COG 133

Background:Galantamine (also called galanthamine, marketed as Reminyl (Janssen)) was isolated from several plants, including daffodil bulbs, but is now synthesized. Galantamine is a specific, competitive, and reversible acetylcholinesterase inhibitor. It is also an allosteric modulator at nicotinic cholinergic receptor sites potentiating cholinergic nicotinic neurotransmission. A small number of early studies showed mild cognitive and global benefits for patients with Alzheimer's disease (AD), and recently several multicenter clinical trials have been published with positive findings. Galantamine has received regulatory approval in 29 counties: Argentina, Australia, Canada, Czechia, the European Union (except for The Netherlands), Iceland, Korea, Mexico, Norway, Poland, Singapore, South Africa, Switzerland, Thailand, and the United States.Objectives:The objective of this overview is to assess the clinical effects of galantamine in patients with probable AD, and to investigate potential moderators of an effect.Search strategy:The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 4 July 2001 using the terms galantamine and Reminyl. The Specialized Register at that time contained records from the following databases: CCTR/Central:April 2001 (issue 2); Medline: 1966 to June 2001; Embase: 1980 to April 2001; PsycLit: 1887 to April 2001; Cinahl: 1982 to March 2001; SIGLE (Grey Literature in Europe): 1980 to December 2000; ISTP (Index to Scientific and Technical Proceedings): to May 2000; INSIDE (BL database of Conference Proceedings and Journals): to June 2000; Aslib Index to Theses (UK and Ireland theses): 1970 to June 2001; Dissertation Abstract (USA): 1861 to June 2001; ADEAR (Alzheimer's Disease Clinical Trials Database): to June 2001; National Research Register (including the MRC Clinical Trials Directory): April 2001 (issue 2) Alzheimers Society Trials Database: to June 2001; Glaxo-Wellcome Trials Database: to June 2001; Centerwatch Trials Database: to December 2000. Published reviews were inspected for further sources. Additional information was collected from an unpublished investigational brochure for galantamine.Selection criteria:Trials selected were randomized, double-blind, parallel-group, and unconfounded comparisons of galantamine with placebo for a treatment duration of greater than 4 weeks in subjects with AD.Data collection and analysis:Data were extracted independently by the reviewers and pooled where appropriate and possible. The pooled odds ratios (95%CI) or the average differences (95%CI) were estimated. Intention-to-treat and observed cases data were both reported, if the data were available to be reported. Outcomes of interest include the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), clinical global impression of change (CIBIC-plus or CGIC), Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL), Disability Assessment for Dementia scale (DAD) and Neuropsychiatric Inventory (NPI). Potential moderating variables of a treatment effect included trial duration and dose.Main results:Seven trials were identified that met criteria for entry, with six being Phase II or III industry-sponsored multicenter trials. Two were of 12 weeks duration; one of 13 weeks, one of 5 months; one of 29 weeks; and two of 6 months duration. Trials of 5 months or more were aggregated together in the analyses as '6 months.' Overall, galantamine showed significant treatment effects at daily doses of 16-32 mg/d for trials of 3- to 6-months duration. For global ratings, trials of 3 months duration with doses of 24-32mg/d (Odds Ratio (OR) 2.3; 95%CI 1.3 - 3.9) and 36mg/d (OR 3.3; 95%CI 1.2 - 9.3) were statistically significant in favor of treatment. For trials of 6 months duration (5-months to 29 weeks), only doses of 8mg/d failed to be statistically significant (16mg: OR 2.25; 95% CI 1.6 - 3.3; 24mg: OR 2.0; 95%CI 1.5 -2.5; 32mg: OR 1.9; 95%CI 1.4 - 2.5). For cognitive function over 6 months duration: at 16mg/d, improvements measured -3.3 points (k=1; 95%CI -4.4 - -2.1) on weighted mean difference on the ADAS-Cog scale; -3.5 points at 24mg/d (k=3; 95%CI -4.3 - -2.8), and -4.0 points at 32mg/d (k=2; 95%CI -5.0 - -3.0). The single 3 month trial with ADAS-Cog data also showed statistically significant improvement. Both observed cases (WMD 3.8; 95%CI 0.3 - 7.3) and intent to treat analyses using the Disability Assessment of Dementia scale gave statistically significant results in favor of treatment for daily doses of 32mg for 6 months duration (as did the single 3 month trial of 24-32mg/d treatment that used this scale) The small number of trials available for analysis, however, limited the power of subgroup analyses to detect differences. Galantamine consistently failed to show statistically significant treatment effects at doses of 8mg/day. Galantamine's adverse effects appear similar to those of other cholinesterase inhibitors, in that it tends to produce gastrointestinal effects acutely and with dosage increases. Overall, subjects treated with galantamine at doses of 24-32 mg/d were more likely to discontinue participation in most trials compared to subjects treated with lower doses or placebo, but in the one trial with a slower rate of titration the discontinuation rate was not significantly greater than placebo for the 16 mg/day dose.Reviewer's conclusions:Patients in these trials were similar to those seen in earlier antidementia AD trials, and consisted primarily of mildly to moderately impaired outpatients. Galantamine's effects on more severely impaired subjects has not yet been assessed. Nevertheless, this review shows consistent positive effects for galantamine for trials of 3 months, 5 months and 6 months duration. In addition, although there was not a statistically significant dose-response effect, doses above 8mg/d were, for the most part, consistently statistically significant. Thus, there is evidence demonstrating efficacy for galantamine on global ratings, cognitive tests, assessments of ADLs and behavior. This magnitude for the cognitive effect is similar to other cholinesterase inhibitors including donepezil, rivastigmine, and tacrine. Galantamine's safety profile is similar to other cholinesterase inhibitors with respect to cholinergically mediated gastrointestinal symptoms. No information is available on adverse events that occurred less than 5% of the time. It appears that doses of 16 mg/d were best tolerated in the single trial where medication was titrated over 4 week periods, and because this dose showed statistically indistinguishable efficacy with higher doses, it is probably most preferable initially.

Background:Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory deficits, cognitive decline, and spatial disorientation. Non-pharmacological interventions to treat AD have been reported in many meta-analyses (MAs), but robust conclusions have not been made because of variations in the scope, quality, and findings of these reviews.Objective:This work aimed to review existing MAs to provide an overview of existing evidence on the effects of five non-pharmacological interventions in AD patients on three outcomes: Mini-Mental State Examination (MMSE), activities of daily living (ADL), and Alzheimer's Disease Assessment Scale-cognitive section (ADAS-cog).Methods:The databases PubMed, Cochrane Library, Embase, and Web of Science were searched to collect MAs of non-pharmacological interventions for AD. Two reviewers independently conducted literature screening, data extraction, and quality assessment. We assessed the quality of MAs with the Measurement Tool to Assess Systematic Reviews (AMSTAR) 2 and assessed the evidence quality for significant outcomes using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system.Results:We found 10 eligible MAs, which included between three (133 patients) and 15 randomized trials (1,217 patients), and five non-pharmacological interventions, namely, acupuncture therapy (40%), exercise intervention (30%), music therapy (10%), cognitive intervention (10%), and repetitive transcranial magnetic stimulation (rTMS) (10%). All the included MAs were critically low to low quality by AMSTAR 2. Acupuncture therapy and exercise intervention showed the preliminary potential to improve ADL and MMSE. rTMS and acupuncture therapy show benefits in decreasing ADAS-cog, and there were some evidence of improved MMSE with cognitive intervention. All these outcomes scored very low quality to moderate quality of evidence on the GRADE system.Conclusions:Non-pharmacological therapy shows promise for the treatment of AD, but there is still a lack of high-quality evidence. In the future, the quality of the original research needs to be improved, and strictly designed MAs should be carried out following methodological requirements.

Chemoresistance and inadequate therapeutics transport across the blood brain barrier (BBB) remain the major barriers to treating medulloblastoma (MB). Hedgehog (Hh) and IGF/PI3K pathways regulate tumor cell proliferation and resistance in MB. Current Hh inhibitors are effective initially to treat SHH-MB but acquire resistance. Herein, we showed that Hh inhibitor MDB5 and BRD4/PI3K dual inhibitor SF2523 synergistically inhibited the proliferation of DAOY and HD-MB03 cells when used in combination. Treatment of these MB cells with the combination of MDB5 and SF2523 significantly decreased colony formation and expression of MYCN, p-AKT, and cyclin D1 but significantly increased in Bax expression, compared to individual drugs. We used our previously reported copolymer mPEG-b-PCC-g-DC copolymer, which showed 8.7 ± 1.0 and 6.5 ± 0.1% loading for MDB5 and SF2523 when formulated into nanoparticles (NPs). There was sustained drug release from NPs, wherein 100% of MDB5 was released in 50 h, but only 60% of SF2523 was released in 80 h. Targeted NPs prepared by mixing 30:70 ratio of COG-133-PEG-b-PBC and mPEG-b-PCC-g-DC copolymer delivered a significantly higher drug concentration in the cerebellum at 6 and 24h after intravenous injection into orthotopic SHH-MB tumor-bearing NSG mice. Moreover, systemic administration of COG-133-NPs loaded with MDB5 and SF2523 resulted in decreased tumor burden compared to non-targeted drug-loaded NPs, without any hepatic toxicity. In conclusion, our nanomedicine of MDB5 and SF2523 offers a novel therapeutic strategy to treat chemoresistant MB.