RESUMO
BACKGROUND: Intranasal insulin is a potential treatment for neurodegenerative disease shown to increase cerebral glucose uptake, reduce amyloid plaques, and improve verbal memory in cognitively impaired as well as healthy adults. Investigations have suggested rapid-acting insulins such as glulisine may result in superior cognitive benefits compared with regular insulin. OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of rapid-acting intranasal glulisine in subjects with amnestic mild cognitive impairment (MCI) or mild probable Alzheimer's disease (AD). METHODS: We performed a single-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy of intranasal glulisine 20 IU twice daily versus saline placebo in 35 memory-impaired (MCI/AD) subjects using the Impel NeuroPharma I109 Precision Olfactory Delivery (POD®) device. The 13-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), Clinical Dementia Rating (CDR) global score, and Functional Assessment Questionnaire (FAQ) were measured at baseline and 3 and 6 months. Secondary outcome measures included digit span forward/backwards, Trail Making Test Parts A/B, Controlled Oral Word Association Test (COWAT), and Weschler Memory Scale (WMS)-IV logical memory. Adverse effects (AEs) and serious adverse effects (SAEs) were measured along with blood glucose/insulin levels. RESULTS: No significant difference in ADAS-Cog13, CDR Sum of Boxes (CDR-SOB), or FAQ scores were found between treatment groups at 3 and 6 months. Subjects in the saline group were significantly older than those in the glulisine group (p = 0.022). No significant differences in sex, education, apolipoprotein E4 (ApoE4) status, and Montreal Cognitive Assessment (MoCA) score existed between treatment groups. Overall, the number of adverse events per person was similar between groups (2.32 vs. 2.24; p = 0.824), although subjects receiving intranasal glulisine had higher rates of nasal irritation (25.0% vs. 13.9%) and respiratory symptoms (15.9% vs. 8.3%) compared with placebo. There were no differences in blood sugar or rate of hypoglycemia between the treatment and placebo groups. CONCLUSIONS: Intranasal glulisine was relatively safe and well-tolerated and did not consistently impact peripheral glucose or insulin levels. There were no enhancing effects of intranasal glulisine on cognition, function, or mood, but the ability to detect significance was limited by the number of subjects successfully enrolled and the study duration. CLINICALTRIALS. GOV REGISTRATION: NCT02503501.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Insulina/análogos & derivados , Administração Intranasal , Doença de Alzheimer/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Humanos , Insulina/administração & dosagem , Memória , Testes NeuropsicológicosRESUMO
BACKGROUND: Individuals with Down syndrome are likely to develop clinical and neuropathological brain changes resembling Alzheimer's disease dementia by the ages of 35-40 years. Intranasal insulin is a potential treatment for neurodegenerative disease that has been shown to reduce amyloid plaque burden and improve verbal memory performance in normal as well as memory-impaired adults. Investigations have shown that rapid-acting insulins may result in superior cognitive benefits compared with regular insulin. OBJECTIVES: The primary objective of this study was to measure the safety and feasibility of intranasal rapid-acting glulisine in subjects with Down syndrome. Secondarily, we estimated the effects of intranasal glulisine on cognition and memory in Down syndrome. METHODS: A single-center, single-dose, randomized, double-blind, placebo-controlled, cross-over pilot study was performed to test the safety of intranasal glulisine vs placebo in 12 subjects with Down syndrome aged ≥ 35 years. Intranasal administration utilized the Impel NeuroPharma I109 Precision Olfactory Delivery (POD®) device. The primary outcomes were the occurrence of any or related adverse and serious adverse events. Secondary post-treatment cognitive outcome measures included performance on the Fuld Object-Memory Evaluation and Rivermead Behavioral Memory Test. RESULTS: Intranasal glulisine was safe and well tolerated in the Down syndrome population. No adverse or serious adverse events were observed. CONCLUSIONS: Further investigations are necessary to better evaluate the potential cognitive-enhancing role of intranasal insulin in the Down syndrome population. CLINICALTRIALS. GOV ID: NCT02432716.
Assuntos
Síndrome de Down/tratamento farmacológico , Insulina/administração & dosagem , Insulina/uso terapêutico , Administração Intranasal , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos PilotoRESUMO
INTRODUCTION: Intranasal (IN) insulin acutely improves verbal memory in mild cognitive impairment (MCI)/Alzheimer's disease (AD), but its therapeutic effects may be attenuated in apolipoprotein E4 (ApoE4) carriers. Furthermore, rapid-acting (RA) insulins may have superior therapeutic effects compared with regular insulin types. OBJECTIVES: To measure the safety and efficacy of intranasally delivered RA glulisine in ApoE4 carriers with mild-moderate AD. METHODS: We performed a double-blinded, randomized, cross-over study of RA insulin glulisine in nine mild-moderate AD subjects to better understand the relationship between RA insulin, ApoE4 carrier status and memory performance. RESULTS: IN glulisine was well tolerated but failed to have an acute impact on cognition in ApoE4 carriers with AD. Serum insulin levels acutely dropped following treatment, but peripheral glucose levels remained unchanged. CONCLUSION: Larger clinical trials of longer duration are necessary to better understand the relationships between RA insulin, ApoE4 carrier status and cognitive performance in AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Insulina de Ação Curta/administração & dosagem , Nootrópicos/administração & dosagem , Administração Intranasal , Idoso , Doença de Alzheimer/sangue , Doença de Alzheimer/psicologia , Biomarcadores Farmacológicos , Glicemia/efeitos dos fármacos , Cognição/efeitos dos fármacos , Estudos Cross-Over , Método Duplo-Cego , Feminino , Heterozigoto , Humanos , Insulina/sangue , Masculino , Memória/efeitos dos fármacos , Escalas de Graduação Psiquiátrica , Resultado do TratamentoRESUMO
Various concentrations of hypochlorite (12.5 to 200 ppm) and sodium bisulfite (0.15 to 2.50%) applied singly and as successive dips were compared for their effect on the microbial flora of shrimp. It was found that sodium bisulfite exhibited antimicrobial activity at all concentrations tested, with a 50% reduction in bacterial numbers at a concentration of 2.5%. Hypochlorite reduced the bacterial load 75% at a concentration of 200 ppm. Under certain conditions a sequential treatment of shrimp with bisulfite, followed by a hypochlorite dip, significantly increased the antimicrobial effectiveness of the hypochlorite. This synergistic effect, however, was not apparent on shrimp following 24 h of iced storage.