Memantine Research Articles

Potential Pharmacokinetic Drug⁻Drug Interaction Between Harmine, a Cholinesterase Inhibitor, and Memantine, a Non-Competitive N-Methyl-d-Aspartate Receptor Antagonist.

Harmine (HAR) is a beta-carboline alkaloid widely distributed in nature. It exhibits psychopharmacological effects of improving learning and memory. However, excessive dose of HAR can cause central tremor toxicity, which may be related to the glutamate system. Memantine (MEM) is a non-competitive N-methyl-d-aspartate receptor antagonist. It can be used for the treatment of Alzheimer’s disease and also can block the neurotoxicity caused by glutamate. Therefore, combination of HAR and MEM would be meaningful and the pharmacokinetics investigation of HAR and MEM in combination is necessary. A ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was established and validated for the simultaneous quantitative determination of MEM, HAR and harmol (HOL), a main metabolite of HAR, in rat plasma after oral administration of HAR and MEM in combination (5.0 mg/kg of MEM combined with 20.0, 40.0, 80.0 mg/kg of HAR). The contents of HAR and HOL were determined after oral administration of HAR (20.0, 40.0 and 80.0 mg/kg), and the content of MEM was determined after oral administration of MEM (5.0 mg/kg). Blood samples were collected from each rat at 0 (pre-dose), 0.08, 0.17, 0.25, 0.33, 0.50, 0.75, 1.0, 2.0, 4.0, 8.0, 12.0 and 24.0 h after administration. The maximum peak concentration (Cmax) of MEM was obviously decreased, and the area under the plasma concentration versus time curve from zero to time t (AUC(0-t)) and mean residence time (MRT) were significantly increased after combination with HAR. The Cmax and AUC(0-t) of HAR and its metabolite HOL were increased after combination with MEM. These findings suggested that co-administration of HAR and MEM could extend their residence time in rats, and then might increase the efficacy for treatment of Alzheimer’s disease. Therefore, this study will provide a basis for the rational combined application of HAR and MEM.

EFFECT OF MEMANTINE ON BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS OF DEMENTIA (BPSD) OF ALZHEIMER'S DISEASE - STUDY OF CHANGES IN CEREBRAL BLOOD FLOW BY SPECT IMAGING-

Introduction The mechanism of the onset of BPSD associated with Alzheimer's disease (AD) is unclear, and the incidence and frequency of these symptoms are difficult. We conducted a retrospective study on sites of decreased cerebral blood flow(CBF) during onset along with sites of increased blood flow following administration of memantine (MEM) for three BPSD parameters consisting of “agitation/irritability”, “hallucinations/delusions” and “wandering/appeal to return home” using SPECT imaging. Methods The study was targeted at 41 outpatients diagnosed with AD and presenting with BPSD (agitation/irritability: 11 cases, hallucinations/delusions: 19 cases, wandering/appeal to return home: 11 cases). Sites of decreased CBF during onset of BPSD were extracted using the statistical parametric mapping (SPM8) followed by an examination of their responsible lesions. SPECT was repeated about six months after additional administration of MEM followed by an examination of the correlation between sites of increased CBF attributable to MEM and improvement of symptoms. Results • 1 With respect to agitation/irritability, decreases in CBF were observed in the dorsolateral prefrontal cortex bilaterally, angular gyrus, right-dominant parietal association area and posterior cingulate gyrus, while increases in CBF following administration of MEM were observed in the orbital gyri bilaterally, right occipital lobe and left ventral prefrontal cortex. • 2 With respect to hallucinations/delusions, decreases in CBF were observed in the posterior cingulate gyrus, occipital lobe and lt.-dominant parietal association area, while increases in CBF following administration of MEM were observed in the parietal lobe, orbital gyrus and prefrontal cortex bilaterally. • 3 With respect to wandering/appeal to return home, decreases in CBF were observed in the mid-cerebellum, occipital lobe and parietal lobe, while increases in CBF following administration of MEM were observed in mid-cerebellum, left parietal lobe, occipital lobe, posterior cingulate gyrus, prefrontal cortex and ventral central pons. Conclusions There was suggested to be a correlation between sites of CBF following administration of MEM and improvement of BPSD.

The role of LINC00094/miR-224-5p (miR-497-5p)/Endophilin-1 axis in Memantine mediated protective effects on blood-brain barrier in AD microenvironment.

The dysfunction of the blood‐brain barrier (BBB) is one of the main pathological features of Alzheimer's disease (AD). Memantine (MEM), an N‐methyl‐d‐aspartate (NMDA) receptor antagonist, has been reported that been used widely for AD therapy. This study was performed to demonstrate the role of the MEM in regulating BBB permeability in AD microenvironment as well as its possible mechanisms. The present study showed that LINC00094 was dramatically increased in Abeta1‐42‐incubated microvascular endothelial cells (ECs) of BBB model in vitro. Besides, it was decreased in MEM‐incubated ECs. Silencing LINC00094 significantly decreased BBB permeability, meanwhile up‐regulating the expression of ZO‐1, occludin and claudin‐5. Furthermore, silencing LINC00094 enhance the effect of MEM on decreasing BBB permeability in AD microenvironment. The analysis of the mechanism demonstrated that reduction of LINC00094 inhibited Endophilin‐1 expression by up‐regulating miR‐224‐4p/miR‐497‐5p, promoted the expression of ZO‐1, occludin and claudin‐5, and ultimately alleviated BBB permeability in AD microenvironment. Taken together, the present study suggests that the MEM/LINC00094/miR‐224‐5p (miR‐497‐5p)/Endophilin‐1 axis plays a crucial role in the regulation of BBB permeability in AD microenvironment. Silencing LINC00094 combined with MEM provides a novel target for the therapy of AD.

Memantine protects thalamocortical hyper-glutamatergic transmission induced by NMDA receptor antagonism via activation of system xc.

Deficiencies in N‐methyl‐d‐aspartate (NMDA)/glutamate receptor (NMDAR) signaling have been considered central to the cognitive impairments of schizophrenia; however, an NMDAR antagonist memantine (MEM) improves cognitive impairments of Alzheimer's disease and schizophrenia. These mechanisms of paradoxical clinical effects of NMDAR antagonists remain unclear. To explore the mechanisms by which MK801 and MEM affect thalamocortical transmission, we determined interactions between local administrations of MK801, MEM, system xc− (Sxc), and metabotropic glutamate receptors (mGluRs) on extracellular glutamate and GABA levels in the mediodorsal thalamic nucleus (MDTN) and medial prefrontal cortex (mPFC) using dual‐probe microdialysis with ultra‐high‐pressure liquid chromatography. Effects of MK801 and MEM on Sxc activity were also determined using primary cultured astrocytes. Sxc activity was enhanced by MEM, but was unaffected by MK801. MK801 enhanced thalamocortical glutamatergic transmission by GABAergic disinhibition in the MDTN. In the MDTN and the mPFC, MEM weakly increased glutamate release by activating Sxc, whereas MEM inhibited thalamocortical glutamatergic transmission. Paradoxical effects of MEM were induced following secondary activation of inhibitory II‐mGluR and III‐mGluR by exporting glutamate from astroglial Sxc. The present results suggest that the effects of therapeutically relevant concentrations of MEM on thalamocortical glutamatergic transmission are predominantly caused by activation of Sxc rather than inhibition of NMDAR. These demonstrations suggest that the combination between reduced NMDAR and activated Sxc contribute to the neuroprotective effects of MEM. Furthermore, activation of Sxc may compensate for the cognitive impairments that are induced by hyperactivation of thalamocortical glutamatergic transmission following activation of Sxc/II‐mGluR in the MDTN and Sxc/II‐mGluR/III‐mGluR in the mPFC.

Neuroprotective potential of solanesol in intracerebroventricular propionic acid induced experimental model of autism: Insights from behavioral and biochemical evidence.

Autism is the category used within the newest edition of the diagnostic and statistical manual of neurodevelopmental disorders. Autism is a spectrum of disorder where a variety of behavioural patterns observed in autistic patients, such as stereotypes and repetitive behavior, hyperexcitability, depression-like symptoms, and memory and cognitive dysfunctions. Neuropathological hallmarks that associated with autism are mitochondrial dysfunction, oxidative stress, neuroinflammation, Neuro-excitation, abnormal synapse formation, overexpression of glial cells in specific brain regions like cerebellum, cerebral cortex, amygdala, and hippocampus. ICV injection of propionic acid (PPA) (4 μl/0.26 M) mimics autistic-like behavioral and biochemical alterations in rats. Literature findings reveal that there is a link between autism neuronal mitochondrial coenzyme-Q10 (CoQ10) and ETC-complexes dysfunctions are the keys pathogenic events for autism. Therefore, in the current study, we explore the neuroprotective interventions of Solanesol (SNL) 40 and 60 mg/kg alone and in combination with standard drugs Aripiprazole (ARP) 5 mg/kg, Citalopram (CTP) 10 mg/kg, Memantine (MEM) 5 mg/kg and Donepezil (DNP) 3 mg/kg to overcome behavioral and biochemical alterations in PPA induced experimental model of Autism. Chronic treatment with SNL 60 mg/kg in combination with standard drug shows a marked improvement in locomotion, muscle coordination, long-term memory and the decrease in depressive behavior. While, chronic treatment of SNL alone and in combination with standard drug aripiprazole, citalopram, donepezil, and memantine shows the Neuroprotective potential by enhancing the cognitive deficits, biochemical alterations along with reducing the level of inflammatory mediators and oxidative stress.

Basic Study of Drug-Drug Interaction between Memantine and the Traditional Japanese Kampo Medicine Yokukansan.

Several basic pharmacokinetic and pharmacological studies were conducted as part of a group of studies to clarify the drug-drug interaction (DDI) between memantine (MEM), a drug used to treat Alzheimer’s disease, and yokukansan (YKS), a traditional Japanese Kampo medicine used to treat behavioral and psychological symptoms of dementia. The pharmacokinetic studies showed that there were no statistically significant differences in MEM concentrations in the plasma, brain, and urine between mice treated with MEM alone and with MEM plus YKS. Regarding candidate active ingredients of YKS, there were also no statistically significant differences in concentrations of geissoschizine methyl ether in the plasma and brain, urine, glycyrrhetinic acid in the plasma, and isoliquiritigenin in the urine, in mice treated with YKS alone or with MEM plus YKS. The pharmacological studies showed that isoliquiritigenin, which has an N-methyl-d-aspartic acid (NMDA) receptor antagonistic effect, did not affect the inhibitory effect of MEM on NMDA-induced intracellular Ca2+ influx in primary cultured rat cortical neurons. Moreover, YKS did not affect either the ameliorative effects of MEM on NMDA-induced learning and memory impairment, or the MEM-induced decrease in locomotor activities in mice. These results suggest that there is probably no pharmacokinetic or pharmacological interaction between MEM and YKS in mice, but more detailed studies are needed in the future. Our findings provide important information for future studies, to clarify the DDI more regarding the efficacy and safety of combined use of these drugs in a clinical situation.

Memantine mediates astrocytic activity in response to excitotoxicity induced by PP2A inhibition

Reduced activity of protein phosphatase 2 A (PP2A) is a common feature in Alzheimer’s disease (AD) and non-AD tauopathies. The administration of okadaic acid (OKA), a potent PP2A and PP1 inhibitor, is a common research tool for inducing AD-like alterations such as tau hyperphosphorylation and cognitive decline. Recently, we showed that OKA increases cerebrospinal fluid (CSF) glutamate levels, which was strongly correlated with cognitive decline. Also, we demonstrated that memantine (MN), a glutamatergic NMDAR channel blocker, was capable of preventing the increase in CSF glutamate levels and cognitive decline. Here, we aimed to analyze whether the protective effects of MN involve intrinsic astrocytic properties, particularly related to glutamate uptake and astrocytic reactivity – indexed by the expression of S100B and glial fibrillary acidic protein (GFAP). Rats received intraperitoneal injections of MN or saline over 3 consecutive days before receiving intrahippocampal infusion of OKA or saline. Afterward, they were submitted to behavioral tasks and then, euthanatized for neurochemical analysis. Here, we showed that the neuroprotective effects of MN in response to OKA neurotoxicity involve astrocytic activation. MN decreased glutamate uptake in the hippocampus and increased the release of S100B protein in the CSF in response to OKA neurotoxicity, which indicates a possible neurons-astrocyte coupling protective mechanism. These findings shed light on astrocytes as potential targets for treating neurological disorders associated with decreased PP2A activity.

Efficacy and tolerability of adjunctive gabapentin and memantine in obsessive compulsive disorder: Double-blind, randomized, placebo-controlled trial

BackgroundIn the search for additional pharmacologic treatments of patients with obsessive-compulsive disorders (OCD), the glutamatergic system is attracting growing interest. While adjuvant memantine to a standard medication with a selective serotonin-reuptake inhibitor (SSRI) appears to reduce OCD symptoms, the adjuvant effect of gabapentin is less certain. The aim of the present randomized, double-blind and three-arm clinical trial was therefore to assess whether, compared to placebo, gabapentin (GAB) or memantine (MEM) adjuvant to a standard medication with an SSRI (fluoxetine; FLU) might lead to further improvements. MethodsA total of 99 outpatients (mean age: 29.59 years; 49.5% females) diagnosed with OCD were randomly assigned to one of the following three conditions: FLU + gabapentin (FLU + GAB); FLU + memantine (FLU + MEM); FLU + placebo (FLU + PLA). Experts rated patients' symptoms of OCD with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) at baseline, and 4 and 8 weeks later. ResultsYBOCS scores did not decrease over time. No group differences were observed. However, the significant Time by Group interaction showed that Y-BOCS scores decreased significantly over time in the FLU + PLA group. Response rates did not differ between the three study conditions. Typical side-effects were rash (FLU + MEM), drowsiness (FLU + GAB), anxiety (FLU + GAB; FLU + PLA), and drowsiness plus anxiety (FLU + GAB). ConclusionsThe present pattern of results suggests that glutamatergic medications such as gabapentin and memantine adjuvant to a standard treatment with an SSRI have no additional positive impact on patients with OCD, as measured with the Y-BOCS. Additionally, side-effects were reported. Future studies should use more fine-grained tools to assess, for example, patients' sleep and cognitive functioning, and patients' view of symptoms.

Combination Therapy of Serotonin Reuptake Inhibitors and Memantine for Obsessive- Compulsive Disorder: A Meta-Analysis of Double-Blind, Randomized, Placebo-Controlled Trials.

We performed a meta-analysis to determine whether combination therapy with serotonin reuptake inhibitors (SRIs) and memantine (MEM) was beneficial for the treatment of obsessive- compulsive disorder. This study included three double-blind, randomized, placebo-controlled trials. MEM+SRI was superior to placebo+SRI with regard to response rate [primary outcome, n = 97; risk ratio = 0.22; 95% confidence intervals (CI) = 0.12-0.42; p < 0.00001; I2 = 0%; number needed to treat = 2], the Yale- Brown Obsessive- Compulsive Scale total [standardized mean difference (SMD) = - 4.56; 95% CI = - 8.50, - 0.62; p = 0.02], obsession subscale (SMD = - 4.39; 95% CI = - 5.94, - 2.85; p < 0.00001), and compulsion subscale score (SMD = - 4.60; 95% CI = - 7.64, - 1.55; p = 0.003). No significant differences in any safety outcome were found between the groups.

In Depth Analysis of Pressure-Sensitive Adhesive Patch-Assisted Delivery of Memantine and Donepezil Using Physiologically Based Pharmacokinetic Modeling and in Vitro/in Vivo Correlations.

The objective of this work was to evaluate the feasibility of transdermal delivery of two widely prescribed dementia drugs for the Alzheimer's disease. In this regard, the drug in adhesive patches of memantine (ME) co-loaded with donepezil (DO) was prepared using an ethylene vinyl acetate polymer and characterized for drug content, the crystallinity of drugs in the polymer matrix, and in vitro permeation. To understand the different physical and chemical processes underlying the percutaneous absorption, it is required to employ a comprehensive model that accounts for the anatomy and physiology of the skin. A transdermal physiologically based pharmacokinetic (TPBPK) model was developed and was integrated in a compartmental pharmacokinetic model to predict the plasma drug concentrations in rats. The model predictions showed a good fit with the experimental data, as evaluated by the prediction error calculated for both drugs. It was evident from the simulations that the drug diffusivity and partition coefficient in the polymer matrix are the critical parameters that affect the drug release from the vehicle and subsequently influence the in vivo pharmacokinetic profile. Moreover, a correlation function was built between the in vitro permeation data and in vivo absorption for both ME and DO. A good point-to-point in vitro/in vivo correlation (IVIVC, Level A correlation) was achieved by predicting the plasma concentrations with convolution for the entire study duration. The results of our study suggested that the implementation of mechanistic modeling along with IVIVC can be a valuable tool to evaluate the relative effects of formulation variables on the bioavailability from transdermal delivery systems.

Huatuo Zaizao pill ameliorates cognitive impairment of APP/PS1 transgenic mice by improving synaptic plasticity and reducing A\u03b2 deposition

BackgroundIt is well known that Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by memory deficits and cognitive decline. Amyloid-β (Aβ) deposition and synaptic dysfunction play important roles in the pathophysiology of Alzheimer’s disease (AD). The Huatuo Zaizao pill (HT) is a Traditional Chinese Medicine (TCM) that has been used clinically for many years in China, mainly for post-stroke rehabilitation and cognitive decline; however, the mechanism of cognitive function is not clear. In this study, we investigated the effect of HT on hippocampal synaptic function, Amyloid-β (Aβ) deposition in APP/PS1 AD transgenic mice.MethodSix-month-old APP/PS1 transgenic (Tg) mice were randomly divided into control, HT-treated, and memantine (MEM)-treated groups. Then, these groups were orally administered vehicle (for the control), HT (0.25 g/kg) and MEM (5 mg/kg) respectively for 4 weeks. The Morris water maze, Novel Object Recognition, and Open field tests were used to assess cognitive behavioral changes. We evaluated the effects of HT on neuronal excitability, membrane ion channel activity, and synaptic plasticity in acute hippocampal slices by combining electrophysiological extracellular tests. Synaptic morphology in the hippocampus was investigated by electron microscopy. Western blotting was used to assess synaptic-associated protein and Aβ production and degrading levels. Immunofluorescence staining was used to determine the relative integrated density.ResultsHT can ameliorate hippocampus-dependent memory deficits and improve synaptic dysfunction by reversing LTP impairment in APP/PS1 transgenic mice. Moreover, HT reduces amyloid plaque deposition by regulating α-secretase and γ-secretase levels.ConclusionHT can improve the learning and memory function of APP/PS1 transgenic mice by improving synaptic function and reducing amyloid plaque deposition.

Memantine ameliorates depressive-like behaviors by regulating hippocampal cell proliferation and neuroprotection in olfactory bulbectomized mice

Our previous study suggested that the non-competitive N-methyl-d-aspartate receptor antagonist memantine (MEM) inhibits dopamine (DA) reuptake and turnover by inhibiting brain monoamine oxidase. Clinical studies have reported that MEM may improve depressive symptoms; however, specific mechanisms underlying this effect are unclear. We performed emotional behavior, tail suspension, and forced swimming tests to examine whether MEM has antidepressant effects in olfactory bulbectomized (OBX) mice, an animal model of depression. Subsequently, we investigated the effects of MEM on the distribution of tyrosine hydroxylase (TH), altered microglia morphometry, and astrocyte and cell proliferation in the hippocampus with immunohistochemistry. We also investigated MEM effects on the levels of norepinephrine (NE), DA, and their metabolites with high performance liquid chromatography, and of neurotrophic, proinflammatory, and apoptotic molecules in the hippocampus with western blotting. Forty-two days after surgery, OBX mice showed depressive-like behaviors, as well as decreased levels of monoamines, reduced cell proliferation, and lower levels of TH, phospho(p)-TH (ser31 and ser40), p-protein kinase A (PKA), p-DARPP-32, p-ERK1/2, p-CREB, brain-derived neurotrophic factor (BDNF), doublecortin, NeuN, and Bcl-2 levels. In contrast, the number of activated microglia and astrocytes and the levels of Iba1, GFAP, p-IκB-α, p-NF-κB p65, TNF-α, IL-6, Bax, and cleaved caspase-3 were increased in the hippocampus. These changes (except for those in NE and Bax) were reversed with chronic administration of MEM. These results suggest that MEM-induced antidepressant effects are associated with enhanced hippocampal cell proliferation and neuroprotection via the PKA-ERK-CREB-BDNF/Bcl-2-caspase-3 pathway and increased DA levels.

Memantine for the Treatment of Dementia: A Review on its Current and Future Applications.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the presence in the brain of extracellular amyloid-β protein (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. The N-Methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptor, are essential for processes like learning and memory. An excessive activation of NMDARs has been associated with neuronal loss. The discovery of extrasynaptic NMDARs provided a rational and physiological explanation between physiological and excitotoxic actions of glutamate. Memantine (MEM), an antagonist of extrasynaptic NMDAR, is currently used for the treatment of AD jointly with acetylcholinesterase inhibitors. It has been demonstrated that MEM preferentially prevents the excessive continuous extrasynaptic NMDAR disease activation and therefore prevents neuronal cell death induced by excitotoxicity without disrupting physiological synaptic activity. The problem is that MEM has shown no clear positive effects in clinical applications while, in preclinical stages, had very promising results. The data in preclinical studies suggests that MEM has a positive impact on improving AD brain neuropathology, as well as in preventing Aβ production, aggregation, or downstream neurotoxic consequences, in part through the blockade of extrasynaptic NMDAR. Thus, the focus of this review is primarily to discuss the efficacy of MEM in preclinical models of AD, consider possible combinations of this drug with others, and then evaluate possible reasons for its lack of efficacy in clinical trials. Finally, applications in other pathologies are also considered.

Memantine decreases neuronal degeneration in young rats submitted to LiCl-pilocarpine-induced status epilepticus

Several works have demonstrated that status epilepticus (SE) induced-neurodegeneration appears to involve an overactivation of N-methyl-d-aspartate receptors and treatment with high-affinity NMDAR antagonists is neuroprotective against this brain damage. However, these compounds display undesirable side effects for patients since they block physiological NMDA receptor dependent-activity. In this context, memantine (MN), a well tolerable low-affinity NMDAR channel blocker, will be a promising alternative, since it does not compromise the physiological role of NMDA receptors on synaptic transmission. The aim of the present study was to investigate if MN could attenuate seizure severity and neuronal cell death caused by SE induced early in life. Wistar rats (15 days old; n = 6–8 per group) received memantine (20 mg/kg i.p.) in six different treatments: 6 and 3 h before SE onset; concomitant with pilocarpine; 15min and 1h after SE onset; and four consecutive administrations (15 min, 6 h, 12 h, and 18 h) after pilocarpine injection. Neurodegeneration was quantified by fluoro-jade C staining. Treatment with memantine increase latency to SE onset only in groups treated 3 h before or concomitant with pilocarpine. In CA1 hippocampal subfield, memantine significantly reduced neurodegeneration at the following times: 3 h prior SE-onset, concomitant with pilocarpine, and 15 min after pilocarpine injection. For amygdala and thalamus, all post-SE onset treatments were able to decrease neurodegeneration. In conclusion, the present study showed that MN was neuroprotective against SE-induced neuronal death and this neuroprotection appears to be time- and region-dependent.

Peripheral and Central Effects of Memantine in a Mixed Preclinical Mice Model of Obesity and Familial Alzheimer's Disease.

There is growing evidence that obesity associated with type 2 diabetes mellitus (T2DM) and aging are risk factors for the development of Alzheimer's disease (AD). However, the molecular mechanisms through which obesity interacts with β-amyloid (Aβ) to promote cognitive decline remains poorly understood. Memantine (MEM), a N-methyl-D-aspartate receptor antagonist, is currently used for the treatment of AD. Nonetheless, few studies have reported its effects on genetic preclinical models of this neurodegenerative disease exacerbated with high-fat diet (HFD)-induced obesity. Therefore, the present research aims to elucidate the effects of MEM on familial AD HFD-induced insulin resistance and learning and memory impairment. Furthermore, it aspires to determine the possible underlying mechanisms that connect AD to T2DM. Wild type and APPswe/PS1dE9 mice were used in this study. The animals were fed with either chow or HFD until 6months of age, and they were treated with MEM-supplemented water (30mg/kg) during the last 12weeks. Our study demonstrates that MEM improves the metabolic consequences produced by HFD in this model of familial AD. Behavioural assessments confirmed that the treatment also improves animals learning abilities and decreases memory loss. Moreover, MEM treatment improves brain insulin signalling upregulating AKT, as well as cyclic adenosine monophosphate response element binding (CREB) expression, and modulates the amyloidogenic pathway, which, in turn, reduced the accumulation of Aβ. Moreover, this drug increases the activation of molecules involved with insulin signalling in the liver, such as insulin receptor substrate 2 (IRS2), which is a key protein regulating hepatic resistance to insulin. These results provide new insight into the role of MEM not only in the occurrence of AD treatment, but also in its potential application on peripheral metabolic disorders where Aβ plays a key role, as is the case of T2DM.

A Guide to Follow-on Biologics and Biosimilars with a Focus on Insulin

Many healthcare providers in the U.S. are not familiar with follow-on biologics and biosimilars nor with their critical distinctions from standard generics. Our aim is to provide a detailed review of both, with a focus on insulins in the U.S. regulatory system. Literature has been reviewed to provide information on various aspects of biosimilars and a follow-on biologic of insulin. This will include structure, efficacy, cost, switching, and legal issues. Biologic products are large, complex molecules derived from living sources. Follow-on biologics are copies of the original innovator biologics. It is not possible to copy their structure exactly, leading to possible differences in efficacy and safety. Thus, regulations involving biologics are complex. Follow-on biologics are regulated under two Federal laws until March 23, 2020: the Public Health Service Act (PHS Act) and the Federal Food, Drug, and Cosmetic Act. Biosimilars are follow-on biologics which have been approved via the PHS Act. They consist of those which are "highly similar" to the reference drug and those which are "expected" to produce the same clinical result as the reference drug (interchangeable biosimilars). Interchangeable biosimilars have been determined by the U.S. Food and Drug Administration to be substitutable by the pharmacist "without the intervention" of the prescriber. From the patient perspective, switching to a follow-on biologic may necessitate a change in delivery device, which may create issues for patient adherence and dosing. Although they present several challenges in terms of regulation and acceptance, follow-on biologics have the potential to significantly reduce costs for patients requiring insulin therapy. BLA = biologics license application EU = European Union FDA = Food and Drug Administration FD&C = Food, Drug, and Cosmetic HCPCS = Healthcare Common Procedure Coding System INN = internatinal nonproprietary name NDA = new drug application PHS = Public Health Service.

Idalopirdine for Alzheimer Disease

Although anticholinesterase medications and memantine have been widely used for the treatment of Alzheimer disease (AD), they are by no means panaceas.

Comparative study of citalopram in treatment of behavioral and psychological symptoms of dementia and cognitive function in Alzheimer's disease patients

Objective To observe the efficacy and safety of citalopram in the treatment of behavioural and psychological symptoms of dementia (BPSD)and cognitive function of Alzheimer's disease(AD) patients. Methods From April 2015 to February 2016, 80 cases of moderate Alzheimer's disease (according to the clinical dementia rating scale, CDR) with symptoms of BPSD in Qingdao Mental Health Center were collected and randomly divided into treatment group and control group.Treatment group was given citalopram (10 to 30 mg/d ), the control group was given the same dose of placebo, and the patients in both group were given memantine (10 mg/bid) for 12 weeks.Simple mental state examination (MMSE) was used to measure cognitive function.Neural psychiatric questionnaire (NPI) measurement was used to evaluate BPSD and the TESS was used to assess adverse effects. Results Decreased scores of MMSE between the treatment group and the control group were respectively (0.67±0.77) and (0.26±0.68) after 12 weeks of treatment.There was significant difference in decreased scores of MMSE between the two groups (t=2.49, P=0.02) .The scores of NPI in agitation/attack(t=2.986, P=0.04), apathy(t=3.144, P=0.002), indifference/dysthymia (t=6.094, P=0.000)and anxiety(t=6.496, P=0.000) showed statistically significant differences between the two groups.There were no significant difference in TESS scores(P>0.05). The most frequently adverse events in the study included dizziness, headache, fatigue and nausea.QTc interval prolongation were found in participants treated with 30 mg citalopram per day in the study group. Conclusion Citalopram is an effective and safe drug in the treatment of BPSD and cognitive function associated with moderate AD. Key words: Citalopram; Alzheimer's disease; Behavioral and psychological symptoms of dementia; Cognitive function

Lamotrigine enhances the neuroprotective effects of memantine on aluminum chloride-induced behavioral changes in rats

Background and aimAlzheimer's disease (AD) is the most common reason for dementia in the aged population. AD increases the risk of seizures. Management of epilepsy in AD is difficult because of the possibility of drug interactions. Moreover, antiepileptic drug selection in the elderly needs special attention due to numerous pharmacokinetic factors. In the present study, the effect of lamotrigine (LTG) on the neuroprotective effect of memantine (MEM) was assessed. Materials and methodsA total of 32 adult male Wistar rats were divided into four groups: saline-treated group, aluminum chloride (AlCl3)-treated group, AlCl3+ MEM-treated group, and AlCl3+ MEM + LTG-treated group. AD was induced by intraperitoneal injection of AlCl3 (75 mg/kg/day) for 60 days, then the rats were evaluated using the Morris water maze, radial arm maze, novel object recognition, and passive avoidance tests. After accomplishing the behavioral tests, the rats were killed and their kidneys and brains were used for estimation of acetyl cholinesterase levels and histopathological studies. ResultsAlCl3 significantly impaired the performance in the Morris water maze, radial arm maze, novel object recognition test, and passive avoidance test and elevated acetyl cholinesterase levels in the cerebral cortex, hippocampus, serum, and kidneys. Moreover, the brain of AlCl3-treated rats showed an increased number of damaged neurons and glial cells. Concurrent administration of MEM and LTG significantly reversed behavioral and cognitive deficits induced by AlCl3. ConclusionLTG significantly potentiated the behavioral and cognitive improvement induced by MEM, a finding that suggests a neuroprotective profile of LTG and may hold promise in the management of dementia with epilepsy.

An analytical review on method development and validation of drugs used for alzheimers disease

Alzheimers disease (AD) is a neurodegenerative disorder characterized by progressive memory defeat and impairment in behavior, language, and visuospatial skills. Current approved drugs for the treatment of Alzheimer disease (AD) include cholinesterase inhibitors (donepezil, galantamine and rivastigmine,) and the NMDA receptor antagonist memantine. These drugs can provide a symptomatic relief but they poorly affect the progression of the disease. There are several risk factors for the development of Alzheimers disease which include factors like age, genetic factor family history, Downs syndrome, head injury and cardiovascular diseases. Cardio vascular risk factors may include blood pressure, cholesterol, diabetes, obesity and smoking. People may experience cognitive mental illness, difficulty in understanding and thinking, forgetting things easily, making things complicated, mental confusion, difficulty in concentrating, inability to create old memories, inability to do simple things, or inability to recognize common things. The main objective of this review is discussion on various analytical methods used, different solvents used as mobile phase and their retention time. This review includes method development and validation of cholinesterase inhibitors like Donepezil, Galantamine, Rivastigmine and Tacrine combination of drugs which include cholinesterase inhibitors like Donepezil and NMDA receptor antagonist Memantine. The review is a collection of data including various analytical methods used, the different columns used, mobile phase used, flow rate, different detectors and detection wavelength and retention time. This review includes discussion on method development and validation of Alzheimers drugs and newly developed compounds which have lesser side effects and are proving more efficient for treatment of Alzheimers disease.