Rivastigmine Research Articles

Discovery of novel substituted (Z)-N′-hydroxy-3-(3-phenylureido)benzimidamide derivatives as multifunctional molecules targeting pathological hallmarks of Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disorder marked by significant loss of central cholinergic neurons. This progressive deterioration leads to cognitive dysfunction and impaired motor activity, culminating in the brain cell's death at the later stages of the disease. The approved drugs for AD are limited to providing symptomatic relief for an initial period due to the multifaceted etiology of the disease. Several studies have demonstrated that rivastigmine (RIV) is a selectively potent inhibitor of butyrylcholinesterase and devoid of antioxidant, Aβ, and tau protein aggregation inhibition and anti-inflammatory properties. Therefore, to address these issues associated with RIV, novel rivastigmine-based molecules were rationally designed, synthesized, and evaluated in various in-vitro and in-vivo AD models. In in-vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition studies revealed that 3q &6e as promising leads (AChE, IC50 1.72 ± 0.15, 0.91 ± 0.016 μM, BChE, IC50 6.69 ± 0.28 μM, 1.19 ± 0.026 μM, for 3q &6e, respectively). The computational studies (molecular docking and dynamics) further corroborated the in-vitro studies. Further, 3q and 6e were found to be potent antioxidants in the DPPH assay (IC50 16.15 ± 1.05 & 15.17 ± 0.07 μM, for 3q &6e, respectively). Interestingly, 3q, and 6e could effectively inhibit self-induced full-length tau and Aβ1-42 aggregation. Treatment with 3q &6e inhibited microglial activation by attenuating ROS release and mitochondrial damage. Further, 3q &6e also suppressed NLRP3 inflammasome and NF-κB expression levels in microglial cells and halted the release of pro-inflammatory cytokines in human microglial cells. Finally, 3q &6e were found to be efficacious in reversing the scopolamine-induced memory impairment in the Morris water maze test. The expression of various neuroprotection markers, such as BDNF and TRKB, was significantly overexpressed compared to the disease control group.

Supramolecular cyclodextrin-based reservoir as nasal delivery vehicle for rivastigmine to brain

The purpose of this study involved the synthesis of supramolecular reservoir (i.e. cyclodextrin metal-organic framework, MOF) using cyclodextrins as building blocks, followed by cross-linking to obtain crosslinked CD framework (CDF) using CD-MOF as template and functionalized with borneol (BO) to enhance rivastigmine (RIV) permeation and facilitate brain targeting via intranasal administration. Utilizing BO modified CDF (BO-CDF) with cubic shape as a carrier for the encapsulation of RIV, a nasal RIV delivery system (RIV@BO-CDF) was fabricated. The particle size of RIV@BO-CDF was approximately 250 nm, and the drug loading capacity reached 15 ± 2 %. BO-CDF improved the mucoadhesion and enhanced RIV permeability with the plasma concentration-time curve (AUC), the brain AUC and the peak drug concentration within brain in rats 1.7, 2.3 and 8 times than that of oral RIV solution, respectively. The relative drug targeting efficiency percentage (DTE, 139.4 %) and direct drug transfer percentage (DTP, 28.3 %) of RIV@BO-COF indicated good targeting efficiency and direct nose-to-brain drug delivery. Overall, this study provides a potential application of supramolecular cyclodextrin-based reservoir to enhance the brain targeting and efficacy of the RIV via nasal delivery.

Exploiting the potential of rivastigmine-melatonin derivatives as multitarget metal-modulating drugs for neurodegenerative diseases

The multifaceted nature of the neurodegenerative diseases, as Alzheimer's disease (AD) and Parkinson's disease (PD) with several interconnected etiologies, and the absence of effective drugs, led herein to the development and study of a series of multi-target directed ligands (MTDLs). The developed RIV-IND hybrids, derived from the conjugation of an approved anti-AD drug, rivastigmine (RIV), with melatonin analogues, namely indole (IND) derivatives, revealed multifunctional properties, by associating the cholinesterase inhibition of the RIV drug with antioxidant activity, biometal (Cu(II), Zn(II), Fe(III)) chelation properties, inhibition of amyloid-β (Aβ) aggregation (self- and Cu-induced) and of monoamine oxidases (MAOs), as well as neuroprotection capacity in cell models of AD and PD. In particular, two hybrids with hydroxyl-substituted indoles (5a2 and 5a3) could be promising multifunctional compounds that inspire further development of novel anti-neurodegenerative drugs.

Implantable trilayer microneedle transdermal delivery system to enhance bioavailability and brain delivery of rivastigmine for Alzheimer treatment: A proof-of-concept study

Alzheimer’s disease (ALZ) is a neurological disorder characterized by cognitive decline. Rivastigmine (RV), an acetylcholinesterase inhibitor, is commonly used to treat ALZ. Unfortunately, RV is availablein capsule form, which is associated with low drug bioavailability, and in patch form, which can lead to skin irritation upon repeated use. This study successfully fabricated a trilayer dissolving microneedle (TDMN) containing RV with adequate mechanical strength by using the molding method. In vitro release and ex vivo permeation showed that the release and permeation of RV were significantly sustained compared to control without PCL. The release and permeation percentages were 91.34 ± 11.39 % and 13.76 ± 1.49 μg/cm2, respectively. In addition, the concentration of RV in plasma and brain after 168 h was measured to be 0.44 ± 0.09 µg/mL and 1.23 ± 0.26 µg/g, respectively, which reached the minimum concentration to inhibit AcHE and BuChe. Pharmacokinetic testing revealed higher AUC values after administration of TDMN, indicating better bioavailability and RV concentrations in the brain were twice as high as those achieved with oral administration. This study suggests TDMN may enhance the bioavailability and brain delivery of RV.

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.

Formulation and characterization of polymeric nanoparticle of Rivastigmine for effective management of Alzheimer’s disease

Memory loss or dementia is a progressive disorder, and one of its common forms is Alzheimer’s disease (AD), effecting mostly middle aged and older adults. In the present study, we developed Rivastigmine (RIV) nanoparticles using poly(lactic-co-glycolic acid) (RIV-loaded PLGA NPs) and polyvinyl alcohol (PVA). The prepared RIV-PLGA nanoparticles was evaluated for the management of Alzheimer's disease (AD). The nanoparticles were prepared by the slightly modified nano-precipitation technique. The developed formulations were evaluated for particle size, zeta potential (ZP), polydispersibility index (PDI) and surface morphology and drug content. The experimental result revealed that prepared RIV-loaded PLGA NPs (F1) was optimized having particle size (61.2 ± 4.6 nm), PDI (0.292), ZP (−11.2 ± 1.2). SEM study confirms the prepared nanoparticles depicted non-aggregated as well smooth surface particles without any fracture. This formulation (F1) was further assessed for in vivo studies on animal model. A pharmacological screening on an animal model of Alzheimer's disease revealed that RIV-loaded PLGA NPs formulations treat CNS disorders like Alzheimer's effectively. In addition to that, an in-vivo brain cholinesterase estimation study found that, animals treated with optimized formulation significantly (p < 0.01) reduced brain cholinesterase activity when compared to scopolamine-treated animals. According to the above results, it can be concluded that RIV-loaded PLGA NPs are ideal carriers for delivering the drug at a specific target site in the brain, thus may treat Alzheimer's disease efficiently and improve patient compliance.

Development of hyaluronic acid-based microneedles for improved brain delivery of rivastigmine nanoparticles via mystacial pad region

In this study, for the first time, we developed the novel combinatorial approach of poly-lactid-co-glycolid acid (PLGA)-based nanoparticles (PLGA-NPs) containing rivastigmine (RV) and hyaluronic acid-based two-layered dissolving microneedles (DMNs) for the effective delivery of RV through the trigeminal pathway of nasal cavity to the brain via mystacial pad region. In order to optimize the formulations, several evaluations were conducted, producing nanoparticles with particle size of <200 nm with the release percentage of RV from the PLGA-NPs up to 95.42 ± 8.76 % in sustained-manner after 48 h of investigation. Following the incorporation of PLGA-NPs into hyaluronic acid-based DMNs, the formulations showed the adequate mechanical and insertion properties, exhibiting the suitability of the system. In the ex vivo studies, DMNs exhibited higher dermatokinetic profiles compared to needle-free patch formulation. The formulations were found to cytocompatible to neuro-2a and hCMEC/D3 cell lines. Importantly, in the in vivo studies, with respect to the effectiveness of the brain targeting, the drug targeting effeciency (DTE) value up to > 60-fold and the direct transport percentage (DTP) to > 90 % compared to the oral conventional administration, injection and polyvynyl pyrrolidone-based DMNs without affecting the brain examined through histopathology evaluations. All the results showed the advantageous of delivering RV through the trigeminal pathway to the brain, using the combination of PLGA-NPs and two-layered DMNs. This approach was considered to be a future-novel treatment of Alzheimer's disease that can promote numerous advantages compared to the conventional oral preparation of RV.

Synthesis and characterization of magnetic molecularly imprinted polymer of polydopamine/graphene oxide as drug carrier for rivastigmine

In this study, a magnetic molecularly imprinted polymer based on magnetic graphene oxide and polydopamine (PDA) was synthesized, and its application in a drug delivery system (DDS) for rivastigmine (RIV) was investigated. In order to investigate the effect of imprinting on the performance of the MIP-GO/Fe3O4/PDA, its non-imprinted polymer (NIP-GO/Fe3O4/PDA) was also synthesized. Various analyses such as Fourier transform infrared spectrometer (FT-IR), scanning electron microscopy (SEM), thermal gravimetric analysis (TGA), vibrating-sample magnetometer (VSM), N2 adsorption and desorption (Brunauer-Emmett-Teller, BET), energy dispersive X-ray analysis (EDX), and X-ray diffraction analysis (XRD) were used to characterize the prepared polymers. The isotherm and kinetics studies for the drug loading process were done and modeled by various models. Drug release was performed in buffers with different pHs of 2.2, 6.4, 7.4, and 9, and in addition, in simulated nasal electrolyte solution (SNES) buffer. In addition, to investigate the drug release mechanisms, different models were studied. The results of this study showed that the drug loading process in this polymer follows the Freundlich isotherm model and the pseud-second-order model. The maximum efficiency of drug loading on the MIP and NIP was 96.44% and 72.78% at 400 ppm drug concentration, respectively. The results of drug release by these two polymers showed that molecularly imprinted techniques caused controlled drug release carriers, and the maximum amount of drug released from this polymer was 78.65% (301.98 ppm) at pH 9. In addition, the results of drug release modeling showed that the mechanism of rivastigmine release from MIP-GO/Fe3O4/PDA is Fickian diffusion.

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.

An In vivo Investigation of Ascorbic Acid Tethered Polymeric Nanoparticles for Effectual Brain Transport of Rivastigmine.

The goal of this study was to see if ascorbic acid grafted polylactic glycolic acid-b-polyethylene glycol nanoparticles (PLGA-b-PEG NPs) might boost the carrying or transport capacity of rivastigmine(RSM) to the brain via choroid plexus Sodium-dependent vitamin C transporter 2 (SVCT2 transporters). The IR and 1H NMR, were used to characterise the PLGA-b-PEG copolymer. Nanoprecipitation method was used to make PLGA-b-PEG NPs. To promote SVCT2- mediated transportation of ascorbic acid (Asc) into the brain, PLGA-b-PEG NPs of acceptable size, polydispersity, and drug loading were bound with ascorbic acid (PLGA-b-PEG-Asc). When compared to PLGA-b-mPEG NPs, the surface functionalization of NPs with ascorbic acid dramatically improved the cellular uptake of NPs in SVCT2 expressing NIH/3T3 cells. Radial Arm Maze Test, and Acetylcholinesterase (AChE) activity in scopolamine-induced amnetic rats were used to assess in vivo pharmacodynamic effectiveness. In vivo pharmacodynamic tests revealed that drug loaded PLGA-b-PEG-Asc NPs had much greater therapeutic and sustained activity than free drugs, and PLGA-b-mPEG NPs to the brain. As a consequence, the findings revealed that using ascorbic acid grafted PLGA-b-PEG NPs to deliver bioactives to the brain is a potential strategy.

Formulation and Optimization of Rivastigmine-Loaded PLGA and Chitosan Nanoparticles for Transdermal Delivery

Rivastigmine (RVT) is anti-Alzheimer with low bioavailability and with short elimination half-life due to significant first-pass metabolism. RVT is a hydrophilic drug because it has low permeability tothe skin. Therefore, in the present study, RVT-loaded polymeric nanoparticles (NPs) were formulated to improve drug permeation through the transdermal route. A polymeric nanoparticle of RVT was prepared (using the factorial design) and characterized using the biodegradable polymers, Poly (lactic-co-glycolic) acid (PLGA) and Chitosan (CH) as carriers.PLGA NPs were prepared by the nano-precipitation method, while CH NPs were prepared by the ionic gelation method. The effect of formulation variables on particle size (PS), PDI, and percentage entrapment efficiency (%EE) of NPs were studied using factorial design and were optimized based on the responses' desirability, i.e., minimum particle size and PDI and maximum entrapment efficiency. The optimized PLGA NPs showed PS of 291.3nm, PDI of 0.296, and %EE of 75.31%, whereas CH NPS showed PS of 339.3 nm, PDI of 0.264, and %EE of 83.91%. DSC thermograms indicated that RT was dispersed as an amorphous state in both PLGA and CH NPs. TEM and SEM studies indicated that the NPs were spherical and smooth. In vitro release studies showed 52.7±1.07 and 75.02±0.97% release from PLGA NPs and CH NPs in 24 h, respectively, whereas from drug solution 92.21±1.11% with 2h.Optimized NPs were incorporated in the patch, and in vitro permeation studies were performed across the pork ear skin.The steady-state flux of PLGA and CH NPs merged patch, i.e., PPN and PCN, was 223.64 and 265.18µg/cm2.h respectively, whereas for pure RVT containing patch (PD) was shown to be 55.01µg/cm2. h after 24 hrs. Results indicated that the flux of PPN and PCN was 4.06 and 4.82 fold higher than PD. Proposed comparative studies of developed patches with marketed patches showed that the developed patch of drug-loaded in polymeric nanoparticles could be a potential alternative for exiting sold Exelon® patch.

In vitro and in vivo evaluation of multi-target-directed Rivastigmine/Memantine/Gingko biloba-loaded nanofibers against Alzheimer's disease

The highly complex pathophysiology of Alzheimer's disease (AD) and the low bioavailability of the currently used drugs make it necessary to offer versatile treatment options. In this study, polyvinyl alcohol (PVA)/polyvinylpyrrolidone (PVP) nanofibers (NFs) were loaded with rivastigmine (RIV), memantine (MM), and Gingko biloba (GB) extract, and their anti-Alzheimer's effects were investigated in vitro by cell culture and in vivo by animal experiments. The characterization studies, including FTIR, XRD, and DSC analysis, showed that the fibers exhibited a good compatibility. The rapid disintegration (in 5.2 s) and complete dissolution (in 120 s) of RIV/MM/GB-loaded NF indicated their suitability for sublingual application. Cell viability analysis revealed that RIV/MM/GB-loaded NFs can be considered as safe and promising candidates. RIV/MM/GB-loaded NFs tremendously improved the learning and memory impairment seen in the AD model created by the injection of intracerebroventricular-streptozotocin into rats. Moreover, RIV/MM/GB-loaded NF stimulated stem cells to improve neuronal differentiation properties and significantly decreased the level of β-amyloid, tau, APP, TNF-α, AChE, and GSK-3β in the brain. The histopathological and immunostaining assays demonstrated that RIV/MM/GB-loaded NF reduced β-amyloid formation and tau hyperphosphorylation in the hippocampus and cerebral cortex. Thus, a novel and promising treatment strategy could be developed that has several advantages, such as ease of sublingual administration, reduced frequency of administration associated with lower drug amounts, and finally reduced toxicity and cost.

Assessment of Anti-Alzheimer Pursuit of Jambolan Fruit Extract and/or Choline against AlCl3 Toxicity in Rats

Jambolan fruit extract and choline were investigated for Aluminum tri chloride (AlCl3)-induced Alzheimer’s disease in rats. Thirty-six male “Sprague Dawley” rats weighing (150 ± 10 g) were allocated into six groups; the first group was fed a baseline diet and served as a negative control. Alzheimer’s disease (AD) was induced in Group 2 rats by oral administration of AlCl3 (17 mg/kg body weight) dissolved in distilled water (served as a positive control). Rats in Group 3 were orally supplemented concomitantly with both 500 mg/kg BW of an ethanolic extract of jambolan fruit once daily for 28 days and AlCl3 (17 mg/kg body weight). Group 4: Rivastigmine (RIVA) aqueous infusion (0.3 mg/kg BW/day) was given orally to rats as a reference drug concomitantly with oral supplementation of AlCl3 (17 mg/kg body weight) for 28 days. Group 5 rats were orally treated with choline (1.1 g/kg) concomitantly with oral supplementation of AlCl3 (17 mg/kg body weight). Group 6 was given 500 mg/kg of jambolan fruit ethanolic extract and 1.1 g/kg of choline orally to test for additive effects concurrently with oral supplementation of AlCl3 (17 mg/kg bw) for 28 days. Body weight gain, feed intake, feed efficiency ratio, and relative brain, liver, kidney, and spleen weight were calculated after the trial. Brain tissue assessment was analyzed for antioxidant/oxidant markers, biochemical analysis in blood serum, a phenolic compound in Jambolan fruits extracted by high-performance liquid chromatography (HPLC), and histopathology of the brain. The results showed that Jambolan fruit extract and choline chloride improved brain functions, histopathology, and antioxidant enzyme activity compared with the positive group. In conclusion, administering jambolan fruit extract and choline can lower the toxic impacts of aluminum chloride on the brain.

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.

Amitriptyline improves cognitive and neuronal function in a rat model that mimics dementia with lewy bodies

Dementia with Lewy bodies (DLB), a highly prevalent neurodegenerative disorder, causes motor and cognitive deficits. The main pathophysiologies of DLB are glutamate excitotoxicity and accumulation of Lewy bodies comprising α-synuclein (α-syn) and β-amyloid (Aβ). Amitriptyline (AMI) promotes expression of glutamate transporter-1 and glutamate reuptake. In this study, we measured the effects of AMI on behavioral and neuronal function in a DLB rat model. We used rivastigmine (RIVA) as a positive control. To establish the DLB rat model, male Wistar rats were stereotaxically injected with recombinant adenoassociated viral vector with the SNCA gene (10 μg/10 μL) and Aβ (5 μg/2.5 μL) into the left ventricle and prefrontal cortex, respectively. AMI (10 mg/kg/day, i.p.), RIVA (2 mg/kg/day, i.p.), or saline was injected intraperitoneally after surgery. From the 29th day, behavioral tests were performed to evaluate the motor and cognitive functions of the rats. Immunohistochemical staining was used to assess neuronal changes. We measured the α-syn level, number of newborn cells, and neuronal density in the hippocampus and in the nigrostriatal dopaminergic system. The DLB group exhibited deficit in object recognition. Both the AMI and RIVA treatments reversed these deficits. Histologically, the DLB rats exhibited cell loss in the substantia nigra pars compacta and in the hippocampal CA1 area. AMI reduced this cell loss, but RIVA did not. In addition, the DLB rats exhibited a lower number of newborn cells and higher α-syn levels in the dentate gyrus (DG). AMI did not affect α-syn accumulation but recovered neurogenesis in the DG of the rats, whereas RIVA reversed the α-syn accumulation but did not affect neurogenesis in the rats. We suggest that AMI may have potential for use in the treatment of DLB.

Attenuated effects of rivastigmine in induced cytokine storm in mice

Background: A cytokine storm is a serious clinical condition that complicates infectious diseases, for example, coronavirus disease 2019 (COVID-19), and non-infectious diseases such as autoimmune diseases and cancer and may often lead to death. The patients who are affected by the cytokine storm are almost always severe/critical and at risk for acute respiratory distress syndrome or eventually death. Pro-inflammatory cytokines such as interleukin 6 (IL-6), IL-1 beta, and tumor necrosis factor alpha (TNF-α) have been repeatedly shown to be related to the COVID-19 disease severity and mortality. In this study, our objective was to evaluate the attenuated effect of rivastigmine (RA) in a cytokine storm in Swiss Albino mice in which the cytokine storm was induced by lipopolysaccharide (LPS) and to explore their effects on IL-1 β, IL-6, and TNF-α levels. Methods: This study was carried with 60 male Swiss albino mice that were divided equally and randomly into six groups as follows: • Group AH: Apparently healthy control group which received no induction, not treated. • Group LPS: Induced using LPS at 5 mg/kg and no treatment administered. • Group DMSO: Induced and treated with 1% dimethyl sulfoxide (DMSO). • Group RA: Induced and treated with 0.5 mg/kg RA. • Group MPA: Induced and treated with 50 mg/kg methylprednisolone (MPA). • Group RMPA: Induced and treated with 0.25 mg/kg rivastigmine and 25 mg/kg of methylprednisolone. All the mice were treated with drugs or vehicles for three consecutive days before LPS induction. The mice were then injected with LPS intraperitoneally at a dosage of 5 mg/kg for systematic inflammatory stimulation. After 48 hours of LPS induction, all the mice were euthanized by light anesthesia with chloroform, and blood was collected for the quantitative determination of IL-1β, IL-6, and TNF-α levels using the enzyme-linked immunosorbent assay (ELISA) technique. Results: Administration of LPS to Swiss albino mice caused a significant elevation of IL-1β, IL-6, and TNF-α levels than in the healthy control group. Significant reduction of these parameters were observed in the RA and MPA groups when compared with those in the non-treated group. Conclusion: RA was found to be effective in attenuating the induced cytokine storm by suppressing IL-1β, IL-6, and TNF-α levels, and the results with RA were comparable to that of MPA. A combination of half-doses of both RA and MPA administered together shows no obvious advantage when compared with that of each of them alone.

Novel Rivastigmine Derivatives as Promising Multi-Target Compounds for Potential Treatment of Alzheimer's Disease.

Alzheimer’s disease (AD) is the most serious and prevalent neurodegenerative disorder still without cure. Since its aetiology is diverse, recent research on anti-AD drugs has been focused on multi-target compounds. In this work, seven novel hybrids (RIV–BIM) conjugating the active moiety of the drug rivastigmine (RIV) with 2 isomeric hydroxyphenylbenzimidazole (BIM) units were developed and studied. While RIV assures the inhibition of cholinesterases, BIM provides further appropriate properties, such as inhibition of amyloid β-peptide (Aβ) aggregation, antioxidation and metal chelation. The evaluated biological properties of these hybrids included antioxidant activity; inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and Aβ42 aggregation; as well as promotion of cell viability and neuroprotection. All the compounds are better inhibitors of AChE than rivastigmine (IC50 = 32.1 µM), but compounds of series 5 are better inhibitors of BChE (IC50 = 0.9−1.7 µM) than those of series 4. Series 5 also showed good capacity to inhibit self- (42.1−58.7%) and Cu(II)-induced (40.3−60.8%) Aβ aggregation and also to narrow (22.4−42.6%) amyloid fibrils, the relevant compounds being 5b and 5d. Some of these compounds can also prevent the toxicity induced in SH-SY5Y cells by Aβ42 and oxidative stress. Therefore, RIV–BIM hybrids seem to be potential drug candidates for AD with multi-target abilities.

Rivastigmine ameliorates indomethacin experimentally induced gastric mucosal injury via activating α7nAChR with inhibiting oxidative stressand 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.

An In-silico Approach to Identify Potential Drug Molecules for Alzheimer’s Disease: A Case Involving Four Therapeutic Targets

Background: Computational methods in the ‘omics’ era have proved to be a boon in the drug discovery field. Bioinformatics and cheminformatics databases and tools complement the successful discovery of promising lead compounds in the treatment of several disease conditions, including neurodegenerative diseases, such as Alzheimer’s Disease (AD). However, commercially available drugs in the market to alleviate the disease progression in AD patients are sparse. The current research aims to apply an in-silico approach involving multi-therapeutic agents against multi-therapeutic targets through docking studies to explore potential lead compounds for AD clinical trials. Method: In the proposed research, virtual screening was performed on four US FDA-approved control drugs (donepezil (DON), galantamine (GAL), rivastigmine (RIV), and tacrine (TAC)) in order to be used for mild-moderate-severe stages of AD treatment. The panel of compounds identified through virtual screening was assessed for chemical absorption, distribution, metabolism, excretion, and toxicity (ADMET) and Pharmacokinetics (PK). The compound with good ADMET and PK score was investigated further with molecular docking against the four therapeutic targets involved in AD. Ligands showing the highest binding affinity against cholinesterase inhibitors (AChE, BuChE), receptor antagonists (NMDA), and β-amyloid peptide (Aβ), were computed. Result: The compounds quinazolidinone analogue, 2b, isoquinoline-pyridine, 1, benzylmorphine and coelenteramide, were found to be the lead candidates having least side effects and better efficacy. Conclusion: The predicted lead candidates are suitable for further investigation in the drug discovery pipeline.

Polymeric Microneedles for Transdermal Delivery of Rivastigmine: Design and Application in Skin Mimetic Model.

In the last years, microneedles (MNs) have been considered a valuable, painless, and minimally invasive approach for controlled transdermal drug delivery (TDD). Rivastigmine (RV), a drug administered to patients suffering from dementia, is currently delivered by oral or transdermal routes; however, both present limitations, mainly gastrointestinal adverse symptoms or local skin irritation and drug losses, respectively, for each route. Given this, the objective of the present work was to develop and evaluate the potential of polymeric MNs for RV transdermal delivery in a controlled manner. Polymeric MNs with two needle heights and different compositions were developed with calcein as a fluorescent model molecule. Morphology and mechanical characterisation were accessed. Skin permeation experiments showed the ability of the devices to deliver calcein and confirmed that the arrays were able to efficiently pierce the skin. To obtain a new TDD anti-dementia therapeutic solution, RV was loaded in 800 µm polymeric MNs of alginate and alginate/k-carrageenan MNs. In the presence of RV, the MN’s morphology was maintained; however, the presence of RV influenced the compression force. Skin permeation studies revealed that RV-loaded MNs allowed a more efficient controlled release of the drug than the commercial patch. In vivo, skin irritation tests in rabbits revealed that the developed MNs were innocuous upon removal, in contrast with the evidence found for Exelon®, the commercial patch, which caused slight mechanical damage to the skin. The herein-produced MNs demonstrated a more controlled release of the drug, being the more suitable option for the transdermal delivery of RV.