysis. The solution conformation of 1, 2 and 3 has been investigated by 1H NMR spectroscopy. In the solid state, the main feature consists of the similar structural parameters and conformations, with the exception of the conformation adopted by the 5-ethoxy moiety which changes on passing from 1 to 2. The solid state overall enveloped conformation of the 2-pyrrolidinone ring for the three nootropics is found to be retained in solution on the basis of NMR evidence. Comparison between calculated and experimental coupling constant values shows that one of the two possible puckered opposite conformational isomers (half-chair shapes) occurs in solution. The relative pharmacological potencies of 1, 2 and 3 cannot therefore be interpreted in terms of the different conformation features presently detectable by available experimental methods.

Study of the deposition process of vinpocetine on the surface of porous silicon

NASA Astrophysics Data System (ADS)

Lenshin, A. S.; Polkovnikova, Yu. A.; Seredin, P. V.

Currently the most prospective way in pharmacotherapy is the obtaining of nanoparticles involving pharmaceutical substances. Application of porous inorganic materials on the basis of silicon is among the main features in solving of this problem. The present work is concerned with the problem of the deposition of pharmaceutical drug with nootropic activity - vinpocetine - into porous silicon. Silicon nanoparticles were obtained by electrochemical anodic etching of Si plates. The process of vinpocetine deposition was studied in dependence of the deposition time. As a result of the investigations it was found that infrared transmission spectra of porous silicon with the deposited vinpocetine revealed the absorption bands characteristic of vinpocetine substance.

Substituted piperazines as nootropic agents: 2- or 3-phenyl derivatives structurally related to the cognition-enhancer DM235.

PubMed

Guandalini, Luca; Martino, Maria Vittoria; Di Cesare Mannelli, Lorenzo; Bartolucci, Gianluca; Melani, Fabrizio; Malik, Ruchi; Dei, Silvia; Floriddia, Elisa; Manetti, Dina; Orlandi, Francesca; Teodori, Elisabetta; Ghelardini, Carla; Romanelli, Maria Novella

2015-04-15

A series of 2-phenyl- or 3-phenyl piperazines, structurally related to DM235 and DM232, two potent nootropic agents, have been prepared and tested in the mouse passive-avoidance test, to assess their ability to revert scopolamine-induced amnesia. Although the newly synthesized molecules were less potent than the parent compounds, some useful information has been obtained from structure-activity relationships. A small but significant enantioselectivity has been found for the most potent compound 5a. Copyright © 2015 Elsevier Ltd. All rights reserved.

Piracetam and vinpocetine ameliorate rotenone-induced Parkinsonism in rats.

PubMed

Zaitone, Sawsan A; Abo-Elmatty, Dina M; Elshazly, Shimaa M

2012-01-01

To evaluate the neuroprotective effect of the nootropic drugs, piracetam (PIR) and vinpocetine (VIN), in rotenone-induced Parkinsonism in rats. Sixty male rats were divided into 6 groups of 10 rats each. The groups were administered vehicle, control (rotenone, 1.5 mg/kg/48 h/6 doses, s.c.), PIR (100 and 200 mg/kg/day, p.o.) and VIN (3 and 6 mg/kg/day, p.o.). The motor performance of the rats was evaluated by the open field and pole test. Striatal dopamine level, malondialdehyde (MDA), reduced glutathione (GSH) and tumor necrosis factor-α (TNF-α) were assayed. Histopathological study of the substantia nigra was also done. Results showed that rotenone-treated rats exhibited bradykinesia and motor impairment in the open-field test. In addition, GSH level was decreased whereas MDA and TNF-α increased in striata of rotenone-treated rats as compared to vehicle-treated rats. Marked degeneration of the substantia nigra pars compacta (SNpc) neurons and depletion of striatal dopamine was also observed in the rotenone-treated rats. Treatment with PIR or VIN significantly reversed the locomotor deficits and increased striatal dopamine level. Treatment with VIN significantly (P<0.05) reduced the striatal level of MDA and GSH in comparison to rotenone group whereas TNF-α production was found to be significantly decreased in PIR group (P<0.05). VIN and PIR exhibit neuroprotective activity in rotenone-induced Parkinsonism. Hence, these nootropic agents may be considered as possible candidates in the treatment of Parkinson's disease.

Relationship between changes in rat behavior and integral biochemical indexes determined by laser correlation spectroscopy after photothrombosis of the prefrontal cortex.

PubMed

Romanova, G A; Shakova, F M; Kovaleva, O I; Pivovarov, V V; Khlebnikova, N N; Karganov, M Yu

2004-02-01

Experiments on rats showed that Noopept improved retention and retrieval of conditioned passive avoidance response after phototrombosis of the prefrontal cortex (a procedure impairing retention of memory traces). The impairment of mnesic functions was accompanied by changes in integral biochemical indexes of the plasma determined by laser correlation spectroscopy. Treatment of behavioral disorders with Noopepet normalized biochemical indexes.

Immunostimulant, cerebroprotective & nootropic activities of Andrographis paniculata leaves extract in normal & type 2 diabetic rats.

PubMed

Radhika, P; Annapurna, A; Rao, S Nageswara

2012-05-01

A large number of plants have been recognized to be effective in the treatment of diabetes mellitus. Persistent hyperglycaemia is associated with decreased function of immune system and cerebral ischaemia mainly due to increased oxidative stress and inflammatory response. Andrographis paniculata is a medicinal plant widely used in folk medicine for various purposes. In this study the effect of chronic administration (7 days) of methanolic extract of A. paniculata leaves was studied in rats with experimentally induced diabetes, nootropic and immunostimulant activities were evaluated. The effect of acute administration of methanolic extract of A. paniculata leaves was also studied for cerebroprotective activity. Type 2 diabetes was induced in rats by streptozotocin (STZ) (65 mg/kg) + nicotinamide (150 mg/kg). Various biochemical parameters were estimated using standard methods. A significant (P<0.05) increase in cognitive function was observed in both normal and type 2 diabetic rats. Nootropic activity in terms of per cent reduction in latency period was more in type 2 diabetic rats. A significant increase in blood lymphocyte count, splenic lymphocyte count and peritoneal macrophage count was observed in both normal and type 2 diabetic rats. Immunostimulant activity was observed more in type 2 diabetic rats. The per cent decrease in cerebral infarction was more in type 2 diabetic rats when compared to normal rats. The per cent increase in superoxide dismutase (SOD) levels was more in type 2 diabetic rats. The antioxidant activity of the methanolic extract of A. paniculata leaves was evident by decreased tissue malondialdehyde (MDA) levels and increased SOD levels. These properties may be responsible for the observed cerebroprotective activity. The methanolic leaf extract of A. paniculata showed significant immunostimulant, cerebroprotective and nootropic activities in normal and type 2 diabetic rats.

Immunostimulant, cerebroprotective & nootropic activities of Andrographis paniculata leaves extract in normal & type 2 diabetic rats

PubMed Central

Radhika, P.; Annapurna, A.; Rao, S. Nageswara

2012-01-01

Background & objectives: A large number of plants have been recognized to be effective in the treatment of diabetes mellitus. Persistent hyperglycaemia is associated with decreased function of immune system and cerebral ischaemia mainly due to increased oxidative stress and inflammatory response. Andrographis paniculata is a medicinal plant widely used in folk medicine for various purposes. In this study the effect of chronic administration (7 days) of methanolic extract of A. paniculata leaves was studied in rats with experimentally induced diabetes, nootropic and immunostimulant activities were evaluated. The effect of acute administration of methanolic extract of A. paniculata leaves was also studied for cerebroprotective activity. Methods: Type 2 diabetes was induced in rats by streptozotocin (STZ) (65 mg/kg) + nicotinamide (150 mg/kg). Various biochemical parameters were estimated using standard methods. Results: A significant (P<0.05) increase in cognitive function was observed in both normal and type 2 diabetic rats. Nootropic activity in terms of per cent reduction in latency period was more in type 2 diabetic rats. A significant increase in blood lymphocyte count, splenic lymphocyte count and peritoneal macrophage count was observed in both normal and type 2 diabetic rats. Immunostimulant activity was observed more in type 2 diabetic rats. The per cent decrease in cerebral infarction was more in type 2 diabetic rats when compared to normal rats. The per cent increase in superoxide dismutase (SOD) levels was more in type 2 diabetic rats. Interpretation & conclusions: The antioxidant activity of the methanolic extract of A. paniculata leaves was evident by decreased tissue malondialdehyde (MDA) levels and increased SOD levels. These properties may be responsible for the observed cerebroprotective activity. The methanolic leaf extract of A. paniculata showed significant immunostimulant, cerebroprotective and nootropic activities in normal and type 2 diabetic rats. PMID:22771592

Novel nootropic drug sunifiram improves cognitive deficits via CaM kinase II and protein kinase C activation in olfactory bulbectomized mice.

PubMed

Moriguchi, Shigeki; Tanaka, Tomoya; Tagashira, Hideaki; Narahashi, Toshio; Fukunaga, Kohji

2013-04-01

Alzheimer's disease (AD) shows degeneration of the cholinergic system in the medial septum, thereby eliciting down-regulation of the olfactory function in patients. We have previously reported that olfactory bulbectomized (OBX) mice show hippocampus-dependent memory impairment as assessed by memory-related behavioral tasks and hippocampal long-term potentiation (LTP). In the present study, we focused whether novel pyrrolidone nootropic drug sunifiram improves both memory impairment and depression observed in OBX mice. OBX mice were administered once a day for 7-12 days with sunifiram (0.01-1.0mg/kg p.o.) from 10 days after operation with or without gavestinel (10mg/kg i.p.), which is glycine-binding site inhibitor of N-methyl-d-aspartate receptor (NMDAR). The spatial reference memory assessed by Y-maze and short-term memory assessed by novel object recognition task were significantly improved by sunifiram treatment in OBX mice. Sunifiram also restored hippocampal LTP injured in OBX mice without treatment with gavestinel. By contrast, sunifiram treatment did not ameliorate the depressive behaviors assessed by tail suspension task in OBX mice. Notably, sunifiram treatment restored CaMKIIα (Thr-286) autophosphorylation and GluR1 (Ser-831) phosphorylation in the hippocampal CA1 region from OBX mice to the levels of control mice. Likewise, sunifiram treatment improved PKCα (Ser-657) autophosphorylation and NR1 (Ser-896) phosphorylation to the control levels. Stimulation of CaMKII and PKC autophosphorylation by sunifiram was significantly inhibited by pre-treatment with gavestinel. However, sunifiram treatment did not affect the phosphorylation of CaMKIV (Thr-196) and ERK. Taken together, sunifiram ameliorates OBX-induced deficits of memory-related behaviors and impaired LTP in the hippocampal CA1 region via stimulation of glycine-binding site of NMDAR. Copyright © 2013 Elsevier B.V. All rights reserved.

Receptor changes and LTP: an analysis using aniracetam, a drug that reversibly modifies glutamate (AMPA) receptors.

PubMed

Staubli, U; Ambros-Ingerson, J; Lynch, G

1992-01-01

The hypothesis that long-term potentiation (LTP) involves receptor modifications was tested with aniracetam, a nootropic drug that selectively increases currents mediated by the AMPA subclass of glutamate receptors. Aniracetam had different effects on the waveform of synaptic potentials in hippocampus before and after induction of LTP: (1) the drug caused a slight reduction (or delay) of the initial segment of the response after LTP; and (2) the facilitatory effects of aniracetam occurred at a later time point in the response after LTP than before. The interactions between LTP and aniracetam were still present when synaptic responses were greatly reduced by partial blockade of postsynaptic receptors and were not reproduced by increasing release or the number of stimulated synapses. A mathematical treatment of synaptic currents produced the following results: (1) if aniracetam facilitates AMPA receptor currents simply by reducing desensitization, then its complex interaction with LTP emerges when potentiation changes the kinetic and conductance properties of receptor channels; (2) if aniracetam also significantly increases conductance, then the experimental data can be reproduced by modeling LTP as an increase in channel conductance alone.

Brivaracetam: a rational drug discovery success story

PubMed Central

Rogawski, M A

2008-01-01

Levetiracetam, the α-ethyl analogue of the nootropic piracetam, is a widely used antiepileptic drug (AED) that provides protection against partial seizures and is also effective in the treatment of primary generalized seizure syndromes including juvenile myoclonic epilepsy. Levetiracetam was discovered in 1992 through screening in audiogenic seizure susceptible mice and, 3 years later, was reported to exhibit saturable, stereospecific binding in brain to a ∼90 kDa protein, later identified as the ubiquitous synaptic vesicle glycoprotein SV2A. A large-scale screening effort to optimize binding affinity identified the 4-n-propyl analogue, brivaracetam, as having greater potency and a broadened spectrum of activity in animal seizure models. Recent phase II clinical trials demonstrating that brivaracetam is efficacious and well tolerated in the treatment of partial onset seizures have validated the strategy of the discovery programme. Brivaracetam is among the first clinically effective AEDs to be discovered by optimization of pharmacodynamic activity at a molecular target. PMID:18552880

Piracetam and vinpocetine ameliorate rotenone-induced Parkinsonism in rats

PubMed Central

Zaitone, Sawsan A.; Abo-Elmatty, Dina M.; Elshazly, Shimaa M.

2012-01-01

Objective: To evaluate the neuroprotective effect of the nootropic drugs, piracetam (PIR) and vinpocetine (VIN), in rotenone-induced Parkinsonism in rats. Materials and Methods: Sixty male rats were divided into 6 groups of 10 rats each. The groups were administered vehicle, control (rotenone, 1.5 mg/kg/48 h/6 doses, s.c.), PIR (100 and 200 mg/kg/day, p.o.) and VIN (3 and 6 mg/kg/day, p.o.). The motor performance of the rats was evaluated by the open field and pole test. Striatal dopamine level, malondialdehyde (MDA), reduced glutathione (GSH) and tumor necrosis factor-α (TNF-α) were assayed. Histopathological study of the substantia nigra was also done. Results: Results showed that rotenone-treated rats exhibited bradykinesia and motor impairment in the open-field test. In addition, GSH level was decreased whereas MDA and TNF-α increased in striata of rotenone-treated rats as compared to vehicle-treated rats. Marked degeneration of the substantia nigra pars compacta (SNpc) neurons and depletion of striatal dopamine was also observed in the rotenone-treated rats. Treatment with PIR or VIN significantly reversed the locomotor deficits and increased striatal dopamine level. Treatment with VIN significantly (P < 0.05) reduced the striatal level of MDA and GSH in comparison to rotenone group whereas TNF-α production was found to be significantly decreased in PIR group (P < 0.05). Conclusion: VIN and PIR exhibit neuroprotective activity in rotenone-induced Parkinsonism. Hence, these nootropic agents may be considered as possible candidates in the treatment of Parkinson's disease. PMID:23248410

Phenibut (β-Phenyl-γ-aminobutyric Acid) Dependence and Management of Withdrawal: Emerging Nootropics of Abuse.

PubMed

Ahuja, Tania; Mgbako, Ofole; Katzman, Caroline; Grossman, Allison

2018-01-01

This case report describes the development of withdrawal from phenibut, a gamma-aminobutyric acid-receptor type B agonist. Although phenibut is not an FDA-approved medication, it is available through online retailers as a nootropic supplement. There are reports of dependence in patients that misuse phenibut. We report a case in which a patient experienced withdrawal symptoms from phenibut and was successfully treated with a baclofen taper. This case report highlights the development of phenibut use disorder with coingestion of alcohol and potential management for phenibut withdrawal. We believe clinicians must be aware of how phenibut dependence may present and how to manage the withdrawal syndrome.

Astrocytes mediated the nootropic and neurotrophic effects of Sarsasapogenin-AA13 via upregulating brain-derived neurotrophic factor.

PubMed

Dong, Dong; Mao, Yu; Huang, Cui; Jiao, Qian; Pan, Hui; Ma, Lei; Wang, Rui

2017-01-01

Rhizoma Anemarrhena , a widely used traditional Chinese medicine, has previously been shown to have neuroprotective effect. Sarsasapogenin-AA13 (AA13) is a novel synthetic derivative of Sarsasapogenin, which is extracted from Rhizoma Anemarrhena . The aim of this study is to investigate the nootropic and neurotrophic effects of AA13 and underlying mechanisms. In vitro , cell viability of rat primary astrocytes treated with AA13 and neurons cultured with conditioned medium of AA13-treated rat primary astrocytes was tested by MTT assays. In vivo , a pharmacological model of cognitive impairment induced by scopolamine was employed and spatial memory of the mice was assessed by Morris water maze. This study found that AA13 increased cell viability of primary astrocytes and AA13-treated astrocyte-conditioned medium enhanced the survival rate of primary neurons. Interestingly, AA13 markedly enhanced the level of BDNF in astrocytes. Furthermore, AA13 (6 mg/kg) improved the cognitive deficits in animal models (p<0.05) and BDNF and PSD95 levels were increased in brain. Therefore, we hypothesize that AA13 exerts nootropic and neurotrophic activities through astrocytes mediated upregulation of BDNF secretion. The results suggest that AA13 could be a potential compound for cognitive impairment after further research.

Evaluation of nootropic and neuroprotective effects of low dose aspirin in rats.

PubMed

Ghosh, Arijit; Dhumal, V R; Tilak, A V; Das, Nina; Singh, Amarinder; Bondekar, Abhijit A

2011-01-01

To evaluate the nootropic and neuroprotective effects of aspirin in Sprague Dawley rats. Retention of conditioned avoidance response (CAR) and central 5-HT-mediated behavior (lithium-induced head twitches) were assessed using repeated electroconvulsive shock (ECS) in rats. Rats were divided into eight groups: control (pretreated with distilled water), scopolamine (0.5 mg/kg i.p.), ECS (150 V, 50 Hz sinusoidal with intensity of 210 mA for 0.5 s) pretreated, aspirin (6.75 mg/kg orally) pretreated, combined scopolamine and aspirin pretreated, ondansetron (0.36 mg/kg orally) pretreated, combined ECS and ondansetron pretreated and combined ECS and aspirin pretreated groups. Data was analyzed by the chi-square test and ANOVA. Findings show that administration of single ECS daily for consecutive 8 days results in enhancement of 5-HT-mediated behavior (lithium-induced head twitches) and in disruption of the retention of CAR. Aspirin and ondansetron administration significantly increased the retention of conditioned avoidance response compared to control. Ondansetron and aspirin significantly prevented ECS-induced attenuation of the retention of conditioned avoidance response also. On the other hand, ondansetron and aspirin significantly retarded the ECS-induced enhancement of 5-HT-mediated behavior. Inhibition of the serotonergic transmission by aspirin is responsible for its nootropic and neuroprotective actions.

Evaluation of nootropic and neuroprotective effects of low dose aspirin in rats

PubMed Central

Ghosh, Arijit; Dhumal, V. R.; Tilak, A. V.; Das, Nina; Singh, Amarinder; Bondekar, Abhijit A.

2011-01-01

Objective: To evaluate the nootropic and neuroprotective effects of aspirin in Sprague Dawley rats. Materials and Methods: Retention of conditioned avoidance response (CAR) and central 5-HT-mediated behavior (lithium-induced head twitches) were assessed using repeated electroconvulsive shock (ECS) in rats. Rats were divided into eight groups: control (pretreated with distilled water), scopolamine (0.5 mg/kg i.p.), ECS (150 V, 50 Hz sinusoidal with intensity of 210 mA for 0.5 s) pretreated, aspirin (6.75 mg/kg orally) pretreated, combined scopolamine and aspirin pretreated, ondansetron (0.36 mg/kg orally) pretreated, combined ECS and ondansetron pretreated and combined ECS and aspirin pretreated groups. Data was analyzed by the chi-square test and ANOVA. Results: Findings show that administration of single ECS daily for consecutive 8 days results in enhancement of 5-HT-mediated behavior (lithium-induced head twitches) and in disruption of the retention of CAR. Aspirin and ondansetron administration significantly increased the retention of conditioned avoidance response compared to control. Ondansetron and aspirin significantly prevented ECS-induced attenuation of the retention of conditioned avoidance response also. On the other hand, ondansetron and aspirin significantly retarded the ECS-induced enhancement of 5-HT-mediated behavior. Conclusion: Inhibition of the serotonergic transmission by aspirin is responsible for its nootropic and neuroprotective actions. PMID:21701638

The Combination of Antidepressant Duloxetine with Piracetam in Mice does not Produce Enhancement of Nootropic Activity.

PubMed

Kale, Pravin Popatrao; Addepalli, Veeranjaneyulu; Sarkar, Amrita; Patel, Sonam; Savai, Jay

2014-09-01

There is a strong association between depression and memory impairment. The present study aims to assess the nootropic activity of duloxetine and piracetam combination. Male Swiss Albino mice were divided randomly into 4 groups. Treatment of normal saline (10 ml/kg), duloxetine (10 mg/kg), piracetam (100 mg/kg), and duloxetine (5 mg/kg) plus piracetam (50 mg/kg) were given through intra-peritoneal route to group I-IV, respectively. Transfer latency in elevated plus maze (EPM) and time spent in target quadrant in Morris water maze (MWM) were recorded. Estimation of brain monoamines in hippocampus, cerebral cortex, and whole brain were done using HPLC with fluorescence detector. Piracetam treated group showed significant decrease in transfer latency in EPM and increase in time spent in target quadrant recorded in MWM. Combination treated group failed to produce statistically significant nootropic effect in both EPM and MWM. Combination treated group failed to increase brain monoamine levels when compared against duloxetine and piracetam treated groups, separately. But there was exception of significant increase in norepinephrine levels in hippocampi when compared against duloxetine treated group. Results indicate no cognitive benefits with piracetam plus duloxetine combination. These findings can be further probed with the aim of understanding the interaction between duloxetine and piracetam as a future endeavor.

Adaptogenic and nootropic activities of aqueous extract of Vitis vinifera (grape seed): an experimental study in rat model

PubMed Central

Sreemantula, Satyanarayana; Nammi, Srinivas; Kolanukonda, Rajabhanu; Koppula, Sushruta; Boini, Krishna M

2005-01-01

Background The aerial parts of Vitis vinifera (common grape or European grape) have been widely used in Ayurveda to treat a variety of common and stress related disorders. In the present investigation, the seed extract of V. vinifera was evaluated for antistress activity in normal and stress induced rats. Furthermore, the extract was studied for nootropic activity in rats and in-vitro antioxidant potential to correlate its antistress activity. Methods For the evaluation of antistress activity, groups of rats (n = 6) were subjected to forced swim stress one hour after daily treatment of V. vinifera extract. Urinary vanillylmandelic acid (VMA) and ascorbic acid were selected as non-invasive biomarkers to assess the antistress activity. The 24 h urinary excretion of vanillylmandelic acid (VMA) and ascorbic acid were determined by spectrophotometric methods in all groups under normal and stressed conditions. The nootropic activity of the extract as determined from acquisition, retention and retrieval in rats was studied by conditioned avoidance response using Cook's pole climbing apparatus. The in vitro antioxidant activity was determined based on the ability of V. vinifera to scavenge hydroxyl radicals. Results Daily administration of V. vinifera at doses of 100, 200 and 300 mg/kg body weight one hour prior to induction of stress inhibited the stress induced urinary biochemical changes in a dose dependent manner. However, no change in the urinary excretion of VMA and ascorbic acid was observed in normal animals at all the doses studied. The cognition, as determined by the acquisition, retention and recovery in rats was observed to be dose dependent. The extract also produced significant inhibition of hydroxyl radicals in comparison to ascorbic acid in a dose dependent manner. Conclusion The present study provides scientific support for the antistress (adaptogenic), antioxidant and nootropic activities of V. vinifera seed extract and substantiate the traditional claims for the usage of grape fruits and seeds in stress induced disorders. PMID:15656916

Comment on 'Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets' by Lam et al.

PubMed

Hill, W David

2018-04-01

Intelligence and educational attainment are strongly genetically correlated. This relationship can be exploited by Multi-Trait Analysis of GWAS (MTAG) to add power to Genome-wide Association Studies (GWAS) of intelligence. MTAG allows the user to meta-analyze GWASs of different phenotypes, based on their genetic correlations, to identify association's specific to the trait of choice. An MTAG analysis using GWAS data sets on intelligence and education was conducted by Lam et al. (2017). Lam et al. (2017) reported 70 loci that they described as 'trait specific' to intelligence. This article examines whether the analysis conducted by Lam et al. (2017) has resulted in genetic information about a phenotype that is more similar to education than intelligence.

Aniracetam (Ro 13-5057) in the treatment of senile dementia of Alzheimer type (SDAT): results of a placebo controlled multicentre clinical study.

PubMed

Senin, U; Abate, G; Fieschi, C; Gori, G; Guala, A; Marini, G; Villardita, C; Parnetti, L

1991-12-01

One hundred and nine elderly patients suffering from mild to moderate cognitive impairment fulfilling NINCDS-ADRDA criteria for probable dementia of the Alzheimer type were treated for 6 months with a new nootropic drug, aniracetam (Ro 13-5057) in a double-blind randomized study versus placebo. The two treatment groups were comparable at baseline for demographic and behaviourial parameters and symptomatology. Patients underwent clinical, behaviourial and psychometric evaluation every other month. The aniracetam group differed significantly from the placebo group by the end of the study and also showed a statistically significant improvement versus baseline in the psychobehavioural parameters, while in the placebo group a steady deterioration was observed. Tolerability to aniracetam was excellent.

Nootropic activity of Albizzia lebbeck in mice.

PubMed

Chintawar, S D; Somani, R S; Kasture, Veena S; Kasture, S B

2002-08-01

The effect of saponin containing n-butanolic fraction (BF) extracted from dried leaves of Albizzia lebbeck on learning and memory was studied in albino mice using passive shock avoidance paradigm and the elevated plus maze. Significant improvement was observed in the retention ability of the normal and amnesic mice as compared to their respective controls. We have also studied the effects of BF on the behavior influenced by serotonin (5-HT), noradrenaline and dopamine. The brain levels of serotonin, gamma-aminobutyric acid (GABA) and dopamine were also estimated to correlate the behavior with neurotransmitter levels. The brain concentrations of GABA and dopamine were decreased, whereas the 5-HT level was increased. The data indicate the involvement of monoamine neurotransmitters in the nootropic action of BF of A. lebbeck.

Classification and evaluation of the pharmacodynamics of psychotropic drugs by single-lead pharmaco-EEG, EEG mapping and tomography (LORETA).

PubMed

Saletu, B; Anderer, P; Saletu-Zyhlarz, G M; Arnold, O; Pascual-Marqui, R D

2002-01-01

Utilizing computer-assisted quantitative analyses of human scalp-recorded electroencephalogram (EEG) in combination with certain statistical procedures (quantitative pharmaco-EEG) and mapping techniques (pharmaco-EEG mapping), it is possible to classify psychotropic substances and objectively evaluate their bioavailability at the target organ: the human brain. Specifically, one may determine at an early stage of drug development whether a drug is effective on the central nervous system (CNS) compared with placebo, what its clinical efficacy will be like, at which dosage it acts, when it acts and the equipotent dosages of different galenic formulations. Pharmaco-EEG profiles and maps of neuroleptics, antidepressants, tranquilizers, hypnotics, psychostimulants and nootropics/cognition-enhancing drugs will be described in this paper. Methodological problems, as well as the relationships between acute and chronic drug effects, alterations in normal subjects and patients, CNS effects, therapeutic efficacy and pharmacokinetic and pharmacodynamic data will be discussed. In recent times, imaging of drug effects on the regional brain electrical activity of healthy subjects by means of EEG tomography such as low-resolution electromagnetic tomography (LORETA) has been used for identifying brain areas predominantly involved in psychopharmacological action. This will be demonstrated for the representative drugs of the four main psychopharmacological classes, such as 3 mg haloperidol for neuroleptics, 20 mg citalopram for antidepressants, 2 mg lorazepam for tranquilizers and 20 mg methylphenidate for psychostimulants. LORETA demonstrates that these psychopharmacological classes affect brain structures differently.

Candyflipping and Other Combinations: Identifying Drug–Drug Combinations from an Online Forum

PubMed Central

Chary, Michael; Yi, David; Manini, Alex F.

2018-01-01

Novel psychoactive substances (NPS) refer to synthetic compounds or derivatives of more widely known substances of abuse that have emerged over the last two decades. Case reports suggest that users combine substances to achieve desired psychotropic experiences while reducing dysphoria and unpleasant somatic effects. However, the pattern of combining NPS has not been studied on a large scale. Here, we show that posts discussing NPS describe combining nootropics with sedative-hypnotics and stimulants with plant hallucinogens or psychiatric medications. Discussions that mention sedative-hypnotics most commonly also mention hallucinogens and stimulants. We analyzed 20 years of publicly available posts from Lycaeum, an Internet forum dedicated to sharing information about psychoactive substance use. We used techniques from natural language processing and machine learning to identify NPS and correlate patterns of co-mentions of substances across posts. We found that conversations mentioning synthetic hallucinogens tended to divide into those mentioning hallucinogens derived from amphetamine and those derived from ergot. Conversations that mentioned synthetic hallucinogens tended not to mention plant hallucinogens. Conversations that mention bath salts commonly mention sedative-hypnotics or nootropics while more canonical stimulants are discussed with plant hallucinogens and psychiatric medications. All types of substances are frequently compared to MDMA, DMT, cocaine, or atropine when trying to describe their effects. Our results provide the largest analysis to date of online descriptions of patterns of polysubstance use and further demonstrate the utility of social media in learning about trends in substance use. We anticipate this work to lead to a more detailed analysis of the knowledge contained online about the patterns of usage and effects of novel psychoactive substances. PMID:29760666

Nootropic and hypophagic effects following long term intake of almonds (Prunus amygdalus) in rats.

PubMed

Haider, S; Batool, Z; Haleem, D J

2012-01-01

Over a period of time researchers have become more interested in finding out the potential of various foods to maintain the general health and to treat diseases. Almonds are a very good source of many nutrients which may help to sharpen the memory and to reduce cardiovascular risk factors. The present study was conducted to evaluate the nootropic effects of almonds. Effect of oral intake of almond was also monitored on food intake and plasma cholesterol levels. Rats were given almond paste orally with the help of feeding tube for 28 days. Memory function in rats was assessed by Elevated Plus Maze (EPM) and Radial Arm Maze (RAM). Brain tryptophan, 5-HT and 5-HIAA were estimated at the end of the treatment by HPLC-EC method. A significant improvement in learning and memory of almond treated rats compared to controls was observed. Almond treated rats also exhibited a significant decrease in food intake and plasma cholesterol levels while the change in growth rate (in terms of percentage) remained comparable between the two groups. Analysis of brain tryptophan (TRP) monoamines exhibited enhanced TRP levels and serotonergic turnover in rat brain following oral intake of almonds. The findings show that almonds possess significant hypophagic and nootropic effects. Results are discussed in context of enhanced 5-HT metabolism following almond administration.

EEG topography and tomography (LORETA) in the classification and evaluation of the pharmacodynamics of psychotropic drugs.

PubMed

Saletu, Bernd; Anderer, Peter; Saletu-Zyhlarz, Gerda M

2006-04-01

By multi-lead computer-assisted quantitative analyses of human scalp-recorded electroencephalogram (QEEG) in combination with certain statistical procedures (quantitative pharmaco-EEG) and mapping techniques (pharmaco-EEG mapping or topography), it is possible to classify psychotropic substances and objectively evaluate their bioavailability at the target organ, the human brain. Specifically, one may determine at an early stage of drug development whether a drug is effective on the central nervous system (CNS) compared with placebo, what its clinical efficacy will be like, at which dosage it acts, when it acts and the equipotent dosages of different galenic formulations. Pharmaco-EEG maps of neuroleptics, antidepressants, tranquilizers, hypnotics, psychostimulants and nootropics/cognition-enhancing drugs will be described. Methodological problems, as well as the relationships between acute and chronic drug effects, alterations in normal subjects and patients, CNS effects and therapeutic efficacy will be discussed. Imaging of drug effects on the regional brain electrical activity of healthy subjects by means of EEG tomography such as low-resolution electromagnetic tomography (LORETA) has been used for identifying brain areas predominantly involved in psychopharmacological action. This will be shown for the representative drugs of the four main psychopharmacological classes, such as 3 mg haloperidol for neuroleptics, 20 mg citalopram for antidepressants, 2 mg lorazepam for tranquilizers and 20 mg methylphenidate for psychostimulants. LORETA demonstrates that these psychopharmacological classes affect brain structures differently. By considering these differences between psychotropic drugs and placebo in normal subjects, as well as between mental disorder patients and normal controls, it may be possible to choose the optimum drug for a specific patient according to a key-lock principle, since the drug should normalize the deviant brain function. Thus, pharmaco-EEG topography and tomography are valuable methods in human neuropsychopharmacology, clinical psychiatry and neurology.

Prosopis cineraria: a potential nootropic agent.

PubMed

Bithu, Bhawani Singh; Reddy, N Ranga; Prasad, Satyendra K; Sairam, Krishnamurthy; Hemalatha, S

2012-10-01

Prosopis cineraria (L.) Druce (Leguminosae), a plant of the Thar Desert of India and Pakistan is used traditionally by local people for the treatment of memory disorders and to arrest wandering of the mind. The study includes scientific validation of P. cineraria for nootropic activity. To elucidate the possible mechanism, the anticholinesterase activity was also investigated in different parts of the brain. Methanol extract of P. cineraria stem bark (200, 400 and 600 mg/kg body weight p.o.) was administered once in a day for 7 days to rats and these rats were then subjected to Morris water-maze (MWM) test for spatial reference memory (SRM) and spatial working memory (SWM) versions of memory testing. The inhibitory effect of the extract on acetylcholinesterase (AChE) in discrete rat brain regions (prefrontal cortex [PFC], hippocampus [HIP] and amygdala [AMY]) was also investigated using acetyl thiocholine iodide and dithiobisnitrobenzoic acid reagent. The oral administrations of methanol extract of P. cineraria in all doses tested, significantly (p < 0.05) improved both spatial reference and working memories in the MWM test in terms of decrease in escape latency during SRM and increase in time spent in the target quadrant during SWM probe trial. A ceiling effect was observed at 400 mg/kg. Pre-treatment for 7 days significantly inhibited the activity of AChE in the HIP, PFC and AMY. The extract exerted significant nootropic activity in the MWM test which may be attributed to the inhibition of brain AChE.

Could piracetam potentiate behavioural effects of psychostimulants?

PubMed

Slais, Karel; Machalova, Alena; Landa, Leos; Vrskova, Dagmar; Sulcova, Alexandra

2012-08-01

Press and internet reports mention abuse of nootropic drug piracetam (PIR) in combination with psychostimulants methamphetamine (MET) or 4-methylenedioxymethamphetamine (MDMA). These combinations are believed to produce more profound desirable effects, while decreasing hangover. However, there is a lack of valid experimental studies on such drug-drug interactions in the scientific literature available. Our hypothesis proposes that a functional interaction exists between PIR and amphetamine psychostimulants (MET and MDMA) which can potentiate psychostimulant behavioural effects. Our hypothesis is supported by the results of our pilot experiment testing acute effects of drugs given to mice intraperitoneally (Vehicle, n=12; MET 2.5mg/kg, n=10; MDMA 2.5mg/kg, n=11; PIR 300 mg/kg, n=12; PIR+MET, n=12; PIR+MDMA, n=11) in the Open Field Test (Actitrack, Panlab, Spain). PIR given alone caused no significant changes in mouse locomotor/exploratory behaviour, whereas the same dose combined with either MET or MDMA significantly enhanced their stimulatory effects. Different possible neurobiological mechanism underlying drug-drug interaction of PIR with MET or MDMA are discussed, as modulation of dopaminergic, glutamatergic or cholinergic brain systems. However, the interaction with membrane phospholipids seems as the most plausible mechanism explaining PIR action on activities of neurotransmitter systems. Despite that our behavioural experiment cannot serve for explanation of the pharmacological mechanisms of these functional interactions, it shows that PIR effects can increase behavioural stimulation of amphetamine drugs. Thus, the reported combining of PIR with MET or MDMA by human abusers is not perhaps a coincidental phenomenon and may be based on existing PIR potential to intensify acute psychostimulant effects of these drugs of abuse. Copyright © 2012 Elsevier Ltd. All rights reserved.

Interesting asian plants: their compounds and effects on electrophysiology and behaviour.

PubMed

Abdullah, Jafri Malin

2011-10-01

There have been numerous non-scientific reports on the behavioural effects of Asian plants in humans who consumed these plants wholly or part thereof. Knowledge passed from generation to generation informs us of plants that increase effort and stamina, such as during paddy planting after the ingestion of Mitragyna speciosa Korth (ketum) as a tea supplement. Centella asiatica and Myristica fragrans are used as herbs to improve memory and to treat epilepsy, respectively. Zizyphus mauritiana is used to treat headache and burn pain, acts as an antitussive, and reduces rigor mortis immediately after death. These plants, which have been identified to exhibit analgaesic, muscle-relaxing, and nootropic effects, may contain important bio-compounds for medicinal chemistry and pharmaceutical research in Malaysia. The electrophysiology properties of these plants and their effects on epilepsy, behaviour, and pain will lead Malaysia to future new drug discoveries.

[Multicomponent antithrombotic effect of the neuroprotective prolyl dipeptide GVS-111 and its major metabolite cyclo-L-prolylglycine].

PubMed

Ostrovskaia, R U; Liapina, L A; Pastorova, V E; Mirzoev, T Kh; Gudasheva, T A; Seredenin, S B; Ashmarin, I P

2002-01-01

The experiments in vivo showed that the new nootropic prolyl-containing GVS-111 produces an antithrombotic effect, influencing various stages of the blood coagulation process. GVS-111 exhibits anticoagulant and fibrinolytic properties and enhances fibrin destabilization by reducing the XIIIa factor activity. These effects are manifested upon both intraperitoneal (1 mg/kg) and peroral (10 mg/kg) administration of GVS-111 (in both cases, a single daily treatment over a period of 10 days). The same effects (anticoagulant, fibrinolytic, antifibrin-stabilizing) were observed in in vitro experiments with both GVS-111 (10(-3)-10(-6) M) and its main metabolite cyclo-L-prolylglycine (up to 10(-10) M). In addition, the latter metabolite exhibited an antiaggregant effect. The antithrombotic activity of GVS-111, together with previously established neuroprotector properties, low toxicity, and the absence of complications, makes this compound a promising antistroke drug.

Comparison of Nootropic and Neuroprotective Features of Aryl-Substituted Analogs of Gamma-Aminobutyric Acid.

PubMed

Tyurenkov, I N; Borodkina, L E; Bagmetova, V V; Berestovitskaya, V M; Vasil'eva, O S

2016-02-01

GABA analogs containing phenyl (phenibut) or para-chlorophenyl (baclofen) substituents demonstrated nootropic activity in a dose of 20 mg/kg: they improved passive avoidance conditioning, decelerated its natural extinction, and exerted antiamnestic effect on the models of amnesia provoked by scopolamine or electroshock. Tolyl-containing GABA analog (tolibut, 20 mg/kg) exhibited antiamnestic activity only on the model of electroshock-induced amnesia. Baclofen and, to a lesser extent, tolibut alleviated seizures provoked by electroshock, i.e. both agents exerted anticonvulsant effect. All examined GABA aryl derivatives demonstrated neuroprotective properties on the maximum electroshock model: they shortened the duration of coma and shortened the period of spontaneous motor activity recovery. In addition, these agents decreased the severity of passive avoidance amnesia and behavioral deficit in the open field test in rats exposed to electroshock. The greatest neuroprotective properties were exhibited by phenyl-containing GABA analog phenibut.

Nootropic activity of lipid-based extract of Bacopa monniera Linn. compared with traditional preparation and extracts.

PubMed

Lohidasan, Sathiyanarayanan; Paradkar, Anant R; Mahadik, Kakasaheb R

2009-11-01

The aim was to design an alternative solvent-free extraction method using the hydrophilic lipid Gelucire (polyethylene glycol glycerides) for herbal extraction and to confirm the efficacy of extraction using biological screening. Bacopa monniera Linn. (BM) was selected for the study. Conventional methanolic extract (MEBM), Ayurvedic ghrita (AGBM) and lipid extracts (LEBM) were prepared and standardised by high-performance thin-layer chromatography (HPTLC). Nootropic activity in rats was evaluated using the two-trial Y-maze test and the anterograde amnesia induced by scopolamine (1 mg/kg i.p.) determined by the conditioned avoidance response. The extracts were administered daily at doses of 100, 200 and 400 mg/kg orally. At the end of the conditioned avoidance response test, brain monoamine levels were estimated by HPLC. The LEBM, MEBM and AGBM contained 3.56%, 4.10% and 0.005% bacoside A, respectively. Significantly greater spatial recognition was observed with LEBM (P < 0.001 at 400 and 200 mg/kg) and MEBM (P < 0.001 at 400 mg/kg, P < 0.01 at 200 mg/kg) than AGBM. The conditioned avoidance response was significantly higher in the groups treated with high doses of LEBM and MEBM than AGBM. There were significant decreases in brain noradrenaline (P < 0.001) and 5-hydroxytryptamine (P < 0.01) levels and an increase in dopamine levels (P < 0.05) in the LEBM-treated groups compared with the stress control group. The proposed LEBM is solvent free, does not have the shortcomings associated with conventional extraction, and had comparable nootropic activity to the MEBM.

Piracetam and other structurally related nootropics.

PubMed

Gouliaev, A H; Senning, A

1994-05-01

Nearly three decades have now passed since the discovery of the piracetam-like nootropics, compounds which exhibit cognition-enhancing properties, but for which no commonly accepted mechanism of action has been established. This review covers clinical, pharmacokinetic, biochemical and behavioural results presented in the literature from 1965 through 1992 (407 references) of piracetam, oxiracetam, pramiracetam, etiracetam, nefiracetam, aniracetam and rolziracetam and their structural analogues. The piracetam-like nootropics are capable of achieving reversal of amnesia induced by, e.g., scopolamine, electroconvulsive shock and hypoxia. Protection against barbiturate intoxication is observed and some benefit in clinical studies with patients suffering from mild to moderate degrees of dementia has been demonstrated. No affinity for the alpha 1-, alpha 2-, beta-, muscarinic, 5-hydroxytryptamine-, dopamine, adenosine-A1-, mu-opiate, gamma-aminobutyric acid (GABA) (except for nefiracetam (GABAA)), benzodiazepine and glutamate receptors has been found. The racetams possess a very low toxicity and lack serious side effects. Increased turnover of different neurotransmitters has been observed as well as other biochemical findings, e.g., inhibition of enzymes such as prolylendopeptidase. So far, no generally accepted mechanism of action has, however, emerged. We believe that the effect of the racetams is due to a potentiation of already present neurotransmission and that much evidence points in the direction of a modulated ion flux by, e.g., potentiated calcium influx through non-L-type voltage-dependent calcium channels, potentiated sodium influx through alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor gated channels or voltage-dependent channels or decreases in potassium efflux. Effects on carrier mediated ion transport are also possible.

Novel nootropic drug sunifiram enhances hippocampal synaptic efficacy via glycine-binding site of N-methyl-D-aspartate receptor.

PubMed

Moriguchi, Shigeki; Tanaka, Tomoya; Narahashi, Toshio; Fukunaga, Kohji

2013-10-01

Sunifiram is a novel pyrrolidone nootropic drug structurally related to piracetam, which was developed for neurodegenerative disorder like Alzheimer's disease. Sunifiram is known to enhance cognitive function in some behavioral experiments such as Morris water maze task. To address question whether sunifiram affects N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic function in the hippocampal CA1 region, we assessed the effects of sunifiram on NMDAR-dependent long-term potentiation (LTP) by electrophysiology and on phosphorylation of synaptic proteins by immunoblotting analysis. In mouse hippocampal slices, sunifiram at 10-100 nM significantly enhanced LTP in a bell-shaped dose-response relationship which peaked at 10 nM. The enhancement of LTP by sunifiram treatment was inhibited by 7-chloro-kynurenic acid (7-ClKN), an antagonist for glycine-binding site of NMDAR, but not by ifenprodil, an inhibitor for polyamine site of NMDAR. The enhancement of LTP by sunifilam was associated with an increase in phosphorylation of α-amino-3-hydroxy-5-methylisozazole-4-propionate receptor (AMPAR) through activation of calcium/calmodulin-dependent protein kinase II (CaMKII) and an increase in phosphorylation of NMDAR through activation of protein kinase Cα (PKCα). Sunifiram treatments at 1-1000 nM increased the slope of field excitatory postsynaptic potentials (fEPSPs) in a dose-dependent manner. The enhancement was associated with an increase in phosphorylation of AMPAR receptor through activation of CaMKII. Interestingly, under the basal condition, sunifiram treatments increased PKCα (Ser-657) and Src family (Tyr-416) activities with the same bell-shaped dose-response curve as that of LTP peaking at 10 nM. The increase in phosphorylation of PKCα (Ser-657) and Src (Tyr-416) induced by sunifiram was inhibited by 7-ClKN treatment. The LTP enhancement by sunifiram was significantly inhibited by PP2, a Src family inhibitor. Finally, when pretreated with a high concentration of glycine (300 μM), sunifiram treatments failed to potentiate LTP in the CA1 region. Taken together, sunifiram stimulates the glycine-binding site of NMDAR with concomitant PKCα activation through Src kinase. Enhancement of PKCα activity triggers to potentiate hippocampal LTP through CaMKII activation. Copyright © 2013 Wiley Periodicals, Inc.

Neuropeptide S receptor ligands: a patent review (2005-2016).

PubMed

Ruzza, Chiara; Calò, Girolamo; Di Maro, Salvatore; Pacifico, Salvatore; Trapella, Claudio; Salvadori, Severo; Preti, Delia; Guerrini, Remo

2017-03-01

Neuropeptide S (NPS) is a 20-residue peptide and endogenous ligand of the NPS receptor (NPSR). This receptor was a formerly orphan GPCR whose activation increases calcium and cyclic adenosine monophosphate levels. The NPS/NPSR system is expressed in several brain regions where it controls important biological functions including locomotor activity, arousal and sleep, anxiety, food intake, memory, pain, and drug addiction. Areas covered: This review furnishes an updated overview of the patent literature covering NPSR ligands since 2005, when the first example of an NPSR antagonist was disclosed. Expert opinion: Several potent NPSR antagonists are available as valuable pharmacological tools despite showing suboptimal pharmacokinetic properties in vivo. The optimization of these ligands is needed to speed up their potential clinical advancement as pharmaceuticals to treat drug addiction. In order to support the design of novel NPSR antagonists, we performed a ligand-based conformational analysis recognizing some structural requirements for NPSR antagonism. The identification of small-molecule NPSR agonists now represents an unmet challenge to be addressed. These molecules will allow investigation of the beneficial effects of selective NPSR activation in a large panel of psychiatric disorders and to foresee their therapeutic potential as anxiolytics, nootropics, and analgesics.

Prolongevity medicine: Antagonic-Stress drug in distress, geriatrics, and related diseases. II. Clinical review--2003.

PubMed

Riga, S; Riga, D; Schneider, F

2004-06-01

Distress and senescence, their reciprocal aggravating-quickening connections, and their related pathologies have a large worldwide impact on healthcare systems in this new millennium. For this reason, Antagonic-Stress (AS)--an advanced integrative therapy, with specific synergistic composition, and patented internationally--represents a significant strategy in health, aging, and longevity. Clinical research with AS proves the drug's efficacy in the management of distress (neurotic, stress-related, and affective disorders; behavioral syndromes associated with physiological disturbances and physical factors; mental and behavioral disorders due to psychoactive substance uses) and psychogeriatrics [organic, including symptomatic, mental disorders (OMD)]. Specific multiaxial psychopathological instruments and psychometric tests in multiple assessments used for gerontopsychiatry demonstrated strong improvements after AS administration in early-moderate stages of Alzheimer or vascular dementia, as well as in other OMD. In addition, comparative clinical studies evinced the superiority of AS (synergistic multitherapy) versus monotherapy [meclofenoxate (MF), piracetam (PA), pyritinol (PT), and nicergoline (NE), respectively]. These comparative clinical trials agreed closely with comparative preclinical research and confirmed AS synergistic homeostatic, adaptogenic, antioxidative, cerebrovascular, neurometabolic, and nootropic actions. Also, the AS protective actions against oxidative stress recommend this orthomolecular therapy in stress, aging, and free radical pathology.

Smart Drugs and Synthetic Androgens for Cognitive and Physical Enhancement: Revolving Doors of Cosmetic Neurology

PubMed Central

Frati, Paola; Kyriakou, Chrystalla; Del Rio, Alessandro; Marinelli, Enrico; Vergallo, Gianluca Montanari; Zaami, Simona; Busardò, Francesco P.

2015-01-01

Cognitive enhancement can be defined as the use of drugs and/or other means with the aim to improve the cognitive functions of healthy subjects in particular memory, attention, creativity and intelligence in the absence of any medical indication. Currently, it represents one of the most debated topics in the neuroscience community. Human beings always wanted to use substances to improve their cognitive functions, from the use of hallucinogens in ancient civilizations in an attempt to allow them to better communicate with their gods, to the widespread use of caffeine under various forms (energy drinks, tablets, etc.), to the more recent development of drugs such as stimulants and glutamate activators. In the last ten years, increasing attention has been given to the use of cognitive enhancers, but up to now there is still only a limited amount of information concerning the use, effect and functioning of cognitive enhancement in daily life on healthy subjects. The first aim of this paper was to review current trends in the misuse of smart drugs (also known as Nootropics) presently available on the market focusing in detail on methylphenidate, trying to evaluate the potential risk in healthy individuals, especially teenagers and young adults. Moreover, the authors have explored the issue of cognitive enhancement compared to the use of Anabolic Androgenic Steroids (AAS) in sports. Finally, a brief overview of the ethical considerations surrounding human enhancement has been examined. PMID:26074739

Classification and determination of cerebral biovailability of psychotropic drugs by quantitative "pharmaco-EEG" and psychometric investigations (studies with AX-A411-BS).

PubMed

Saletu, B; Grünberger, J; Linzmayer, L

1977-10-01

Utilizing computerized quantitative analysis of the human scalp recorded electroencephalogram (EEG), it is possible to classify psychotropic drugs. While neuroleptic compounds produce an increase of slow and decrease of fast activities, anxiolytic substances induce an augmentation of fast waves, decrease of alpha waves and--according to the sedative properties of the drug--an increase or decrease of slow waves. Antidepressants produce a concomitant augmentation of slow and fast activities as well as an attenuation of alpha waves. Nootropic substances attenuate slow activities, augment alpha and slow beta waves and decrease fast beta waves. The latter alterations are quite opposite to age-related changes. Since the main psychopharmacological classes seem to have characteristic pharmaco-EEG profiles, the method proved to be useful for determination of psychoactivity and cerebral bioavailability of newly developed substances as for instance AX-A411-BS, a new benzodiazepine. The latter substance was found to be CNS-active and was classified as anxiolytic. It induced dosedependent changes, which were barely visible in the 2nd hour post-drug, became quite obvious in the 4th hour and increased until the 8th hour after oral administration of one single dose. In the higher dosage range, slow activities came to the fore, indicating aoditional sedative properties. Psychometric tests measuring attention, psychomotor activity. mood, vigilance, extroversion, concentration aith a long-lasting effect. The implications of these methods are discussed.

Smart drugs and synthetic androgens for cognitive and physical enhancement: revolving doors of cosmetic neurology.

PubMed

Frati, Paola; Kyriakou, Chrystalla; Del Rio, Alessandro; Marinelli, Enrico; Vergallo, Gianluca Montanari; Zaami, Simona; Busardò, Francesco P

2015-01-01

Cognitive enhancement can be defined as the use of drugs and/or other means with the aim to improve the cognitive functions of healthy subjects in particular memory, attention, creativity and intelligence in the absence of any medical indication. Currently, it represents one of the most debated topics in the neuroscience community. Human beings always wanted to use substances to improve their cognitive functions, from the use of hallucinogens in ancient civilizations in an attempt to allow them to better communicate with their gods, to the widespread use of caffeine under various forms (energy drinks, tablets, etc.), to the more recent development of drugs such as stimulants and glutamate activators. In the last ten years, increasing attention has been given to the use of cognitive enhancers, but up to now there is still only a limited amount of information concerning the use, effect and functioning of cognitive enhancement in daily life on healthy subjects. The first aim of this paper was to review current trends in the misuse of smart drugs (also known as Nootropics) presently available on the market focusing in detail on methylphenidate, trying to evaluate the potential risk in healthy individuals, especially teenagers and young adults. Moreover, the authors have explored the issue of cognitive enhancement compared to the use of Anabolic Androgenic Steroids (AAS) in sports. Finally, a brief overview of the ethical considerations surrounding human enhancement has been examined.

In vitro characterization of transport and metabolism of the alkaloids: vincamine, vinpocetine and eburnamonine.

PubMed

Fandy, Tamer E; Abdallah, Inas; Khayat, Maan; Colby, David A; Hassan, Hazem E

2016-02-01

Vincamine, vinpocetine and eburnamonine are alkaloids known for their neuroprotective attributes, enhancement of cerebrovascular blood flow and antitumor effect of their derivatives. However, the relative metabolic stability of these alkaloids and their extrusion by the drug efflux transporters expressed at the blood-brain barrier (BBB) are not clear. In this study, we developed rapid and sensitive methods for the detection of these alkaloids and investigated their relative metabolic stability and their interaction with drug efflux transporters. UPLC methods were developed to analyze metabolic in vitro samples. Intrinsic clearance was determined using rat liver microsomal enzymes. Drug-stimulated transporter activity was estimated by measuring inorganic phosphate released from ATP spectrophotometrically. The UPLC methods quantification level ranged from 0.02 to 0.025 µg/mL, indicating high sensitivity. The intrinsic clearance of eburnamonine was significantly less than both vincamine and vinpocetine. Different concentrations of the three drugs (4, 20 and 100 µM) induced minimal stimulation of the ATPase activity of the Bcrp and Pgp membrane transporters. The developed simple, sensitive and reliable UPLC analysis methods can be utilized in future in vitro and in vivo studies. The three alkaloids demonstrated minimal interaction with the drug efflux transporters Pgp and Bcrp, concordant with the ability of these alkaloids to cross the BBB. The relative metabolic stability of eburnamonine compared to the other alkaloids suggests the use of eburnamonine or its derivatives as lead compounds for the development of antitumor and nootropic agents that need to cross the BBB and produce their pharmacological effects in the CNS.

Аnticonvulsant effects of citicoline and diazepam at their combined application on model of the acute generalized convulsions induced by pentylenetetrazole in Wistar rats.

PubMed

Kuznetsova, L V; Karpova, M N; Zinkovski, K A; Klishina, N Yu

2016-01-01

Studying of efficiency of the combined application of the citicoline possessing nootropic and anticonvulsive action and antiepileptic drug of diazepam on the acute generalized convulsions (AGC) caused by a convulsant pentylentetrazole (PTZ). Experiments are executed on the male Wistar rats (n = 68) weighing 160-190 g on the AGС model caused by of PTZ in a dose of 80 mg/kg, intraperitoneally (i.p.). For studying of efficiency of the combined use of drugs determined the minimum anticonvulsive action of a citicoline (Tserakson, «Nicomed Ferrer Internacional, S.A.») and diazepam (Relanium, Warsaw pharmaceutical plant of Polf AO, Warsaw, Poland). For this citicoline were administered i.p. in doses 500 and 300 mg/kg 1 hour before the PTZ and diazepam - in doses of 0,5 and 0,25 mg/kg 30 min before administration of PTZ. Control animals were injected with saline to the same extent and under the same experimental conditions. It is shown that the combined administration of a citicoline and diazepam in minimum active doses (300 and 0.25 mg/kg respectively), increases anticonvulsive properties of both drugs. The combined administration of citicoline with diazepam in minimally active doses enhances anticonvulsant properties of both drugs, thereby reducing the risk of development of side effects. In addition, the research may serve as experimental justification for the use of drugs in case of convulsions for the purpose beneficial effect on cognitive function and delays of progressing of neurodegenerative processes.

Vinpocetine reduces diclofenac-induced acute kidney injury through inhibition of oxidative stress, apoptosis, cytokine production, and NF-κB activation in mice.

PubMed

Fattori, Victor; Borghi, Sergio M; Guazelli, Carla F S; Giroldo, Andressa C; Crespigio, Jefferson; Bussmann, Allan J C; Coelho-Silva, Letícia; Ludwig, Natasha G; Mazzuco, Tânia L; Casagrande, Rubia; Verri, Waldiceu A

2017-06-01

Acute kidney injury (AKI) represents a complex clinical condition associated with significant morbidity and mortality. Approximately, 19-33% AKI episodes in hospitalized patients are related to drug-induced nephrotoxicity. Although, considered safe, non-steroidal anti-inflammatory drugs such as diclofenac have received special attention in the past years due to the potential risk of renal damage. Vinpocetine is a nootropic drug known to have anti-inflammatory properties. In this study, we investigated the effect and mechanisms of vinpocetine in a model of diclofenac-induced AKI. We observed that diclofenac increased proteinuria and blood urea, creatinine, and oxidative stress levels 24h after its administration. In renal tissue, diclofenac also increased oxidative stress and induced morphological changes consistent with renal damage. Moreover, diclofenac induced kidney cells apoptosis, up-regulated proinflammatory cytokines, and induced the activation of NF-κB in renal tissue. On the other hand, vinpocetine reduced diclofenac-induced blood urea and creatinine. In the kidneys, vinpocetine inhibited diclofenac-induced oxidative stress, morphological changes, apoptosis, cytokine production, and NF-κB activation. To our knowledge, this is the first study demonstrating that diclofenac-induced AKI increases NF-κB activation, and that vinpocetine reduces the nephrotoxic effects of diclofenac. Therefore, vinpocetine is a promising molecule for the treatment of diclofenac-induced AKI. Copyright © 2017 Elsevier Ltd. All rights reserved.

An acute, double-blind, placebo-controlled cross-over study of 320 mg and 640 mg doses of Bacopa monnieri (CDRI 08) on multitasking stress reactivity and mood.

PubMed

Benson, Sarah; Downey, Luke A; Stough, Con; Wetherell, Mark; Zangara, Andrea; Scholey, Andrew

2014-04-01

Little research exists in humans concerning the anxiolytic, antidepressant, sedative, and adaptogenic actions the traditional Ayurvedic medicine Bacopa monnieri (BM) possesses in addition to its documented cognitive-enhancing effects. Preclinical work has identified a number of acute anxiolytic, nootropic, and adaptogenic effects of BM that may also co-occur in humans. The current double-blind, placebo-controlled cross-over study assessed the acute effects of a specific extract of BM (KeenMind® - CDRI 08) in normal healthy participants during completion of a multitasking framework (MTF). Seventeen healthy volunteers completed the MTF, at baseline, then 1 h and 2 h after consuming a placebo, 320 mg BM and 640 mg of BM. Treatments were separated by a 7-day washout with order determined by Latin Square. Outcome measures included cognitive outcomes from the MTF, with mood and salivary cortisol measured before and after each completion of the MTF. Change from baseline scores indicated positive cognitive effects, notably at both 1 h post and 2 h post BM consumption on the Letter Search and Stroop tasks, suggesting an earlier nootropic effect of BM than previously investigated. There were also some positive mood effects and reduction in cortisol levels, pointing to a physiological mechanism for stress reduction associated with BM consumption. It was concluded that acute BM supplementation produced some adaptogenic and nootropic effects that need to be replicated in a larger sample and in isolation from stressful cognitive tests in order to quantify the magnitude of these effects. The study was registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12612000834853). Copyright © 2013 John Wiley & Sons, Ltd.

Neuropharmacological Review of the Nootropic Herb Bacopa monnieri

PubMed Central

Borowski, Thomas

2013-01-01

Abstract This review synthesizes behavioral research with neuromolecular mechanisms putatively involved with the low-toxicity cognitive enhancing action of Bacopa monnieri (BM), a medicinal Ayurvedic herb. BM is traditionally used for various ailments, but is best known as a neural tonic and memory enhancer. Numerous animal and in vitro studies have been conducted, with many evidencing potential medicinal properties. Several randomized, double-blind, placebo-controlled trials have substantiated BM's nootropic utility in humans. There is also evidence for potential attenuation of dementia, Parkinson's disease, and epilepsy. Current evidence suggests BM acts via the following mechanisms—anti-oxidant neuroprotection (via redox and enzyme induction), acetylcholinesterase inhibition and/or choline acetyltransferase activation, β-amyloid reduction, increased cerebral blood flow, and neurotransmitter modulation (acetylcholine [ACh], 5-hydroxytryptamine [5-HT], dopamine [DA]). BM appears to exhibit low toxicity in model organisms and humans; however, long-term studies of toxicity in humans have yet to be conducted. This review will integrate molecular neuroscience with behavioral research. PMID:23772955

[Dipeptide nootropic agent GVS-111 prevents accumulation of the lipid peroxidation products during immobilization].

PubMed

Lysenko, A V; Uskova, N I; Ostrovskaia, R U; Gudasheva, T A; Voronina, T A

1997-01-01

Immobilization of rats in a narrow plastic chamber for 24 h caused a sharp increase in the level of diene conjugates and the content of schiff bases in the synaptosomes of the brain cortex as well as accumulation of extraerythrocytic hemoglobin in blood serum. The dipeptide nootropic agent GVS-111 (ethyl ether of phenylacetylprolylglycine), when administered 15 and particularly 60 min before immobilization reduced the accumulation of these products of lipid peroxidation in the brain and blood. GVS-111 demonstrated these signs of its antioxidant effect after a single i.p. injection in doses of 0.12 and 0.5 mg/kg. Pyracetam produced a similar effect on the listed parameters in injection in a dose of 300 mg/kg for three successive days. The protective effect of the new pyracetam dipeptide analog GVS-111 in relation to activation of free-radical processes induced by immobilization is additional proof of the antistress action of this dipeptide.

Neuropharmacological review of the nootropic herb Bacopa monnieri.

PubMed

Aguiar, Sebastian; Borowski, Thomas

2013-08-01

This review synthesizes behavioral research with neuromolecular mechanisms putatively involved with the low-toxicity cognitive enhancing action of Bacopa monnieri (BM), a medicinal Ayurvedic herb. BM is traditionally used for various ailments, but is best known as a neural tonic and memory enhancer. Numerous animal and in vitro studies have been conducted, with many evidencing potential medicinal properties. Several randomized, double-blind, placebo-controlled trials have substantiated BM's nootropic utility in humans. There is also evidence for potential attenuation of dementia, Parkinson's disease, and epilepsy. Current evidence suggests BM acts via the following mechanisms-anti-oxidant neuroprotection (via redox and enzyme induction), acetylcholinesterase inhibition and/or choline acetyltransferase activation, β-amyloid reduction, increased cerebral blood flow, and neurotransmitter modulation (acetylcholine [ACh], 5-hydroxytryptamine [5-HT], dopamine [DA]). BM appears to exhibit low toxicity in model organisms and humans; however, long-term studies of toxicity in humans have yet to be conducted. This review will integrate molecular neuroscience with behavioral research.

Neurological Effects of Honey: Current and Future Prospects

PubMed Central

Mijanur Rahman, Mohammad; Gan, Siew Hua; Khalil, Md. Ibrahim

2014-01-01

Honey is the only insect-derived natural product with therapeutic, traditional, spiritual, nutritional, cosmetic, and industrial value. In addition to having excellent nutritional value, honey is a good source of physiologically active natural compounds, such as polyphenols. Unfortunately, there are very few current research projects investigating the nootropic and neuropharmacological effects of honey, and these are still in their early stages. Raw honey possesses nootropic effects, such as memory-enhancing effects, as well as neuropharmacological activities, such as anxiolytic, antinociceptive, anticonvulsant, and antidepressant activities. Research suggests that the polyphenol constituents of honey can quench biological reactive oxygen species and counter oxidative stress while restoring the cellular antioxidant defense system. Honey polyphenols are also directly involved in apoptotic activities while attenuating microglia-induced neuroinflammation. Honey polyphenols are useful in improving memory deficits and can act at the molecular level. Therefore, the ultimate biochemical impact of honey on specific neurodegenerative diseases, apoptosis, necrosis, neuroinflammation, synaptic plasticity, and behavior-modulating neural circuitry should be evaluated with appropriate mechanistic approaches using biochemical and molecular tools. PMID:24876885

Traditional Chinese Nootropic Medicine Radix Polygalae and Its Active Constituent Onjisaponin B Reduce β-Amyloid Production and Improve Cognitive Impairments

PubMed Central

Li, Xiaohang; Cui, Jin; Yu, Yang; Li, Wei; Hou, Yujun; Wang, Xin; Qin, Dapeng; Zhao, Cun; Yao, Xinsheng; Zhao, Jian; Pei, Gang

2016-01-01

Decline of cognitive function is the hallmark of Alzheimer’s disease (AD), regardless of the pathological mechanism. Traditional Chinese medicine has been used to combat cognitive impairments and has been shown to improve learning and memory. Radix Polygalae (RAPO) is a typical and widely used herbal medicine. In this study, we aimed to follow the β-amyloid (Aβ) reduction activity to identify active constituent(s) of RAPO. We found that Onjisaponin B of RAPO functioned as RAPO to suppress Aβ production without direct inhibition of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and γ-secretase activities. Our mechanistic study showed that Onjisaponin B promoted the degradation of amyloid precursor protein (APP). Further, oral administration of Onjisaponin B ameliorated Aβ pathology and behavioral defects in APP/PS1 mice. Taken together, our results indicate that Onjisaponin B is effective against AD, providing a new therapeutic agent for further drug discovery. PMID:26954017

Nootropic activity of Celastrus paniculatus seed.

PubMed

Bhanumathy, M; Harish, M S; Shivaprasad, H N; Sushma, G

2010-03-01

The effect of Celastrus paniculatus Willd. (Celastraceae) seed aqueous extract on learning and memory was studied using elevated plus maze and passive avoidance test (sodium nitrite induced amnesia rodent model). The aqueous seed extract was administered orally in two different doses to rats (350 and 1050 mg/kg) and to mice (500 and 1500 mg/kg). The results were compared to piracetam (100 mg/kg, p.o.) used as a standard drug. Chemical hypoxia was induced by subcutaneous administration of sodium nitrite (35 mg/kg), immediately after acquisition training. In elevated plus maze and sodium nitrite-induced amnesia model, Celastrus paniculatus extract has showed statistically significant improvement in memory process when compared to control. The estimation of acetylcholinesterase enzyme in rat brain supports the plus maze and passive avoidance test by reducing acetylcholinesterase activity which helps in memory performance. The study reveals that the aqueous extract of Celastrus paniculatus seed has dose-dependent cholinergic activity, thereby improving memory performance. The mechanism by which Celastrus paniculatus enhances cognition may be due to increased acetylcholine level in rat brain.

Traditional Chinese Nootropic Medicine Radix Polygalae and Its Active Constituent Onjisaponin B Reduce β-Amyloid Production and Improve Cognitive Impairments.

PubMed

Li, Xiaohang; Cui, Jin; Yu, Yang; Li, Wei; Hou, Yujun; Wang, Xin; Qin, Dapeng; Zhao, Cun; Yao, Xinsheng; Zhao, Jian; Pei, Gang

2016-01-01

Decline of cognitive function is the hallmark of Alzheimer's disease (AD), regardless of the pathological mechanism. Traditional Chinese medicine has been used to combat cognitive impairments and has been shown to improve learning and memory. Radix Polygalae (RAPO) is a typical and widely used herbal medicine. In this study, we aimed to follow the β-amyloid (Aβ) reduction activity to identify active constituent(s) of RAPO. We found that Onjisaponin B of RAPO functioned as RAPO to suppress Aβ production without direct inhibition of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and γ-secretase activities. Our mechanistic study showed that Onjisaponin B promoted the degradation of amyloid precursor protein (APP). Further, oral administration of Onjisaponin B ameliorated Aβ pathology and behavioral defects in APP/PS1 mice. Taken together, our results indicate that Onjisaponin B is effective against AD, providing a new therapeutic agent for further drug discovery.

Aniracetam reduces glutamate receptor desensitization and slows the decay of fast excitatory synaptic currents in the hippocampus.

PubMed Central

Isaacson, J S; Nicoll, R A

1991-01-01

Aniracetam is a nootropic drug that has been shown to selectively enhance quisqualate receptor-mediated responses in Xenopus oocytes injected with brain mRNA and in hippocampal pyramidal cells [Ito, I., Tanabe, S., Kohda, A. & Sugiyama, H. (1990) J. Physiol. (London) 424, 533-544]. We have used patch clamp recording techniques in hippocampal slices to elucidate the mechanism for this selective action. We find that aniracetam enhances glutamate-evoked currents in whole-cell recordings and, in outside-out patches, strongly reduces glutamate receptor desensitization. In addition, aniracetam selectively prolongs the time course and increases the peak amplitude of fast synaptic currents. These findings indicate that aniracetam slows the kinetics of fast synaptic transmission and are consistent with the proposal [Trussell, L. O. & Fischbach, G. D. (1989) Neuron 3, 209-218; Tang, C.-M., Dichter, M. & Morad, M. (1989) Science 243, 1474-1477] that receptor desensitization governs the strength of fast excitatory synaptic transmission in the brain. PMID:1660156

Aniracetam reduces glutamate receptor desensitization and slows the decay of fast excitatory synaptic currents in the hippocampus.

PubMed

Isaacson, J S; Nicoll, R A

1991-12-01

Aniracetam is a nootropic drug that has been shown to selectively enhance quisqualate receptor-mediated responses in Xenopus oocytes injected with brain mRNA and in hippocampal pyramidal cells [Ito, I., Tanabe, S., Kohda, A. & Sugiyama, H. (1990) J. Physiol. (London) 424, 533-544]. We have used patch clamp recording techniques in hippocampal slices to elucidate the mechanism for this selective action. We find that aniracetam enhances glutamate-evoked currents in whole-cell recordings and, in outside-out patches, strongly reduces glutamate receptor desensitization. In addition, aniracetam selectively prolongs the time course and increases the peak amplitude of fast synaptic currents. These findings indicate that aniracetam slows the kinetics of fast synaptic transmission and are consistent with the proposal [Trussell, L. O. & Fischbach, G. D. (1989) Neuron 3, 209-218; Tang, C.-M., Dichter, M. & Morad, M. (1989) Science 243, 1474-1477] that receptor desensitization governs the strength of fast excitatory synaptic transmission in the brain.

Selective effects of aniracetam across receptor types and forms of synaptic facilitation in hippocampus.

PubMed

Xiao, P; Staubli, U; Kessler, M; Lynch, G

1991-10-01

Aniracetam reversibly increased synaptic responses mediated by the AMPA but not the NMDA subclass of glutamate receptors in hippocampus and was considerably more potent than structurally similar nootropics. The drug had greater effects on field excitatory postsynaptic potentials (EPSPs) in the dentate gyrus and CA1 region than it did in the CA3 region, suggesting that it differentiates between variants of the AMPA receptor. Ligand binding to glutamate receptors in synaptosomal membrane fractions was minimally changed by aniracetam. Finally, the percent facilitation produced by aniracetam in the CA1 region was not reduced by any of three treatments (4-aminopyridine, changes in extracellular calcium concentrations, paired-pulse stimulation) that affect release but, in accord with a previous report, was substantially decreased by long-term potentiation. These results support the conclusion that aniracetam selectively increases the conductance of a subgroup of synaptic AMPA receptors in hippocampus and suggest that receptor changes underlie the expression of long-term potentiation.

Trace metals accumulation in Bacopa monnieri and their bioaccessibility.

PubMed

Srikanth Lavu, Rama Venkata; Prasad, Majeti Narasimha Vara; Pratti, Varalakshmi Lalithya; Meißner, Ralph; Rinklebe, Jörg; Van De Wiele, Tom; Tack, Filip; Du Laing, Gijs

2013-08-01

Bacopa monnieri is commonly known as "Brahmi" or "Water hyssop" and is a source of nootropic drugs. Aboveground parts of plant samples collected from peri-urban Indian areas were analysed for total trace metal concentrations. Subsequently, three samples with high concentrations of Cd and Pb were subjected to in vitro gastrointestinal digestion to assess the bioaccessibility of the trace metals in these plants. The total concentrations of trace metals on a dry weight basis were 1.3 to 6.7 mg·kg⁻¹ Cd, 1.5 to 22 mg·kg⁻¹ Pb, 36 to 237 mg·kg⁻¹ Cu, and 78 to 186 mg·kg⁻¹ Zn. The majority of Bacopa monnieri samples exceeded threshold limits of Cd, Pb, Cu, and Zn for use as raw medicinal plant material or direct consumption. Therefore, it is necessary to evaluate Bacopa monnieri collected in nature for their trace metal content prior to human consumption and preparation of herbal formulations. Georg Thieme Verlag KG Stuttgart · New York.

Effects of piracetam on behavior and memory in adult zebrafish.

PubMed

Grossman, Leah; Stewart, Adam; Gaikwad, Siddharth; Utterback, Eli; Wu, Nadine; Dileo, John; Frank, Kevin; Hart, Peter; Howard, Harry; Kalueff, Allan V

2011-04-25

Piracetam, a derivative of γ-aminobutyric acid, exerts memory-enhancing and mild anxiolytic effects in human and rodent studies. To examine the drug's behavioral profile further, we assessed its effects on behavioral and endocrine (cortisol) responses of adult zebrafish (Danio rerio)--a novel model species rapidly gaining popularity in neurobehavioral research. Overall, acute piracetam did not affect zebrafish novel tank and light-dark box behavior at mild doses (25-400mg/L), but produced nonspecific behavioral inhibition at 700mg/L. No effects on cortisol levels or inter-/intra-session habituation in the novel tank test were observed for acute or chronic mild non-sedative dose of 200mg/L. In contrast, fish exposed to chronic piracetam at this dose performed significantly better in the cued learning plus-maze test. This observation parallels clinical and rodent literature on the behavioral profile of piracetam, supporting the utility of zebrafish paradigms for testing nootropic agents. Copyright © 2011 Elsevier Inc. All rights reserved.

[Melatonin as a universal stabilizing factor of mental activity].

PubMed

Arushanian, Ē B

2011-01-01

Pineal hormone melatonin stabilizes mental activity of man and animals due to its somnogenic, anxiolytic, antidepressant and nootropic properties. Melatonin effects are based on the synchronization of biological rhythms via the influence on the cerebral structures which control biological rhythms and emotions and normalize endocrine and immune state.

Improving General Intelligence with a Nutrient-Based Pharmacological Intervention

ERIC Educational Resources Information Center

Stough, Con; Camfield, David; Kure, Christina; Tarasuik, Joanne; Downey, Luke; Lloyd, Jenny; Zangara, Andrea; Scholey, Andrew; Reynolds, Josh

2011-01-01

Cognitive enhancing substances such as amphetamine and modafinil have become popular in recent years to improve acute cognitive performance particularly in environments in which enhanced cognition or intelligence is required. Nutraceutical nootropics, which are natural substances that have the ability to bring about acute or chronic changes in…

Exploring neuroprotective potential of Withania somnifera phytochemicals by inhibition of GluN2B-containing NMDA receptors: An in silico study.

PubMed

Kumar, Gaurav; Patnaik, Ranjana

2016-07-01

N-methyl-d-aspartate receptors (NMDARs) mediated excitotoxicity has been implicated in multi-neurodegenerative diseases. Due to lack of efficacy and adverse effects of NMDA receptor antagonists, search for herbal remedies that may act as therapeutic agents is an active area of research to combat these diseases. Withania somnifera (WS) is being used for centuries as a nerve tonic and Nootropic agents. The present study targets the in silico evaluation of the neuroprotective efficacy of W. somnifera phytochemicals by inhibition of NMDA receptor-mediated excitotoxicity through allosteric inhibition of the GluN2B containing NMDARs. We predict Blood Brain Barrier (BBB) penetration, mutagenicity, drug-likeness and Human Intestinal Absorption properties of 25 WS phytochemicals. Further, molecular docking was performed to know whether these phytochemicals inhibit the GluN2B containing NMDARs or not. The results suggest that Anaferine, Beta-Sitosterol, Withaferin A, Withanolide A, Withanolide B and Withanolide D inhibit GluN2B containing NMDARs through allosteric mode similar to the well-known selective antagonist Ifenprodil. These phytochemicals have potential as an essentially useful oral drug to counter NMDARs mediated excitotoxicity and to treat multi-neurodegenerative diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.

Piracetam and aniracetam antagonism of centrally active drug-induced antinociception.

PubMed

Galeotti, N; Ghelardini, C; Bartolini, A

1996-04-01

The effects of the nootropic drugs piracetam and aniracetam on antinociception induced by baclofen, bicuculline, and picrotoxin and on baclofen-induced muscle relaxation were studied in mice. Antinociception was investigated using both the hot plate (thermal stimulus) and abdominal constriction (chemical stimulus) tests. Both behaviour inhibition and muscle relaxation were observed by using the rota-rod test. Piracetam (30 mg/kg, IP) and aniracetam (10 mg/kg, PO) reduced baclofen, bicuculline, and picrotoxin antinociception without modifying analgesia induced by non-GABAergic drugs such as morphine, physostigmine, clomipramine, and diphenhydramine. In this concentration range, piracetam, and aniracetam were also able to reduce the inhibition of rota-rod performance. At higher doses piracetam (100 mg/kg, IP) and aniracetam (100 mg/kg, PO) were able to completely prevent baclofen antinociception. However, when prevention of GABAergic antinociception was complete, piracetam and aniracetam were able to block non-GABAergic antinociception also. comparing the effects of piracetam and aniracetam with those exerted by the GABAB antagonist CGP 35348, a reduction of non-GABAergic analgesia was also observed using higher doses of CGP 35348 (2.5 micrograms per mouse ICV). The present results indicate that piracetam and aniracetam, by preventing both of the investigated effects of baclofen, have some selectivity against GABAB-mediated inhibition. The well-known activity of piracetam and aniracetam on learning and memory might, therefore, depend, at least in part, on the removal of inhibitory GABAB mechanisms that impair attention and cognitive functions.

Inefficacy of piracetam in the prevention of painful crises in children and adolescents with sickle cell disease.

PubMed

Alvim, R C; Viana, M B; Pires, M A S; Franklin, H M O H; Paula, M J; Brito, A C; Oliveira, T F; Rezende, P V

2005-01-01

Analgesia and hydration remain the only safe treatment for painful crises of sickle cell disease; hydroxyurea is effective, but the toxicity is still a problem. Piracetam is a nootropic drug that has reportedly been effective and non-toxic in sickle cell patients, but most studies were not placebo-controlled and included a small number of patients. The present study evaluated the drug in a double-blind crossed placebo-controlled clinical trial in 73 children and adolescents suffering from moderate to severe painful crises for 13 months. Information regarding frequency and severity of pain was acquired through monthly clinical evaluation, visits and house calls, and 4,300 weekly questionnaires filled out by the patients in their domiciles. A monthly pain score was calculated for each patient. Pain was the most frequent adverse manifestation of the disease stressing its significant bio-psycho-social impact. Although nearly all patients and relatives reported a better clinical course throughout the whole study, the drug was ineffective in the prevention of painful crises. This placebo effect may be ascribed to an unplanned and unsystematic 'cognitive-behavioural' management of the children. The pain score in the second semester of the study - both in the experimental and in the control groups - was significantly smaller than that in the first semester. In conclusion, piracetam was found to be ineffective in the prevention of painful crises; a powerful placebo effect due to adequate patient care was demonstrated. Copyright (c) 2005 S. Karger AG, Basel

"Asparagus Racemosus" Enhances Memory and Protects against Amnesia in Rodent Models

ERIC Educational Resources Information Center

Ojha, Rakesh; Sahu, Alakh N.; Muruganandam, A. V.; Singh, Gireesh Kumar; Krishnamurthy, Sairam

2010-01-01

"Asparagus Racemosus" (AR) is an Ayurvedic rasayana possessing multiple neuropharmacological activities. The adpatogenic and antidepressant activity of AR is well documented. The present study was undertaken to assess nootropic and anti-amnesic activities of MAR in rats. The Morris water maze (MWM) and elevated plus maze (EPM) models were employed…

In vitro screening of major neurotransmitter systems possibly involved in the mechanism of action of antibodies to S100 protein in released-active form

PubMed Central

Gorbunov, Evgeniy A; Ertuzun, Irina A; Kachaeva, Evgeniya V; Tarasov, Sergey A; Epstein, Oleg I

2015-01-01

Experimentally and clinically, it was shown that released-active form of antibodies to S100 protein (RAF of Abs to S100) exerts a wide range of pharmacological activities: anxiolytic, antiasthenic, antiaggressive, stress-protective, antihypoxic, antiischemic, neuroprotective, and nootropic. The purpose of this study was to determine the influence of RAF of Abs to S100 on major neurotransmitter systems (serotoninergic, GABAergic, dopaminergic, and on sigma receptors as well) which are possibly involved in its mechanism of pharmacological activity. Radioligand binding assays were used for assessment of the drug influence on ligand–receptor interaction. [35S]GTPγS binding assay, cyclic adenosine monophosphate HTRF™, cellular dielectric spectroscopy assays, and assays based on measurement of intracellular concentration of Ca2+ ions were used for assessment of agonist or antagonist properties of the drug toward receptors. RAF of Abs to S100 increased radioligand binding to 5-HT1F, 5-HT2B, 5-HT2Cedited, 5-HT3, and to D3 receptors by 142.0%, 131.9%, 149.3%, 120.7%, and 126.3%, respectively. Also, the drug significantly inhibited specific binding of radioligands to GABAB1A/B2 receptors by 25.8%, and to both native and recombinant human sigma1 receptors by 75.3% and 40.32%, respectively. In the functional assays, it was shown that the drug exerted antagonism at 5-HT1B, D3, and GABAB1A/B2 receptors inhibiting agonist-induced responses by 23.24%, 32.76%, and 30.2%, respectively. On the contrary, the drug exerted an agonist effect at 5-HT1A receptors enhancing receptor functional activity by 28.0%. The pharmacological profiling of RAF of Abs to S100 among 27 receptor provides evidence for drug-related modification of major neurotransmitter systems. PMID:26604768

Organic brain syndrome treated with oxiracetam. A double-blind randomized controlled trial.

PubMed

Hjorther, A; Browne, E; Jakobsen, K; Viskum, P; Gyntelberg, F

1987-04-01

In a 12-week double-blind study, oxiracetam (CGP 21690 E), a new nootropic drug, at a dose of 2.4 mg per day, was compared to placebo in the treatment of 106 middle-aged patients suffering from mild to moderate organic brain syndrome due to prolonged exposure to organic solvents. At the beginning of the study and after 12 weeks treatment, the patients underwent a battery of neuropsychological tests to determine their mental and memory functioning. A symptom questionnaire consisting of 21 items was rated pre-treatment, and improvement or worsening of any of the symptoms recorded monthly. At the end of the study a global evaluation was performed by the patients themselves, their relatives, the psychologist and the doctor. The code was not broken until the final writing of this paper. No statistically significant differences were observed between the treatment groups in any of the above-mentioned evaluations; neither were any differences in the neuropsychological tests performance observed. Thus, oxiracetam seems to have no effect in the treatment of organic brain syndrome.

Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets.

PubMed

Lam, Max; Trampush, Joey W; Yu, Jin; Knowles, Emma; Davies, Gail; Liewald, David C; Starr, John M; Djurovic, Srdjan; Melle, Ingrid; Sundet, Kjetil; Christoforou, Andrea; Reinvang, Ivar; DeRosse, Pamela; Lundervold, Astri J; Steen, Vidar M; Espeseth, Thomas; Räikkönen, Katri; Widen, Elisabeth; Palotie, Aarno; Eriksson, Johan G; Giegling, Ina; Konte, Bettina; Roussos, Panos; Giakoumaki, Stella; Burdick, Katherine E; Payton, Antony; Ollier, William; Chiba-Falek, Ornit; Attix, Deborah K; Need, Anna C; Cirulli, Elizabeth T; Voineskos, Aristotle N; Stefanis, Nikos C; Avramopoulos, Dimitrios; Hatzimanolis, Alex; Arking, Dan E; Smyrnis, Nikolaos; Bilder, Robert M; Freimer, Nelson A; Cannon, Tyrone D; London, Edythe; Poldrack, Russell A; Sabb, Fred W; Congdon, Eliza; Conley, Emily Drabant; Scult, Matthew A; Dickinson, Dwight; Straub, Richard E; Donohoe, Gary; Morris, Derek; Corvin, Aiden; Gill, Michael; Hariri, Ahmad R; Weinberger, Daniel R; Pendleton, Neil; Bitsios, Panos; Rujescu, Dan; Lahti, Jari; Le Hellard, Stephanie; Keller, Matthew C; Andreassen, Ole A; Deary, Ian J; Glahn, David C; Malhotra, Anil K; Lencz, Todd

2017-11-28

Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Piracetam induces plasma membrane depolarization in rat brain synaptosomes.

PubMed

Fedorovich, Sergei V

2013-10-11

Piracetam is a cyclic derivative of γ-aminobutyric acid (GABA). It was the first nootropic drug approved for clinical use. However, mechanism of its action is still not clear. In present paper, I investigated effects of piracetam on neurotransmitter release, plasma membrane potential monitored by fluorescent dye DiSC3(5) and chloride transport monitored by fluorescent dye SPQ in rat brain synaptosomes. It was shown that piracetam (1 mM) induces slow weak plasma membrane depolarization. This effect was decreased on 43% and 58% by both AMPA/kainate receptor blockers NBQX (10 μM) and CNQX (100 μM), respectively, on 84% by GABA ionotropic receptor blocker picrotoxin (50 μM) and on 91% upon withdrawal of HCO(3-) ions from incubation medium. GABA (1 mM) and kainate (100 μM) were found not to produce changes of plasma membrane potential. Also, it was found that piracetam induces chloride efflux which seems to be the reason of depolarization. Thereby, piracetam induces depolarization of plasma membrane of isolated neuronal presynaptic endings by picrotoxin-sensitive way. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Spontaneous and drug-induced remission of alcoholic organic brain syndrome: clinical, psychometric, and neurophysiological studies.

PubMed

Saletu, B; Saletu, M; Grünberger, J; Mader, R

1983-09-01

The spontaneous and drug-induced remission of alcoholic organic brain syndrome was studied in a double-blind, placebo-controlled trial. Forty patients with alcoholic organic brain syndrome (OBS) were randomly assigned to a 6-week treatment with either placebo or piridoxilate, a reciprocal salt between two stereoisomers of the glyoxylic acid-substituted piridoxine. Clinical, psychometric, and computer-assisted spectral analyses of the electroencephalogram (EEG) were carried out in weeks 0, 2, 4, and 6. Piridoxale-5-phosphate (PLP) blood level determination and laboratory investigations were performed before therapy and also in weeks 4 and 6. Both groups of patients demonstrated significant clinical improvement over 6 weeks of treatment, but the improvement in the piridoxilate-treated group was significantly greater than that in the placebo group. This conclusion was also confirmed by psychometric tests demonstrating a greater improvement in attention, concentration, attention variability, tapping, visual and numerical memory, and aftereffect (Archimedean spiral) in the piridoxilate than in the placebo group. Spectral analysis of the EEG showed an increase in alpha and a decrease in fast beta activities in both groups, while delta activity was attenuated only in the piridoxilate-treated group. The latter was found to be significantly correlated with the improvement in psychopathology. The present data confirm previous predictions about the encephalotropic and psychotropic properties of piridoxilate; these predictions were based on pharmaco-EEG trials in the elderly that suggested vigilance-improving qualities of piridoxilate. The reversible alcoholic OBS appears to be a suitable model for the assessment of therapeutic efficacy of nootropic drugs.

Neuroprotective properties of nootropic dipeptide GVS-111 in in vitro oxygen-glucose deprivation, glutamate toxicity and oxidative stress.

PubMed

Andreeva, N A; Stel'mashuk, E V; Isaev, N K; Ostrovskaya, R U; Gudasheva, T A; Viktorov, I V

2000-10-01

Argon anoxia and glucose deprivation were used for modeling of ischemic damage in the cultures of cerebellar granule cells. Protective effect of peptide piracetam analogue GVS-111 was demonstrated. GVS-111 prevented neurodegeneration induced by glutamate and oxidative stress. In contrast to GVS-111, piracetam did not attenuate neurocytotoxic effect of glutamate.

JPRS Report - Science & Technology USSR: Life Sciences.

DTIC Science & Technology

1988-06-17

No 6. Nov-Dec 87] 11 Electron Microscopic and Radioautographic Investigation of Bronchi in Chronic Inflammation Upon Exposure to Helium-Neon...87] 22 Functional and Morphological Characteristics of Stress-Protective Action of Piracetam [V. M. Vinogradov, A. A. Klishov et al; FARMAKOLOGIYA...I TOKSIKOLOGIYA No 6, Nov-Dec 87] 23 Comparative Neurophysiological Studies on Nootropic Agents Piracetam and Centrophenoxine [S. V Krapivin, T. A

Hypericum perforatum as a cognitive enhancer in rodents: A meta-analysis

PubMed Central

Ben-Eliezer, Daniel; Yechiam, Eldad

2016-01-01

Considered an antidepressant and anti-anxiety agent, Hypericum perforatum affects multiple neurotransmitters in a non-competitive synergistic manner, and may have nootropic potential. We quantitatively reviewed the pre-clinical literature to examine if there is a cognitive-enhancing effect of H. perforatum in healthy rodents. Additionally, within these studies, we compared the effects observed in intact rodents versus those whose performance has been impaired, mostly through stress manipulations. The meta-analysis incorporated studies that examined the effect of H. perforatum versus placebo on memory indices of task performance. All analyses were based on weighting different studies according to their inverse variance. Thirteen independent studies (published 2000–2014) involving 20 experimental comparisons met our inclusion criteria. The results showed a large positive effect of H. perforatum on cognitive performance for intact, healthy rodents (d = 1.11), though a larger effect emerged for stress-impaired rodents (d = 3.10 for restraint stress). The positive effect on intact rodents was observed in tasks assessing reference memory as well as working memory, and was not moderated by the type of memory or motivation (appetitive versus aversive). Thus, while primarily considered as a medication for depression, H. perforatum shows considerable nootropic potential in rodents. PMID:27762349

Brahmi rasayana Improves Learning and Memory in Mice

PubMed Central

Joshi, Hanumanthachar; Parle, Milind

2006-01-01

Cure of cognitive disorders such as amnesia, attention deficit and Alzheimer's disease is still a nightmare in the field of medicine. Nootropic agents such as piracetam, aniracetam and choline esterase inhibitors like Donepezil® are being used to improve memory, mood and behavior, but the resulting side effects associated with these agents have made their use limited. The present study was undertaken to assess the potential of Brahmi rasayana (BR) as a memory enhancer. BR (100 and 200 mg kg−1 p.o.) was administered for eight successive days to both young and aged mice. Elevated plus maze and passive-avoidance paradigm were employed to evaluate learning and memory parameters. Scopolamine (0.4 mg kg−1 i.p.) was used to induce amnesia in mice. The effect of BR on whole brain AChE activity was also assessed. Piracetam (200 mg kg−1 i.p.) was used as a standard nootropic agent. BR significantly improved learning and memory in young mice and reversed the amnesia induced by both scopolamine (0.4 mg kg−1 i.p.) and natural aging. BR significantly decreased whole brain acetyl cholinesterase activity. BR might prove to be a useful memory restorative agent in the treatment of dementia seen in elderly. PMID:16550227

Peptide profiling of Internet-obtained Cerebrolysin using high performance liquid chromatography - electrospray ionization ion trap and ultra high performance liquid chromatography - ion mobility - quadrupole time of flight mass spectrometry.

PubMed

Gevaert, Bert; D'Hondt, Matthias; Bracke, Nathalie; Yao, Han; Wynendaele, Evelien; Vissers, Johannes Petrus Cornelis; De Cecco, Martin; Claereboudt, Jan; De Spiegeleer, Bart

2015-09-01

Cerebrolysin, a parenteral peptide preparation produced by controlled digestion of porcine brain proteins, is an approved nootropic medicine in some countries. However, it is also easily and globally available on the Internet. Nevertheless, until now, its exact chemical composition was unknown. Using high performance liquid chromatography (HPLC) coupled to ion trap and ultra high performance liquid chromatography (UHPLC) coupled to quadrupole-ion mobility-time-of-flight mass spectrometry (Q-IM-TOF MS), combined with UniProt pig protein database search and PEAKS de novo sequencing, we identified 638 unique peptides in an Internet-obtained Cerebrolysin sample. The main components in this sample originate from tubulin alpha- and beta-chain, actin, and myelin basic protein. No fragments of known neurotrophic factors like glial cell-derived neurotrophic factor (GDNF), neurotrophin nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and ciliary neurotrophic factor (CNTF) were found, suggesting that the activities reported in the literature are likely the result of new, hitherto unknown cryptic peptides with nootropic properties. Copyright © 2015 John Wiley & Sons, Ltd.

Drug treatment of poststroke aphasia.

PubMed

Bakheit, A M O

2004-03-01

Impairment of language function (aphasia) is one of the most common neurological symptoms after stroke. Approximately one in every three patients who have an acute stroke will suffer from aphasia. The estimated incidence and prevalence of stroke in Western Europe is 140 and 800 per 100,000 of the population. Aphasia often results in significant disability and handicap. It is a major obstacle for patients to live independently in the community. When recovery from aphasia occurs, it is usually incomplete and patients are rarely able to return to full employment and other social activities. Currently, the main treatment for aphasia is conventional speech and language therapy. However, the effectiveness of this intervention has not been conclusively demonstrated and empirical observations suggest that spontaneous biological recovery may explain most of the improvement in language function that occurs in aphasics. The generally poor prognosis of the severe forms of poststroke language impairment (Broca, Wernicke and global aphasia), coupled with the limited effectiveness of conventional speech and language therapy has stimulated the search for other treatments that may be used in conjunction with speech and language therapy, including the use of various drugs. Dopamine agonists, piracetam (Nootropil), amphetamines, and more recently donepezil (Aricept), have been used in the treatment of aphasia in both the acute and chronic phase. The justification for the use of drugs in the treatment of aphasia is based on two types of evidence. Some drugs, such as dextroamphetamine (Dexedrine), improve attention span and enhance learning and memory. Learning is an essential mechanism for the acquisition of new motor and cognitive skills, and hence, for recovery from aphasia. Second, laboratory and clinical data suggest that drug treatment may partially restore the metabolic function in the ischemic zone that surrounds the brain lesion and also has a neuroprotective effect following acute brain damage. An example of this is the nootropic agent piracetam. Extensive animal studies have demonstrated the beneficial effects of this and other drugs on neural plasticity, but data on humans are still sparse. This review provides a critical analysis of the current evidence of the effectiveness of these drugs in the treatment of acute and chronic aphasia.

Nootropic, neuroprotective and neurotrophic effects of phloretin in scopolamine induced amnesia in mice.

PubMed

Ghumatkar, Priya J; Patil, Sachin P; Jain, Pankaj D; Tambe, Rufi M; Sathaye, Sadhana

2015-08-01

Phloretin (PHL), a dihydrochalcone flavonoid usually present in the roots and leaves of apple tree. In vitro study on GT1-7 immortalized hypothalamic neurons exposed to amyloid beta (25-35), demonstrated that PHL significantly influenced membrane fluidity and potential. PHL also significantly decreased excitotoxicity by restoring the calcium homeostasis in the same. Thus, PHL proves to be a promising therapeutic moiety which should be further screened in the treatment of Alzheimer's disease. The objective of the present study was to evaluate the nootropic, neuroprotective and neurotrophic roles of PHL in the subacute scopolamine induced amnesia in mice. In this study, mice were pretreated with PHL 2.5mg/kg, 5mg/kg, 10mg/kg and Donepezil (DON) 1mg/kg intraperitoneally (i.p) for 14days. The last 7days of treatment regimen included daily injection of SCP 1.5mg/kg to induce cognitive deficits. Mice were subjected to behavioral analysis. Biochemical estimation of the brain homogenates for acetylcholinesterase and oxidative stress biomarkers were conducted. Furthermore, immunohistochemical analysis for the brain derived neurotrophic factor (BDNF) was carried out particularly in the hippocampus. PHL was found to significantly improve the performance of mice in Morris water maze test (P<0.001) and significantly decreased the acetylcholinesterase activity (P<0.001) at all doses compared to SCP treated mice. Also, PHL significantly elevated the activity of antioxidant enzymes viz. superoxide dismutase, catalase, reduced glutathione levels (P<0.001) and decreased malonaldehyde levels (P<0.001) in comparison with the SCP group. Immunohistochemistry revealed that PHL treatment dose dependently improved BDNF levels in the hippocampus which were found to be significantly depleted (P<0.001) in the SCP group. Additionally, PHL (10mg/kg) significantly enhanced the spatial memory formation (P<0.05) and neurotrophicity (P<0.001) compared to DON (1mg/kg). The aforementioned research findings suggested that PHL has nootropic, neuroprotective and neurotrophic activities in SCP induced memory impaired mice and hence, is a promising therapeutic moiety in the treatment of AD. Copyright © 2015 Elsevier Inc. All rights reserved.

[Drug dependence test on a cerebral insufficiency improver, aniracetam].

PubMed

Kuwahara, A; Kubota, A; Hakkei, M; Nakamura, K

1987-01-01

Aniracetam, 1-p-anisoyl-2-pyrrolidinone, is known to be a nootropic or cognitive activator. Aniracetam protects against memory and learning deficits without causing effects on motor function and the autonomic nervous system. A drug dependence study on aniracetam utilizing the intragastric route of administration was performed in male cynomolgus monkeys. The behavioral observation test after acute administration revealed that aniracetam at the dose of 25-400 mg/kg did not change the gross behavior. In the self-administration initiation test, animals were exposed to two or three unit doses of aniracetam and references for a total available period of 7 weeks. Aniracetam at the dose of 25, 50 and 75 mg/kg/injection did not initiate self-administration in the respective group of 4, 4 and 2 animals. In the study with d-methamphetamine hydrochloride at the dose of 0.1 mg/kg/injection, 1 out of 4 animals started to consistently self-administer the drug. Self-administration of cocaine hydrochloride at the dose of 10 mg/kg/injection was confirmed in 3 out of 5 animals, and these 3 animals died from overdosing later. In the physical dependence direct induction test, animals received aniracetam (50 mg/kg) and sodium pentobarbital (25 mg/kg: the dose inducing intermediate CNS depression) intragastrically twice a day for 31 consecutive days. Abrupt withdrawal of aniracetam did not elicit abstinent signs (including changes in appetite and body weight) in all 6 animals, whereas withdrawal of pentobarbital produced typical abstinent behavioral signs and decreases in appetite and body weight. In conclusion, aniracetam was confirmed to develop neither physical dependence nor psychic dependence in cynomolgus monkeys.

In vitro evaluation of Bacopa monniera extract and individual constituents on human recombinant monoamine oxidase enzymes.

PubMed

Singh, Rajbir; Ramakrishna, Rachumallu; Bhateria, Manisha; Bhatta, Rabi Sankar

2014-09-01

Bacopa monniera is a traditional Ayurvedic medicinal plant that has been used worldwide for its nootropic action. Chemically standardized extract of B. monniera is now available as over the counter herbal remedy to enhance memory in children and adults. Considering the nootropic action of B. monniera, we evaluated the effect of clinically available B. monniera extract and six of B. monniera constituents (bacoside A3, bacopaside I, bacopaside II, bacosaponin C, bacosine, and bacoside A mixture) on recombinant human monoamine oxidase (MAO) enzymes. The effect of B. monniera extract and individual constituents on human recombinant MAO-A and MAO-B enzymes was evaluated using MAO-Glo(TM) assay kit (Promega Corporation, USA), following the instruction manual. IC50 and mode of inhibition were measured for MAO enzymes. Bacopaside I and bacoside A mixture inhibited the MAO-A and MAO-B enzymes. Bacopaside I exhibited mixed mode of inhibition with IC50 and Ki values of 17.08 ± 1.64 and 42.5 ± 3.53 µg/mL, respectively, for MAO-A enzyme. Bacopaside I is the major constituent of B. monniera, which inhibited the MAO-A enzyme selectively. Copyright © 2014 John Wiley & Sons, Ltd.

[Asthenic syndrome in clinical course of acute period of brain concussion during complex treatment using nootropic agents].

PubMed

Tkachov, A V

2008-01-01

The comparative analysis of a complex examination of 108 persons aged from 16 till 60 years in acute period of closed craniocerebral injury (CCCT) has been done. Every participants have been divided into 2 groups depending on a nootrop medication they receive in a complex treatment. A control group consisted of 30 practically healthy people. Objective examination by means of tests was done on the 1-st, 10-th that 30-th day of treatment. Patients of 1-st (37 persons) group received piracetam in complex treatment and patients of the 2-nd group (71 persons) pramistar. Patients of the first group received a base treatment (analgetics, tranquilizers, vitamins of group B, magnesium sulfate, diuretic preparations) as well as piracetam at dosage 0.2, two tablets three times per day. The Patients of the 2-nd group received a base treatment as well as pramistar at dosage 0.6, one tablet 2 times per day. Specially developed multiaspects scales and questionnaires, MRT of the brain and EEG have been used for objectification of patient, complaints. During a complex clinico-neuropsychological examination it was found that all cases of concussion of the brain are accompanied by those or other asthenic disorders.

A randomized, double-blind, placebo controlled, parallel group, efficacy study of alpha BRAIN® administered orally.

PubMed

Solomon, Todd M; Leech, Jarrett; deBros, Guy B; Murphy, Cynthia A; Budson, Andrew E; Vassey, Elizabeth A; Solomon, Paul R

2016-03-01

Alpha BRAIN® is a nootropic supplement that purports to enhance cognitive functioning in healthy adults. The goal of this study was to investigate the efficacy of this self-described cognitive enhancing nootropic on cognitive functioning in a group of healthy adults by utilizing a randomized, double blind, placebo-controlled design. A total of 63-treatment naïve individuals between 18 and 35 years of age completed the randomized, double-blind, placebo controlled trial. All participants completed a 2-week placebo run in before receiving active product, Alpha BRAIN® or new placebo, for 6 weeks. Participants undertook a battery of neuropsychological tests at randomization and at study completion. Primary outcome measures included a battery of neuropsychological tests and measures of sleep. Compared with placebo, Alpha BRAIN® significantly improved on tasks of delayed verbal recall and executive functioning. Results also indicated significant time-by-group interaction in delayed verbal recall for the Alpha BRAIN® group. The use of Alpha BRAIN® for 6 weeks significantly improved recent verbal memory when compared with controls, in a group of healthy adults. While the outcome of the study is encouraging, this is the first randomized controlled trial of Alpha BRAIN®, and the results merit further study. Copyright © 2016 John Wiley & Sons, Ltd.

Ginkgo Biloba Extract and Long-Term Cognitive Decline: A 20-Year Follow-Up Population-Based Study

PubMed Central

Amieva, Hélène; Meillon, Céline; Helmer, Catherine; Barberger-Gateau, Pascale; Dartigues, Jean François

2013-01-01

Background Numerous studies have looked at the potential benefits of various nootropic drugs such as Ginkgo biloba extract (EGb761®; Tanakan®) and piracetam (Nootropyl®) on age-related cognitive decline often leading to inconclusive results due to small sample sizes or insufficient follow-up duration. The present study assesses the association between intake of EGb761® and cognitive function of elderly adults over a 20-year period. Methods and Findings The data were gathered from the prospective community-based cohort study ‘Paquid’. Within the study sample of 3612 non-demented participants aged 65 and over at baseline, three groups were compared: 589 subjects reporting use of EGb761® at at least one of the ten assessment visits, 149 subjects reporting use of piracetam at one of the assessment visits and 2874 subjects not reporting use of either EGb761® or piracetam. Decline on MMSE, verbal fluency and visual memory over the 20-year follow-up was analysed with a multivariate mixed linear effects model. A significant difference in MMSE decline over the 20-year follow-up was observed in the EGb761® and piracetam treatment groups compared to the ‘neither treatment’ group. These effects were in opposite directions: the EGb761® group declined less rapidly than the ‘neither treatment’ group, whereas the piracetam group declined more rapidly (β = −0.6). Regarding verbal fluency and visual memory, no difference was observed between the EGb761® group and the ‘neither treatment’ group (respectively, β = 0.21 and β = −0.03), whereas the piracetam group declined more rapidly (respectively, β = −1.40 and β = −0.44). When comparing the EGb761® and piracetam groups directly, a different decline was observed for the three tests (respectively β = −1.07, β = −1.61 and β = −0.41). Conclusion Cognitive decline in a non-demented elderly population was lower in subjects who reported using EGb761® than in those who did not. This effect may be a specific medication effect of EGb761®, since it was not observed for another nootropic medication, piracetam. PMID:23326356

Herbal extracts and phytochemicals: plant secondary metabolites and the enhancement of human brain function.

PubMed

Kennedy, David O; Wightman, Emma L

2011-01-01

Humans consume a wide range of foods, drugs, and dietary supplements that are derived from plants and which modify the functioning of the central nervous sytem (CNS). The psychoactive properties of these substances are attributable to the presence of plant secondary metabolites, chemicals that are not required for the immediate survival of the plant but which are synthesized to increase the fitness of the plant to survive by allowing it to interact with its environment, including pathogens and herbivorous and symbiotic insects. In many cases, the effects of these phytochemicals on the human CNS might be linked either to their ecological roles in the life of the plant or to molecular and biochemical similarities in the biology of plants and higher animals. This review assesses the current evidence for the efficacy of a range of readily available plant-based extracts and chemicals that may improve brain function and which have attracted sufficient research in this regard to reach a conclusion as to their potential effectiveness as nootropics. Many of these candidate phytochemicals/extracts can be grouped by the chemical nature of their potentially active secondary metabolite constituents into alkaloids (caffeine, nicotine), terpenes (ginkgo, ginseng, valerian, Melissa officinalis, sage), and phenolic compounds (curcumin, resveratrol, epigallocatechin-3-gallate, Hypericum perforatum, soy isoflavones). They are discussed in terms of how an increased understanding of the relationship between their ecological roles and CNS effects might further the field of natural, phytochemical drug discovery.

Herbal Extracts and Phytochemicals: Plant Secondary Metabolites and the Enhancement of Human Brain Function1

PubMed Central

Kennedy, David O.; Wightman, Emma L.

2011-01-01

Humans consume a wide range of foods, drugs, and dietary supplements that are derived from plants and which modify the functioning of the central nervous sytem (CNS). The psychoactive properties of these substances are attributable to the presence of plant secondary metabolites, chemicals that are not required for the immediate survival of the plant but which are synthesized to increase the fitness of the plant to survive by allowing it to interact with its environment, including pathogens and herbivorous and symbiotic insects. In many cases, the effects of these phytochemicals on the human CNS might be linked either to their ecological roles in the life of the plant or to molecular and biochemical similarities in the biology of plants and higher animals. This review assesses the current evidence for the efficacy of a range of readily available plant-based extracts and chemicals that may improve brain function and which have attracted sufficient research in this regard to reach a conclusion as to their potential effectiveness as nootropics. Many of these candidate phytochemicals/extracts can be grouped by the chemical nature of their potentially active secondary metabolite constituents into alkaloids (caffeine, nicotine), terpenes (ginkgo, ginseng, valerian, Melissa officinalis, sage), and phenolic compounds (curcumin, resveratrol, epigallocatechin-3-gallate, Hypericum perforatum, soy isoflavones). They are discussed in terms of how an increased understanding of the relationship between their ecological roles and CNS effects might further the field of natural, phytochemical drug discovery. PMID:22211188

Human Neural Stem Cell Aging Is Counteracted by α-Glycerylphosphorylethanolamine.

PubMed

Daniele, Simona; Da Pozzo, Eleonora; Iofrida, Caterina; Martini, Claudia

2016-07-20

Neural stem cells (NSCs) represent a subpopulation of cells, located in specific regions of the adult mammalian brain, with the ability of self-renewing and generating neurons and glia. In aged NSCs, modifications in the amount and composition of membrane proteins/lipids, which lead to a reduction in membrane fluidity and cholinergic activities, have been reported. In this respect, molecules that are effective at normalizing the membrane composition and cholinergic signaling could counteract stem cell aging. α-Glycerylphosphorylethanolamine (GPE), a nootropic drug, plays a role in phospholipid biosynthesis and acetylcholine release. Herein, GPE was assayed on human NSC cultures and on hydroxyurea-aged cells. Using cell counting, colorimetric, and fluorimetric analyses, immunoenzymatic assays, and real time PCR experiments, NSC culture proliferation, senescence, reactive oxygen species, and ADP/ATP levels were assessed. Aged NSCs exhibited cellular senescence, decreased proliferation, and an impairment in mitochondrial metabolism. These changes included a substantial induction in the nuclear factor NF-κB, a key inflammatory mediator. GPE cell treatment significantly protected the redox state and functional integrity of mitochondria, and counteracted senescence and NF-κB activation. In conclusion, our data show the beneficial properties of GPE in this model of stem cell aging.

Aniracetam restores object recognition impaired by age, scopolamine, and nucleus basalis lesions.

PubMed

Bartolini, L; Casamenti, F; Pepeu, G

1996-02-01

Object recognition was investigated in adult and aging male rats in a two-trials, unrewarded, test that assessed a form of working-episodic memory. Exploration time in the first trial, in which two copies of the same object were presented, was recorded. In the second trial, in which one of the familiar objects and a new object were presented, the time spent exploring the two objects was separately recorded and a discrimination index was calculated. Adult rats explored the new object longer than the familiar object when the intertrial time ranged from 1 to 60 min. Rats older than 20 months of age did not discriminate between familiar and new objects. Object discrimination was lost in adult rats after scopolamine (0.2 mg/kg SC) administration and with lesions of the nucleus basalis, resulting in a 40% decrease in cortical ChAT activity. Both aniracetam (25, 50, 100 mg/kg os) and oxiracetam (50 mg/kg os) restored object recognition in aging rats, in rats treated with scopolamine, and with lesions of the nucleus basalis. In the rat, object discrimination appears to depend on the integrity of the cholinergic system, and nootropic drugs can correct its disruption.

Aniracetam tested in chronic psychosyndrome after long-term exposure to organic solvents. A randomized, double-blind, placebo-controlled cross-over study with neuropsychological tests.

PubMed

Somnier, F E; Ostergaard, M S; Boysen, G; Bruhn, P; Mikkelsen, B O

1990-01-01

In order to examine if the nootropic drug, aniracetam, was capable of improving cognitive performance, 44 subjects suffering from chronic psychosyndrome after long-term exposure to organic solvents were included in a randomized, double-blind, placebo-controlled, cross-over study. The treatment periods were 3 months with aniracetam 1 g daily and 3 months with placebo. Neuropsychological tests as well as a physical and neurological examination were performed at entry into the study and after each treatment period, together with an evaluation of the subjects' overall condition. Neither the doctors' nor the subjects' own assessment of the overall condition indicated that the trial medication had had any effect. No significant changes in neuropsychological symptoms were observed. A statistically significant difference in favour of antiracetam was found in only 1 of the 19 neuropsychological test measures, namely a test for constructional ability. However, in another test on visuo-spatial function, a statistically significant result was found in favour of placebo. Thus, aniracetam was found to be ineffective in the treatment of subjects suffering from chronic psychosyndrome after long-term exposure to organic solvents.

Examining the nootropic effects of a special extract of Bacopa monniera on human cognitive functioning: 90 day double-blind placebo-controlled randomized trial.

PubMed

Stough, Con; Downey, Luke A; Lloyd, Jenny; Silber, Beata; Redman, Stephanie; Hutchison, Chris; Wesnes, Keith; Nathan, Pradeep J

2008-12-01

While Ayurvedic medicine has touted the cognitive enhancing effects of Bacopa monniera for centuries, there is a need for double-blind placebo-controlled investigations. One hundred and seven healthy participants were recruited for this double-blind placebo-controlled independent group design investigation. Sixty-two participants completed the study with 80% treatment compliance. Neuropsychological testing using the Cognitive Drug Research cognitive assessment system was conducted at baseline and after 90 days of treatment with a special extract of Bacopa monniera (2 x 150 mg KeenMind) or placebo. The Bacopa monniera product significantly improved performance on the 'Working Memory' factor, more specifically spatial working memory accuracy. The number of false-positives recorded in the Rapid visual information processing task was also reduced for the Bacopa monniera group following the treatment period. The current study provides support for the two other published studies reporting cognitive enhancing effects in healthy humans after a 90 day administration of the Bacopa monniera extract. Further studies are required to ascertain the effective dosage range, the time required to attain therapeutic levels and the effects over a longer term of administration. (c) 2008 John Wiley & Sons, Ltd.

Design, synthesis and nootropic activity of new analogues of sunifiram and sapunifiram, two potent cognition-enhancers.

PubMed

Martini, Elisabetta; Salvicchi, Alberto; Ghelardini, Carla; Manetti, Dina; Dei, Silvia; Guandalini, Luca; Martelli, Cecilia; Melchiorre, Michele; Cellai, Cristina; Scapecchi, Serena; Teodori, Elisabetta; Romanelli, Maria Novella

2009-11-01

A series of amides and sulfonamides, structurally related to DM235 (sunifiram) and MN19 (sapunifiram), derived by ring expansion or contraction, or by inversion of the exocyclic amide function, have been synthesized and tested for cognition-enhancing activity in the mouse passive-avoidance test. Some of the compounds display good antiamnesic and procognitive activity, with higher potency than piracetam, and with a potency similar to the parent compounds.

Comparative study of the neuroprotective and nootropic activities of the carboxylate and amide forms of the HLDF-6 peptide in animal models of Alzheimer's disease.

PubMed

Bogachouk, Anna P; Storozheva, Zinaida I; Solovjeva, Olga A; Sherstnev, Vyacheslav V; Zolotarev, Yury A; Azev, Vyacheslav N; Rodionov, Igor L; Surina, Elena A; Lipkin, Valery M

2016-01-01

A comparative study of the neuroprotective and nootropic activities of two pharmaceutical substances, the HLDF-6 peptide (HLDF-6-OH) and its amide form (HLDF-6-NH2), was conducted. The study was performed in male rats using two models of a neurodegenerative disorder. Cognitive deficit in rats was induced by injection of the beta-amyloid fragment 25-35 (βA 25-35) into the giant-cell nucleus basalis of Meynert or by coinjection of βA 25-35 and ibotenic acid into the hippocampus. To evaluate cognitive functions in animals, three tests were used: the novel object recognition test, the conditioned passive avoidance task and the Morris maze. Comparative analysis of the data demonstrated that the neuroprotective activity of HLDF-6-NH2, evaluated by improvement of cognitive functions in animals, surpassed that of the native HLDF-6-OH peptide. The greater cognitive/ behavioral effects can be attributed to improved kinetic properties of the amide form of the peptide, such as the character of biodegradation and the half-life time. The effects of HLDF-6-NH2 are comparable to, or exceed, those of the reference compounds. Importantly, HLDF-6-NH2 exerts its effects at much lower doses than the reference compounds. © The Author(s) 2015.

Phytochemical analysis, antioxidant, antistress, and nootropic activities of aqueous and methanolic seed extracts of ladies finger (Abelmoschus esculentus L.) in mice.

PubMed

Doreddula, Sathish Kumar; Bonam, Srinivasa Reddy; Gaddam, Durga Prasad; Desu, Brahma Srinivasa Rao; Ramarao, Nadendla; Pandy, Vijayapandi

2014-01-01

Abelmoschus esculentus L. (ladies finger, okra) is a well-known tropical vegetable, widely planted from Africa to Asia and from South Europe to America. In the present study, we investigated the in vitro antioxidant capacity and in vivo protective effect of the aqueous and methanolic seed extracts of Abelmoschus esculentus against scopolamine-induced cognitive impairment using passive avoidance task and acute restraining stress-induced behavioural and biochemical changes using elevated plus maze (EPM) and forced swimming test (FST) in mice. Our results demonstrated that the pretreatment of mice with aqueous and methanolic seed extracts of Abelmoschus esculentus (200 mg/kg, p.o.) for seven days significantly (P < 0.01) attenuated scopolamine-induced cognitive impairment in the passive avoidance test. In addition, these extracts significantly reduced the blood glucose, corticosterone, cholesterol, and triglyceride levels elevated by acute restraint stress and also significantly increased the time spent in open arm in EPM and decreased the immobility time in FST. It has also been revealed that these extracts showed a significant antioxidant activity and no signs of toxicity or death up to a dose of 2000 mg/kg, p.o. These results suggest that the seed extracts of Abelmoschus esculentus L. possess antioxidant, antistress, and nootropic activities which promisingly support the medicinal values of ladies finger as a vegetable.

Phytochemical Analysis, Antioxidant, Antistress, and Nootropic Activities of Aqueous and Methanolic Seed Extracts of Ladies Finger (Abelmoschus esculentus L.) in Mice

PubMed Central

Doreddula, Sathish Kumar; Bonam, Srinivasa Reddy; Gaddam, Durga Prasad; Desu, Brahma Srinivasa Rao; Ramarao, Nadendla; Pandy, Vijayapandi

2014-01-01

Abelmoschus esculentus L. (ladies finger, okra) is a well-known tropical vegetable, widely planted from Africa to Asia and from South Europe to America. In the present study, we investigated the in vitro antioxidant capacity and in vivo protective effect of the aqueous and methanolic seed extracts of Abelmoschus esculentus against scopolamine-induced cognitive impairment using passive avoidance task and acute restraining stress-induced behavioural and biochemical changes using elevated plus maze (EPM) and forced swimming test (FST) in mice. Our results demonstrated that the pretreatment of mice with aqueous and methanolic seed extracts of Abelmoschus esculentus (200 mg/kg, p.o.) for seven days significantly (P < 0.01) attenuated scopolamine-induced cognitive impairment in the passive avoidance test. In addition, these extracts significantly reduced the blood glucose, corticosterone, cholesterol, and triglyceride levels elevated by acute restraint stress and also significantly increased the time spent in open arm in EPM and decreased the immobility time in FST. It has also been revealed that these extracts showed a significant antioxidant activity and no signs of toxicity or death up to a dose of 2000 mg/kg, p.o. These results suggest that the seed extracts of Abelmoschus esculentus L. possess antioxidant, antistress, and nootropic activities which promisingly support the medicinal values of ladies finger as a vegetable. PMID:25401145

Effects of aniracetam on one-trial passive avoidance tests and cholinergic neurons in discrete brain regions of rats.

PubMed

Toide, K

1989-01-01

Using rats in one-trial passive avoidance tests, the anti-amnesic effects of the nootropic drug aniracetam were investigated; moreover, the action of aniracetam upon the cholinergic system in the brain was studied. In one-trial passive avoidance tests, aniracetam prolonged significantly the retention time for 100 mg/kg, p.o. However, the retention-prolonging effect was diminished when the dose was increased to 300 mg/kg p.o. Investigation of the action of the drug upon the cholinergic system revealed that ACh and choline content in the corpus striatum was not increased by any doses of aniracetam. ACh content in the hippocampus was increased by doses of 100-300 mg/kg, p.o., but choline was not significantly increased by any doses, while in the cerebral cortex ACh content was significantly increased by a dose of 300 mg/kg, p.o. In addition, the decrease in hippocampal ACh and choline content following an injection of scopolamine was lessened by aniracetam 100 mg/kg, p.o. and 100-300 mg/kg, respectively. In order to elucidate the mechanism of these actions of aniracetam, the ACh-releasing action and changes in choline content of the extracellular spaces in the hippocampus were investigated, but no effects were observed. The results obtained indicate that aniracetam has an inhibitory effect upon scopolamine-induced amnesia. The mechanism of this effect may be an action upon the cholinergic system; therefore, some action with respect to the impairment of cholinergic neurotransmission in the hippocampus induced by scopolamine appears to be of particular importance.

Aniracetam. An overview of its pharmacodynamic and pharmacokinetic properties, and a review of its therapeutic potential in senile cognitive disorders.

PubMed

Lee, C R; Benfield, P

1994-03-01

Aniracetam is a member of the nootropic class of drugs, which have possible cognition enhancing effects. It appears to positively modulate metabotropic glutamate receptors and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-sensitive glutamate receptors, and may facilitate cholinergic transmission, effects which are possibly related to its mechanism of action. Results from trials in elderly patients with mild to moderate cognitive impairment due to senile dementia of the Alzheimer type suggest that aniracetam may be of benefit, with further trials required to confirm its efficacy profile and to define more precisely those patients most likely to respond to treatment. Aniracetam 1500 mg/day was significantly more effective than placebo in all tests at 4 and 6 months, and in a further 6-month trial was more effective than piracetam 2400 mg/day in 8 of 18 tests. Preliminary evidence in the treatment of patients with cognitive impairment of cerebrovascular origin suggests aniracetam may also be of benefit in this condition. Whilst incidence rates of adverse effects are not yet available, data from trials suggest aniracetam is well tolerated. In particular, aniracetam does not appear to cause increases in liver enzyme levels. The evaluation of drugs for patients with senile cognitive disorders is a difficult area and therapeutic options are currently limited. Preliminary evidence of the potential benefits and good tolerability profile of aniracetam support continued evaluation of its use in patients with mild to moderate senile dementia of the Alzheimer type.

Methyl jasmonate mediates upregulation of bacoside A production in shoot cultures of Bacopa monnieri.

PubMed

Sharma, Poojadevi; Yadav, Sheetal; Srivastava, Anshu; Shrivastava, Neeta

2013-07-01

Methyl jasmonate (MJ) enhances the production of a range of secondary metabolites including triterpenoid saponins in a variety of plant species. Here, it enhanced production of bacoside A, a valuable triterpenoid saponin having nootropic therapeutic activity in in vitro shoot cultures of Bacopa monnieri, the only known source of bacoside A. The highest yield was with 50 μM MJ giving 4.4 mg bacoside A/g dry wt; an 1.8-fold increase (compared to control) after 1 week.

Analgesic activity of piracetam: effect on cytokine production and oxidative stress.

PubMed

Navarro, Suelen A; Serafim, Karla G G; Mizokami, Sandra S; Hohmann, Miriam S N; Casagrande, Rubia; Verri, Waldiceu A

2013-04-01

Piracetam is a prototype of nootropic drugs used to improve cognitive impairment. However, recent studies suggest that piracetam can have analgesic and anti-inflammatory effects. Inflammatory pain is the result of a process that depends on neutrophil migration, cytokines and prostanoids release and oxidative stress. We analyze whether piracetam has anti-nociceptive effects and its mechanisms. Per oral pretreatment with piracetam reduced in a dose-dependent manner the overt pain-like behavior induced by acetic acid, phenyl-p-benzoquinone, formalin and complete Freund's adjuvant. Piracetam also diminished carrageenin-induced mechanical and thermal hyperalgesia, myeloperoxidase activity, and TNF-α-induced mechanical hyperalgesia. Piracetam presented analgesic effects as post-treatment and local paw treatment. The analgesic mechanisms of piracetam were related to inhibition of carrageenin- and TNF-α-induced production of IL-1β as well as prevention of carrageenin-induced decrease of reduced glutathione, ferric reducing ability and free radical scavenging ability in the paw. These results demonstrate that piracetam presents analgesic activity upon a variety of inflammatory stimuli by a mechanism dependent on inhibition of cytokine production and oxidative stress. Considering its safety and clinical use for cognitive function, it is possible that piracetam represents a novel perspective of analgesic. Copyright © 2013 Elsevier Inc. All rights reserved.

Preventive effect of piracetam and vinpocetine on hypoxia-reoxygenation induced injury in primary hippocampal culture.

PubMed

Solanki, P; Prasad, D; Muthuraju, S; Sharma, A K; Singh, S B; Ilavzhagan, G

2011-04-01

The present study investigates the potential of Piracetam and Vinpocetine (nootropic drugs, known to possess neuroprotective properties) in preventing hypoxia-reoxygenation induced oxidative stress in primary hippocampal cell culture. The hippocampal culture was exposed to hypoxia (95% N(2), 5% CO(2)) for 3h and followed by 1h of reoxygenation (21% O(2) and 5% CO(2)) at 37 °C. The primary hippocampal cultures were supplemented with the optimum dose of Piracetam and Vinpocetine, independently, and the cultures were divided into six groups, viz. Control/Normoxia, Hypoxia, Hypoxia+Piracetam, Hypoxia+Vinpocetine, Normoxia + Piracetam and Normoxia+Vinpocetine. The cell-viability assays and biochemical oxidative stress parameters were evaluated for each of the six groups. Administration of 1mM Piracetam or 500 nM Vinpocetine significantly prevents the culture from hypoxia-reoxygenation injury when determined by Neutral Red assay, LDH release and Acetylcholine esterase activity. Results showed that Piracetam and Vinpocetine supplementation significantly prevented the fall of mitochondrial membrane potential, rise in ROS generation and reduction in antioxidant levels associated with the hypoxia-reoxygenation injury. In conclusion, the present study establishes that both Piracetam and Vinpocetine give neuroprotection against hypoxia-reoxygenation injury in primary hippocampal cell culture. Copyright © 2010 Elsevier Ltd. All rights reserved.

Nootropic potential of Ashwagandha leaves: Beyond traditional root extracts.

PubMed

Wadhwa, Renu; Konar, Arpita; Kaul, Sunil C

2016-05-01

Rapidly increasing aging population and environmental stressors are the two main global concerns of the modern society. These have brought in light rapidly increasing incidence of a variety of pathological conditions including brain tumors, neurodegenerative & neuropsychiatric disorders, and new challenges for their treatment. The overlapping symptoms, complex etiology and lack of full understanding of the brain structure and function to-date further complicate these tasks. On the other hand, several herbal reagents with a long history of their use have been asserted to possess neurodifferentiation, neuroregenerative and neuroprotective potentials, and hence been recommended as supplement to enhance and maintain brain health and function. Although they have been claimed to function by holistic approach resulting in maintaining body homeostasis and brain health, there are not enough laboratory studies in support to these and mechanism(s) of such beneficial activities remain largely undefined. One such herb is Ashwagandha, also called "Queen of Ayurveda" for its popular use in Indian traditional home medicine because of its extensive benefits including anticancer, anti-stress and remedial potential for aging and neurodegenerative pathologies. However, active principles and underlying mechanism(s) of action remain largely unknown. Here we provide a review on the effects of Ashwagandha extracts and active principles, and underlying molecular mechanism(s) for brain pathologies. We highlight our findings on the nootropic potential of Ashwagandha leaves. The effects of Ashwagandha leaf extracts are multidimensional ranging from differentiation of neuroblastoma and glioma cells, reversal of Alzheimer and Parkinson's pathologies, protection against environmental neurotoxins and enhancement of memory. Copyright © 2015 Elsevier Ltd. All rights reserved.

Molecular docking, spectroscopic studies and quantum calculations on nootropic drug.

PubMed

Uma Maheswari, J; Muthu, S; Sundius, Tom

2014-04-05

A systematic vibrational spectroscopic assignment and analysis of piracetam [(2-oxo-1-pyrrolidineacetamide)] have been carried out using FT-IR and FT-Raman spectral data. The vibrational analysis was aided by an electronic structure calculation based on the hybrid density functional method B3LYP using a 6-311G++(d,p) basis set. Molecular equilibrium geometries, electronic energies, IR and Raman intensities, and harmonic vibrational frequencies have been computed. The assignments are based on the experimental IR and Raman spectra, and a complete assignment of the observed spectra has been proposed. The UV-visible spectrum of the compound was recorded and the electronic properties, such as HOMO and LUMO energies and the maximum absorption wavelengths λmax were determined by the time-dependent DFT (TD-DFT) method. The geometrical parameters, vibrational frequencies and absorption wavelengths were compared with the experimental data. The complete vibrational assignments are performed on the basis of the potential energy distributions (PED) of the vibrational modes in terms of natural internal coordinates. The simulated FT-IR, FT-Raman, and UV spectra of the title compound have been constructed. Molecular docking studies have been carried out in the active site of piracetam by using Argus Lab. In addition, the potential energy surface, HOMO and LUMO energies, first-order hyperpolarizability and the molecular electrostatic potential have been computed. Copyright © 2014 Elsevier B.V. All rights reserved.

Antioxidant effects of rice bran oil mitigate repeated haloperidol-induced tardive dyskinesia in male rats.

PubMed

Samad, Noreen; Haleem, Darakhshan Jabeen

2017-08-01

Tardive dyskinesia (TD) is associated with the use of antipsychotic drugs such as D2 antagonist haloperidol (HP). The chronic use of HP is involved in the causation of free radicals and/or oxidative stress. In view of the nootropic, anti-anxiety, anti-inflammatory-like effects of rice bran oil (RBO) in a variety of investigations, we assessed the protective properties of RBO on HP-induced TD and neurochemical alteration. Rats treated with HP orally at a dose of 0.2 mg/kg/day for a period of 5 weeks developed VCMs which increased progressively as the treatment continued for 5 weeks. Co-administration of RBO by oral tubes at a dose of 0.4 ml/day prevented the induction of HP-induced VCMs. Repeated administration of HP increases the turnover of dopamine metabolism in the striatum. Conversely animals treated with HP + RBO decrease the metabolism of DA than water + HP treated animals. Striatal, malondieldehyde (MDA), hydrogen peroxide (H 2 O 2 ) and antioxidant enzyme superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were also determined. It is suggested that beneficial role of RBO in attenuation of HP-induced TD. The results therefore recommended that supplementation of RBO may be useful in the HP-induced TD. The findings have also potential implication in the treatment of schizophrenia and motor disorders.

Phenomenology of Polymorphism, III: p, TDiagram and Stability of Piracetam Polymorphs

NASA Astrophysics Data System (ADS)

Céolin, R.; Agafonov, V.; Louër, D.; Dzyabchenko, V. A.; Toscani, S.; Cense, J. M.

1996-02-01

The nootropic drug Piracetam is known to crystallize in three phases. In order to obtain their stability hierarchy from sublimation pressure inequalities, the drawing of a topologicalp,Tdiagram was attempted. For such a purpose and also for quality control, crystallographic and thermodynamic data were required. Powder X-ray diffractometry (XRD) and differential scanning calorimetry (DSC) were used. Molecular energy calculations were performed. Phase I melts at 426 K (ΔfusH(I) = +180 J·g-1). Phase II transforms into Phase I at 399 K (Δ(II→I)H= +24 J·g-1). Phase III transforms into phase I at 392 K (Δ(III→I)H= +28 J·g-1) or melts at 412 K (ΔfusH(III) = +210 J·g-1). Thep,Tdiagram shows that phase I is stable at higher temperature and phase II at lower temperature, like phase III, which is stable under high pressure. At room temperature, phase II is the more stable form, and phase I the less stable one. This agrees with the spontaneous I → II transformation observed at 298 K within a few hours, and with lattice energies, calculated previously. Molecular energy calculations and crystal structure comparison show how intermolecular hydrogen bonds and H-bonded dimers, in phases II and III, may stabilize conformations higher in energy than those of the isolated molecule and of phase I.

Analgesic effect of piracetam on peripheral neuropathic pain induced by chronic constriction injury of sciatic nerve in rats.

PubMed

Mehta, Ashish K; Bhati, Yogendra; Tripathi, Chakra D; Sharma, Krishna K

2014-08-01

Despite immense advances in the treatment strategies, management of neuropathic pain remains unsatisfactory. Piracetam is a prototype of nootropic drugs, used to improve cognitive impairment. The present study was designed to investigate the effect of piracetam on peripheral neuropathic pain in rats. Neuropathic pain was induced by the chronic constriction injury of the sciatic nerve. Following this, piracetam was intraperitoneally administered for 2 weeks in doses of 50, 100 and 200 mg/kg, and pain was assessed by employing the behavioural tests for thermal hyperalgesia (hot plate and tail flick tests) and cold allodynia (acetone test). After the induction of neuropathic pain, significant development of thermal hyperalgesia and cold allodynia was observed. The administration of piracetam (50 mg/kg) did not have any significant effect on all the behavioural tests. Further, piracetam (100 mg/kg) also had no effect on the hot plate and tail flick tests; however it significantly decreased the paw withdrawal duration in the acetone test. Piracetam in a dose of 200 mg/kg significantly modulated neuropathic pain as observed from the increased hot plate and tail flick latencies, and decreased paw withdrawal duration (in acetone test). Therefore, the present study suggests the potential use of piracetam in the treatment of neuropathic pain, which merits further clinical investigation.

Design and study of some novel ibuprofen derivatives with potential nootropic and neuroprotective properties.

PubMed

Siskou, Ioanna C; Rekka, Eleni A; Kourounakis, Angeliki P; Chrysselis, Michael C; Tsiakitzis, Kariofyllis; Kourounakis, Panos N

2007-01-15

Six novel ibuprofen derivatives and related structures, incorporating a proline moiety and designed for neurodegenerative disorders, are studied. They possess anti-inflammatory properties and three of them inhibited lipoxygenase. One compound was found to inhibit cyclooxygenase (COX)-2 production in spleenocytes from arthritic rats. The HS-containing compounds are potent antioxidants and one of them protected against glutathione loss after cerebral ischemia/reperfusion. They demonstrated lipid-lowering ability and seem to acquire low gastrointestinal toxicity. Acetylcholinesterase inhibitory activity, found in two of these compounds, may be an asset to their actions.

Adaptogenic Activity of Lyophilized Hydroethanol Extract of Pandanus odoratissimus in Swiss Albino Mice

PubMed Central

Jadhav, Pranita P.; Ambavade, Shirishkumar D.; Shelke, Tushar

2014-01-01

Background. The leaves of Pandanus odoratissimus Linn have been widely used in Ayurveda to treat a variety of common and stress related disorders. In the present investigation, hydroethanol extract of leaves of Pandanus odoratissimus Linn (LEPO) were evaluated for antistress activity in normal and stress induced mice. Furthermore, the extract was studied for nootropic (adaptogenic) activity in mice and in vitro antioxidant potential to correlate with its adaptogenic and antistress activity. LEPO (100 and 200 mg/kg p.o) was evaluated against forced swimming endurance stress test, anoxia stress tolerance and immobilization stress and chronic cold resistant stress tests, and biomarkers (serum glucose, Corticosterone, WBC, RBC, and DLC count) to assess the antistress activity in mice. Withania somnifera (WS) (100 mg/kg p.o) was selected as reference standard. The parameters like anoxia stress tolerance time were recorded in anoxia stress and estimation of biochemical marker levels and determination of organs weight were carried out in immobilization stress models. Results. Concomitant treatment with LEPO 200 mg/kg significantly increased in anoxia stress tolerance time. Dose dependent significant reduction in serum glucose, corticosterone, and WBC, RBC, and DLC was observed in immobilisation stress model as compared to stressed group. LEOP 200 mg/kg and WS 100 mg/kg significantly reversed/inhibited the stress induced changes in these parameters. The results from the present study indicate that these values also express that dose dependent significant adaptogenic activity in stressed animals. Conclusion. The present study provides scientific support for the antistress (adaptogenic) and nootropic activities of lyophilized hydroethanol extract of Pandanus odoratissimus Linn and substantiate the traditional claims for the usage of Pandanus in stress induced disorders. PMID:27379263

Nootropic nanocomplex with enhanced blood-brain barrier permeability for treatment of traumatic brain injury-associated neurodegeneration.

PubMed

Park, Jeongmin; Choi, Eunshil; Shin, Seulgi; Lim, Sungsu; Kim, Dohee; Baek, Suji; Lee, Kang Pa; Lee, Jae Jun; Lee, Byeong Han; Kim, Bokyung; Jeong, Keunsoo; Baik, Ja-Hyun; Kim, Yun Kyung; Kim, Sehoon

2018-06-15

Traumatic brain injury (TBI) is an intracranial injury which can induce immediate neuroinflammation and long-term neurological deficits. Methylene blue (MB) as a nootropic has a great potential to treat neurodegeneration after TBI because of its anti-inflmmatory and neuroprotective functions. However, its limited accumulation to the brain across the blood-brain barrier (BBB) remains a major hurdle to be overcome. In this paper, we present a polymer surfactant-encapsulated nanocomplex of MB as a delivery system with high BBB permeability for efficacious treatment of TBI-induced neurodegeneration. MB was formulated via electrostatically/hydrophobically directed assembly with fatty acid and Pluronic surfactant (F-127 or F-68) to construct nanocomplexes of two different colloidal sizes (<10 nm and ~108 nm in hydrodynamic diameter for NanoMB-127 and NanoMB-68, respectively). Compared to uncomplexed free MB, formulation into the ultrasmall nanocomplex (NanoMB-127) significantly enhanced the uptake of MB by blood-brain vascular endothelial bEnd3 cells in vitro, and indeed improved its BBB penetration upon systemic administration to normal mice in vivo. However, large-size NanoMB-68 showed negligible BBB crossing despite the efficient bEnd3 cell internalization in vitro, probably due to the unfavorable pharmacokinetic profile associated with its large particle size. By virtue of the efficient BBB penetration and cellular uptake, ultrasmall NanoMB-127 was shown to distinctively reduce the expression level of an inflammatory cytokine with no notable toxicity in vitro and also considerably prevent the neurodegeneration after TBI in mice at much lower doses than free MB. Overall, the Pluronic-supported nanocomplexation method allows efficient brain delivery of MB, offering a novel way of enhancing the efficacy of neurotherapeutics to treat brain diseases. Copyright © 2018. Published by Elsevier B.V.

[Characteristics of antiischemic and nootropic properties of ademol in a rat model of acute brain ischemia].

PubMed

Khodakivs'kyĭ, O A

2013-01-01

In experiments with the rat model of acute disorder of encephalic circulation (bilateral carotid occlusion) it was found that introduction of derivate of adamantan 1-adamantiloxy-3-morfolino-2 propanol (under conventional name ademol) in the dose 2 mg/kg intraabdominal in treatment regimen (in an hour after reconstruction of insult and further 1 time every 24 hours during 21 days) was accompanied by a recovery of mnemotropic properties and is more effective than cytikolin, resulting in a decreased lethality and neurological deficiency in acute and recovery periods of insults. The data received proved the usefulness of development of ademol based cerebroprotective remedy.

S-phenylpiracetam, a selective DAT inhibitor, reduces body weight gain without influencing locomotor activity.

PubMed

Zvejniece, Liga; Svalbe, Baiba; Vavers, Edijs; Makrecka-Kuka, Marina; Makarova, Elina; Liepins, Vilnis; Kalvinsh, Ivars; Liepinsh, Edgars; Dambrova, Maija

2017-09-01

S-phenylpiracetam is an optical isomer of phenotropil, which is a clinically used nootropic drug that improves physical condition and cognition. Recently, it was shown that S-phenylpiracetam is a selective dopamine transporter (DAT) inhibitor that does not influence norepinephrine (NE) or serotonin (5-HT) receptors. The aim of the present study was to study the effects of S-phenylpiracetam treatment on body weight gain, blood glucose and leptin levels, and locomotor activity. Western diet (WD)-fed mice and obese Zucker rats were treated daily with peroral administration of S-phenylpiracetam for 8 and 12weeks, respectively. Weight gain and plasma metabolites reflecting glucose metabolism were measured. Locomotor activity was detected in an open-field test. S-phenylpiracetam treatment significantly decreased body weight gain and fat mass increase in the obese Zucker rats and in the WD-fed mice. In addition, S-phenylpiracetam reduced the plasma glucose and leptin concentration and lowered hyperglycemia in a glucose tolerance test in both the mice and the rats. S-phenylpiracetam did not influence locomotor activity in the obese Zucker rats or in the WD-fed mice. The results demonstrate that S-phenylpiracetam reduces body weight gain and improves adaptation to hyperglycemia without stimulating locomotor activity. Our findings suggest that selective DAT inhibitors, such as S-phenylpiracetam, could be potentially useful for treating obesity in patients with metabolic syndrome with fewer adverse health consequences compared to other anorectic agents. Copyright © 2017. Published by Elsevier Inc.

Vasodilators and nootropics as predictors of dementia and mortality in the PAQUID cohort.

PubMed

Dartigues, Jean-François; Carcaillon, Laure; Helmer, Catherine; Lechevallier, Nathalie; Lafuma, Antoine; Khoshnood, Babak

2007-03-01

To assess the effects of treatment for memory impairment and the Ginkgo biloba extract (EGb 761) on dementia, mortality, and survival without dementia. Prospective community-based cohort study. France. Three thousand five hundred thirty-four subjects aged 65 and older. Information on drug consumption was obtained by interview and visual assessment of patients' medicine chests. Active screening of dementia was performed every 2 years over a 13-year period. The independent effects of treatment for memory impairment and the Ginkgo biloba extract on the risks of dementia and death were estimated using Cox proportional hazards models, adjusted for potentially confounding factors (including comorbidities). The initial consumption of Ginkgo biloba did not modify the risk of dementia (relative risk (RR)=1.16, 95% confidence interval (CI)=0.84-1.60), whereas the consumption of other treatments for memory impairment was associated with a higher risk of dementia (RR=1.35, 95% CI=1.11-1.63). Subjects who took Ginkgo biloba had a significantly lower risk of mortality in the long term (RR=0.76, 95% CI=0.62-0.93), even after adjustment for potentially confounding factors. The initial consumption of treatment for memory impairment other than Ginkgo biloba did not modify the risk of mortality. These results suggest that treatment with EGb 761 may increase the probability of survival in the elderly population. These findings need to be corroborated and further assessed using randomized, controlled trials.

Changes in the brain biogenic monoamines of rats, induced by piracetam and aniracetam.

PubMed

Petkov, V D; Grahovska, T; Petkov, V V; Konstantinova, E; Stancheva, S

1984-01-01

Single oral dose of 600 mg/kg weight piracetam, respectively 50 mg/kg aniracetam, causes essential changes in the level and turnover of dopamine (DA) and serotonin (5-HT) in some rat cerebral structures. When the animals were killed one hour after the administration of the drugs, piracetam significantly increased the DA level in the cerebral cortex and in the striatum, as well as the 5-HT level in the cortex, reducing the 5-HT level in the striatum, brain stem and hypothalamus. At the same time, under the effect of piracetam the DA turnover was accelerated in the cortex and hypothalamus and delayed in the striatum, the noradrenaline turnover was accelerated in the brain stem, the 5-HT turnover was accelerated in the cortex and delayed in the striatum, stem and hypothalamus. Under the effect of aniracetam the DA level was reduced in the striatum and hypothalamus; the 5-HT level was also decreased in the hypothalamus and increased in the cortex and striatum. Aniracetam delayed the DA turnover in the striatum and the 5-HT turnover in the hypothalamus, accelerating the 5-HT turnover in the cortex, striatum and stem. The results obtained show that the changes induced in the cerebral biogenic monoamines participate in the mechanism of action of piracetam and aniracetam, whereby it seems that the analogies and differences in their effects on the cerebral biogenic monoamines play a definite role for the observed analogies and differences in the behavioural effects of these two "nootropic" compounds.

Vinpocetine Ameliorates Acetic Acid-Induced Colitis by Inhibiting NF-κB Activation in Mice.

PubMed

Colombo, Bárbara B; Fattori, Victor; Guazelli, Carla F S; Zaninelli, Tiago H; Carvalho, Thacyana T; Ferraz, Camila R; Bussmann, Allan J C; Ruiz-Miyazawa, Kenji W; Baracat, Marcela M; Casagrande, Rúbia; Verri, Waldiceu A

2018-04-10

The idiopathic inflammatory bowel diseases (IBD) comprise two types of chronic intestinal disorders: Crohn's disease and ulcerative colitis. Recruited neutrophils and macrophages contribute to intestinal tissue damage via production of ROS and NF-κB-dependent pro-inflammatory cytokines. The introduction of anti-TNF-α therapies in the treatment of IBD patients was a seminal advance. This therapy is often limited by a loss of efficacy due to the development of adaptive immune response, underscoring the need for novel therapies targeting similar pathways. Vinpocetine is a nootropic drug and in addition to its antioxidant effect, it is known to have anti-inflammatory and analgesic properties, partly by inhibition of NF-κB and downstream cytokines. Therefore, the present study evaluated the effect of the vinpocetine in a model of acid acetic-induced colitis in mice. Treatment with vinpocetine reduced edema, MPO activity, microscopic score and macroscopic damage, and visceral mechanical hyperalgesia. Vinpocetine prevented the reduction of colonic levels of GSH, ABTS radical scavenging ability, and normalized levels of anti-inflammatory cytokine IL-10. Moreover, vinpocetine reduced NF-κB activation and thereby NF-κB-dependent pro-inflammatory cytokines IL-1β, TNF-α, and IL-33 in the colon. Thus, we demonstrate for the first time that vinpocetine has anti-inflammatory, antioxidant, and analgesic effects in a model of acid acetic-induced colitis in mice and deserves further screening to address its suitability as an approach for the treatment of IBD.

Sauroxine reduces memory retention in rats and impairs hippocampal long-term potentiation generation.

PubMed

Vallejo, Mariana; Carlini, Valeria; Gabach, Laura; Ortega, M G; L Cabrera, José; de Barioglio, Susana Rubiales; Pérez, Mariela; Agnese, Alicia M

2017-07-01

In the present paper it was investigated the role of sauroxine, an alkaloid of Phlegmariurus saururus, as a modulator of some types of learning and memory, considering the potential nootropic properties previously reported for the alkaloid extract and the main alkaloid sauroine. Sauroxine was isolated by means of an alkaline extraction, purified by several chromatographic techniques, and assayed in electrophysiological experiments on rat hippocampus slices, tending towards the elicitation of the long-term potentiation (LTP) phenomena. It was also studied the effects of intrahippocampal administration of sauroxine on memory retention in vivo using a Step-down test. Being the bio distribution of a drug an important parameter to be considered, the concentration of sauroxine in rat brain was determined by GLC-MS. Sauroxine blocked LTP generation at both doses used, 3.65 and 3.610 -2 μM. In the behavioral test, the animals injected with this alkaloid (3.6510 -3 nmol) exhibited a significant decrease on memory retention compared with control animals. It was also showed that sauroxine reached the brain (3.435μg/g tissue), after an intraperitoneal injection, displaying its ability to cross the blood-brain barrier. Thus, sauroxine demonstrated to exert an inhibition on these mnemonic phenomena. The effect here established for 1 is defeated by other constituents according to the excellent results obtained for P. saururus alkaloid extract as well as for the isolated alkaloid sauroine. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Piracetam inhibits ethanol (EtOH)-induced memory deficit by mediating multiple pathways.

PubMed

Yang, Yifan; Feng, Jian; Xu, Fangyuan; Wang, Jianglin

2017-12-01

Excessive ethanol (EtOH) intake, especially to prenatal exposure, can significantly affect cognitive function and cause permanent learning and memory injures in children. As a result, how to protect children from EtOH neurotoxicity has gained increasing attention in recent years. Piracetam (Pir) is a nootropic drug derived from c-aminobutyric acid and can manage cognition impairments in multiple neurological disorders. Studies have shown that Pir can exert therapeutic effects on EtOH-induced memory impairments, but the underlying mechanism is still unknown. In this study, we found that Pir inhibited ethanol-induced memory deficit by mediating multiple pathways. Treatment with EtOH could cause cognitive deficit in juvenile rats, and triggered the alteration of synaptic plasticity. Administration with Pir significantly increased long-term potentiation and protected hippocampus neurons from EtOH neurotoxicity. Pir intervention ameliorated EtOH-induced cell apoptosis and inhibited the activation of Caspase-3 in vitro, suggesting that Pir protected neurons by anti-apoptotic effects. Pir could decrease the expression of LC3-II and Beclin-1 induced by EtOH, and increase the phosphorylation of mTOR and reduce the phosphorylation of Akt, which suggested that the protective effect of Pir was involved in regulation of autophagic process and mTOR/Akt pathways. In conclusion, we speculate that Pir reduces EtOH-induced neuronal damage by regulation of apoptotic action and autophagic action, and our research offers preclinical evidence for the application of Pir in ethanol toxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

Treatment of the alcoholic organic brain syndrome with EMD 21657. A derivative of a pyritinolmetabolite: double-blind clinical, quantitative EEG and psychometric studies.

PubMed

Saletu, B; Grünberger, J; Saletu, M; Mader, R; Volavka, J

1978-01-01

The efficacy of EMD 21657--a derivative of a pyritinolmetabolite--with regard to the improvement of the organic brain syndrome (OBS) of chronic alcoholics was investigated in a double-blind study utilizing clinical, psychometric and quantitative EEG evaluation. Nineteen patients received 3 x 300 mg EMD and 21 patients 3 x 1 dragee placebo for 6 weeks. The groups did not differ in regard to age, sex, weight, height, alcohol anamnesis or IQ. The hospitalized patients were examined before as well as at the end of the second, fourth and sixth week of drug treatment. While the overall evaluation by the psychiatrist and patients at the end of the period of treatment did not show marked intergroup differences, the clinical global impression scale and the OBS rating scale demonstrated that both groups showed a significant reduction in their OBS and that improvement with EMD 21657 therapy was significantly superior to the one with placebo. Psychometric analysis also exhibited a significant superiority of EMD in regard to the general, associative, numeric and total verbal memory, concentration and attention variability. Psychovisual memory and the quantative aspects of attention showed opposite findings. Flickerlight fusion frequency, reaction time and after-image did not change significantly. The psychomotor activity improved significantly more with EMD than placebo; this was especially pronounced in the left hand. Affect and mood improved also more with EMD than placebo. Side effects were observed more frequently under active treatment and were characterized by temporary headaches. Power spectral density analysis of the EEG revealed in both groups a decrease of delta, fast alpha and beta activities and an increase in theta and slow alpha activity, but changes during EMD treatment more frequently reached the level of statistical significance than with placebo. The most consistant finding was the theta augmentation under EMD treatment. It was concluded that EMD 21657 is a CNS-effective drug with pronounced nootropic and slight thymotropic properties.

Pharmaco-electroencephalographic and clinical effects of the cholinergic substance--acetyl-L-carnitine--in patients with organic brain syndrome.

PubMed

Herrmann, W M; Dietrich, B; Hiersemenzel, R

1990-01-01

In two double-blind, placebo-controlled clinical studies of the nootropic compound acetyl-L-carnitine on the electroencephalogram (EEG) and impaired brain functions of elderly outpatients with mild to moderate cognitive decline of the organic brain syndrome, statistically significant effects could be detected after eight weeks (on the EEG), and after 12 weeks of treatment (on the physician's clinical global impression and the patient-rated level of activities of daily living). Side-effects of acetyl-L-carnitine were generally minor and overall rare. Longer treatment periods and further specifications with regard to the aetiopathology and degree of cognitive impairment are recommended for further clinical studies of this promising compound.

The cognitive-enhancing effects of Bacopa monnieri: a systematic review of randomized, controlled human clinical trials.

PubMed

Pase, Matthew P; Kean, James; Sarris, Jerome; Neale, Chris; Scholey, Andrew B; Stough, Con

2012-07-01

Traditional knowledge suggests that Bacopa monnieri enhances cognitive performance. Such traditional beliefs have now been scientifically tested through a handful of randomized, controlled human clinical trials. The current systematic review aimed to examine the scientific evidence as to whether Bacopa can enhance cognitive performance in humans. A systematic review of randomized controlled trials is presented. Multiple databases were systematically searched by multiple authors. Relevant trials were objectively assessed for methodological quality. The subjects studied were adult humans without dementia or significant cognitive impairment. B. monnieri, including Bacopa extracts, were administered over long-term supplementation periods. Any validated cognitive test, whether a primary or secondary outcome. Six (6) studies met the final inclusion criteria and were included in review. Trials were all conducted over 12 weeks. Across trials, three different Bacopa extracts were used at dosages of 300-450 mg extract per day. All reviewed trials examined the effects of Bacopa on memory, while other cognitive domains were less well studied. There were no cognitive tests in the areas of auditory perceptual abilities or idea production and only a paucity of research in the domains of reasoning, number facility, and language behavior. Across studies, Bacopa improved performance on 9 of 17 tests in the domain of memory free recall. There was little evidence of enhancement in any other cognitive domains. There is some evidence to suggest that Bacopa improves memory free recall with evidence for enhancement in other cognitive abilities currently lacking perhaps due to inconsistent measures employed by studies across these cognitive domains. Research into the nootropic effects of Bacopa is in its infancy, with research still yet to investigate the effects of Bacopa across all human cognitive abilities. Similarly, future research should examine the nootropic effects of Bacopa at varied dosages and across different extracts.

[3H]aniracetam binds to specific recognition sites in brain membranes.

PubMed

Fallarino, F; Genazzani, A A; Silla, S; L'Episcopo, M R; Camici, O; Corazzi, L; Nicoletti, F; Fioretti, M C

1995-08-01

[3H]Aniracetam bound to specific and saturable recognition sites in membranes prepared from discrete regions of rat brain. In crude membrane preparation from rat cerebral cortex, specific binding was Na+ independent, was still largely detectable at low temperature (4 degrees C), and underwent rapid dissociation. Scatchard analysis of [3H]aniracetam binding revealed a single population of sites with an apparent KD value of approximately 70 nM and a maximal density of 3.5 pmol/mg of protein. Specifically bound [3H]aniracetam was not displaced by various metabolites of aniracetam, nor by other pyrrolidinone-containing nootropic drugs such as piracetam or oxiracetam. Subcellular distribution studies showed that a high percentage of specific [3H]aniracetam binding was present in purified synaptosomes or mitochondria, whereas specific binding was low in the myelin fraction. The possibility that at least some [3H]aniracetam binding sites are associated with glutamate receptors is supported by the evidence that specific binding was abolished when membranes were preincubated at 37 degrees C under fast shaking (a procedure that substantially reduced the amount of glutamate trapped in the membranes) and could be restored after addition of either glutamate or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) but not kainate. The action of AMPA was antagonized by DNQX, which also reduced specific [3H]aniracetam binding in unwashed membranes. High levels of [3H]aniracetam binding were detected in hippocampal, cortical, or cerebellar membranes, which contain a high density of excitatory amino acid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Agonist- and subunit-dependent potentiation of glutamate receptors by a nootropic drug aniracetam.

PubMed

Tsuzuki, K; Takeuchi, T; Ozawa, S

1992-11-01

GluR1 and GluR2 cDNAs encoding non-NMDA subtypes of glutamate receptor were isolated from a rat brain cDNA library by Boulter et al. (Science, 249 (1990) 1033-1037). Functional receptors activated by kainate, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and glutamate were expressed in Xenopus oocytes injected with GluR1, GluR2 or a mixture of GluR1 and GluR2 RNAs. In GluR1-expressed oocytes, 1 mM aniracetam potentiated AMPA-induced currents by 99 +/- 10% (mean +/- S.E.M., n = 5) and glutamate-induced currents by 140 +/- 8% (n = 4), but little affected kainate-induced currents. Aniracetam was effective from a concentration of 0.1 mM, and it exhibited more conspicuous effects with the increase of the dose. In oocytes injected with GluR1 plus GluR2 RNAs, aniracetam more markedly potentiated current responses to AMPA and glutamate than those in oocytes injected with GluR1 RNA alone. For example, 1 mM aniracetam potentiated AMPA-induced currents by 396 +/- 76% (n = 4) and glutamate-induced currents by 970 +/- 65% (n = 5) in oocytes injected with 10% GluR1 and 90% GluR2 RNAs. In these oocytes, however, the potentiation of kainate-induced currents by 1 mM aniracetam was only 8 +/- 5% (n = 4). Thus, we conclude that the potentiation of the AMPA/kainate receptor by aniracetam depends on both species of agonists and subunit composition of the receptor.

Double-blind, placebo-controlled, clinical, psychometric and neurophysiological investigations with oxiracetam in the organic brain syndrome of late life.

PubMed

Saletu, B; Linzmayer, L; Grünberger, J; Pietschmann, H

1985-01-01

The therapeutic efficacy and safety of oxiracetam (ISF 2522), a new nootropic cyclic GABA derivative, were investigated in a double-blind, placebo-controlled study in 40 patients with organic brain syndrome in late life. The psychopathology was characterized by memory deficits, intellectual dysfunction, lack of drive, and disturbance of affectivity. Patients were randomly assigned to a 4-week treatment with either 2 X 400 mg oxiracetam capsules t.i.d. or identical placebo capsules in the same dosing schedule. Evaluation of the psychopathology and side effects was carried out at weeks 0, 1 and 4; laboratory tests (hematology, blood chemistry and urinalysis), a battery of psychometric tests and quantitative EEG investigations were done at weeks 0 and 4. In the oxiracetam group a slight but significant improvement in global symptomatology was observed within 1 week, with further improvement after 4 weeks. In the placebo group, an improvement was seen only in the 4th week. Evaluation of the detailed psychopathology by means of the Sandoz clinical assessment geriatric scale (SCAG) showed in the oxiracetam group significant improvements in loss of appetite and vertigo after 1 week and in short-term memory, anxiety, emotional lability, fatigue, loss of appetite and vertigo after 4 weeks. In contrast, not a single item improved significantly during placebo treatment. Although the differences in SCAG scores between the two groups failed to reach statistical significance, the overall trend towards improvement was significantly better in the oxiracetam group. The tolerability of the drug was good.(ABSTRACT TRUNCATED AT 250 WORDS)

New therapeutic activity of metabolic enhancer piracetam in treatment of neurodegenerative disease: Participation of caspase independent death factors, oxidative stress, inflammatory responses and apoptosis.

PubMed

Verma, Dinesh Kumar; Gupta, Sonam; Biswas, Joyshree; Joshi, Neeraj; Singh, Abhishek; Gupta, Parul; Tiwari, Shubhangini; Sivarama Raju, K; Chaturvedi, Swati; Wahajuddin, M; Singh, Sarika

2018-06-01

Piracetam, a nootropic drug that has been clinically used for decades but remains enigmatic due to no distinct understanding of its mechanism of action. The present study aimed to investigate the role of caspase independent pathway in piracetam mediated neuroprotection. LPS administration caused significant alterations in oxidative stress related parameters like glutathione, glutathione reductase and increased lipid peroxidation. LPS administration also caused augmented expression of inflammatory cytokines and astrocytes activation. Piracetam treatment offered significant protection against LPS induced oxidative and inflammatory parameters and inhibited astrocytes activation. LPS administration caused augmented level of reactive oxygen species and depleted mitochondrial membrane potential which were attenuated with piracetam treatment. This study for the first time demonstrates the role of caspase independent death factors in piracetam induced neuroprotective effects in rat brain. Translocation of mitochondrial resident apoptosis inducing factor and endonuclease G to nucleus through cytosol after LPS administration was significantly blocked with piracetam treatment. Further, LPS induced DNA fragmentation along with up regulated Poly [ADP-ribose] polymerase 1 (PARP1) levels were also inhibited with piracetam treatment. Apoptotic death was confirmed by the cleavage of caspase 3 as well as histological alteration in rat brain regions. LPS administration caused significantly increased level of cleaved caspase 3, altered neuronal morphology and decreased neuronal density which were restored with piracetam treatment. Collectively our findings indicate that piracetam offered protection against LPS induced inflammatory responses and cellular death including its antioxidative antiapoptotic activity with its attenuation against mitochondria mediated caspase independent pathway. Copyright © 2018 Elsevier B.V. All rights reserved.

Pharmaceutical cognitive doping in students: A chimeric way to get-a-head?

PubMed

Carton, Louise; Cabé, Nicolas; Ménard, Olivier; Deheul, Sylvie; Caous, Anne-Sylvie; Devos, David; Cottencin, Olivier; Bordet, Régis

2018-03-06

For students, the pressing demands for memorization, top-level performance, and peer competition create an environment favorable for pharmaceutical cognitive doping behavior. We aimed to describe recent practices and the benefit/risk ratio of such behavior and to discuss the issues at stake. The prevalence of pharmaceutical cognitive doping among students has been reported from 1.3% to 33% across studies, with variations depending on country and definition of pharmaceutical cognitive doping. The therapeutic classes most frequently cited as being diverted for doping purposes are psychostimulants and nootropics (methylphenidate, modafinil, piracetam), corticosteroids, sedative drugs and beta-blockers. Some illegal substances such as cannabis, amphetamines and cocaine are also consumed in order to boost mental function. Finally, over-the-counter products, such as caffeine-based tablets or energy drinks, or alcohol, are also widely used by students whose motivations involve enhanced performance, concentration, memory, and staying awake during the revision and exam period. However, the expected (often fantasized) effectiveness of these products does not correspond to the reality of a modest controversial impact on cognitive performance. There appears to be an emerging profile of the student more inclined to doping behavior. Cognitive doping thus raises the question of its regulation, opening a debate opposing, on one hand, individual freedom and supposed collective benefits and, on the other hand, health consequences, educational (in)equality, and the risk of tarnished academic success. Strengthening school and university medicine, through prevention campaigns and the identification of subjects at risk, is essential to limit the extent, risk, and damages associated with such practices. Copyright © 2018. Published by Elsevier Masson SAS.

Senile dementia of the Alzheimer type treated with aniracetam: a new nootropic agent.

PubMed

Sourander, L B; Portin, R; Mölsä, P; Lahdes, A; Rinne, U K

1987-01-01

Forty-four patients with senile dementia of the Alzheimer type were randomly allocated into double-blind treatment with either aniracetam (RO 13-5057) 1 g or placebo daily for 3 months. Neurological examinations were made before and after treatment and psychometric tests were performed before and after 1 month's and after 3 month's treatment. Treatment was interrupted due to occurrence of confusion in four cases in the aniracetam group and in one case in the placebo group. During treatment, an improvement was seen in several cognitive tests, especially those associated with memory, but this improvement occurred in the placebo as well as in the aniracetam-treated group. In clinical evaluation no difference was seen in efficacy between the two treatment groups.

Piracetam and piracetam-like drugs: from basic science to novel clinical applications to CNS disorders.

PubMed

Malykh, Andrei G; Sadaie, M Reza

2010-02-12

There is an increasing interest in nootropic drugs for the treatment of CNS disorders. Since the last meta-analysis of the clinical efficacy of piracetam, more information has accumulated. The primary objective of this systematic survey is to evaluate the clinical outcomes as well as the scientific literature relating to the pharmacology, pharmacokinetics/pharmacodynamics, mechanism of action, dosing, toxicology and adverse effects of marketed and investigational drugs. The major focus of the literature search was on articles demonstrating evidence-based clinical investigations during the past 10 years for the following therapeutic categories of CNS disorders: (i) cognition/memory; (ii) epilepsy and seizure; (iii) neurodegenerative diseases; (iv) stroke/ischaemia; and (v) stress and anxiety. In this article, piracetam-like compounds are divided into three subgroups based on their chemical structures, known efficacy and intended clinical uses. Subgroup 1 drugs include piracetam, oxiracetam, aniracetam, pramiracetam and phenylpiracetam, which have been used in humans and some of which are available as dietary supplements. Of these, oxiracetam and aniracetam are no longer in clinical use. Pramiracetam reportedly improved cognitive deficits associated with traumatic brain injuries. Although piracetam exhibited no long-term benefits for the treatment of mild cognitive impairments, recent studies demonstrated its neuroprotective effect when used during coronary bypass surgery. It was also effective in the treatment of cognitive disorders of cerebrovascular and traumatic origins; however, its overall effect on lowering depression and anxiety was higher than improving memory. As add-on therapy, it appears to benefit individuals with myoclonus epilepsy and tardive dyskinesia. Phenylpiracetam is more potent than piracetam and is used for a wider range of indications. In combination with a vasodilator drug, piracetam appeared to have an additive beneficial effect on various cognitive disabilities. Subgroup 2 drugs include levetiracetam, seletracetam and brivaracetam, which demonstrate antiepileptic activity, although their cognitive effects are unclear. Subgroup 3 includes piracetam derivatives with unknown clinical efficacies, and of these nefiracetam failed to improve cognition in post-stroke patients and rolipram is currently in clinical trials as an antidepressant. The remaining compounds of this subgroup are at various preclinical stages of research. The modes of action of piracetam and most of its derivatives remain an enigma. Differential effects on subtypes of glutamate receptors, but not the GABAergic actions, have been implicated. Piracetam seems to activate calcium influx into neuronal cells; however, this function is questionable in the light of findings that a persistent calcium inflow may have deleterious impact on neuronal cells. Although subgroup 2 compounds act via binding to another neuronal receptor (synaptic vesicle 2A), some of the subgroup 3 compounds, such as nefiracetam, are similar to those of subgroup 1. Based on calculations of the efficacy rates, our assessments indicate notable improvements in clinical outcomes with some of these agents.

Excitatory synapse in the rat hippocampus in tissue culture and effects of aniracetam.

PubMed

Ozawa, S; Iino, M; Abe, M

1991-10-01

Excitatory synaptic connections between rat hippocampal neurons were established in tissue culture. The electrophysiological and pharmacological properties of these synapses were studied with the use of the tight-seal whole-cell recording technique. The excitatory postsynaptic current (EPSC) in a dissociated CA1 neuron evoked by stimulation of an explant from the CA3/CA4 region of the hippocampus had two distinct components in Mg(2+)-free medium. The fast component was abolished by the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (2 microM), whereas the slow component was abolished by the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphonovalerate (D-APV) (50 microM). In solution containing 1 mM Mg2+, the peak amplitude of the fast component was almost linearly related to the membrane potential. In contrast, the conductance change underlying the slow component of the EPSC was voltage-dependent with a region of negative-slope conductance in the range of -80 to -20 mV. A nootropic drug, aniracetam, increased both the amplitude and duration of the fast component of the EPSC in a concentration-dependent manner in the range of 0.1-5 mM, whereas it had no potentiating effect on the slow component. Aniracetam (0.1-5 mM) similarly increased current responses of the postsynaptic neuron to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA). Current responses to quisqualate and glutamate in the presence of D-APV were also potentiated by aniracetam. However, neither NMDA- nor kainate-induced current was potentiated by 1 mM aniracetam.

Indentification of vincamine indole alkaloids producing endophytic fungi isolated from Nerium indicum, Apocynaceae.

PubMed

Na, Ren; Jiajia, Liu; Dongliang, Yang; Yingzi, Peng; Juan, Hong; Xiong, Liu; Nana, Zhao; Jing, Zhou; Yitian, Luo

2016-11-01

Vincamine, a monoterpenoid indole alkaloid which had been marketed as nootropic drugs for the treatment of cerebral insufficiencies, is widely found in plants of the Apocynaceae family. Nerium indicum is a plant belonging to the Apocynaceae family. So, the purpose of this research was designed to investigate the vincamine alkaloids producing endophytic fungi from Nerium indicum, Apocynaceae. 11 strains of endophytic fungi, isolated from the stems and roots of the plant, were grouped into 5 genera on the basis of morphological characteristics. All fungal isolates were fermented and their extracts were preliminary screened by Dragendorff's reagent and thin layer chromatography (TLC). One isolated strain CH1, isolated from the stems of Nerium indicum, had the same Rf value (about 0.56) as authentic vincamine. The extracts of strain CH1 were further analyzed by high performance liquid chromatography (HPLC) and liquid chromatograph-mass spectrometry (LC-MS), and the results showed that the strain CH1 could produce vincamine and vincamine analogues. The acetylcholinesterase (AchE) inhibitory activity assays using Ellman's method revealed that the metabolites of strain CH1 had significant AchE inhibitory activity with an IC50 value of 5.16μg/mL. The isolate CH1 was identified as Geomyces sp. based on morphological and molecular identification, and has been deposited in the China Center for Type Culture Collection (CCTCCM 2014676). This study first reported the natural compounds tabersonine and ethyl-vincamine from endophytic fungi CH1, Geomyces sp. In conclusion, the fungal endophytes from Nerium indicum can be used as alternative source for the production of vincamine and vincamine analogues. Copyright © 2016 Elsevier GmbH. All rights reserved.

Cognitive aspects of congenital learned helplessness and its reversal by the monoamine oxidase (MAO)-B inhibitor deprenyl

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schulz, D.; Schulz, D.; Mirrione, M.

2009-11-29

Cognitive processes are assumed to change with learned helplessness, an animal model of depression, but little is known about such deficits. Here we investigated the role of cognitive and related functions in selectively bred helpless (cLH, n = 10), non-helpless (cNLH, n = 12) and wild type (WT, n = 8) Sprague Dawley rats. The animals were exposed to an open field for 10 min on each of two test days. On the third day, an object exploration paradigm was carried out. The animals were later tested for helplessness. Both cLH and cNLH rats were more active than WTs onmore » the first day in the open field. Over trials, cNLH and WT rats lowered their activity less than cLH rats. This resistance-to-habituation co-varied with a resistance to develop helplessness. In cLH rats, higher 'anxiety' or less time spent in the center of the open field co-varied with severe helplessness. In WTs, a greater reactivity to novel objects and to a spatially relocated object predicted lower levels of helplessness. In cLH rats (n = 4-5 per group), chronic treatment with a high dose of the monoamineoxidase (MAO)-Binhibitordeprenyl (10 mg/kg; i.p.), an anti-Parkinson, nootropic and antidepressant drug, attenuated helplessness. Remarkably, helplessness reversal required the experience of repeated test trials, reminiscent of a learning process. Chronic deprenyl (10 mg/kg; i.p.) did not alter locomotion/exploration or 'anxiety' in the open field. In conclusion, helplessness may be related to altered mechanisms of reinforcement learning and working memory, and to abnormalities in MAO-A and/or MAO-B functioning.« less

Metabolic Enhancer Piracetam Attenuates the Translocation of Mitochondrion-Specific Proteins of Caspase-Independent Pathway, Poly [ADP-Ribose] Polymerase 1 Up-regulation and Oxidative DNA Fragmentation.

PubMed

Verma, Dinesh Kumar; Gupta, Sonam; Biswas, Joyshree; Joshi, Neeraj; Sivarama Raju, K; Wahajuddin, Mu; Singh, Sarika

2018-03-12

Piracetam, a nootropic drug, has been clinically used for decades; however, its mechanism of action still remains enigmatic. The present study was undertaken to evaluate the role of mitochondrion-specific factors of caspase-independent pathway like apoptotic-inducing factor (AIF) and endonuclease-G (endo-G) in piracetam-induced neuroprotection. N2A cells treated with lipopolysaccharide (LPS) exhibited significant cytotoxicity, impaired mitochondrial activity, and reactive oxygen species generation which was significantly attenuated with piracetam co-treatment. Cells co-treated with LPS and piracetam exhibited significant uptake of piracetam in comparison to only piracetam-treated cells as estimated by liquid chromatography-mass spectrometry (LC-MSMS). LPS treatment caused significant translocation of AIF and endonuclease-G in neuronal N2A cells which were significantly attenuated with piracetam co-treatment. Significant over-expression of proinflammatory cytokines was also observed after treatment of LPS to cells which was inhibited with piracetam co-treatment demonstrating its anti-inflammatory property. LPS-treated cells exhibited significant oxidative DNA fragmentation and poly [ADP-ribose] polymerase-1 (PARP-1) up-regulation in nucleus, both of which were attenuated with piracetam treatment. Antioxidant melatonin but not z-VAD offered the inhibited LPS-induced DNA fragmentation indicating the involvement of oxidative DNA fragmentation. Further, we did not observe the altered caspase-3 level after LPS treatment initially while at a later time point, significantly augmented level of caspase-3 was observed which was not inhibited with piracetam treatment. In total, our findings indicate the interference of piracetam in mitochondrion-mediated caspase-independent pathway, as well as its anti-inflammatory and antioxidative properties. Graphical Abstract Graphical abstract indicating the novel interference of metabolic enhancer piracetam (P) in neuronal death mechanisms.

Cognitive aspects of congenital learned helplessness and its reversal by the monoamine oxidase (MAO)-B inhibitor deprenyl.

PubMed

Schulz, Daniela; Mirrione, Martine M; Henn, Fritz A

2010-02-01

Cognitive processes are assumed to change with learned helplessness, an animal model of depression, but little is known about such deficits. Here we investigated the role of cognitive and related functions in selectively bred helpless (cLH, n=10), non-helpless (cNLH, n=12) and wild type (WT, n=8) Sprague Dawley rats. The animals were exposed to an open field for 10min on each of two test days. On the third day, an object exploration paradigm was carried out. The animals were later tested for helplessness. Both cLH and cNLH rats were more active than WTs on the first day in the open field. Over trials, cNLH and WT rats lowered their activity less than cLH rats. This resistance-to-habituation co-varied with a resistance to develop helplessness. In cLH rats, higher 'anxiety' or less time spent in the center of the open field co-varied with severe helplessness. In WTs, a greater reactivity to novel objects and to a spatially relocated object predicted lower levels of helplessness. In cLH rats (n=4-5 per group), chronic treatment with a high dose of the monoamine oxidase (MAO)-B inhibitor deprenyl (10mg/kg; i.p.), an anti-Parkinson, nootropic and antidepressant drug, attenuated helplessness. Remarkably, helplessness reversal required the experience of repeated test trials, reminiscent of a learning process. Chronic deprenyl (10mg/kg; i.p.) did not alter locomotion/exploration or 'anxiety' in the open field. In conclusion, helplessness may be related to altered mechanisms of reinforcement learning and working memory, and to abnormalities in MAO-A and/or MAO-B functioning. Copyright 2009 Elsevier Inc. All rights reserved.

[Pharmaceutical cognitive doping in students: a chimeric way to get-a-head?

PubMed

Carton, Louise; Cabé, Nicolas; Ménard, Olivier; Deheul, Sylvie; Caous, Anne-Sylvie; Devos, David; Cottencin, Olivier; Bordet, Régis

2017-11-22

For students, the pressing demands for memorization, top-level performance, and peer competition create an environment favorable for pharmaceutical cognitive doping behavior. We aimed to describe recent practices and the benefit / risk ratio of such behavior and to discuss the issues at stake. The prevalence of pharmaceutical cognitive doping among students has been reported from 1.3% to 33% across studies, with variations depending on country and definition of pharmaceutical cognitive doping. The therapeutic classes most frequently cited as being diverted for doping purposes are psychostimulants and nootropics (methylphenidate, modafinil, piracetam), corticosteroids, sedative drugs and beta-blockers. Some illegal substances such as cannabis, amphetamines and cocaine are also consumed in order to boost mental function. Finally, over-the-counter products, such as caffeine-based tablets or energy drinks, or alcohol, are also widely used by students whose motivations involve enhanced performance, concentration, memory, and staying awake during the revision and exam period. However, the expected (often fantasized) effectiveness of these products does not correspond to the reality of a modest controversial impact on cognitive performance. There appears to be an emerging profile of the student more inclined to doping behavior. Cognitive doping thus raises the question of its regulation, opening a debate opposing, on one hand, individual freedom and supposed collective benefits and, on the other hand, health consequences, educational (in)equality, and the risk of tarnished academic success. Strengthening school and university medicine, through prevention campaigns and the identification of subjects at risk, is essential to limit the extent, risk, and damages associated with such practices. Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

[Application of nootropic agents in complex treatment of patients with concussion of the brain].

PubMed

Tkachev, A V

2007-01-01

65 patients with a mild craniocereberal trauma have been observed. Medical examination included among general clinical methods the following methods: KT (MRT) of the brain, oculist examination including the observation of eye fundus. For objectification of a patient' complaints the authors used orientation and Galvestona's amnesia tests, feeling scale (psychological test), the table to determine the level of memory. Tests have been carried out on the first, tenth and thirty day of the treatment. Patients of the first group received in a complex treatment -pramistar, patients of the second group - piracetam. Patients of both groups noted considerable improvement during a complex treatment (disappearance of headache, dizziness and nausea) and at the same time patients receiving pramistar had better restoration of orientation and feeling. Pramistar was also more effective in patients with amnesia.

Inhibitory effect of aniracetam on N-type calcium current in acutely isolated rat neuronal cells.

PubMed

Koike, H; Saito, H; Matsuki, N

1993-04-01

Effects of aniracetam on whole-cell calcium currents were studied in acutely isolated neuronal cells from postnatal rat ventromedial hypothalamus. There were three types of inward calcium currents, one low-threshold transient current and two high-threshold sustained currents. The nicardipine sensitive L-type current was activated at -20 mV or more depolarized potentials, and the omega-conotoxin sensitive N-type current was recorded at more positive potentials than the L-type. Aniracetam inhibited the N-type current in a dose-dependent manner without affecting the other two types of calcium currents. The effect appeared soon after the addition and lasted for several minutes during washing. Since the N-type current is thought to regulate the release of transmitters, the inhibitory effect may contribute to the nootropic property of aniracetam by modifying the neurotransmission.

[Complex application 2-ethyl-6-methyl-3-hydroxypyridine-succinate and vinpocetine in cerebrovascular disorder.

PubMed

Solovyeva, E Yu; Karneev, A N; Chekanov, A V; Baranova, O A; Choi, I V

Developing brain ischemia due to cerebral vascularization leads to disruption of brain metabolism. Chronic cerebral hypoperfusion leads to irreversible brain damage and plays an important role in the development of some types of dementia. Early use of antioxidants such as ethyl ether apovincamine acid (vinpocetine) and 2-ethyl-6-methyl-3-hydroxypyridine-succinate in the treatment of this pathology is seen as a real pathogenetically based method of correction of cerebral metabolism with cerebral vascular disorders, demonstrating the increase in cerebral blood flow and also neuroprotective effects. Clinical studies and studies on biological models show that the main mechanisms of action of vinpocetine and 2-ethyl-6-methyl-3-hydroxypyridine-succinate, although have a similar focus, but implementing neuroprotective and nootropic effects via various links in the pathogenesis of ischemic brain damage.

Hypotensive and neurometabolic effects of intragastric Reishi (Ganoderma lucidum) administration in hypertensive ISIAH rat strain.

PubMed

Shevelev, Oleg B; Seryapina, Alisa A; Zavjalov, Evgenii L; Gerlinskaya, Lyudmila A; Goryachkovskaya, Tatiana N; Slynko, Nikolay M; Kuibida, Leonid V; Peltek, Sergey E; Markel, Arcady L; Moshkin, Mikhail P

2018-03-01

As the standard clinically used hypotensive medicines have many undesirable side effects, there is a need for new therapeutic agents, especially ones of a natural origin. One possible candidate is extract from the mushroom Reishi (Ganoderma lucidum), which is used in the treatment and prevention of many chronic diseases. To study the effectiveness of Reishi, which grows in the Altai Mountains, as an antihypertensive agent, we intragastrically administered Reishi water extract to adult male hypertensive ISIAH (inherited stress-induced arterial hypertension) rats. After seven weeks, Reishi therapy reduced blood pressure in experimental animals at a level comparable to that of losartan. Unlike losartan, intragastric Reishi introduction significantly increases cerebral blood flow and affects cerebral cortex metabolic patterns, shifting the balance of inhibitory and excitatory neurotransmitters toward excitation. Changes in cerebral blood flow and ratios of neurometabolites suggests Reishi has a potential nootropic effect. Copyright © 2018 Elsevier GmbH. All rights reserved.

Enhancement of nootropic effect of duloxetine and bupropion by caffeine in mice.

PubMed

Kale, Pravin Popatrao; Addepalli, Veeranjaneyulu

2015-01-01

The existing evidence suggests an association between depression and memory impairment. The objective of present study was to assess the effect of low dose caffeine with duloxetine and bupropion on memory. Mice were divided randomly into seven groups. Intra-peritoneal treatment of normal saline (10 ml/kg), caffeine (10 mg/kg), duloxetine (10 mg/kg), bupropion alone (10 mg/kg), caffeine + duloxetine (5 mg/kg, each), caffeine + bupropion (5 mg/kg, each), and bupropion + duloxetine (5 mg/kg, each) were given to groups I-VII, respectively. Elevated plus maze was used to evaluate transfer latency (TL) and Morris water maze was used to estimate the time spent in target quadrant. Caffeine with duloxetine treated group was better than other combination treated groups in terms of a significant decrease in TL and increase in the time spent in target quadrant recorded. Combining lower dose of caffeine with duloxetine may enhance cognitive benefits than respective monotherapies.

Role of vinpocetine in cerebrovascular diseases.

PubMed

Patyar, Sazal; Prakash, Ajay; Modi, Manish; Medhi, Bikash

2011-01-01

A cerebrovascular accident, or stroke, is defined as the abrupt onset of a neurological deficit, which can be due to ischemia. Cerebral ischemia is caused by a reduction in blood flow that thereby decreases cerebral metabolism. Chronic cerebral hypoperfusion leads to irreversible brain damage and plays an important role in the development of certain types of dementia. Vinpocetine, chemically known as ethyl apovincaminate, is a vinca alkaloid that exhibits cerebral blood-flow enhancing and neuroprotective effects. Non-clinical and clinical studies have suggested multiple mechanisms responsible for the beneficial neuroprotective effects of vinpocetine. As no significant side effects related to vinpocetine treatment have been reported, it is considered to be safe for long-term use. This vasoactive alkaloid is widely marketed as a supplement for vasodilation and as a nootropic for the improvement of memory. The present review focuses on studies investigating the role of vinpocetine in cerebrovascular diseases.

Improved Mitochondrial Function in Brain Aging and Alzheimer Disease – the New Mechanism of Action of the Old Metabolic Enhancer Piracetam

PubMed Central

Leuner, Kristina; Kurz, Christopher; Guidetti, Giorgio; Orgogozo, Jean-Marc; Müller, Walter E.

2010-01-01

Piracetam, the prototype of the so-called nootropic drugs’ is used since many years in different countries to treat cognitive impairment in aging and dementia. Findings that piracetam enhances fluidity of brain mitochondrial membranes led to the hypothesis that piracetam might improve mitochondrial function, e.g., might enhance ATP synthesis. This assumption has recently been supported by a number of observations showing enhanced mitochondrial membrane potential, enhanced ATP production, and reduced sensitivity for apoptosis in a variety of cell and animal models for aging and Alzheimer disease. As a specific consequence, substantial evidence for elevated neuronal plasticity as a specific effect of piracetam has emerged. Taken together, this new findings can explain many of the therapeutic effects of piracetam on cognition in aging and dementia as well as different situations of brain dysfunctions. PMID:20877425

Aniracetam, 1-BCP and cyclothiazide differentially modulate the function of NMDA and AMPA receptors mediating enhancement of noradrenaline release in rat hippocampal slices.

PubMed

Pittaluga, A; Bonfanti, A; Arvigo, D; Raiteri, M

1999-04-01

Aniracetam, 1-(1,3-benzodioxol-5-yl-carbonyl)piperidine (1-BCP) and cyclothiazide, three compounds considered to enhance cognition through modulation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors, were evaluated in the 'kynurenate test', a biochemical assay in which some nootropics have been shown to prevent the antagonism by kynurenic acid of the N-methyl-D-aspartate (NMDA)-evoked [3H]noradrenaline ([3H]NA) release from rat hippocampal slices. Aniracetam attenuated the kynurenate (100 microM) antagonism of the [3H]NA release elicited by 100 microM NMDA with high potency (EC50< or =0.1 microM). Cyclothiazide and 1-BCP were about 10 and 100 times less potent than aniracetam, respectively. The effect of aniracetam persisted in the presence of the AMPA receptor antagonist 6-nitro-7-sulphamoyl-benzo[f]quinoxaline-2,3-dione (NBQX) added at 5 microM, a concentration that did not affect NMDA receptors; in contrast, NBQX reduced the effect of 1-BCP and abolished that of cyclothiazide. The AMPA-evoked release of [3H]NA from hippocampal slices or synaptosomes was enhanced by cyclothiazide, less potently by 1-BCP and weakly by aniracetam. High concentrations of kynurenate (1 mM) antagonized the AMPA-evoked [3H]NA release in slices; this antagonism was attenuated by 1 microM cyclothiazide and reversed to an enhancement of AMPA-evoked [3H]NA release by 10 microM of the drug, but was insensitive to 1-BCP or aniracetam. It is concluded that aniracetam exerts a dual effect on glutamatergic transmission: modulation of NMDA receptor function at nanomolar concentrations, and modulation of AMPA receptors at high micromolar concentrations. As to cyclothiazide and 1-BCP, our data concur with the idea that both compounds largely act through AMPA receptors, although an NMDA component may be involved in the effect of 1-BCP.

Vinpocetine reduces lipopolysaccharide-induced inflammatory pain and neutrophil recruitment in mice by targeting oxidative stress, cytokines and NF-κB.

PubMed

Ruiz-Miyazawa, Kenji W; Pinho-Ribeiro, Felipe A; Zarpelon, Ana C; Staurengo-Ferrari, Larissa; Silva, Rangel L; Alves-Filho, Jose C; Cunha, Thiago M; Cunha, Fernando Q; Casagrande, Rubia; Verri, Waldiceu A

2015-07-25

In response to lipopolysaccharide (LPS), tissue resident macrophages and recruited neutrophils produce inflammatory mediators through activation of Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway. These mediators include inflammatory cytokines and reactive oxygen species that, in turn, sensitize nociceptors and lead to inflammatory pain. Vinpocetine is a nootropic drug widely used to treat cognitive and neurovascular disorders, and more recently its anti-inflammatory properties through inhibition of NF-κB activation have been described. In the present study, we used the intraplantar and intraperitoneal LPS stimulus in mice to investigate the effects of vinpocetine pre-treatment (3, 10, or 30mg/kg by gavage) in hyperalgesia, leukocyte recruitment, oxidative stress, and pro-inflammatory cytokine production (TNF-α, IL-1β, and IL-33). LPS-induced NF-κB activation and cytokine production were investigated using RAW 264.7 macrophage cell in vitro. Vinpocetine (30mg/kg) significantly reduces hyperalgesia to mechanical and thermal stimuli, and myeloperoxidase (MPO) activity (a neutrophil marker) in the plantar paw skin, and also inhibits neutrophil and mononuclear cell recruitment, superoxide anion and nitric oxide production, oxidative stress, and cytokine production (TNF-α, IL-1β and IL-33) in the peritoneal cavity. At least in part, these effects seem to be mediated by direct effects of vinpocetine on macrophages, since it inhibited the production of the same cytokines (TNF-α, IL-1β and IL-33) and the NF-κB activation in LPS-stimulated RAW 264.7 macrophages. Our results suggest that vinpocetine represents an important therapeutic approach to treat inflammation and pain induced by a gram-negative bacterial component by targeting NF-κB activation and NF-κB-related cytokine production in macrophages. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Cholinesterase inhibitory activities of Apai-sa-le recipe and its ingredients.

PubMed

Senavong, Pimolvan; Sattaponpan, Chitsanucha; Silavat Suk-um; Itharat, Arunporn

2014-08-01

Acetylcholinesterase and butyrylcholoinesterase inhibitors are well-known drugs commonly used in the treatment ofAlzheimer's disease (AD) to improve cognitive function. These enzyme inhibitors were reported to be found in manyplants. Apai-sa-le recipe was a Thai tradition used as nootropic recipe and formerly claimed to improve memory. Therefore, it is interesting to investigate cholinesterase inhibitory activity ofthe recipe and its ingredients. To determine the whole recipe ofApai-sa-le and its ingredients for inhibitory effect on acetylcholinesterase (AChE) and human butyrylcholinesterase (BuChE) activities. Thirty grams of each plant and 181 grams of the whole recipe were separately extracted by 95% ethanol, after filtered the filtrate were evaporated and vacuum-dried at 45°C. By Elman method, the inhibitory activities of both enzymes were assessed. The volatile constituents ofeach extract were determined by GCMS. The constituents in the non- volatile extract were examined by TLC and the antioxidant activity was determined. Four plants exhibited specific BuChE inhibitor were Lepidium sativum Linn. (Ls), Piper nigrum L. (Pn), Angelica dahurica Benth (Ad) andAtractylodes lancea DC. (Al), which shown the lC50 of 5.59, 24.52, 73.23, 96.25 μg/ml, respectively whereas galantamine and the whole recipe showed IC50 of 0.59 and 236 μg/ml. Only Pn extract inhibited AChE at lCso of 25.46 μg/ml. By GCMS and TLC fingerprints revealed the main constituents in LS, Ad, Al andPn as apiol, cumialdehyde, furanodiene and piperine. Moreover nine plant extracts and the whole recipe showed antioxidant activity. Lepidium sativum Linn. (Ls) extract showed the most potency on BuChE inhibitory effect. Three ingredients and the whole recipe exhibited mild activity. Only Piper nigrum L demonstrated inhibition effect on both AChE and BuChE.

The major metabolite of dipeptide piracetam analogue GVS-111 in rat brain and its similarity to endogenous neuropeptide cyclo-L-prolylglycine.

PubMed

Gudasheva, T A; Boyko, S S; Ostrovskaya, R U; Voronina, T A; Akparov, V K; Trofimov, S S; Rozantsev, G G; Skoldinov, A P; Zherdev, V P; Seredenin, S B

1997-01-01

The metabolism of a new piracetam analogue, the dipeptide cognitive enhancer N-phenylacetyl-L-prolylglycine ethyl ester (GVS-111) was studied in vivo. GVS-111 itself was not found in rat brain 1 h after 5 mg/kg i.p. administration up to limit of detection (LOD) under high performance liquid chromatography (HPLC) conditions. Three substances corresponding to the three possible GVS-111 metabolites, namely phenylacetic acid, prolylglycine and cyclo-prolylglycine, were found in experimental rat brain samples as well as in controls using HPLC, gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS) methods. Only cyclo-prolylglycine concentration increased (2.5-fold) 1 h after GVS-111 administration. Cyclo-prolylglycine formation from GVS-111 in the presence of plasma and brain enzymes was shown in vitro. These data could be considered as evidence that GVS-111 is prodrug which converts in the body to cyclo-prolylglycine, and which is identical to the endogenous cyclopeptide that produces the nootropic activity.

Nootropic α7 nicotinic receptor allosteric modulator derived from GABAA receptor modulators

PubMed Central

Ng, Herman J.; Whittemore, Edward R.; Tran, Minhtam B.; Hogenkamp, Derk J.; Broide, Ron S.; Johnstone, Timothy B.; Zheng, Lijun; Stevens, Karen E.; Gee, Kelvin W.

2007-01-01

Activation of brain α7 nicotinic acetylcholine receptors (α7 nAChRs) has broad therapeutic potential in CNS diseases related to cognitive dysfunction, including Alzheimer's disease and schizophrenia. In contrast to direct agonist activation, positive allosteric modulation of α7 nAChRs would deliver the clinically validated benefits of allosterism to these indications. We have generated a selective α7 nAChR-positive allosteric modulator (PAM) from a library of GABAA receptor PAMs. Compound 6 (N-(4-chlorophenyl)-α-[[(4-chloro-phenyl)amino]methylene]-3-methyl-5-isoxazoleacet-amide) evokes robust positive modulation of agonist-induced currents at α7 nAChRs, while preserving the rapid native characteristics of desensitization, and has little to no efficacy at other ligand-gated ion channels. In rodent models, it corrects sensory-gating deficits and improves working memory, effects consistent with cognitive enhancement. Compound 6 represents a chemotype for allosteric activation of α7 nAChRs, with therapeutic potential in CNS diseases with cognitive dysfunction. PMID:17470817

Enhancement of nootropic effect of duloxetine and bupropion by caffeine in mice

PubMed Central

Kale, Pravin Popatrao; Addepalli, Veeranjaneyulu

2015-01-01

Objective: The existing evidence suggests an association between depression and memory impairment. The objective of present study was to assess the effect of low dose caffeine with duloxetine and bupropion on memory. Materials and Methods: Mice were divided randomly into seven groups. Intra-peritoneal treatment of normal saline (10 ml/kg), caffeine (10 mg/kg), duloxetine (10 mg/kg), bupropion alone (10 mg/kg), caffeine + duloxetine (5 mg/kg, each), caffeine + bupropion (5 mg/kg, each), and bupropion + duloxetine (5 mg/kg, each) were given to groups I-VII, respectively. Elevated plus maze was used to evaluate transfer latency (TL) and Morris water maze was used to estimate the time spent in target quadrant. Results: Caffeine with duloxetine treated group was better than other combination treated groups in terms of a significant decrease in TL and increase in the time spent in target quadrant recorded. Conclusion: Combining lower dose of caffeine with duloxetine may enhance cognitive benefits than respective monotherapies. PMID:25878382

Aniracetam reverses memory impairment in rats.

PubMed

Martin, J R; Moreau, J L; Jenck, F

1995-02-01

The pyrrolidinone derivative aniracetam given orally immediately after acquisition of an inhibitory avoidance response reproducibly ameliorated scopolamine-induced amnesia in female rats in an extensive series of test sessions conducted over a 1-year period. In a dose-response experiment it was demonstrated that 50 mg kg-1 was the lowest oral dose of aniracetam to significantly ameliorate scopolamine-induced amnesia. Combined results from these numerous test sessions demonstrated that 50 mg kg-1 aniracetam administered to scopolamine-treated rats resulted in 53% of the animals exhibiting correct passive avoidance responding in the retention evaluation versus 9% of the scopolamine-treated rats given vehicle (in comparison, 64% of the rats injected with vehicle rather than scopolamine in this experimental situation exhibited correct responding in the retention test). There was minimal variation in this pattern of results over the successive 1-month blocks constituting the complete experimental period. Thus, the nootropic compound aniracetam replicably exhibited memory enhancing effects in this animal model of reduced cholinergic function.

Postnatal aniracetam treatment improves prenatal ethanol induced attenuation of AMPA receptor-mediated synaptic transmission.

PubMed

Wijayawardhane, Nayana; Shonesy, Brian C; Vaglenova, Julia; Vaithianathan, Thirumalini; Carpenter, Mark; Breese, Charles R; Dityatev, Alexander; Suppiramaniam, Vishnu

2007-06-01

Aniracetam is a nootropic compound and an allosteric modulator of AMPA receptors (AMPARs) which mediate synaptic mechanisms of learning and memory. Here we analyzed impairments in AMPAR-mediated synaptic transmission caused by moderate prenatal ethanol exposure and investigated the effects of postnatal aniracetam treatment on these abnormalities. Pregnant Sprague-Dawley rats were gavaged with ethanol or isocaloric sucrose throughout pregnancy, and subsequently the offspring were treated with aniracetam on postnatal days (PND) 18 to 27. Hippocampal slices prepared from these pups on PND 28 to 34 were used for the whole-cell patch-clamp recordings of AMPAR-mediated spontaneous and miniature excitatory postsynaptic currents in CA1 pyramidal cells. Our results indicate that moderate ethanol exposure during pregnancy results in impaired hippocampal AMPAR-mediated neurotransmission, and critically timed aniracetam treatment can abrogate this deficiency. These results highlight the possibility that aniracetam treatment can restore synaptic transmission and ameliorate cognitive deficits associated with the fetal alcohol syndrome.

Health and Social Problems Associated with Recent Novel Psychoactive Substance (NPS) Use Amongst Marginalised, Nightlife and Online Users in Six European Countries.

PubMed

Van Hout, Marie Claire; Benschop, Annemieke; Bujalski, Michal; Dąbrowska, Katarzyna; Demetrovics, Zsolt; Felvinczi, Katalin; Hearne, Evelyn; Henriques, Susana; Kaló, Zsuzsa; Kamphausen, Gerrit; Korf, Dirk; Silva, Joana Paula; Wieczorek, Łukasz; Werse, Bernd

2018-01-01

Continued diversification and use of new psychoactive substances (NPS) across Europe remains a public health challenge. The study describes health and social consequences of recent NPS use as reported in a survey of marginalised, nightlife and online NPS users in the Netherlands, Hungary, Portugal, Ireland, Germany and Poland ( n  = 3023). Some respondents were unable to categorise NPS they had used. Use of ' herbal blends ' and ' synthetic cannabinoids obtained pure ' was most reported in Germany, Poland and Hungary, and use of ' branded stimulants ' and ' stimulants/empathogens/nootropics obtained pure ' was most reported in the Netherlands. Increased heart rate and palpitation, dizziness, anxiety, horror trips and headaches were most commonly reported acute side effects. Marginalised users reported substantially more acute side effects, more mid- and long-term mental and physical problems, and more social problems. Development of country-specific NPS awareness raising initiatives, health and social service needs assessments, and targeted responses are warranted.

Structural study of piracetam polymorphs and cocrystals: crystallography redetermination and quantum mechanics calculations.

PubMed

Tilborg, Anaëlle; Jacquemin, Denis; Norberg, Bernadette; Perpète, Eric; Michaux, Catherine; Wouters, Johan

2011-12-01

Pharmaceutical compounds are mostly developed as solid dosage forms containing a single-crystal form. It means that the selection of a particular crystal state for a given molecule is an important step for further clinical outlooks. In this context, piracetam, a pharmaceutical molecule known since the sixties for its nootropic properties, is considered in the present work. This molecule is analyzed using several experimental and theoretical approaches. First, the conformational space of the molecule has been systematically explored by performing a quantum mechanics scan of the two most relevant dihedral angles of the lateral chain. The predicted stable conformations have been compared to all the reported experimental geometries retrieved from the Cambridge Structural Database (CSD) covering polymorphs and cocrystals structures. In parallel, different batches of powders have been recrystallized. Under specific conditions, single crystals of polymorph (III) of piracetam have been obtained, an outcome confirmed by crystallographic analysis. © 2011 International Union of Crystallography. Printed in Singapore – all rights reserved.

[Investigation of the effects of cytoflavin on symptoms of depression and autonomic dysfunction in patients with organic depressive disorder].

PubMed

Gudkova, A N; Osinovskaia, N A; Polunina, A G; Gekht, A B

2013-01-01

The present observational study addressed effects of cytoflavin as an adjunctive nootropic therapy in patients with organic depressive disorder (F06.36). 54 female and 46 male in-patients were included into the study. All patients received standard antidepressant therapy (controls) and 48 patients additionally received 2 pills of cytoflavin twice per day. Age, gender distribution, education and severity of depression were equal in cytoflavin and control groups. The follow-up assessment at discharge showed a significantly more pronounced decline in the severity of depression symptoms in patients receiving cytoflavin in comparison with the controls. Importantly, the effect of cytoflavin on the depression symptoms was prominent only in females. Moreover, women receiving cytoflavin demonstrated the more pronounced normalization of autonomic regulation in comparison with control women. The present results allow to recommend cytoflavin in dose 4 pills daily as an adjunctive therapy in female patients with organic depressive disorder.

The effects of huperzine A and IDRA 21 on visual recognition memory in young macaques

PubMed Central

Malkova, Ludise; Kozikowski, Alan P.; Gale, Karen

2011-01-01

Nootropic agents or cognitive enhancers are purported to improve mental functions such as cognition, memory, or attention. The aim of our study was to determine the effects of two possible cognitive enhancers, huperzine A and IDRA 21, in normal young adult monkeys performing a visual memory task of varying degrees of difficulty. Huperzine A is a reversible acetylcholinesterase (AChE) inhibitor, its administration results in regionally specific increases in acetylcholine levels in the brain. In human clinical trials, Huperzine A resulted in cognitive improvement in patients with mild to moderate form of Alzheimer's disease (AD) showing its potential as a palliative agent in the treatment of AD. IDRA 21 is a positive allosteric modulator of glutamate AMPA receptors. It increases excitatory synaptic strength by attenuating rapid desensitization of AMPA receptors and may thus have beneficial therapeutic effects to ameliorate memory deficits in patients with cognitive impairments, including AD. The present study evaluated the effects of the two drugs in normal, intact, young adult monkeys to determine whether they can result in cognitive enhancement in a system that is presumably functioning optimally. Six young pigtail macaques (Macaca nemestrina) were trained on delayed non-matching-to-sample task, a measure of visual recognition memory, up to criterion of 90% correct responses on each of the four delays (10s, 30s, 60s, and 90s). They were then tested on two versions of the task: Task 1 included the four delays intermixed within a session and the monkeys performed it with the accuracy of 90%. Task 2 included, in each of 24 trials, a list of six objects presented in succession. Two objects from the list were then presented for choice paired with novel objects and following two of the four delays intermixed within a session. This task with a higher mnemonic demand yielded an average performance of 64% correct. Oral administration of huperzine A did not significantly affect the monkeys' performance on either task. However, a significant negative correlation was found between the baseline performance on each delay and the change in performance under huperzine A, suggesting that under conditions in which the subjects were performing poorly (55 – 69%), the drug resulted in improved performance, whereas no improvement was obtained when the baseline was close to 90%. In fact, when the subjects were performing very well, huperzine A tended to reduce the performance accuracy, indicating that in a system that functions optimally, the increased availability of acetylcholine does not improve performance or memory, especially when the animals are close to the maximum performance. In contrast, oral administration of IDRA 21 significantly improved performance on Task 2, especially on the longest delay. This finding supports the potential use of this drug in treatment of cognitive and memory disorders. PMID:21185313

[Analytic evaluation of potential nootropic agents].

PubMed

Opatrilová, R; Sokolová, P

2004-01-01

The paper deals with analytical evaluation of newly prepared substances, derivatives of N-(4-alkoxy-phenyl)-2-(2-oxo-azepan-1-yl)-acetamide. The substances are a homological series (methyl- to hexyl-). The purity of the substances was verified by thin-layer adsorption chromatography, and the principal physical characteristics--melting point and solubility--were determined. Experimental determination of the partition coefficient, extraction of the substances between two liquids miscible to a limited degree (n-octanol--water), determination of RM values by means of TLC partition chromatography (glass plates DC-Fertigplatten RP-8 F254S), determination of the capacity factor by means of HPLC (column C18 Plaris), and calculation by means of computer programmes were employed to determine the lipophilicity of this series of substances. The antiradical activity of the substances was evaluated by the method of extinguishing the stable radical 2,2-diphenyl-1-picryl-hydrazyl. Ascorbic acid, in which an antiradical effect had been demonstrated, was used for the sake of comparison. The substances show a certain activity, but they do not reach the antioxidative effect of ascorbic acid.

[Transcranial magnetic therapy in the complex treatment of affective disorders in patients with alcoholism].

PubMed

Staroverov, A T; Vil'ianov, V B; Raĭgorodskiĭ, Iu M; Rogozina, M A

2008-01-01

A main group--32 patients receiving transcranial magnetic therapy (TMT) in addition to the basic treatment (nootrops, hepatoprotectors, vitamins/minerals etc)--was compared to a control group (30 patients) receiving placebo instead of TMT. All patients, aged from 35 to 64 years, had the second stage of alcoholism with illness duration from 4 to 12 years and were in the postabstinent state at the moment of treatment. The TMT course included 10 daily sessions with a 10-20 min exposure. A somatic, neurological and instrumental study, including cardiointervalography, electroencephalography, assessment of autonomic system state and psychometric scales for depression and anxiety, was conducted before, during and after the therapy. The improvement of health, mood and sleep, increase of tolerability to physical loading and reduction of alcohol craving were observed after TMT in 75% of patients in the main group and in 30% in the control one. The improvement of patient's state was correlated with the data of the paraclinical study (electrophysiological parameters of the autonomic nervous system and psychometric scales scores).

The hypoxia model in human psychopharmacology: neurophysiological and psychometric studies with aniracetam i.v.

PubMed

Saletu, B; Grünberger, J

1984-01-01

Changes in human brain function and mental performance under hypoxic hypoxidosis as well as after intravenous injection of aniracetam - a new potentially nootropic 2-pyrrolidinone derivative - were investigated in a double-blind placebo-controlled study utilizing computer-assisted spectral analysis of the EEG and psychometric tests. Hypoxic hypoxidosis was induced by a fixed gas combination of 11.2% O2 and 88.8% N2, which was inhaled under normobaric conditions by 10 male healthy volunteers. The following substances were injected intravenously at weekly intervals according to a latin square design: placebo, 10 mg and 100 mg aniracetam and the solvent under hypoxic conditions as well as placebo under normoxic conditions. Spectral analysis of the EEG recorded under hypoxia demonstrated neurophysiological alterations indicative of a deterioration in vigilance, which was also reflected by a deterioration in psychomotor activity and mnestic performance in the psychometric tests. Aniracetam i.v. attenuated the hypoxia-induced deterioration of brain function and mental performance, thus exhibiting protective properties against hypoxia in man. The usefulness of the hypoxia model in the screening of antihypoxidotic compounds is discussed.

Bacopa monnieri (L.) exerts anti-inflammatory effects on cells of the innate immune system in vitro.

PubMed

Williams, Roderick; Münch, Gerald; Gyengesi, Erika; Bennett, Louise

2014-03-01

Bacopa monnieri (L., BM) is a traditional Ayurvedic medicinal herb recognised for its efficacy in relieving acute pain and inflammation, as related to selective inhibition of cyclo-oxygenase-2 (COX-2) enzyme and consequent reduction in COX-2-mediated prostanoid mediators. BM is also associated with cognitive enhancing (nootropic) activity including improving memory free recall, observed after prolonged intake (>3 months). It is likely that the time frame required to exert an effect in the brain reflects regulation by BM of chronic inflammation and oxidative stress associated with aging and chronic diseases, and other polypharmacological effects. We report down-regulation by BM of NO and TNF-α in stimulated RAW 246.7 macrophages and of IFN-γ in stimulated human blood cells. Furthermore, in human blood cells, IL-10 was slightly elevated indicating polarisation towards a regulatory T cell phenotype. These results provide further supportive evidence to justify the clinical evaluation of BM for managing diseases involving chronic systemic and brain inflammation driven by the innate immune system.

Outsmarted by nootropics? An investigation into the thermal degradation of modafinil, modafinic acid, adrafinil, CRL-40,940 and CRL-40,941 in the GC injector: formation of 1,1,2,2-tetraphenylethane and its tetra fluoro analog.

PubMed

Dowling, Geraldine; Kavanagh, Pierce V; Talbot, Brian; O'Brien, John; Hessman, Gary; McLaughlin, Gavin; Twamley, Brendan; Brandt, Simon D

2017-03-01

2-[(Diphenylmethyl)sulfinyl]acetamide (modafinil) is commonly prescribed for the treatment of narcolepsy. Increasing popularity and off-label use as a cognitive enhancer has resulted in a reputation as an intelligence boosting 'wonder drug'. Common alternatives available from online shops and other retail outlets include 2-[(diphenylmethyl)sulfinyl]-N-hydroxyacetamide (adrafinil), 2-{[bis(4-fluorophenyl)methyl]sulfinyl}acetamide (CRL-40,940), 2-{[bis(4-fluorophenyl)methyl]sulfinyl}-N-hydroxyacetamide (CRL-40,941), and N-methyl-4,4-difluoro-modafinil (modafiendz), respectively. Gas chromatography-mass spectrometry (GC-MS) is a common tool used in forensic and clinical analysis but there is a potential for inducing analysis-related ambiguities. This study reports on the thermal degradation of modafinil, modafinic acid, adrafinil, CRL-40,940, and CRL-40,941 due to exposure to the heated GC injection port dissolved in a variety of solvents. Key degradation products common to modafinil, modafinic acid, and adrafinil analysis included diphenylmethanol and 1,1,2,2-tetraphenylethane (TPE), the latter of which was verified by its synthesis and characterization by x-ray crystallography. The investigated compounds were also characterized by 1 H and 13 C NMR. Diphenylmethane and thiobenzophenone were also identified in some instances. TPE formation was suggested to involve the generation of a benzhydrylium ion and its reaction with the sulfoxide oxygen of the parent compound to give an oxysulfonium intermediate. Correspondingly, the fluorinated TPE analogue was formed during heat-induced degradation of modafiendz, CRL-40,940 and CRL-40,941, respectively. When a mixture of modafinil (non-fluorinated) and modafiendz (fluorinated) were subjected to GC analysis, 4,4'-(2,2-diphenylethane-1,1-diyl)bis(fluorobenzene) was detected as a third cross reaction product in addition to the two expected TPE analogues. These observations served as a reminder that the seemingly straightforward implementation of GC-MS analysis can lead to challenges during routine analysis. Copyright © 2016 John Wiley & Sons, Ltd.

Metabolic enhancer piracetam attenuates rotenone induced oxidative stress: a study in different rat brain regions.

PubMed

Verma, Dinesh Kumar; Joshi, Neeraj; Raju, Kunumuri Sivarama; Wahajuddin, Muhammad; Singh, Rama Kant; Singh, Sarika

2015-01-01

Piracetam is clinically being used nootropic drug but the details of its neuroprotective mechanism are not well studied. The present study was conducted to assess the effects of piracetam on rotenone induced oxidative stress by using both ex vivo and in vivo test systems. Rats were treated with piracetam (600 mg/kg b.w. oral) for seven constitutive days prior to rotenone administration (intracerebroventricular, 12 µg) in rat brain. Rotenone induced oxidative stress was assessed after 1 h and 24 h of rotenone administration. Ex vivo estimations were performed by using two experimental designs. In one experimental design the rat brain homogenate was treated with rotenone (1 mM, 2 mM and 4 mM) and rotenone+piracetam (10 mM) for 1 h. While in second experimental design the rats were pretreated with piracetam for seven consecutive days. On eighth day the rats were sacrificed, brain homogenate was prepared and treated with rotenone (1 mM, 2 mM and 4mM) for 1h. After treatment the glutathione (GSH) and malondialdehyde (MDA) levels were estimated in brain homogenate. In vivo study showed that pretreatment of piracetam offered significant protection against rotenone induced decreased GSH and increased MDA level though the protection was region specific. But the co-treatment of piracetam with rotenone did not offer significant protection against rotenone induced oxidative stress in ex vivo study. Whereas ex vivo experiments in rat brain homogenate of piracetam pretreated rats, showed the significant protection against rotenone induced oxidative stress. Findings indicated that pretreatment of piracetam significantly attenuated the rotenone induced oxidative stress though the protection was region specific. Piracetam treatment to rats led to its absorption and accumulation in different brain regions as assessed by liquid chromatography mass spectrometry/mass spectrometry. In conclusion, study indicates the piracetam is able to enhance the antioxidant capacity in brain cells in region specific manner. The study is also revealing the rationale for its clinical use in cognitive impairment and other neurological diseases.

Inhibitory effect of bacopasides on spontaneous morphine withdrawal induced depression in mice.

PubMed

Rauf, Khalid; Subhan, Fazal; Abbas, Muzaffar; Ali, Syed Mobasher; Ali, Gowhar; Ashfaq, Muhammad; Abbas, Ghulam

2014-06-01

Bacopa monnieri is a perennial herb with a world known image as a nootropic. We investigated the effect of Bacopa monnieri methanolic extract (Mt Ext BM) 10, 20, and 30 mg/kg body weight (b.w) on acquisition and expression of morphine withdrawal induced depression in mice. Locally available Bacopa monnieri (BM) was screened for contents of Bacoside A3, Bacopasaponin C, and Bacopaside II using HPLC with UV. Morphine dependence was induced in mice using twice daily escalating chronic morphine treatments (20-65 mg/kg b.w) for eight consecutive days. Morphine withdrawal induced depression was assayed in animals using forced swimming test (FST), three days after last morphine injection. The HPLC analysis revealed that Mt-ext BM contained Bacoside A3 as major component, i.e. 4 µg in each mg of extract. The chronic treatment with Met Ext BM 10, 20, and 30 mg/kg b.w. dosing significantly inhibited opioid withdrawal induced depression in mice. These findings imply a newer potential role of Bacopa monnieri in the clinical management of opioid withdrawal induced depression which can be attributed to Bacoside A3. Copyright © 2013 John Wiley & Sons, Ltd.

[Behavioral and electrophysiological analysis of the choline-positive effect of nootropic dipeptide acylproline (GVS-111)].

PubMed

Ostrovskaia, R U; Mirzoev, T Kh; Firova, F A; Trofimof, S S; Gudasheva, T A; Grechenko, T N; Gutyrchik, E F; Barkova, E B

2001-01-01

The behavioral experiments using a passive avoidance learning model showed that the new cognition-enhancing acyl-prolyn containing dipeptide GVS-111 promotes recovery of the test performance in animals with a long-term memory deficit caused by the M-cholinolytic scopolamine (1 mg/kg/day scopolamine for 20 days, followed by 0.5 mg/kg/day GVS-111 for 10 days). At the same time, GVS-111 increased the duration of tremor induced by the M-cholinomimetic arecoline. The results of electrophysicological experiments showed that GVS-111 in a concentration range from 10(-11) to 10(-9) M increased amplitude of the neural response to acetylcholine (Ach) microappications in 75% of the isolated neurons of Helix Pomatum and produced a predominantly facilitating effect upon the endoneuronal pacemaker activity. The effect of GVS-111 upon the Ach response in a part of neurons was attenuated or even blocked by scopolamine, and in the other neurons--by the N-cholinolytic d-tubocurarine. This fact indicates that both muscarinic and nicotinic receptors are involved in the mechanism of the cholino-sensitizing action of GVS-111 upon the neuronal activity.

Effects of Adaptogens on the Central Nervous System and the Molecular Mechanisms Associated with Their Stress—Protective Activity

PubMed Central

Panossian, Alexander; Wikman, Georg

2010-01-01

Adaptogens were initially defined as substances that enhance the “state of non-specific resistance” in stress, a physiological condition that is linked with various disorders of the neuroendocrine-immune system. Studies on animals and isolated neuronal cells have revealed that adaptogens exhibit neuroprotective, anti-fatigue, antidepressive, anxiolytic, nootropic and CNS stimulating activity. In addition, a number of clinical trials demonstrate that adaptogens exert an anti-fatigue effect that increases mental work capacity against a background of stress and fatigue, particularly in tolerance to mental exhaustion and enhanced attention. Indeed, recent pharmacological studies of a number of adaptogens have provided a rationale for these effects also at the molecular level. It was discovered that the stress—protective activity of adaptogens was associated with regulation of homeostasis via several mechanisms of action, which was linked with the hypothalamic-pituitary-adrenal axis and the regulation of key mediators of stress response, such as molecular chaperons (e.g., HSP70), stress-activated c-Jun N-terminal protein kinase 1 (JNK1), Forkhead box O (FOXO) transcription factor DAF-16, cortisol and nitric oxide. PMID:27713248

Transcranial magnetotherapy in the complex treatment of affective disorders in patients with alcoholism.

PubMed

Staroverov, A T; Vil'yanov, V B; Raigorodskii, Yu M; Rogozina, M A

2009-06-01

Transcranial magnetotherapy (TMT) was used in 32 patients with alcoholism (study group) on the background of basal treatment (nootropes, hepatoprotectors, vitamin/mineral formulations, etc.). The influence of this treatment was compared with a control group (30 subjects), in which TMT was replaced with an appropriate (placebo) procedure. All patients, who were aged from 35 to 64 years, had second-degree alcoholism with disease durations of 4-12 years. Patients were in a post-abstinence state during the treatment period. Courses of TMT consisted of 10 daily procedures with exposures of 10-20 min. Somatic, neurological, and laboratory studies were performed before and after treatment and included cardiointervalography, electroencephalography, assessments of the state of the autonomic nervous system, and use of psychometric scales to evaluate levels of anxiety and depression. TMT was followed by improvements in wellbeing, mood, and sleep, with increases in physical exercise tolerance and decreases in alcohol craving in 75% of patients in the study group and 30% of patients in the control group. Improvements in patients' status were supported by paraclinical investigations (electrophysiological, measures of the state of the autonomic nervous system, etc.) and psychometric scales.

Protective effect of a phenolic extract containing indoline amides from Portulaca oleracea against cognitive impairment in senescent mice induced by large dose of D-galactose /NaNO2.

PubMed

Wang, Peipei; Sun, Hongxiang; Liu, Dianyu; Jiao, Zezhao; Yue, Su; He, Xiuquan; Xia, Wen; Ji, Jianbo; Xiang, Lan

2017-05-05

Portulaca oleracea L. is a potherb and also a widely used traditional Chinese medicine. In accordance with its nickname "longevity vegetable", pharmacological study demonstrated that this plant possessed antioxidant, anti-aging, and cognition-improvement function. Active principles pertaining to these functions of P. oleracea need to be elucidated. The present study evaluated the effect of a phenolic extract (PAAs) from P. oleracea which contained specific antioxidant indoline amides on cognitive impairment in senescent mice. PAAs was prepared through AB-8 macroporous resin column chromatography. Total phenol content was determined using colorimetric method, and contents of indoline amides were determined using HPLC-UV method. Senescent Kunming mice with cognitive dysfunction were established by intraperitoneal injection of D-galactose (D-gal, 1250mg/kg/day) and NaNO 2 (90mg/kg/day) for 8 weeks, L-PAAs (360mg/kg/day), H-PAAs (720mg/kg/day), and nootropic drug piracetam (PA, 400mg/kg/day) as the positive control were orally administered. Spatial learning and memory abilities were evaluated by Morris water maze experiment. Activities of AChE, SOD, CAT, and levels of GSH and MDA in the brain or plasma were measured. Hippocampal morphology was observed by HE staining. Chronic treatment of large dose of D-gal/NaNO 2 significantly reduced lifespan, elevated AChE activity, decreased CAT activity, compensatorily up-regulated SOD activity and GSH level, increased MDA level, induced neuronal damage in hippocampal CA1, CA3 and CA4 regions, and impaired cognitive function. Similar to PA, PAAs prolonged the lifespan and improved spatial memory ability. Moreover, PAAs improved learning ability. H-PAAs significantly reversed compensatory increase in SOD activity to the normal level, elevated serum CAT activity, and reduced MDA levels in brain and plasma, more potent than L-PAAs. Besides these, PAAs evidently inhibited hippocampal neuronal damage. However, it had no effect on brain AChE activity. PAAs as the bioactive principles of P. oleracea attenuated oxidative stress, improved survival rate, and enhanced cognitive function in D-gal/NaNO 2 -induced senile mice, similar to piracetam. This phenolic extract provides a promising candidate for prevention of aging and aging-related cognitive dysfunction in clinic. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Beta-hydroxy-beta-methylbutyrate (HMB) ameliorates age-related deficits in water maze performance, especially in male rats.

PubMed

Kougias, Daniel G; Hankosky, Emily R; Gulley, Joshua M; Juraska, Janice M

2017-03-01

Beta-hydroxy-beta-methylbutyrate (HMB) is commonly supplemented to maintain muscle in elderly and clinical populations and has potential as a nootropic. Previously, we have shown that in both male and female rats, long-term HMB supplementation prevents age-related dendritic shrinkage within the medial prefrontal cortex (mPFC) and improves cognitive flexibility and working memory performance that are both age- and sex-specific. In this study, we further explore the cognitive effects by assessing visuospatial learning and memory with the Morris water maze. Female rats were ovariectomized at 11months of age to model human menopause. At 12months of age, male and female rats received relatively short- or long-term (1- or 7-month) dietary HMB (450mg/kg/dose) supplementation twice a day prior to testing. Spatial reference learning and memory was assessed across four days in the water maze with four trials daily and a probe trial on the last day. Consistent with previous work, there were age-related deficits in water maze performance in both sexes. However, these deficits were ameliorated in HMB-treated males during training and in both sexes during probe trial performance. Thus, HMB supplementation prevented the age-related decrement in water maze performance, especially in male rats. Copyright © 2016 Elsevier Inc. All rights reserved.

Pharmacological treatment for attention deficit hyperactivity disorder: functional outcomes in children and adolescents from non-Western countries.

PubMed

Altin, Murat; El-Shafei, Ahmed A; Yu, Maria; Desaiah, Durisala; Treuer, Tamas; Zavadenko, Nikolay; Gao, Hong Yun

2013-09-13

Functional outcomes were measured over a 12-month period in children and adolescents with attention deficit hyperactivity disorder (ADHD) after they received monotherapy. Prospective, observational, noninterventional study. Conducted in six non-Western countries. Outpatients 6 to 17 years of age with a verified diagnosis of ADHD in accordance with the Diagnostic and Statistical Manual, Fourth Edition, Text Revision (DSM-IV-TR), together with their physicians, decided to initiate or switch treatment for ADHD. Patients were prescribed pharmacological monotherapy: methylphenidate (n=221), nootropic agents (n=91), or atomoxetine (n=234). Patients were followed for changes in their functional status and quality of life, which were assessed with the Child Health and Illness Profile-Child Edition (CHIP-CE) Achievement domain. At the end of the study, a mean improvement on the CHIP-CE Achievement domain score was observed for all countries and therapies except in Taiwan, where patients received atomoxetine, and in Lebanon, where patients received methylphenidate. No patient experienced a serious adverse event during the study. Four patients discontinued due to a treatment-emergent adverse event. After 12 months of treatment, clinical and functional outcomes were improved in children and adolescents from non-Western countries who initiated and remained on their prescribed pharmacological monotherapy.

Moringa oleifera mitigates memory impairment and neurodegeneration in animal model of age-related dementia.

PubMed

Sutalangka, Chatchada; Wattanathorn, Jintanaporn; Muchimapura, Supaporn; Thukham-mee, Wipawee

2013-01-01

To date, the preventive strategy against dementia is still essential due to the rapid growth of its prevalence and the limited therapeutic efficacy. Based on the crucial role of oxidative stress in age-related dementia and the antioxidant and nootropic activities of Moringa oleifera, the enhancement of spatial memory and neuroprotection of M. oleifera leaves extract in animal model of age-related dementia was determined. The possible underlying mechanism was also investigated. Male Wistar rats, weighing 180-220 g, were orally given M. oleifera leaves extract at doses of 100, 200, and 400 mg/kg at a period of 7 days before and 7 days after the intracerebroventricular administration of AF64A bilaterally. Then, they were assessed memory, neuron density, MDA level, and the activities of SOD, CAT, GSH-Px, and AChE in hippocampus. The results showed that the extract improved spatial memory and neurodegeneration in CA1, CA2, CA3, and dentate gyrus of hippocampus together with the decreased MDA level and AChE activity but increased SOD and CAT activities. Therefore, our data suggest that M. oleifera leaves extract is the potential cognitive enhancer and neuroprotectant. The possible mechanism might occur partly via the decreased oxidative stress and the enhanced cholinergic function. However, further explorations concerning active ingredient(s) are still required.

From 'Hard' Neuro-Tools to 'Soft' Neuro-Toys? Refocussing the Neuro-Enhancement Debate.

PubMed

Brenninkmeijer, Jonna; Zwart, Hub

2017-01-01

Since the 1990's, the debate concerning the ethical, legal and societal aspects of 'neuro-enhancement' has evolved into a massive discourse, both in the public realm and in the academic arena. This ethical debate, however, tends to repeat the same sets of arguments over and over again. Normative disagreements between transhumanists and bioconservatives on invasive or radical brain stimulators, and uncertainties regarding the use and effectivity of nootropic pharmaceuticals dominate the field. Building on the results of an extensive European project on responsible research and innovation in neuro-enhancement (NERRI), we observe and encourage that the debate is now entering a new and, as we will argue, more realistic and societally relevant stage. This new stage concerns those technologies that enter the market as ostensibly harmless contrivances that consumers may use for self-care or entertainment. We use the examples and arguments of participants in NERRI debates to describe three case studies of such purportedly innocent 'toys'. Based upon this empirical material, we argue that these 'soft' enhancement gadgets are situated somewhere in the boundary zone between the internal and the external, between the intimate and the intrusive, between the familiar and the unfamiliar, between the friendly and the scary and, in Foucauldian terms, between technologies of the self and technologies of control. Therefore, we describe their physiognomy with the help of a term borrowed from Jacques Lacan, namely as "extimate" technologies.

CDRI-08 Attenuates REST/NRSF-Mediated Expression of NMDAR1 Gene in PBDE-209-Exposed Mice Brain.

PubMed

Verma, Priya; Gupta, Rajaneesh K; Gandhi, Behrose S; Singh, Poonam

2015-01-01

CDRI-08 is a standardized bacoside enriched ethanolic extract of Bacopa monnieri, a nootropic plant. We reported that CDRI-08 attenuated oxidative stress and memory impairment in mice, induced by a flame retardant, PBDE-209. In order to explore the mechanism, present study was designed to examine the role of CDRI-08 on the expression of NMDAR1 (NR1) and the binding of REST/NRSF to NR1 promoter against postnatal exposure of PBDE-209. Male mice pups were orally supplemented with CDRI-08 at the doses of 40, 80, or 120 mg/kg along with PBDE-209 (20 mg/kg) during PND 3-10 and frontal cortex and hippocampus were collected at PND 11 and 60 to study the expression and regulation of NR1 by RT-PCR and electrophoretic mobility shift assay, respectively. The findings showed upregulated expression of NR1 and decreased binding of REST/NRSF to NR1 promoter after postnatal exposure of PBDE-209. Interestingly, supplementation with CDRI-08 significantly restored the expression of NR1 and binding of REST/NRSF to NR1 promoter near to the control value at the dose of 120 mg/kg. In conclusion, the results suggest that CDRI-08 possibly acts on glutamatergic system through expression and regulation of NR1 and may restore memory, impaired by PBDE-209 as reported in our previous study.

A Bacoside containing Bacopa monnieri extract reduces both morphine hyperactivity plus the elevated striatal dopamine and serotonin turnover.

PubMed

Rauf, Khalid; Subhan, Fazal; Sewell, Robert D E

2012-05-01

Bacopa monnieri (BM) has been used in Ayurvedic medicine as a nootropic, anxiolytic, antiepileptic and antidepressant. An n-butanol extract of the plant (nBt-ext BM) was analysed and found to contain Bacoside A (Bacoside A3, Bacopaside II and Bacopasaponin C). The effects of the BM extract were then studied on morphine-induced hyperactivity as well as dopamine and serotonin turnover in the striatum since these parameters have a role in opioid sensitivity and dependence. Mice were pretreated with saline or nBt-ext BM (5, 10 and 15 mg/kg, orally), 60 min before morphine administration and locomotor activity was subsequently recorded. Immediately after testing, striatal tissues were analysed for dopamine (DA), serotonin (5HT) and their metabolites using HPLC coupled with electrochemical detection. The results indicated that nBt-ext BM significantly (p < 0.001) decreased locomotor activity in both the saline and morphine treated groups. Additionally, nBt-ext BM significantly lowered morphine-induced dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-H1AA) upsurges in the striatum but failed to affect DA, 5-HT and their metabolites in the saline treated group. These findings suggest that nBt-ext BM has an antidopaminergic/serotonergic effect and may have potential beneficial effects in the treatment of morphine dependence. Copyright © 2011 John Wiley & Sons, Ltd.

Moringa oleifera Mitigates Memory Impairment and Neurodegeneration in Animal Model of Age-Related Dementia

PubMed Central

Sutalangka, Chatchada; Wattanathorn, Jintanaporn; Muchimapura, Supaporn; Thukham-mee, Wipawee

2013-01-01

To date, the preventive strategy against dementia is still essential due to the rapid growth of its prevalence and the limited therapeutic efficacy. Based on the crucial role of oxidative stress in age-related dementia and the antioxidant and nootropic activities of Moringa oleifera, the enhancement of spatial memory and neuroprotection of M. oleifera leaves extract in animal model of age-related dementia was determined. The possible underlying mechanism was also investigated. Male Wistar rats, weighing 180–220 g, were orally given M. oleifera leaves extract at doses of 100, 200, and 400 mg/kg at a period of 7 days before and 7 days after the intracerebroventricular administration of AF64A bilaterally. Then, they were assessed memory, neuron density, MDA level, and the activities of SOD, CAT, GSH-Px, and AChE in hippocampus. The results showed that the extract improved spatial memory and neurodegeneration in CA1, CA2, CA3, and dentate gyrus of hippocampus together with the decreased MDA level and AChE activity but increased SOD and CAT activities. Therefore, our data suggest that M. oleifera leaves extract is the potential cognitive enhancer and neuroprotectant. The possible mechanism might occur partly via the decreased oxidative stress and the enhanced cholinergic function. However, further explorations concerning active ingredient(s) are still required. PMID:24454988

Wound healing activity of Argyreia nervosa leaves extract

PubMed Central

Singhal, AK; Gupta, H; Bhati, VS

2011-01-01

Background: Argyreia nervosa (Convolvulaceae) plant is an example of hallucinogenic plant. The antiseptic, anti-inflammatory, antispasmodic, antibacterial, antiviral, antifungal, anticonvulsant, nootropic, antifertility and aphrodisiac properties have already been reported for this plant. Aim: The aim of present work was to evaluate the wound healing property in normal and diabetic animals by oral and topical administration of ethanolic extract of leaves. Materials and Methods: Phytochemical investigations showed the presence of various biochemicals (alkaloids, flavonoids, carbohydrates, triterpenoids, proteins, saponins, steroids, tannins). A single injection of alloxan monohydrate (120 mg/kg, i.p.) prepared in citrate buffer (0.1 M, pH 4.5) was administered to produce diabetes in rats and mice, after overnight fasting. Excision wounds (sized 300 mm2 and of 2 mm depth) were used for the study of rate of contraction of wound and epithelization. The means of wound area measurement between groups at different time intervalswere compared using one-way analysis of variance (ANOVA), followed by Dunnet's test. Results: Extracts of A. nervosa showed significant wound healing effect in normal (topically treated) and diabetic (both topically and orally treated) rats. In diabetic rats, the topically treated group showed more significant effect than the orally treated groups. Conclusion: The present study demonstrates that A. nervosa leaves extract applied topically promotes healing of wounds more significantly as compared to oral application, in both normal rats and alloxan induced diabetic rats, where healing is otherwise delayed. PMID:23776770

A Systematic Review of Intervention Studies Examining Nutritional and Herbal Therapies for Mild Cognitive Impairment and Dementia Using Neuroimaging Methods: Study Characteristics and Intervention Efficacy

PubMed Central

MacMillan, Freya; Camfield, David A.; Seto, Sai W.

2017-01-01

Neuroimaging facilitates the assessment of complementary medicines (CMs) by providing a noninvasive insight into their mechanisms of action in the human brain. This is important for identifying the potential treatment options for target disease cohorts with complex pathophysiologies. The aim of this systematic review was to evaluate study characteristics, intervention efficacy, and the structural and functional neuroimaging methods used in research assessing nutritional and herbal medicines for mild cognitive impairment (MCI) and dementia. Six databases were searched for articles reporting on CMs, dementia, and neuroimaging methods. Data were extracted from 21/2,742 eligible full text articles and risk of bias was assessed. Nine studies examined people with Alzheimer's disease, 7 MCI, 4 vascular dementia, and 1 all-cause dementia. Ten studies tested herbal medicines, 8 vitamins and supplements, and 3 nootropics. Ten studies used electroencephalography (EEG), 5 structural magnetic resonance imaging (MRI), 2 functional MRI (fMRI), 3 cerebral blood flow (CBF), 1 single photon emission tomography (SPECT), and 1 positron emission tomography (PET). Four studies had a low risk of bias, with the majority consistently demonstrating inadequate reporting on randomisation, allocation concealment, blinding, and power calculations. A narrative synthesis approach was assumed due to heterogeneity in study methods, interventions, target cohorts, and quality. Eleven key recommendations are suggested to advance future work in this area. PMID:28303161

Effect of Withinia Somnifera and Shilajit on Alcohol Addiction in Mice.

PubMed

Bansal, Priya; Banerjee, Sugato

2016-05-01

Alcohol addiction is a social problem leading to both loss of health and economic prosperity among addicted individuals. Common properties of anti-addictive compounds include anti-anxiety, anticonvulsants, anti-depressant, and nootropic actions primarily through modulation of gamma-aminobutyric acid (GABA) and serotonergic systems. Here, we screen ashwagandha and shilajit known ethnopharmacologically as nervine tonic and adaptogenic herbs for possible anti-addictive potential. Effect of ashwagandha churna and shilajit was measured on ethanol withdrawal anxiety using elevated plus maze. Role of ashwagandha and shilajit on chronic ethanol consumption (21 days) was measured using two bottle choice protocol of voluntary drinking. We also measured the effect of the above herbs on corticohippocampal GABA, dopamine, and serotonin levels. Both ashwagandha and shilajit were found to reduce alcohol withdrawal anxiety in a dose-dependent manner. These herbs alone or in combination also decreased ethanol intake and increased water intake significantly after 21 days of chronic administration. Chronic administration of ashwagandha was found to significantly increase GABA and serotonin levels whereas shilajit altered cortico-hippocampal dopamine in mice. These central nervous system active herbs alone or in combination reduced both alcohol dependence and withdrawal thus showing promising anti-addictive potential. Withinia Somnifera alone and in combination with Shilajeet prevented ethanol withdrawal and alcohol addiction Abbreviations used: GABA: Gama aminobutyric acid, CNS: Central Nervous System, CPP:Condition place preference, DA: Dopamine, 5-HT: 5-hydroxytryptamine, NMDA:N-methyl-D-aspartate.

PASS assisted prediction and pharmacological evaluation of hesperidin against scopolamine induced amnesia in mice.

PubMed

Habibyar, Ahmad Farid; Sharma, Neha; Khurana, Navneet

2016-10-15

Alzheimer's disease (AD) is a neurodegenerative disorder that leads to memory impairment. However, the exact etiology of AD is not clear but cholinergic dysfunction and oxidative stress are considered to play an important role in its pathogenesis. Because of this reason, antioxidant compounds are expected to play potential beneficial role in this disease. Among number of antioxidant compounds, hesperidin (HSD) was selected for this study on the basis of its reported antioxidant and neuroprotective effects. Moreover, it has shown higher probable activity value for scavenging free radical along with anti-dementia effects, predicted by PASS online computer program. Current study was designed to evaluate the nootropic and antioxidant effects of HSD. The different groups of animals received scopolamine (2mg/kg) along with co-treamtment of HSD (100, 200mg/kg) and donepezil HCl (3mg/kg) i.p. for consecutive 10 days. Behavioral tests were carried out, 30min after respective treatment on 2nd, 5th and 9th day for memory evaluation. On 10th day of treatment, the animals were sacrificed and the homogenates of brain hippocampus and cortex were used for biochemical estimation. Co-treatment with HSD at both doses significantly reversed the changes in memory and biochemical alterations, induced by scopolamine administration. It can be concluded that HSD has strong memory enhancing and anti-oxidant effects, therefore, it can be considered as a potential candidate for its further pharmacological evaluation for AD-induced dementia. Copyright © 2016 Elsevier B.V. All rights reserved.

CDRI-08 Attenuates REST/NRSF-Mediated Expression of NMDAR1 Gene in PBDE-209-Exposed Mice Brain

PubMed Central

Verma, Priya; Gupta, Rajaneesh K.; Gandhi, Behrose S.; Singh, Poonam

2015-01-01

CDRI-08 is a standardized bacoside enriched ethanolic extract of Bacopa monnieri, a nootropic plant. We reported that CDRI-08 attenuated oxidative stress and memory impairment in mice, induced by a flame retardant, PBDE-209. In order to explore the mechanism, present study was designed to examine the role of CDRI-08 on the expression of NMDAR1 (NR1) and the binding of REST/NRSF to NR1 promoter against postnatal exposure of PBDE-209. Male mice pups were orally supplemented with CDRI-08 at the doses of 40, 80, or 120 mg/kg along with PBDE-209 (20 mg/kg) during PND 3–10 and frontal cortex and hippocampus were collected at PND 11 and 60 to study the expression and regulation of NR1 by RT-PCR and electrophoretic mobility shift assay, respectively. The findings showed upregulated expression of NR1 and decreased binding of REST/NRSF to NR1 promoter after postnatal exposure of PBDE-209. Interestingly, supplementation with CDRI-08 significantly restored the expression of NR1 and binding of REST/NRSF to NR1 promoter near to the control value at the dose of 120 mg/kg. In conclusion, the results suggest that CDRI-08 possibly acts on glutamatergic system through expression and regulation of NR1 and may restore memory, impaired by PBDE-209 as reported in our previous study. PMID:26413122

[Regulation of the neuronal functional state by ultra low doses of different biologically active substances. Nonspecific effect ].

PubMed

Terekhova, S F; Grechenko, T N

2003-01-01

The role of biologically active substances in ultra-low doses (10(-15)-10(-27) mol/l) is discussed from the different points of view. The most detailed analysis of neurobiological effects produced by these doses can be studied on the preparate of completely isolated molluscan neurones. In this case the possibility arises to control the first modifications of action at the electrophysiological characteristics of neuronal activity. These changes of electrical activity can be regarded as a reaction to biologically active substance. The following characteristics were controlled: the level of membrane resting potential (MP), the electroexcitable membrane and pacemaker mechanism, chemical sensitivity of somatic membrane loci to neurotransmitter acetylcholine (Ach). Several substances were used in these experiments: two kinds of synthetic antioxidant, GABA, ethanol, serotonine, DSIP (delta-sleep inducing peptide), antibiotic ruboxil, nootrop GVS-111. The isolated neurones were placed into the special chamber. All these substances (0.35 ml) were added single dosing into this chamber with living physiological solution in concentration 10(-15)-10(-27) mol/l. The results demonstrated that all substances had initiated the development of prolonged neurophysiological responses. The intensities of neuronal reactions didn't depend in contact period on the concentration and on the type of substance. It is suggested that these data reveal the existence of unknown modes of regulation of neuronal functional states and presence of hidden channel for information transfer and receiving. This different way of regulation is extremely important influence living organisms.

An acute, double-blind, placebo-controlled crossover study of 320 mg and 640 mg doses of a special extract of Bacopa monnieri (CDRI 08) on sustained cognitive performance.

PubMed

Downey, Luke A; Kean, James; Nemeh, Fiona; Lau, Angela; Poll, Alex; Gregory, Rebecca; Murray, Margaret; Rourke, Johanna; Patak, Brigit; Pase, Matthew P; Zangara, Andrea; Lomas, Justine; Scholey, Andrew; Stough, Con

2013-09-01

Standardized extracts of the traditional Ayurvedic medicine Bacopa monnieri (BM) (Brahmi) have been recently shown to have cognitive enhancing effects in chronic administration studies. Pre-clinical work has also identified a number of acute anxiolytic, nootropic, and cardiovascular effects of BM. There has, however, been little research on the acute effects of BM on cognitive function. The current study aimed to assess the acute effects of a specific extract of BM (KeenMind®-CDRI 08) in a double-blind, placebo-controlled study in normal healthy participants who completed a cognitively demanding series of tests. Twenty-four healthy volunteers completed six repetitions of the Cognitive Demand Battery (CDB) after consuming a placebo, 320 mg BM or 640 mg of BM in a cross-over design and provided cardiovascular and mood assessments before and after treatment. Change from baseline scores indicated that the 320 mg dose of BM improved performance at the first, second, and fourth repetition post-dosing on the CDB, and the treatments had no effect upon cardiovascular activity or in attenuating task-induced ratings of stress and fatigue. It was concluded that assessment of an earlier pharmacological window and use of less memory-specific cognitive tests together with more temporally sensitive measures of brain activity may improve our understanding of the acute neurocognitive properties of BM. Copyright © 2012 John Wiley & Sons, Ltd.

Prophylaxis with Bacopa monnieri attenuates acrylamide induced neurotoxicity and oxidative damage via elevated antioxidant function.

PubMed

Shinomol, George Kunnel; Raghunath, Narayanareddy; Bharath, Muchukunte Mukunda Srinivas; Muralidhara

2013-03-01

Acrylamide (ACR) is a water-soluble, vinyl monomer that has multiple chemical and industrial applications. Exposure to ACR causes neuropathy and associated neurological defects including gait abnormalities and skeletal muscle weakness, due to impaired neurotransmitter release and eventual neurodegeneration. Using in vivo and in vitro models, we examined whether oxidative events are involved in ACR-mediated neurotoxicity and whether these could be prevented by natural plant extracts. Administration (i.p.) of ACR in mice (40 mg/kg bw/ d for 5d) induced significant oxidative damage in the brain cortex and liver as evidenced by elevated lipid peroxidation, reactive oxygen species and protein carbonyls. This was associated with lowered antioxidant activities including antioxidant enzymes (catalase, glutathione-s-transferase) and reduced glutathione (GSH) compared to untreated controls. Similarly, exposure of N27 neuronal cells in culture to ACR (1-5 mM) caused dose-dependent neuronal death and lowered GSH. Interestingly, dietary supplementation with the leaf powder of Bacopa monnieri (BM) (which possesses neuroprotective properties and nootropic activity) in mice for 30 days offered significant protection against ACR toxicity and oxidative damage in vivo. Similarly, pretreatment with BM protected the N27 cells against ACR-induced cell death and associated oxidative damage. Co-treatment and pre-treatment of Drosophila melanogaster with BM extract protected against ACR-induced locomotor dysfunction and GSH depletion. We infer that BM displays prophylactic effects against ACR induced oxidative damage and neurotoxicity with potential therapeutic application in human pathology associated with neuropathy.

Cotinine reduces depressive-like behavior, working memory deficits, and synaptic loss associated with chronic stress in mice.

PubMed

Grizzell, J Alex; Iarkov, Alexandre; Holmes, Rosalee; Mori, Takahashi; Echeverria, Valentina

2014-07-15

Chronic stress underlies and/or exacerbates many psychiatric conditions and often results in memory impairment as well as depressive symptoms. Such afflicted individuals use tobacco more than the general population and this has been suggested as a form of self-medication. Cotinine, the predominant metabolite of nicotine, may underlie such behavior as it has been shown to ameliorate anxiety and memory loss in animal models. In this study, we sought to investigate the effects of cotinine on working memory and depressive-like behavior in mice subjected to prolonged restraint. Cotinine-treated mice displayed better performance than vehicle-treated cohorts on the working memory task, the radial arm water maze test. In addition, with or without chronic stress exposure, cotinine-treated mice engaged in fewer depressive-like behaviors as assessed using the tail suspension and Porsolt's forced swim tests. These antidepressant and nootropic effects of cotinine were associated with an increase in the synaptophysin expression, a commonly used marker of synaptic density, in the hippocampus as well as the prefrontal and entorhinal cortices of restrained mice. The beneficial effects of cotinine in preventing various consequences of chronic stress were underscored by the inhibition of the glycogen synthase kinase 3 β in the hippocampus and prefrontal cortex. Taken together, our results show for the first time that cotinine reduces the negative effects of stress on mood, memory, and the synapse. Published by Elsevier B.V.

Effects of Ganglioside on Working Memory and the Default Mode Network in Individuals with Subjective Cognitive Impairment: A Randomized Controlled Trial.

PubMed

Jeon, Yujin; Kim, Binna; Kim, Jieun E; Kim, Bori R; Ban, Soonhyun; Jeong, Jee Hyang; Kwon, Oran; Rhie, Sandy Jeong; Ahn, Chang-Won; Kim, Jong-Hoon; Jung, Sung Ug; Park, Soo-Hyun; Lyoo, In Kyoon; Yoon, Sujung

2016-01-01

This randomized, double-blind, placebo-controlled trial examined whether the administration of ganglioside, an active ingredient of deer bone extract, can improve working memory performance by increasing gray matter volume and functional connectivity in the default mode network (DMN) in individuals with subjective cognitive impairment. Seventy-five individuals with subjective cognitive impairment were chosen to receive either ganglioside (330[Formula: see text][Formula: see text]g/day or 660[Formula: see text][Formula: see text]g/day) or a placebo for 8 weeks. Changes in working memory performance with treatment of either ganglioside or placebo were assessed as cognitive outcome measures. Using voxel-based morphometry and functional connectivity analyses, changes in gray matter volume and functional connectivity in the DMN were also assessed as brain outcome measures. Improvement in working memory performance was greater in the ganglioside group than in the placebo group. The ganglioside group, relative to the placebo group, showed greater increases in gray matter volume and functional connectivity in the DMN. A significant relationship between increased functional connectivity of the precuneus and improved working memory performance was observed in the ganglioside group. The current findings suggest that ganglioside has cognitive-enhancing effects in individuals with subjective cognitive impairment. Ganglioside-induced increases in gray matter volume and functional connectivity in the DMN may partly be responsible for the potential nootropic effects of ganglioside. The clinical trial was registered with ClinicalTrials.gov (identifier: NCT02379481).

Effect of Withinia Somnifera and Shilajit on Alcohol Addiction in Mice

PubMed Central

Bansal, Priya; Banerjee, Sugato

2016-01-01

Background: Alcohol addiction is a social problem leading to both loss of health and economic prosperity among addicted individuals. Common properties of anti-addictive compounds include anti-anxiety, anticonvulsants, anti-depressant, and nootropic actions primarily through modulation of gamma-aminobutyric acid (GABA) and serotonergic systems. Objective: Here, we screen ashwagandha and shilajit known ethnopharmacologically as nervine tonic and adaptogenic herbs for possible anti-addictive potential. Materials and Methods: Effect of ashwagandha churna and shilajit was measured on ethanol withdrawal anxiety using elevated plus maze. Role of ashwagandha and shilajit on chronic ethanol consumption (21 days) was measured using two bottle choice protocol of voluntary drinking. We also measured the effect of the above herbs on corticohippocampal GABA, dopamine, and serotonin levels. Results: Both ashwagandha and shilajit were found to reduce alcohol withdrawal anxiety in a dose-dependent manner. These herbs alone or in combination also decreased ethanol intake and increased water intake significantly after 21 days of chronic administration. Chronic administration of ashwagandha was found to significantly increase GABA and serotonin levels whereas shilajit altered cortico-hippocampal dopamine in mice. Conclusion: These central nervous system active herbs alone or in combination reduced both alcohol dependence and withdrawal thus showing promising anti-addictive potential. SUMMARY Withinia Somnifera alone and in combination with Shilajeet prevented ethanol withdrawal and alcohol addiction Abbreviations used: GABA: Gama aminobutyric acid, CNS: Central Nervous System, CPP:Condition place preference, DA: Dopamine, 5-HT: 5-hydroxytryptamine, NMDA:N-methyl-D-aspartate PMID:27279696

Acetylcholinesterase inhibition in cognition-relevant brain areas of mice treated with a nootropic Amazonian herbal (Marapuama).

PubMed

Figueiró, M; Ilha, J; Pochmann, D; Porciúncula, L O; Xavier, L L; Achaval, M; Nunes, D S; Elisabetsky, E

2010-10-01

The goal of acetylcholinesterase inhibitors (AChEIs) used to treat Alzheimer's patients is an improvement in cholinergic transmission. While currently available AChEIs have limited success, a huge impediment to the development of newer ones is access to the relevant brain areas. Promnesic, anti-amnesic and AChEI properties were identified in a standardized ethanol extract from Ptychopetalum olacoides (POEE), a medicinal plant favored by the elderly in Amazon communities. The purpose of this study was to provide conclusive evidence that orally given POEE induces AChE inhibition in brain areas relevant to cognition. Histochemistry experiments confirmed that the anticholinesterase compound(s) present in POEE are orally bioavailable, inducing meaningful AChE inhibition in the hippocampus CA1 (∼33%) and CA3 (∼20%), and striatum (∼17%). Ellman's colorimetric analysis revealed that G1 and G4 AChE isoforms activities were markedly inhibited (66 and 72%, respectively) in hippocampus and frontal cortex (50 and 63%, respectively), while G4 appeared to be selectively inhibited (72%) in the striatum. Western blotting showed that POEE did not induce significant changes in the AChE immunocontent suggesting that its synthesis is not extensively modified. This study provides definitive proof of meaningful anticholinesterase activity compatible with the observed promnesic and anti-amnesic effects of POEE in mice, reaffirming the potential of this extract for treating neurodegenerative conditions where a hypofunctioning cholinergic neurotransmission is prominent. Adequate assessment of the safety and efficacy of this extract and/or its isolated active compound(s) are warranted. 2010 Elsevier GmbH. All rights reserved.

Aniracetam reversed learning and memory deficits following prenatal ethanol exposure by modulating functions of synaptic AMPA receptors.

PubMed

Vaglenova, Julia; Pandiella, Noemi; Wijayawardhane, Nayana; Vaithianathan, Tiru; Birru, Sandjay; Breese, Charles; Suppiramaniam, Vishnu; Randal, Clark

2008-04-01

Specific pharmacological treatments are currently not available to address problems resulting from fetal ethanol exposure, described as Fetal Alcohol Syndrome or Fetal Alcohol Spectrum Disorders (FASD). The present study evaluated the therapeutic effects of aniracetam against cognitive deficits in a well-characterized and sensitive FASD Sprague-Dawley rat model. Ethanol, administered orally at a moderate dose (4 g/kg/24 h; 38% v/v) during the entire course of pregnancy, caused severe cognitive deficits in offspring. Furthermore, both progeny genders were affected by a spectrum of behavioral abnormalities, such as a delay in the development of the righting reflex, poor novelty seeking behavior, and high anxiety levels in female rats. Cognitive disabilities, monitored in adult rats by a two-way active avoidance task, correlated well with a significant reduction of AMPA (alpha-amino-3 hydro-5 methyl-isoxazole propionic acid) receptor-mediated miniature excitatory postsynaptic responses (mEPSCs) in the hippocampus. Administration of aniracetam for 10 days (post-natal days (PND) 18-27), at a dose of 50 mg/kg reversed cognitive deficits in both rat genders, indicated by a significant increase in the number of avoidances and the number of 'good learners'. After the termination of the nootropic treatment, a significant increase in both amplitude and frequency of AMPA receptor-mediated mEPSCs in hippocampal CA-1 pyramidal cells was observed. Significant anxiolytic effects on PND 40 also preceded acquisition improvements in the avoidance task. This study provides evidence for the therapeutic potential of aniracetam in reversing cognitive deficits associated with FASD through positive post-natal modulation of AMPA receptors.

Comparative evaluation of ethanolic extracts of Bacopa monnieri, Evolvulus alsinoides, Tinospora cordifolia and their combinations on cognitive functions in rats.

PubMed

Gupta, Avneet; Raj, Hem; Karchuli, Manvender Singh; Upmanyu, Neeraj

2013-12-01

The effects of ethanolic extracts of whole plants of Bacopa monnieri (BME), Evolvulus alsinoides (EAE), Tinospora cordifolia (TCE) and their combinations in equal proportion [CEP-1 (BME+EAE), CEP-2 (BME+TCE), CEP-3 (EAE+TCE) and CEP-4 (BME+EAE+TCE)] were tested in amnesic rats using Radial arm maze task performance (RAM) and Barnes maze test at 200 mg/kg p.o. The latency to find food and target hole was observed in RAM and Barnes maze respectively. Cognitive dysfunction was induced by scopolamine (0.3 mg/kg i.p.) treatment. BME, EAE, TCE and their combinations of equal proportion (CEPs) showed significant decrease in latency to find food and target hole in RAM and Barnes maze respectively. Inter comparison among single extract alone treated groups revealed that BME treated animals showed significant difference as compared to EAE and TCE treated animals. All combinations of equal proportion (CEPs) of these extracts showed significant difference in latency to find food and target hole as compared to single extracts treated animals. CEP-1 showed significantly better effect as compared to CEP-2 and CEP-3. Significant difference in latency to find food and target hole was also present between CEP-2 and CEP-3. Effect of CEP-4 was found to be significantly better than CEP-1, CEP-2 and CEP-3 treated rats in both models. From present investigation, it was concluded that ethanolic extract of Bacopa monnieri, Evolvulus alsinoides and Tinospora cordifolia provided better nootropic effect when used in combination.

Piracetam improves mitochondrial dysfunction following oxidative stress

PubMed Central

Keil, Uta; Scherping, Isabel; Hauptmann, Susanne; Schuessel, Katin; Eckert, Anne; Müller, Walter E

2005-01-01

Mitochondrial dysfunction including decrease of mitochondrial membrane potential and reduced ATP production represents a common final pathway of many conditions associated with oxidative stress, for example, hypoxia, hypoglycemia, and aging. Since the cognition-improving effects of the standard nootropic piracetam are usually more pronounced under such pathological conditions and young healthy animals usually benefit little by piracetam, the effect of piracetam on mitochondrial dysfunction following oxidative stress was investigated using PC12 cells and dissociated brain cells of animals treated with piracetam. Piracetam treatment at concentrations between 100 and 1000 μM improved mitochondrial membrane potential and ATP production of PC12 cells following oxidative stress induced by sodium nitroprusside (SNP) and serum deprivation. Under conditions of mild serum deprivation, piracetam (500 μM) induced a nearly complete recovery of mitochondrial membrane potential and ATP levels. Piracetam also reduced caspase 9 activity after SNP treatment. Piracetam treatment (100–500 mg kg−1 daily) of mice was also associated with improved mitochondrial function in dissociated brain cells. Significant improvement was mainly seen in aged animals and only less in young animals. Moreover, the same treatment reduced antioxidant enzyme activities (superoxide dismutase, glutathione peroxidase, and glutathione reductase) in aged mouse brain only, which are elevated as an adaptive response to the increased oxidative stress with aging. In conclusion, therapeutically relevant in vitro and in vivo concentrations of piracetam are able to improve mitochondrial dysfunction associated with oxidative stress and/or aging. Mitochondrial stabilization and protection might be an important mechanism to explain many of piracetam's beneficial effects in elderly patients. PMID:16284628

Piracetam attenuates binge eating disorder related symptoms in rats.

PubMed

Hussain, Yusuf; Krishnamurthy, Sairam

2018-06-01

Binge eating disorder (BED) is a stress-related disorder characterized by acute episodes of excessive food intake. Piracetam, a nootropic agent has been reported to show several other neuropharmacological properties. The present study, evaluated the pharmacological effect of piracetam (200 mg/kg i.p.) on BED in female rats, induced by free access to palatable cookies for 2 h on alternate days. BED was confirmed by an increase in binge eating behavior and weight gain. BED leads to anxiety, cognitive and memory deficits, as evaluated by EPM (Elevated plus maze), OFT (open field test), and Y-maze tests. Increased levels of plasma corticosterone (CORT), glutamate in nucleus accumbens (NAC), hypothalamus (HYP) and prefrontal cortex (PFC) indicate stress and excitotoxicity. Moreover, it was observed that the levels of dopamine were higher in NAC and PFC, and less in HYP which may be responsible for motivational behavior for palatable feeding and cognitive deficits. More surprisingly, feeding behaviour regulating hormones namelyleptin was increased and ghrelin level was decreased in BED. Further, level of acetylcholine which regulates cognitive behaviour was compromised in BED. Piracetam significantly decreased binge eating behavior and associated body weight and regulated the levels of concerned neurotransmitters in respective regions. However, piracetam did not alter normal feeding behavior in the fast-refed model. Further, piracetam showed brain region-specific decrease in vascular endothelial growth factor expression. Piracetam showed anxiolytic activity and also alleviated cognitive deficit observed in BED. Hence, preclinical evidence indicates the potential use of piracetam for the treatment of BED. Copyright © 2018 Elsevier Inc. All rights reserved.

The effects of piracetam and its novel peptide analogue GVS-111 on neuronal voltage-gated calcium and potassium channels.

PubMed

Solntseva, E I; Bukanova, J V; Ostrovskaya, R U; Gudasheva, T A; Voronina, T A; Skrebitsky, V G

1997-07-01

1. With the use of the two-microelectrode voltage-clamp method, three types of voltage-activated ionic currents were examined in isolated neurons of the snail Helix pomatia: high-threshold Ca2+ current (ICa), high-threshold Ca(2+)-dependent K+ current (IK(Ca)) and high-threshold K+ current independent of Ca2+ (IK(V)). 2. The effect of bath application of the nootropics piracetam and a novel piracetam peptide analog, ethyl ester of N-phenyl-acetyl-L-prolyl-glycine (GVS-111), on these three types of voltage-activated ionic currents was studied. 3. In more than half of the tested cells, ICa was resistant to both piracetam and GVS-111. In the rest of the cells, ICa decreased 19 +/- 7% with 2 mM of piracetam and 39 +/- 14% with 2 microM of GVS-111. 4. IK(V) in almost all cells tested was resistant to piracetam at concentrations up to 2 mM. However, IK(V) in two-thirds of the cells was sensitive to GVS-111, being suppressed 49 +/- 18% with 1 microM GVS-111. 5. IK(Ca) appeared to be the most sensitive current of those studied to both piracetam and GVS-111. Piracetam at 1 mM and GVS-111 at 0.1 microM decreased the amplitude of IK(Ca) in most of the cells examined by 49 +/- 19% and 69 +/- 24%, respectively. 6. The results suggest that piracetam and GVS-111 suppression of voltage-activated calcium and potassium currents of the neuronal membrane may regulate (both up and down) Ca2+ influx into neurons.

Nootropic and anti-stress effects of rice bran oil in male rats.

PubMed

Mehdi, Bushra Jabeen; Tabassum, Saiqa; Haider, Saida; Perveen, Tahira; Nawaz, Amber; Haleem, Darakhshan Jabeen

2015-07-01

Rice bran oil (RBO) is an important product of rice bran. It is considered to be one of the most important nutritious oil due to its favorable fatty acid composition and unique composition of naturally occurring biologically active antioxidant compounds. This study was designed to monitor the effects of oral intake of RBO on stress response in rats. RBO was extracted using hexane. Rats were divided into Control and test (RBO-treated). RBO-treated rats were given 0.2 ml/day RBO for 6 weeks. Food intake and body weight changes were monitored weekly. After 6 weeks open field activity and Morris Water Maze (MWM) test were performed. Results showed that weekly cumulative food intake but not body weight were lower in RBO-treated rats during 1st to 5th week of treatment, which were normalized at the end of treatment. Exploratory activity of RBO-treated rats in an open field was increased. Spatial memory in Morris water maze was enhanced in RBO-treated than control rats. An episode of 2 h restraint stress decreased the 24 h food intake of both control and RBO-treated animals. Behavioral deficits were lower in RBO-treated rats. Exposure of 2 h restraint stress increased brain serotonin (5-hydroxytryptamine: 5-HT) metabolism. These increases were lower in RBO-treated restrained than their respective control animals. Serotonergic neurotransmitter mechanism is implicated in stress. The findings of the study show beneficial effects of RBO in learning and memory functions. Moreover, the study also highlights the attenuating effect of RBO on stress induced behavioral and neurochemical effects in rats.

A NMDA receptor glycine site partial agonist, GLYX-13, simultaneously enhances LTP and reduces LTD at Schaffer collateral-CA1 synapses in hippocampus.

PubMed

Zhang, Xiao-lei; Sullivan, John A; Moskal, Joseph R; Stanton, Patric K

2008-12-01

N-methyl-D-aspartate glutamate receptors (NMDARs) are a key route for Ca2+ influx into neurons important to both activity-dependent synaptic plasticity and, when uncontrolled, triggering events that cause neuronal degeneration and death. Among regulatory binding sites on the NMDAR complex is a glycine binding site, distinct from the glutamate binding site, which must be co-activated for NMDAR channel opening. We developed a novel glycine site partial agonist, GLYX-13, which is both nootropic and neuroprotective in vivo. Here, we assessed the effects of GLYX-13 on long-term synaptic plasticity and NMDAR transmission at Schaffer collateral-CA1 synapses in hippocampal slices in vitro. GLYX-13 simultaneously enhanced the magnitude of long-term potentiation (LTP) of synaptic transmission, while reducing long-term depression (LTD). GLYX-13 reduced NMDA receptor-mediated synaptic currents in CA1 pyramidal neurons evoked by low frequency Schaffer collateral stimulation, but enhanced NMDAR currents during high frequency bursts of activity, and these actions were occluded by a saturating concentration of the glycine site agonist d-serine. Direct two-photon imaging of Schaffer collateral burst-evoked increases in [Ca2+] in individual dendritic spines revealed that GLYX-13 selectively enhanced burst-induced NMDAR-dependent spine Ca2+ influx. Examining the rate of MK-801 block of synaptic versus extrasynaptic NMDAR-gated channels revealed that GLYX-13 selectively enhanced activation of burst-driven extrasynaptic NMDARs, with an action that was blocked by the NR2B-selective NMDAR antagonist ifenprodil. Our data suggest that GLYX-13 may have unique therapeutic potential as a learning and memory enhancer because of its ability to simultaneously enhance LTP and suppress LTD.

Clinical efficacy of aniracetam, either as monotherapy or combined with cholinesterase inhibitors, in patients with cognitive impairment: a comparative open study.

PubMed

Koliaki, Chrysi C; Messini, Chaido; Tsolaki, Magda

2012-04-01

Dementia constitutes an increasingly prevalent cognitive disorder with serious socioeconomic implications. In the present study, we aimed to evaluate the efficacy of aniracetam, either as monotherapy or combined with cholinesterase inhibitors (ChEIs), in terms of several neuropsychological parameters, in a considerable number of patients with dementia. In our prospective, open-label study, we enrolled a total of 276 patients (mean age 71 ± 8 years, 95 males) with cognitive disorders. Our study population comprised four groups: no treatment group (n = 75), aniracetam monotherapy group (n = 58), ChEIs monotherapy group (n = 68), and group of combined treatment (n = 68). Patients were examined with validated neuropsychological tests at baseline, 3, 6, and 12 months of treatment. In patients treated with aniracetam, all studied parameters were adequately maintained at 6 and 12 months, while emotional state was significantly improved at 3 months. In patients treated with ChEIs, we observed a significant cognitive deterioration at 12 months. The comparison between aniracetam and ChEIs in patients with relatively mild dementia (15 ≤ MMSE ≤ 25) revealed a significantly better cognitive performance with aniracetam at 6 months and improved functionality at 3 months. Comparing aniracetam monotherapy with combined treatment in the same population, aniracetam performed better in the cognitive scale at 6 months, and displayed a notable tendency for enhanced mood at 12 months and improved functionality at 6 months. Our findings indicate that aniracetam (a nootropic compound with glutamatergic activity and neuroprotective potential) is a promising option for patients with cognitive deficit of mild severity. It preserved all neuropsychological parameters for at least 12 months, and seemed to exert a favorable effect on emotional stability of demented patients. © 2011 Blackwell Publishing Ltd.

Vinpocetine Reduces Carrageenan-Induced Inflammatory Hyperalgesia in Mice by Inhibiting Oxidative Stress, Cytokine Production and NF-κB Activation in the Paw and Spinal Cord

PubMed Central

Ruiz-Miyazawa, Kenji W.; Zarpelon, Ana C.; Pinho-Ribeiro, Felipe A.; Pavão-de-Souza, Gabriela F.; Casagrande, Rubia; Verri, Waldiceu A.

2015-01-01

Vinpocetine is a safe nootropic agent used for neurological and cerebrovascular diseases. The anti-inflammatory activity of vinpocetine has been shown in cell based assays and animal models, leading to suggestions as to its utility in analgesia. However, the mechanisms regarding its efficacy in inflammatory pain treatment are still not completely understood. Herein, the analgesic effect of vinpocetine and its anti-inflammatory and antioxidant mechanisms were addressed in murine inflammatory pain models. Firstly, we investigated the protective effects of vinpocetine in overt pain-like behavior induced by acetic acid, phenyl-p-benzoquinone (PBQ) and formalin. The intraplantar injection of carrageenan was then used to induce inflammatory hyperalgesia. Mechanical and thermal hyperalgesia were evaluated using the electronic von Frey and the hot plate tests, respectively, with neutrophil recruitment to the paw assessed by a myeloperoxidase activity assay. A number of factors were assessed, both peripherally and in the spinal cord, including: antioxidant capacity, reduced glutathione (GSH) levels, superoxide anion, tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) levels, as well as nuclear factor kappa B (NF-κB) activation. Vinpocetine inhibited the overt pain-like behavior induced by acetic acid, PBQ and formalin (at both phases), as well as the carrageenan-induced mechanical and thermal hyperalgesia and associated neutrophil recruitment. Both peripherally and in the spinal cord, vinpocetine also inhibited: antioxidant capacity and GSH depletion; increased superoxide anion; IL-1β and TNF-α levels; and NF-κB activation. As such, vinpocetine significantly reduces inflammatory pain by targeting oxidative stress, cytokine production and NF-κB activation at both peripheral and spinal cord levels. PMID:25822523

Vinpocetine reduces carrageenan-induced inflammatory hyperalgesia in mice by inhibiting oxidative stress, cytokine production and NF-κB activation in the paw and spinal cord.

PubMed

Ruiz-Miyazawa, Kenji W; Zarpelon, Ana C; Pinho-Ribeiro, Felipe A; Pavão-de-Souza, Gabriela F; Casagrande, Rubia; Verri, Waldiceu A

2015-01-01

Vinpocetine is a safe nootropic agent used for neurological and cerebrovascular diseases. The anti-inflammatory activity of vinpocetine has been shown in cell based assays and animal models, leading to suggestions as to its utility in analgesia. However, the mechanisms regarding its efficacy in inflammatory pain treatment are still not completely understood. Herein, the analgesic effect of vinpocetine and its anti-inflammatory and antioxidant mechanisms were addressed in murine inflammatory pain models. Firstly, we investigated the protective effects of vinpocetine in overt pain-like behavior induced by acetic acid, phenyl-p-benzoquinone (PBQ) and formalin. The intraplantar injection of carrageenan was then used to induce inflammatory hyperalgesia. Mechanical and thermal hyperalgesia were evaluated using the electronic von Frey and the hot plate tests, respectively, with neutrophil recruitment to the paw assessed by a myeloperoxidase activity assay. A number of factors were assessed, both peripherally and in the spinal cord, including: antioxidant capacity, reduced glutathione (GSH) levels, superoxide anion, tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) levels, as well as nuclear factor kappa B (NF-κB) activation. Vinpocetine inhibited the overt pain-like behavior induced by acetic acid, PBQ and formalin (at both phases), as well as the carrageenan-induced mechanical and thermal hyperalgesia and associated neutrophil recruitment. Both peripherally and in the spinal cord, vinpocetine also inhibited: antioxidant capacity and GSH depletion; increased superoxide anion; IL-1β and TNF-α levels; and NF-κB activation. As such, vinpocetine significantly reduces inflammatory pain by targeting oxidative stress, cytokine production and NF-κB activation at both peripheral and spinal cord levels.

Embryo-fetal development studies with the dietary supplement vinpocetine in the rat and rabbit.

PubMed

Catlin, Natasha; Waidyanatha, Suramya; Mylchreest, Eve; Miller-Pinsler, Lutfiya; Cunny, Helen; Foster, Paul; Sutherland, Vicki; McIntyre, Barry

2018-06-01

Dietary supplement and natural product use is increasing within the United States, resulting in growing concern for exposure in vulnerable populations, including young adults and women of child-bearing potential. Vinpocetine is a semisynthetic derivative of the Vinca minor extract, vincamine. Human exposure to vinpocetine occurs through its use as a dietary supplement for its purported nootropic and neuroprotective effects. To investigate the effects of vinpocetine on embryo-fetal development, groups of 25 pregnant Sprague-Dawley rats and 8 pregnant New Zealand White rabbits were orally administered 0, 5, 20, or 60 mg vinpocetine/kg and 0, 25, 75, 150, or 300 mg/kg daily from gestational day (GD) 6-20 and GD 7-28, respectively. Pregnant rats dosed with vinpocetine demonstrated dose-dependent increases in postimplantation loss, higher frequency of early and total resorptions, lower fetal body weights, and fewer live fetuses following administration of 60 mg/kg, in the absence of maternal toxicity. Additionally, the rat fetuses displayed dose-dependent increases in the incidences of ventricular septum defects and full supernumerary thoracolumbar ribs. Similarly, albeit at higher doses than the rats, pregnant rabbits administered vinpocetine displayed an increase in postimplantation loss and fewer live fetuses (300 mg/kg), in addition to significantly lower fetal body weights (≥75 mg/kg). In conclusion, vinpocetine exposure resulted in similar effects on embryo-fetal development in the rat and rabbit. The species differences in sensitivity and magnitude of response is likely attributable to a species difference in metabolism. Taken together, these data suggest a potential hazard for pregnant women who may be taking vinpocetine. © 2018 Wiley Periodicals, Inc.

Moringa oleifera with promising neuronal survival and neurite outgrowth promoting potentials.

PubMed

Hannan, Md Abdul; Kang, Ji-Young; Mohibbullah, Md; Hong, Yong-Ki; Lee, Hyunsook; Choi, Jae-Suk; Choi, In Soon; Moon, Il Soo

2014-02-27

Moringa oleifera Lam. (Moringaceae) by virtue of its high nutritional as well as ethnomedical values has been gaining profound interest both in nutrition and medicinal research. The leaf of this plant is used in ayurvedic medicine to treat paralysis, nervous debility and other nerve disorders. In addition, research evidence also suggests the nootropic as well as neuroprotective roles of Moringa oleifera leaf in animal models. The aim of the present study was to evaluate the effect of Moringa oleifera leaf in the primary hippocampal neurons regarding its neurotrophic and neuroprotective properties. The primary culture of embryonic hippocampal neurons was incubated with the ethanol extract of Moringa oleifera leaf (MOE). After an indicated time, cultures were either stained directly with a lipophilic dye, DiO, or fixed and immunolabeled to visualize the neuronal morphology. Morphometric analyses for neurite maturation and synaptogenesis were performed using Image J software. Neuronal viability was evaluated using trypan blue exclusion and lactate dehydrogenase assays. MOE promoted neurite outgrowth in a concentration-dependent manner with an optimal concentration of 30 μg/mL. As a very initial effect, MOE significantly promoted the earlier stages of neuronal differentiation. Subsequently, MOE significantly increased the number and length of dendrites, the length of axon, and the number and length of both dendrite and axonal branches, and eventually facilitated synaptogenesis. The β-carotene, one major compound of MOE, promoted neuritogensis, but the increase was not comparable with the effect of MOE. In addition, MOE supported neuronal survival by protecting neurons from naturally occurring cell death in vitro. Our findings indicate that MOE promotes axodendritic maturation as well as provides neuroprotection suggesting a promising pharmacological importance of this nutritionally and ethnomedically important plant for the well-being of nervous system. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

[Study of acetylsalicylic acid role in the potentiation of antiamnesic and neuroprotective properties of piracetam in rats with alloxan diabetes].

PubMed

Zhiliuk, V I; Levykh, A E; Mamchur, V I

2013-01-01

It has been established that prolonged alloxan-induced hyperglycemia in rats potentiates amnesic properties of scopolamine hydrobromide. It was characterized by shortening of the latent period by 44% (p<0,01) and by 47,7% (p<0,05) after 24 hours and on the 20th day of conditioned passive avoidance test. This effect was accompanied by increase in oxidative modification of proteins and nitric oxide synthesis in the cerebral cortex. Along with this, a significant enhancement of ADP- and collagen-induced platelet aggregation was observed. These processes may play the leading role in the development of cognitive deficit in diabetes. Meanwhile, co-administration of piracetam with acetylsalicylic acid was accompanied by an expressed antiamnetic potential - the reduction of early markers of proteins degradation (aldehydephenylhydrazones, APH) by 21,7% (p<0,05) and late markers of proteins degradation (ketonephenylhydrazones, KPH) by 23,8% (p<0,001) was noted. This combination was 15,7% (p<0,05) more active than piracetam according to the effect upon KPH. NO2-/NO3- level was also decreased by 30,3% (p<0,05) in comparison with alloxan-diabetic rats. The significant anti-platelet effect was observed: degree of collagen-induced platelet aggregation was reduced by 56,8% (p<0,01), ADP (5 μmol/l)-induced - by 31,7% (p<0,01), ADP (20 μmol/l)-induced - by 47,3% (p<0,01) as compared to the hyperglycemic rats. Such an increase in nootropic activity of piracetam may be assumed to be directly related to the ability of acetylsalicylic acid to improve microcirculation in the ischemic areas of the brain in diabetes and probably to its neuroprotective potential.

Effect of piracetam on the cognitive performance of patients undergoing coronary bypass surgery: A meta-analysis

PubMed Central

FANG, YU; QIU, ZHANDONG; HU, WENTAO; YANG, JIA; YI, XIYAN; HUANG, LIANGJIANG; ZHANG, SUMING

2014-01-01

Cognitive impairments are observed in numerous patients following coronary bypass surgery, and piracetam are nootropic compounds that modulate cerebral functions by directly enhancing cognitive processes. The present meta-analysis was conducted to evaluate the protective effect of piracetam on the cognitive performance of patients undergoing coronary bypass surgery. The relevant studies were identified by searching Medline, EMBASE, PubMed and the Cochrane Library up to June 2013 and the pertinent bibliographies from the retrieved studies were reviewed. Data were selected from the studies according to predefined criteria. The meta-analysis included two randomized control trials involving 184 patients and including the Syndrom-Kurz test (SKT). Findings of the meta-analysis showed that following treatment the change from baseline observed in five SKT subtest scores, conducted with piracetam patients, indicated a significant advantage over those patients that were in the placebo group. The subtests included immediate pictured object recall, weighted mean difference (WMD)=0.91, 95% confidence interval (CI) 0.51–1.31, P<0.00001; delayed pictured object recall, WMD=0.74, 95% CI 0.19–1.28, P=0.008; delayed picture recognition, WMD=0.82, 95% CI 0.31–1.31, P=0.001; immediate word recall, WMD=0.87, 95% CI 0.47–1.28, P<0.0001; and letter interference, WMD=3.46, 95% CI −5.69 to −1.23, P=0.002. These results indicated that piracetam may have been effective in improving the short-term cognitive performance of patients undergoing coronary bypass surgery. High quality, well-controlled and longer randomized trials are required to corroborate this result. PMID:24396419

Facilitatory effects of piracetam on excitability of motor nerve terminals and neuromuscular transmission.

PubMed

Hall, E D; Von Voigtlander, P F

1987-11-01

The possible in vivo facilitatory effects of the pyrrolidine acetamide no-otropic agent piracetam on neuromuscular transmission, were studied based upon reports of enhancement of central cholinergic function. Piracetam was shown to antagonize the lethal effects of the neuromuscular blocking agent hemicholinium-3 (HC-3), in female CF-1 mice when administered in a dose of 100 mg/kg (i.p.) simultaneously with HC-3. A 30 mg/kg (i.p.) dose of piracetam was ineffective by itself, although it potentiated the protective effects of choline (25 mg/kg i.p.). The analogs of piracetam, aniracetam, oxiracetam, pramiracetam and dupracetam also significantly antagonized the lethality of HC-3 at doses over a 30-300 mg/kg range. The acute facilitatory properties of piracetam on neuromuscular transmission were examined in more detail in vivo in the soleus nerve muscle preparation of the cat. A 100 mg/kg (i.v.) dose of piracetam, while having no effect on its own, significantly enhanced the ability of a 200 micrograms/kg (i.v.) dose of edrophonium to produce a potentiation of muscle contraction dependent on repetitive discharges in the soleus motor nerve terminals. In preparations in which the motor nerve terminals of the soleus were in a partially degenerated state as a result of section of the motor axons 48 hr earlier, piracetam acted to restore their sensitivity to edrophonium. Furthermore, in both normal and partially degenerated preparations, piracetam significantly decreased the neuromuscular blocking effects of a 150 micrograms/kg (i.v.) dose of d-tubocurarine. The mechanism of the neuromuscular facilitatory effects of piracetam on neuromuscular transmission is discussed in terms of an enhanced excitability of motor nerve terminals together with an action to increase the synthesis and/or release of acetylcholine.

Extracts and constituents of Leontopodium alpinum enhance cholinergic transmission: Brain ACh increasing and memory improving properties

PubMed Central

Hornick, Ariane; Schwaiger, Stefan; Rollinger, Judith M.; Vo, Nguyen Phung; Prast, Helmut; Stuppner, Hermann

2012-01-01

Leontopodium alpinum (‘Edelweiss’) was phytochemically investigated for constituents that might enhance cholinergic neurotransmission. The potency to increase synaptic availability of acetylcholine (ACh) in rat brain served as key property for the bioguided isolation of cholinergically active compounds using different chromatographic techniques. The dichlormethane (DCM) extract of the root, fractions and isolated constituents were injected i.c.v. and the effect on brain ACh was detected via the push–pull technique. The DCM extract enhanced extracellular ACh concentration in rat brain and inhibited acetylcholinesterase (AChE) in vitro. The extracellular level of brain ACh was significantly increased by the isolated sesquiterpenes, isocomene and 14-acetoxyisocomene, while silphiperfolene acetate and silphinene caused a small increasing tendency. Only silphiperfolene acetate showed in vitro AChE inhibitory activity, thus suggesting the other sesquiterpenes to stimulate cholinergic transmission by an alternative mechanism of action. Isocomene was further investigated with behavioural tasks in mice. It restored object recognition in scopolamine-impaired mice and showed nootropic effects in the T-maze alternation task in normal and scopolamine-treated mice. Additionally, this sesquiterpene reduced locomotor activity of untreated mice in the open field task, while the activity induced by scopolamine was abolished. The enhancement of synaptic availability of ACh, the promotion of alternation, and the amelioration of scopolamine-induced deficit are in accordance with a substance that amplifies cholinergic transmission. Whether the mechanism of action is inhibition of AChE or another pro-cholinergic property remains to be elucidated. Taken together, isocomene and related constituents of L. alpinum deserve further interest as potential antidementia agents in brain diseases associated with cholinergic deficits. PMID:18541221

Precision medicine for suicidality: from universality to subtypes and personalization

PubMed Central

Niculescu, A B; Le-Niculescu, H; Levey, D F; Phalen, P L; Dainton, H L; Roseberry, K; Niculescu, E M; Niezer, J O; Williams, A; Graham, D L; Jones, T J; Venugopal, V; Ballew, A; Yard, M; Gelbart, T; Kurian, S M; Shekhar, A; Schork, N J; Sandusky, G E; Salomon, D R

2017-01-01

Suicide remains a clear, present and increasing public health problem, despite being a potentially preventable tragedy. Its incidence is particularly high in people with overt or un(der)diagnosed psychiatric disorders. Objective and precise identification of individuals at risk, ways of monitoring response to treatments and novel preventive therapeutics need to be discovered, employed and widely deployed. We sought to investigate whether blood gene expression biomarkers for suicide (that is, a ‘liquid biopsy’ approach) can be identified that are more universal in nature, working across psychiatric diagnoses and genders, using larger cohorts than in previous studies. Such markers may reflect and/or be a proxy for the core biology of suicide. We were successful in this endeavor, using a comprehensive stepwise approach, leading to a wealth of findings. Steps 1, 2 and 3 were discovery, prioritization and validation for tracking suicidality, resulting in a Top Dozen list of candidate biomarkers comprising the top biomarkers from each step, as well as a larger list of 148 candidate biomarkers that survived Bonferroni correction in the validation step. Step 4 was testing the Top Dozen list and Bonferroni biomarker list for predictive ability for suicidal ideation (SI) and for future hospitalizations for suicidality in independent cohorts, leading to the identification of completely novel predictive biomarkers (such as CLN5 and AK2), as well as reinforcement of ours and others previous findings in the field (such as SLC4A4 and SKA2). Additionally, we examined whether subtypes of suicidality can be identified based on mental state at the time of high SI and identified four potential subtypes: high anxiety, low mood, combined and non-affective (psychotic). Such subtypes may delineate groups of individuals that are more homogenous in terms of suicidality biology and behavior. We also studied a more personalized approach, by psychiatric diagnosis and gender, with a focus on bipolar males, the highest risk group. Such a personalized approach may be more sensitive to gender differences and to the impact of psychiatric co-morbidities and medications. We compared testing the universal biomarkers in everybody versus testing by subtypes versus personalized by gender and diagnosis, and show that the subtype and personalized approaches permit enhanced precision of predictions for different universal biomarkers. In particular, LHFP appears to be a strong predictor for suicidality in males with depression. We also directly examined whether biomarkers discovered using male bipolars only are better predictors in a male bipolar independent cohort than universal biomarkers and show evidence for a possible advantage of personalization. We identified completely novel biomarkers (such as SPTBN1 and C7orf73), and reinforced previously known biomarkers (such as PTEN and SAT1). For diagnostic ability testing purposes, we also examined as predictors phenotypic measures as apps (for suicide risk (CFI-S, Convergent Functional Information for Suicidality) and for anxiety and mood (SASS, Simplified Affective State Scale)) by themselves, as well as in combination with the top biomarkers (the combination being our a priori primary endpoint), to provide context and enhance precision of predictions. We obtained area under the curves of 90% for SI and 77% for future hospitalizations in independent cohorts. Step 5 was to look for mechanistic understanding, starting with examining evidence for the Top Dozen and Bonferroni biomarkers for involvement in other psychiatric and non-psychiatric disorders, as a mechanism for biological predisposition and vulnerability. The biomarkers we identified also provide a window towards understanding the biology of suicide, implicating biological pathways related to neurogenesis, programmed cell death and insulin signaling from the universal biomarkers, as well as mTOR signaling from the male bipolar biomarkers. In particular, HTR2A increase coupled with ARRB1 and GSK3B decreases in expression in suicidality may provide a synergistic mechanistical corrective target, as do SLC4A4 increase coupled with AHCYL1 and AHCYL2 decrease. Step 6 was to move beyond diagnostics and mechanistical risk assessment, towards providing a foundation for personalized therapeutics. Items scored positive in the CFI-S and subtypes identified by SASS in different individuals provide targets for personalized (psycho)therapy. Some individual biomarkers are targets of existing drugs used to treat mood disorders and suicidality (lithium, clozapine and omega-3 fatty acids), providing a means toward pharmacogenomics stratification of patients and monitoring of response to treatment. Such biomarkers merit evaluation in clinical trials. Bioinformatics drug repurposing analyses with the gene expression biosignatures of the Top Dozen and Bonferroni-validated universal biomarkers identified novel potential therapeutics for suicidality, such as ebselen (a lithium mimetic), piracetam (a nootropic), chlorogenic acid (a polyphenol) and metformin (an antidiabetic and possible longevity promoting drug). Finally, based on the totality of our data and of the evidence in the field to date, a convergent functional evidence score prioritizing biomarkers that have all around evidence (track suicidality, predict it, are reflective of biological predisposition and are potential drug targets) brought to the fore APOE and IL6 from among the universal biomarkers, suggesting an inflammatory/accelerated aging component that may be a targetable common denominator. PMID:28809398

Precision medicine for suicidality: from universality to subtypes and personalization.

PubMed

Niculescu, A B; Le-Niculescu, H; Levey, D F; Phalen, P L; Dainton, H L; Roseberry, K; Niculescu, E M; Niezer, J O; Williams, A; Graham, D L; Jones, T J; Venugopal, V; Ballew, A; Yard, M; Gelbart, T; Kurian, S M; Shekhar, A; Schork, N J; Sandusky, G E; Salomon, D R

2017-09-01

Suicide remains a clear, present and increasing public health problem, despite being a potentially preventable tragedy. Its incidence is particularly high in people with overt or un(der)diagnosed psychiatric disorders. Objective and precise identification of individuals at risk, ways of monitoring response to treatments and novel preventive therapeutics need to be discovered, employed and widely deployed. We sought to investigate whether blood gene expression biomarkers for suicide (that is, a 'liquid biopsy' approach) can be identified that are more universal in nature, working across psychiatric diagnoses and genders, using larger cohorts than in previous studies. Such markers may reflect and/or be a proxy for the core biology of suicide. We were successful in this endeavor, using a comprehensive stepwise approach, leading to a wealth of findings. Steps 1, 2 and 3 were discovery, prioritization and validation for tracking suicidality, resulting in a Top Dozen list of candidate biomarkers comprising the top biomarkers from each step, as well as a larger list of 148 candidate biomarkers that survived Bonferroni correction in the validation step. Step 4 was testing the Top Dozen list and Bonferroni biomarker list for predictive ability for suicidal ideation (SI) and for future hospitalizations for suicidality in independent cohorts, leading to the identification of completely novel predictive biomarkers (such as CLN5 and AK2), as well as reinforcement of ours and others previous findings in the field (such as SLC4A4 and SKA2). Additionally, we examined whether subtypes of suicidality can be identified based on mental state at the time of high SI and identified four potential subtypes: high anxiety, low mood, combined and non-affective (psychotic). Such subtypes may delineate groups of individuals that are more homogenous in terms of suicidality biology and behavior. We also studied a more personalized approach, by psychiatric diagnosis and gender, with a focus on bipolar males, the highest risk group. Such a personalized approach may be more sensitive to gender differences and to the impact of psychiatric co-morbidities and medications. We compared testing the universal biomarkers in everybody versus testing by subtypes versus personalized by gender and diagnosis, and show that the subtype and personalized approaches permit enhanced precision of predictions for different universal biomarkers. In particular, LHFP appears to be a strong predictor for suicidality in males with depression. We also directly examined whether biomarkers discovered using male bipolars only are better predictors in a male bipolar independent cohort than universal biomarkers and show evidence for a possible advantage of personalization. We identified completely novel biomarkers (such as SPTBN1 and C7orf73), and reinforced previously known biomarkers (such as PTEN and SAT1). For diagnostic ability testing purposes, we also examined as predictors phenotypic measures as apps (for suicide risk (CFI-S, Convergent Functional Information for Suicidality) and for anxiety and mood (SASS, Simplified Affective State Scale)) by themselves, as well as in combination with the top biomarkers (the combination being our a priori primary endpoint), to provide context and enhance precision of predictions. We obtained area under the curves of 90% for SI and 77% for future hospitalizations in independent cohorts. Step 5 was to look for mechanistic understanding, starting with examining evidence for the Top Dozen and Bonferroni biomarkers for involvement in other psychiatric and non-psychiatric disorders, as a mechanism for biological predisposition and vulnerability. The biomarkers we identified also provide a window towards understanding the biology of suicide, implicating biological pathways related to neurogenesis, programmed cell death and insulin signaling from the universal biomarkers, as well as mTOR signaling from the male bipolar biomarkers. In particular, HTR2A increase coupled with ARRB1 and GSK3B decreases in expression in suicidality may provide a synergistic mechanistical corrective target, as do SLC4A4 increase coupled with AHCYL1 and AHCYL2 decrease. Step 6 was to move beyond diagnostics and mechanistical risk assessment, towards providing a foundation for personalized therapeutics. Items scored positive in the CFI-S and subtypes identified by SASS in different individuals provide targets for personalized (psycho)therapy. Some individual biomarkers are targets of existing drugs used to treat mood disorders and suicidality (lithium, clozapine and omega-3 fatty acids), providing a means toward pharmacogenomics stratification of patients and monitoring of response to treatment. Such biomarkers merit evaluation in clinical trials. Bioinformatics drug repurposing analyses with the gene expression biosignatures of the Top Dozen and Bonferroni-validated universal biomarkers identified novel potential therapeutics for suicidality, such as ebselen (a lithium mimetic), piracetam (a nootropic), chlorogenic acid (a polyphenol) and metformin (an antidiabetic and possible longevity promoting drug). Finally, based on the totality of our data and of the evidence in the field to date, a convergent functional evidence score prioritizing biomarkers that have all around evidence (track suicidality, predict it, are reflective of biological predisposition and are potential drug targets) brought to the fore APOE and IL6 from among the universal biomarkers, suggesting an inflammatory/accelerated aging component that may be a targetable common denominator.

Stimulation of brain glucose uptake by cannabinoid CB2 receptors and its therapeutic potential in Alzheimer's disease.

PubMed

Köfalvi, Attila; Lemos, Cristina; Martín-Moreno, Ana M; Pinheiro, Bárbara S; García-García, Luis; Pozo, Miguel A; Valério-Fernandes, Ângela; Beleza, Rui O; Agostinho, Paula; Rodrigues, Ricardo J; Pasquaré, Susana J; Cunha, Rodrigo A; de Ceballos, María L

2016-11-01

Cannabinoid CB2 receptors (CB2Rs) are emerging as important therapeutic targets in brain disorders that typically involve neurometabolic alterations. We here addressed the possible role of CB2Rs in the regulation of glucose uptake in the mouse brain. To that aim, we have undertaken 1) measurement of (3)H-deoxyglucose uptake in cultured cortical astrocytes and neurons and in acute hippocampal slices; 2) real-time visualization of fluorescently labeled deoxyglucose uptake in superfused hippocampal slices; and 3) in vivo PET imaging of cerebral (18)F-fluorodeoxyglucose uptake. We now show that both selective (JWH133 and GP1a) as well as non-selective (WIN55212-2) CB2R agonists, but not the CB1R-selective agonist, ACEA, stimulate glucose uptake, in a manner that is sensitive to the CB2R-selective antagonist, AM630. Glucose uptake is stimulated in astrocytes and neurons in culture, in acute hippocampal slices, in different brain areas of young adult male C57Bl/6j and CD-1 mice, as well as in middle-aged C57Bl/6j mice. Among the endocannabinoid metabolizing enzymes, the selective inhibition of COX-2, rather than that of FAAH, MAGL or α,βDH6/12, also stimulates the uptake of glucose in hippocampal slices of middle-aged mice, an effect that was again prevented by AM630. However, we found the levels of the endocannabinoid, anandamide reduced in the hippocampus of TgAPP-2576 mice (a model of β-amyloidosis), and likely as a consequence, COX-2 inhibition failed to stimulate glucose uptake in these mice. Together, these results reveal a novel general glucoregulatory role for CB2Rs in the brain, raising therapeutic interest in CB2R agonists as nootropic agents. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

A bacosides containing Bacopa monnieri extract alleviates allodynia and hyperalgesia in the chronic constriction injury model of neuropathic pain in rats.

PubMed

Shahid, Muhammad; Subhan, Fazal; Ahmad, Nisar; Ullah, Ihsan

2017-06-05

The current therapy of neuropathic pain is inadequate and is limited by the extent of pain relief and the occurrence of dose dependant side effects. Insufficient control of pain with conventional medications prompts the use of complementary and alternative medicine therapies by patients with neuropathic pain. This study therefore investigated a standardized methanolic extract of Bacopa monnieri, a widely reputed nootropic plant, for prospective antinociceptive effect in the chronic constriction injury (CCI) model of neuropathic pain. Placement of four loose ligatures around the sciatic nerve produced partial denervation of the hindpaw in rats. Bacopa monnieri (40 and 80 mg/kg, p.o) and the positive control, gabapentin (75 mg/kg, i.p), were administered daily after CCI or sham surgery and the behavioral paradigms of static- and dynamic-allodynia (paw withdrawal threshold to von Frey filament stimulation [PWT] and paw withdrawal latency to light-brushing [PWL]), cold-allodynia (paw withdrawal duration [PWD] to acetone), heat- (PWL to heat-stimulus) and punctate-hyperalgesia (PWD to pin-prick) were assessed on days 3, 7, 14 and 21. CCI consistently generated static- (days 3-21), dynamic- (days 14-21) and cold-allodynia (days 3-21) plus heat- and mechano-hyperalgesia (days 3-21). The tested doses of Bacopa monnieri significantly attenuated the CCI-induced allodynia and hyperalgesia, exemplified by increased PWT (days 7-21), PWL to light brushing (days 14-21) and heat (days 7-21) as well as decreased PWD to pin prick and cold stimuli (days 3-21). The extract also counterbalanced the CCI-induced aberrations in the nociceptive behaviors by increasing the pain threshold to that of pre-surgery baseline. Gabapentin also afforded analogous beneficial behavioral profile but of higher magnitude. Our findings suggest that Bacopa monnieri can be used as adjuvant therapy for neuropathic pain conditions afflicted with allodynia and hyperalgesia.

The genus Desmodium (Fabaceae)-traditional uses in Chinese medicine, phytochemistry and pharmacology.

PubMed

Ma, Xueqin; Zheng, Chengjian; Hu, Changling; Rahman, Khalid; Qin, Luping

2011-11-18

Plants of the genus Desmodium (Fabaceae), such as Desmodium styracifolium (Osbeck) Merr. and Desmodium gyrans (L. f.) DC., have a long history of medical use in Traditional Chinese Medicine to treat various ailments including rheumatism, pyrexia, dysentery, wounds, cough, malaria, hepatitis, hemoptysis, etc. In the theory of Traditional Chinese Medicine, most species have the effect of relieving internal heat or fever, neutralizing toxins, inhibiting pain, invigorating blood circulation, suppressing cough and alleviating dyspnea. A bibliographic investigation was accomplished by analyzing secondary sources including Chinese Herbal Classics, and worldwide accepted scientific databases (Pubmed, Scopus and Web of Science, SciFinder) were scrutinized for the available information on the ethnopharmacological uses in Chinese medicine, phytochemistry, pharmacology and toxicology of Desmodium species. The genus Desmodium is a large member of the Papilionaceae (Fabaceae) family. It contains about 350 plant species used for both feeding stuffs and herbal medicines, of which only about 30 species have been phytochemically or pharmacologically investigated. Desmodium plant extracts, as well as the active principles, have been experimentally studied for their anti-inflammatory, cytotoxic, antidiabetic, antinephrolithic, antibacterial, and nootropic activities in vitro or in vivo. And so far, a total of 212 compounds have been isolated from 15 Desmodium species and characterized mainly as flavonoids and alkaloids, followed by terpenoids, steroids, phenols, phenylpropanoids, glycosides and a number of volatile oils. The remaining unrevealed species are recorded chiefly in Asia and Africa being used in empirical treatment for various diseases. Desmodium species have long been used in TCM to treat various ailments. Available scientific references revealed that the traditional medical uses of some important Desmodium species in TCM have been evaluated by modern pharmacological studies. As literature demonstrated, flavonoids and alkaloids are perhaps responsible for most of the activities shown by the plants of this genus. Further studies are still required to reveal the structure-activity relationship of these active constituents. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

The Ayurvedic plant Bacopa monnieri inhibits inflammatory pathways in the brain.

PubMed

Nemetchek, Michelle D; Stierle, Andrea A; Stierle, Donald B; Lurie, Diana I

2017-02-02

Bacopa monnieri (L) Wettst (common name, bacopa) is a medicinal plant used in Ayurveda, the traditional system of medicine of India, as a nootropic. It is considered to be a "medhya rasayana", an herb that sharpens the mind and the intellect. Bacopa is an important ingredient in many Ayurvedic herbal formulations designed to treat conditions such as memory loss, anxiety, poor cognition and loss of concentration. It has also been used in Ayurveda to treat inflammatory conditions such as arthritis. In modern biomedical studies, bacopa has been shown in animal models to inhibit the release of the pro-inflammatory cytokines TNF-α and IL-6. However, less is known regarding the anti-inflammatory activity of Bacopa in the brain. The current study examines the ability of Bacopa to inhibit the release of pro-inflammatory cytokines from microglial cells, the immune cells of the brain that participate in inflammation in the CNS. The effect of Bacopa on signaling enzymes associated with CNS inflammatory pathways was also studied. Various extracts of Bacopa were prepared and examined in the N9 microglial cell line in order to determine if they inhibited the release of the proinflammatory cytokines TNF-α and IL-6. Extracts were also tested in cell free assays as inhibitors of caspase-1 and matrix metalloproteinase-3 (enzymes associated with inflammation) and caspase-3, which has been shown to cleave protein Tau, an early event in the development of Alzheimer's disease. The tea, infusion, and alkaloid extracts of bacopa, as well as Bacoside A significantly inhibited the release of TNF-α and IL-6 from activated N9 microglial cells in vitro. In addition, the tea, infusion, and alkaloid extracts of Bacopa effectively inhibited caspase 1 and 3, and matrix metalloproteinase-3 in the cell free assay. Bacopa inhibits the release of inflammatory cytokines from microglial cells and inhibits enzymes associated with inflammation in the brain. Thus, Bacopa can limit inflammation in the CNS, and offers a promising source of novel therapeutics for the treatment of many CNS disorders. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The Ayurvedic plant Bacopa Monnieri inhibits inflammatory pathways in the brain

PubMed Central

Nemetchek, Michelle D.; Stierle, Andrea A.; Stierle, Donald B.; Lurie, Diana I.

2016-01-01

Ethnopharmacological Relevance Bacopa monnieri (L) Wettst (common name, bacopa) is a medicinal plant used in Ayurveda, the traditional system of medicine of India, as a nootropic. It is considered to be a “medhya rasayana”, an herb that sharpens the mind and the intellect. Bacopa is an important ingredient in many Ayurvedic herbal formulations designed to treat conditions such as memory loss, anxiety, poor cognition and loss of concentration. It has also been used in Ayurveda to treat inflammatory conditions such as arthritis. In modern biomedical studies, bacopa has been shown in animal models to inhibit the release of the pro-inflammatory cytokines TNF-α and IL-6. However, less is known regarding the anti-inflammatory activity of Bacopa in the brain. Aim Of The Study The current study examines the ability of Bacopa to inhibit the release of pro-inflammatory cytokines from microglial cells, the immune cells of the brain that participate in inflammation in the CNS. The effect of Bacopa on signaling enzymes associated with CNS inflammatory pathways was also studied. Materials And Methods Various extracts of Bacopa were prepared and examined in the N9 microglial cell line in order to determine if they inhibited the release of the proinflammatory cytokines TNF-α and IL-6. Extracts were also tested in cell free assays as inhibitors of caspase-1 and matrix metalloproteinase-3 (enzymes associated with inflammation) and caspase-3, which has been shown to cleave protein Tau, an early event in the development of Alzheimer's disease. Results The tea, infusion, and alkaloid extracts of bacopa, as well as Bacoside A significantly inhibited the release of TNF-α and IL-6 from activated N9 microglial cells in vitro. In addition, the tea, infusion, and alkaloid extracts of Bacopa effectively inhibited caspase 1 and 3, and matrix metalloproteinase-3 in the cell free assay. Conclusions Bacopa inhibits the release of inflammatory cytokines from microglial cells and inhibits enzymes associated with inflammation in the brain. Thus, Bacopa can limit inflammation in the CNS, and offers a promising source of novel therapeutics for the treatment of many CNS disorders. PMID:27473605

Effects of pharmacological treatments on hippocampal NCAM1 and ERK2 expression in epileptic rats with cognitive dysfunction

PubMed Central

Kong, Qingxia; Min, Xia; Sun, Ran; Gao, Jianying; Liang, Ruqing; Li, Lei; Chu, Xu

2016-01-01

The present study aimed to investigate the effects of various pharmacological agents on the hippocampal expression of neural cell adhesion molecule 1 (NCAM1) and extracellular signal-regulated kinase 2 (ERK2) in epileptic rats with cognitive dysfunction. The experiments were conducted using 120 Wistar rats: 20 controls and 100 with pilocarpine-induced status epilepticus (SE). The SE rats were randomly assigned to 5 groups (n=20/group) that received daily treatments for 1 month with one of the following: (i) saline (no effect on epilepsy); (ii) carbamazepine (an anticonvulsant); (iii) oxcarbazepine (an anticonvulsant); (iv) aniracetam (a nootropic); or (v) donepezil (an acetylcholinesterase inhibitor). Spatial learning and memory were assessed using a Morris Water Maze (MWM). Hippocampal tissue was assessed for NCAM1 and ERK2 messenger RNA (mRNA) expression by reverse transcription polymerase chain reaction, and protein expression by immunochemistry. The results revealed that SE rats had significantly poorer MWM performances compared with controls (P<0.01). Performance in SE rats was improved with donepezil treatment (P<0.01), but declined with carbamazepine (P<0.01). Compared with controls, saline-treated SE rats exhibited increased hippocampal NCAM1 mRNA expression (P<0.01). Among SE rats, NCAM1 mRNA expression was highest in those treated with donepezil, followed by aniracetam-, saline-, oxcarbazepine- and carbamazepine-treated rats. Compared to controls, saline-treated SE rats exhibited decreased hippocampal ERK2 mRNA expression (P<0.01). Among SE rats, ERK2 mRNA expression was highest in those treated with donepezil, followed by aniracetam, saline, oxcarbazepine and carbamazepine. NCAM1 and ERK2 protein expression levels were parallel to those of the mRNA. In saline-treated SE rats, hippocampal ERK2 expression was decreased and NCAM1 expression was increased; thus, these two molecules may be involved in the impairment of spatial memory. Carbamazepine augmented this impairment, whereas donepezil was found to ameliorate the dysfunction associated with epilepsy. In conclusion, ERK2 and NCAM1 have significant roles in impairment of spatial memory in SE rats. Carbamazepine may increase this impairment, while donepezil may decrease this impairment. PMID:27588125

Effects of stevia on synaptic plasticity and NADPH oxidase level of CNS in conditions of metabolic disorders caused by fructose.

PubMed

Chavushyan, V A; Simonyan, K V; Simonyan, R M; Isoyan, A S; Simonyan, G M; Babakhanyan, M A; Hovhannisyian, L E; Nahapetyan, Kh H; Avetisyan, L G; Simonyan, M A

2017-12-19

Excess dietary fructose intake associated with metabolic syndrome and insulin resistance and increased risk of developing type 2 diabetes. Previous animal studies have reported that diabetic animals have significantly impaired behavioural and cognitive functions, pathological synaptic function and impaired expression of glutamate receptors. Correction of the antioxidant status of laboratory rodents largely prevents the development of fructose-induced plurimetabolic changes in the nervous system. We suggest a novel concept of efficiency of Stevia leaves for treatment of central diabetic neuropathy. By in vivo extracellular studies induced spike activity of hippocampal neurons during high frequency stimulation of entorhinal cortex, as well as neurons of basolateral amygdala to high-frequency stimulation of the hippocampus effects of Stevia rebaudiana Bertoni plant evaluated in synaptic activity in the brain of fructose-enriched diet rats. In the conditions of metabolic disorders caused by fructose, antioxidant activity of Stevia rebaudiana was assessed by measuring the NOX activity of the hippocampus, amygdala and spinal cord. In this study, the characteristic features of the metabolic effects of dietary fructose on synaptic plasticity in hippocampal neurons and basolateral amygdala and the state of the NADPH oxidase (NOX) oxidative system of these brain formations are revealed, as well as the prospects for development of multitarget and polyfunctional phytopreparations (with adaptogenic, antioxidant, antidiabetic, nootropic activity) from native raw material of Stevia rebaudiana. Stevia modulates degree of expressiveness of potentiation/depression (approaches but fails to achieve the norm) by shifting the percentage balance in favor of depressor type of responses during high-frequency stimulation, indicating its adaptogenic role in plasticity of neural networks. Under the action of fructose an increase (3-5 times) in specific quantity of total fraction of NOX isoforms isolated from the central nervous system tissue (amygdala, hippocampus, spinal cord) was revealed. Stevia exhibits an antistress, membrane-stabilizing role reducing the level of total fractions of NOX isoforms from central nervous system tissues and regulates NADPH-dependent O 2 - -producing activity. Generally, in condition of metabolic disorders caused by intensive consumption of dietary fructose Stevia leaves contributes to the control of neuronal synaptic plasticity possibly influencing the conjugated NOX-specific targets.

Piracetam for Aphasia in Post-stroke Patients: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

PubMed

Zhang, Jie; Wei, Ruili; Chen, Zhongqin; Luo, Benyan

2016-07-01

Aphasia is a common symptom in post-stroke patients. Piracetam is a commonly used nootropic agent that promises various benefits to brain function, including language improvement. We performed a systematic review and meta-analysis to assess whether piracetam facilitates the rehabilitation of language performance in post-stroke patients. Randomized controlled trials (RCTs) of piracetam treatment in post-stroke patients published in any language were included, excluding those involving pre-existing cognitive disorders such as dementia and mood disturbances. We searched several databases including PubMed, EMBASE, Cochrane Central, CINAHL, Web of Science, and PsycINFO for RCTs published up to 31 December 2015. We conducted a meta-analysis using RevMan (version 5.3), with standardized mean differences (SMDs) and fixed-effect models, and used StataSE (version 13) for the detection of publication bias. This study has been submitted to PROSPERO, and its registration number is CRD42016034088. We identified 1180 titles and abstracts, and finally included seven RCTs in this meta-analysis. The number of participants in each study ranged from 19 to 66, summing up to 261 patients overall. The dose of piracetam was consistent while the frequency and time of therapy varied. The assessment of the language at the end of trials showed no significant improvement in overall severity of aphasia [SMD 0.23, 95 % confidence interval (CI) -0.03 to 0.49, P = 0.08], but written language (SMD 0.35, 95 % CI 0.04 to 0.66, P = 0.03) showed pronounced improvement. Subgroup analyses indicated a dissociation of effectiveness between short- and long-term assessment in overall severity (P = 0.008, I (2) = 85.6 %) in terms of tests for subgroup differences, and a mild trend toward dissociation in written subtests (P = 0.30, I (2) = 5.1 %). Funnel plots and Egger's test identified no obvious publication bias in the primary variable. Piracetam plays a limited role in the rehabilitation of overall language impairment and only benefits written language ability at the end of trials. Its effect on overall linguistic level and written language tends to emerge within a short period and declines thereafter.

DrugBank: a knowledgebase for drugs, drug actions and drug targets

PubMed Central

Wishart, David S.; Knox, Craig; Guo, An Chi; Cheng, Dean; Shrivastava, Savita; Tzur, Dan; Gautam, Bijaya; Hassanali, Murtaza

2008-01-01

DrugBank is a richly annotated resource that combines detailed drug data with comprehensive drug target and drug action information. Since its first release in 2006, DrugBank has been widely used to facilitate in silico drug target discovery, drug design, drug docking or screening, drug metabolism prediction, drug interaction prediction and general pharmaceutical education. The latest version of DrugBank (release 2.0) has been expanded significantly over the previous release. With ∼4900 drug entries, it now contains 60% more FDA-approved small molecule and biotech drugs including 10% more ‘experimental’ drugs. Significantly, more protein target data has also been added to the database, with the latest version of DrugBank containing three times as many non-redundant protein or drug target sequences as before (1565 versus 524). Each DrugCard entry now contains more than 100 data fields with half of the information being devoted to drug/chemical data and the other half devoted to pharmacological, pharmacogenomic and molecular biological data. A number of new data fields, including food–drug interactions, drug–drug interactions and experimental ADME data have been added in response to numerous user requests. DrugBank has also significantly improved the power and simplicity of its structure query and text query searches. DrugBank is available at http://www.drugbank.ca PMID:18048412

Intravascular Drug Release Kinetics Dictate Arterial Drug Deposition, Retention, and Distribution

PubMed Central

Balakrishnan, Brinda; Dooley, John F.; Kopia, Gregory; Edelman, Elazer R.

2007-01-01

Millions of patients worldwide have received drug-eluting stents to reduce their risk for in-stent restenosis. The efficacy and toxicity of these local therapeutics depend upon arterial drug deposition, distribution, and retention. To examine how administered dose and drug release kinetics control arterial drug uptake, a model was created using principles of computational fluid dynamics and transient drug diffusion-convection. The modeling predictions for drug elution were validated using empiric data from stented porcine coronary arteries. Inefficient, minimal arterial drug deposition was predicted when a bolus of drug was released and depleted within seconds. Month-long stent-based drug release efficiently delivered nearly continuous drug levels, but the slow rate of drug presentation limited arterial drug uptake. Uptake was only maximized when the rates of drug release and absorption matched, which occurred for hour-long drug release. Of the two possibly means for increasing the amount of drug on the stent, modulation of drug concentration potently impacts the magnitude of arterial drug deposition, while changes in coating drug mass affect duration of release. We demonstrate the importance of drug release kinetics and administered drug dose in governing arterial drug uptake and suggest novel drug delivery strategies for controlling spatio-temporal arterial drug distribution. PMID:17868948

Drug-disease and drug-drug interactions: systematic examination of recommendations in 12 UK national clinical guidelines.

PubMed

Dumbreck, Siobhan; Flynn, Angela; Nairn, Moray; Wilson, Martin; Treweek, Shaun; Mercer, Stewart W; Alderson, Phil; Thompson, Alex; Payne, Katherine; Guthrie, Bruce

2015-03-11

To identify the number of drug-disease and drug-drug interactions for exemplar index conditions within National Institute of Health and Care Excellence (NICE) clinical guidelines. Systematic identification, quantification, and classification of potentially serious drug-disease and drug-drug interactions for drugs recommended by NICE clinical guidelines for type 2 diabetes, heart failure, and depression in relation to 11 other common conditions and drugs recommended by NICE guidelines for those conditions. NICE clinical guidelines for type 2 diabetes, heart failure, and depression Potentially serious drug-disease and drug-drug interactions. Following recommendations for prescription in 12 national clinical guidelines would result in several potentially serious drug interactions. There were 32 potentially serious drug-disease interactions between drugs recommended in the guideline for type 2 diabetes and the 11 other conditions compared with six for drugs recommended in the guideline for depression and 10 for drugs recommended in the guideline for heart failure. Of these drug-disease interactions, 27 (84%) in the type 2 diabetes guideline and all of those in the two other guidelines were between the recommended drug and chronic kidney disease. More potentially serious drug-drug interactions were identified between drugs recommended by guidelines for each of the three index conditions and drugs recommended by the guidelines for the 11 other conditions: 133 drug-drug interactions for drugs recommended in the type 2 diabetes guideline, 89 for depression, and 111 for heart failure. Few of these drug-disease or drug-drug interactions were highlighted in the guidelines for the three index conditions. Drug-disease interactions were relatively uncommon with the exception of interactions when a patient also has chronic kidney disease. Guideline developers could consider a more systematic approach regarding the potential for drug-disease interactions, based on epidemiological knowledge of the comorbidities of people with the disease the guideline is focused on, and should particularly consider whether chronic kidney disease is common in the target population. In contrast, potentially serious drug-drug interactions between recommended drugs for different conditions were common. The extensive number of potentially serious interactions requires innovative interactive approaches to the production and dissemination of guidelines to allow clinicians and patients with multimorbidity to make informed decisions about drug selection. © Dumbreck et al 2015.

Drug interactions evaluation: An integrated part of risk assessment of therapeutics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Lei; Reynolds, Kellie S.; Zhao, Ping

2010-03-01

Pharmacokinetic drug interactions can lead to serious adverse events or decreased drug efficacy. The evaluation of a new molecular entity's (NME's) drug-drug interaction potential is an integral part of risk assessment during drug development and regulatory review. Alteration of activities of enzymes or transporters involved in the absorption, distribution, metabolism, or excretion of a new molecular entity by concomitant drugs may alter drug exposure, which can impact response (safety or efficacy). The recent Food and Drug Administration (FDA) draft drug interaction guidance ( (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072101.pdf)) highlights the methodologies and criteria that may be used to guide drug interaction evaluation by industrymore » and regulatory agencies and to construct informative labeling for health practitioner and patients. In addition, the Food and Drug Administration established a 'Drug Development and Drug Interactions' website to provide up-to-date information regarding evaluation of drug interactions ( (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm)). This review summarizes key elements in the FDA drug interaction guidance and new scientific developments that can guide the evaluation of drug-drug interactions during the drug development process.« less

Projecting future drug expenditures--2009.

PubMed

Hoffman, James M; Shah, Nilay D; Vermeulen, Lee C; Doloresco, Fred; Martin, Patrick K; Blake, Sharon; Matusiak, Linda; Hunkler, Robert J; Schumock, Glen T

2009-02-01

Drug expenditure trends in 2007 and 2008, projected drug expenditures for 2009, and factors likely to influence drug expenditures are discussed. Various factors are likely to influence drug expenditures in 2009, including drugs in development, the diffusion of new drugs, drug safety concerns, generic drugs, Medicare Part D, and changes in the drug supply chain. The increasing availability of important generic drugs and drug safety concerns continue to moderate growth in drug expenditures. The drug supply chain remains dynamic and may influence drug expenditures, particularly in specialized therapeutic areas. Initial data suggest that the Medicare Part D benefit has influenced drug expenditures, but the ultimate impact of the benefit on drug expenditures remains unclear. From 2006 to 2007, total U.S. drug expenditures increased by 4.0%, with total spending rising from $276 billion to $287 billion. Drug expenditures in clinics continue to grow more rapidly than in other settings, with a 9.9% increase from 2006 to 2007. Hospital drug expenditures increased at a moderate rate of only 1.6% from 2006 to 2007; through the first nine months of 2008, hospital drug expenditures increased by only 2.8% compared with the same period in 2007. In 2009, we project a 0-2% increase in drug expenditures in outpatient settings, a 1-3% increase in expenditures for clinic-administered drugs, and a 1-3% increase in hospital drug expenditures.

21 CFR 201.129 - Drugs; exemption for radioactive drugs for research use.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 4 2010-04-01 2010-04-01 false Drugs; exemption for radioactive drugs for research use. 201.129 Section 201.129 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... Drugs; exemption for radioactive drugs for research use. A radioactive drug intended for administration...

Injection drug users’ involvement in drug dealing in the downtown eastside of Vancouver: Social organization and systemic violence

PubMed Central

Small, Will; Maher, Lisa; Lawlor, Jeff; Wood, Evan; Shannon, Kate; Kerr, Thomas

2014-01-01

Background Illicit drug markets are a key component of the risk environment surrounding injection drug use. However, relatively few studies have explored how injection drug users’ (IDUs) involvement in drug dealing shapes their experiences of drug market-related harm. This exploratory qualitative study aims to understand IDUs’ dealing activities and roles, as well as the perceived benefits and risks related to participation in illicit drug markets, including experiences of drug market violence. Methods Ten IDUs with extensive involvement in drug dealing activities were recruited from the Vancouver Injection Drug User Study (VIDUS) and participated in semi-structured qualitative interviews, which elicited discussion of experiences dealing drugs, perceived benefits and hazards related to dealing, and understandings of drug market violence. Results Participant's involvement in drug market activities included corporate sales, freelance or independent sales, and opportunistic sales termed “middling” as well as drug market-related hustles entailing selling bogus drugs and robbing dealers. Participants primarily dealt drugs to support their own illicit drug use, and we found that arrest and criminal justice involvement, hazards stemming from drug debts, and drug market-related violence were key risks related to dealing activities. Conclusion The challenges of managing personal consumption while selling drugs exacerbates the hazards associated with drug dealing. Efforts to address drug dealing among IDUs should consider both drug dependency and the material conditions that propel drug users towards dealing activities. Interventions should explore the potential of combining enhanced drug treatment programs with low threshold employment and alternative income generation opportunities. PMID:23664788

Herb-drug, food-drug, nutrient-drug, and drug-drug interactions: mechanisms involved and their medical implications.

PubMed

Sørensen, Janina Maria

2002-06-01

Adverse drug reactions (ADRs) and iatrogenic diseases have been identified as significant factors responsible for patient morbidity and mortality. Significant studies on drug metabolism in humans have been published during the last few years, offering a deeper comprehension of the mechanisms underlying adverse drug reactions and interactions. More understanding of these mechanisms, and of recent advances in laboratory technology, can help to evaluate potential drug interactions when drugs are prescribed concurrently. Increasing knowledge of interindividual variation in drug breakdown capacity and recent findings concerning the influence of environment, diet, nutrients, and herbal products can be used to reduce ADRs and iatrogenic diseases. Reviewed data suggest that drug treatment should be increasingly custom tailored to suit the individual patient and that appropriately co-prescribed diet and herbal remedies, could increase drug efficacy and lessen drug toxicity. This review focuses mainly on recently published research material. The cytochrome p450 enzymes, their role in metabolism, and their mechanisms of action are reviewed, and their role in drug-drug interactions are discussed. Drug-food and drug-herb interactions have garnered attention. Interdisciplinary communication among medical herbalists, medical doctors, and dietetic experts needs to be improved and encouraged. Internet resources for obtaining current information regarding drug-drug, drug-herb, and drug-nutrient interactions are provided.

21 CFR 201.2 - Drugs and devices; National Drug Code numbers.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 4 2014-04-01 2014-04-01 false Drugs and devices; National Drug Code numbers. 201.2 Section 201.2 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL LABELING General Labeling Provisions § 201.2 Drugs and devices; National Drug Code...

21 CFR 201.2 - Drugs and devices; National Drug Code numbers.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 4 2012-04-01 2012-04-01 false Drugs and devices; National Drug Code numbers. 201.2 Section 201.2 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL LABELING General Labeling Provisions § 201.2 Drugs and devices; National Drug Code...

21 CFR 201.2 - Drugs and devices; National Drug Code numbers.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 4 2011-04-01 2011-04-01 false Drugs and devices; National Drug Code numbers. 201.2 Section 201.2 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL LABELING General Labeling Provisions § 201.2 Drugs and devices; National Drug Code...

21 CFR 201.2 - Drugs and devices; National Drug Code numbers.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 4 2013-04-01 2013-04-01 false Drugs and devices; National Drug Code numbers. 201.2 Section 201.2 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL LABELING General Labeling Provisions § 201.2 Drugs and devices; National Drug Code...

21 CFR 201.2 - Drugs and devices; National Drug Code numbers.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 4 2010-04-01 2010-04-01 false Drugs and devices; National Drug Code numbers. 201.2 Section 201.2 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL LABELING General Labeling Provisions § 201.2 Drugs and devices; National Drug Code...

Therapeutic effects of drug-nutrient interactions in the elderly.

PubMed

Roe, D A

1985-02-01

The elderly are the major drug users both because they need specific prescription drugs for control of chronic diseases and because they make excessive use of over-the-counter (OTC) drugs. Therapeutic drugs that are required may be discontinued because the individuals suffer side effects or because the drug is ineffective. Adverse drug reactions in the elderly may result from drug overuse or misuse, slowed drug metabolism or elimination secondary to aging or to age-related chronic disease, intake of alcohol, food-drug incompatibilities, or nutrient-drug interactions. The timing of drug intake in relation to food intake is an important determinant of therapeutic efficacy in the elderly. Food-drug interactions in the gastrointestinal tract may reduce drug absorption. Enteral formula feeding may also interfere with drug absorption. Conversely, absorption of certain drugs (e.g., thiazides) may be promoted by meal-induced slowing of gastric emptying time. Therapeutic diet prescription can influence drug responses in the elderly because the protein composition of the diet influences the rate of drug metabolism. Nutrient depletion secondary to the effect of drugs may be recognized as an important and often avoidable type of adverse drug reaction.

Substance use - prescription drugs

MedlinePlus

Substance use disorder - prescription drugs; Substance abuse - prescription drugs; Drug abuse - prescription drugs; Drug use - prescription drugs; Narcotics - substance use; Opioid - substance use; Sedative - substance ...

Drugs@FDA: FDA Approved Drug Products

MedlinePlus

... Cosmetics Tobacco Products Home Drug Databases Drugs@FDA Drugs@FDA: FDA Approved Drug Products Share Tweet Linkedin Pin it More sharing ... Download Drugs@FDA Express for free Search by Drug Name, Active Ingredient, or Application Number Enter at ...

Controlling and policing substance use(rs).

PubMed

White, Tony

2002-01-01

Controlling drug use--a dynamic, global, politicalized process--is reviewed in terms of selected types of drugs, "natural levels" of drug demand and use, drug markets and the drug market environment, types of traffickers, illicit drug trade profits, approaches to drug control ("War on Drugs", "Zero Tolerance" programs and policies, "normalizing" and legalizing selected drugs), including UN's then relatively recent "Balanced Approach" and facets of drug law enforcement (drug prices and purity levels and values of drug seizures), including various rarely noted benefits to intervention programs and control agents. Unresolved issues and needed "tools" are noted while considering the implications of the first UN's World Drug Report data.

DrugBank 3.0: a comprehensive resource for ‘Omics’ research on drugs

PubMed Central

Knox, Craig; Law, Vivian; Jewison, Timothy; Liu, Philip; Ly, Son; Frolkis, Alex; Pon, Allison; Banco, Kelly; Mak, Christine; Neveu, Vanessa; Djoumbou, Yannick; Eisner, Roman; Guo, An Chi; Wishart, David S.

2011-01-01

DrugBank (http://www.drugbank.ca) is a richly annotated database of drug and drug target information. It contains extensive data on the nomenclature, ontology, chemistry, structure, function, action, pharmacology, pharmacokinetics, metabolism and pharmaceutical properties of both small molecule and large molecule (biotech) drugs. It also contains comprehensive information on the target diseases, proteins, genes and organisms on which these drugs act. First released in 2006, DrugBank has become widely used by pharmacists, medicinal chemists, pharmaceutical researchers, clinicians, educators and the general public. Since its last update in 2008, DrugBank has been greatly expanded through the addition of new drugs, new targets and the inclusion of more than 40 new data fields per drug entry (a 40% increase in data ‘depth’). These data field additions include illustrated drug-action pathways, drug transporter data, drug metabolite data, pharmacogenomic data, adverse drug response data, ADMET data, pharmacokinetic data, computed property data and chemical classification data. DrugBank 3.0 also offers expanded database links, improved search tools for drug–drug and food–drug interaction, new resources for querying and viewing drug pathways and hundreds of new drug entries with detailed patent, pricing and manufacturer data. These additions have been complemented by enhancements to the quality and quantity of existing data, particularly with regard to drug target, drug description and drug action data. DrugBank 3.0 represents the result of 2 years of manual annotation work aimed at making the database much more useful for a wide range of ‘omics’ (i.e. pharmacogenomic, pharmacoproteomic, pharmacometabolomic and even pharmacoeconomic) applications. PMID:21059682

Do drug prices reflect development time and government investment?

PubMed

Keyhani, Salomeh; Diener-West, Marie; Powe, Neil

2005-08-01

Lengthy development times are cited by the pharmaceutical industry as one reason for high drug prices. We compared the prices of different groups of drugs after accounting for development time, government support, market size, and other drug characteristics. We conducted a retrospective study of 180 human therapeutic drugs categorized into 8 drug groups by assembling data on drug development times, government support, drug characteristics, and prices. First, we compared the development time and level of government support across the 8 drug groups. Second, we assessed the independent effect of drug group on median price per day in a multivariable analysis, controlling for development time and all other variables. Thirty percent of antiretroviral drugs had government patents compared with 16% of other infectious disease drugs, 6% of cancer drugs, and less than 6% of any other drug group (P < 0.002). Fifty percent of antiretrovirals had NIH trials listed in the new drug application for approval by the Food and Drug Administration compared with less than 6% of any other drug group (P < 0.001). More antiretroviral and cancer drugs received fast track status and accelerated review during regulatory review by the Food and Drug Administration (P < 0.001). The median price of antiretrovirals was 8 US dollars per day more, cancer drugs 11 US dollars per day more, than the reference group after adjustment for other variables (P < 0.001). Development time was not associated with drug price. Antiretroviral and cancer drugs, even after accounting for development time, are among the most highly priced medications. Notably, drugs with rapid development and more government support did not have lower drug prices.

21 CFR 316.24 - Granting orphan-drug designation.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Granting orphan-drug designation. 316.24 Section 316.24 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.24 Granting orphan-drug designation...

21 CFR 316.24 - Granting orphan-drug designation.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Granting orphan-drug designation. 316.24 Section 316.24 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.24 Granting orphan-drug designation...

21 CFR 316.24 - Granting orphan-drug designation.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Granting orphan-drug designation. 316.24 Section 316.24 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.24 Granting orphan-drug designation...

21 CFR 316.24 - Granting orphan-drug designation.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Granting orphan-drug designation. 316.24 Section 316.24 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.24 Granting orphan-drug designation...

21 CFR 310.502 - Certain drugs accorded new drug status through rulemaking procedures.

Code of Federal Regulations, 2010 CFR

2010-04-01

... for human use. (10) Parenteral drug products in plastic containers. (11) Sterilization of drugs by... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Certain drugs accorded new drug status through rulemaking procedures. 310.502 Section 310.502 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF...

21 CFR 310.502 - Certain drugs accorded new drug status through rulemaking procedures.

Code of Federal Regulations, 2014 CFR

2014-04-01

... for human use. (10) Parenteral drug products in plastic containers. (11) Sterilization of drugs by... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Certain drugs accorded new drug status through rulemaking procedures. 310.502 Section 310.502 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF...

21 CFR 310.502 - Certain drugs accorded new drug status through rulemaking procedures.

Code of Federal Regulations, 2013 CFR

2013-04-01

... for human use. (10) Parenteral drug products in plastic containers. (11) Sterilization of drugs by... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Certain drugs accorded new drug status through rulemaking procedures. 310.502 Section 310.502 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF...

21 CFR 310.502 - Certain drugs accorded new drug status through rulemaking procedures.

Code of Federal Regulations, 2011 CFR

2011-04-01

... for human use. (10) Parenteral drug products in plastic containers. (11) Sterilization of drugs by... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Certain drugs accorded new drug status through rulemaking procedures. 310.502 Section 310.502 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF...

21 CFR 310.502 - Certain drugs accorded new drug status through rulemaking procedures.

Code of Federal Regulations, 2012 CFR

2012-04-01

... for human use. (10) Parenteral drug products in plastic containers. (11) Sterilization of drugs by... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Certain drugs accorded new drug status through rulemaking procedures. 310.502 Section 310.502 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF...

Projecting future drug expenditures--2010.

PubMed

Hoffman, James M; Doloresco, Fred; Vermeulen, Lee C; Shah, Nilay D; Matusiak, Linda; Hunkler, Robert J; Schumock, Glen T

2010-06-01

Drug expenditure trends in 2008 and 2009, projected drug expenditures for 2010, and factors likely to influence drug expenditures are discussed. Various factors are likely to influence drug expenditures in 2010, including drugs in development, the diffusion of new drugs, generic drugs, health care reform, drug safety concerns, and comparative effectiveness research. The increasing availability of important generic drugs continues to moderate growth in drug expenditures. Health care reform initiatives, including the potential for biosimilars legislation, will influence drug expenditures in all settings. From 2007 to 2008, total U.S. drug expenditures increased by 1.8%, with total spending rising from $279.6 billion to $284.7 billion. Growth in drug expenditures in clinics declined to the lowest level in a decade, a 1.0% increase from 2007 to 2008. Hospital drug expenditures increased at a moderate rate of only 2.1% from 2007 to 2008; through the first nine months of 2009, hospital drug expenditures increased by 3.0% compared with the same period in 2008. In 2010, we project a 3-5% increase in drug expenditures in outpatient settings, a 6-8% increase in expenditures for clinic-administered drugs, and a 2-4% increase in hospital drug expenditures.

e-Drug3D: 3D structure collections dedicated to drug repurposing and fragment-based drug design.

PubMed

Pihan, Emilie; Colliandre, Lionel; Guichou, Jean-François; Douguet, Dominique

2012-06-01

In the drug discovery field, new uses for old drugs, selective optimization of side activities and fragment-based drug design (FBDD) have proved to be successful alternatives to high-throughput screening. e-Drug3D is a database of 3D chemical structures of drugs that provides several collections of ready-to-screen SD files of drugs and commercial drug fragments. They are natural inputs in studies dedicated to drug repurposing and FBDD. e-Drug3D collections are freely available at http://chemoinfo.ipmc.cnrs.fr/e-drug3d.html either for download or for direct in silico web-based screenings.

21 CFR 201.115 - New drugs or new animal drugs.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 4 2013-04-01 2013-04-01 false New drugs or new animal drugs. 201.115 Section 201.115 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL LABELING Exemptions From Adequate Directions for Use § 201.115 New drugs or new animal...

21 CFR 201.115 - New drugs or new animal drugs.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 4 2011-04-01 2011-04-01 false New drugs or new animal drugs. 201.115 Section 201.115 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL LABELING Exemptions From Adequate Directions for Use § 201.115 New drugs or new animal...

21 CFR 201.115 - New drugs or new animal drugs.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 4 2014-04-01 2014-04-01 false New drugs or new animal drugs. 201.115 Section 201.115 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL LABELING Exemptions From Adequate Directions for Use § 201.115 New drugs or new animal...

21 CFR 201.115 - New drugs or new animal drugs.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 4 2012-04-01 2012-04-01 false New drugs or new animal drugs. 201.115 Section 201.115 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL LABELING Exemptions From Adequate Directions for Use § 201.115 New drugs or new animal...

21 CFR 201.115 - New drugs or new animal drugs.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 4 2010-04-01 2010-04-01 false New drugs or new animal drugs. 201.115 Section 201.115 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL LABELING Exemptions From Adequate Directions for Use § 201.115 New drugs or new animal...

DrugBank 4.0: shedding new light on drug metabolism.

PubMed

Law, Vivian; Knox, Craig; Djoumbou, Yannick; Jewison, Tim; Guo, An Chi; Liu, Yifeng; Maciejewski, Adam; Arndt, David; Wilson, Michael; Neveu, Vanessa; Tang, Alexandra; Gabriel, Geraldine; Ly, Carol; Adamjee, Sakina; Dame, Zerihun T; Han, Beomsoo; Zhou, You; Wishart, David S

2014-01-01

DrugBank (http://www.drugbank.ca) is a comprehensive online database containing extensive biochemical and pharmacological information about drugs, their mechanisms and their targets. Since it was first described in 2006, DrugBank has rapidly evolved, both in response to user requests and in response to changing trends in drug research and development. Previous versions of DrugBank have been widely used to facilitate drug and in silico drug target discovery. The latest update, DrugBank 4.0, has been further expanded to contain data on drug metabolism, absorption, distribution, metabolism, excretion and toxicity (ADMET) and other kinds of quantitative structure activity relationships (QSAR) information. These enhancements are intended to facilitate research in xenobiotic metabolism (both prediction and characterization), pharmacokinetics, pharmacodynamics and drug design/discovery. For this release, >1200 drug metabolites (including their structures, names, activity, abundance and other detailed data) have been added along with >1300 drug metabolism reactions (including metabolizing enzymes and reaction types) and dozens of drug metabolism pathways. Another 30 predicted or measured ADMET parameters have been added to each DrugCard, bringing the average number of quantitative ADMET values for Food and Drug Administration-approved drugs close to 40. Referential nuclear magnetic resonance and MS spectra have been added for almost 400 drugs as well as spectral and mass matching tools to facilitate compound identification. This expanded collection of drug information is complemented by a number of new or improved search tools, including one that provides a simple analyses of drug-target, -enzyme and -transporter associations to provide insight on drug-drug interactions.

The anti-hepatitis drug use effect and inventory management optimization from the perspective of hospital drug supply chain.

PubMed

Liu, Zhanyu

2017-09-01

By analyzing the current hospital anti hepatitis drug use, dosage, indications and drug resistance, this article studied the drug inventory management and cost optimization. The author used drug utilization evaluation method, analyzed the amount and kind distribution of anti hepatitis drugs and made dynamic monitoring of inventory. At the same time, the author puts forward an effective scheme of drug classification management, uses the ABC classification method to classify the drugs according to the average daily dose of drugs, and implements the automatic replenishment plan. The design of pharmaceutical services supply chain includes drug procurement platform, warehouse management system and connect to the hospital system through data exchange. Through the statistical analysis of drug inventory, we put forward the countermeasures of drug logistics optimization. The results showed that drug replenishment plan can effectively improve drugs inventory efficiency.

Examining the effects of mass media campaign exposure and interpersonal discussions on youth's drug use: the mediating role of visiting pro-drug websites.

PubMed

Kam, Jennifer A; Lee, Chul-Joo

2013-01-01

To extend past research on interpersonal communication and campaign effects, we hypothesized that anti-drug mass media campaign message exposure indirectly affects visiting anti- and pro-drug websites through targeted parent-child and friend-to-friend communication against drugs, as well as through having drug-related discussions during organized group activities. Second, we posited that engaging in anti-drug interpersonal communication indirectly affects adolescents' drug use through two intervening variables: visiting anti-drug websites and visiting pro-drug websites. Using self-reported longitudinal data from 2,749 youth, we found that as youth reported higher levels of anti-drug mass media campaign message exposure, they were more likely to talk to friends about the bad consequences of drugs, how to avoid drugs, and anti-drug ads. In turn, however, they were more likely to visit pro-drug websites, and subsequently, to smoke cigarettes.

Black Youths and Illegal Drugs.

ERIC Educational Resources Information Center

Joseph, Janice; Pearson, Patricia G.

2002-01-01

Examines the effect of drugs on black youths, discussing different types of drug involvement, reasons for drug involvement, extent and nature of involvement, drugs and crime, drugs and health issues, drug control strategies, and prevention. Policy implications include prioritizing drug prevention among black youths, providing alternatives to drug…

A Memory Retrieval-Extinction Procedure to Prevent Drug Craving and Relapse

PubMed Central

Xue, Yan-Xue; Luo, Yi-Xiao; Wu, Ping; Shi, Hai-Shui; Xue, Li-Fen; Chen, Chen; Zhu, Wei-Li; Ding, Zeng-Bo; Bao, Yan-ping; Shi, Jie; Epstein, David H.; Shaham, Yavin; Lu, Lin

2013-01-01

Drug use and relapse involve learned associations between drug-associated environmental cues and drug effects. Extinction procedures in the clinic can suppress conditioned responses to drug cues, but the extinguished responses typically reemerge after exposure to the drug itself (reinstatement), the drug-associated environment (renewal), or the passage of time (spontaneous recovery). We describe a memory retrieval-extinction procedure that decreases conditioned drug effects and drug seeking in rat models of relapse, and drug craving in abstinent heroin addicts. In rats, daily retrieval of drug-associated memories 10 minutes or 1 hour but not 6 hours before extinction sessions attenuated drug-induced reinstatement, spontaneous recovery, and renewal of conditioned drug effects and drug seeking. In heroin addicts, retrieval of drug-associated memories 10 minutes before extinction sessions attenuated cue-induced heroin craving 1, 30, and 180 days later. The memory retrieval-extinction procedure is a promising nonpharmacological method for decreasing drug craving and relapse during abstinence. PMID:22499948

Exploring drug-target interaction networks of illicit drugs.

PubMed

Atreya, Ravi V; Sun, Jingchun; Zhao, Zhongming

2013-01-01

Drug addiction is a complex and chronic mental disease, which places a large burden on the American healthcare system due to its negative effects on patients and their families. Recently, network pharmacology is emerging as a promising approach to drug discovery by integrating network biology and polypharmacology, allowing for a deeper understanding of molecular mechanisms of drug actions at the systems level. This study seeks to apply this approach for investigation of illicit drugs and their targets in order to elucidate their interaction patterns and potential secondary drugs that can aid future research and clinical care. In this study, we extracted 188 illicit substances and their related information from the DrugBank database. The data process revealed 86 illicit drugs targeting a total of 73 unique human genes, which forms an illicit drug-target network. Compared to the full drug-target network from DrugBank, illicit drugs and their target genes tend to cluster together and form four subnetworks, corresponding to four major medication categories: depressants, stimulants, analgesics, and steroids. External analysis of Anatomical Therapeutic Chemical (ATC) second sublevel classifications confirmed that the illicit drugs have neurological functions or act via mechanisms of stimulants, opioids, and steroids. To further explore other drugs potentially having associations with illicit drugs, we constructed an illicit-extended drug-target network by adding the drugs that have the same target(s) as illicit drugs to the illicit drug-target network. After analyzing the degree and betweenness of the network, we identified hubs and bridge nodes, which might play important roles in the development and treatment of drug addiction. Among them, 49 non-illicit drugs might have potential to be used to treat addiction or have addictive effects, including some results that are supported by previous studies. This study presents the first systematic review of the network characteristics of illicit drugs, their targets, and other drugs that share the targets of these illicit drugs. The results, though preliminary, provide some novel insights into the molecular mechanisms of drug addiction. The observation of illicit-related drugs, with partial verification from previous studies, demonstrated that the network-assisted approach is promising for the identification of drug repositioning.

Exploring drug-target interaction networks of illicit drugs

PubMed Central

2013-01-01

Background Drug addiction is a complex and chronic mental disease, which places a large burden on the American healthcare system due to its negative effects on patients and their families. Recently, network pharmacology is emerging as a promising approach to drug discovery by integrating network biology and polypharmacology, allowing for a deeper understanding of molecular mechanisms of drug actions at the systems level. This study seeks to apply this approach for investigation of illicit drugs and their targets in order to elucidate their interaction patterns and potential secondary drugs that can aid future research and clinical care. Results In this study, we extracted 188 illicit substances and their related information from the DrugBank database. The data process revealed 86 illicit drugs targeting a total of 73 unique human genes, which forms an illicit drug-target network. Compared to the full drug-target network from DrugBank, illicit drugs and their target genes tend to cluster together and form four subnetworks, corresponding to four major medication categories: depressants, stimulants, analgesics, and steroids. External analysis of Anatomical Therapeutic Chemical (ATC) second sublevel classifications confirmed that the illicit drugs have neurological functions or act via mechanisms of stimulants, opioids, and steroids. To further explore other drugs potentially having associations with illicit drugs, we constructed an illicit-extended drug-target network by adding the drugs that have the same target(s) as illicit drugs to the illicit drug-target network. After analyzing the degree and betweenness of the network, we identified hubs and bridge nodes, which might play important roles in the development and treatment of drug addiction. Among them, 49 non-illicit drugs might have potential to be used to treat addiction or have addictive effects, including some results that are supported by previous studies. Conclusions This study presents the first systematic review of the network characteristics of illicit drugs, their targets, and other drugs that share the targets of these illicit drugs. The results, though preliminary, provide some novel insights into the molecular mechanisms of drug addiction. The observation of illicit-related drugs, with partial verification from previous studies, demonstrated that the network-assisted approach is promising for the identification of drug repositioning. PMID:24268016

Potential drug-drug interactions between anti-cancer agents and community pharmacy dispensed drugs.

PubMed

Voll, Marsha L; Yap, Kim D; Terpstra, Wim E; Crul, Mirjam

2010-10-01

To identify the prevalence of potential drug-drug interactions between hospital pharmacy dispensed anti-cancer agents and community pharmacy dispensed drugs. A retrospective cohort study was conducted on the haematology/oncology department of the internal medicine ward in a large teaching hospital in Amsterdam, the Netherlands. Prescription data from the last 100 patients treated with anti-cancer agents were obtained from Paracelsus, the chemotherapy prescribing system in the hospital. The community pharmacy dispensed drugs of these patients were obtained by using OZIS, a system that allows regionally linked pharmacies to call up active medication on any patient. Both medication lists were manually screened for potential drug-drug interactions by using several information sources on interactions, e.g. Pubmed, the Flockhart P450 table, Micromedex and Dutch reference books. Prevalence of potential drug-drug interactions between anti-cancer agents provided by the hospital pharmacy and drugs dispensed by the community pharmacy. Ninety-one patients were included in the study. A total of 31 potential drug-drug interactions were found in 16 patients, of which 15 interactions were clinically relevant and would have required an intervention. Of these interactions 1 had a level of severity ≥ D, meaning the potential drug-drug interaction could lead to long lasting or permanent damage, or even death. The majority of the interactions requiring an intervention (67%) had a considerable level of evidence (≥ 2) and were based on well-documented case reports or controlled interaction studies. Most of the potential drug-drug interactions involved the antiretroviral drugs (40%), proton pump inhibitors (20%) and antibiotics (20%). The anti-cancer drug most involved in the drug-drug interactions is methotrexate (33%). This study reveals a high prevalence of potential drug-drug interactions between anti-cancer agents provided by the hospital pharmacy and drugs dispensed by the community pharmacy. It shows us there is need for an optimal medication surveillance mechanism to detect potential drug-drug interactions between these two groups of medication, especially because of the high toxicity of anticancer drugs and thus the severe consequences these interactions can have for the patient.

The new pattern of drug abuse in China.

PubMed

Sun, Hong-qiang; Bao, Yan-ping; Zhou, Shuang-jiang; Meng, Shi-qiu; Lu, Lin

2014-07-01

Drug abuse has resulted in a huge burden on public health and the economy in China. Since the reemergence of drug abuse in China in the 1980s, the number of drug addicts has increased dramatically, especially the proportion of users of synthetic drugs, such as amphetamine-type stimulant (ATS). Further, the proportion of opiate addicts has decreased among the new initiates. This review describes the new pattern of drug abuse and the resultant intervention strategy in China. The demographics regarding drug abuse in China point to a trend of younger users, and indicate that Internet and telephone are facilitating drug trafficking. Furthermore, polydrug use is common. Many heroin addicts have used ATS and other synthetic drugs, and some synthetic drug abusers have used opiate drugs too. HIV infection and psychosis comorbidity are primarily associated with drug abuse in China. Although opiate drug use and its associated harm have been controlled effectively in some areas, the synthetic drugs and new designer drugs have complicated the drug abuse scene. A national system of management and intervention for synthetic drugs and associated diseases urgently needs to be established in China.

21 CFR 1310.11 - Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 9 2014-04-01 2014-04-01 false Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. 1310.11 Section 1310.11 Food and Drugs DRUG ENFORCEMENT... Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. (a) The...

21 CFR 1310.10 - Removal of the exemption of drugs distributed under the Food, Drug and Cosmetic Act.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 9 2011-04-01 2011-04-01 false Removal of the exemption of drugs distributed under the Food, Drug and Cosmetic Act. 1310.10 Section 1310.10 Food and Drugs DRUG ENFORCEMENT... Removal of the exemption of drugs distributed under the Food, Drug and Cosmetic Act. (a) The Administrator...

21 CFR 1310.11 - Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 9 2013-04-01 2013-04-01 false Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. 1310.11 Section 1310.11 Food and Drugs DRUG ENFORCEMENT... Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. (a) The...

21 CFR 1310.11 - Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 9 2012-04-01 2012-04-01 false Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. 1310.11 Section 1310.11 Food and Drugs DRUG ENFORCEMENT... Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. (a) The...

21 CFR 1310.10 - Removal of the exemption of drugs distributed under the Food, Drug and Cosmetic Act.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Removal of the exemption of drugs distributed under the Food, Drug and Cosmetic Act. 1310.10 Section 1310.10 Food and Drugs DRUG ENFORCEMENT... Removal of the exemption of drugs distributed under the Food, Drug and Cosmetic Act. (a) The Administrator...

21 CFR 1310.11 - Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 9 2011-04-01 2011-04-01 false Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. 1310.11 Section 1310.11 Food and Drugs DRUG ENFORCEMENT... Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. (a) The...

Influence of drug colour on perceived drug effects and efficacy.

PubMed

Tao, Da; Wang, Tieyan; Wang, Tieshan; Qu, Xingda

2018-02-01

A drug's physical characteristics, such as colour, could be factors influencing its therapeutic effects. It is not well understood whether people's expectations on drug effects and efficacy are affected by colour, especially among Chinese population. This study was conducted to examine people's expectations on drug effects and efficacy on the basis of drug colour, and to reveal possible gender differences in colour-related drug expectations. Participants (n = 224) were asked to classify seven single-coloured and six two-coloured capsules into one of four categories of drug effects, and to indicate the strength of drug efficacy. It is found that all the coloured capsules yielded non-chance distributions in classifications of drug effects, with six single-coloured and four two-coloured capsules associated with specific drug effects. Colour also conveyed differential strengths of drug efficacy in general and in relation to specific drug effects. There were gender differences in drug expectations for some colours and colour combinations. Practitioner Summary: Drug colour was found to have impacts on perceived drug effects and efficacy. The findings from the present study can be used by ergonomics practitioners to design appropriate drug colours in support of drug differentiation, therapeutic effects and medication adherence.

Drug-loaded electrospun mats of poly(vinyl alcohol) fibres and their release characteristics of four model drugs

NASA Astrophysics Data System (ADS)

Taepaiboon, Pattama; Rungsardthong, Uracha; Supaphol, Pitt

2006-05-01

Mats of PVA nanofibres were successfully prepared by the electrospinning process and were developed as carriers of drugs for a transdermal drug delivery system. Four types of non-steroidal anti-inflammatory drug with varying water solubility property, i.e. sodium salicylate (freely soluble in water), diclofenac sodium (sparingly soluble in water), naproxen (NAP), and indomethacin (IND) (both insoluble in water), were selected as model drugs. The morphological appearance of the drug-loaded electrospun PVA mats depended on the nature of the model drugs. The 1H-nuclear magnetic resonance results confirmed that the electrospinning process did not affect the chemical integrity of the drugs. Thermal properties of the drug-loaded electrospun PVA mats were analysed by differential scanning calorimetry and thermogravimetric analysis. The molecular weight of the model drugs played a major role on both the rate and the total amount of drugs released from the as-prepared drug-loaded electrospun PVA mats, with the rate and the total amount of the drugs released decreasing with increasing molecular weight of the drugs. Lastly, the drug-loaded electrospun PVA mats exhibited much better release characteristics of the model drugs than drug-loaded as-cast films.

Clustering drug-drug interaction networks with energy model layouts: community analysis and drug repurposing.

PubMed

Udrescu, Lucreţia; Sbârcea, Laura; Topîrceanu, Alexandru; Iovanovici, Alexandru; Kurunczi, Ludovic; Bogdan, Paul; Udrescu, Mihai

2016-09-07

Analyzing drug-drug interactions may unravel previously unknown drug action patterns, leading to the development of new drug discovery tools. We present a new approach to analyzing drug-drug interaction networks, based on clustering and topological community detection techniques that are specific to complex network science. Our methodology uncovers functional drug categories along with the intricate relationships between them. Using modularity-based and energy-model layout community detection algorithms, we link the network clusters to 9 relevant pharmacological properties. Out of the 1141 drugs from the DrugBank 4.1 database, our extensive literature survey and cross-checking with other databases such as Drugs.com, RxList, and DrugBank 4.3 confirm the predicted properties for 85% of the drugs. As such, we argue that network analysis offers a high-level grasp on a wide area of pharmacological aspects, indicating possible unaccounted interactions and missing pharmacological properties that can lead to drug repositioning for the 15% drugs which seem to be inconsistent with the predicted property. Also, by using network centralities, we can rank drugs according to their interaction potential for both simple and complex multi-pathology therapies. Moreover, our clustering approach can be extended for applications such as analyzing drug-target interactions or phenotyping patients in personalized medicine applications.

Clustering drug-drug interaction networks with energy model layouts: community analysis and drug repurposing

PubMed Central

Udrescu, Lucreţia; Sbârcea, Laura; Topîrceanu, Alexandru; Iovanovici, Alexandru; Kurunczi, Ludovic; Bogdan, Paul; Udrescu, Mihai

2016-01-01

Analyzing drug-drug interactions may unravel previously unknown drug action patterns, leading to the development of new drug discovery tools. We present a new approach to analyzing drug-drug interaction networks, based on clustering and topological community detection techniques that are specific to complex network science. Our methodology uncovers functional drug categories along with the intricate relationships between them. Using modularity-based and energy-model layout community detection algorithms, we link the network clusters to 9 relevant pharmacological properties. Out of the 1141 drugs from the DrugBank 4.1 database, our extensive literature survey and cross-checking with other databases such as Drugs.com, RxList, and DrugBank 4.3 confirm the predicted properties for 85% of the drugs. As such, we argue that network analysis offers a high-level grasp on a wide area of pharmacological aspects, indicating possible unaccounted interactions and missing pharmacological properties that can lead to drug repositioning for the 15% drugs which seem to be inconsistent with the predicted property. Also, by using network centralities, we can rank drugs according to their interaction potential for both simple and complex multi-pathology therapies. Moreover, our clustering approach can be extended for applications such as analyzing drug-target interactions or phenotyping patients in personalized medicine applications. PMID:27599720

77 FR 71802 - Guidance on Investigational New Drug Applications for Positron Emission Tomography Drugs...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-04

...] Guidance on Investigational New Drug Applications for Positron Emission Tomography Drugs; Availability... Positron Emission Tomography (PET) Drugs.'' The guidance is intended to assist manufacturers of PET drugs... ``Investigational New Drug Applications for Positron Emission Tomography (PET) Drugs.'' The guidance summarizes the...

Potential drug-drug and drug-disease interactions in well-functioning community-dwelling older adults.

PubMed

Hanlon, J T; Perera, S; Newman, A B; Thorpe, J M; Donohue, J M; Simonsick, E M; Shorr, R I; Bauer, D C; Marcum, Z A

2017-04-01

There are few studies examining both drug-drug and drug-disease interactions in older adults. Therefore, the objective of this study was to describe the prevalence of potential drug-drug and drug-disease interactions and associated factors in community-dwelling older adults. This cross-sectional study included 3055 adults aged 70-79 without mobility limitations at their baseline visit in the Health Aging and Body Composition Study conducted in the communities of Pittsburgh PA and Memphis TN, USA. The outcome factors were potential drug-drug and drug-disease interactions as per the application of explicit criteria drawn from a number of sources to self-reported prescription and non-prescription medication use. Over one-third of participants had at least one type of interaction. Approximately one quarter (25·1%) had evidence of had one or more drug-drug interactions. Nearly 10·7% of the participants had a drug-drug interaction that involved a non-prescription medication. % The most common drug-drug interaction was non-steroidal anti-inflammatory drugs (NSAIDs) affecting antihypertensives. Additionally, 16·0% had a potential drug-disease interaction with 3·7% participants having one involving non-prescription medications. The most common drug-disease interaction was aspirin/NSAID use in those with history of peptic ulcer disease without gastroprotection. Over one-third (34·0%) had at least one type of drug interaction. Each prescription medication increased the odds of having at least one type of drug interaction by 35-40% [drug-drug interaction adjusted odds ratio (AOR) = 1·35, 95% confidence interval (CI) = 1·27-1·42; drug-disease interaction AOR = 1·30; CI = 1·21-1·40; and both AOR = 1·45; CI = 1·34-1·57]. A prior hospitalization increased the odds of having at least one type of drug interaction by 49-84% compared with those not hospitalized (drug-drug interaction AOR = 1·49, 95% CI = 1·11-2·01; drug-disease interaction AOR = 1·69, CI = 1·15-2·49; and both AOR = 1·84, CI = 1·20-2·84). Drug interactions are common among community-dwelling older adults and are associated with the number of medications and hospitalization in the previous year. Longitudinal studies are needed to evaluate the impact of drug interactions on health-related outcomes. © 2017 John Wiley & Sons Ltd.

Clustered patterns of species origins of nature-derived drugs and clues for future bioprospecting.

PubMed

Zhu, Feng; Qin, Chu; Tao, Lin; Liu, Xin; Shi, Zhe; Ma, Xiaohua; Jia, Jia; Tan, Ying; Cui, Cheng; Lin, Jinshun; Tan, Chunyan; Jiang, Yuyang; Chen, Yuzong

2011-08-02

Many drugs are nature derived. Low drug productivity has renewed interest in natural products as drug-discovery sources. Nature-derived drugs are composed of dozens of molecular scaffolds generated by specific secondary-metabolite gene clusters in selected species. It can be hypothesized that drug-like structures probably are distributed in selective groups of species. We compared the species origins of 939 approved and 369 clinical-trial drugs with those of 119 preclinical drugs and 19,721 bioactive natural products. In contrast to the scattered distribution of bioactive natural products, these drugs are clustered into 144 of the 6,763 known species families in nature, with 80% of the approved drugs and 67% of the clinical-trial drugs concentrated in 17 and 30 drug-prolific families, respectively. Four lines of evidence from historical drug data, 13,548 marine natural products, 767 medicinal plants, and 19,721 bioactive natural products suggest that drugs are derived mostly from preexisting drug-productive families. Drug-productive clusters expand slowly by conventional technologies. The lack of drugs outside drug-productive families is not necessarily the result of under-exploration or late exploration by conventional technologies. New technologies that explore cryptic gene clusters, pathways, interspecies crosstalk, and high-throughput fermentation enable the discovery of novel natural products. The potential impact of these technologies on drug productivity and on the distribution patterns of drug-productive families is yet to be revealed.

Toward better drug repositioning: prioritizing and integrating existing methods into efficient pipelines.

PubMed

Jin, Guangxu; Wong, Stephen T C

2014-05-01

Recycling old drugs, rescuing shelved drugs and extending patents' lives make drug repositioning an attractive form of drug discovery. Drug repositioning accounts for approximately 30% of the newly US Food and Drug Administration (FDA)-approved drugs and vaccines in recent years. The prevalence of drug-repositioning studies has resulted in a variety of innovative computational methods for the identification of new opportunities for the use of old drugs. Questions often arise from customizing or optimizing these methods into efficient drug-repositioning pipelines for alternative applications. It requires a comprehensive understanding of the available methods gained by evaluating both biological and pharmaceutical knowledge and the elucidated mechanism-of-action of drugs. Here, we provide guidance for prioritizing and integrating drug-repositioning methods for specific drug-repositioning pipelines. Copyright © 2013 Elsevier Ltd. All rights reserved.

Projecting future drug expenditures--2012.

PubMed

Hoffman, James M; Li, Edward; Doloresco, Fred; Matusiak, Linda; Hunkler, Robert J; Shah, Nilay D; Vermeulen, Lee C; Schumock, Glen T

2012-03-01

Factors likely to influence drug expenditures, drug expenditure trends in 2010 and 2011, and projected drug expenditures for 2012 are discussed. Data were analyzed to provide drug expenditure trends for total drug expenditures and the hospital and clinic sectors. Data were obtained from the IMS Health National Sales Perspectives database. From 2009 to 2010, total U.S. drug expenditures increased by 2.7%, with total spending rising from $299.2 billion to $307.5 billion. Drug expenditures in clinics grew by 6.0% from 2009 to 2010. Hospital drug expenditures increased at the moderate rate of 1.5% from 2009 to 2010; through the first nine months of 2011, hospital drug expenditures increased by only 0.3% compared with the same period in 2010. The dominant trend over the past several years is substantial moderation in expenditure growth for widely used drugs, primarily due to the ongoing introduction and wide use of generic versions of high-cost, frequently used medications. At the end of 2010, generic drugs accounted for 78% of all retail prescriptions dispensed. Another pattern is substantial increases in expenditures for specialized medications, particularly in the outpatient setting as growth in prescription drug expenditures for clinic-administered drugs consistently outpaces growth in total expenditures. Various factors are likely to influence drug expenditures in 2012, including drugs in development, the diffusion of new drugs, generic drugs, drug shortages, and biosimilars. For 2012, we project a 3-5% increase in total drug expenditures across all settings, a 5-7% increase in expenditures for clinic-administered drugs, and a 0-2% increase in hospital drug expenditures.

Drug-Induced Dental Caries: A Disproportionality Analysis Using Data from VigiBase.

PubMed

de Campaigno, Emilie Patras; Kebir, Inès; Montastruc, Jean-Louis; Rueter, Manuela; Maret, Delphine; Lapeyre-Mestre, Maryse; Sallerin, Brigitte; Despas, Fabien

2017-12-01

Dental caries is defined as a pathological breakdown of the tooth. It is an infectious phenomenon involving a multifactorial aetiology. The impact of drugs on cariogenic risk has been poorly investigated. In this study, we identified drugs suspected to induce dental caries as adverse drug reactions (ADRs) and then studied a possible pathogenic mechanism for each drug that had a statistically significant disproportionality. We extracted individual case safety reports of dental caries associated with drugs from VigiBase ® (the World Health Organization global individual case safety report database). We calculated disproportionality for each drug with a reporting odds ratio (ROR) and 99% confidence interval. We analysed the pharmacodynamics of each drug that had a statistically significant disproportionality. In VigiBase ® , 5229 safety reports for dental caries concerning 733 drugs were identified. Among these drugs, 88 had a significant ROR, and for 65 of them (73.9%), no information about dental caries was found in the summaries of the product characteristics, the Micromedex ® DRUGDEX, or the Martindale databases. Regarding the pharmacological classes of drugs involved in dental caries, we identified bisphosphonates, atropinic drugs, antidepressants, corticoids, immunomodulating drugs, antipsychotics, antiepileptics, opioids and β 2 -adrenoreceptor agonist drugs. Regarding possible pathogenic mechanisms for these drugs, we identified changes in salivary flow/composition for 54 drugs (61.4%), bone metabolism changes for 31 drugs (35.2%), hyperglycaemia for 32 drugs (36.4%) and/or immunosuppression for 23 drugs (26.1%). For nine drugs (10.2%), the mechanism was unclear. We identified 88 drugs with a significant positive disproportionality for dental caries. Special attention has to be paid to bisphosphonates, atropinic drugs, immunosuppressants and drugs causing hyperglycaemia.

21 CFR 299.5 - Drugs; compendial name.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 4 2012-04-01 2012-04-01 false Drugs; compendial name. 299.5 Section 299.5 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL DRUGS; OFFICIAL NAMES AND ESTABLISHED NAMES General Provisions § 299.5 Drugs; compendial name. (a...

21 CFR 201.105 - Veterinary drugs.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 4 2011-04-01 2011-04-01 false Veterinary drugs. 201.105 Section 201.105 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL LABELING Exemptions From Adequate Directions for Use § 201.105 Veterinary drugs. A drug subject to the...

21 CFR 299.5 - Drugs; compendial name.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 4 2014-04-01 2014-04-01 false Drugs; compendial name. 299.5 Section 299.5 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL DRUGS; OFFICIAL NAMES AND ESTABLISHED NAMES General Provisions § 299.5 Drugs; compendial name. (a...

21 CFR 1405.625 - Criminal drug statute.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 9 2012-04-01 2012-04-01 false Criminal drug statute. 1405.625 Section 1405.625 Food and Drugs OFFICE OF NATIONAL DRUG CONTROL POLICY GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Definitions § 1405.625 Criminal drug statute. Criminal drug statute means a...

21 CFR 207.31 - Additional drug listing information.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 4 2012-04-01 2012-04-01 false Additional drug listing information. 207.31 Section 207.31 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL REGISTRATION OF PRODUCERS OF DRUGS AND LISTING OF DRUGS IN COMMERCIAL DISTRIBUTION...

21 CFR 201.105 - Veterinary drugs.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 4 2010-04-01 2010-04-01 false Veterinary drugs. 201.105 Section 201.105 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL LABELING Exemptions From Adequate Directions for Use § 201.105 Veterinary drugs. A drug subject to the...

21 CFR 207.30 - Updating drug listing information.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 4 2012-04-01 2012-04-01 false Updating drug listing information. 207.30 Section 207.30 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL REGISTRATION OF PRODUCERS OF DRUGS AND LISTING OF DRUGS IN COMMERCIAL DISTRIBUTION...

21 CFR 1405.635 - Drug-free workplace.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 9 2012-04-01 2012-04-01 false Drug-free workplace. 1405.635 Section 1405.635 Food and Drugs OFFICE OF NATIONAL DRUG CONTROL POLICY GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Definitions § 1405.635 Drug-free workplace. Drug-free workplace means a...

21 CFR 207.30 - Updating drug listing information.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 4 2014-04-01 2014-04-01 false Updating drug listing information. 207.30 Section 207.30 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL REGISTRATION OF PRODUCERS OF DRUGS AND LISTING OF DRUGS IN COMMERCIAL DISTRIBUTION...

21 CFR 299.5 - Drugs; compendial name.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 4 2013-04-01 2013-04-01 false Drugs; compendial name. 299.5 Section 299.5 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL DRUGS; OFFICIAL NAMES AND ESTABLISHED NAMES General Provisions § 299.5 Drugs; compendial name. (a...

21 CFR 201.105 - Veterinary drugs.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 4 2012-04-01 2012-04-01 false Veterinary drugs. 201.105 Section 201.105 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL LABELING Exemptions From Adequate Directions for Use § 201.105 Veterinary drugs. A drug subject to the...

21 CFR 207.30 - Updating drug listing information.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 4 2013-04-01 2013-04-01 false Updating drug listing information. 207.30 Section 207.30 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL REGISTRATION OF PRODUCERS OF DRUGS AND LISTING OF DRUGS IN COMMERCIAL DISTRIBUTION...

21 CFR 1405.635 - Drug-free workplace.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 9 2013-04-01 2013-04-01 false Drug-free workplace. 1405.635 Section 1405.635 Food and Drugs OFFICE OF NATIONAL DRUG CONTROL POLICY GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Definitions § 1405.635 Drug-free workplace. Drug-free workplace means a...

21 CFR 1405.625 - Criminal drug statute.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 9 2013-04-01 2013-04-01 false Criminal drug statute. 1405.625 Section 1405.625 Food and Drugs OFFICE OF NATIONAL DRUG CONTROL POLICY GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Definitions § 1405.625 Criminal drug statute. Criminal drug statute means a...

21 CFR 1405.625 - Criminal drug statute.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 9 2014-04-01 2014-04-01 false Criminal drug statute. 1405.625 Section 1405.625 Food and Drugs OFFICE OF NATIONAL DRUG CONTROL POLICY GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Definitions § 1405.625 Criminal drug statute. Criminal drug statute means a...

21 CFR 201.105 - Veterinary drugs.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 4 2014-04-01 2014-04-01 false Veterinary drugs. 201.105 Section 201.105 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL LABELING Exemptions From Adequate Directions for Use § 201.105 Veterinary drugs. A drug subject to the...

21 CFR 1405.635 - Drug-free workplace.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 9 2014-04-01 2014-04-01 false Drug-free workplace. 1405.635 Section 1405.635 Food and Drugs OFFICE OF NATIONAL DRUG CONTROL POLICY GOVERNMENTWIDE REQUIREMENTS FOR DRUG-FREE WORKPLACE (FINANCIAL ASSISTANCE) Definitions § 1405.635 Drug-free workplace. Drug-free workplace means a...

21 CFR 207.31 - Additional drug listing information.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 4 2014-04-01 2014-04-01 false Additional drug listing information. 207.31 Section 207.31 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL REGISTRATION OF PRODUCERS OF DRUGS AND LISTING OF DRUGS IN COMMERCIAL DISTRIBUTION...

21 CFR 201.105 - Veterinary drugs.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 4 2013-04-01 2013-04-01 false Veterinary drugs. 201.105 Section 201.105 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL LABELING Exemptions From Adequate Directions for Use § 201.105 Veterinary drugs. A drug subject to the...

21 CFR 207.31 - Additional drug listing information.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 4 2013-04-01 2013-04-01 false Additional drug listing information. 207.31 Section 207.31 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL REGISTRATION OF PRODUCERS OF DRUGS AND LISTING OF DRUGS IN COMMERCIAL DISTRIBUTION...

21 CFR 207.31 - Additional drug listing information.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 4 2011-04-01 2011-04-01 false Additional drug listing information. 207.31 Section 207.31 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL REGISTRATION OF PRODUCERS OF DRUGS AND LISTING OF DRUGS IN COMMERCIAL DISTRIBUTION...

21 CFR 299.5 - Drugs; compendial name.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 4 2011-04-01 2011-04-01 false Drugs; compendial name. 299.5 Section 299.5 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL DRUGS; OFFICIAL NAMES AND ESTABLISHED NAMES General Provisions § 299.5 Drugs; compendial name. (a...

21 CFR 207.30 - Updating drug listing information.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 4 2011-04-01 2011-04-01 false Updating drug listing information. 207.30 Section 207.30 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL REGISTRATION OF PRODUCERS OF DRUGS AND LISTING OF DRUGS IN COMMERCIAL DISTRIBUTION...

21 CFR 1310.10 - Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic Act.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 9 2013-04-01 2013-04-01 false Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic Act. 1310.10 Section 1310.10 Food and Drugs DRUG ENFORCEMENT... Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic Act. (a) The...

21 CFR 1310.10 - Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic Act.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 9 2014-04-01 2014-04-01 false Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic Act. 1310.10 Section 1310.10 Food and Drugs DRUG ENFORCEMENT... Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic Act. (a) The...

21 CFR 1310.10 - Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic Act.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 9 2012-04-01 2012-04-01 false Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic Act. 1310.10 Section 1310.10 Food and Drugs DRUG ENFORCEMENT... Removal of the exemption of drugs distributed under the Federal Food, Drug and Cosmetic Act. (a) The...

Dynamic enhancement of drug product labels to support drug safety, efficacy, and effectiveness.

PubMed

Boyce, Richard D; Horn, John R; Hassanzadeh, Oktie; Waard, Anita de; Schneider, Jodi; Luciano, Joanne S; Rastegar-Mojarad, Majid; Liakata, Maria

2013-01-26

Out-of-date or incomplete drug product labeling information may increase the risk of otherwise preventable adverse drug events. In recognition of these concerns, the United States Federal Drug Administration (FDA) requires drug product labels to include specific information. Unfortunately, several studies have found that drug product labeling fails to keep current with the scientific literature. We present a novel approach to addressing this issue. The primary goal of this novel approach is to better meet the information needs of persons who consult the drug product label for information on a drug's efficacy, effectiveness, and safety. Using FDA product label regulations as a guide, the approach links drug claims present in drug information sources available on the Semantic Web with specific product label sections. Here we report on pilot work that establishes the baseline performance characteristics of a proof-of-concept system implementing the novel approach. Claims from three drug information sources were linked to the Clinical Studies, Drug Interactions, and Clinical Pharmacology sections of the labels for drug products that contain one of 29 psychotropic drugs. The resulting Linked Data set maps 409 efficacy/effectiveness study results, 784 drug-drug interactions, and 112 metabolic pathway assertions derived from three clinically-oriented drug information sources (ClinicalTrials.gov, the National Drug File - Reference Terminology, and the Drug Interaction Knowledge Base) to the sections of 1,102 product labels. Proof-of-concept web pages were created for all 1,102 drug product labels that demonstrate one possible approach to presenting information that dynamically enhances drug product labeling. We found that approximately one in five efficacy/effectiveness claims were relevant to the Clinical Studies section of a psychotropic drug product, with most relevant claims providing new information. We also identified several cases where all of the drug-drug interaction claims linked to the Drug Interactions section for a drug were potentially novel. The baseline performance characteristics of the proof-of-concept will enable further technical and user-centered research on robust methods for scaling the approach to the many thousands of product labels currently on the market.

Patterns of Drugs and Drug Metabolites Observed in Meconium: What Do They Mean?

PubMed

McMillin, Gwendolyn A; Wood, Kelly E; Strathmann, Frederick G; Krasowski, Matthew D

2015-10-01

Meconium drug testing is performed to detect potentially harmful drug exposures in a newborn. Interpretation of meconium drug testing results can be complicated based on the patterns and proportional concentrations of the drug(s) and/or drug metabolite(s) detected. The objective of this study was to analyze meconium drug testing patterns in a de-identified dataset from a national reference laboratory (n = 76,631) and in a subset of the data, wherein specimens originated at a single academic medical center for which detailed chart review was possible (n = 3635). Meconium testing was performed using 11 immunoassay-based drug screens. Specimens that were positive for one or more drug screens were reflexed to corresponding confirmation tests performed by gas chromatography or liquid chromatography with mass spectrometric detection, targeted to identify and quantitate specific parent drug(s) and metabolite(s). The positivity rate was the highest for the cannabis metabolite 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (25.2%, n = 18,643), followed by opiates/oxycodone (23.2%, n = 17,778), amphetamine/methamphetamine (6.7%, n = 5134), cocaine metabolites (5.5%, n = 4205), methadone (5.3%, n = 4093), benzodiazepines (3.4%, n = 2603), barbiturates (1.1%, n = 834), propoxyphene (1.0%, n = 749), and phencyclidine (0.1%, n = 44). Based on documented pharmacy history, drugs administered to either the mother or newborn during the birth hospitalization were detected in meconium, providing evidence that drugs can be incorporated into meconium rapidly. Drugs administered directly to the newborn after birth were recovered in meconium as both parent drug and metabolites, providing evidence of neonatal metabolism. Overall, patterns observed in meconium exhibited many similarities to those patterns commonly reported with urine drug testing. Interpretation of meconium drug testing results requires comparison of results with clinical and analytical expectations, including maternal admissions to drug use, pharmacy history, recognized metabolic patterns for drugs of interest, cutoff concentrations, and other performance characteristics of the test. Concentrations of drug(s) and drug metabolites(s) may not reliably predict timing of drug use, extent of drug use, or frequency of drug exposures.

[War on Drugs or War against Health? The pitfalls for public health of Puerto Rican drug policy].

PubMed

Santiago-Negrón, Salvador; Albizu-García, Carmen E

2003-03-01

Puerto Rico has followed the United States in adopting drug policy sustained on a criminal justice model that limits the opportunities to address problematic drug use through public health interventions. Demand for illegal drugs is controlled by criminalizing drug use and applying jail sentences for drug offenses. These strategies marginalize drug users and reduce opportunities to minimize health risks applying public health measures. Production and sale of illegal drugs is criminalized with the intent of dissuading drug use, with adverse unintended health effects that impact both drug users and non-drug users in the community. The present work reviews the assumptions of the punitive prohibitionist model and its outcomes that present themselves as public health challenges in Puerto Rico. It also presents those principles that should sustain pragmatic drug policy to address problematic drug use from a health and social perspective.

Biomimetics in drug delivery systems: A critical review.

PubMed

Sheikhpour, Mojgan; Barani, Leila; Kasaeian, Alibakhsh

2017-05-10

Today, the advanced drug delivery systems have been focused on targeted drug delivery fields. The novel drug delivery is involved with the improvement of the capacity of drug loading in drug carriers, cellular uptake of drug carriers, and the sustained release of drugs within target cells. In this review, six groups of therapeutic drug carriers including biomimetic hydrogels, biomimetic micelles, biomimetic liposomes, biomimetic dendrimers, biomimetic polymeric carriers and biomimetic nanostructures, are studied. The subject takes advantage of the biomimetic methods of productions or the biomimetic techniques for the surface modifications, similar to what accrues in natural cells. Moreover, the effects of these biomimetic approaches for promoting the drug efficiency in targeted drug delivery are visible. The study demonstrates that the fabrication of biomimetic nanocomposite drug carriers could noticeably promote the efficiency of drugs in targeted drug delivery systems. Copyright © 2017 Elsevier B.V. All rights reserved.

Direct-to-consumer ads can influence behavior. Advertising increases consumer knowledge and prescription drug requests.

PubMed

Peyrot, M; Alperstein, N M; Van Doren, D; Poli, L G

1998-01-01

This study examines the impact of direct-to-consumer (DTC) pharmaceutical advertising on prescription drug knowledge and the requesting behavior of consumers. The authors developed and tested a conceptual model of prescription drug knowledge and requests. Consumers' belief that drug advertising can educate them was associated with a greater amount of drug knowledge, and the belief they would upset physicians by asking for specific drugs was associated with less knowledge. The belief that drug advertising reduces prices was associated with greater probability of drug requests, and the belief that physicians should be the sole source of drug information was associated with lesser probability of request. Preference for generic drugs was associated with a lesser likelihood of requesting a specific drug. Media exposure and drug advertising awareness were associated with higher drug knowledge and a greater probability of drug requesting.

Multifunctional High Drug Loading Nanocarriers for Cancer Drug Delivery

NASA Astrophysics Data System (ADS)

Jin, Erlei

2011-12-01

Most anticancer drugs have poor water-solubility, rapid blood clearance, low tumor-selectivity and severe systemic toxicity to healthy tissues. Thus, polymeric nanocarriers have been widely explored for anticancer drugs to solve these problems. However, polymer nanocarriers developed to date still suffer drawbacks including low drug loading contents, premature drug release, slow cellular internalization, slow intracellular drug release and thereby low therapeutic efficiency in cancer thermotherapy. Accordingly, in this dissertation, functional nanocapsules and nanoparticles including high drug loading liposome-like nanocapsules, high drug loading phospholipid-mimic nanocapsules with fast intracellular drug release, high drug loading charge-reversal nanocapsules, TAT based long blood circulation nanoparticles and charge-reversal nuclear targeted nanoparticles are designed and synthesized. These functional carriers have advantages such as high drug loading contents without premature drug release, fast cellular internalization and intracellular drug release, nuclear targeted delivery and long blood circulation. As a result, all these drug carriers show much higher in vitro and in vivo anti-cancer activities.

21 CFR 201.6 - Drugs; misleading statements.

Code of Federal Regulations, 2010 CFR

2010-04-01

... representation with respect to another drug or a device or a food or cosmetic. (b) The labeling of a drug which... 21 Food and Drugs 4 2010-04-01 2010-04-01 false Drugs; misleading statements. 201.6 Section 201.6 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS...

21 CFR 203.33 - Drug sample forms.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 4 2010-04-01 2010-04-01 false Drug sample forms. 203.33 Section 203.33 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL PRESCRIPTION DRUG MARKETING Samples § 203.33 Drug sample forms. A sample request or receipt form may be...

21 CFR 203.33 - Drug sample forms.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 4 2011-04-01 2011-04-01 false Drug sample forms. 203.33 Section 203.33 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL PRESCRIPTION DRUG MARKETING Samples § 203.33 Drug sample forms. A sample request or receipt form may be...

21 CFR 314.420 - Drug master files.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Drug master files. 314.420 Section 314.420 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG Miscellaneous Provisions § 314.420 Drug...

21 CFR 299.4 - Established names for drugs.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 4 2014-04-01 2014-04-01 false Established names for drugs. 299.4 Section 299.4 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL DRUGS; OFFICIAL NAMES AND ESTABLISHED NAMES General Provisions § 299.4 Established names for drugs...

21 CFR 299.4 - Established names for drugs.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 4 2013-04-01 2013-04-01 false Established names for drugs. 299.4 Section 299.4 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL DRUGS; OFFICIAL NAMES AND ESTABLISHED NAMES General Provisions § 299.4 Established names for drugs...

21 CFR 203.33 - Drug sample forms.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 4 2013-04-01 2013-04-01 false Drug sample forms. 203.33 Section 203.33 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL PRESCRIPTION DRUG MARKETING Samples § 203.33 Drug sample forms. A sample request or receipt form may be...

21 CFR 299.4 - Established names for drugs.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 4 2011-04-01 2011-04-01 false Established names for drugs. 299.4 Section 299.4 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL DRUGS; OFFICIAL NAMES AND ESTABLISHED NAMES General Provisions § 299.4 Established names for drugs...

21 CFR 314.420 - Drug master files.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Drug master files. 314.420 Section 314.420 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG Miscellaneous Provisions § 314.420 Drug...

21 CFR 299.4 - Established names for drugs.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 4 2012-04-01 2012-04-01 false Established names for drugs. 299.4 Section 299.4 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL DRUGS; OFFICIAL NAMES AND ESTABLISHED NAMES General Provisions § 299.4 Established names for drugs...

21 CFR 314.420 - Drug master files.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Drug master files. 314.420 Section 314.420 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG Miscellaneous Provisions § 314.420 Drug...

21 CFR 203.33 - Drug sample forms.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 4 2012-04-01 2012-04-01 false Drug sample forms. 203.33 Section 203.33 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL PRESCRIPTION DRUG MARKETING Samples § 203.33 Drug sample forms. A sample request or receipt form may be...

21 CFR 203.33 - Drug sample forms.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 4 2014-04-01 2014-04-01 false Drug sample forms. 203.33 Section 203.33 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL PRESCRIPTION DRUG MARKETING Samples § 203.33 Drug sample forms. A sample request or receipt form may be...

21 CFR 314.420 - Drug master files.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Drug master files. 314.420 Section 314.420 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG Miscellaneous Provisions § 314.420 Drug...

21 CFR 203.39 - Donation of drug samples to charitable institutions.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 4 2014-04-01 2014-04-01 false Donation of drug samples to charitable... SERVICES (CONTINUED) DRUGS: GENERAL PRESCRIPTION DRUG MARKETING Samples § 203.39 Donation of drug samples... donation record accurately describes the drug sample delivered and that no drug sample is adulterated or...

21 CFR 203.39 - Donation of drug samples to charitable institutions.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 4 2012-04-01 2012-04-01 false Donation of drug samples to charitable... SERVICES (CONTINUED) DRUGS: GENERAL PRESCRIPTION DRUG MARKETING Samples § 203.39 Donation of drug samples... donation record accurately describes the drug sample delivered and that no drug sample is adulterated or...

21 CFR 203.39 - Donation of drug samples to charitable institutions.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 4 2013-04-01 2013-04-01 false Donation of drug samples to charitable... SERVICES (CONTINUED) DRUGS: GENERAL PRESCRIPTION DRUG MARKETING Samples § 203.39 Donation of drug samples... donation record accurately describes the drug sample delivered and that no drug sample is adulterated or...

21 CFR 250.102 - Drug preparations intended for human use containing certain “coronary vasodilators”.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 4 2011-04-01 2011-04-01 false Drug preparations intended for human use... ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL SPECIAL REQUIREMENTS FOR SPECIFIC HUMAN DRUGS New Drug or Prescription Status of Specific Drugs § 250.102 Drug preparations intended...

21 CFR 250.102 - Drug preparations intended for human use containing certain “coronary vasodilators”.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 4 2012-04-01 2012-04-01 false Drug preparations intended for human use... ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL SPECIAL REQUIREMENTS FOR SPECIFIC HUMAN DRUGS New Drug or Prescription Status of Specific Drugs § 250.102 Drug preparations intended...

NLLSS: Predicting Synergistic Drug Combinations Based on Semi-supervised Learning

PubMed Central

Chen, Ming; Wang, Quanxin; Zhang, Lixin; Yan, Guiying

2016-01-01

Fungal infection has become one of the leading causes of hospital-acquired infections with high mortality rates. Furthermore, drug resistance is common for fungus-causing diseases. Synergistic drug combinations could provide an effective strategy to overcome drug resistance. Meanwhile, synergistic drug combinations can increase treatment efficacy and decrease drug dosage to avoid toxicity. Therefore, computational prediction of synergistic drug combinations for fungus-causing diseases becomes attractive. In this study, we proposed similar nature of drug combinations: principal drugs which obtain synergistic effect with similar adjuvant drugs are often similar and vice versa. Furthermore, we developed a novel algorithm termed Network-based Laplacian regularized Least Square Synergistic drug combination prediction (NLLSS) to predict potential synergistic drug combinations by integrating different kinds of information such as known synergistic drug combinations, drug-target interactions, and drug chemical structures. We applied NLLSS to predict antifungal synergistic drug combinations and showed that it achieved excellent performance both in terms of cross validation and independent prediction. Finally, we performed biological experiments for fungal pathogen Candida albicans to confirm 7 out of 13 predicted antifungal synergistic drug combinations. NLLSS provides an efficient strategy to identify potential synergistic antifungal combinations. PMID:27415801

Drug-drug interactions involving lysosomes: mechanisms and potential clinical implications.

PubMed

Logan, Randall; Funk, Ryan S; Axcell, Erick; Krise, Jeffrey P

2012-08-01

Many commercially available, weakly basic drugs have been shown to be lysosomotropic, meaning they are subject to extensive sequestration in lysosomes through an ion trapping-type mechanism. The extent of lysosomal trapping of a drug is an important therapeutic consideration because it can influence both activity and pharmacokinetic disposition. The administration of certain drugs can alter lysosomes such that their accumulation capacity for co-administered and/or secondarily administered drugs is altered. In this review the authors explore what is known regarding the mechanistic basis for drug-drug interactions involving lysosomes. Specifically, the authors address the influence of drugs on lysosomal pH, volume and lipid processing. Many drugs are known to extensively accumulate in lysosomes and significantly alter their structure and function; however, the therapeutic and toxicological implications of this remain controversial. The authors propose that drug-drug interactions involving lysosomes represent an important potential source of variability in drug activity and pharmacokinetics. Most evaluations of drug-drug interactions involving lysosomes have been performed in cultured cells and isolated tissues. More comprehensive in vivo evaluations are needed to fully explore the impact of this drug-drug interaction pathway on therapeutic outcomes.

Drug-Path: a database for drug-induced pathways

PubMed Central

Zeng, Hui; Cui, Qinghua

2015-01-01

Some databases for drug-associated pathways have been built and are publicly available. However, the pathways curated in most of these databases are drug-action or drug-metabolism pathways. In recent years, high-throughput technologies such as microarray and RNA-sequencing have produced lots of drug-induced gene expression profiles. Interestingly, drug-induced gene expression profile frequently show distinct patterns, indicating that drugs normally induce the activation or repression of distinct pathways. Therefore, these pathways contribute to study the mechanisms of drugs and drug-repurposing. Here, we present Drug-Path, a database of drug-induced pathways, which was generated by KEGG pathway enrichment analysis for drug-induced upregulated genes and downregulated genes based on drug-induced gene expression datasets in Connectivity Map. Drug-Path provides user-friendly interfaces to retrieve, visualize and download the drug-induced pathway data in the database. In addition, the genes deregulated by a given drug are highlighted in the pathways. All data were organized using SQLite. The web site was implemented using Django, a Python web framework. Finally, we believe that this database will be useful for related researches. Database URL: http://www.cuilab.cn/drugpath PMID:26130661

Drug-Path: a database for drug-induced pathways.

PubMed

Zeng, Hui; Qiu, Chengxiang; Cui, Qinghua

2015-01-01

Some databases for drug-associated pathways have been built and are publicly available. However, the pathways curated in most of these databases are drug-action or drug-metabolism pathways. In recent years, high-throughput technologies such as microarray and RNA-sequencing have produced lots of drug-induced gene expression profiles. Interestingly, drug-induced gene expression profile frequently show distinct patterns, indicating that drugs normally induce the activation or repression of distinct pathways. Therefore, these pathways contribute to study the mechanisms of drugs and drug-repurposing. Here, we present Drug-Path, a database of drug-induced pathways, which was generated by KEGG pathway enrichment analysis for drug-induced upregulated genes and downregulated genes based on drug-induced gene expression datasets in Connectivity Map. Drug-Path provides user-friendly interfaces to retrieve, visualize and download the drug-induced pathway data in the database. In addition, the genes deregulated by a given drug are highlighted in the pathways. All data were organized using SQLite. The web site was implemented using Django, a Python web framework. Finally, we believe that this database will be useful for related researches. © The Author(s) 2015. Published by Oxford University Press.

New era in drug interaction evaluation: US Food and Drug Administration update on CYP enzymes, transporters, and the guidance process.

PubMed

Huang, Shiew-Mei; Strong, John M; Zhang, Lei; Reynolds, Kellie S; Nallani, Srikanth; Temple, Robert; Abraham, Sophia; Habet, Sayed Al; Baweja, Raman K; Burckart, Gilbert J; Chung, Sang; Colangelo, Philip; Frucht, David; Green, Martin D; Hepp, Paul; Karnaukhova, Elena; Ko, Hon-Sum; Lee, Jang-Ik; Marroum, Patrick J; Norden, Janet M; Qiu, Wei; Rahman, Atiqur; Sobel, Solomon; Stifano, Toni; Thummel, Kenneth; Wei, Xiao-Xiong; Yasuda, Sally; Zheng, Jenny H; Zhao, Hong; Lesko, Lawrence J

2008-06-01

Predicting clinically significant drug interactions during drug development is a challenge for the pharmaceutical industry and regulatory agencies. Since the publication of the US Food and Drug Administration's (FDA's) first in vitro and in vivo drug interaction guidance documents in 1997 and 1999, researchers and clinicians have gained a better understanding of drug interactions. This knowledge has enabled the FDA and the industry to progress and begin to overcome these challenges. The FDA has continued its efforts to evaluate methodologies to study drug interactions and communicate recommendations regarding the conduct of drug interaction studies, particularly for CYP-based and transporter-based drug interactions, to the pharmaceutical industry. A drug interaction Web site was established to document the FDA's current understanding of drug interactions (http://www.fda.gov/cder/drug/drugInteractions/default.htm). This report provides an overview of the evolution of the drug interaction guidances, includes a synopsis of the steps taken by the FDA to revise the original drug interaction guidance documents, and summarizes and highlights updated sections in the current guidance document, Drug Interaction Studies-Study Design, Data Analysis, and Implications for Dosing and Labeling.

Dosing of antirheumatic drugs in renal disease and dialysis.

PubMed

Swarup, Areena; Sachdeva, Namita; Schumacher, H Ralph

2004-08-01

Many patients with rheumatic diseases have their management complicated by renal problems. Renal failure modifies the metabolism of many drugs, especially by retention. Questions often arise about the effects of renal failure on the handling of drugs commonly used in rheumatology. For which drugs must we be especially concerned about increased toxicity? Patients on chronic dialysis may also need a variety of drugs for rheumatic disease. How are our drugs dialyzed, and which of these can be safety used and how best to use them?Decisions about dosing of rheumatic drugs are often required for the patients with chronic renal insufficiency or on long-term dialysis, although many drugs have not been formally studied in these settings. Patients with renal insufficiency are excluded from most drug trials. Data for some of these drugs have to be extrapolated based on the information available about the pharmacokinetics of the drug.This review addresses dosing of commonly used drugs in rheumatology in patients with chronic renal insufficiency or failure. It is compiled from a MEDLINE search of papers dealing with renal handling of antirheumatic drugs and suggestions for dose adjustments for these drugs. Drugs reviewed include commonly used disease-modifying antirheumatic drugs (DMARDS), drugs used for treatment of gout, commonly used nonsteroidal antnflammatory drugs (NSAIDS) and the newer COX-2 inhibitors.

Romania's drug policy from 2005 to 2012: experiences with implementation.

PubMed

Dégi, Csaba László

2014-05-01

Even with the relatively high rate of illicit drug use in Romania, drug prevention remains a relatively low political and professional priority. Policies focus primarily on the criminalization of drug use rather than on prevention and treatment. By studying official Romanian drug policies and legislative documents, as well as national and European reports on the state of the ''drug problem,'' this article focuses on the impact of policy on drug use, treatment, and prevention, with an emphasis on the criminalization of drug use and the resultant trends and practical impacts. The reported lifetime use of illicit drugs has been rising slowly but steadily over the last few years. Contraction of communicable diseases among intravenous drug users is also trending upwards. And with the emphasis on criminalization of drug use and the accompanying marginalization of users, drug-law-related offences are also likely to increase. Unmet needs in drug prevention, a declining tendency to seek drug treatment, and an increase in drug-related deaths are also indicators of the negative effects of the current policy on drug use, criminalization, infections, and the lack of effective prevention. As Romania continues to face serious financial limitations, evidence-based research on drug use is needed; best practice guidelines have to be followed in order to improve access to drug prevention, treatment, and harm-reduction services.

Drugs as instruments: a new framework for non-addictive psychoactive drug use.

PubMed

Müller, Christian P; Schumann, Gunter

2011-12-01

Most people who are regular consumers of psychoactive drugs are not drug addicts, nor will they ever become addicts. In neurobiological theories, non-addictive drug consumption is acknowledged only as a "necessary" prerequisite for addiction, but not as a stable and widespread behavior in its own right. This target article proposes a new neurobiological framework theory for non-addictive psychoactive drug consumption, introducing the concept of "drug instrumentalization." Psychoactive drugs are consumed for their effects on mental states. Humans are able to learn that mental states can be changed on purpose by drugs, in order to facilitate other, non-drug-related behaviors. We discuss specific "instrumentalization goals" and outline neurobiological mechanisms of how major classes of psychoactive drugs change mental states and serve non-drug-related behaviors. We argue that drug instrumentalization behavior may provide a functional adaptation to modern environments based on a historical selection for learning mechanisms that allow the dynamic modification of consummatory behavior. It is assumed that in order to effectively instrumentalize psychoactive drugs, the establishment of and retrieval from a drug memory is required. Here, we propose a new classification of different drug memory subtypes and discuss how they interact during drug instrumentalization learning and retrieval. Understanding the everyday utility and the learning mechanisms of non-addictive psychotropic drug use may help to prevent abuse and the transition to drug addiction in the future.

Food-Drug Interactions

PubMed Central

Bushra, Rabia; Aslam, Nousheen; Khan, Arshad Yar

2011-01-01

The effect of drug on a person may be different than expected because that drug interacts with another drug the person is taking (drug-drug interaction), food, beverages, dietary supplements the person is consuming (drug-nutrient/food interaction) or another disease the person has (drug-disease interaction). A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. These interactions may occur out of accidental misuse or due to lack of knowledge about the active ingredients involved in the relevant substances. Regarding food-drug interactions physicians and pharmacists recognize that some foods and drugs, when taken simultaneously, can alter the body's ability to utilize a particular food or drug, or cause serious side effects. Clinically significant drug interactions, which pose potential harm to the patient, may result from changes in pharmaceutical, pharmacokinetic, or pharmacodynamic properties. Some may be taken advantage of, to the benefit of patients, but more commonly drug interactions result in adverse drug events. Therefore it is advisable for patients to follow the physician and doctors instructions to obtain maximum benefits with least food-drug interactions. The literature survey was conducted by extracting data from different review and original articles on general or specific drug interactions with food. This review gives information about various interactions between different foods and drugs and will help physicians and pharmacists prescribe drugs cautiously with only suitable food supplement to get maximum benefit for the patient. PMID:22043389

Factors influencing the difference between forecasted and actual drug sales volumes under the price-volume agreement in South Korea.

PubMed

Park, Sun-Young; Han, Euna; Kim, Jini; Lee, Eui-Kyung

2016-08-01

This study analyzed factors contributing to increases in the actual sales volumes relative to forecasted volumes of drugs under price-volume agreement (PVA) policy in South Korea. Sales volumes of newly listed drugs on the national formulary are monitored under PVA policy. When actual sales volume exceeds the pre-agreed forecasted volume by 30% or more, the drug is subject to price-reduction. Logistic regression assessed the factors related to whether drugs were the PVA price-reduction drugs. A generalized linear model with gamma distribution and log-link assessed the factors influencing the increase in actual volumes compared to forecasted volume in the PVA price-reduction drugs. Of 186 PVA monitored drugs, 34.9% were price-reduction drugs. Drugs marketed by pharmaceutical companies with previous-occupation in the therapeutic markets were more likely to be PVA price-reduction drugs than drugs marketed by firms with no previous-occupation. Drugs of multinational pharmaceutical companies were more likely to be PVA price-reduction drugs than those of domestic companies. Having more alternative existing drugs was significantly associated with higher odds of being PVA price-reduction drugs. Among the PVA price-reduction drugs, the increasing rate of actual volume compared to forecasted volume was significantly higher in drugs with clinical usefulness. By focusing the negotiation efforts on those target drugs, PVA policy can be administered more efficiently with the improved predictability of the drug sales volumes. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Projecting future drug expenditures--2006.

PubMed

Hoffman, James M; Shah, Nilay D; Vermeulen, Lee C; Schumock, Glen T; Grim, Penny; Hunkler, Robert J; Hontz, Karrie M

2006-01-15

Drug expenditure trends in 2004 and 2005, projected drug expenditures for 2006, and factors likely to influence drug costs are discussed. Various factors are likely to affect drug costs, including drug prices, drugs in development, and generic drugs. In 2004 there was a continued moderation of the increase in drug expenditures. Drug expenditures increased by 8.7% from 2003 to 2004. Through the first nine months of 2005, expenditures increased by only 8.1% compared with 2004. This moderation can be attributed to several factors, including the continued trend toward higher prescription drug cost sharing for insured consumers, growing availability of generic drugs, and lack of "blockbuster" new drugs in recent years. Drug expenditures in 2006 will likely be influenced by similar factors, with few costly new products reaching the market, increased concern over product safety slowing the diffusion of those new agents that do reach the market, and several important patent expirations, leading to slower growth in expenditures. Forecasting and managing rising drug expenditures remains a challenge. Pharmacy managers must remain vigilant in monitoring drug costs in their health system and take a proactive role in pursuing efficient drug utilization. The dynamic health policy environment further complicates drug budgeting and must be considered, especially in integrated health systems responsible for managing inpatient, outpatient, and clinic drug costs. The comparison of health-system-specific data and trends with the national information presented in this article may provide a useful context when presenting institutional drug costs to senior management.

Clustered patterns of species origins of nature-derived drugs and clues for future bioprospecting

PubMed Central

Zhu, Feng; Qin, Chu; Tao, Lin; Liu, Xin; Shi, Zhe; Ma, Xiaohua; Jia, Jia; Tan, Ying; Cui, Cheng; Lin, Jinshun; Tan, Chunyan; Jiang, Yuyang; Chen, Yuzong

2011-01-01

Many drugs are nature derived. Low drug productivity has renewed interest in natural products as drug-discovery sources. Nature-derived drugs are composed of dozens of molecular scaffolds generated by specific secondary-metabolite gene clusters in selected species. It can be hypothesized that drug-like structures probably are distributed in selective groups of species. We compared the species origins of 939 approved and 369 clinical-trial drugs with those of 119 preclinical drugs and 19,721 bioactive natural products. In contrast to the scattered distribution of bioactive natural products, these drugs are clustered into 144 of the 6,763 known species families in nature, with 80% of the approved drugs and 67% of the clinical-trial drugs concentrated in 17 and 30 drug-prolific families, respectively. Four lines of evidence from historical drug data, 13,548 marine natural products, 767 medicinal plants, and 19,721 bioactive natural products suggest that drugs are derived mostly from preexisting drug-productive families. Drug-productive clusters expand slowly by conventional technologies. The lack of drugs outside drug-productive families is not necessarily the result of under-exploration or late exploration by conventional technologies. New technologies that explore cryptic gene clusters, pathways, interspecies crosstalk, and high-throughput fermentation enable the discovery of novel natural products. The potential impact of these technologies on drug productivity and on the distribution patterns of drug-productive families is yet to be revealed. PMID:21768386

DrugBank 4.0: shedding new light on drug metabolism

PubMed Central

Law, Vivian; Knox, Craig; Djoumbou, Yannick; Jewison, Tim; Guo, An Chi; Liu, Yifeng; Maciejewski, Adam; Arndt, David; Wilson, Michael; Neveu, Vanessa; Tang, Alexandra; Gabriel, Geraldine; Ly, Carol; Adamjee, Sakina; Dame, Zerihun T.; Han, Beomsoo; Zhou, You; Wishart, David S.

2014-01-01

DrugBank (http://www.drugbank.ca) is a comprehensive online database containing extensive biochemical and pharmacological information about drugs, their mechanisms and their targets. Since it was first described in 2006, DrugBank has rapidly evolved, both in response to user requests and in response to changing trends in drug research and development. Previous versions of DrugBank have been widely used to facilitate drug and in silico drug target discovery. The latest update, DrugBank 4.0, has been further expanded to contain data on drug metabolism, absorption, distribution, metabolism, excretion and toxicity (ADMET) and other kinds of quantitative structure activity relationships (QSAR) information. These enhancements are intended to facilitate research in xenobiotic metabolism (both prediction and characterization), pharmacokinetics, pharmacodynamics and drug design/discovery. For this release, >1200 drug metabolites (including their structures, names, activity, abundance and other detailed data) have been added along with >1300 drug metabolism reactions (including metabolizing enzymes and reaction types) and dozens of drug metabolism pathways. Another 30 predicted or measured ADMET parameters have been added to each DrugCard, bringing the average number of quantitative ADMET values for Food and Drug Administration-approved drugs close to 40. Referential nuclear magnetic resonance and MS spectra have been added for almost 400 drugs as well as spectral and mass matching tools to facilitate compound identification. This expanded collection of drug information is complemented by a number of new or improved search tools, including one that provides a simple analyses of drug–target, –enzyme and –transporter associations to provide insight on drug–drug interactions. PMID:24203711

DrugBank 5.0: a major update to the DrugBank database for 2018.

PubMed

Wishart, David S; Feunang, Yannick D; Guo, An C; Lo, Elvis J; Marcu, Ana; Grant, Jason R; Sajed, Tanvir; Johnson, Daniel; Li, Carin; Sayeeda, Zinat; Assempour, Nazanin; Iynkkaran, Ithayavani; Liu, Yifeng; Maciejewski, Adam; Gale, Nicola; Wilson, Alex; Chin, Lucy; Cummings, Ryan; Le, Diana; Pon, Allison; Knox, Craig; Wilson, Michael

2018-01-04

DrugBank (www.drugbank.ca) is a web-enabled database containing comprehensive molecular information about drugs, their mechanisms, their interactions and their targets. First described in 2006, DrugBank has continued to evolve over the past 12 years in response to marked improvements to web standards and changing needs for drug research and development. This year's update, DrugBank 5.0, represents the most significant upgrade to the database in more than 10 years. In many cases, existing data content has grown by 100% or more over the last update. For instance, the total number of investigational drugs in the database has grown by almost 300%, the number of drug-drug interactions has grown by nearly 600% and the number of SNP-associated drug effects has grown more than 3000%. Significant improvements have been made to the quantity, quality and consistency of drug indications, drug binding data as well as drug-drug and drug-food interactions. A great deal of brand new data have also been added to DrugBank 5.0. This includes information on the influence of hundreds of drugs on metabolite levels (pharmacometabolomics), gene expression levels (pharmacotranscriptomics) and protein expression levels (pharmacoprotoemics). New data have also been added on the status of hundreds of new drug clinical trials and existing drug repurposing trials. Many other important improvements in the content, interface and performance of the DrugBank website have been made and these should greatly enhance its ease of use, utility and potential applications in many areas of pharmacological research, pharmaceutical science and drug education. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Online availability and safety of drugs in shortage: a descriptive study of internet vendor characteristics.

PubMed

Liang, Bryan A; Mackey, Tim K

2012-02-09

Unprecedented drug shortages announced by the US Food and Drug Administration (FDA) have severely affected therapeutic access, patient safety, and public health. With continued shortages, patients may seek drugs online. To assess the prevalence of online marketing for current FDA shortage drugs and potential patient safety risks. We performed a descriptive study of the prevalence of online marketing for shortage drugs-that is, offers for sale of each drug, including characteristics of online drug sellers and intermediary sites marketing these drugs. Of the 72 FDA shortage-listed drugs, 68 (94%) were offered for sale online. We found 291 offers for these drugs, the vast majority (n = 207, 71.1%) by online drug sellers selling direct to consumers. Intermediary sites included data aggregators (n = 22, 8%), forum links (n = 23, 8%), and personal page data links (n = 34, 12%), as well as Flickr social media links (n = 5, 2%), all advertising drugs without a prescription. Of the 91 online drug sellers identified, 31 (34%) had more than 1 shortage drug offered for sale, representing most (n = 148, 71%) of all online drug seller sales offers. The majority of these online drug sellers (n = 21, 68%) were on the National Association of Boards of Pharmacy (NABP) Not Recommended Sites list. Finally, for shortage drugs with an online drug seller (n = 58, 85%), 53 (91%) had at least one site on the Not Recommended list and 21 (36%) had only sites on the Not Recommended list. FDA shortage drugs are widely marketed over the Internet. Suspect online drug sellers and intermediaries dominate these sales offers. As a critical risk management issue, patients, providers, and policymakers should be extremely cautious in procuring shortage drugs through Internet sourcing.

Characteristics and drug utilization patterns for heavy users of prescription drugs among the elderly: a Danish register-based drug utilization study.

PubMed

Øymoen, Anita; Pottegård, Anton; Almarsdóttir, Anna Birna

2015-06-01

The objectives of this study were to (1) identify and characterize heavy users of prescription drugs among persons aged 60 years and above; (2) investigate the association of demographic, socioeconomic, and health-related variables with being a heavy drug user; and (3) study the most frequently used drugs among heavy drug users and development in use over time. This is a descriptive study. Heavy drug users were defined as the accumulated top 1 percentile who accounted for the largest share of prescription drug use measured in number of dispensed defined daily doses (DDDs). The nationwide Danish registers were used to obtain data. Multivariable logistic binary regression was used to determine which factors were associated with being a heavy drug user. Heavy drug users among persons aged 60 years and above accounted for 6.8, 6.0, and 5.5% of prescription drug use in 2002, 2007, and 2012, respectively. Male gender, those aged 60-69 years, being divorced, shorter education, low annual income, and recent hospitalization were all significantly associated with being in the top 1 percentile group of drug users (p < 0.05). The ten most frequently used drug classes among heavy drug users accounted for 75.4% of their use in 2012, and five of these were cardiovascular drugs. The development over time for the ten most used drug classes followed the same pattern among heavy drug users and in the general population. There is a skewed utilization of prescription drugs. Contrary to earlier findings, being male was associated with heavy prescription drug use both with respect to number of drugs used and drug expenditure.

Drugs and Diseases Interacting with Cigarette Smoking in US Prescription Drug Labelling.

PubMed

Li, Haibo; Shi, Qiang

2015-05-01

The US Food and Drug Administration (FDA) draft guidance for industry on drug interaction studies recommends, but does not mandate, that both cigarette smokers and non-smokers can be used to study drug metabolism in clinical trials, and that important results related to smoking should be included in drug labelling to guide medication usage. This study aimed to provide a comprehensive review of drugs or diseases interacting with smoking, as presented in all US drug labelling. The 62,857 drug labels deposited in the FDA Online Label Repository were searched using the keywords 'smoke', 'smoker(s)', 'smoking', 'tobacco' and 'cigarette(s)' on 19 June 2014. The resultant records were refined to include only human prescription drug labelling, for manual examination. For 188 single-active-ingredient drugs and 36 multiple-active-ingredient drugs, the labelling was found to contain smoking-related information. The pharmacokinetics of 29 and 21 single-active-ingredient drugs were affected and unaffected, respectively, by smoking. For the remaining drugs, the provided information related to smoking affecting efficacy, safety or diseases but not pharmacokinetics. Depending on the nature of specific drugs, the perturbation in pharmacokinetic parameters in smokers ranged from 13 to 500%, in comparison with non-smokers. Dosage modifications in smokers are necessary for four drugs and may be necessary for six drugs, but are unnecessary for seven drugs although the pharmacokinetic parameters of four of them are affected by smoking. Cigarette smoking is a risk factor for 16 types of diseases or adverse drug reactions. For one single-active-ingredient contraceptive drug and 10 multiple-active-ingredient contraceptive drugs, a black box warning (the FDA's strongest safety warning) is included in the labelling for increased risks of heart attacks and strokes in female smokers, and "women are strongly advised not to smoke" when using these drugs. This study presents the first comprehensive overview of cigarette smoking interacting with drugs and/or diseases, as presented in US drug labelling.

Policing, massive street drug testing and poly-substance use chaos in Georgia - a policy case study.

PubMed

Otiashvili, David; Tabatadze, Mzia; Balanchivadze, Nino; Kirtadze, Irma

2016-01-16

Since early 2000, intensive policing, wide scale street drug testing, and actions aimed at limiting the availability of specific drugs have been implemented in Georgia. Supporters of this approach argue that fear of drug testing and resulting punishment compels drug users to stop using and prevents youth from initiating drug use. It has been also stated that reduction in the availability of specific drugs should be seen as an indication of the overall success of counter-drug efforts. The aim of the current review is to describe the drug-related law enforcement response in Georgia and its impact on illicit drug consumption and drug-related harm. We reviewed relevant literature that included peer-reviewed scientific articles, stand-alone research reports, annual drug situation reports, technical reports and program data. This was also supplemented by the review of relevant legislation and judicial practices for the twelve year period between 2002 and 2014. Every episode of reduced availability of any "traditional" injection drug was followed by the discovery/introduction of a new injection preparation. The pattern of drug consumption was normally driven by users' attempts to substitute their drug of choice through mixing together available alternative substances. Chaotic poly-substance use and extensive utilization of home-made injection drugs, prepared from toxic precursors, became common. Massive random street drug testing had little or no effect on the prevalence of problem drug use. Intensive harassment of drug users and exclusive focus on reducing the availability of specific drugs did not result in reduction of the prevalence of injecting drug use. Repressive response of Georgian anti-drug authorities relied heavily on consumer sanctions, which led to shifts in drug users' behavior. In most cases, these shifts were associated with the introduction and use of new toxic preparations and subsequent harm to the physical and mental health of drug consumers.

Agreement between PRE2DUP register data modeling method and comprehensive drug use interview among older persons

PubMed Central

Taipale, Heidi; Tanskanen, Antti; Koponen, Marjaana; Tolppanen, Anna-Maija; Tiihonen, Jari; Hartikainen, Sirpa

2016-01-01

Background PRE2DUP is a modeling method that generates drug use periods (ie, when drug use started and ended) from drug purchases recorded in dispensing-based register data. It is based on the evaluation of personal drug purchasing patterns and considers hospital stays, possible stockpiling of drugs, and package information. Objective The objective of this study was to investigate person-level agreement between self-reported drug use in the interview and drug use modeled from dispensing data with PRE2DUP method for various drug classes used by older persons. Methods Self-reported drug use was assessed from the GeMS Study including a random sample of persons aged ≥75 years from the city of Kuopio, Finland, in 2006. Drug purchases recorded in the Prescription register data of these persons were modeled to determine drug use periods with PRE2DUP modeling method. Agreement between self-reported drug use on the interview date and drug use calculated from register-based data was compared in order to find the frequently used drugs and drug classes, which was evaluated by Cohen’s kappa. Kappa values 0.61–0.80 were considered to represent good and 0.81–1.00 as very good agreement. Results Among 569 participants with mean age of 82 years, the agreement between interview and register data was very good for 75% and very good or good for 93% of the studied drugs or drug classes. Good or very good agreement was observed for drugs that are typically used on regular bases, whereas “as needed” drugs represented poorer results. Conclusion PRE2DUP modeling method validly describes regular drug use among older persons. For most of drug classes investigated, PRE2DUP-modeled register data described drug use as well as interview-based data which are more time-consuming to collect. Further studies should be conducted by comparing it with other methods and in different drug user populations. PMID:27785101

Clinical nutrition and drug interactions

PubMed Central

Ekincioğlu, Aygin Bayraktar; Demirkan, Kutay

2013-01-01

A drug’s plasma level, pharmacological effects or side effects, elimination, physicochemical properties or stability could be changed by interactions of drug-drug or drug-nutrition products in patients who receive enteral or parenteral nutritional support. As a result, patients might experience ineffective outcomes or unexpected effects of therapy (such as drug toxicity, embolism). Stability or incompatibility problems between parenteral nutrition admixtures and drugs might lead to alterations in expected therapeutic responses from drug and/or parenteral nutrition, occlusion in venous catheter or symptoms or mortality due to infusion of composed particles. Compatibilities between parenteral nutrition and drugs are not always guaranteed in clinical practice. Although the list of compatibility or incompatibilities of drugs are published for the use of clinicians in their practices, factors such as composition of parenteral nutrition admixture, drug concentration, contact time in catheter, temperature of the environment and exposure to light could change the status of compatibilities between drugs and nutrition admixtures. There could be substantial clinical changes occurring in the patient’s nutritional status and pharmacological effects of drugs due to interactions between enteral nutrition and drugs. Drug toxicity and ineffective nutritional support might occur as a result of those predictable interactions. Although administration of drugs via feeding tube is a complex and problematic route for drug usage, it is possible to minimise the risk of tube occlusion, decreased effects of drug and drug toxicity by using an appropriate technique. Therefore, it is important to consider pharmacological dosage forms of drugs while administering drugs via a feeding tube. In conclusion, since the pharmacists are well-experienced and more knowledgeable professionals in drugs and drug usage compared to other healthcare providers, it is suggested that provision of information and drug counselling by pharmacists in terms of detection and prevention of problems (such as interactions, stability, incompatibility) related with enteral/parenteral nutrition and drugs are invaluable in clinical practice. PMID:25931873

Dynamic enhancement of drug product labels to support drug safety, efficacy, and effectiveness

PubMed Central

2013-01-01

Out-of-date or incomplete drug product labeling information may increase the risk of otherwise preventable adverse drug events. In recognition of these concerns, the United States Federal Drug Administration (FDA) requires drug product labels to include specific information. Unfortunately, several studies have found that drug product labeling fails to keep current with the scientific literature. We present a novel approach to addressing this issue. The primary goal of this novel approach is to better meet the information needs of persons who consult the drug product label for information on a drug’s efficacy, effectiveness, and safety. Using FDA product label regulations as a guide, the approach links drug claims present in drug information sources available on the Semantic Web with specific product label sections. Here we report on pilot work that establishes the baseline performance characteristics of a proof-of-concept system implementing the novel approach. Claims from three drug information sources were linked to the Clinical Studies, Drug Interactions, and Clinical Pharmacology sections of the labels for drug products that contain one of 29 psychotropic drugs. The resulting Linked Data set maps 409 efficacy/effectiveness study results, 784 drug-drug interactions, and 112 metabolic pathway assertions derived from three clinically-oriented drug information sources (ClinicalTrials.gov, the National Drug File – Reference Terminology, and the Drug Interaction Knowledge Base) to the sections of 1,102 product labels. Proof-of-concept web pages were created for all 1,102 drug product labels that demonstrate one possible approach to presenting information that dynamically enhances drug product labeling. We found that approximately one in five efficacy/effectiveness claims were relevant to the Clinical Studies section of a psychotropic drug product, with most relevant claims providing new information. We also identified several cases where all of the drug-drug interaction claims linked to the Drug Interactions section for a drug were potentially novel. The baseline performance characteristics of the proof-of-concept will enable further technical and user-centered research on robust methods for scaling the approach to the many thousands of product labels currently on the market. PMID:23351881

Prescription Drug Abuse

MedlinePlus

... drug abuse. And it's illegal, just like taking street drugs. Why Do People Abuse Prescription Drugs? Some people abuse prescription drugs ... common risk of prescription drug abuse is addiction . People who abuse ... as if they were taking street drugs. That's one reason most doctors won't ...

Government Publications

ERIC Educational Resources Information Center

Whitlatch, Jo Bell

1977-01-01

This essay lists resources on drug information. Topics include classes of drugs, drugs which are abused, identification of drug abusers, drug education, national patterns of abuse and treatment, drug toxicity and poisoning, federal regulations, federal enforcement efforts and strategies, and the relationship of drugs and crime. (JAB)

10 CFR 26.133 - Cutoff levels for drugs and drug metabolites.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 10 Energy 1 2013-01-01 2013-01-01 false Cutoff levels for drugs and drug metabolites. 26.133... § 26.133 Cutoff levels for drugs and drug metabolites. Subject to the provisions of § 26.31(d)(3)(iii), licensees and other entities may specify more stringent cutoff levels for drugs and drug metabolites than...

10 CFR 26.133 - Cutoff levels for drugs and drug metabolites.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 10 Energy 1 2012-01-01 2012-01-01 false Cutoff levels for drugs and drug metabolites. 26.133... § 26.133 Cutoff levels for drugs and drug metabolites. Subject to the provisions of § 26.31(d)(3)(iii), licensees and other entities may specify more stringent cutoff levels for drugs and drug metabolites than...

10 CFR 26.133 - Cutoff levels for drugs and drug metabolites.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 10 Energy 1 2014-01-01 2014-01-01 false Cutoff levels for drugs and drug metabolites. 26.133... § 26.133 Cutoff levels for drugs and drug metabolites. Subject to the provisions of § 26.31(d)(3)(iii), licensees and other entities may specify more stringent cutoff levels for drugs and drug metabolites than...

75 FR 18219 - Drug and Medical Device Forum on Food and Drug Administration Drug and Device Requirements and...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-09

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2010-N-0142] Drug and Medical Device Forum on Food and Drug Administration Drug and Device Requirements and Supplier Controls; Public Educational Forum AGENCY: Food and Drug Administration, HHS. ACTION: Notice of public...