A retrospective review of isolated gliptin-exposure cases reported to a state poison control system.

BACKGROUND: The dipeptidyl peptidase-4 (DPP-4) inhibitors sitagliptin, saxagliptin, and linagliptin are approved by the US Food and Drug Administration in the treatment of type-2 diabetes. Given the limited published information regarding human overdoses to these medications, our goal was to characterize such exposures. METHODS: A state poison system database was retrospectively reviewed for all single-agent exposures to sitagliptin, saxagliptin, and linagliptin from 2006 to 2012. Case notes were reviewed and an observational case series was constructed from the data collected including age, weight, gender, circumstances surrounding exposure, symptoms, and outcome. Patients with co-ingestants, confirmed non-exposure, unknown outcomes, or other coding errors were excluded. RESULTS: A total of 197 cases were identified: 135 cases were excluded (123 cases were excluded due to co-ingestants and 12 cases were lost to follow-up); 62 were included for review. No patients experienced hypoglycemia. One of 19 exposed pediatric (0-9 years of age) patients experienced symptoms and was safely managed at home after one episode of emesis. No symptom was experienced following unintentional ingestion by three adolescent (10-18 years of age) patients. Forty single-agent adult exposures to gliptins were included. Thirty-seven involved non-self-harm exposures resulting from double or triple doses; all were safely managed at home without reported symptoms. The majority of these ingestions involved sitagliptin. Three self-harm-adult exposures to gliptins were included for review. All the three were evaluated in a healthcare facility. One patient experienced abdominal discomfort after ingesting 700 mg of sitagliptin and was ultimately discharged from the emergency department. The other two patients experienced no reported symptoms. CONCLUSION: The majority of gliptin-exposed adult and pediatric/adolescent patients were safely managed at home and when evaluated in a healthcare facility, did not require hospitalization. Intentional self-harm-adult gliptin exposures were managed in a healthcare facility but rarely resulted in hospitalization or serious morbidity at doses up to 18 times the adult therapeutic dose. Additional studies are necessary to determine precise triage guidelines for the management of gliptin overdose.

Nontropic actions of neurotrophins: subcortical nerve growth factor gene delivery reverses age-related degeneration of primate cortical cholinergic innervation.

Normal aging is associated with a significant reduction in cognitive function across primate species. However, the structural and molecular basis for this age-related decline in neural function has yet to be defined clearly. Extensive cell loss does not occur as a consequence of normal aging in human and nonhuman primate species. More recent studies have demonstrated significant reductions in functional neuronal markers in subcortical brain regions in primates as a consequence of aging, including dopaminergic and cholinergic systems, although corresponding losses in cortical innervation from these neurons have not been investigated. In the present study, we report that aging is associated with a significant 25% reduction in cortical innervation by cholinergic systems in rhesus monkeys (P < 0.001). Further, these age-related reductions are ameliorated by cellular delivery of human nerve growth factor to cholinergic somata in the basal forebrain, restoring levels of cholinergic innervation in the cortex to those of young monkeys (P = 0.89). Thus, (i) aging is associated with a significant reduction in cortical cholinergic innervation; (ii) this reduction is reversible by growth-factor delivery; and (iii) growth factors can remodel axonal terminal fields at a distance, representing a nontropic action of growth factors in modulating adult neuronal structure and function (i.e., administration of growth factors to cholinergic somata significantly increases axon density in terminal fields). These findings are relevant to potential clinical uses of growth factors to treat neurological disorders.