Interaction between buprenorphine and norbuprenorphine in neonatal opioid withdrawal syndrome.

Buprenorphine (BUP) is the preferred treatment for opioid use disorder during pregnancy but can cause neonatal opioid withdrawal syndrome (NOWS). Norbuprenorphine (NorBUP), an active metabolite of BUP, is implicated in BUP-associated NOWS. We hypothesized that BUP, a low-efficacy agonist of mu opioid receptors, will not antagonize NorBUP, a high-efficacy agonist of mu opioid receptors, in producing NOWS. To test this hypothesis, we treated pregnant Long-Evans rats with BUP (0, 0.01, 0.1 or 1mg/kg/day) ± NorBUP (1mg/kg/day) from gestation day 9 until pup delivery, and tested pups for opioid dependence using our established NOWS model. We used LC-MS-MS to quantify brain concentrations of BUP, NorBUP, and their glucuronide conjugates. BUP had little effect on NorBUP-induced NOWS, with the exception of 1mg/kg/day BUP significantly increasing NorBUP-induced NOWS by 58% in females. BUP and NorBUP brain concentrations predicted NOWS in multiple linear regression models. Interestingly, NorBUP contributed more to NOWS in females (ßNorBUP = 51.34, p = 0.0001) than in males (ßNorBUP = 19.21, P = 0.093), while BUP was similar for females (ßBUP = 10.62, P = 0.0017) and males (ßBUP = 11.38, P = 0.009). We are the first to report that NorBUP induces NOWS in the presence of BUP and it is more influential in females than males in the contribution of NorBUP to BUP-associated NOWS. These findings suggest that females are more susceptible to NorBUP-induced NOWS, and that treatment strategies that reduce prenatal NorBUP exposure may be more effective for females than males.

Deuterated buprenorphine retains pharmacodynamic properties of buprenorphine and resists metabolism to the active metabolite norbuprenorphine in rats.

Introduction: An active metabolite of buprenorphine (BUP), called norbuprenorphine (NorBUP), is implicated in neonatal opioid withdrawal syndrome when BUP is taken during pregnancy. Therefore, reducing or eliminating metabolism of BUP to NorBUP is a novel strategy that will likely lower total fetal exposure to opioids and thus improve offspring outcomes. Precision deuteration alters pharmacokinetics of drugs without altering pharmacodynamics. Here, we report the synthesis and testing of deuterated buprenorphine (BUP-D2). Methods: We determined opioid receptor affinities of BUP-D2 relative to BUP with radioligand competition receptor binding assays, and the potency and efficacy of BUP-D2 relative to BUP to activate G-proteins via opioid receptors with [35S]GTPγS binding assays in homogenates containing the human mu, delta, or kappa opioid receptors. The antinociceptive effects of BUP-D2 and BUP were compared using the warm-water tail withdrawal assay in rats. Blood concentration versus time profiles of BUP, BUP-D2, and NorBUP were measured in rats following intravenous BUP-D2 or BUP injection. Results: The synthesis provided a 48% yield and the product was ≥99% deuterated. Like BUP, BUP-D2 had sub-nanomolar affinity for opioid receptors. BUP-D2 also activated opioid receptors and induced antinociception with equal potency and efficacy as BUP. The maximum concentration and the area under the curve of NorBUP in the blood of rats that received BUP-D2 were over 19- and 10-fold lower, respectively, than in rats that received BUP. Discussion: These results indicate that BUP-D2 retains key pharmacodynamic properties of BUP and resists metabolism to NorBUP and therefore holds promise as an alternative to BUP.

Autocuidado de idosos diagnosticados com hipertensão arterial e/ou diabetes mellitus / Self-care of elderly diagnosed with arterial hypertension and/or diabetes mellitus

Objetivo: conhecer como o idoso diagnosticado com hipertensão arterial e/oudiabetes mellitus desenvolve o seu autocuidado, bem como as dificuldades que ele possaenfrentar. Método: estudo de abordagem qualitativa realizado com 20 idosos diagnosticadoscom hipertensão arterial e/ou diabetes mellitus. As entrevistas semiestruturadas foramrealizadas no domicílio dos idosos. Os dados foram coletados nos meses de junho e julho de2016 e analisados de acordo com a análise de conteúdo. Resultados: elencaram-se trêscategorias mediante a análise dos dados: Identificação do diagnóstico da hipertensão arterial edo diabetes mellitus; O conhecimento do idoso sobre hipertensão arterial e/ou diabetesmellitus; Os recursos que o idoso utiliza para cuidar da hipertensão arterial e/ou diabetesmellitus. Considerações finais: os resultados obtidos revelaram a necessidade dosprofissionais de saúde que assistem esses idosos repensem medidas e ações reais, voltadaspara a educação em saúde, capacitando-os para o autocuidado de maneira efetiva.

Aim: to understand how the elderly diagnosed with arterial hypertension and / ordiabetes mellitus develops their self-care as well as the difficulties they may face. Method:qualitative study with 20 elderly patients diagnosed with arterial hypertension and / or diabetesmellitus. Semi-structured interviews were carried out in a home environment. The data werecollected in the months of June and July 2016 and analyzed according to the Content Analysis.Results: three categories were listed through data analysis: Identification of the diagnosis ofhypertension and diabetes mellitus; Knowledge of the elderly about arterial hypertension and /or diabetes mellitus; The resources that the elderly uses to take care of arterial hypertension and / or diabetes mellitus. Final considerations: the results revealed that health professionalswho assist these elderly people need to rethink effective measures and actions aimed at healtheducation, enabling them to self-care of themselves effectively.

Objetivo: entender como los ancianos con hipertensión arterial y/o diabetesmellitus desarrollan su autocuidado y las dificultades que pueden enfrentar. Método: estudiocualitativo con 20 pacientes ancianos con hipertensión arterial y/o diabetes mellitus. Lasentrevistas semiestructuradas fueron realizadas en el domicilio de los ancianos. Los datosfueron recolectados en los meses de junio y julio de 2016 y analizados con base en Análisisde Contenido. Resultados: a partir del análisis de los datos fueron identificadas trescategorías: Identificación del diagnóstico de hipertensión y de diabetes mellitus; elconocimiento de los ancianos sobre hipertensión y/o diabetes mellitus; y los recursos que losancianos usan para cuidar de la hipertensión y/o diabetes mellitus. Consideraciones finales:los resultados obtenidos revelaron la necesidad de los profesionales de salud, que asisten aestos ancianos, repensen medidas y acciones efectivas direccionadas a la educación en salud,capacitando estos sujetos para el autocuidado de manera efectiva.