Continuous flow Aza-Michael reaction for preparing the fast-acting synthetic opioid drug Remifentanil

Abstract Remifentanil is a modern fentanyl analogue with ultrashort-action granted by an esterase-labile methyl propanoate chain. Here, we present the development of a continuous flow methodology for the key N-alkylation step of remifentanil preparation in a biphasic, "slug-flow" regime. We screened parameters under microwave-assisted reactions, translated conditions to flow settings, and obtained remifentanil under 15-min residence time in a 1-mL microreactor, with a space-time yield of 89 mg/mL·h and 94% yield.

Antagonista de opioides para o tratamento do prurido associado à colestase. Relato de caso / Opiate antagonist therapy for the cholestasis pruritus. Case report

JUSTIFICATIVA E OBJETIVOS: Pacientes com lep­tospirose podem desenvolver colestase, levando à queixa de prurido. Existem vários tratamentos propostos para o prurido, porém nenhum deles é satisfatoriamente efetivo. O objetivo deste artigo foi relatar o emprego de um antagonista opioide para o tratamento de prurido associado à 3 colestase em paciente com leptospirose.RELATO DO CASO: Paciente do sexo masculino, 51 anos, apresentou quadro de leptospirose, referindo dentre 11 as principais queixas prurido intenso. A queixa manteve-se até o quarto dia de internação, quando se optou pelaprescrição de um antagonista opioide, levando à remissão completa do quadro. CONCLUSÃO: O sucesso da terapia no caso apresentado soma-se a outros relatos da literatura que demonstram evidências de que os antagonistas opioides são bem tolerados e rêduzem significativamente o prurido associado à colestase.

O papel dos antagonistas periféricos dos opióides no tratamento da dor e nos cuidados perioperatórios / El papel de los antagonistas periféricos de los opioides en el tratamiento del dolor y en los cuidados perioperatorios / The role of peripheral opiate antagonists in pain medicine and perioperative care

JUSTIFICATIVA E OBJETIVOS: Estudos clínicos e pré-clínicos sobre os antagonistas periféricos dos opióides aumentaram nosso conhecimento sobre os efeitos dos opióides exógenos e endógenos. CONTEÚDO: Este artigo faz uma revisão dos estudos clínicos e pré-clínicos sobre a disfunção intestinal secundária ao uso de opióides. CONCLUSÕES: Se forem aprovados, esses fármacos podem representar soluções importantes para os problemas encontrados na prática médica com relação ao tratamento da dor.

BACKGROUND AND OBJECTIVES: Pre-clinical and clinical trials of peripheral opiate antagonists have shed new light on the effects of exogenous and endogenous opioids. CONTENTS: This article review preclinical studies and clinical opioid bowel disfunction trials. CONCLUSIONS: If approved these drugs may offer potential solutions to important clinical problems in pain management.

JUSTIFICATIVA Y OBJETIVOS: Estudios clínicos y preclínicos sobre los antagonistas periféricos de los opioides aumentaron nuestro conocimiento sobre los efectos de los opioides exógenos y endógenos. CONTENIDO: Este artículo nos trae una reflexión de los estudios clínicos y preclínicos sobre la disfunción intestinal secundaria al uso de opioides. CONCLUSIONES: Si se aprueban, los referidos fármacos pueden representar soluciones importantes para los problemas encontrados en la práctica médica en relación con el tratamiento del dolor.

Participation of ATP-sensitive K+ channels in the peripheral antinociceptive effect of fentanyl in rats

We examined the effect of several K+ channel blockers such as glibenclamide, tolbutamide, charybdotoxin (ChTX), apamin, tetraethylammonium chloride (TEA), 4-aminopyridine (4-AP), and cesium on the ability of fentanyl, a clinically used selective æ-opioid receptor agonist, to promote peripheral antinociception. Antinociception was measured by the paw pressure test in male Wistar rats weighing 180-250 g (N = 5 animals per group). Carrageenan (250 æg/paw) decreased the threshold of responsiveness to noxious pressure (delta = 188.1 ± 5.3 g). This mechanical hyperalgesia was reduced by fentanyl (0.5, 1.5 and 3 æg/paw) in a peripherally mediated and dose-dependent fashion (17.3, 45.3 and 62.6 percent, respectively). The selective blockers of ATP-sensitive K+ channels glibenclamide (40, 80 and 160 æg/paw) and tolbutamide (80, 160 and 240 æg/paw) dose dependently antagonized the antinociception induced by fentanyl (1.5 æg/paw). In contrast, the effect of fentanyl was unaffected by the large conductance Ca2+-activated K+ channel blocker ChTX (2 æg/paw), the small conductance Ca2+-activated K+ channel blocker apamin (10 æg/paw), or the non-specific K+ channel blocker TEA (150 æg/paw), 4-AP (50 æg/paw), and cesium (250 æg/paw). These results extend previously reported data on the peripheral analgesic effect of morphine and fentanyl, suggesting for the first time that the peripheral æ-opioid receptor-mediated antinociceptive effect of fentanyl depends on activation of ATP-sensitive, but not other, K+ channels.

Efficacy of exogenous gonadotropins on the maintenance of spermatogenesis in pethidine treated albino rats.

An attempt is made to induce the pethidine suppressed gonadal activities by the administration of exogenous gonadotropins (hCG, PMSG, hCG + PMSG). Administration of 5 IU gonadotropins either separately or in combination to the rats treated with pethidine for 30 days resulted in the significant increase in the weight of testis, diameter of testis and seminiferous tubules. Gonadotropin(s) treatment stimulated the spermatogenic activity which was inhibited by pethidine. Therefore the number of spermatogonia, spermatocytes, spermatids in the seminiferous tubules and spermatozoa in cauda epididymis is increased significantly. Decreased testicular cholesterol, increased protein content and weight of accessory sex organs indicate the rejuvenation of steroidogenesis. Combination of both the gonadotropins is more effective in bringing all these activities.