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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.

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.

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.

Delirium is frequently diagnosed in critically ill patients and is associated with adverse outcome. Impaired cholinergic neurotransmission seems to have an important role in the development of delirium. We aimed to establish the effect of the cholinesterase inhibitor rivastigmine on the duration of delirium in critically ill patients. Patients (aged ≥18 years) who were diagnosed with delirium were enrolled from six intensive care units in the Netherlands, and treated between November, 2008, and January, 2010. Patients were randomised (1:1 ratio) to receive an increasing dose of rivastigmine or placebo, starting at 0·75 mL (1·5 mg rivastigmine) twice daily and increasing in increments to 3 mL (6 mg rivastigmine) twice daily from day 10 onwards, as an adjunct to usual care based on haloperidol. The trial pharmacist generated the randomisation sequence by computer, and consecutively numbered bottles of the study drug according to this sequence to conceal allocation. The primary outcome was the duration of delirium during hospital admission. Analysis was by intention to treat. Duration of delirium was censored for patients who died or were discharged from hospital while delirious. Patients, medical staff, and investigators were masked to treatment allocation. Members of the data safety and monitoring board (DSMB) were unmasked and did interim analyses every 3 months. This trial is registered with ClinicalTrials.gov, number NCT00704301. Although a sample size of 440 patients was planned, after inclusion of 104 patients with delirium who were eligible for the intention-to-treat analysis (n=54 on rivastigmine, n=50 on placebo), the DSMB recommended that the trial be halted because mortality in the rivastigmine group (n=12, 22%) was higher than in the placebo group (n=4, 8%; p=0·07). Median duration of delirium was longer in the rivastigmine group (5·0 days, IQR 2·7–14·2) than in the placebo group (3·0 days, IQR 1·0–9·3; p=0·06). Rivastigmine did not decrease duration of delirium and might have increased mortality so we do not recommend use of rivastigmine to treat delirium in critically ill patients. ZonMw, the Netherlands Brain Foundation, and Novartis.

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 patient compliance. Here we report the outcome of a study designed to assess the relative bioavailability of ZUNVEYL DR tablets to galantamine hydrobromide extended-release (ER) capsules, under steady state conditions. This was an open-label, balanced, randomized, multiple dose, two-treatment, two-arm, two-period, comparative steady state study of ZUNVEYL DR tablets, 5 mg (BID, for 7 days) compared to galantamine hydrobromide ER, 8 mg (QD, for 7 days), in healthy adult subjects (N=40). The study protocol underwent ethics review and was conducted under GCP conditions. Table 1 and Figure 1 describe the pharmacokinetic parameters calculated from the plasma analysis of galantamine derived from ZUNVEYL and galantamine hydrobromide ER. ZUNVEYL represented less than 1% of total circulating drug, which provided further evidence of safety. ZUNVEYL was well-tolerated with no serious adverse event noted. The steady state study established a scientific bridge to the LD, galantamine hydrobromide ER capsules. Although the extent of absorption measured by the AUC[0-24]ss was comparable between ZUNVEYL and the LD, the Cmaxss was slightly higher than the LD. The safety of the higher Cmax of galantamine derived from ZUNVEYL compared to galantamine hydrobromide ER capsules is supported by the lower Cmax of galantamine derived from ZUNVEYL compared to the galantamine hydrobromide immediate release tablets [see abstract # 107030].

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.

Acetylcholinesterase inhibitors are used to delay cognitive decline due to Alzheimer's disease (AD) by preventing breakdown of acetylcholine. Such treatment appears to be associated with cerebral changes, although the mechanism of action has not been clarified yet. This study aimed at assessing rivastigmine-induced changes in acetylcholine-related functional connectivity (FC) and cognitive performance in patients with prodromal to mild AD. Thirty-two patients with prodromal to mild AD recruited consecutively from a memory clinic were randomly assigned either to a 12-week rivastigmine patch treatment (ADt; n = 16) or to an untreated control group (ADu; n = 16). Participants underwent comprehensive neuropsychological and MRI assessments at baseline (T0) and after 12 weeks (T1). Functional MRI scans were pre-processed with the REACT pipeline to extract whole-brain FC maps weighted by the expected distribution of the vesicular acetylcholine transporter, the α4β2 nicotinic and the M1 muscarinic receptors using publicly available atlases. Between-group differences in T0-to-T1changes in cognitive performance and neurotransmitter-related FC were investigated. A regression model was used to assess the association between longitudinal changes (T1-T0) in cognitive performance and FC in the ADt group. At T0, the ADt group had worse visual long-term memory and higher α4β2-related FC in frontal and occipito-cerebellar cortices compared with the ADu group. Compared with the ADu group, the ADt group showed a greater longitudinal reduction in frontal α4β2-related FC and a greater improvement in visual memory. Changes in α4β2-related FC were significantly associated with memory improvements. Rivastigmine treatment induced FC changes in frontal and occipito-cerebellar areas in patients with prodromal to mild AD that were associated with long-term memory performance improvements over 12 weeks. These rivastigmine-induced effects on resting-state brain activity and the mediating role of the α4β2 nicotinic receptor for acetylcholine are in line with previous findings. Neurotransmitter-related FC can be an MRI biomarker sensitive to test mechanisms of actions and to track neuroplastic changes induced by pharmacological treatments targeting specific neurotransmitter systems in people with AD.

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).

Background/Aims: A phase II study of the peroxisome proliferator-activated receptor-γ agonist rosiglitazone extended release (RSG XR) in mild-to-moderate Alzheimer’s disease (AD) detected a treatment benefit to cognition in apolipoprotein E(APOE)-Ε4-negative subjects. The current phase III study with prospective stratification by APOE genotype was conducted to confirm the efficacy and safety of RSG XR in mild-to-moderate AD. An open-label extension study assessed the long-term safety and tolerability of 8 mg RSG XR. Methods: This double-blind, randomized, placebo-controlled study enrolled 693 subjects. Within 2 APOE allelic strata (Ε4-positive, Ε4-negative), subjects were randomized (2:2:2:1) to once-daily placebo, 2 mg RSG XR, 8 mg RSG XR or 10 mg donepezil (control). Coprimary endpoints were change from baseline to week 24 in the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) score, and week 24 Clinician’s Interview-Based Impression of Change plus caregiver input (CIBIC+). Results: At week 24, no significant differences from placebo in change from baseline in coprimary endpoints were detected with either the RSG XR dose in APOE-Ε4-negative subjects or overall. For donepezil, no significant treatment difference was detected in ADAS-Cog; however, a significant difference was detected (p = 0.009) on the CIBIC+. Peripheral edema was the most common adverse event for 8 mg RSG XR (15%) and placebo (5%), and nasopharyngitis for 2 mg RSG XR (7%). Conclusion: No evidence of efficacy of 2 mg or 8 mg RSG XR monotherapy in cognition or global function was detected in the APOE-Ε4-negative or other analysis populations. The safety and tolerability of RSG XR was consistent with its known pharmacology.

Background: Currently approved Alzheimer's disease (AD) treatments have been reported to provide symptomatic benefit, without proven impact on clinical progression. We hypothesized that the loss of initial therapeutic benefit over time may be mitigated by higher doses of a cholinesterase inhibitor. Objective: The aim of this study was to determine the effectiveness and tolerability of increasing donepezil from 10 to 23 mg/d in patients with moderate to severe AD. Methods: This randomized, double-blind study was conducted at 219 sites in Asia, Europe, Australia, North America, South Africa, and South America from June 6, 2007, to March 27, 2009. Patients aged 45 to 90 years with probable AD, Mini-Mental State Examination score 0 to 20 (moderate to severe impairment), and who were receiving donepezil 10 mg once daily for ≥12 weeks before the start of the study were eligible. Patients (n = 1467) were randomly assigned to receive high-dose donepezil (23 mg once daily) or standard-dose donepezil (10 mg once daily) for 24 weeks. Coprimary effectiveness measures were changes in cognition and global functioning, as assessed using least squares mean changes from baseline (LSM [SE] A) scores (last observation carried forward) on the Severe Impairment Battery (SIB; cognition) and the Clinician's Interview-Based Impression of Change Plus Caregiver Input scale (CIBIC+; global function rating) overall change score (mean [SD]) at week 24. Treatmentemergent adverse events (TEAEs) were assessed using spontaneous patient/caregiver reporting and open-ended questioning; clinical laboratory testing (hematology, biochemistry, and urinalysis panels analyzed by a central laboratory); 12-lead ECG; and physical and neurologic examinations, including vital sign measurements. Results: The effectiveness analyses included 1371 patients (mean age, 73.8 years; 62.8% female; 73.5% white; weight range, 34.0–138.7 kg). A total of 296 of 981 patients (30.2%) withdrew from the donepezil 23-mg/d group; 87 of 486 patients (17.9%) withdrew from the donepezil 10-mg/d group. At study end (week 24), the LSM (SE) Δ in SIB score was significantly greater with donepezil 23 mg/d than with donepezil 10 mg/d (+2.6 [0.58] vs +0.4 [0.66], respectively; difference, 2.2; P < 0.001). The between-treatment difference in CIBIC+ score was nonsignificant (4.23 [1.07] vs 4.29 [1.07]). In post hoc analysis, LSM Δ in SIB score and CIBIC+ treatment effect at end point were greater with donepezil 23 mg/d than 10 mg/d in patients with more advanced AD compared with less impaired patients (SIB, +1.6 [0.78] vs −1.5 [0.88], respectively [ P < 0.001]; CIBIC+, 4.31 [1.09] vs 4.42 [1.10] [ P = 0.028]). TEAEs were reported in 710 of 963 patients (73.7%) who received donepezil 23 mg/d and in 300 of 471 patients (63.7%) who received donepezil 10 mg/d. With donepezil 23 mg/d, mild, moderate, and severe TEAEs were reported in 297 (30.8%), 332 (34.5%), and 81 (8.4%) patients, respectively; with donepezil 10 mg/d, these proportions were 147 (31.2%), 119 (25.3%), and 34 (7.2%). The 3 most common severe AEs reported with the 23-mg/d dose were nausea (9 patients [0.9%] vs 1 [0.2%] with the 10-mg/d dose), dizziness (7 [0.7%] vs 1 [0.2%]), and vomiting (6 [0.6%] vs 0). The most commonly reported TEAEs considered probably related to treatment with the 23-mg/d dose were nausea (59 patients [6.1%] vs 9 [1.9%] with the 10-mg/d dose), vomiting (48 [5.0%] vs 4 [0.8%]), and diarrhea (31 [3.2%] vs 7 [1.5%]).Thirteen deaths were reported during the study or within 30 days of study discontinuation (23 mg/d, 8 patients [0.8%]; 10 mg/d, 5 patients [1.1%]); all were considered unrelated to the study medication. Conclusions: In this study in patients with moderate to severe AD, donepezil 23 mg/d was associated with greater benefits in cognition compared with donepezil 10 mg/d. The between-treatment difference in global functioning was not significant in the overall population. Patients with more advanced AD appeared to benefit from donepezil 23 mg/d on the assessment of global functioning, but this observation requires additional studies for confirmation. ClinicalTrials.gov identifier: NCT00478205.