Explore the vast range of titles available.

Falls are a frequent and serious complication of Parkinson's disease and are related partly to an underlying cholinergic deficit that contributes to gait and cognitive dysfunction in these patients. Gait dysfunction can lead to an increased variability of gait from one step to another, raising the likelihood of falls. In the ReSPonD trial we aimed to assess whether ameliorating this cholinergic deficit with the acetylcholinesterase inhibitor rivastigmine would reduce gait variability. We did this randomised, double-blind, placebo-controlled, phase 2 trial at the North Bristol NHS Trust Hospital, Bristol, UK, in patients with Parkinson's disease recruited from community and hospital settings in the UK. We included patients who had fallen at least once in the year before enrolment, were able to walk 18 m without an aid, had no previous exposure to an acetylcholinesterase inhibitor, and did not have dementia. Our clinical trials unit randomly assigned (1:1) patients to oral rivastigmine or placebo capsules (both taken twice a day) using a computer-generated randomisation sequence and web-based allocation. Rivastigmine was uptitrated from 3 mg per day to the target dose of 12 mg per day over 12 weeks. Both the trial team and patients were masked to treatment allocation. Masking was achieved with matched placebo capsules and a dummy uptitration schedule. The primary endpoint was difference in step time variability between the two groups at 32 weeks, adjusted for baseline age, cognition, step time variability, and number of falls in the previous year. We measured step time variability with a triaxial accelerometer during an 18 m walking task in three conditions: normal walking, simple dual task with phonemic verbal fluency (walking while naming words beginning with a single letter), and complex dual task switching with phonemic verbal fluency (walking while naming words, alternating between two letters of the alphabet). Analysis was by modified intention to treat; we excluded from the primary analysis patients who withdrew, died, or did not attend the 32 week assessment. This trial is registered with ISRCTN, number 19880883. Between Oct 4, 2012 and March 28, 2013, we enrolled 130 patients and randomly assigned 65 to the rivastigmine group and 65 to the placebo group. At week 32, compared with patients assigned to placebo (59 assessed), those assigned to rivastigmine (55 assessed) had improved step time variability for normal walking (ratio of geometric means 0·72, 95% CI 0·58–0·88; p=0·002) and the simple dual task (0·79; 0·62–0·99; p=0·045). Improvements in step time variability for the complex dual task did not differ between groups (0·81, 0·60–1·09; p=0·17). Gastrointestinal side-effects were more common in the rivastigmine group than in the placebo group (p<0·0001); 20 (31%) patients in the rivastigmine group versus three (5%) in the placebo group had nausea and 15 (17%) versus three (5%) had vomiting. Rivastigmine can improve gait stability and might reduce the frequency of falls. A phase 3 study is needed to confirm these findings and show cost-effectiveness of rivastigmine treatment. Parkinson's UK.

Alzheimer's disease (AD) is one of the most common forms of dementia. AD is a chronic syndrome of the central nervous system that causes a decline in cognitive function and language ability. Cholinergic deficiency is associated with AD, and various cholinesterase inhibitors have been developed for the treatment of AD, including naturally-derived inhibitors, synthetic analogues and hybrids. Currently, the available drugs for AD are predominantly cholinesterase inhibitors. However, the efficacy of these drugs is limited as they may cause adverse side effects and are not able to completely arrest the progression of the disease. Since AD is multifactorial disease, dual and multi-target inhibitors have been developed. The clinical applications and the limitations of the inhibitors used to treat AD are discussed in the present review. Additionally, this review presents the current status and future directions for the development of novel drugs with reduced toxicity and preserved pharmacological activity.

ZUNVEYL (benzgalantamine, galantamine benzoate gluconate), is a pharmacologically inactive prodrug of galantamine. ZUNVEYL was FDA approved in 2024 for BID dosing for the treatment of mild to moderate Alzheimer's dementia, via the 505(b)(2) regulatory pathway, relying on FDA's previous finding of safety and efficacy for the listed drugs (LDs) Razadyne® (galantamine hydrobromide tablets), and Razadyne® ER (galantamine hydrobromide extended-release capsules). When dosed as a delayed-release (DR) tablet, ZUNVEZYL bypasses the stomach and, is absorbed in the small intestine potentially reducing the gastrointestinal side effects common for acetylcholinesterase inhibitors. Consequently, ZUNVEYL may offer advantages over the other acetylcholinesterase inhibitors by reducing gastrointestinal adverse effects which limit compliance. Here we describe the outcomes of two studies designed to assess the relative bioavailability of ZUNVEYL DR tablets to galantamine hydrobromide immediate release (IR) tablets under fed and fasting conditions. The studies were open-label, balanced, randomized, single-dose, two-treatment, two-period, two-way crossover designs to evaluate the relative bioavailability of ZUNVEYL DR 5 mg tablet compared to galantamine hydrobromide 4 mg IR tablet, in healthy adult subjects under fed (Study ALPHA-1062-01; N=34) and fasting (Study ALPHA-1062-02; N=34) conditions. Study protocols underwent ethics review and were conducted to GCP standards. Table 1 documents plasma pharmacokinetic parameters calculated from the analysis of galantamine (from ZUNVEYL) and galantamine hydrobromide IR. ZUNVEYL (prodrug) was inconsistently detected in plasma and represented approximately 1% of total circulating drug. The low percentage of circulating prodrug provides a greater margin of safety. ZUNVEYL was well-tolerated with no serious adverse events noted. Bioequivalence assessment demonstrated that ZUNVEYL was bioequivalent to galantamine hydrobromide IR for AUC0-t and AUC0-∞, under fed and fasting conditions, and for Cmax under fed conditions. These results combined with those of a steady state study [abstract # 107147], established a scientific bridge to the LDs and the approval of ZUNVEYL, relying on FDA's previous finding of safety and efficacy of the LDs.

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is a major global health concern, affecting millions worldwide, with its prevalence expected to triple by 2050. Despite the widespread use of traditional drugs like cholinesterase inhibitors and NMDA receptor antagonists, their limited effectiveness requires innovative therapeutic approaches. This work used Computer-Aided Drug Design (CADD) to renovate AD therapies aimed at both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) using fungal secondary metabolites. Subsequent pharmacokinetic profiles indicated that all metabolites had significant gastrointestinal absorption, blood-brain barrier permeability, and adherence to Lipinski’s Rule of Five, suggesting favourable drug-like properties. Furthermore, these metabolites exhibited little toxicity, except for Lovastatin, which indicated possible carcinogenicity. Molecular docking revealed three main candidates—Fumitremorgin C, Hericenone J, and Lovastatin—with notable binding affinities for AChE and BuChE. Consequently, the Fumitremorgin C showed the highest affinity for AChE (−10.0 kcal/mol), but Hericenone J showed enhanced inhibition of BuChE (−9.2 kcal/mol), suggesting its potential use in advanced stages of AD. Molecular dynamics simulations spanning 100 ns validated the stability of enzyme-ligand complexes, with Hericenone J exhibiting the greatest stability, low RMSD, and strong hydrogen bond interactions. The RMSF analysis further demonstrated that Hericenone J preserved structural integrity, whereas ROG and SASA values validated its compactness and stability. As determined by binding energy calculations, Hericenone J had the most inhibitory potential, followed by Lovastatin. However, Hericenone J’s constant adoption of low-energy conformations, as shown by the principal component and Gibbs free energy analyses, suggested robust and stable interactions with both cholinesterases. With its superior pharmacokinetic profiles, significant binding affinity, and high stability, Hericenone J is the most promising dual cholinesterase inhibitor. These results support the notion that Hericenone J might be an effective treatment for AD if subjected to more preclinical trials.

ZUNVEYL (benzgalantamine, galantamine benzoate gluconate), is a pharmacologically inactive prodrug of galantamine. ZUNVEYL was FDA approved in 2024 for BID dosing for the treatment of mild to moderate Alzheimer's dementia, via the 505(b)(2) regulatory pathway, relying on FDA's previous finding of safety and efficacy for the listed drugs (LDs) Razadyne® (galantamine hydrobromide tablets), and Razadyne® ER (galantamine hydrobromide extended-release capsules). When dosed as a delayed-release (DR) tablet, ZUNVEYL bypasses the stomach and, is absorbed in the small intestine potentially reducing the gastrointestinal side effects common for acetylcholinesterase inhibitors. Consequently, ZUNVEYL may offer advantages over the other acetylcholinesterase inhibitors by reducing gastrointestinal adverse effects which limit patient compliance. Here we report the outcome of a study designed to assess the dose proportionality of ZUNVEYL DR tablets over a dosage range of 5-15 milligrams. This was an open-label, balanced, randomized, three-arm, three-treatment, single-dose parallel study to evaluate the pharmacokinetics and dose proportionality of ZUNVEYL DR tablets of 5, 10 and 15 mg strength in healthy adult subjects (N=42), under fasting conditions. The study protocol underwent ethics review and was conducted under GCP conditions. The dose proportionality of ZUNVEYL based on the plasma analysis of galantamine derived from ZUNVEYL (Table 1), and the pharmacokinetic profiles of all three doses (Figure 1) are presented below. Fifteen milligrams of ZUNVEYL administered to drug naïve subjects, provoked one gastrointestinal adverse event (1/14), a lower incidence than that expected with an equivalent dose of Galantamine hydrobromide. ZUNVEYL was well-tolerated, no serious adverse events were observed. Statistical analysis confirmed the dose proportionality for Cmax, AUC0-t, & AUC0-∞ over the entire 5 mg to 15 mg dose range for ZUNVEYL. The studies demonstrating bioequivalence, under fed and fasted (abstract #107030), and steady state (abstract #107147) conditions, and dose proportionality studies, lead to the conclusion that one ZUNVEYL 5 mg DR tablet is equivalent to one galantamine hydrobromide 4 mg immediate release tablet.

Cholinesterase inhibitors produce small improvements in cognitive and global assessments in Alzheimer's disease. We aimed to determine whether donepezil produces worthwhile improvements in disability, dependency, behavioural and psychological symptoms, carers' psychological wellbeing, or delay in institutionalisation. If so, which patients benefit, from what dose, and for how long? 565 community-resident patients with mild to moderate Alzheimer's disease entered a 12-week run-in period in which they were randomly allocated donepezil (5 mg/day) or placebo. 486 who completed this period were rerandomised to either donepezil (5 or 10 mg/day) or placebo, with double-blind treatment continuing as long as judged appropriate. Primary endpoints were entry to institutional care and progression of disability, defined by loss of either two of four basic, or six of 11 instrumental, activities on the Bristol activities of daily living scale (BADLS). Outcome assessments were sought for all patients and analysed by logrank and multilevel models. Cognition averaged 0·8 MMSE (mini-mental state examination) points better (95% Cl 0·5–1·2; p<0·0001) and functionality 1·0 BADLS points better (0·5–1·6; p<0·0001) with donepezil over the first 2 years. No significant benefits were seen with donepezil compared with placebo in institutionalisation (42%vs 44% at 3 years; p=0·4) or progression of disability (58%vs 59% at 3 years; p=0·4). The relative risk of entering institutional care in the donepezil group compared with placebo was 0·97 (95% Cl 0·72–1·30; p=0·8); the relative risk of progression of disability or entering institutional care was 0·96 (95% Cl 0·74–1·24; p=0·7). Similarly, no significant differences were seen between donepezil and placebo in behavioural and psychological symptoms, carer psychopathology, formal care costs, unpaid caregiver time, adverse events or deaths, or between 5 mg and 10 mg donepezil. Donepezil is not cost effective, with benefits below minimally relevant thresholds. More effective treatments than Cholinesterase inhibitors are needed for Alzheimer's disease.

Objectives Chronic constipation in diabetes mellitus is associated with colonic motor dysfunction and is managed with laxatives. Cholinesterase inhibitors increase colonic motility. This study evaluated the effects of a cholinesterase inhibitor on gastrointestinal and colonic transit and bowel function in diabetic patients with constipation. Design After a 9-day baseline period, 30 patients (mean±SEM age 50±2 years) with diabetes mellitus (18 type 1, 12 type 2) and chronic constipation without defaecatory disorder were randomised to oral placebo or pyridostigmine, starting with 60 mg three times a day, increasing by 60 mg every third day up to the maximum tolerated dose or 120 mg three times a day; this dose was maintained for 7 days. Gastrointestinal and colonic transit (assessed by scintigraphy) and bowel function were evaluated at baseline and the final 3 and 7 days of treatment, respectively. Treatment effects were compared using analysis of covariance, with gender, body mass index and baseline colonic transit as covariates. Results 19 patients (63%) had moderate or severe autonomic dysfunction; 16 (53%) had diabetic retinopathy. 14 of 16 patients randomised to pyridostigmine tolerated 360 mg daily; two patients took 180 mg daily. Compared with placebo (mean±SEM 1.98±0.17 (baseline), 1.84±0.16 (treatment)), pyridostigmine accelerated (1.96±0.18 (baseline), 2.45±0.2 units (treatment), p<0.01) overall colonic transit at 24 h, but not gastric emptying or small-intestinal transit. Treatment effects on stool frequency, consistency and ease of passage were significant (p≤0.04). Cholinergic side effects were somewhat more common with pyridostigmine (p=0.14) than with placebo. Conclusions Cholinesterase inhibition with oral pyridostigmine accelerates colonic transit and improves bowel function in diabetic patients with chronic constipation. Clinical trial registration number TrialRegNo (NCT 00276406).

Cognitive impairment is a common complication observed after a stroke. Currently there are no definitively proven pharmacologic therapies for recovery from post-stroke cognitive impairment and vascular dementia. In this meta-analysis, we evaluated the efficacy and safety of cholinesterase inhibitors in their improvement of cognition in patients with post-stroke cognitive impairment and vascular dementia. We conducted a meta-analysis using seven eligible studies from 305 published articles. We investigated the differences in Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores, before and after cholinergic augmentation in patients with post-stroke cognitive impairment and vascular dementia. MMSE and ADAS-cog scores were also compared during the subsequent follow-up periods. MMSE score of patients with post-stroke cognitive impairment was increased after cholinergic augmentation throughout the 24 weeks with mean differences [MD] of 3.000, 1.732, 1.578 1.516, and 1.222, at 4, 4-8, 8-12, 12-18, and 18-24 weeks, respectively. In addition, ADAS-cog scores decreased at 6, 12, 18, and 24 weeks by pharmaceutical augmentation, but not with placebo with mean differences [MD] of -2.333, -2.913, -2.767, -2.416, and -1.859, respectively. This meta-analysis shows that acetylcholinesterase inhibitors maintain a stable pattern of improved cognitive function in patients with post stroke cognitive impairment and vascular dementia without the increased risk of side effects.

The actions of many drugs involve enzyme inhibition. This is exemplified by the inhibitors of monoamine oxidases (MAO) and the cholinsterases (ChE) that have been used for several pharmacological purposes. This review describes key principles and approaches for the reliable determination of enzyme activities and inhibition as well as some of the methods that are in current use for such studies with these two enzymes. Their applicability and potential pitfalls arising from their inappropriate use are discussed. Since inhibitor potency is frequently assessed in terms of the quantity necessary to give 50% inhibition (the IC50 value), the relationships between this and the mode of inhibition is also considered, in terms of the misleading information that it may provide. Incorporation of more than one functionality into the same molecule to give a multi-target-directed ligands (MTDLs) requires careful assessment to ensure that the specific target effects are not significantly altered and that the kinetic behavior remains as favourable with the MTDL as it does with the individual components. Such factors will be considered in terms of recently developed MTDLs that combine MAO and ChE inhibitory functions.

Introduction Immediate-release memantine (10 mg, twice daily) is approved in the USA for moderate-to-severe Alzheimer’s disease (AD). This study evaluated the efficacy, safety, and tolerability of a higher-dose, once-daily, extended-release formulation in patients with moderate-to-severe AD concurrently taking cholinesterase inhibitors. Methods In this 24-week, double-blind, multinational study (NCT00322153), outpatients with AD (Mini-Mental State Examination scores of 3–14) were randomized to receive once-daily, 28-mg, extended-release memantine or placebo. Co-primary efficacy parameters were the baseline-to-endpoint score change on the Severe Impairment Battery (SIB) and the endpoint score on the Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus). The secondary efficacy parameter was the baseline-to-endpoint score change on the 19-item Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS–ADL 19 ); additional parameters included the baseline-to-endpoint score changes on the Neuropsychiatric Inventory (NPI) and verbal fluency test. Data were analyzed using a two-way analysis of covariance model, except for CIBIC-Plus (Cochran–Mantel–Haenszel test). Safety and tolerability were assessed through adverse events and physical and laboratory examinations. Results A total of 677 patients were randomized to receive extended-release memantine ( n  = 342) or placebo ( n  = 335); completion rates were 79.8 and 81.2 %, respectively. At endpoint (week 24, last observation carried forward), memantine-treated patients significantly outperformed placebo-treated patients on the SIB (least squares mean difference [95 % CI] 2.6 [1.0, 4.2]; p   =  0.001), CIBIC-Plus ( p  = 0.008), NPI ( p  = 0.005), and verbal fluency test ( p  = 0.004); the effect did not achieve significance on ADCS–ADL 19 ( p  = 0.177). Adverse events with a frequency of ≥5.0 % that were more prevalent in the memantine group were headache (5.6 vs. 5.1 %) and diarrhea (5.0 vs. 3.9 %). Conclusion Extended-release memantine was efficacious, safe, and well tolerated in this population.