RESUMO
A systematic review and random-effects model network meta-analysis was conducted to compare the efficacy, acceptability, tolerability, and safety of pharmacological interventions for adults with acute bipolar mania. We searched PubMed, the Cochrane Library, and Embase databases for eligible studies published before March 14, 2021. Randomized controlled trials (RCTs) of oral medication monotherapy lasting ≥10 days in adults with mania were included, and studies that allowed the use of antipsychotics as a rescue medication during a trial were excluded. The primary outcomes were response to treatment (efficacy) and all-cause discontinuation (acceptability). The secondary outcomes were the improvement of mania symptoms and discontinuation due to inefficacy. Of the 79 eligible RCTs, 72 double-blind RCTs of 23 drugs and a placebo were included in the meta-analysis (mean study duration = 3.96 ± 2.39 weeks, n = 16442, mean age = 39.55 years, with 50.93% males). Compared with the placebo, aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone outperformed response to treatment (N = 56, n = 14503); aripiprazole, olanzapine, quetiapine, and risperidone had lower all-cause discontinuation; however, topiramate had higher all-cause discontinuation (N = 70, n = 16324). Compared with the placebo, aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone outperformed the improvement of mania symptoms (N = 61, n = 15466), and aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, valproate, and ziprasidone had lower discontinuation due to inefficacy (N = 50, n = 14284). In conclusions, these antipsychotics, carbamazepine, lithium, tamoxifen, and valproate were effective for acute mania. However, only aripiprazole, olanzapine, quetiapine, and risperidone had better acceptability than the placebo.
Assuntos
Antipsicóticos , Transtorno Bipolar , Adulto , Antipsicóticos/uso terapêutico , Aripiprazol , Benzodiazepinas/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Carbamazepina/uso terapêutico , Feminino , Haloperidol/uso terapêutico , Humanos , Lítio/uso terapêutico , Masculino , Mania , Metanálise em Rede , Olanzapina/uso terapêutico , Palmitato de Paliperidona , Fumarato de Quetiapina/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Risperidona/uso terapêutico , Tamoxifeno/uso terapêutico , Ácido ValproicoRESUMO
Most conventional insomnia medications are gamma-aminobutylic acid receptor agonists. However, physical dependence is a concern and one of the major limiting factors for long-term treatment. The dual orexin receptor antagonists, suvorexant and lemborexant, were recently approved for treating chronic insomnia, giving a novel pharmacotherapeutic option. Because there are no comparative studies on these drugs, a network meta-analysis was conducted, which is suitable for comparing interventions. According to this analysis, 5- and 10-mg lemborexant were superior to 20-mg suvorexant because of the greater improvement in initiating sleep after 1-week administration. Furthermore, 5-mg lemborexant (not 10 mg) and suvorexant were similarly well tolerated, without requiring discontinuation due to adverse events. We also overviewed the pharmacological and pharmacokinetic properties of lemborexant and suvorexant that may support these clinical outcomes. When compared to suvorexant, lemborexant quickly binds to the orexin receptors. The time to reach the maximum concentration after multiple administrations is shorter for lemborexant than for suvorexant. Considering these results, we recommend 5-mg lemborexant as an initial treatment for insomnia, followed by 10-mg lemborexant or suvorexant.
Assuntos
Distúrbios do Início e da Manutenção do Sono , Humanos , Metanálise em Rede , Antagonistas dos Receptores de Orexina/efeitos adversos , Receptores de Orexina/metabolismo , Orexinas , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológicoRESUMO
For developing oral drugs, it is necessary to predict the oral absorption of new chemical entities accurately. However, it is difficult because of the involvement of efflux transporters, including P-glycoprotein (P-gp), in their absorption process. In this study, we conducted a comparative analysis on the inhibitory activities of seven P-gp inhibitors (cyclosporin A, GF120918, LY335979, XR9576, WK-X-34, VX-710, and OC144-093) to evaluate the effect of P-gp on drug absorption. GF120918, LY335979, and XR9576 significantly decreased the basal-to-apical transport of paclitaxel, a P-gp substrate, across Caco-2 cell monolayers. GF120918 also inhibited the basal-to-apical transport of mitoxantrone, a breast cancer resistance protein (BCRP) substrate, in Caco-2 cells, whereas LY335979 hardly affected the mitoxantrone transport. In addition, the absorption rate of paclitaxel after oral administration in wild-type mice was significantly increased by pretreatment with LY335979, and it was similar to that in mdr1a/1b knockout mice. Moreover, the absorption rate of topotecan, a BCRP substrate, in wild-type mice pretreated with LY335979 was similar to that in mdr1a/1b knockout mice but significantly lower than that in bcrp knockout mice. These results indicate that LY335979 has a selective inhibitory activity for P-gp, and would be useful for evaluating the contribution of P-gp to drug absorption.
Assuntos
Transtorno Bipolar/tratamento farmacológico , Lacosamida/administração & dosagem , Bloqueadores do Canal de Sódio Disparado por Voltagem/administração & dosagem , Adulto , Transtorno Bipolar/fisiopatologia , Feminino , Humanos , Lacosamida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Resultado do Tratamento , Bloqueadores do Canal de Sódio Disparado por Voltagem/efeitos adversos , Adulto JovemRESUMO
We conducted a random-effects model network meta-analysis to examine differences between lemborexant and suvorexant in efficacy and safety outcomes for treating patients with insomnia. We searched Embase, MEDLINE, and CENTRAL from their inception until April/28/2020. Primary outcomes were subjective time to sleep onset (sTSO), subjective total sleep time (sTST), and subjective wake-after-sleep onset (sWASO) at week 1. Four double-blind, randomized controlled trials were identified (n = 3237; 72.4% female; mean age 58.0 years). The treatment arm consisted of lemborexant 10 mg/d (LEM10, n = 592), lemborexant 5 mg/d (LEM5, n = 589), suvorexant 20/15 mg/d (SUV20/15, n = 493), zolpidem tartrate extended release 6.25 mg/d (ZOL6.25, n = 263), and placebo (n = 1300). All active treatments outperformed placebo regarding sTSO at week 1; standardized mean differences (95% credible interval): LEM10 = -0.51 (-0.63, -0.39), LEM5 = -0.48 (-0.60, -0.36), SUV20/15 = -0.21 (-0.33, -0.10), and ZOL6.25 = -0.30 (-0.46, -0.14); sTST at week 1: LEM10 = -0.58 (-0.70, -0.45), LEM5 = -0.33 (-0.46, -0.21), SUV20/15 = -0.34 (-0.46, -0.23), and ZOL6.25 = -0.42 (-0.59, -0.25); and sWASO at week 1: LEM10 = -0.42 (-0.57, -0.28), LEM5 = -0.26 (-0.40, -0.11), SUV20/15 = -0.18 (-0.32, -0.05), and ZOL6.25 = -0.37 (-0.56, -0.18). Although no significant differences were found in discontinuation due to adverse events between each active drug and placebo, LEM10 and SUV20/15 were associated with greater somnolence compared with placebo. LEM10 had the largest effect size compared with placebo for all primary outcomes, although with a risk of somnolence.
Assuntos
Distúrbios do Início e da Manutenção do Sono , Azepinas , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metanálise em Rede , Piridinas , Pirimidinas , Ensaios Clínicos Controlados Aleatórios como Assunto , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Resultado do Tratamento , TriazóisRESUMO
BACKGROUND: This systematic review and meta-analysis included double-blind, randomized, placebo-controlled trials of brexpiprazole adjunctive treatment (0.5-3 mg/d) for major depressive disorder where antidepressant treatment had failed. METHODS: The outcomes were the response rate (primary), remission rate (secondary), Montgomery Åsberg Depression Rating Scale score (secondary), Sheehan Disability Scale scores (secondary), Clinical Global Impression-Improvement/Severity scores, discontinuation rate, and individual adverse events. A subgroup meta-analysis of the data at week 6 compared outcomes by dose >2 mg/d or ≤2 mg/d (2 mg/d is the recommended dose). RESULTS: We identified 9 studies (n = 3391). Compared with placebo, brexpiprazole (any dose) was superior for response rate (risk ratio [RR] = 0.93, 95% confidence interval [95% CI] = 0.89-0.97, number needed to treat = 17), remission rate (RR = 0.95, 95% CI = 0.93-0.98, number needed to treat = 25), Montgomery Åsberg Depression Rating Scale score (standardized mean difference = -0.20, 95% CI = -0.29, -0.11), Sheehan Disability Scale score (standardized mean difference = -0.12, 95% CI = -0.21, -0.04), and Clinical Global Impression-Improvement/Severity scores but was associated with a higher discontinuation rate, akathisia, insomnia, restlessness, somnolence, and weight increase. Doses >2 mg/d had a significantly higher RR for response rate than ≤2 mg/d (0.96 vs 0.89); moreover, compared with placebo, doses >2 mg/d were associated with higher incidences of akathisia (RR = 4.58) and somnolence (RR = 7.56) as well as were marginally associated with a higher incidence of weight increase (RR = 3.14, P = .06). Compared with placebo, doses ≤2 mg/d were associated with higher incidences of akathisia (RR = 2.28) and weight increase (RR = 4.50). CONCLUSIONS: Brexpiprazole adjunctive treatment is effective for major depressive disorder when antidepressant treatment fails. At 6 weeks, doses ≤2 mg/d presented a better risk/benefit balance than >2 mg/d.
Assuntos
Antidepressivos/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Quimioterapia Combinada , Avaliação de Resultados em Cuidados de Saúde , Quinolonas/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Serotoninérgicos/farmacologia , Tiofenos/farmacologia , Antidepressivos/administração & dosagem , Antidepressivos/efeitos adversos , Humanos , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos , Serotoninérgicos/administração & dosagem , Serotoninérgicos/efeitos adversos , Tiofenos/administração & dosagem , Tiofenos/efeitos adversosRESUMO
AIM: There have been no previous reports on the efficacy and safety of suvorexant for insomnia in people with psychiatric disorders. METHODS: This one-week, prospective, single-arm, clinical trial of fixed dose of suvorexant (20 mg if ages 18-64 or 15 mg if age ≥ 65 years) for insomnia included 57 patients with psychiatric disorders who had experienced any of the following insomnia symptoms for four or more nights during the week prior to the start of the study: total sleep time (TST) <6 hours, time to sleep onset (TSO) ≥30 minutes, or two or more episodes of wake after sleep onset. RESULTS: The mean age of the patients was 49.4 ± 17.3 years; 54.4% were women, 49.1% had a major depressive disorder, and 77.2% completed the trial. Compared with the baseline scores (the mean scores for the two days before the start of the study), taking suvorexant was associated with significant improvements in TST, TSO, wake time after sleep onset, and the patients' sleep satisfaction level at week 1. Adverse events included at least one adverse event (43.9%), sleepiness (28.8%), fatigue (11.5%), nightmares (5.8%), headache (3.8%), dizziness (3.8%), and vomiting (1.9%). CONCLUSION: Suvorexant was beneficial for the treatment of insomnia in people with psychiatric disorders. However, this study was of short duration and included only a relatively small number of patients. A larger, long-term study is needed to investigate the efficacy and safety of suvorexant for insomnia in people with psychiatric disorders.
Assuntos
Azepinas/uso terapêutico , Transtornos Mentais/complicações , Medicamentos Indutores do Sono/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Triazóis/uso terapêutico , Adulto , Idoso , Azepinas/administração & dosagem , Azepinas/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medicamentos Indutores do Sono/administração & dosagem , Medicamentos Indutores do Sono/efeitos adversos , Distúrbios do Início e da Manutenção do Sono/complicações , Triazóis/administração & dosagem , Triazóis/efeitos adversosRESUMO
Objective: This study was a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials, investigating the efficacy and tolerability/safety of melatonin receptor agonists, such as ramelteon and melatonin, for patients with bipolar disorder. Methods: We carried out a literature search through PubMed and the Cochrane Library from the date of inception to January 6, 2019. The risk ratio (RR), number needed to treat (NNT), and standardized mean difference (SMD) ±95% CI were calculated. The primary outcome was all-cause discontinuation. Results: We identified three ramelteon (n=746) and two melatonin (n=53) studies. One of these two melatonin studies reported only data on all-cause discontinuation, whereas the other study did not report data relevant for a meta-analysis. We found no significant differences between the treatment and placebo groups regarding all-cause discontinuation, neither individually (p: ramelteon=0.86, melatonin=1.00) nor pooled together (p=0.85). Although we found no significant differences between ramelteon and placebo regarding the relapse due to mania/hypomania or mixed episode; Pittsburgh Sleep Quality Index scores; depression scales scores; Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form scores; and the incidence of individual adverse events, such as headaches, insomnia, somnolence, anxiety, and dizziness, ramelteon was associated with a lower incidence of relapse due to depression than placebo (RR=0.67, 95% CI=0.48-0.94, p=0.02, NNT=14). Conclusion: Ramelteon might prevent relapse due to depression in patients with bipolar disorder. However, because of the small number of studies included in the present systematic review and meta-analysis, further studies comparing ramelteon and placebo with larger samples of patients with bipolar disorder are warranted. We also did not evaluate the efficacy and safety of melatonin for patients with bipolar disorder in detail.
RESUMO
AIM: Whether patients with adult bipolar disorder (BD) who have been clinically stabilized with lithium or lamotrigine should continue this medication is not established fully. This systematic review and meta-analysis evaluated the efficacy and safety of lithium and lamotrigine for maintenance treatment in clinically stable patients with adult BD. METHODS: This meta-analysis included only double-blind, randomized, placebo-controlled trials with an enrichment design that selected patients who responded acutely to lithium or lamotrigine. Reports prior to November 15, 2018, were retrieved from the PubMed/Cochrane Library/Embase. The primary outcome was the relapse rate due to any mood episode at the study endpoint. Other outcomes were relapse rates due to a manic/hypomanic/mixed episode or depression at the study endpoint, discontinuation rate, death, and death by suicide. Risk ratios (RRs) (95% confidence intervals) were calculated. When the random-effects model showed significant differences between groups, the number-needed-to-treat (NNT) was estimated. RESULTS: The search retrieved two studies regarding lithium (N = 218) and four evaluating lamotrigine (N = 706). Both drugs were superior to placebo for reducing the relapse rate due to any mood episode [lithium: RR = 0.52 (0.41-0.66), P < 0.00001, I2 = 0%, NNT = 2.3 (1.6-4.2); lamotrigine: RR = 0.81 (0.70-0.93), P = 0.004, I2 = 0%, NNT = 8.3 (5.0-25.0)] and all-cause discontinuation. There were no significant differences in other outcomes between lithium or lamotrigine and the placebo groups. CONCLUSION: Both drugs showed benefit for preventing relapse in clinically stable patients with adult BD. However, the number of studies and patients in this analysis was small.
Assuntos
Antipsicóticos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Lamotrigina/uso terapêutico , Lítio/uso terapêutico , Adulto , Antipsicóticos/efeitos adversos , Depressão/epidemiologia , Depressão/etiologia , Método Duplo-Cego , Feminino , Humanos , Lamotrigina/efeitos adversos , Lítio/efeitos adversos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , RecidivaRESUMO
PURPOSE: The purpose of this study was to compare the efficacy and safety of brexpiprazole 4 mg/day (B4) and 2 mg/day (B2) for treating acute schizophrenia. PATIENTS AND METHODS: We performed three categorical meta-analyses (B4 vs placebo, B2 vs placebo, and B4 vs B2) of double-blind, randomized placebo-controlled trials (DBRCTs) that reported improvements in the Positive and Negative Syndrome Scale (PANSS) scores, response rate, Clinical Global Impression-Improvement and Severity (CGI-I and CGI-S) scores, discontinuation rate, and incidence of individual adverse events. RESULTS: We identified three DBRCTs with 1,444 patients. Both B4 and B2 were superior to placebo for PANSS total score (B4: standardized mean difference [SMD] =-0.30, 95% CI =-0.43, -0.17; B2: SMD =-0.30, 95% CI =-0.46, -0.13), PANSS negative score, response rate, CGI-S score, and CGI-I score. B2, but not B4, was superior to placebo for the PANSS positive score. However, there was considerable heterogeneity in the meta-analysis for B4's PANSS positive score, which disappeared after excluding a 2018 Japanese study from the meta-analysis that included more patients on a high-dose antipsychotic prior to their participation. A meta-analysis that excluded the data from the abovementioned patients showed B4 to be superior to the placebo in terms of the PANSS positive score (SMD =-0.22, 95% CI =-0.40, -0.03). B2, but not B4, was associated with a lower incidence of all-cause discontinuation compared with placebo. Both B4 and B2 were superior to placebo for discontinuation due to adverse events and schizophrenia, but both were associated with a higher incidence of weight gain compared with placebo. B4 was also associated with a higher risk of extrapyramidal symptoms than B2. CONCLUSION: Both B4 and B2 benefitted patients with schizophrenia, particularly those who were not previously on high-dose antipsychotics. Both the regimens were well-tolerated, but carried a risk of weight gain and extrapyramidal symptoms, although the latter risk was higher for B4 than B2.
RESUMO
INTRODUCTION: Currently, five pharmacotherapeutic options are available to treat Alzheimer's disease: memantine; the three cholinesterase inhibitors donepezil, galantamine, and rivastigmine; and combination treatments with memantine and one cholinesterase inhibitor. Selection of the best course of treatment is based upon the evidence gathered by systematic reviews and meta-analyses of randomized controlled trials. Areas covered: This article provides a risk-benefit analysis of these treatments using evidence from meta-analyses on their safety and their efficacy. Expert opinion: Memantine improves cognitive functions and behavioral disturbances more efficiently than the placebo, both as monotherapy and in combination with donepezil. Although memantine monotherapy and combination therapy are associated with a few individual adverse events such as somnolence, it is well-tolerated and its safety (all-cause discontinuation) is comparable or superior to that of the placebo (agitation). Pooled cholinesterase inhibitors are superior to the placebo in the improvement of cognitive functions, but not behavioral disturbances and they are not well-tolerated, as evaluated by the high discontinuation rate. Donepezil (10 mg/day) and oral rivastigmine and galantamine monotherapies carry the risk for some adverse events including gastrointestinal symptoms. Therefore, we consider that combined treatment with memantine and donepezil is the most useful treatment for Alzheimer's disease.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Memantina/administração & dosagem , Doença de Alzheimer/fisiopatologia , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/efeitos adversos , Cognição/efeitos dos fármacos , Donepezila , Quimioterapia Combinada , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Humanos , Indanos/administração & dosagem , Indanos/efeitos adversos , Memantina/efeitos adversos , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
RATIONALE: This study aims to examine whether folate/folic acid/methylfolate/folinic acid supplemented to antipsychotics (FA + AP) is beneficial in schizophrenia treatment. OBJECTIVE: We conducted a comprehensive systematic review and meta-analysis of double-blind, placebo-controlled, randomized clinical trials (RCTs) of FA + AP for schizophrenia. METHODS: The primary outcome was an improvement in total symptoms. Other outcomes were psychopathology subscales (positive, negative, general, and depressive symptoms), discontinuation due to all-cause and adverse events, and individual adverse events. The meta-analysis evaluated the effect size based on a random-effects model. RESULTS: Although we included ten RCTs with 925 patients in total (seven folic acid RCTs (n = 789), two methylfolate RCTs (n = 96), and one folinic acid RCT (n = 40)) in the systematic review, only seven RCTs were included in the meta-analysis. Pooled FA + AP treatments were not superior to placebo + AP in the improvement of total (N = 7, n = 340; standardized mean difference (SMD) = - 0.20, 95% confidence interval (CI) = - 0.41, 0.02, p = 0.08, I2 = 0%), positive, general, or depressive symptoms. Pooled FA + AP treatments were more effective than placebo + AP for negative symptoms (N = 5, n = 281; SMD = -0.25, 95% CI = -0.49, -0.01, p = 0.04, I2 = 0%). Although pooled FA + AP treatments were associated with a lower incidence of serious adverse events than placebo treatments (N = 4, n = 241; risk ratio = 0.32, 95% CI = 0.12-0.82, p = 0.02, I2 = 0%; number needed to harm = not significant), there were no significant differences in other safety outcomes between both treatments. CONCLUSIONS: Our findings suggest that pooled FA + AP treatment improves negative symptoms in schizophrenia patients. Moreover, this treatment was well tolerated. However, because our results might exhibit a small-study effect, future studies with a larger sample should be conducted to obtain more robust results.
Assuntos
Antipsicóticos/administração & dosagem , Depressão/tratamento farmacológico , Ácido Fólico/administração & dosagem , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Tetra-Hidrofolatos/administração & dosagem , Depressão/epidemiologia , Depressão/psicologia , Método Duplo-Cego , Quimioterapia Combinada , Humanos , Psicopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Esquizofrenia/epidemiologia , Resultado do TratamentoRESUMO
A comprehensive meta-analysis of statin add-on therapy in the antipsychotic treatment of schizophrenia was conducted. Data from previous studies, prior to 8/21/2017, was obtained from Scopus, PubMed, PsycINFO, and Cochrane Library. Both a systematic review and meta-analysis were conducted with patient data from randomized placebo-controlled trials (RCTs) to compare statins with placebo in order to calculate effect size. Across the five RCTs (mean duration: 9.2 weeks), 236 adult patients with schizophrenia were randomly selected to receive either placebo (n=117) or statins (n=119). Pooled statin add-on therapy showed significant superiority over placebo in the improvement of Positive and Negative Syndrome Scale (PANSS) total scores (mean difference=-1.96; 95% confidence interval, -2.94 to -0.98; p<0.0001; I2=0%; N=4, n=174). However, there were no statistically significant differences in other efficacy outcomes between the two treatment groups. Statin did not have a significant difference in its incidence of discontinuation or have individual adverse events compared to placebo. Our results suggest that statins may have considerable potential as an add-on therapy for schizophrenia. However, determining the effectiveness of this treatment in clinical practice requires future investigation due to limitations of the current evidence-base including small sample, potential for publication and selection biases and short duration of follow-up.
Assuntos
Antipsicóticos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Esquizofrenia/tratamento farmacológico , Adolescente , Adulto , Quimioterapia Combinada , Feminino , Humanos , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The clinical benefit of memantine for Alzheimer's disease (AD) remains inconclusive. OBJECTIVE: We performed an updated systematic review and meta-analysis of the efficacy/safety of memantine in AD. METHODS: We included randomized trials of memantine for AD patients. Cognitive function scores (CF), behavioral disturbances scores (BD), and all-cause discontinuation were used as primary measures. Effect size based on a random-effects model was evaluated in the meta-analyses. RESULTS: Thirty studies (nâ=â7,567; memantine versus placebo: Nâ=â11, nâ=â3,298; memantine + cholinesterase inhibitors (M+ChEIs) versus ChEIs: Nâ=â17, nâ=â4,175) were identified. Memantine showed a significant improvement in CF [standardized mean difference (SMD)â=â-0.24, 95% confidence intervals (95% CIs)â=â-0.34, -0.15, pâ<â0.00001, I2â=â35% ] and BD (SMDâ=â-0.16, 95% CIsâ=â-0.29, -0.04, pâ=â0.01, I2â=â52%) compared with placebo. In the sensitivity analysis including only patients with moderate-severe AD, memantine was superior to the placebo in reducing BD without considerable heterogeneity (SMDâ=â-0.20, 95% CIsâ=â-0.34, -0.07, pâ=â0.003, I2â=â36%). Compared with ChEIs, M+ChEIs showed a greater reduction in BD (SMDâ=â-0.20, 95% CIsâ=â-0.36, -0.03, pâ=â0.02, I2â=â77%) and a trend of CF improvement (SMDâ=â-0.11, 95% CIsâ=â-0.22, 0.01, pâ=â0.06, I2â=â56%). However, in the sensitivity analysis of double-blind, placebo-controlled studies only, M+ChEIs showed a significant reduction in BD compared with ChEIs without considerable heterogeneity (SMDâ=â-0.11, 95% CIsâ=â-0.21, -0.01, pâ=â0.04, I2â=â40%). When performing the sensitivity analysis of donepezil studies only, M+ChEIs was superior to ChEIs in improving CF without considerable heterogeneity (SMDâ=â-0.18, 95% CIsâ=â-0.31, -0.05, pâ=â0.006, I2â=â49%). No differences were detected in all-cause discontinuation between the groups. CONCLUSIONS: The meta-analyses suggest the credible efficacy and safety of memantine in treating AD when used alone or in combination with ChEIs.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Memantina/uso terapêutico , HumanosRESUMO
BACKGROUND: An epidemiological approach to preventing the development or progression of chronic kidney disease (CKD) is necessary, while few effective preventive measures are currently available. We conducted a community-based, cohort study to identify the factors associated with the development of CKD in the general population. METHODS: We examined 1876 local residents of a Japanese community who had an annual health check-up and, of those, 1506 residents judged not to have CKD (473 men and 1033 women) were followed for the development of CKD over 10 years. RESULTS: The numbers of male and female residents who developed CKD during the follow-up period were 167 (35.3%) and 299 (28.9%), respectively. As compared to those without CKD development, the residents who developed CKD were older, and had a higher body mass index (BMI), systolic blood pressure, and creatinine in both genders. The rate of CKD development in obese female residents was higher than in non-obese women, but such a difference was not noted in male residents. In addition to age and serum creatinine, we identified BMI as an independently significant factor for the development of CKD in women, but not in men. CONCLUSIONS: Increased BMI is a significant risk factor for the development of CKD in women, and there seems to be a gender difference in the association between increased BMI and the development of CKD in the general population.
Assuntos
Índice de Massa Corporal , Obesidade/epidemiologia , Insuficiência Renal Crônica/epidemiologia , Adulto , Idoso , Pressão Sanguínea , Creatinina/sangue , Progressão da Doença , Feminino , Humanos , Japão/epidemiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/patologia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/patologia , Fatores de Risco , Fatores SexuaisRESUMO
Adrenomedullin (AM) is a cardiovascular protective peptide produced in various organs and tissues including adipose tissue. In the present study, we measured the plasma AM levels of subjects with or without obesity by two assay methods to separately evaluate the biologically active AM-NH(2) and the intermediate form of AM-glycine (AM-Gly). We measured the total AM and AM-NH(2) levels of plasma in 52 obese and 172 non-obese residents of a Japanese community, who received regular health check-ups and had no overt cardiovascular disease. AM-Gly values were obtained by subtracting AM-NH(2) levels from those of total AM. Both the AM-NH(2) and AM-Gly levels of the subjects with obesity were higher than those without obesity, and significant relationships were noted between body mass index (BMI) and the plasma levels of the two molecular forms of AM in a simple regression analysis. Moreover, the significant factors identified by multivariate analyses were BMI and serum triglyceride for AM-NH(2) and diastolic blood pressure, insulin, high-density lipoprotein-cholesterol, and plasma renin activity for AM-Gly. These results suggest active roles for the two molecular forms of AM in metabolic disorders associated with obesity in subjects without overt cardiovascular disease.
Assuntos
Adrenomedulina/sangue , Obesidade/sangue , Idoso , Pressão Sanguínea , Índice de Massa Corporal , Estudos de Casos e Controles , HDL-Colesterol/sangue , Feminino , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Radioimunoensaio , Renina/sangue , Triglicerídeos/sangueRESUMO
Chronic kidney disease (CKD) has recently been recognized as a risk factor for cardiovascular disease, while the mechanism by which CKD develops remained to be clarified. In the present study, we conducted a cross-sectional, community-based study to identify the factor(s) associated with CKD. We examined 1978 local residents of the Kiyotake area of Japan (697 males and 1281 females; age, 60.8 +/- 11.0 years; mean +/- SD), who had an annual health check-up. Diagnosis of CKD was made based on dipstick proteinuria of +1 or higher, or on a reduced glomerular filtration rate (GFR) estimated from serum creatinine level to less than 60 ml/min/1.73 m(2). Body mass index (BMI) and prevalence of obesity in the residents with CKD were found to be higher than in those without CKD in both genders. When compared with the residents without CKD, the ratios of residents taking antihypertensive medicines were higher in both genders, and the blood pressure and fasting blood glucose levels of males and the triglyceride level of females were elevated in those with CKD. These parameters or factors were found to be significant for CKD by a univariate logistic analysis. We further analyzed the data with a multivariate logistic method using age, BMI, antihypertensive and antidyslipidemic medicines, blood pressure, serum lipid and glucose as independent covariates, and found that BMI was a significant parameter independently correlated with CKD in both genders. Thus, increased BMI is associated with CKD independently of blood pressure, serum lipid and glucose levels in the general population.
Assuntos
Povo Asiático , Índice de Massa Corporal , Nefropatias/etiologia , Obesidade/complicações , Idoso , Povo Asiático/estatística & dados numéricos , Doença Crônica , Estudos Transversais , Feminino , Humanos , Japão/epidemiologia , Nefropatias/etnologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Obesidade/etnologia , Razão de Chances , Vigilância da População , Prevalência , Medição de Risco , Fatores de RiscoRESUMO
BACKGROUND: Both irinotecan (CPT) and paclitaxel (Pac) are effective against non-small cell lung cancer (NSCLC), and besides, preclinical studies have demonstrated an additive or synergistic interaction between camptothecin and taxane. METHODS: We conducted a phase I/II study of combination chemotherapy consisting of Pac and CPT to determine qualitative and quantitative toxicities and efficacy of the combination against advanced NSCLC. We fixed the dose of CPT at 60 mg/m(2) and escalated the Pac dose in 10 or 20 mg/m(2) increments from a starting dose of 80 mg/m(2), and repeated the cycle every 2 weeks. Prophylactic G-CSF was also administered. RESULTS: Between February 1999 and April 2001, 24 patients were registered in the study. None of the patients had a history of prior chemotherapy, but surgical resection had been performed in 3 of them. None of the patients experienced dose-limiting toxicity (DLT) up to and including level 6. At dose level 7 of Pac, 180 mg/m(2), 2 patients experienced DLT, that is grades 2 and 3 dyspnea due to pneumonitis. Another patient experienced grade 1 dyspnea due to pneumonitis. Neutropenia, diarrhea, and other toxicities were mild; however, we concluded that dose level 7 of Pac was the maximum-tolerated dose. An objective response was observed in 58.3%. The median survival time was 370 days, and the 1-year survival rate was 54.2%. CONCLUSION: Pneumonitis was the DLT in this study, and Pac 160 mg/m(2) and CPT 60 mg/m(2) every 2 weeks are recommended for the phase II study. This combination shows appreciable activity against NSCLC.