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Abnormal involuntary movement (AIM) rating scales are frequently used to study the mechanisms underlying L-DOPA-induced dyskinesia (LID) in 6-OHDA lesioned rodents and the propensity of novel treatments for Parkinson's disease to induce or alleviate similar abnormal behaviours. Despite the existence of at least one well validated method, other AIM scales are also in use. Moreover, there have been developments and variations in the original scales and their methods of use, without re-validation. In this study, 6-OHDA medial forebrain bundle lesioned Sprague-Dawley rats were treated with chronic L-DOPA 6 mg/kg/day for 5 weeks followed by 12 mg/kg/day for another 5 weeks. Rats were assessed weekly by simultaneous ratings on four published AIM and stereotypy scales with concurrent recording of rotation, over 3 hours following L-DOPA injection. Three contemporary AIM scales have then been validated pharmacologically using agents that are known to reduce LID clinically and in primates (amantadine) or to interfere with the activity of L-DOPA (the D(1) and D(2) dopamine receptor antagonists, SCH-23390 and raclopride) respectively. We also demonstrate that AIM, stereotypic and rotational behaviour are distinct motor dysfunctions induced by chronic and acute treatment of L-DOPA, and should be assessed separately. The undertaking of assessments at multiple time points is essential especially when testing the efficacy of new potential anti-dyskinetic treatments. Importantly critical to all AIM and rotation testing is the internal validation of both the scale being used and the environment being used.
1. Tardive dyskinesia (TD) is a serious side-effect of long-term treatment with neuroleptics. To investigate if neuroleptic-induced excessive stimulation of striatal glutamate receptors may underlie TD development, the effect of the NMDA antagonist, memantine (1-amino-3,5-dimethyladamantane), was studied in a rat model of TD. 2. In an acute experiment, six groups of rats were treated daily for 1 week with either vehicle or memantine 20 or 40 mg kg-1 day-1, and on the seventh day they received one injection of either haloperidol 1.0 mg kg-1 i.p. or saline i.p. In a subsequent long-term experiment lasting 20 weeks, the same treatment was continued, except that haloperidol was injected i.m. as decanoate (38 mg kg-1 every 4 weeks) and control rats received sesame oil. The behaviour was videotaped and scored at intervals during both experiments, and for 16 weeks after cessation of the long-term treatment. 3. In the acute experiment, haloperidol decreased motor activity and memantine increased moving and tended to attenuate the immobility induced by haloperidol. Memantine also enhanced the haloperidol-induced increase in the putative TD-analogue vacuous chewing movements (VCM). 4. In the long-term experiment, the most marked effect of haloperidol was a gradual increase in VCM and the increase persisted significantly for 12 weeks after cessation of treatment. Memantine dose-dependently increased VCM and moving during long-term treatment. However, only one week after stopping treatment, both these effects of memantine disappeared. In contrast to rats previously treated with haloperidol alone, rats co-treated with memantine (both doses) and haloperidol had VCM at the level of controls two weeks after stopping treatment. The blood levels of drugs were within the therapeutic range achieved in human subjects. 5. These results suggest that long-lasting changes induced by haloperidol are prevented by memantine, which supports the theory that excessive NMDA receptor stimulation may be a mechanism underlying the development of persistent VCM in rats and maybe also TD in human subjects.
Notwithstanding the advent of clozapine and other 'atypical' antipsychotic agents, the conventional ('typical') antipsychotic agents remain in widespread use. Antipsychotic-induced parkinsonism is a highly prevalent adverse effect that may result in increased morbidity and noncompliance. Bedside examination is generally sufficient for the detection of the onset of parkinsonism and should be carried out frequently in the first 3 months of treatment. In addition to decreasing patient discomfort, monitoring for antipsychotic-induced parkinsonism also serves to identify the minimally effective dosage required for the individual patient. Several strategies are utilised in the management of antipsychotic-induced parkinsonism including dosage reduction, switching to other antipsychotic agents and the use of antiparkinsonian drugs such as anticholinergic agents and amantadine. Anticholinergic agents remain the mainstay of the pharmacological management of antipsychotic-induced parkinsonism in younger patients. Amantadine is a better tolerated agent for elderly patients, with similar efficacy to the anticholinergic agents. The routine use of prophylactic anticholinergics is not recommended and is clearly contraindicated in the elderly. An individualised risk-benefit assessment is necessary for the younger patient in whom prophylactic use of anticholinergic drugs is considered.
Amantadine hydrochloride decreases the sensitivity of denervated mammalian muscle to iontophoretically applied acetylcholine. The drug depresses the amplitude of the end-plate current and reverses the slope of the relation between half-decay time and membrane potential suggesting that it alters the ionic conductance that is mediated by the acetylcholine receptor. Binding studies confirm that amantadine acts on the ion conductance modulator rather than the acetylcholine receptor.
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Isolation and characterization of the influenza virus A/H5N1 strains, isolated from chicken in the Yandovka village (Tula Region) and from wild swan near the orifice of the Volga River that died during an outbreak of avian flu in autumn 2005, were carried out. Genetic and phylogenetic analyses were performed. The goals of the analysis were to determine possible geographical origin of the strain, genetic similarity of isolated strains to earlier sequenced isolates, epidemic potential, existence of pathogenicity markers, and resistance to antiviral drugs. It was shown that the isolated influenza virus belonged to highly pathogenic variants of China origin by a reassortment of viruses genotypes Z and V circulated in poultry and wild birds. A number of molecular markers of pathogenicity to gallinaceous birds and mammals were found out. Mutations in the hemagglutinin gene promoting potentially high rate of replication in humans as well as mutations causing the resistance to amantadine/rimantadine were not found. The strain isolated from wild swan had the mutation causing resistance to tamiflu/ozeltamivir.
Early pharmacological treatment has the potential to reduce some of the disabling cognitive and behavioral problems that result from traumatic brain injury (TBI). Although a large number of treatments have been developed, clinical research has yielded inconsistent findings with respect to the effectiveness of these pharmacological treatments on cognitive and behavioral outcomes. Furthermore, their relative efficacy has not been evaluated, thereby hindering advances in the treatment of TBI. A meta-analysis of research that examined the impact of pharmacological treatments on cognitive and behavioral outcomes in the early stages after TBI between January 1980 and May 2008 was therefore undertaken. The PubMed and PsycINFO databases were searched using 35 terms. All articles were screened using detailed inclusion criteria. Weighted Cohen's d effect sizes, percent overlap statistics, and fail-safe N statistics were calculated for each pharmacological agent. Studies that used different experimental designs were examined separately. Eleven pharmacological treatments were investigated by 22 clinical studies, comprising 6472 TBI patients in the treatment groups and 6460 TBI controls. One dopamine agonist (amantadine) and 1 bradykinin antagonist (CP-0127 [Bradycor]) produced marked treatment benefits (d > or = 0.8) for a single measure of arousal (Glasgow Coma Scale). Notably, drug dosage and the measure chosen to assess outcome influenced the probability of finding a treatment benefit.
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A dramatic surge in oseltamivir-resistant A(H1N1) viruses possessing the NA-H274Y substitution was detected in Japan during the 2008-2009 season. The emergence of oseltamivir-resistant viruses was facilitated by mutations in the viral genome. Intensified surveillance, including phenotypic assays and sequencing of the hemagglutinin, neuraminidase, and M2 gene would allow monitoring of the spread and evolution of drug-resistant influenza virus variants.
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The recently announced discontinuation of Namenda (memantine HCl) and consequent shortage of Namenda XR (memantine HCl extended-release) is a matter that affects physicians, patients with Alzheimer's disease, caregivers, and consultant pharmacists. The manufacturer's announcement to discontinue standard-release product came eight months after the extended-release formulation became available in June 2013. The manufacturer planned to discontinue the standard-release tablets to focus on XR capsules by August 2014, giving patients and their caregivers-who prefer immediate-release formulations-no other options except the oral solution formulation. This article updates pharmacists with the current development on the various pharmacy and therapeutic issues on memantine products. Consultant pharmacists play an important role in educating prescribers and caregivers of the recent changes on this matter. They shall help to ensure proper dosage switching among various formulations. Consultant pharmacists can also help caregivers to identify the most cost-effective options when generic memantine becomes available in the future.
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Over the last six years, eight new substances for the treatment of idiopathic parkinsonism (IP) have been approved for use: four oral and one parenteral dopamine agonist (apomorphine), two COMT-inhibitors and budipine. The old drug amantadine has experienced a renaissance in the treatment of a complication occurring during long-term treatment of IP, namely levodopa-induced dyskinesia. Deep brain stimulation with programmable pulse generators and stereotactically implanted electrodes are increasingly being used in patients with severe on-off phases and levodopa dyskinesia. The treatment of Parkinson's disease unresponsive to dopaminergic substances and that associated with dementia remains problematical. In combinations of parkinsonism and dementia, the cholinesterase inhibitors are being used in particular for Lewy body dementia.
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Alzheimer's disease (AD) is the most common form of dementia in Western countries. The benefits presently observed with the approved treatments are mainly symptomatic without clear evidence of neuroprotection. N-methyl-D-aspartate (NMDA) receptor antagonists have very extensive therapeutic potential in several central nervous system disorders and can be used as neuroprotective treatment in chronic neurodegenerative diseases and as symptomatic treatment in other neurologic diseases as epilepsy. Memantine, an antagonist of the glutamatergic NMDA receptor, has been recently approved for the treatment of advanced AD. Due to its action mechanism, memantine is considered a neuroprotective drug, whose utility has been demonstrated in preclinical studies, and a useful symptomatic treatment for AD and vascular dementia. We will review both aspects as well as the basic mechanisms mediating glutamatergic neurodegeneration and the implication of glutamate in cognition.
The comparative preventive effect of curcumin, memantine, and diclofenac on scopolamine-induced memory dysfunction was investigated in a controlled study. A group of male and female rats was treated with one of these compounds for 15 days, after which a single dosage of scopolamine was administered. The preventive activity of curcumin on memory dysfunction was higher than that of diclofenac or memantine, that was, however, administered at lower dosages. Gender differences were observed.
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Spiro[aziridine-2,2'-adamantanes] 1 and 2, spiro[azetidine-2,2'-adamantanes] 3 and 5, spiro[azetidine-3,2'-adamantane] 13, spiro[piperidine-4,2'-adamantanes] 25 and 27, and spiro barbituric analog 18 were synthesized and tested for their anti-influenza A virus properties and for trypanocidal activity. The effect of ring size on potency was investigated. Piperidine 25 showed significant anti-influenza A virus activity, being 12-fold more active than amantadine, about 2-fold more active than rimantadine, and 54-fold more potent than ribavirin. It also proved to be the most active of the compounds tested against bloodstream forms of the African trypanosome, Trypanosoma brucei, being 1.5 times more potent than rimantadine and at least 25 times more active than amantadine.
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In a review of 734 published cases of neuroleptic malignant syndrome (NMS), we found 665 with sufficient data to allow statistical analyses. Forty-eight received ECT either during or shortly after an episode of NMS and were compared to control cases who received no specific treatment for their episode. We also compared the mortality rates in these two groups to data previously analyzed for specific drug treatments (i.e., amantadine, bromocriptine, L-dopa, and dantrolene). We find a substantially better outcome in the specific drug-treated (mortality rate of 9.7%) or ECT-treated (mortality rate of 10.3%) groups compared to the group receiving no specific treatment (mortality rate of 21%). We conclude that ECT is safe to use shortly after an episode of acute NMS has resolved and, furthermore, that ECT is probably safe in the actual treatment of NMS provided concomitant neuroleptics are discontinued.
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To determine, using anatomic measurements, whether daily oral dosing with memantine is both safe and effective to reduce the injury associated with experimental glaucoma in primates.
The emergence of resistance to amantadine in influenza A viruses has been shown to occur rapidly during treatment as a result of single-amino-acid substitutions at position 26, 27, 30, 31, or 34 within the transmembrane domain of the matrix-(M)-2 protein. In this study, reverse genetics was used to generate and characterize recombinant influenza A (H1N1) viruses harboring L26F, V27A, A30T, S31N, G34E, and V27A/S31N mutations in the M2 gene. In plaque reduction assays, all mutations conferred amantadine resistance, with drug concentrations resulting in reduction of plaque number by 50% (IC(50)s) 154- to 3,300-fold higher than those seen for the wild type (WT). M2 mutants had no impairment in their replicative capacities in vitro on the basis of plaque size and replication kinetics experiments. In addition, all mutants were at least as virulent as the WT in experimentally infected mice, with the highest mortality rate being obtained with the recombinant harboring a double V27A/S31N mutation. These findings could help explain the frequent emergence and transmission of amantadine-resistant influenza viruses during antiviral pressure in the clinical setting.
We evaluated the effect of memantine administration from baseline on Clinical Global Impression-Improvement scale, mini mental state examination (MMSE), Clock Drawing Test (CDT), Neuropsychiatric Inventory (NPI), Japanese version of the Zarit Burden Interview (J-ZBI) and NIRS in two groups, donepezil administration memantine combination group (combination group, n = 19) donepezil administration memantine non-administration group (control group, n = 18) were assessed at weeks 0, 4, 12, and 24.
Rimantadine-resistant and -sensitive influenza A variants were assayed for their sialidase (neuraminidase, EC 184.108.40.206) activity. The kinetic parameters determined (pH optimum, stability against different pH values, thermal stability, activity on methylumbelliferyl-alpha-D-N-acetylneuraminic acid, N-acetylneuraminyl-lactose, fetuin and bovine submandibular gland mucin as substrates, Km with the former substrate, inhibition by two competitive inhibitors, and behavior towards amantadine) revealed the same results for both variants of the virus. Thus, it can be deduced that resistance to rimantadine does not influence the sialidase activity of influenza A virus.
Memantine at a dose of 30 mg/day may induce transient worsening of neurologic symptoms of multiple sclerosis.
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The aim of this study was to review the current literature on the efficacy and tolerability of memantine in the treatment of AD and VD.
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The current study confirms that CD81 expression is down regulated by SOC on CD4(+), CD8(+) and CD56(+) cells. Amantadine treatment was not associated with CD81 expression. Interaction between amantadine and CD81 is unlikely to be involved in potential antiviral activity of amantadine in chronic HCV infection.
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OKA (200 ng) intracerebroventricular (i.c.v.) was administered in rats. Memory was assessed by Morris water maze test. Biochemical marker of neuroinflammation (TNF-α, IL-β), total nitrite, mRNA (RT PCR) and protein expression (WB) of iNOS and nNOS were estimated in rat brain areas.
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Physiological levels of H(2)S exert neuroprotective effects, whereas high concentrations of H(2)S may cause neurotoxicity in part via activation of NMDAR. To characterize the neuroprotective effects of combination of exogenous H(2)S and NMDAR antagonism, we synthesized a novel H(2)S-releasing NMDAR antagonist N-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-4-(3-thioxo-3H-1,2-dithiol-4-yl)-benzamide (S-memantine) and examined its effects in vitro and in vivo. S-memantine was synthesized by chemically combining a slow releasing H(2)S donor 4-(3-thioxo-3H-1,2-dithiol-4-yl)-benzoic acid (ACS48) with a NMDAR antagonist memantine. S-memantine increased intracellular sulfide levels in human neuroblastoma cells (SH-SY5Y) 10-fold as high as that was achieved by ACS48. Incubation with S-memantine after reoxygenation following oxygen and glucose deprivation (OGD) protected SH-SY5Y cells and murine primary cortical neurons more markedly than did ACS48 or memantine. Glutamate-induced intracellular calcium accumulation in primary cortical neurons were aggravated by sodium sulfide (Na(2)S) or ACS48, but suppressed by memantine and S-memantine. S-memantine prevented glutamate-induced glutathione depletion in SH-SY5Y cells more markedly than did Na(2)S or ACS48. Administration of S-memantine after global cerebral ischemia and reperfusion more robustly decreased cerebral infarct volume and improved survival and neurological function of mice than did ACS48 or memantine. These results suggest that an H(2)S-releasing NMDAR antagonist derivative S-memantine prevents ischemic neuronal death, providing a novel therapeutic strategy for ischemic brain injury.
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Alzheimer's disease (AD) prevalence rates in the United States are expected to triple over the next 50 years, a consequence of the overall aging of the U.S. population. Because of the profound and far-reaching impact of AD, this projected increase in prevalence is expected to pose a tremendous challenge. Alzheimer's disease results in the cognitive and functional deterioration of the affected patient, and behavioral disturbances frequently accompany the disease. Furthermore, because of its progressive and debilitating nature, AD takes a dramatic emotional, physical, and financial toll on the patient's primary caregiver. Nonetheless, despite the burden experienced by both patients and caregivers, strategies for minimizing the negative consequences of AD are well characterized. Central to the successful management of AD is the prompt and accurate diagnosis of the disease, with current guidelines calling for a 2-tiered approach in which patients first undergo screening using a brief cognitive assessment tool, followed by a comprehensive battery of physical, psychological, and neurologic tests if signs of possible cognitive impairment are evident upon screening. Once a conclusive diagnosis of AD has been made, the development of a disease management approach targeting the needs of the patient and his or her caregiver becomes a primary concern. Pharmacologic interventions may play an important role in such approaches, as agents such as cholinesterase inhibitors and the N-methyl-D-aspartate receptor antagonist memantine have been associated with favorable outcomes for patients and caregivers alike. However, in addition to the therapeutic benefits of these agents, associated side effects and potential drug-drug interactions must also factor into decisions regarding the pharmacologic treatment of AD.
Concurrent potent therapy of hepatitis C (HCV) and HIV includes at least five antiviral drugs. Drug interactions, toxicity, tolerance and acceptance by patients of such treatment regimens are unknown.
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These results suggest that while memantine may attenuate the conditioned reinforcing effects of cocaine-associated stimuli, it may also occasion increase levels of cocaine self-administration. These findings support the hypothesis that the NMDA receptor can play a role in modulating the conditioned and primary reinforcing effects of cocaine.
This study suggests that specific drugs for AD, especially memantine and rivastigmine, may be effective in the improvement of BPSD in patients with mild to moderate AD, without major side effects.
In our non-blind comparative study, amantadine was as effective as the standard medications, benztropine and ethopropazine, in controlling drug-induced extrapyramidal signs. However, statistically significant improvement was noted a week after all the three medications. In addition, extrapyramidal signs were not completely controlled in most patients even after weeks, even though substantial improvement was noted. This indicates the limitations of the currently available antiparkinsonian medications. Amantadine produced least side effects. Therefore, it may be particulary useful in patients who may not tolerate antiparkinsonian medication with anticholinergic properties. Our clinical finding that two patients with depression improved was rather interesting and needs further exploration. In summary, anamtadine is a valuable addition to our armamentarium of antiparkinsonian drugs. The drug compared favourably with other standard medications. The problem of dissipation of the therapeutic effects over time was not studied in our trial.