Memantine (MEM) is currently in clinical use in Europe for the treatment of various neurological disorders. It is a low-affinity channel blocker of N-methyl-D-aspartate (NMDA) receptors whose voltage-dependent, rapid binding kinetics are believed to limit its phencyclidine (PCP)-like side effects. MEM, and its analog amantadine (AMA), which has also been demonstrated to have some NMDA antagonist activity, were evaluated for PCP-like behavioral effects. The discriminative stimulus properties of MEM and AMA were tested in monkeys and rats trained to discriminate PCP from saline using a standard two-lever drug discrimination paradigm under a fixed ratio (FR) schedule of food reinforcement. In rats, MEM resulted in a dose-dependent substitution for PCP; however, full substitution occurred only at response rate suppressing doses. AMA failed to substitute for PCP at any dose tested. For MEM, all four monkeys showed complete substitution for PCP at doses which did not greatly decrease rates of responding. Conversely, AMA occasioned little or no responding on the PCP-associated level in any of the subjects. Intravenous self-administration of MEM and AMA was tested under a FR schedule of reinforcement in four monkeys trained to lever press for infusions of PCP. MEM served as a reinforcer in all subjects at one or more doses tested. For two of the subjects, at least one dose of AMA maintained rates of self-administration above those for saline. For both MEM and AMA, maximal response rates were considerably lower than with PCP self-administration and both drugs were much less potent in monkeys than would be predicted from rodent studies. The data show that MEM shares discriminative stimulus effects with PCP under these testing conditions, whereas the chemically similar compound AMA does not. MEM also serves as a positive reinforcer in rhesus monkeys, whereas AMA can serve as a weak reinforcer in only some subjects. Both AMA and MEM are reported to function as NMDA antagonists, yet clear differences exist in their behavioral effects with MEM acting more like a PCP-like antagonist. In addition, despite the rapid channel kinetics of MEM's NMDA receptor blockade, it may have some PCP-like abuse potential in humans at doses above the normal therapeutic levels.
Similar to RCTs, LTOCs have shown that both monotherapy and combination therapy are associated with slower cognitive and functional decline. Combination therapy is associated with better cognitive outcomes and greater delays in time to nursing home admission versus monotherapy or no treatment. Persistent antidementia drug treatment is associated with slower decline in cognition, daily function, and global severity, even in patients with advanced disease.
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In the YAC128 mouse model of Huntington disease (HD), elevated extrasynaptic NMDA receptor (Ex-NMDAR) expression contributes to the onset of striatal dysfunction and atrophy. A shift in the balance of synaptic-extrasynaptic NMDAR signaling and localization is paralleled by early stage dysregulation of intracellular calcium signaling pathways, including calpain and p38 MAPK activation, that couple to pro-death cascades. However, whether aberrant calcium signaling is a consequence of elevated Ex-NMDAR expression in HD is unknown. Here, we aimed to identify calcium-dependent pathways downstream of Ex-NMDARs in HD. Chronic (2-month) treatment of YAC128 and WT mice with memantine (1 and 10mg/kg/day), which at a low dose selectively blocks Ex-NMDARs, reduced striatal Ex-NMDAR expression and current in 4-month old YAC128 mice without altering synaptic NMDAR levels. In contrast, calpain activity was not affected by memantine treatment, and was elevated in untreated YAC128 mice at 1.5months but not 4months of age. In YAC128 mice, memantine at 1mg/kg/day rescued CREB shut-off, while both doses suppressed p38 MAPK activation to WT levels. Taken together, our results indicate that Ex-NMDAR activity perpetuates increased extrasynaptic NMDAR expression and drives dysregulated p38 MAPK and CREB signaling in YAC128 mice. Elucidation of the pathways downstream of Ex-NMDARs in HD could help provide novel therapeutic targets for this disease.
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The eight-week repeated-measures mixed-effect model for HDRS was not significant for memantine (n = 14) versus placebo (n = 15). Exploratory mixed-effect analyses for the first four weeks, while the memantine dose was being titrated up every week, revealed a significant decrease in HDRS scores from baseline (p = 0.007).
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Eight boys and one girl ages 9-16 years and their parents consented to an open trial of amantadine 100 mg po bid or tid for weight gain in children. Side effects and body mass index were determined at baseline and during amantadine treatment.
A tertiary referral center.
Adamantanamines 16, 18, 21, 24, 27, 28, 30, 32, 35, 36, 37, 40, 46 and 48 were synthesized and tested for anti-influenza A virus and trypanocidal activity. The stereoelectronic requirements for optimal antiviral and trypanocidal potency were investigated. The effect of introducing a hydroxyl group close to the amino group on this class of compounds was examined for the first time. Aminoalcohol 24 proved to be the most active of the compounds tested against influenza A virus, being 6-fold more active than amantadine, equipotent to rimantadine and 26-fold more potent than ribavirin. Aminoalcohols 36 and 37 were found to have considerable activity against bloodstream forms of the African trypanosome, Trypanosoma brucei, being almost 10 times more potent than rimantadine.
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To determine (i) whether early viral kinetics or other markers during a modified treatment regimen are predictors of treatment outcome and (ii) whether fast responders can be treated for 24 weeks, without compromising the sustained virologic response (SVR) rate.
The course of pathological gambling (PG) in women has been described as having a later age of initiation but a shorter time to problematic gambling ("telescoped"). This study examined evidence for telescoping and its relationship with comorbidities. Seventy-one treatment-seeking individuals with PG underwent a diagnostic interview to examine gambling behaviors, age at initiation of gambling, and time from initiation to meeting criteria for PG. The women had a higher mean age at gambling initiation compared with that of the men (mean [SD] age, 31.3 [13.0] years, compared with 22.4 [7.9] years; p = 0.0003) and a significantly shorter time from initiation of gambling to meeting the criteria for PG (8.33 [8.7] years compared with 11.97 [9.1] years; p = 0.0476) after controlling for demographic and clinical variables. This study presents evidence for a gender-specific course of PG unrelated to psychiatric comorbidities and suggests a need for greater clinical focus on the gender differences of gambling behavior.
Rage reaction was induced in mice by ip amphetamine sulfate (APT) 15 mg/kg. Mice appeared hyperreactive after 6 min and then squeaked and fought each other. These manifestations were most distinct in 15-30 min and subsided after 40-70 min. At 20 degrees C and 25 degrees C, the occurrence of rage reaction was 85.0% and 90.0% respectively. The ED50 of APT for eliciting rage reaction was 11.8 +/- 2.1 mg/kg ip. No significant difference in the induction of rage reaction was observed between male and female mice but ambient temperature affected the occurrence of this reaction. Neuroleptic drugs (chlorpromazine, haloperidol, tardan and clozapine), anxiolytic drugs (diazepam and meprobamate) and reserpine suppressed the rage reaction induced by APT in mice. Phenobarbital and pentobarbital (at sedative doses), atropine, scopolamine, phentolamine and propranolol exerted no influence on APT--induced rage reaction. Amantadine, levodopa and apomorphine at lower doses potentiated the rage inducing effect of APT. Moreover, at higher doses amantadine or levodopa alone also evoked rage reaction similar to that induced by APT. Therefore, it may be deduced that the APT-induced rage reaction results from increased release of dopamine in limbic system and has nothing to do with the simultaneous epinephrine release. The available data indicate that the APT--induced rage reaction in mice deserves to be recommended as an animal model for screening potential neuroleptic drugs. The merits and shortcomings of this new model are discussed.
The association between weight gain and lack of cognitive restraint in the presence of increased appetite suggests potential benefit of psychoeducational counseling in conjunction with adjunctive pharmacotherapeutic agents in limiting weight gain during antipsychotic drug therapy.
Initially, participants were trained to discriminate 10 mg methamphetamine from placebo using a standard two-response procedure (drug versus placebo). Then, the effects of memantine (0, 40 mg) on methamphetamine discrimination were examined across several methamphetamine doses (0, 5, 10, 20 mg) using a novel-response procedure (drug versus placebo versus novel).
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A fast and reliable nuclear magnetic resonance spectroscopic method for quantitative determination (qNMR) of targeted molecules in reference materials has been established using the ERETIC2 methodology (electronic reference to access in vivo concentrations) based on the PULCON principle (pulse length based concentration determination). The developed approach was validated for the analysis of pharmaceutical samples in the context of official medicines control, including ibandronic acid, amantadine, ambroxol and lercanidipine. The PULCON recoveries were above 94.3% and coefficients of variation (CVs) obtained by quantification of different targeted resonances ranged between 0.7% and 2.8%, demonstrating that the qNMR method is a precise tool for rapid quantification (approximately 15min) of reference materials and medicinal products. Generally, the values were within specification (certified values) provided by the manufactures. The results were in agreement with NMR quantification using an internal standard and validated reference HPLC analysis. The PULCON method was found to be a practical alternative with competitive precision and accuracy to the classical internal reference method and it proved to be applicable to different solvent conditions. The method can be recommended for routine use in medicines control laboratories, especially when the availability and costs of reference compounds are problematic.
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Electrophysiological assays on mammalian central neurons in monolayer dissociated cell culture allow classification of clinically used anticonvulsant drugs on a mechanistic basis and predict their clinical spectrum of anticonvulsant efficacy consistently in comparison with data from animal models. Clinical anticonvulsant efficacy of memantine and flunarizine against tonic-donic and partial seizures is predicted on the basis of ability to limit sustained high efficacy frequency repetitive firing of sodium-dependent action potentials and to suppress depolarizing burst firing of neocortical, hippocampal and spinal cord neurons in cell culture. Effects on voltage-sensitive sodium channels, and possibly potassium channels, may explain, at least in part, the mechanism of anticonvulsant efficacy of memantine and flunarizine.
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The action of the amantadine derivative memantine on the dopamine metabolism in the striatum and the n. accumbens of the rat was studied in vivo with different voltammetrical techniques. It was shown by differential pulse voltammetry that memantine enhanced extracellular levels of dopamine (DA) in the striatum of the anaesthetized rat, whereas an increase of 3,4 dihydroxyphenylacetic acid (DOPAC) could be observed only under freely moving conditions using square wave voltammetry. Under chloral hydrate anaesthesia the effect of memantine on extracellular DOPAC levels in the striatum and the n. accumbens was compared with MK-801, a well-known non-competitive NMDA-antagonist. Memantine did not affect striatal DOPAC concentrations under these conditions whereas MK-801 reduced the DOPAC signal. In the n. accumbens memantine enhanced the levels of extracellular DOPAC, while after MK-801 the signal was only slightly different from control. These findings suggest that in addition to its NMDA receptor antagonism, memantine affects dopaminergic transmission also by other mechanisms.
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Amantadine may be an effective and safe treatment for TD. The severity of TD movements in patients receiving amantadine improved significantly more than in those receiving placebo, as measured by the AIMS score.
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Both groups were treated with the standard therapy of severe head injury accepted in our institution. In addition, group 1 patients received amantadine sulphate in a dose of 200 mg i.v. twice daily for 3 days, starting on day 3 of hospitalisation. The reason for amantadin sulphate administration was persistent comatos condition.
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Alzheimer's disease is characterized by a progressive decline in cognitive function and involves β-amyloid (Aβ) in its pathogenesis. To characterize cognitive deficits associated with Aβ accumulation, we analyzed PS1/APP mice overexpressing mutant presenilin-1 (PS1, M146L; line 6.2) and amyloid precursor protein (APP, K670N/M671L; line Tg2576), a mouse model of Alzheimer's disease with accelerated Aβ production. Age-dependent changes in working and spatial memory behaviors were investigated using Y-maze and Morris water maze tasks, respectively, in female PS1/APP mice at ages of 2, 4, 6, and 12 months. Significant deficits in working and spatial memory were observed from 4 and 6 months of age, respectively. Acute single-dose administrations of memantine, a low-to-moderate-affinity N-methyl-d-aspartate (NMDA) antagonist, showed improvements in working memory deficits at 4 months of age, whereas donepezil, an acetylcholinesterase (AChE) inhibitor, did not. However, both drugs improved spatial memory dysfunction at 6 months of age at therapeutically relevant doses. No age-related dramatic changes were observed in expression levels of several proteins relating to memory dysfunction and also the mechanisms of donepezil and memantine in the cerebral cortex of PS1/APP mice until 6 months of age. Taken together, these results suggest dysfunctions in cholinergic and/or glutamatergic transmissions may be involved in the cognitive deficits associated with Aβ toxicity. Since donepezil and memantine have been widely used for treating patients of Alzheimer's disease, these results also suggest that cognitive deficits in PS1/APP mice assessed in the Y-maze and Morris water maze tasks are a useful animal model for evaluating novel Alzheimer's disease therapeutics.
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This trial did not detect significant statistical or effect size differences between memantine and placebo augmentation among nonresponders or poor responders to conventional antidepressants. While the small number of participants is a limitation, this study suggests memantine lacks substantial efficacy as an augmentation treatment for major depressive disorder.
Senior management representatives from affected parts of the Regional Health Authority.
Delayed cerebral vasospasm is an important pathological feature of subarachnoid hemorrhage (SAH). The cause of vasospasm is multifactorial. Impairs nitric oxide availability and endothelial nitric oxide synthase (eNOS) dysfunction has been reported to underlie vasospasm. Memantine, a low-affinity uncompetitive N-methyl-d-aspartate (NMDA) blocker has been proven to reduce early brain injury after SAH. This study investigated the effect of memantine on attenuation of vasospasm and restoring eNOS functionality. Male Sprague-Dawley rats weighing 350-450 g were randomly divided into three weight-matched groups, sham surgery, SAH + vehicle, and SAH + memantine groups. The effects of memantine on SAH were evaluated by assessing the severity of vasospasm and the expression of eNOS. Memantine effectively ameliorated cerebral vasospasm by restoring eNOS functionality. Memantine can prevent vasospasm in experimental SAH. Treatment strategies may help combat SAH-induced vasospasm in the future.
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Amantadine-HC1, an antiviral drug clinically effective against most strains of influenza A virus, was evaluated in a double-blind trial in 153 children with cystic fibrosis during the initial appearance of influenza A/England/42 virus in the New England area. Infection with this variant strain of influenza virus did not reach epidemic proportions during the study, so that the effectiveness of amantadine in this study population could not be fully assessed. However, the potential symptomatic and biochemical toxicity of amantadine was carefully monitored in a pediatric population. Serologic screening by complement fixation tests indicated that respiratory viruses may be important pathogens in exacerbations of respiratory disease in patients with cystic fibrosis.
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The effect of L(+)-, D(-)- and racemic (DL)-lactate on the energy-dependent renal uptake of the achiral organic cation amantadine was determined with purified proximal and distal cortical tubule fragments isolated from rat kidneys. Kinetic parameters for uptake of amantadine were measured, under constant pH, in bicarbonate buffer (Krebs-Henseleit [KHS]), and in lactate buffers (5 mM) with different proportions of the enantiomers. Km for amantadine uptake increased in all lactate buffers compared with KHS for both proximal and distal tubules. Km for uptake in DL-lactate was similar to that in D(-)-lactate for proximal tubules and to L(+)-lactate in distal tubules, but Km in L(+)-lactate was higher than in D(-)-lactate for both tubules. Maximal transport capacity (Vmax) in DL-lactate and mixtures of enantiomers were similar to KHS but higher than in pure L(+)- and D(-)-lactate. In KHS, lactate inhibited energy-dependent amantadine uptake in a biphasic manner. Graded competitive inhibition of amantadine uptake was observed between 1 and 15 mM lactate for both proximal and distal tubules. This first phase (1-15 mM) inhibited 60% of amantadine uptake. The second phase (15-20 mM lactate) showed a much steeper slope and inhibited the remaining amantadine uptake. There were no differences in inhibitory potencies of the lactate enantiomers for either proximal tubules or distal tubules amantadine tubule uptake. Our present studies suggest that L(+)- and D(-)-lactate modulate amantadine transport by interacting directly with the bicarbonate-dependent transport mechanism(s).
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The full-size genomes of 2 highly pathogenetic avian influenza (HPAI) virus strains isolated from a wild great-crested grebe (A/Grebe/Novosibirsk/29/05) and a domestic duck (A/Duck/Novosibirsk/56/05) in the tract of the Chany hollow, Barabino forest-steppe (Novosibirsk Region) during the epizootic outbreak in the summer of 2005. The reproductive properties of these strains successively increase in the series of cell lines BHK-2 --> LEH --> Vero-E6 --> MDCK --> PS. A/Grebe/Novosibirsk/29/05 and A/Duck/Novosibirsk/56/05 were shown to be genetically close in all genomic segments to both each other and a group of HPAI/H5N1 A/Qinghai 05 strains isolated from wild birds on the Kukunor Lake in the northwestern province of Tsinkhai, China, in May 2005. All the above strains have the HPAI/H5-specific amino acid sequence of a proteolytic cleavage site (PQGERRRKKRGLF) with Lys-627 in the protein PB2 (which is associated with increased virulence to mammalian cells), Glu-92 in the protein NS1 (that suppresses an antiviral response in the host), Ser-31 in M2 (that is a marker of rimantadine/amantadine sensitivity), 20-member amino acid deletion in the protein NA (positions 49-68) that is a marker of affiliation to the so-called genotype Z and of increased tropism to poultry.
We herein report the findings of a 2-year-6-month-old boy, who had been experiencing monocular pendular nystagmus, strabismus, and episodic eye deviation nystagmus, intractable dystonia and apneic attack which all began when he was 2 days of age. He underwent a complete blood count test, blood chemistry test, analysis of amino acids in the blood and urine, analysis of pyruvate/lactate in blood and cerebrospinal fluid, head computed tomography and magnetic resonance imaging and no abnormal results were identified. His attacks were resistant to multiple antiepileptic and dopaminergic drugs. He showed transient left and/or right hemiplegia after nystagmus, dystonia and/or apneic attacks at 8-months of age with retardation in intelligence. We diagnosed him to have alternating hemiplegia of childhood (AHC). We were unsure how to deal with his attacks after he was discharged from the hospital, however, resuscitation with the ambu bag by his mother at home and the intravenous infusion of diazepam or thiamylal at the hospital together was proven to be an effective method for treating his severe apneic attacks. The effect of diazepam and amantadine on these attacks was transient, however, the administration of flunarizine with amantadine resulted in an improvement in his attacks. We therefore consider the administration of flunarizine to be essential for the effective treatment of AHC in this case.
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Despite evidence of "bioactivity", under the specific experimental conditions of this study, neither direct nor indirect DA agonists had robust effects on startle or PPI. In some cases (for example, amantadine), a time course was identified that will facilitate future studies of DA agonist effects on PPI in humans.
The results demonstrated that N30 inhibited the replication of H1N1, H3N2, influenza B viruses, including oseltamivir and amantadine resistant strains in vitro. Mechanistically, neuraminidase inhibition assay and hemagglutination inhibition assay suggested that N30 did not directly target the two envelope glycoproteins required for viral adsorption or release. Instead, the compound could depress the activity of IMPDH type II. Based on these findings, we further confirmed that N30 provided a strong inhibition on the replication of respiratory syncytial virus, coronavirus, enterovirus 71 and a diverse strains of coxsackie B virus.
Amantadine (AMA) has been described as dopamine stimulant and norepineprhine release, capable to block the N-methyl-D aspartate (NMDA) glutamatergic and nicotinic receptors, enhancing the sexual behavior of the male rats and inducing hypersexuality in humans. The use of technetium-99m (99mTc) can be justified for its physical and chemical properties. The aim of this study was to label and evaluate the bioavailability of the AMA labelled with 99mTc (99mTc-AMA) in Wistar female rats. The solution of 99mTc-AMA was administered by intraperitoneal way and the animals were sacrificed in CO2 chamber 10 min after the administration of the radiotracer. Various organs were removed, weighted, their radioactivity was determined using an auto-gamma counter and the results were expressed as the percentage of the injected activity per gram of tissue (%ATI/g). In the control group only Na99mTcO4 was administered. The analysis of results shows that the highest uptakes 99mTc-AMA treated group were: ovary (7.11 +/- 1.43), spleen (3.54 +/- 1.05), thyroid (2.67 +/- 0.15), stomach (1.56 +/- 1.10), duodenum (0.87 +/- 0.52), muscular tissue (0.57 +/- 0.06), liver (0.52 +/- 0.25), and at control group: thyroid (16.45 +/- 2.57), ovary (1.28 +/- 0.12), liver (1.10 +/- 0.04), spleen (0.57 +/- 0.07) and muscular tissue (0.26 +/- 0.03). The results obtained suggest that 99mTc-AMA may be used to study the bioavailability of amantadine and evaluate its effect in sexual behavior in female rats.
The high proportion of influenza A viruses currently circulating in the United States demonstrating adamantane resistance highlights the clinical importance of rapid surveillance for antiviral resistance. Our results indicate that these drugs should not be used for the treatment or prophylaxis of influenza in the United States until susceptibility to adamantanes has been reestablished among circulating influenza A isolates.