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Purpose: Due to impairments in memory and judgment, it is difficult for dementia patients to understand why they need medicine. Moreover, they often have swallowing difficulties. In this investigation, an oral dissolving film of rivastigmine tartrate (RT-ODF) was developed, offering a unique and convenient formulation for dementia patients. Methods: RT-ODF was developed using a solvent-casting technique. Sodium alginate and sodium carboxymethyl cellulose were used as film-forming polymers, and glycerol was used as a plasticizer. A full factorial design (32) was employed to estimate the impact of two factors at three levels: polymer concentration (1, 1.5, and 2% w/v) and plasticizer concentration (30, 40, and 50% w/v) on the responses, i.e., the tensile strength (TS), the disintegration time (DT), and the quantity of drug released (Q10 min). Results: The optimized formula (A1) that had the highest desirability value (0.923) exhibited the lowest tensile strength (3.67 ± 0.72 MPa), the shortest disintegration time (20 ± 2.0 s), and the highest percentage of drug released after 10 min (97.12 ± 2.01%). It was composed of 1% w/v sodium alginate (ALG-Na) and plasticized with 30% w/v glycerol. The pharmacokinetic study revealed that the RT-ODFs enhanced the drug's bioavailability by 1.91-fold relative to the reference product (Exelon® capsule). Conclusion: Oral dissolving films of rivastigmine tartrate could be a promising approach to promote drug bioavailability and convenience for geriatric patients. [ABSTRACT FROM AUTHOR]

Anticholinergic toxicity is commonly encountered in the emergency department. However, the availability of physostigmine, a central acetylcholinesterase inhibitor used to reverse anticholinergic delirium, has been significantly limited due to national drug shortages in the United States. Several articles have explored the viability of rivastigmine as an alternative treatment in these patients. A 33-year-old man presented to the emergency department after a suspected suicide attempt. The patient was found with an empty bottle of diphenhydramine at the scene. On arrival, he was tachycardic and delirious, with dilated and nonreactive pupils and dry skin. As the clinical picture was highly suggestive of anticholinergic toxicity, the patient was treated with oral rivastigmine at a starting dose of 4.5 mg to reverse his anticholinergic delirium. Although a repeat dose was required, his delirium resolved without recurrence. Why Should an Emergency Physician Be Aware of This? Oral rivastigmine has been applied successfully here and in other case reports to reverse anticholinergic delirium with the benefit of prolonged agitation control. Emergency physicians may consider this medication in consultation with a specialist, with initial doses starting at 4.5–6 mg, if encountering anticholinergic delirium when physostigmine is not available. [ABSTRACT FROM AUTHOR]

Memory is one of the most important abilities of our brain. The process of memory and learning is necessary for the proper existence of humans in the surrounding environment. However, sometimes there are unfavourable changes in the functioning of the brain and memory deficits occur, which may be associated with various diseases. Disturbances in the cholinergic system lead to abnormalities in memory functioning and are an essential part of clinical symptoms of many neurodegenerative diseases. However, their treatment is difficult and still unsatisfactory; thus, it is necessary to search for new drugs and their targets, being an alternative method of mono- or polypharmacotherapy. One of the possible strategies for the modulation of memory-related cognitive disorders is connected with the endocannabinoid system (ECS). The aim of the present study was to determine for the first time the effect of administration of natural cannabinoid compound (cannabidiol, CBD) and rivastigmine alone and in combination on the memory disorders connected with cholinergic dysfunctions in mice, provoked by using an antagonist of muscarinic cholinergic receptor—scopolamine. To assess and understand the memory-related effects in animals, we used the passive avoidance (PA) test, commonly used to examine the different stages of memory. An acute administration of CBD (1 mg/kg) or rivastigmine (0.5 mg/kg) significantly affected changes in scopolamine-induced disturbances in three different memory stages (acquisition, consolidation, and retrieval). Interestingly, co-administration of CBD (1 mg/kg) and rivastigmine (0.5 mg/kg) also attenuated memory impairment provoked by scopolamine (1 mg/kg) injection in the PA test in mice, but at a much greater extent than administered alone. The combination therapy of these two compounds, CBD and rivastigmine, appears to be more beneficial than substances administered alone in reducing scopolamine-induced cognitive impairment. This polytherapy seems to be favourable in the pharmacotherapy of various cognitive disorders, especially those in which cholinergic pathways are implicated.

Casusbespreking van drie patie¨nten opgenomen in verband met hallucinaties bij de ziekte van Parkinson zonder dementie waarbij naast aanpassing van de anti-parkinson medicatie tevens wordt gestart met rivastigmine waardoor hallucinaties verdwenen en niet meer recidiveerden. Een 79-jarige man kreeg in verband met onrust tevens kortdurend quetiapine, terwijl de anti-parkinson medicatie probleemloos kon worden opgehoogd waardoor mobiliteit verbeterde; een 84-jarige vrouw gaf milde bijwerkingen aan van de rivastigmine, zonder noodzaak tot staken van rivastigmine, terwijl de mobiliteit goed bleek te zijn; een 72-jarige vrouw vertoonde bij opname milde geheugenproblemen die verbeterden, waarbij ook de mobiliteit verbeterde na verdere ophoging van de anti-parkinson medicatie. De behandeling met rivastigmine kan helpen in het therapeutisch dilemma (starten anti-psychoticum of verlagen anti-parkinson medicatie). Naast het aanpassen van de anti-parkinson medicatie en soms het tijdelijk behandelen met een anti-psychoticum lijkt rivastigmine bij hallucinaties bij ziekte van Parkinson in relatief korte tijd verbetering te geven zonder veel bijwerkingen. Deze verbetering bestaat uit verbleken hallucinaties en verbeteren van de mobiliteit, doordat indien nodig anti-parkinson medicatie kan worden opgehoogd. De vele vragen die echter resteren maken prospectief gerandomiseerde trials naar deze indicatie noodzakelijk.

Dementie treft op dit moment in Nederland 195.000 patie¨nten van 65 jaar en ouder. De meest frequente etiologie van dementie is de ziekte van Alzheimer (ZvA). De acetylcholinesteraseremmers rivastigmine en galantamine en de NMDA (N-methyl-D-aspartate) antagonist memantine zijn in ons land geregistreerd voor behandeling van de ZvA, respectievelijk voor de milde tot matig ernstige en matig ernstige tot ernstig vorm. Alle middelen worden op dit moment onder bepaalde voorwaarden vergoed. Rivastigmine en galantamine hebben een gering effect dat goed is onderzocht. Memantine heeft mogelijk bij een klein deel van de patie¨nten een zeer bescheiden effect, de respons op drie domeinen is na een behandeling van zes maanden nog onvoldoende aangetoond. Wij beschrijven een aantal patie¨nten die worden behandeld met deze medicijnen, om de dagelijkse praktijk toe te lichten en bespreken het voor en tegen van medicamenteuze behandeling bij de ziekte van Alzheimer. Voor optimale behandeling van patie¨nten en de juiste advisering en begeleiding van hun verzorgers zijn kennis van farmacotherapie en andere vormen van behandeling en begeleiding en van de diagnostiek van dementie een noodzakelijke voorwaarde.

AbstractTreatment of antimuscarinic toxicity has become more difficult in the United States due to an ongoing national shortage of physostigmine. Rivastigmine has emerged as an alternative, off-label therapy due to its similar mechanism of action as a reversible, centrally-acting acetylcholinesterase inhibitor. We present a case of a diphenhydramine overdose where the patient exhibited classic central antimuscarinic delirium characterized by inattention, floccillation, and deficits in spatial planning manifested by the inability to properly draw a clock. These symptoms rapidly resolved after treatment with oral rivastigmine.

Background. National as well as international Parkinson's disease (PD) treatment guidelines are available to guide clinicians. Previous research has shown that nonmotor symptoms (NMS) are pronounced in late-stage PD and has suggested that current treatment is insufficient and could be improved. Objectives. The aim of this study was to investigate to which degree the national and international treatment guidelines are followed in the treatment of NMS in late-stage PD. Methods. This Swedish cohort was part of the Care of Late-Stage Parkinsonism (CLaSP) study. Late-stage PD was defined as Hoehn and Yahr stages IV-V in "on" and/or ≤50% on the Schwab and England Activities of Daily Living (ADL) scale. NMS were assessed with the NMS scale (NMSS), cognition with the Mini-Mental State Examination (MMSE), and depressive symptoms with the Geriatric Depression Scale (GDS-30). Symptomatic individuals were defined as ≥ 6 on an item of the NMSS; for dementia, a cutoff of ≤18 on the MMSE; for depression, a cutoff of ≥10 on the GDS. Results. All 107 participants exhibited NMS to various degrees and severities; the median NMSS score was 91. Among symptomatic individuals, for depressive symptoms, 37/63 (59%) were treated with antidepressants; for hallucinations and delusions, 9/18 (50%) and 5/13 (38%) were treated with antipsychotics; and for dementia, 9/27 (33%) were treated with rivastigmine and 1 (4%) was treated with donepezil. For orthostatic hypotension, 11/19 (58%) with lightheadedness and 7/8 (88%) with fainting were treated with antihypotensives; for sialorrhea, 2/42 (5%) were treated with botulinum toxin; and for constipation, 19/35 (54%) were treated with laxatives. For insomnia, 4/16 (25%) were treated with hypnotics, and for daytime sleepiness, 1/29 (3%) was treated with psychostimulants. Conclusions. The present analyses suggest a need for clinicians to further screen for and treat NMS. Optimizing treatment of NMS according to the national and international treatment guidelines may improve symptomatology and enhance quality of life in late-stage PD. [ABSTRACT FROM AUTHOR]

BACKGROUND: Transdermal drug delivery has contributed positively to medical practice. However, prescriptions that do not meet minimum quality criteria and medication errors are common. OBJECTIVE: The objective was to determine how transdermal patches are being prescribed to a group of patients in Colombia, the compliance with established requirements of such prescriptions and the comparisons between correct and incorrect prescriptions. METHODS: This was a cross-sectional study of prescriptions for transdermal patches using data from a population-based drug dispensing database between December 1 and 31, 2019. Medical prescriptions were randomly reviewed, establishing whether the drugs were appropriately prescribed by the manufacturer's indications or national regulations. Descriptive and bivariate analysis was performed. RESULTS: A total of 415 prescriptions were reviewed; the prescription was provided to 412 patients with a median age of 76.9 years, and 63.3% were women. Rivastigmine was the most prescribed transdermal patch (57.8%). 66.3% of all prescriptions did not meet the minimum appropriate prescribing standards, especially those for rivastigmine (97.1%). The 7.0% of all prescriptions had posology errors, especially prescriptions for buprenorphine (43.8%). Older patients (84.4% vs 52.5%), from the Pacific region (34.4% vs 23.7%), with manual formulations (22.1% vs 0.8%), dementia (49.0% vs 6.8%), and in management with lipid-lowering drugs (41.8% vs 30.5%), presented incorrect transdermal patch formulations more frequently (p < 0.05). CONCLUSION: The high proportion of inappropriately prescribed transdermal patches should draw the attention of those responsible for health care to improve the training of physicians and create prescription quality verification systems. [ABSTRACT FROM AUTHOR]

[Display omitted] • Intranasal delivery of rivastigmine hydrogen tartrate (RIV-HT) shows limited drug permeation, lower brain concentrations, higher systemic exposure, shorter half-life and rapid mucociliary drug clearance. • RIV-HT and docosahexaenoic acid (DHA) ion-pair complex (RIV:DHA) improved loading in lipid polymeric hybrid (LPH) nanoparticles. • Cationic LPH showed superior amyloid inhibition compared to anionic LPH. • LPH-loaded gel showed efficient nose-to-brain targeting with better targeting to brain. • Cationic LPH exhibited better pharmacokinetics outcomes than anionic LPH. Rivastigmine hydrogen tartrate (RIV-HT) is given orally for Alzheimer's disease. However, oral therapy shows low brain bioavailability, short half-life and gastrointestinal-mediated adverse effects. RIV-HT intranasal delivery can avoid these side effects, but its low brain bioavailability remains challenging. These issues could be solved with hybrid lipid nanoparticles with enough drug loading to enhance RIV-HT brain bioavailability while avoiding oral route side effects. The RIV-HT and docosahexaenoic acid (DHA) ion-pair complex (RIV:DHA) was prepared to improve drug loading into lipid-polymer hybrid (LPH) nanoparticles. Two types of LPH, i.e., cationic (RIV:DHA LPH(+ve)) and anionic LPH (RIV:DHA LPH(-ve)) were developed. The effect of LPH surface charge on in-vitro amyloid inhibition, in-vivo brain concentrations and nose-to-brain drug targeting efficiency were investigated. LPH nanoparticles showed concentration dependant amyloid inhibition. RIV:DHA LPH(+ve) demonstrated relatively enhanced Aβ 1-42 peptide inhibition. The thermoresponsive gel embedded with LPH nanoparticles improved nasal drug retention. LPH nanoparticles gel significantly improved pharmacokinetic parameters compared to RIV-HT gel. RIV:DHA LPH(+ve) gel showed better brain concentrations than RIV:DHA LPH(-ve) gel. The histological examination of nasal mucosa treated with LPH nanoparticles gel showed that the delivery system was safe. In conclusion, the LPH nanoparticle gel was safe and efficient in improving the nose-to-brain targeting of RIV, which can potentially be utilized in managing Alzheimer's. [ABSTRACT FROM AUTHOR]

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-3β (GSK3β) 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 GSK3β 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/GSK3β/GLUT1 signaling pathway. Reversal of Hcy cellular damage by these compounds may be a potential neuroprotective strategy for brain damage. [ABSTRACT FROM AUTHOR]

The rivastigmine patch is the only existing transdermal delivery system used for the treatment of Alzheimer disease. Among the most common adverse events derived from its use are gastrointestinal events, particularly diarrhea. We report a clinical case of an 81-year-old patient admitted to our hospital under long-standing treatment with rivastigmine transdermal patch who presented with atypical watery diarrhea. Anamnesis showed that the patient presented with a likely infectious gastroenteric event, the diarrheal symptoms of which persisted upon resolution of the event and resolved only upon temporary discontinuation of acetylcholinesterase inhibitors. Failure to rapidly identify the causes of profuse diarrhea in older adults can have lethal consequences. When these symptoms occur, quickly recognizing the causes and providing proper management can be lifesaving.

Basal forebrain cholinergic dysfunction, most likely linked with tau protein aggregation, is a characteristic feature of Alzheimer’s disease (AD). Recent evidence suggests that tau protein is a putative target for the treatment of dementia, and the tau aggregation inhibitor, hydromethylthionine mesylate (HMTM), has emerged as a potential disease-modifying treatment. However, its efficacy was diminished in patients already receiving approved acetylcholinesterase inhibitors. In this study, we ask whether this negative interaction can also be mimicked in experimental tau models of AD and whether the underlying mechanism can be understood. From a previous age profiling study, 6-month-old line 1 (L1) tau transgenic mice were characterized by a severe reduction in several cholinergic markers. We therefore assessed whether long-term pre-exposure with the acetylcholinesterase inhibitor rivastigmine alone and in conjunction with the tau aggregation inhibitor HMTM can reverse cholinergic deficits in L1. Rivastigmine and HMTM, and combinations of the two compounds were administered orally for 11 weeks to both L1 and wild-type mice. The brains were sectioned with a focus on the basal forebrain, motor cortex and hippocampus. Immunohistochemical staining and quantification of choline acetyltransferase (ChAT), tyrosine kinase A (TrkA)-positive neurons and relative optical intensity (ROI) for vesicular acetylcholine transporter (VAChT), and acetylcholinesterase (AChE) reactivity confirmed reversal of the diminished cholinergic phenotype of interneurons (nucleus accumbens, striatum) and projection neurons (medial septum, nucleus basalis magnocellularis) by HMTM, to a greater extent than by rivastigmine alone in L1 mice. Combined administration did not yield additivity but, in most proxies, led to antagonistic effects in which rivastigmine decreased the benefits shown with HMTM alone. Local markers (VAChT and AChE) in target structures of the basal forebrain, motor cortex and hippocampal CA3 seemed to be normalized by HMTM, but not by rivastigmine or the combination of both drugs. HMTM, which was developed as a tau aggregation inhibitor, strongly decreased the tau load in L1 mice, however, not in combination with rivastigmine. Taken together, these data confirm a cholinergic phenotype in L1 tau transgenic mice that resembles the deficits observed in AD patients. This phenotype is reversible by HMTM, but at the same time appears to be subject to a homeostatic regulation induced by chronic pre-treatment with an acetylcholinesterase inhibitor, which interferes with the efficacy of HMTM. The strongest phenotypic reversal coincided with a normalization of the tau load in the cortex and hippocampus of L1, suggesting that tau accumulation underpins the loss of cholinergic markers in the basal forebrain and its projection targets.

Treatment of antimuscarinic toxicity has become more difficult in the United States due to an ongoing national shortage of physostigmine. Rivastigmine has emerged as an alternative, off-label therapy due to its similar mechanism of action as a reversible, centrally-acting acetylcholinesterase inhibitor. We present a case of a diphenhydramine overdose where the patient exhibited classic central antimuscarinic delirium characterized by inattention, floccillation, and deficits in spatial planning manifested by the inability to properly draw a clock. These symptoms rapidly resolved after treatment with oral rivastigmine. [ABSTRACT FROM AUTHOR]

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. Key points: 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.In this randomized double‐blind clinical trial, a hundred recruited patients were randomly assigned to either Rivastigmine (n = 50) or placebo (n = 50) groups.The Confusion Assessment Method (CAM) was used to assess delirium as a binomial variable.Mini‐Mental State Examination (MMSE) instruments were also used to assess the patient's cognitive status, performed on the first day after surgery.Treatment with Rivastigmine was significantly associated with decreased day one post‐op delirium. [ABSTRACT FROM AUTHOR]

Objectives: For the quantification of rivastigmine in both its pure form and pharmaceutical formulation, an ultra-performance liquid chromatography method with high speed and sensitivity was created and validated. Materials and Methods: Acquity UPLC BEH C8 (100 mm x 2.1 mm and 1.7 µm) employed to resolve the analysis, and the mobile phase included ammonium phosphate buffer and acetonitrile in a 65:35% v/v ratio. The column temperature was 30°C. The volume of sample injected was 10 µL. The flow rate was 0.5 mL/min, and UV detection was used to detect the analyte at 254 nm. Results: As there was no interferences observed by blank and placebo at the retention time of rivastigmine. According to the results of the degradation investigation, considerable degradation was seen under the conditions of alkali and oxidative stress (peroxide). This led to the conclusion that rivastigmine was susceptible to oxidation and alkali. A study using six replicate injections was carried out to obtain system precision. The predicted % RSD from the rivastigmine peak locations was determined to be 0.2%. The correlation coefficient was determined to be 0.9996, and the suggested UPLC method was linear over the range of 12.5 to 75 g/mL. The accuracy studies were displayed as a % recovery for rivastigmine levels between 50% to 150%. The results obtained were determined to be within the limits, and the maximum percentage of recovery revealed was in between 98 and 102%. As a result, the accuracy of the technique was established. The procedure remains unaffected by variations in column oven temperature and wavelength. All the validation parameters satisfy the ICH Q2 specification acceptance limits, and the technique was validated in accordance with ICH rules. Conclusion: According to ICH criteria, the developed technique was verified for several parameters including accuracy, precision, linearity, specificity, system compatibility, solution stability, and robustness. The results obtained met the requirements for acceptance. It was determined, then, that the proposed UPLC technology was easy to use, precise, and accurate, and that it can be successfully used for the routine analysis of rivastigmine in bulk and pharmaceutical dosage forms. [ABSTRACT FROM AUTHOR]

Tau protein aggregations are important contributors to the etiology of Alzheimer's disease (AD). Hydromethylthionine (HMT) is a potent inhibitor of tau aggregation in vitro and in vivo and is being developed as a possible anti-dementia medication. HMT was also shown to affect the cholinergic system and to interact with mitochondria. Here, we used tau-transgenic (L1 and L66) and wild-type NMRI mice that were treated with HMT, rivastigmine and memantine and with combinations thereof, for 2–4 weeks. We measured HMT concentrations in both brain homogenates and isolated mitochondria and concentrations of glucose, lactate and pyruvate in brain by microdialysis. In isolated brain mitochondria, we recorded oxygen consumption of mitochondrial complexes by respirometry. While rivastigmine and memantine lowered mitochondrial respiration, HMT did not affect respiration in wild-type animals and increased respiration in tau-transgenic L1 mice. Glucose and lactate levels were not affected by HMT administration. The presence of HMT in isolated mitochondria was established. In summary, traditional anti-dementia drugs impair mitochondrial function while HMT has no adverse effects on mitochondrial respiration in tau-transgenic mice. These results support the further development of HMT as an anti-dementia drug. [ABSTRACT FROM AUTHOR]

Prevalence of dementia continues to increase with limited pharmacotherapy options available. Acetylcholinesterase inhibitors remain a mainstay of treatment. The US FDA has approved three oral medications within this class--donepezil, galantamine, and rivastigmine. In 2022, the US Food and Drug Administration approved a novel patch formulation for donepezil that could be beneficial for patients with dysphagia as well as potentially decreasing the side effect burden. The purpose of this analysis is to review the efficacy, safety, tolerability, and clinical considerations related to this novel formulation. [ABSTRACT FROM AUTHOR]

The atom‐ and step‐efficient synthesis of chiral fused tricyclic lactams from readily available ketoesters using cheap ammonium salts as the nitrogen source is reported. This ruthenium‐catalyzed system operates through an efficient tandem dynamic kinetic asymmetric reductive amination (ARA)/lactamization and produces chiral fused tricyclic lactams in high yields with excellent diastereo‐ and enantioselectivity (up to >99 % ee, >20 : 1 dr and 98 % yield). The robust method was also applied to the concise synthesis of key intermediates in the synthesis of rivastigmine analogues and chiral N‐heterocyclic carbene catalysts. [ABSTRACT FROM AUTHOR]

Objective: Anti-dementia medications such as acetylcholinesterase inhibitors are an important part of the management pathway for dementia. However, there are limited data in New Zealand that have examined the rates and patterns of use of funded anti-dementia medication and how use differs with ethnicity, age and sex. Methods: This was a retrospective population-based descriptive study. Using the Integrated Data Infrastructure, we identified individuals of all ages coded for a diagnosis of dementia and estimated the proportion dispensed funded anti-dementia medication – donepezil tablets and rivastigmine patches – between 1 July 2016 and 30 June 2020. Rates of medication use in five main ethnic groups (Māori, Pacific peoples, Asian, European, and Middle Eastern, Latin American and African) in the <65, 65–79 and 80 and over (80+) age groups were compared and also between males and females in all sub-groups. Logbinomial models were used to calculate relative risks to determine any differences in anti-dementia medication use in the five ethnic groups and the three age groups and between males and females in each of the four study years. Results: Overall, one-third of the dementia population received a funded anti-dementia medication in the total population (all ages) between 2016 and 2020. Donepezil tablets were dispensed in 31.6–34.0% and rivastigmine patches in 1.4–2.1% across the four study years. Compared to people of European ethnicity, Māori, Pacific peoples, and Middle Eastern, Latin American and African groups were less likely to be dispensed an anti-dementia medication (Māori: relative risk = 0.79–0.81, p < 0.0001; Pacific peoples: relative risk = 0.72–0.74, p < 0.0001; Middle Eastern, Latin American and African: relative risk = 0.73–0.78, p < 0.05). Compared to the age 80+ group, the 65–79 age group was more likely (relative risk = 1.50–1.54, p < 0.0001), while the age <65 group was less likely (relative risk = 0.67–0.71, p < 0.0001) to be dispensed an anti-dementia medication. There were no statistically significant differences in anti-dementia medication use between males and females. Conclusion: This study provides important information about funded anti-dementia medication use in New Zealand and how this differs by ethnicity, age and sex. Despite higher dementia prevalence in Māori and Pacific peoples, these groups were less likely to receive funded anti-dementia medication. [ABSTRACT FROM AUTHOR]

Background: Rivastigmine is a pseudo-irreversible cholinesterase inhibitor used for therapy of Alzheimer's disease and non-Alzheimer dementia syndromes. In humans, rivastigmine can cause significant gastrointestinal side effects that can limit its clinical use. The aim of this study was to assess the impact of rivastigmine on gastric motor function by means of electrogastrography (EGG) in experimental pigs. Methods: Six experimental adult female pigs (Sus scrofa f. domestica, hybrids of Czech White and Landrace breeds; 3-month-old; mean weight 30.7 ± 1.2 kg) were enrolled into the study twice and created two experimental groups. In group A, a single intragastric dose of 6 mg rivastigmine hydrogen tartate was administered in the morning to fasting pigs before EGG recording. In group B, rivastigmine was administered to overnight fasting animals in a dietary bolus in the morning for 7 days (6 mg per day). On day 8, an intragastric dose of 12 mg rivastigmine was given in the morning to fasting pigs before EGG. EGG recording was accomplished by means of an EGG standalone system. Recordings from both groups were evaluated in dominant frequency and EGG power (areas of amplitudes). Results: In total, 1,980 one-minute EGG intervals were evaluated. In group A, basal EGG power (median 1290.5; interquartile range 736.5–2330 μV2) was significantly higher in comparison with the power of intervals T6 (882; 577–1375; p = 0.001) and T10 (992.5; 385–2859; p = 0.032). In group B, the dominant frequency increased significantly from basal values (1.97 ± 1.57 cycles per minute) to intervals T9 (3.26 ± 2.16; p < 0.001) and T10 (2.14 ± 1.16; p = 0.012), respectively. In group B, basal EGG power (median 1030.5; interquartile range 549–5093) was significantly higher in comparison with the power of intervals T7 (692.5; 434–1476; p = 0.002) and T8 (799; 435–1463 μV2; p = 0.004). Conclusions: Both single as well as repeated intragastric administration of rivastigmine hydrogen tartrate caused a significant decrease of EGG power (areas of amplitudes) in experimental pigs. EGG power may serve as an indirect indicator of gastric motor competence. These findings might provide a possible explanation of rivastigmine-associated dyspepsia in humans. [ABSTRACT FROM AUTHOR]

Molecular docking is widely used in the assessment of the therapeutic potential of pharmaceutical agents. The binding properties of beta-carotene (BC) to acetylcholine esterase (AChE) proteins were characterized using the molecular docking method. The mechanism of AChE inhibition was assessed by an experimental in vitro kinetic study. In addition, the role of BC action was tested by the zebrafish embryo toxicity test (ZFET). The results of the docking ability of BC to AChE showed significant ligand binding mode. The kinetic parameter, i.e., the low AICc value shown as the compound was the competitive type of inhibition of AChE. Further, BC also showed mild toxicity at a higher dose (2200 mg/L) in ZFET assessment with changes in biomarkers. The LC50 value of BC is 1811.94 mg/L. Acetylcholine esterase (AChE) plays a pivotal role in the hydrolysis of acetylcholine, which leads to the development of cognitive dysfunction. BC possesses the regulation of acetylcholine esterase (AChE) and acid phosphatase (AP) activity to prevent neurovascular dysfunction. Therefore, the characterization of BC could be used as a pharmaceutical agent for the treatment of cholinergic neurotoxicity-associated neurovascular disorders such as developmental toxicity, vascular dementia, and Alzheimer's disease due to its AChE and AP inhibitory actions. [ABSTRACT FROM AUTHOR]

Background Pharmacological treatments are very common to be used for alleviating neuropsychiatric symptoms (NPS) in dementia. However, decision on drug selection is still a matter of controversy. Aims To summarise the comparative efficacy and acceptability of currently available monotherapy drug regimens for reducing NPS in dementia. Method We searched PubMed, MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials between inception and 26 December 2022 without language restrictions; and reference lists scanned from selected studies and systematic reviews. Double-blind randomised controlled trials were identified from electronic databases for reporting NPS outcomes in people with dementia. Primary outcomes were efficacy and acceptability. Confidence in the evidence was assessed using Confidence in Network Meta-Analysis (CINeMA). Results We included 59 trials (15,781 participants; mean age, 76.6 years) and 15 different drugs in quantitative syntheses. Risperidone (standardised mean difference [SMD] −0.20, 95% credible interval [CrI] −0.40 to −0.10) and galantamine (−0.20, −0.39 to −0.02) were more effective than placebo in short-term treatment (median duration: 12 weeks). Galantamine (odds ratio [OR] 1.95, 95% CrI 1.38–2.94) and rivastigmine (1.87, 1.24–2.99) were associated with more dropouts than placebo, and some active drugs. Most of the results were rated as low or very low according to CINeMA. Conclusions Despite the scarcity of high-quality evidence, risperidone is probably the best pharmacological option to consider for alleviating NPS in people with dementia in short-term treatment when considering the risk–benefit profile of drugs. [ABSTRACT FROM AUTHOR]

Introduction and Objectives: Alzheimer's disease (AD) is a neurodegenerative disorder that represents the highest form of dementia. The hippocampus is one of the earliest areas affected in AD. Currently, there is no definitive cure for AD. This study was planned to evaluate the effect of rivastigmine and coconut oil (CO), alone or together, on aluminum chloride (AlCl3)- induced AD model in the hippocampus of adult male albino rats. Materials and Methods: Thirty three rats were divided into group I (control) and group II (experimental, subdivided into IIa, IIb, IIc, IId and IIe subgroups). AD was induced in group II by AlCl3 for 45 days. Subgroup IIa was sacrificed at the 45th day, subgroup IIb was left without treatment for 30 days and subgroup IIc received rivastigmine for 30 days. Subgroup IId administered CO simultaneously with AlCl3 then CO treatment continued for 30 days. Subgroup IIe administered CO simultaneously with AlCl3 then CO treatment continued simultaneously with rivastigmine for 30 days. Y-maze memory test was performed and serum acetylcholinesterase (Ach-E) level was measured. After sacrifice, Ach-E and glutathione (GSH) levels were measured in brain homogenates. Brain sections at the hippocampus level were processed for H&E and immunohistochemical staining for glial fibrillary acidic protein (GFAP) and amyloid beta (AP) 1-42. Results: Neurodegenerative changes were decreased in subgroups IIc and IId while the most improved histological picture was displayed by IIe. GFAP mean area % and AP 1-42 optical density and mean area % decreased in subgroups IIc and IId while the least values were recorded in IIe. Ach-E, GSH and memory test results were ameliorated in subgroups IIc and IId while the best improvement was noticed in IIe. Conclusion: CO had a prophylactic role against AD. Combination of rivastigmine and CO exerted a great synergistic effect compared to rivastigmine or CO alone. [ABSTRACT FROM AUTHOR]

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The basis for conducting bioequivalence studies is the determination of the bioavailability of the active substance of the drug at its place of action by establishing the concentration of the drug in biological fluids using sensitive analytical techniques. The bioanalytical technique used should provide reliable results which would lead to satisfactory level of interpretation. To investigate the bioequivalence of rivastigmine preparations, an 8 times more sensitive method (compared to the data in the available literature) for the quantitative determination of rivastigmine in human blood plasma by HPLC-MS/MS was developed. Rivastigmine is extracted from plasma by precipitation of plasma proteins with acetonitrile. Chromatographic separation of rivastigmine and the internal standard was carried out on a YMC Triart C18. 50×2.0 mm (1.9 µm) column in a gradient elution mode with a flow rate of 0.5 ml/min. A 0.1% solution of ammonium hydroxide and acetonitrile were used as mobile phases. The lower limit of the quantitative determination of the method was 25 pg/ml.

Aim:Cholinesterase inhibitors (ChEIs), such as donepezil and rivastigmine, are used safely in the treatment of Alzheimer’s disease (AD). However, the effects of these drugs on the cardiac conduction system are not clear. In this study, we aimed to investigate the effect of donepezil and rivastigmine treatment on the cardiac conduction system in comparison with the controls, especially on the QTc interval.Materials and Methods:We retrospectively enrolled 38 consecutive patients with AD, who were prescribed ChEIs for at least 3 months, and age, sex, and comorbidity-matched treatment-naive 37 control subjects. The electrocardiographic (ECG) parameters including heart rate, PR interval, QRS duration, QT interval, and QTc interval were recorded for each patient and control subject.Results:A total of 24 patients were enrolled in the donepezil treatment group, 14 patients in the rivastigmine treatment group, and 37 patients in the control group. Donepezil treatment resulted in significant prolongation in PR interval, QT interval and QTc interval (p=0.027, p=0.001, p=0.023, respectively). Rivastigmine treatment resulted in significant prolongation only in QTc interval (p=0.018). There was no significant difference between the donepezil and rivastigmine treatment groups for all ECG parameters.Conclusion:Donepezil and rivastigmine treatments significantly prolong QTc interval compared to controls in patients with AD. The donepezil treatment also prolongs PR and QT intervals. The donepezil and rivastigmine therapy had comparable effects on the cardiac conduction system.

The effect of gender and body mass index (BMI) on the pharmacokinetics of rivastigmine was studied in Egyptian human subjects using new bio-analytical validated LC/MS/MS method. In this study, Rivastigmine was estimated in human plasma using Escitalopram as an internal standard (IS). Rivastigmine and Escitalopram were extracted from human plasma samples by liquid–liquid extraction using diethyl ether (DEE)–dichloromethane (DCM) (70:30, v/v). Chromatographic separation was performed on a reversed phase C18 INERTSIL ODS column using 0.05% aqueous formic acid, acetonitrile in the ratio (50:50, v/v) as a mobile phase. Multiple reaction monitoring (MRM) was applied and operated by positive mode electrospray ionization. A significant difference between male and female Cmax (maximum plasma concentration) (P  = 0.0205; CL = 95.4) was found using Mann–Whitney U test. Also, a moderate negative correlation was found between BMI and Tmax (time to peak plasma concentration) using spearman rho test. The calculated results confirm the difference of Rivastigmine pharmacokinetics between male and female subjects. Furthermore, it indicates that Rivastigmine dose adjustment may be necessary. The method was applied for the estimation of pharmacokinetic parameters in volunteers (n  = 26, 17 male and 9 female) and the effects of gender and BMI were investigated. [ABSTRACT FROM AUTHOR]