Implementation of a pharmacogenomic program in a Brazilian public institution.

This narrative review describes implementation, current status and perspectives of a pharmacogenomic (PGx) program at the Brazilian National Cancer Institute (INCA), targeting the cancer chemotherapeutic drugs - fluoropyrimidines, irinotecan and thiopurines. This initiative, designed as a research project, was supported by a grant from the Brazilian Ministry of Health. A dedicated task force developed standard operational procedures from recruitment of patients to creating PGx reports with dosing recommendations, which were successfully applied to test 100 gastrointestinal cancer INCA outpatients and 162 acute lymphoblastic leukemia pediatric patients from INCA and seven other hospitals. The program has been subsequently expanded to include gastrointestinal cancer patients from three additional cancer treatment centers. We anticipate implementation of routine pre-emptive PGx testing at INCA but acknowledge challenges associated with this transition, such as continuous financing support, availability of trained personnel, adoption of the PGx-informed prescription by the clinical staff and, ultimately, evidence of cost-effectiveness.

Vagotomia modifica o efluxo do cálcio nas ilhotas pancreáticas / Vagotomy changes calcium eflux in pancreatic islets

A participação do sistema nervoso parassimpático na modulação da secreção de insulina manifesta-se claramente durante a fase cefálica que se segue ao estímulo iniciado pelo estímulo sensorial provocado pela presença do alimento na cavidade oral. O objetivo deste trabalho foi avaliar se a vagotomia subdiafragmática seletiva do ramo pancreático poderia modificar a permeabilidade ao Ca2+ da membrana plasmática das células beta. Para avaliar os efeitos da vagotomia usamos o principal secretagogo que é a glicose e o potencializador carbamilcolina. Os estudos de e fluxo de 45Ca2+ foram realizados em ilhotas de ratos controle ou desnervados isoladas por digestão com colagenase e perfundidas com KREBS contendo os secretagogos. As ilhotas isoladas de ratos 15 e 30 dias após a vagotomia do ramo pancreático não responderam ao estímulo com 16,7 mM de glicose e também apresentaram alteração na sensibilidade à carbamilcolina (CCh 100 μm) adicionada à solução contendo 5,6 mM de glicose. Nossos resultados sugerem que o nervo vago (ramo pancreático) participa da regulação do processo secretório da insulina pelas células beta pancreáticas. Este efeito pode estar associado à modulação da respostas induzidas pela glicose e reguladas pelo neurotransmissor acetilcolina, considerado modulador da secreção de insulina.

The participation of the parasympathetic nervous system in insulin secretion modulation is clearly evident during the cephalic phase that follows the sensorial stimulus provoked by food in the mouth. The objective of this study was to evaluate if selective subdiaphragmatic vagotomy of the pancreatic branch could alter 45Ca2+ permeability in the plasmatic membrane of pancreatic β cell. To assess the effects of vagotomy, we used glucose and the potentializer carbamylcholine on the glucose effects. Analysis of 45Ca2+ efflux was accomplished in isolated islets by digestion with collagenase and perfused with KREBS and carbamylcholine in rats from groups control and denervaded. After 15 and 30 days of the pancreatic branch vagotomy, the isolated islets did not respond to a glucose stimulus of 16,7 mM and also presented alteration in carbamylcholine sensibility (CCh 100 μm) when added to the solution containing 5,6mM of glucose. Our results suggest that the vagus nerve (pancreatic branch) contributes with regulationof insulin secretory process of pancreatic β cells. This effect could be associated to the modulation of responses induced by glucose and the regulation of acetylcholine, a neurotransmitter modulator of insulin secretion.

Participation of Na(+) channels in the potentiation by Tityus serrulatus alpha-toxin TsTx-V of glucose-induced electrical activity and insulin secretion in rodent islet beta-cells.

The effects of TsTx-V, an alpha-toxin isolated from Tityus serrulatus venom, on electrical activity and insulin secretion by rodent pancreatic islet cells were studied. TsTx-V (5.6 microg/ml) depolarized mouse pancreatic beta-cells, diminished the membrane input resistance and increased the duration of the active phase of glucose-induced electrical activity. Similar results were observed with the Na(+) channel agonist veratridine (110 microM). Both agents potentiated glucose (8.3 mM)-induced insulin secretion in rat islet. In the presence of TsTx-V or veratridine, insulin secretion increased 2- and 1.4-fold over basal values, respectively (P<0.001). The Na(+) channel antagonist tetrodotoxin (6 microM) significantly decreased glucose- and TsTx-V-induced insulin secretion (P<0.001). TsTx-V also stimulated insulin secretion at low glucose concentrations (2.8 mM) whereas the beta-toxin, Ts-gamma (gamma toxin), also obtained from Tityus serrulatus venom, significantly reduced TsTx-V-induced secretion at sub- and suprathreshold concentrations of glucose. These results are consistent with a model whereby Na(+) channels participate in glucose-induced electrical activity. Alteration in the activity of these channels changes the length of time during which the beta-cell depolarizes, thereby altering the secretory behavior of the cell. The construction of a three-dimensional model for TsTx-V revealed a conserved core containing an alpha-helix and three beta-strands, with minor differences when compared with toxins from other scorpion venoms.