Anti-aging effects of chlorpropamide depend on mitochondrial complex-II and the production of mitochondrial reactive oxygen species

Sulfonylureas are widely used oral anti-diabetic drugs. However, its long-term usage effects on patients' lifespan remain controversial, with no reports of influence on animal longevity. Hence, the anti-aging effects of chlorpropamide along with glimepiride, glibenclamide, and tolbutamide were studied with special emphasis on the interaction of chlorpropamide with mitochondrial ATP-sensitive K+ (mitoK-ATP) channels and mitochondrial complex II. Chlorpropamide delayed aging in Caenorhabditis elegans, human lung fibroblast MRC-5 cells and reduced doxorubicin-induced senescence in both MRC-5 cells and mice. In addition, the mitochondrial membrane potential and ATP levels were significantly increased in chlorpropamide-treated worms, which is consistent with the function of its reported targets, mitoK-ATP channels. Increased levels of mitochondrial reactive oxygen species (mtROS) were observed in chlorpropamide-treated worms. Moreover, the lifespan extension by chlorpropamide required complex II and increased mtROS levels, indicating that chlorpropamide acts on complex II directly or indirectly via mitoK-ATP to increase the production of mtROS as a pro-longevity signal. This study provides mechanistic insight into the anti-aging effects of sulfonylureas in C. elegans.

Efeito imunomodulador de hipoglicemiantes orais em cultura de linfócitos de pacientes com diabetes tipo 2 / Immunomodulatory effects of oral antidiabetic drugs in lymphocyte cultures from patients with type 2 diabetes

INTRODUCTION AND OBJECTIVE: It has been suggested that type 2 diabetes is an inflammatory response manifestation. The main drugs used to treat type 2 diabetes are sulphonylureas and biguanides. The aim of this study was to demonstrate the modulatory effects of oral hypoglycemic drugs (chlorpropamide and metformin) on lymphocyte proliferation in vitro and ex vivo. METHODS: Peripheral blood mononuclear cells were isolated from human blood by gradient centrifugation. T-lymphocytes were stimulated by phytohemagglutinin (PHA) and oral hypoglycemic drugs. RESULTS: In both in vitro and ex vivo experiments, there was a reduction in cell proliferation after treatment with oral hypoglycemic drugs. When both drugs were used in combination, a high level of cytotoxicity was observed, which made analysis of immunomodulatory effects unfeasible. DISCUSSION AND CONCLUSION: We demonstrated that diabetes itself may reduce cell proliferation significantly when stimulated by PHA, which may indicate that diabetic patients have difficulties in promoting an efficient inflammatory response. Moreover, the use of oral hypoglycemic drugs may aggravate this situation.

INTRODUÇÃO E OBJETIVOS: Tem sido sugerido que o diabetes mellitus tipo 2 (DM2) é uma manifestação da resposta inflamatória. As principais drogas utilizadas no tratamento do DM2 são as sulfonilureias e as biguanidas. O objetivo deste trabalho é demonstrar os efeitos moduladores na proliferação de linfócitos causada pelos hipoglicemiantes orais (clorpropamida e metformina), in vitro e ex vivo. MÉTODOS: Células mononucleares de sangue periférico foram isoladas de seres humanos por gradiente de centrifugação. Os linfócitos T foram estimulados com fito-hemaglutinina (PHA) e hipoglicemiantes. RESULTADOS: Nos experimentos in vitro e ex vivo, mostramos a redução da proliferação celular quando do tratamento com drogas hipoglicemiantes orais. Quando as drogas foram utilizadas em combinação, foi observado alto grau de citotoxicidade, tornando inviável a análise do efeito imunomodulador. DISCUSSÃO E CONCLUSÃO: Mostramos que o diabetes, por si, pode reduzir significativamente a proliferação celular quando estimulada por PHA, o que pode indicar que o paciente diabético tem dificuldade em promover a eficiente resposta inflamatória e que o uso de hipoglicemiantes pode piorar esta situação.

Decreased Expression of Aquaporin-2 Water Channels in the Kidney in Rats Treated with Chlorpropamide / 대한신장학회잡지

BACKGROUND: Whether blood glucose levels may change the regulation of aquaporin(AQP) water channels in the kidney was investigated. METHODS: Male Sprague-Dawley rats were treated with chlorpropamide(40 mg/100 g body weight per day, per oral, for 7 days), and their expression of AQP1-3 and type VI adenylyl cyclase proteins was determined in the kidney. RESULTS: Following the treatment with chlorpropamide, the blood glucose level was significantly decreased compared with that in the control(64+/-8 vs 106+/-7 mg/dL, n=6 each, p < 0.01). Accordingly, the expression of AQP2 proteins was decreased in the cortex, outer medulla, and inner medulla. The AQP2 targeting was not significantly altered, as evidenced by parallel decreases of its expression in the membrane and the cytoplasmic fractions. No significant changes were observed in the expression of either AQP1 or of AQP3. The protein expression of type VI adenylyl cyclase was not significantly altered. CONCLUSION: These results suggest that hypoglycemia attenuates the expression of AQP2 water channels in the kidney.

Hypoglycemic accidents following oral anti-diabetic therapy

The authors experience on the dangers of oral hypoglycemic agents are discussed. Non-familiarity with the drug, patients non-cooperation, or inadvertence are the causes of accidents mentioned. Case reports of five patients who were given chlorpropamide and "anti-diabetic tablet" are cited. Recommendations regarding close supervision during treatment are also noted

Bioavailability study of chlorpropamide tablets in healthy volunteers.

Bioavailability study was conducted on 250 mg-chlorpropamide tablets from 10 locally manufactured brands and an innovator one (Diabinese). The results of the tests for quality according to the pharmacopoeia were as follows: weight uniformity of all the brands was in accordance with the USP XXII standard, the content of one of them failed, and disintegration test of one brand failed (BP 1,973 and USP XIX). In addition five brands failed to meet the USP XXII dissolution specification, while only 2 brands failed to meet the BP 1,988 specification. Four brands of chlorpropamide tablets were selected for studying their bioequivalence in 20 Thai healthy male volunteers, receiving orally a half dose of 250 mg, using a cross-over randomized design, one representing the rapid dissolution rate group, the innovator one representing the intermediate dissolution rate group and 2 brands representing the slow rate group (one failed the USP XXII, but met the BP 1,900 dissolution specification (a) and the other failed both USP XXII and BP 1,988 dissolution specification (b). Plasma chlorpropamide levels were determined by a specific high performance liquid chromatographic method. Individual plasma profiles were analysed using PC NONLIN computer program-two compartment open model. There was no significant difference (p > 0.05) with regard to extent and rte of absorption between the brand having the intermediate dissolution rate (the innovator one) and the slow dissolution drug (b), while the brand representing rapid dissolution rate was absorbed more rapidly (p < 0.05). However the absorption rate of the local made product had an higher standard error than that of the innovator, absorption rates did not have any effect on the hypoglycemia, because drug levels in the absorption period were lower that the therapeutic level and steady state. Besides, in testing blood glucose level of volunteers before and after having received orally the 4 brands at different times, it was fond that there was no significant difference (p > 0.05) between the level before taking the drugs and that after 2 hours. There was no significant correlation between the in vivo absorption rate and the dissolution, USP XXII method (p > 0.05). The mean peak chlorpropamide concentration in plasma (half dose taken) was between 14.59 and 16.69 ug/ml, and the half-life (T1/2, e) was between 43.73 and 49.42 hours.

A case of chlorpropamide-induced photosensitivity / 대한피부과학회지

We report a case of a photosensitivity reaction in a 76-year-old inale induced by chlorpropamide ingestion. The patient had erythematous scaly patches on the sur. -exposed areas, A phototest revealed the decreased minimal erythemal dose(MED) to UVA(5J/cm). A photopatch test and photo-scartch test with 1% chlorpropamide ointment and 0.1% chlorpropamic!e .olution were all negative. An oral provocation test was performed, which showed a positive result with marked decrease of MED to UVA (5J/cm). After the cessation of chlorpropamide, his skin lesions were improved markedly with complete loss of photosensitivity. Macular hypopigmentations (leukcme.anoderma) appeared on the previous erythematous patchy ereas, but disappeared during the follow-up period.