Memantine and its benefits for cancer, cardiovascular and neurological disorders.

Memantine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist that was initially indicated for the treatment of moderate to severe Alzheimer's disease. It is now also considered for a variety of other pathologies in which activation of NMDA receptors apparently contributes to the pathogenesis and progression of disease. In addition to the central nervous system (CNS), NMDA receptors can be found in non-neuronal cells and tissues that recently have become an interesting research focus. Some studies have shown that glutamate signaling plays a role in cell transformation and cancer progression. In addition, these receptors may play a role in cardiovascular disorders. In this review, we focus on the most recent findings for memantine with respect to its pharmacological effects in a range of diseases, including inflammatory disorders, cardiovascular diseases, cancer, neuropathy, as well as retinopathy.

Lactoferrin Coupled Lower Generation PAMAM Dendrimers for Brain Targeted Delivery of Memantine in Aluminum-Chloride-Induced Alzheimer's Disease in Mice.

Lower generation PAMAM dendrimers have an immense potential for drug delivery with lower toxicity, but these dendrimers yet need certain basic ameliorations. In this study, the brain delivery potential of the synthesized PAMAM-Lf (lower generation PAMAM and lactoferrin conjugate) loaded with memantine (MEM) was explored and evaluated in vitro and in vivo in the disease-induced mouse model. The developed nanoscaffolds were characterized for size, zeta potential and in vitro release. Increase in the average size from 11.54 ± 0.91 to 131.72 ± 4.73 nm, respectively, was observed for drug-loaded PAMAM (i.e., PAMAM-MEM) and PAMAM-Lf (i.e., MEM-PAMAM-Lf).  Release profile of MEM from MEM-PAMAM-Lf was slow and sustained up to 48 h. In vivo biodistribution in the Sprague-Dawley rat model revealed that the brain uptake of MEM-PAMAM-Lf was significantly higher than that of MEM alone. The behavioral response study in the healthy rats did not result in any significant changes. The in vivo study in an AlCl3-induced Alzheimer's (AD) mice model showed a significant improvement in behavioral responses. Optical density, which reflects the acetylcholinesterase (AChE) activity, was highest in the AL group 0.16 ± 0.01 (higher than the CON group, 0.09 ± 0.02; p < 0.05). No significant suppression of AChE activity was recorded in all the other treated groups. Similarly, the DOPAmine and 3,4 dihydroxyphenylacetic acid (DOPAC) levels were unaffected by the developed formulations. The study reported improved brain bioavailability of MEM in AlCl3-induced Alzheimer's mice leading to improved memory, with the resultant mechanism behind in a descriptive manner. This study is among the preliminary studies reporting the memory improvement aspect of PAMAM-Lf conjugates for MEM in AlCl3-AD induced mice. The formulation developed was beneficial in AD-induced mice and had a significant impact on the memory aspects.

Nuevos blancos terapéuticos en el tratamiento de las depresiones resistentes: Moduladores glutamatérgicos / New Therapeutic Targets in the Treatment of Resistant Depression: glutamatergic modulators

Dentro de los trastornos del estado de ánimo, los trastornos depresivos son padecimientos generalmente recurrentes que tienen, según las estadísticas, una prevalencia anual de un 3 % a un 6 % en la población. Desde la década de los 60' la hipótesis aminérgica de Schildkraut y posteriores, establecieron que las depresiones estaban vinculadas a alteraciones en la neurotransmisión catecolaminérgica y serotoninérgica. Los fármacos antidepresivos apuntaron a esas disfunciones pero las dificultades terapéuticas, retraso en el inicio de la acción y limitaciones en la eficacia, llevaron a la búsqueda de otras posibilidades, que surgieron de las investigaciones sobre la neurotransmisión glutamatérgica. En modelos animales se descubrió en los comienzos de los 90' la acción antidepresiva de los fármacos que antagonizaban la neurotransmisión de los receptores N-metil-D-aspartato (NMDA). El objetivo de este trabajo se orienta a establecer los fundamentos de la teoría glutamatérgica de las depresiones y a describir los fármacos que potencialmente podrían utilizarse en la clínica...

Depressive disorders are usually recurrent diseases that, according to statistics, afects from 3 % to 6 % of the population. Since the early '60s the Schildkraut aminergic hypothesis and subsequent, established that depressions were associated with alterations in cahtecolaminegic and serotonergic neurotransmission. Antidepressant drugs aimed at these dysfunctions but the therapeutic difficulties, delayed onset of action and efficacy limitations, led to the search of other possibilities that emerged from the research on glutamatergic neurotransmission. In animal models it was discovered in the early 90's the antidepressant action of drugs antagonized the NMDA receptor neurotransmission. The objective of this work is aimed at establishing the foundations of the glutamatergic theory of depressions and describe drugs that potentially could be used in the clinic...

Memantine pharmacotherapy: a naturalistic study using a population pharmacokinetic approach.

BACKGROUND AND OBJECTIVE: Memantine plasma concentrations show considerable interindividual variability. High memantine plasma concentrations are associated with the occurrence of neuropsychiatric adverse effects such as confusion. The objective of the present study was, therefore, to investigate the reasons for the observed variability of the pharmacokinetics of memantine in a representative patient population and to explore patient covariates on drug disposition. SUBJECTS: Fifty-six ambulatory Western European patients aged 50-91 years. METHODS: This prospective study used a full population pharmacokinetic sampling design. After at least 11 days of continuous memantine intake, the patients provided pharmacokinetic profiles, with six measurements each over a 12-hour period, with a total of 335 serum memantine concentrations. Covariates considered for inclusion in the models were: subject demographic factors (age, total bodyweight, gender), laboratory tests (urinary pH), total daily dose of memantine, memantine formulation type, comedication eliminated via tubular secretion and smoking history. The model development was conducted in three sequential steps. First, an adequate basic structural model was chosen (e.g. a one-, two- or three-compartment pharmacokinetic model). The data were analysed to estimate population pharmacokinetic parameters with the nonlinear mixed-effects model computer program NONMEM. Second, the effects of covariates were investigated on post hoc estimates using multivariate statistics. Third, the covariates with significant effects in the second step were used to build a final covariate pharmacokinetic model, again using NONMEM. RESULTS: A two-compartment model with first-order absorption satisfactorily described memantine pharmacokinetics. In the final regression model, total bodyweight, memantine formulation type (solution vs tablets) and concomitant medication eliminated via tubular secretion were all important determinants of the apparent clearance (CL/F). The final regression model was: CL/F (L/h) = (1.92 + 0.048 x BW (kg)) x 0.530(FRM) x 0.769(CMD) where FRM = 1 for patients receiving memantine solution, otherwise FRM = 0; CMD = 1 for patients receiving a comedication eliminated via tubular secretion, otherwise CMD = 0; and BW is bodyweight. Compared with the basic model, the final population pharmacokinetic model explained 61% of the interindividual variance of the apparent clearance. CONCLUSIONS: The population pharmacokinetic model that was developed identified a set of sources of variability in the apparent clearance of memantine, which can be used as a reference in order to optimise memantine therapy in Western European patients.

19F and 1H MRI detection of amyloid beta plaques in vivo.

Formation of senile plaques composed of amyloid beta peptide, a pathological hallmark of Alzheimer disease, in human brains precedes disease onset by many years. Noninvasive detection of such plaques could be critical in presymptomatic diagnosis and could contribute to early preventive treatment strategies. Using amyloid precursor protein (APP) transgenic mice as a model of amyloid beta amyloidosis, we demonstrate here that an intravenously administered (19)F-containing amyloidophilic compound labels brain plaques and allows them to be visualized in living mice by magnetic resonance imaging (MRI) using (19)F and (1)H. Our findings provide a new direction for specific noninvasive amyloid imaging without the danger of exposure to radiation. This approach could be used in longitudinal studies in mouse models of Alzheimer disease to search for biomarkers associated with amyloid beta pathology as well as to track disease course after treatment with candidate medications.

Quantitative analysis of memantine in human plasma by gas chromatography/negative ion chemical ionization/mass spectrometry.

A sensitive and specific method for the determination of memantine in human plasma is presented. Memantine was extracted from plasma and derivatized to the pentafluorobenzoyl derivative in a one-step procedure avoiding any sample concentration steps. Amantadine was used as an internal standard. The compounds were measured by gas chromatography/negative ion chemical ionization mass spectrometry without any further processing. Using this detection mode, the fragment ions at m/z 353 and 325 were obtained at high relative abundance. Calibration graphs were linear over the range 0.117-30 ng ml(-1). At the limit of quantification (LOQ), the inter-assay precision was 2.00% and the intra-assay variability was 3.22%. The accuracy at the LOQ showed deviations of -1.42% (intra-assay) and -2.47% (inter-assay). The method is rugged, rapid and robust and was applied to the batch determination of memantine during pharmacokinetic profiling of the drug.

Evidence for lysosomotropism of memantine in cultured human cells: cellular kinetics and effects of memantine on phospholipid content and composition, membrane fluidity and beta-adrenergic transmission.

Memantine, an amantadine derivative, is therapeutically used for the treatment of various neurological and psychiatric disorders such as Parkinson's disease, spasticity, and dementia. Pharmacokinetics of memantine and its effects on phospholipid content and composition, on membrane properties and functions such as fluidity and beta-adrenergic transmission were studied in cultured human fibroblasts and macrophages. The kinetic behaviour of memantine was characteristic for a lysosomotropic drug. Fibroblasts exposed to 14C-memantine in the microM range accumulated the drug up to 200 fold above initial medium concentrations. Lysosomal drug storage was proven by indirect evidence and by analyses of subcellular fractions. Repetitive exposure to memantine resulted in a cumulative uptake. While memantine uptake after single exposure was fully reversible, the rate and extent of release of chronically accumulated drug was reduced but could be enhanced by the addition of unlabelled memantine or ammonium chloride to the medium. Chronic, but not single, exposure to memantine above 10 microM resulted in a concentration dependent phospholipid accumulation and in a shift in the phospholipid composition. There was an overproportionate increase in phosphatidylinositol at the expense of phosphatidylserine and sphingomyelin. Chronic exposure of cultured cells to memantine increased fluidity in the superficial layers of the plasma membrane and reduced the isoproterenol-stimulated cAMP-response without affecting beta-adrenoceptor density. All these findings were compatible with the kinetic behaviour and the effectiveness expected of a weak lysosomotropic drug.