RESUMO
PURPOSE: To provide additional efficacy data in patients treated with rabeprazole through week 4, and to validate sustained relief of gastroesophageal reflux disease symptoms through week 8 as well as to further analyze rabeprazole safety in patients with wide-ranging demographic and clinical characteristics. RESULTS: Patients in this study (N = 2,449) demonstrated significant overall improvement versus baseline (P < 0.001). Substantial symptom relief was seen throughout 8 weeks of treatment. By week 4, complete relief of daytime and nighttime heartburn, belching, regurgitation, and dysphagia was observed in 87.5, 90.7, 50.7, 77.6, and 75.1% of patients, respectively. Improvements were seen in rabeprazole-treated patients (<65 or >or=65 years) with a range of baseline symptom severities and across different racial groups. Rabeprazole was well tolerated. CONCLUSIONS: In patients with endoscopy-confirmed erosive esophagitis treated with once-daily rabeprazole 20 mg, prompt and continuing improvements were seen in daytime and nighttime heartburn, belching, regurgitation, and dysphagia.
Assuntos
2-Piridinilmetilsulfinilbenzimidazóis/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Esofagite Péptica/tratamento farmacológico , Idoso , Relação Dose-Resposta a Droga , Endoscopia Gastrointestinal , Esofagite Péptica/complicações , Esofagite Péptica/diagnóstico , Feminino , Seguimentos , Azia/tratamento farmacológico , Azia/epidemiologia , Azia/etiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , ATPases Translocadoras de Prótons/antagonistas & inibidores , Rabeprazol , Fatores de Tempo , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
Altered expression of central muscarinic and nicotinic acetylcholine receptors in hippocampal and cortical regions may contribute to the cognitive impairment exhibited in patients with schizophrenia. Increasing cholinergic activity through the use of a cholinesterase inhibitor (ChEI) therefore represents a possible strategy for cognitive augmentation in schizophrenia. We examined the efficacy and safety of the ChEI donepezil as cotreatment for mild to moderate cognitive impairment in schizophrenia or schizoaffective disorder in a prospective, 12-week, placebo-controlled, double-blind, parallel-group study. In total, 250 patients (18-55 years) with schizophrenia or schizoaffective disorder who were clinically stabilized on risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole, alone or in combination, were enrolled at 38 outpatient psychiatric clinics in the United States. Patients were randomized to donepezil 5 mg q.d. for 6 weeks then 10 mg q.d. for 6 weeks, or placebo administered as oral tablets. The primary outcome measure was the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) neurocognitive battery composite score. In the intent-to-treat sample (donepezil, n=121; placebo, n=124), both treatments showed improvement in the composite score from baseline to week 12. At week 12, cognitive improvement with donepezil was similar to that with placebo (last-observation-carried-forward effect size, 0.277 vs 0.411; p=0.1182) and statistically significantly inferior for the observed-cases analysis (0.257 vs 0.450; p=0.044). There was statistically significant improvement in the Positive and Negative Syndrome Assessment Scale negative symptoms score for placebo compared with donepezil, while total and positive symptom scores were similar between both treatments. Statistically significant improvements in positive symptoms score and Clinical Global Impression-Improvement for donepezil compared with placebo were noted at Week 6. Treatment-emergent adverse events (AEs) were observed for 54.5% of donepezil- and 61.3% of placebo-treated patients; most AEs were rated as mild to moderate in severity. Donepezil was safe and well-tolerated but was not effective compared with placebo as a cotreatment for the improvement of cognitive impairment in this patient population. A significant and surprisingly large placebo/practice effect was observed among placebo-treated patients, and is a serious consideration in future clinical trial study designs for potential cognitive enhancing compounds in schizophrenia.
Assuntos
Inibidores da Colinesterase/uso terapêutico , Transtornos Cognitivos/terapia , Indanos/uso terapêutico , Piperidinas/uso terapêutico , Efeito Placebo , Prática Psicológica , Adulto , Ensaios Clínicos como Assunto , Transtornos Cognitivos/etiologia , Donepezila , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/complicações , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico , Fatores de TempoRESUMO
Neurofibromatosis 2 (NF2) is a dominantly inherited disorder characterized by bilateral vestibular schwannomas and meningiomas. Merlin, the neurofibromatosis 2 tumor suppressor protein, is related to the ERM (ezrin, radixin, moesin) proteins and, like its family members, is thought to play a role in plasma membrane-cytoskeletal interactions. We report a novel protein as a merlin-specific binding partner that we have named magicin (merlin and Grb2 interacting cytoskeletal protein) and show that the two proteins interact in vitro and in vivo as well as colocalize beneath the plasma membrane. Magicin is a 24 kDa protein that is expressed in many cell lines and tissues. Magicin, similar to merlin, associates with the actin cytoskeleton as determined by cofractionation, immunofluorescence and electron microscopy. Analysis of the magicin sequence reveals binding motifs for the adaptor protein Grb2. Employing affinity binding, blot overlay and co-immunoprecipitation assays, we demonstrate an interaction between Grb2 and magicin. In addition, merlin is capable of forming a ternary complex with magicin and Grb2. These results support a role for merlin in receptor-mediated signaling at the cell surface, and may have implications in the regulation of cytoskeletal reorganization.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas do Citoesqueleto/metabolismo , Citoesqueleto/metabolismo , Neurofibromina 2/metabolismo , Actinas/metabolismo , Sequência de Aminoácidos , Animais , Proteínas do Citoesqueleto/química , Imunofluorescência , Proteína Adaptadora GRB2 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Complexo Mediador , Microscopia Eletrônica , Dados de Sequência Molecular , Ligação Proteica , Homologia de Sequência de Aminoácidos , Técnicas do Sistema de Duplo-HíbridoRESUMO
A magnetic resonance imaging (MRI) study was conducted as part of an intervention study in subjects with amnestic mild cognitive impairment (aMCI) to assess donepezil's treatment effect on brain atrophy. Adults with aMCI were randomly assigned to double-blind treatment with 10 mg/day donepezil hydrochloride or placebo for 48 weeks. Brain MRI scans were acquired at baseline and endpoint. The primary outcome measure was annualized percentage change (APC) in hippocampal volume; the main secondary outcome measure was APC in whole brain volumes. An analysis of variance (ANOVA) model including terms for treatment, site, and age was used to compare the treatment groups. APCs for hippocampal volumes were not significantly different between treatment groups. There were significant differences favoring the donepezil group for total (p = 0.001), ventricular region (p = 0.0002), and cortical region (p = 0.003) whole brain volumes. Although the primary MRI outcome measure was negative, the main secondary MRI outcome measure showed a positive result. These findings suggest a treatment effect of donepezil on brain atrophy in aMCI.
Assuntos
Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/tratamento farmacológico , Indanos/uso terapêutico , Imageamento por Ressonância Magnética , Piperidinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Disfunção Cognitiva/psicologia , Donepezila , Método Duplo-Cego , Feminino , Humanos , Indanos/farmacologia , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Piperidinas/farmacologia , Método Simples-CegoRESUMO
BACKGROUND AND OBJECTIVE: Amnestic mild cognitive impairment (aMCI), characterized by episodic memory impairment in the absence of clinical dementia, often represents a transitional stage between normal aging and Alzheimer's disease (AD). It is not known if non-expert primary-care physicians (PCPs) can differentiate individuals with no cognitive impairment (NCI), aMCI and mild AD in a primary-care practice setting. This study develops an approach to this question, which is necessary for aMCI to become a treatment target. METHODS: Fourteen experts assessed subjects with memory complaints in terms of their laboratory test results, magnetic resonance imaging findings and scores on the Mini-Mental State Examination, adapted Clinical Dementia Rating Scale and Alzheimer's Disease Assessment Scale-cognitive subscale Delayed Word Recall before designating each subject as having NCI, aMCI or AD. Subjects agreed upon by a consensus committee were assigned to non-expert PCPs who, following brief training, assessed them using the same clinical information and utilizing the same assessment instruments. The chance-corrected inter-rater reliability (expert versus non-expert) measure κ, based on binary outcome (aMCI/not-aMCI), was estimated. RESULTS: The study recruited 119 evaluable subjects (50 aMCI, 27 mild AD and 42 NCI) and demonstrated fair to moderate agreement (κ = 0.423) between experts and non-experts in designation of aMCI. The percent agreement was 72.3%, sensitivity 62.0% and specificity 79.7%. Overall, non-experts under-rated the level of impairment compared with experts. CONCLUSION: This study established the feasibility of making the aMCI designation in the community and identified some likely sources of error. The results suggest that when drugs with clear benefit for aMCI patients are developed, community-based PCPs, with additional, more optimized training, will be able to accurately identify those patients who should receive treatment.
Assuntos
Doença de Alzheimer/diagnóstico , Amnésia/diagnóstico , Transtornos Cognitivos/diagnóstico , Estudos de Viabilidade , Avaliação Geriátrica/métodos , Atenção Primária à Saúde/métodos , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Amnésia/complicações , Transtornos Cognitivos/complicações , Técnicas e Procedimentos Diagnósticos/instrumentação , Diagnóstico Precoce , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Escalas de Graduação Psiquiátrica , Sensibilidade e EspecificidadeRESUMO
Following a 48-week, double-blind, randomized, placebo-controlled trial of donepezil in 821 patients with amnestic mild cognitive impairment (aMCI), safety and tolerability of donepezil (10 mg) were further evaluated in a 28-week extension study. Of 499 participants who completed the double-blind phase, 145 enrolled in the open-label study. Adverse events (AEs) were recorded throughout. Overall, 57.4% of participants in the donepezil/donepezil group and 62.3% in the placebo/donepezil group experienced an AE, with the most frequent treatment-emergent AEs being diarrhea, muscle spasms, insomnia, and nausea. Most were mild to moderate in severity and were more common in the first several weeks after treatment initiation. More participants in the placebo/donepezil group (22.1%) discontinued donepezil due to an AE compared with the donepezil/donepezil group (10.3%). These findings support the safety of donepezil in patients with aMCI. When compared with other studies, however, the data suggest that patients with Alzheimer's tolerate donepezil better than patients with MCI.
Assuntos
Amnésia/tratamento farmacológico , Inibidores da Colinesterase/efeitos adversos , Transtornos Cognitivos/tratamento farmacológico , Indanos/efeitos adversos , Piperidinas/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Amnésia/psicologia , Inibidores da Colinesterase/administração & dosagem , Transtornos Cognitivos/psicologia , Diarreia/induzido quimicamente , Donepezila , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Indanos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Testes Neuropsicológicos , Piperidinas/administração & dosagem , Escalas de Graduação Psiquiátrica , Índice de Gravidade de Doença , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Espasmo/induzido quimicamente , Fatores de Tempo , Resultado do TratamentoRESUMO
The purpose of this study was to assess the effect of rabeprazole 20 mg once a day on patient-reported health-related quality of life in routine clinical practice. Patients with erosive gastroesophageal reflux disease participating in an open-label, 8-week study completed the SF-36 Health Survey before and after treatment with rabeprazole. For all SF-36 scales, there was a statistically significant (p < or = 0.007) improvement in mean scores from baseline to week 8. Improvements in each of the subscales, except for physical functioning, general health, and mental health, were at least 5% in magnitude, a level considered clinically meaningful. Furthermore, while baseline scores were significantly poorer than general United States population scores, follow-up scores for four of the subscales (role limitations due to physical problems, social functioning, role limitations due to emotional problems, and mental health) were comparable to general population scores. In conclusion, rabeprazole significantly improved health-related quality of life in erosive gastroesophageal reflux disease patients and restored social functioning and emotional well-being to levels comparable to those observed in the United States general population.
Assuntos
Benzimidazóis/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Refluxo Gastroesofágico/tratamento farmacológico , Qualidade de Vida , 2-Piridinilmetilsulfinilbenzimidazóis , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Indicadores Básicos de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Omeprazol/análogos & derivados , RabeprazolRESUMO
OBJECTIVES: To compare directly, in the same patient cohort, the ease of use and tolerability of donepezil and galantamine in the treatment of Alzheimer's disease (AD), and investigate the effects of both treatments on cognition and activities of daily living (ADL). METHODS: Patients with mild to moderate AD from 14 European centres were randomised to receive open-label donepezil (up to 10 mg once daily) or galantamine (up to 12 mg twice daily) for 12 weeks, according to the approved product labelling. Physicians and caregivers completed questionnaires rating satisfaction with treatment/ease of use in daily practice. Secondary assessments were the ADAS-cog, the MMSE, and the DAD scale to assess ADL. Tolerability was evaluated by reporting adverse events (AEs). RESULTS: Both physicians and caregivers reported significantly greater overall satisfaction/ease of use for donepezil (n = 64) compared with galantamine (n = 56) at weeks 4, 12, and endpoint (week 12 LOCF; all p-values <0.05). Significantly greater improvements in cognition were also observed for donepezil versus galantamine on the ADAS-cog at Week 12 and endpoint (p-values <0.05). ADL improved significantly in the donepezil group compared with the galantamine group at weeks 4, 12, and endpoint (p-values <0.05). Most AEs were mild to moderate, however, 46% galantamine-treated patients reported gastrointestinal AEs vs 25% donepezil patients. CONCLUSIONS: Physician and caregiver ease of use/satisfaction scores, and assessments of cognition and ADL, showed significant benefits for donepezil compared with galantamine in this direct comparative trial. Both treatments were well tolerated, with more gastrointestinal AEs reported for galantamine vs donepezil.