Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new ebixa research articles will be listed here shortly after becoming available to us.
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Arzneimittelforschung. 2008; 58(5): 255-8
Erkent U, Koytchev R
The bioequivalence of long terminal half-life drugs, donepezil (CAS 120014-06-4) 10 mg and memantine (CAS 19982-08-2) 10 mg, was evaluated by comparing the results obtained for the total areas under the concentration time curves (AUC(0-inf)) with those for partial AUCs: AUC(0-216h), AUC(0-72h) and AUC(0-48h). Pharmacokinetic endpoints were determined by standard formulas from the concentration-time courses of the parent compounds donepezil and memantine. The results of the bioequivalence assessment based on the 90% confidence intervals calculated by means of ANOVA for logarithmically transformed values (ANOVA log) led to exactly the same decision irrespective of the type of AUC used. The 90% confidence intervals for all types of AUCs were practically identical within each product. These results prove that truncated AUCs, e.g. AUC(0-72h) or even AUC(0-48h), can be adequately used in assessing the relative bioavailability of long terminal half-life drugs. The findings suggest that even for drugs with half-lives between 24 and 60 h and thus shorter than those of donepezil and memantine an AUC truncated to 48 h post dose can be successfully used for the assessment of bioequivalence as this sample collection time ensures a proper comparison of the absorption process as recommended in the CPMP Note for Guidance on the Investigation of Bioavailability and Bioequivalence.
J Palliat Med. 2008 Jun; 11(5): 738-45
Weschules DJ, Maxwell TL, Shega JW
ABSTRACT Objectives: To describe acetylcholinesterase inhibitor (AChEI) and memantine use among persons over the age of 65 admitted to hospice with a primary diagnosis of dementia and identify patient and hospice program characteristics associated with the use of these agents. Design: Retrospective, cross-sectional study. Setting: Administrative database of a national hospice pharmacy provider. Participants: A total of 10,065 persons with end-stage dementia admitted to one of 441 U.S. hospices in 2004. Measurements: The frequency of AChEI and memantine use was determined and utilized as the unit of analysis for bivariate and multivariate comparisons with patient and hospice program characteristics. Results: Twenty-one percent (2148/10,065) of patients were prescribed AChEI and/or memantine therapy at the time of hospice enrollment. Of these, 49.5% were prescribed donepezil. Odds of receiving AChEI and/or memantine therapy were less likely if the patient was female, (odds ratio [OR] 0.68, 0.62-0.76), died while enrolled in hospice (OR 0.75, 0.67-0.85), received care at home (0.80, 0.71-0.89), or had a hospice length of stay (LOS) less than 7 days (0.53, 0.45-0.62). Patients who had a LOS of at least 60 days were significantly more likely to have received such therapies (OR 1.41 [1.24-1.60] for 61-180 days and 1.33 [1.15-1.54] for over 180 days). Conclusion: A notable number of hospice enrollees with a primary diagnosis of dementia were prescribed AChEI and/or NMDA receptor antagonist therapy. Studies are needed to better define the role of these agents as well as the impact of medication discontinuation in persons with end-stage dementia.
J Neurol Neurosurg Psychiatry. 2008 Jun 27;
Schmidt R, Ropele S, Pendl B, Ofner P, Enzinger C, Schmidt H, Berghold A, Windisch M, Kolassa H, Fazekas F
OBJECTIVE: We studied the feasibility of multimodal neuroimaging in mild to moderate Alzheimer's disease (AD) and estimated the size of possible treatment effects of memantine on potential functional, structural, and metabolic biomarkers of disease progression. METHODS: In this randomized, double-blind, placebo-controlled pilot study, 36 patients with moderate AD received 52 weeks of memantine (20mg/day) or placebo. Patients were re-evaluated after 26 and 52 weeks to measure the change from baseline in several outcome measures including global and regional glucose metabolism, total-brain and hippocampal volumes, as well as chemical shift imaging-derived global and regional N-acetylaspartate and myoinositol concentrations. RESULTS: In the total population, global glucose metabolism decreased by 2.3% (p
Memantine prevents the cognitive impairment induced by 3,4-methylenedioxymethamphetamine in rats.
Eur J Pharmacol. 2008 May 20;
Camarasa J, Marimón JM, Rodrigo T, Escubedo E, Pubill D
Amphetamine abuse is an important risk factor for the development of cognitive impairment involving learning and memory. Since in previous studies we have demonstrated the effectiveness of alpha-7 nicotinic receptor antagonists in preventing the neurotoxicity induced by amphetamine derivatives, the present paper seeks to determine whether pre-treatment with memantine (MEM) (an antagonist of both nicotinic and NMDA receptors) counteracts the memory impairment induced by 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) administration in male Long Evans rats. In mice, MDMA and MEM induced a locomotor stimulant response but with a different profile. Moreover, MEM inhibited the rearing and thygmotaxis behaviour induced by MDMA. Non-spatial memory was tested in the object recognition test and the spatial learning and memory was tested in the Morris water maze. In our experimental conditions, rats receiving MEM pre-treatment recovered the ability to discriminate between the familiar and the novel object that had been abolished by MDMA treatment. Animals treated with MDMA showed impaired learning in the Morris water maze. Results of the probe trial demonstrated that MDMA-treated rats did not remember the location of the platform, but this memory impairment was also prevented by the MEM pre-treatment. Moreover, MEM alone improved the learning task. No differences were observed between the different groups as regards swim speed. In conclusion, MEM significantly improved the learning and memory impairment induced by MDMA and constitutes the first approach to the treatment of the long-term cognitive deficits found in ecstasy users.
Biol Psychiatry. 2008 Jun 24;
Brown ES, Vazquez M, Nakamura A
BACKGROUND: In animal models, corticosteroids are associated with changes in hippocampal structure and functioning that are prevented by glutamate release inhibitors or N-methyl-D-aspartate (NMDA) receptor antagonists. Cushing's disease and prescription corticosteroid administration are also associated with memory impairment and hippocampal atrophy. Use of NMDA receptor antagonists to attenuate corticosteroid effects in humans has not been investigated. We examine the NMDA receptor antagonist memantine in patients receiving corticosteroids. METHODS: Twenty outpatients receiving long-term oral corticosteroid therapy were randomized to 8 weeks of memantine (maximum dose 20 mg/day) and 8 weeks of placebo in a double-blind fashion, with a 4-week washout period between courses. Declarative memory was assessed with the Hopkins Verbal Learning Test (HVLT) and mood with the Hamilton Rating Scale for Depression and Young Mania Rating Scale. Changes in outcome measures were compared during memantine and placebo exposure. RESULTS: Seventeen participants completed both treatment phases and were used in the analysis. Significant improvement (p < .05) in total and delayed recall on the HVLT was observed with memantine as compared with placebo. No significant changes in mood were observed. CONCLUSIONS: Memantine therapy was associated with improvement in declarative memory but not mood in patients receiving prescription corticosteroids.
Assessing transneuronal dysfunction utilizing manganese-enhanced MRI (MEMRI).
Magn Reson Med. 2008 Jun 25; 60(1): 169-175
Serrano F, Deshazer M, Smith KD, Ananta JS, Wilson LJ, Pautler RG
In this study we utilized manganese-enhanced MRI (MEMRI) to evaluate the in vivo transneuronal efficiency of manganese ion (Mn(2+)) movement as a means to assess overall changes in neuronal function. We designated this extension the manganese transfer index (MTI) value. To evaluate the MTI value as an index of transneuronal physiology we examined both pharmacological agents and different mouse models of neuronal dysfunction. We found that treatment with isoflurane, which attenuates synaptic vesicle release, or memantine, which attenuates postsynaptic uptake of Ca(2+) as well as Mn(2+), resulted in a decrease in the MTI value. Furthermore, we evaluated if changes in the MTI value can be detected in three knockout mice with altered brain function accompanied either with or without neurodegeneration. Our data demonstrate that the MTI values either decreased or increased in response to different functional as well as anatomical changes. These results demonstrate the potential utility of the MTI value as an in vivo index for the detection of changes in neuronal function in animal models of human disease. Magn Reson Med 60:169-175, 2008. (c) 2008 Wiley-Liss, Inc.
Long-term Course and Effectiveness of Combination Therapy in Alzheimer Disease.
Alzheimer Dis Assoc Disord. 2008 Jun 17;
Atri A, Shaughnessy LW, Locascio JJ, Growdon JH
OBJECTIVE: To compare the real-world clinical effectiveness and long-term clinical trajectory in patients with Alzheimer disease (AD) treated with combination (COMBO) therapy consisting of cholinesterase-inhibitor (CI) plus memantine (MEM) versus CI alone versus no treatment with either. METHODS: Three hundred eighty-two subjects with probable AD underwent serial clinical evaluations at a memory disorders unit. Cognition was assessed by the Information-Memory-Concentration subscale of the Blessed Dementia Scale (BDS) and function was assessed by the Weintraub Activities of Daily Living Scale (ADL) at 6-month intervals. One hundred forty-four subjects received standard care without CI or MEM (NO-RX), 122 received CI monotherapy, and 116 received COMBO therapy with CI plus MEM. Mean follow-up was 30 months (4.1 visits) and mean cumulative medication treatment time was 22.5 months. Rates of decline were analyzed using mixed-effects regression models, and Cohen's d effect sizes were calculated annually for years 1 to 4. RESULTS: Covarying for baseline scores, age, education, and duration of illness, the COMBO group had significantly lower mean annualized rates of deterioration in BDS and ADL scores compared with the CI (P
J Neurosci. 2008 Jun 25; 28(26): 6670-8
Manning SM, Talos DM, Zhou C, Selip DB, Park HK, Park CJ, Volpe JJ, Jensen FE
Hypoxia-ischemia (H/I) in the premature infant leads to white matter injury termed periventricular leukomalacia (PVL), the leading cause of subsequent neurological deficits. Glutamatergic excitotoxicity in white matter oligodendrocytes (OLs) mediated by cell surface glutamate receptors (GluRs) of the AMPA subtype has been demonstrated as one factor in this injury. Recently, it has been shown that rodent OLs also express functional NMDA GluRs (NMDARs), and overactivation of these receptors can mediate excitotoxic OL injury. Here we show that preterm human developing OLs express NMDARs during the PVL period of susceptibility, presenting a potential therapeutic target. The expression pattern mirrors that seen in the immature rat. Furthermore, the uncompetitive NMDAR antagonist memantine attenuates NMDA-evoked currents in developing OLs in situ in cerebral white matter of immature rats. Using an H/I rat model of white matter injury, we show in vivo that post-H/I treatment with memantine attenuates acute loss of the developing OL cell surface marker O1 and the mature OL marker MBP (myelin basic protein), and also prevents the long-term reduction in cerebral mantle thickness seen at postnatal day 21 in this model. These protective doses of memantine do not affect normal myelination or cortical growth. Together, these data suggest that NMDAR blockade with memantine may provide an effective pharmacological prevention of PVL in the premature infant.
[Efficacy and safety of memantine in dementia with Lewy bodies.]
Zh Nevrol Psikhiatr Im S S Korsakova. 2008; 108(5): 39-46
Levin OS, Batukaeva LA, Smolentseva IG, Amosova NA
Dementia with Lewy bodies (DLB) is a progressive disease of the nervous system manifested with dementia, parkinsonism, psychotic and autonomic disturbances. To estimate efficacy and safety of memantine in patients with clinically diagnosed DLB (according to criteria of McKeith et al., 1999), an open controlled 16-week trial was carried out in 23 patients, mean age 69,2+/-5,9 years. Patients were divided into 2 groups: 14 patients who received memantine in dosage 20 mg/d and 9 patients of a control group. A battery of neuropsychological tests, clinical assessment using fluctuation scales, scales for assessment of behavioral and psychotic disturbances, the General Clinical Impression scale were used. Memantine significantly improved cognitive dysfunction throughout the study (the mean MMSE scorer were increased by 1,5 points compared to the baseline) especially due to the improvement of attention and executive functions. The reduction of fluctuations of mental status, aggressiveness, aspontaneity, disinhibition was also observed. There were no significant changes of Parkinsonian and psychotic symptoms severity. Good tolerability of memantine is noted: only 2 patients were withdrawn from the study because of episodes of confusion on the titration phase of the trial.
Eur Neuropsychopharmacol. 2008 Jun 21;
Bisaga A, Danysz W, Foltin RW
Excessive consumption of highly palatable foods may contribute to the development of weight gain. Therefore medications that selectively suppress eating of such foods would be useful in clinical practice. We compared the effects of the glutamatergic antagonists memantine and MTEP to dexfenfluramine in baboons given periodic access to highly palatable food and ad libutum access to a standard chow diet. Three days a week baboons received a sugar-coated candy during the first meal and standard standard-diet chow pellets were available in subsequent meals. All baboons derived a greater amount of energy from the single single-candy meal than from the standard diet across an entire day. Pre-treatment with dexfenfluramine, memantine, and MTEP produced decreases in candy consumption without altering candy-seeking behaviour. At the same time, dexfenfluramine and memantine, but not MTEP, produced a decrease in seeking and consumption of standard chow pellets. Both memantine and MTEP are promising agents for the treatment of obesity.