Development and validation of high-performance liquid chromatography method for the simultaneous quantification of rivastigmine hydrogen tartrate and asiaticoside co-loaded in niosomes: A Box-Behnken design approach.

Rivastigmine hydrogen tartrate (RHT), a reversible cholinesterase inhibitor, is considered as the first-line therapy for mild to moderate Alzheimer's disease. Asiaticoside (AS), a pentacyclic triterpenoid saponin, is well known as cognitive enhancer due to its antioxidant effect. Based on the hypothesis of their synergistic therapeutic potential, RHT and AS were co-encapsulated in niosomal formulation. A simple, precise, and accurate high-performance liquid chromatography method was developed for simultaneous quantitative analysis. The chromatographic parameters were optimized by Box-Behnken experimental design. The separation was performed on a reversed-phase Phenomenex C18 (150 mm × 4.6 mm, 5 µm) column at 30 °C under the UV detection of 210 nm. The optimized mobile phase consisted of a mixture of 20 mM potassium dihydrogen phosphate buffer (pH 2.6) and acetonitrile (72:28 % v/v) under the isocratic mode at the flow rate of 0.9 mL/min. The developed method was fully validated under the ICH guidelines and could be successfully applied for simultaneous quantitative analysis of RHT and AS in niosomal formulation.

Evaluation of 3D-Printed Solid Microneedles Coated with Electrosprayed Polymeric Nanoparticles for Simultaneous Delivery of Rivastigmine and N-Acetyl Cysteine.

In the current study, coated microneedle arrays were fabricated by means of digital light processing (DLP) printing. Three different shapes were designed, printed, and coated with PLGA particles containing two different actives. Rivastigmine (RIV) and N-acetyl-cysteine (NAC) were coformulated via electrohydrodynamic atomization (EHDA), and they were incorporated into the PLGA particles. The two actives are administered as a combined therapy for Alzheimer's disease. The printed arrays were evaluated regarding their ability to penetrate skin and their mechanical properties. Optical microscopy and scanning electron microscopy (SEM) were employed to further characterize the microneedle structure. Confocal laser microscopy studies were conducted to construct 3D imaging of the coating and to simulate the diffusion of the particles through artificial skin samples. Permeation studies were performed to investigate the transport of the drugs across human skin ex vivo. Subsequently, a series of tape strippings were performed in an attempt to examine the deposition of the APIs on and within the skin. Light microscopy and histological studies revealed no drastic effects on the membrane integrity of the stratum corneum. Finally, the cytocompatibility of the microneedles and their precursors was evaluated by measuring cell viability (MTT assay and live/dead staining) and membrane damages followed by LDH release.

Protective effect of rivastigmine against lung injury in acute pancreatitis model in rats via Hsp 70/IL6/ NF-κB signaling cascade.

Acute lung injury (ALI) that develops as a result of AP can progress to acute respiratory distress syndrome. Some hypotheses are proposed to explain the pathophysiology of AP and its related pulmonary hazards. This experiment aimed to evaluate the mitigating action of rivastigmine (Riva) in lung injury that occurs on the top of acute pancreatitis (AP) induced in rats. Thirty-two male Wister rats were randomized to one of four groups: control, Riva-treated, acute pancreatitis (AP), and acute pancreatitis treated by Riva. Serum amylase and lipase levels were assessed. Pulmonary oxidative stress and inflammatory indicators were estimated. A pancreatic and pulmonary histopathological examination, as well as an immunohistochemical study of HSP70, was carried out. Riva significantly attenuated the L-arginine-related lung injury that was characterized by increased pulmonary inflammatory biomarkers (interleukin-6 [IL-6]), nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), increased pulmonary oxidative markers (total nitrite/nitrate [NOx]), MDA, decreased total antioxidant capacity (TAC), and reduced glutathione level (GSH)) with increased caspase-3 expression. Therefore, Riva retains potent ameliorative effects against lung injury that occur on the top of AP by relieving oxidative stress, inflammation, and apoptosis via HSP70/IL6/NF-κB signaling.

Valine conjugated polymeric nanocarriers for targeted co-delivery of rivastigmine and quercetin in rat model of Alzheimer disease.

Multifunctional nanocarriers are increasingly promising for disease treatment aimed at finding effective therapy and overcoming barriers in drug delivery. Herein, valine conjugated chitosan (VLCS) was used for surface modification of nanocarriers (NCs) based on Poly (ε-caprolactone)-Poly (ethylene glycol)-Poly (ε-caprolactone) (PCL-PEG-PCL) triblock copolymers (NCs@VLCS). The nanocarriers were co-loaded with rivastigmine (RV) and quercetin (QT) to yield the final RV/QT-NCs@VLCS as a multifunctional nanocarrier for Alzheimer's disease (AD) treatment. The large amino acid transporter 1 (LAT-1) was selected for the direction of the NCs to the brain. The biocompatibility of the nanocarrier was studied in HEK-293 and SH-SY5Y cells and rats. The Morris water maze test demonstrated a faster regain of memory loss with RV/QT-NCs@VLCS compared to the other groups. Furthermore, RV/QT-NCs@VLCS and RV/QT-NCs improved GSH depletion induced by scopolamine (SCO), with RV/QT-NCs@VLCS having a superior effect. The real-time PCR analysis revealed that co-delivery of RV and QT by NCs@VLCS showed significantly higher efficacy than sole delivery of RV. RV/QT-NCs@VLCS treatment also modulated the expression of BDNF, ACHE, and TNF-α. The findings revealed that NCs@VLCS co-loaded with RV and QT, significantly increased efficacy relative to the single use of RV and could be considered a potent multifunctional drug delivery system for Alzheimer's treatment.

The impact of rivastigmine on post-surgical delirium and cognitive impairment; a randomized clinical trial.

BACKGROUND: Delirium is an acute and transient disorder of brain function that often occurs in post-surgical patients. Rivastigmine is a cholinesterase inhibitor drug that has been proposed as an adjuvant drug in recent years, still, despite significant theoretical evidence, few clinical studies have been performed on its impact on delirium. AIM: Due to the widespread use of cholinesterase inhibitors in pediatric and adult surgery, the present study aims to investigate the impact of Rivastigmine as a cholinesterase inhibitor on delirium after radical surgery. METHODS: In this randomized double-blind clinical trial, a hundred recruited patients were randomly assigned to either Rivastigmine (n = 50) or placebo (n = 50) groups, and we measured post-operative impact on delirium, by Confusion Assessment Method (CAM) score, and cognitive impairment, by the Mini-Mental State Examination (MMSE). Our univariate and multivariate logistical regression models assessed this hypothesized impact. RESULTS: Treatment with Rivastigmine was significantly associated with reduced day one post-op delirium, as measured by CAM score (Odds Ratio (OR) = 0.35, 95% Confidence Interval (CI) 0.11 to 0.97, p = 0.05), and cognitive impairment, as measured by MMSE (OR = 0.25, 95% CI 0.1 to 0.59, p = 0.0022). These associations became stronger after controlling for age, blood loss, and post-op blood sodium levels: Delirium (OR = 0.23, 95% CI 0.05 to 0.92, p = 0.05), cognitive impairment (OR = 0.12, 95% CI 0.03 to 0.42, p = 0.000178). CONCLUSION: The significant result of our randomized clinical trial is that pre-op Rivastigmine treatment may be associated with a substantial drop in patients experiencing post-op delirium and post-op cognitive impairment.

Antidementia medication acetylcholinesterase inhibitors have therapeutic benefits on osteoporotic bone by attenuating osteoclastogenesis and bone resorption.

This study was designed to determine whether the use of acetylcholinesterase inhibitors (AChEIs), a group of drugs that stimulate acetylcholine receptors and are used to treat Alzheimer's disease (AD), is associated with osteoporosis protection and inhibition of osteoclast differentiation and function. Firstly, we examined the effects of AChEIs on RANKL-induced osteoclast differentiation and function with osteoclastogenesis and bone resorption assays. Next, we investigated the impacts of AChEIs on RANKL-induced nuclear factor κB and NFATc1 activation and expression of osteoclast marker proteins CA-2, CTSK and NFATc1, and dissected the MAPK signaling in osteoclasts in vitro by using luciferase assay and Western blot. Finally, we assessed the in vivo efficacy of AChEIs using an ovariectomy-induced osteoporosis mouse model, which was analyzed using microcomputed tomography, in vivo osteoclast and osteoblast parameters were assessed using histomorphometry. We found that Donepezil and Rivastigmine inhibited RANKL-induced osteoclastogenesis and impaired osteoclastic bone resorption. Moreover, AChEIs reduced the RANKL-induced transcription of Nfatc1, and expression of osteoclast marker genes to varying degrees (mainly Donepezil and Rivastigmine but not Galantamine). Furthermore, AChEIs variably inhibited RANKL-induced MAPK signaling accompanied by downregulation of AChE transcription. Finally, AChEIs protected against OVX-induced bone loss mainly by inhibiting osteoclast activity. Taken together, AChEIs (mainly Donepezil and Rivastigmine) exerted a positive effect on bone protection by inhibiting osteoclast function through MAPK and NFATc1 signaling pathways through downregulating AChE. Our findings have important clinical implications that elderly patients with dementia who are at risk of developing osteoporosis may potentially benefit from therapy with the AChEI drugs. Our study may influence drug choice in those patients with both AD and osteoporosis.

Homocysteine May Decrease Glucose Uptake and Alter the Akt/GSK3ß/GLUT1 Signaling Pathway in Hippocampal Slices: Neuroprotective Effects of Rivastigmine and Ibuprofen.

Homocysteine (Hcy) is a risk factor for neurodegenerative diseases, such as Alzheimer's Disease, and is related to cellular and tissue damage. In the present study, we verified the effect of Hcy on neurochemical parameters (redox homeostasis, neuronal excitability, glucose, and lactate levels) and the Serine/Threonine kinase B (Akt), Glucose synthase kinase-3ß (GSK3ß) and Glucose transporter 1 (GLUT1) signaling pathway in hippocampal slices, as well as the neuroprotective effects of ibuprofen and rivastigmine alone or in combination in such effects. Male Wistar rats (90 days old) were euthanized and the brains were dissected. The hippocampus slices were pre-treated for 30 min [saline medium or Hcy (30 µM)], then the other treatments were added to the medium for another 30 min [ibuprofen, rivastigmine, or ibuprofen + rivastigmine]. The dichlorofluorescein formed, nitrite and Na+, K+-ATPase activity was increased by Hcy at 30 µM. Ibuprofen reduced dichlorofluorescein formation and attenuated the effect of Hcy. The reduced glutathione content was reduced by Hcy. Treatments with ibuprofen and Hcy + ibuprofen increased reduced glutathione. Hcy at 30 µM caused a decrease in hippocampal glucose uptake and GLUT1 expression, and an increase in Glial Fibrillary Acidic Protein-protein expression. Phosphorylated GSK3ß and Akt levels were reduced by Hcy (30 µM) and co-treatment with Hcy + rivastigmine + ibuprofen reversed these effects. Hcy toxicity on glucose metabolism can promote neurological damage. The combination of treatment with rivastigmine + ibuprofen attenuated such effects, probably by regulating the Akt/GSK3ß/GLUT1 signaling pathway. Reversal of Hcy cellular damage by these compounds may be a potential neuroprotective strategy for brain damage.

Rivastigmine-Benzimidazole Hybrids as Promising Multitarget Metal-Modulating Compounds for Potential Treatment of Neurodegenerative Diseases.

With the goal of combating the multi-faceted Alzheimer's disease (AD), a series of Rivastigmine-Benzimidazole (RIV-BIM) hybrids was recently reported by us as multitarget-directed ligands, thanks to their capacity to tackle important hallmarks of AD. In particular, they exhibited antioxidant activity, acted as cholinesterase inhibitors, and inhibited amyloid-ß (Aß) aggregation. Herein, we moved forward in this project, studying their ability to chelate redox-active biometal ions, Cu(II) and Fe(III), with widely recognized roles in the generation of oxidative reactive species and in protein misfolding and aggregation in both AD and Parkinson's disease (PD). Although Cu(II) chelation showed higher efficiency for the positional isomers of series 5 than those of series 4 of the hybrids, the Aß-aggregation inhibition appears more dependent on their capacity for fibril intercalation than on copper chelation. Since monoamine oxidases (MAOs) are also important targets for the treatment of AD and PD, the capacity of these hybrids to inhibit MAO-A and MAO-B was evaluated, and they showed higher activity and selectivity for MAO-A. The rationalization of the experimental evaluations (metal chelation and MAO inhibition) was supported by computational molecular modeling studies. Finally, some compounds showed also neuroprotective effects in human neuroblastoma (SH-SY5Y cells) upon treatment with 1-methyl-4-phenylpyridinium (MPP+), a neurotoxic metabolite of a Parkinsonian-inducing agent.

In silico and in vitro studies confirm Ondansetron as a novel acetylcholinesterase and butyrylcholinesterase inhibitor.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is growing rapidly among the elderly population around the world. Studies show that a lack of acetylcholine and butyrylcholine due to the overexpression of enzymes Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE) may lead to reduced communication between neuron cells. As a result, seeking novel inhibitors targeting these enzymes might be vital for the future treatment of AD. Ondansetron is used to prevent nausea and vomiting caused by chemotherapy or radiation treatments and is herein shown to be a potent inhibitor of cholinesterase. Comparison is made between Ondansetron and FDA-approved cholinesterase inhibitors Rivastigmine and Tacrine. Molecular docking demonstrates that interactions between the studied ligand and aromatic residues in the peripheral region of the active site are important in binding. Molecular dynamics simulations and binding pose metadynamics show that Ondansetron is highly potent against both enzymes and far better than Rivastigmine. Inhibitor activities evaluated by in vitro studies confirm that the drug inhibits AChE and BChE by non-competitive and mixed inhibition, respectively, with IC50 values 33 µM (AChE) and 2.5 µM (BChE). Based on the findings, we propose that Ondansetron may have therapeutic applications in inhibiting cholinesterase, especially for BChE.

Rivastigmine ameliorates gentamicin experimentally induced acute renal toxicity.

The current experiment aimed to identify the possible protective role of rivastigmine (RIVA) in gentamicin (GNT)-induced acute kidney injury (AKI) in rats. RIVA was administered in the presence and absence of GNT. Kidney function markers and serum and renal GNT concentrations were measured. Renal oxidative stress parameters as well as inflammatory and apoptotic biomarkers were evaluated. Renal histopathological assessment and nuclear factor kappa-B (NF-κB) immunohistochemical study were performed. GNT administration increased serum creatinine, urea, and cystatin C concentrations. RIVA ameliorated these changes via mitigating GNT-induced increases of renal oxidative stress, inflammation, and apoptotic parameters. RIVA showed a prompt improvement in the histopathological renal damage and a decrease in NF-κB immunoexpression. In conclusion, RIVA protective effects against GNT-induced AKI are mediated by decreasing GNT concentration in renal tissue and other effects like antioxidant and antiapoptotic effects possibly through its cholinergic anti-inflammatory action.

Leflunomide abrogates neuroinflammatory changes in a rat model of Alzheimer's disease: the role of TNF-α/NF-κB/IL-1ß axis inhibition.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and is associated with disrupted cognition and behavior. Neuroinflammatory pathogenesis is the main component that contributes to AD initiation and progression through microglial activation and neuronal damage. Thus, targeting inflammatory pathways may help manage AD. In this study, for the first time, the potential prophylactic and therapeutic effects of leflunomide were investigated either alone or in combination with rivastigmine in aluminum chloride (AlCl3)-induced AD-like rats using behavioral, biochemical, and histological approaches. Thirty-six adult male albino rats were divided into two protocols: the treatment protocol, subdivided into five groups (n = 6)-(1) control group, (2) AlCl3 (50, 70, 100 mg/kg/I.P) group, (3) reference group (rivastigmine 2 mg/kg/P.O.), (4) experimental group (leflunomide 10 mg/kg/P.O.), and (5) combination group (rivastigmine + leflunomide); and the prophylactic protocol (leflunomide 10 mg/kg/P.O.), which started 2 weeks before AlCl3 induction. The results showed that AlCl3 disrupted learning and memory parameters in rats and increased amyloid-ß plaque deposition and neurofibrillary tangle aggregation. Moreover, AlCl3 administration markedly elevated acetylcholinesterase activity, nuclear factor-kappa ß, tumor necrosis factor-α, and interleukin-1 beta, and marked degenerative changes in the pyramidal neurons. However, administration of leflunomide alone or with rivastigmine in AlCl3-induced AD rats restored most of the behavioral, biochemical, and histological parameters triggered by AlCl3 in rats. Our findings suggest that leflunomide can potentially restore most of the neuronal damage in the hippocampal tissues of AlCl3-induced AD rats. However, these preclinical findings still need to be confirmed in clinical trials.

Consumption of drugs for Alzheimer's disease on the Brazilian private market / Consumo de medicamentos para doença de Alzheimer no mercado privado brasileiro

ABSTRACT OBJECTIVE To analyze the consumption of drugs for Alzheimer's disease on the Brazilian private market and its geographical distribution from 2014 to 2020. METHODS National data from the Brazilian National System of Controlled Product Management were used, regarding sales of donepezil, galantamine, rivastigmine, and memantine from January 2014 to December 2020. Sales data were used as a proxy for drug consumption and expressed as defined daily dose/1,000 inhabitants/year at national, regional, federative unit and microregion levels. RESULTS Drug consumption went from 5,000 defined daily doses/1,000 inhabitants, in 2014, to more than 16,000/1,000 inhabitants, in 2020, and all federative units showed positive variation. The Brazilian Northeast had the highest cumulative consumption in the period but displayed microregional disparities while the North region had the lowest consumption. Donepezil and memantine were the most consumed drugs, with the highest growth in consumption from 2014 to 2020. CONCLUSION The consumption of medicines indicated to treat Alzheimer's disease tripled in Brazil between 2014 and 2020, which may relate to the increase in the prevalence of the disease in the country, greater access to health services, and inappropriate use. This challenges managers and healthcare providers due to population aging and the increased prevalence of chronic-degenerative diseases.

RESUMO OBJETIVO Analisar o consumo de medicamentos para a doença de Alzheimer no mercado privado brasileiro e sua distribuição geográfica entre os anos de 2014 e 2020. MÉTODOS Foram utilizados dados do Sistema Nacional de Gerenciamento de Produtos Controlados relativos às vendas de donepezila, galantamina, rivastigmina e memantina, entre janeiro de 2014 a dezembro de 2020, em todo o território nacional. Os dados de venda foram utilizados como proxy para o consumo dos medicamentos, avaliado em dose diária definida (DDD)/1.000 habitantes/ano em nível nacional, regional, por unidade federativa e microrregião. RESULTADOS O consumo dos medicamentos passou de 5.000 DDD/1.000 habitantes em 2014 para mais de 16.000 DDD/1.000 habitantes em 2020, e todas as unidades de federação apresentaram variação positiva. A região Nordeste apresentou o maior consumo acumulado no período, porém exibiu disparidades microrregionais. A região Norte apresentou o menor consumo. Os medicamentos mais consumidos foram donepezila e memantina, os quais também apresentaram maior crescimento do consumo no intervalo de tempo entre os anos de 2014 e 2020. CONCLUSÃO O consumo de medicamentos para o tratamento da doença de Alzheimer triplicou no Brasil entre os anos de 2014 e 2020, o que pode estar relacionado ao aumento da prevalência da doença no país e/ou maior acesso a serviços de saúde, assim como estar ligado, também, à utilização inapropriada destes medicamentos. Este é um desafio para gestores e profissionais de saúde num cenário de envelhecimento populacional e aumento da prevalência de doenças crônico-degenerativas.

Rivastigmine ameliorates indomethacin experimentally induced gastric mucosal injury via activating α7nAChR with inhibiting oxidative stress and apoptosis.

The current study aimed to investigate the potential ameliorative role of Rivastigmine (RIVA), the anti-Alzheimer drug, against the gastric mucosal injury caused by indomethacin (IND). The rats were divided into four groups: group I was given a vehicle as a control, group II was given RIVA (0.3 mg/kg) once daily intraperitoneal (ip) for 2 weeks, group III was given a single IP dose of 30 mg/kg IND, and group IV was given RIVA ip 2 weeks before the administration of IND. The gastric mucosal injury was detected by the estimation of ulcer index, gastric acidity, pepsin, and mucin concentrations. Malondialdehyde (MDA), superoxide dismutase (SOD), reduced glutathione (GSH), total nitrite/nitrate (NOx), and the expression of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), nuclear factor kappa B (NF-κB), Hemoxygenase 1 (HO-1), and caspase-3 were all measured in gastric tissue. In addition, histological assessment and proliferating cell nuclear antigen (PCNA) immuno-expression were studied. Gastric mucosal injury induced by IND was indicated by both biochemical and histopathological assessments. RIVA Pretreatment reduced ulcer index, MDA, TNF-α, IL-6, NF-κB, and caspase-3 and increased SOD, GSH, NOx, and HO-1. RIVA improved the suppressed nuclear immunoreaction for PCNA observed with IND. The current findings provide novel evidence that RIVA possesses a prophylactic action against IND-induced gastric mucosal damage in rats. Despite being a cholinergic drug that is associated with increased pepsin and stomach acidity, RIVA protected against IND-induced gastric mucosal injury via activating α7nAChR and inhibiting oxidative stress and apoptosis.

Differential neuroprotective effect of curcuminoid formulations in aluminum chloride-induced Alzheimer's disease.

Alzheimer's disease (AD) is a slowly progressive brain degenerative disorder which gradually impairs memory, thinking, and ability to perform easy routine tasks. This degenerative disorder mainly targets the elderly people and has imposed an endemic burden on society. Hence, there is a crucial need to investigate the efficacious herbal pharmacotherapies that can effectively mitigate and prevent the pathological hallmarks of AD. The current study aims to explore the potential efficacy of curcuminoid-rich extract (CRE) and its ternary complex (TC). Experimental rodents were administered with AlCl3 (300 mg/kg) to induce AD and treated with rivastigmine, curcuminoid crude extract, CRE, and TC orally for three consecutive weeks. Neurobehavioral, biochemical, and histopathological studies were performed from the last week of the study period. The mRNA expression of different pathological biomarkers was estimated by RT-qPCR analysis. The results of the study suggested that CRE and TC significantly improved the behavioral, biochemical parameters and acetylcholinesterase inhibitory activity in treatment groups. Histological analysis was also carried out indicating that the neurodegenerative changes and neuronal loss were stabilized by CRE and TC supplementation. CRE and TC supplementation remarkably downregulated the interleukin-1α, tumor necrosis factor-α, interleukin-1ß, acetylcholinesterase, and ß-secretase pathological gene expression. Hence, it was concluded that CRE and TC may act as promising candidates in the prevention of AD via numerous underlying signaling pathways.

Association between long-term usage of acetylcholinesterase inhibitors and lung cancer in the elderly: a nationwide cohort study.

This retrospective cohort study aimed to evaluate the association between acetylcholinesterase inhibitors (AChEI) usage and the risk of lung cancer. Data from 116,106 new users of AChEI and 348,318, at a ratio of 1:3, matched by age, sex, and index-year, between 2000 and 2015 controls were obtained from the Taiwan Longitudinal Health Insurance Database in this cohort study. The Cox regression model was used to compare the risk of lung cancer. The adjusted hazard ratio (aHR) of lung cancer for AChEI users was 1.198 (95% confidence interval [CI] = 0.765-1.774, p = 0.167). However, the adjusted HR for patients aged ≥ 65 was adjusted to HR: 1.498 (95% CI = 1.124-1.798, p < 0.001), in contrast to the comparison groups. In addition, patients with comorbidities such as pneumonia, bronchiectasis, pneumoconiosis, pulmonary alveolar pneumonopathy, hypertension, stroke, coronary artery disease, diabetes mellitus, chronic kidney disease, depression, anxiety, smoking-related diseases, dementia, and seeking medical help from medical centers and regional hospitals, were associated with a higher risk in lung cancer. Furthermore, longer-term usage of rivastigmine (366-730 days, ≥ 731 days) and galantamine (≥ 731 days) was associated with the risk of lung cancer. AChEI increased the risk of lung cancer in the older aged patients, several comorbidities, and a longer-term usage of rivastigmine and galantamine. Therefore, physicians should estimate the risks and benefits of AChEI usage and avoid prescribing antidepressants concurrently.

Design of a Long-Acting Rivastigmine Transdermal Delivery System: Based on Computational Simulation.

The purpose of our study was using a computational simulation to develop a long-acting patch of rivastigmine (RVS). A range of patch formulations were screened including pressure sensitive adhesive (PSA), pharmaceutical excipients, and controlled release membranes using transfer simulation based on a mathematical model. Diffusion dynamics parameters for simulated operations were acquired through in vitro release tests (IVRT) and in vitro skin permeation tests (IVPT). The mechanism of controlled release was studied by FTIR (Fourier transform infrared), DSC (differential scanning calorimeter) and molecular docking. Results of a rat in vitro permeation profile showed excellent correlation with the in vivo deconvolution profile (R2=0.998). Experiments testified to transfer of RVS at a relatively uniform speed with high skin permeation (2531.2±142.46 µg/cm2) in 72 h. Pharmacokinetic data obtained in vivo also confirmed stable plasma concentrations over 72 h for the optimized patch, and significant prolongation of both Tmax (11.20±1.79 h) and MRT0-t (33.91±5.33 h). Cmax was controlled with AUC0-t (267.34±24.46 h ng/ml), which was closely comparable to parameters of a commercial Exelon® Patch. The successful development of a long-acting patch of RVS thus underscores the potential of computer aided design in a context of promnesic transdermal delivery. Graphical abstract.

Naproxen as a potential candidate for promoting rivastigmine anti-Alzheimer activity against aluminum chloride-prompted Alzheimer's-like disease in rats; neurogenesis and apoptosis modulation as a possible underlying mechanism.

BACKGROUND AND AIM: Alzheimer's disease (AD) is one of the leading causes of dependence and disability among the elderly worldwide. The traditional anti-Alzheimer medication, rivastigmine, one of the cholinesterase inhibitors (ChEIs), fails to achieve a definitive cure. We tested the hypothesis that naproxen administration to the rivastigmine-treated aluminum chloride (AlCl3) Alzheimer's rat model could provide an additive neuroprotective effect compared to rivastigmine alone. MATERIALS AND METHODS: The studied groups were control (Cont), AlCl3 treated (Al), rivastigmine treated (RIVA), naproxen treated (Napro), and combined rivastigmine and naproxen treated (RIVA + Napro). Rats' memory, spatial learning, and cognitive behavior were assessed followed by evaluation of hippocampal acetylcholinesterase (AChE) activity. Hippocampal and cerebellar histopathology were thoroughly examined. Activated caspase-3 and the neuroepithelial stem cells marker; nestin expressions were immunohistochemically assayed. RESULTS: AD rats displayed significantly impaired memory and cognitive function, augmented hippocampal AChE activity; massive neurodegeneration associated with enhanced astrogliosis, apoptosis, and impaired neurogenesis. Except for the enhancement of neurogenesis and suppression of apoptosis, the combination therapy had no additional neuroprotective benefit over rivastigmine-only therapy. CONCLUSION: Naproxen's efficacy was established by its ability to function at the cellular level, improved neurogenesis, and decreased, apoptosis without having an additional mitigating impact on cognitive impairment in rivastigmine-treated AD rats.

Design, development and in-vitro/in-vivo evaluation of intranasally delivered Rivastigmine and N-Acetyl Cysteine loaded bifunctional niosomes for applications in combinative treatment of Alzheimer's disease.

The present investigation explores the potential of novel dual drug-loaded niosomes for nasal delivery of Rivastigmine (RIV) and N-Acetyl Cysteine (NAC) to the brain. The dual niosomes showed a particle size of 162.4 nm and % entrapment efficiencies of 97.7% for RIV and 85.9% for NAC. The niosomes were statistically validated using Box-Behnken experimental design (BBD) with good significance. Ultrastructural and chemical characterization of the niosomes using various analytical techniques like Fourier Transform Infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC), Transmission electron microscopy (TEM) showcased drug-excipient compatibility and robust stability of 6 months in a liquid state at 4-8 °C. The dual drug-loaded niosomes showed a sustained drug release pattern up to 2 days. Acetylcholinesterase (AChE) and DPPH (1, 1-diphenyl-2- picrylhydrazyl) enzyme inhibition assays showed a better combinative effect than the free drug solutions. A 2-day nasal permeation proved the effectiveness and biocompatibility of the niosomes. In-vivo pharmacokinetic and organ biodistribution studies revealed a better drug profile and greater distribution of the niosomes in the brain compared to other organs, thereby indicating a direct nose-to-brain delivery of the niosomes.

Rivastigmine attenuates the Alzheimer's disease related protein degradation and apoptotic neuronal death signalling.

Rivastigmine is a clinical drug for patients of Alzheimer's disease (AD) exerting its inhibitory effect on acetylcholinesterase activity however, its effect on other disease-related pathological mechanisms are not yet known. This study was conducted to evaluate the effect of rivastigmine on protein aggregation and degradation related mechanisms employing streptozotocin (STZ) induced experimental rat model. The known inhibitory effect of rivastigmine on cognition and acetylcholinesterase activity was observed in both cortex and hippocampus and further its effect on tau level, amyloid aggregation, biochemical alterations, endoplasmic reticulum (ER) stress, calcium homeostasis, proteasome activity and apoptosis was estimated. STZ administration in rat brain caused significant cognitive impairment, augmented acetylcholinesterase activity, tau phosphorylation and amyloid aggregation which were significantly inhibited with rivastigmine treatment. STZ also caused significant biochemical alterations which were attenuated with rivastigmine treatment. Since AD pathology is related to protein aggregation and we have found disease-related amyloid aggregation, further the investigation was done to decipher the ER functionality and apoptotic signalling. STZ caused significantly altered level of ER stress related markers (GRP78, GADD153 and caspase-12) which were significantly inhibited with rivastigmine treatment. Furthermore, the effect of rivastigmine was estimated on proteasome activity in both regions. Rivastigmine treatment significantly enhances the proteasome activity and may contributes in removal of amyloid aggregation. In conclusion, findings suggested that along with inhibitory effect of rivastigmine on acetylcholinesterase activity and up to some extent on cognition, it has significant effect on disease-related biochemical alterations, ER functionality, protein degradation machinery and neuronal apoptosis.

Development of long-acting rivastigmine drug-in-adhesive patch utilizing ion-pair strategy and characterization of controlled release mechanism.

The purpose of present study was to develop a long-acting drug-in-adhesive patch of rivastigmine (RVS) to achieve controlled release under high drug loading. Formulation factors including ion-pair, pressure sensitive adhesive (PSA), drug-loading and permeation enhancers were investigated through in vitro skin permeation experiments. Optimized patch was evaluated by pharmacokinetic study. The mechanism of controlled release was studied by FTIR, Raman, DSC, rheology study and molecular modeling. The optimized patch composed of RVS-SA (equal to 30% RVS), 15% POCC as permeation enhancer and AAOH as PSA matrix. The RVS in optimized patch was basically permeated at a uniform rate, and the ratio of the skin permeation amount (2803.38 ± 153.85 µg/cm2) in 72 hours to that of the control group (1000.89 ± 62.45 µg/cm2) was 2.8. The plasma concentration of RVS was stable for 72 hours in vivo (AUCoptimized = 5721.30 ± 1994.87 h ng/mL, MRT0-t = 29.55 ± 2.49 h), and Cmax was significantly controlled. The results of the study on the controlled release mechanism showed that the addition of counter ion formed hydrogen bonds with RVS and PSA respectively, which reduced the fluidity and molecular mobility of PSA, and enhanced the interaction between RVS and PSA, thus achieving the purpose of long-acting effect. In conclusion, long-acting drug-in-adhesive patch of RVS was developed, and provided a new idea for the long term drug delivery of Alzheimer's disease.