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.

Avaliação de bentonita sódica purificada e bentonita sódica intercalada como promotores de dissolução de clorpropamida em comprimidos preparados por granulação úmida e compressão direta / Evaluation of purified sodium bentonite and intercalated sodium bentonite as dissolution enhancers for chlorpropamide in tablets produced by wet granulation and direct compression

O presente estudo avaliou sistemas baseados em bentonita sódica purificada e bentonita sódica purificada intercalada com colina como promotores de dissolução de clorpropamida. A intercalação da bentonita sódica foi avaliada por difração de raios X, análise termo gravimétrica, análise calorimétricade varredura e espectrometria no infravermelho. Prepararam-se misturas físicas, empastamentos (kneadings) e granulados e comprimidos, por granulação úmida e compressão direta; ambos os sistemas (físicos e comprimidos) com diversas relações fármaco: promotores de dissolução. Todos os sistemas físicos e os comprimidos foram avaliados quanto à dissolução do fármaco segundo metodologia descrita na Farmacopéia Norte-Americana (USP). Os comprimidos ainda foram avaliados quanto à dureza e friabilidade. O empastamento hidroalcoólico mostrou ser o melhor sistema físico para aumento da dissolução, entretanto é inviável para produção industrial de comprimidos. Os comprimidos de clorpropamida preparados por granulação úmida com proporção de fármaco e promotores de dissolução de 1:0,25 p/p apresentaram melhores resultados no teste de dissolução em relação aos comprimidos sem os promotores. Não houve diferença significativa entre a liberação de clorpropamida com a bentonita sódica e bentonita sódica intercalada. Os comprimidos preparados por compressão direta apresentaram, comparativamente, o melhor desempenho no teste de dissolução. Não foi evidenciado perda de cristalinidade do fármaconos sistemas estudados. O poder de desintegração da bentonita e a possível interação molecular entre o fármaco e a bentonita são as prováveis causas do aumento da dissolução da clorpropamida com tais sistemas baseados em bentonita.

Effects of vernonia amygdalina and chlorpropamide on blood glucose

Despite significant achievements in treatment modalities and preventive measures, the prevalence of diabetes has risen exponentially in the last decade. Because of these limitations there is a continued need for new and more effective therapies. An increasing number of people are using dietary and herbal supplements, even though there is a general lack of evidence for their safety and efficacy. Consequently, science-based medical and governmental reg-ulations are needed for more randomized clinical studies to provide evidence of efficacy and safety. The aim of this study was therefore to subject one such promising Vernonia amygdalina [VA], to agents to further investigate the potential function of VA for treatment of diabetes mellitus as potentially emerging alternative therapy for type 2 diabetes. Sixty adult male Sprague-Dawley rats weighing 180-220g were used for the experiment. Half of the animals were randomly rendered diabetic by administering alloxan [150 mg/kg]. Equal numbers [20] of the rats were variously administered aqueous leaf extract of VA [500 mg/kg], chlorpropamide [250 mg/kg] and distilled water [2 ml/kg]. Aqueous leaf extract of VA produced significant [p < 0.05-0.001], reductions in the blood glucose concentrations of normal [normoglycemic] and diabetic [hyperglycemic] rats 1 to 12 hours after acute treatment compared with dis-tilled water-treated control animals. Its blood-glucose-lowering potential in both normoglycemic and alloxan-induced diabetic male Sprague-Dawley rats compared favourably to that of chlorpropamide. Administration of the aqueous extract of VA at a concentration of 500 mg/kg of body weight significantly decreased the levels of blood glucose. The hypoglycemic efficacy was comparable with that of chlorpropamide, a standard hypo-glycemic drug

effect of a 6 month treatment course of male healthy rats by chlorpropamide and glibenclamide on vascular tone of aorta

Diabetes mellitus is the most common endocrine disorder with an ever-increasing prevalence. Cardiovascular complications are the major cause of death in diabetic patients. Type II diabetes mellitus is usually treated by sulfonylureas. There are controversial reports regarding cardiovascular side effects of these drugs. Conflicting evidences exist about side effects of the first and second-generation sulfonylureas. In this study, the vascular effects of chlorpropamide and glibenclamide [first and second generations of sulfonylureas respectively] were investigated in healthy male rats. Male rats were treated by the above-mentioned drugs for six months and the response of aortic rings to acetylcholine, isosorbide dinitrate and phenylephrine were studied and compared to normal control group. Data were analyzed by means of ANOVA test. There was no significant difference between the response of aortic rings of treated and control group to acetylcholine, isosorbide dinitrate and phenylepherine. Sulfonylureas through closing ATP dependent potassium channels, which exist in beta-cells of pancreas and other organs such as heart and vascular smooth muscles may affect the vascular tone. Based on the results of this study long term oral consumption of chlorpropamide and glibenclamide in normal rats did not affect aortic contractile property. Further studies are needed to clarify the vascular effects of sulfonylureas

Correlations of Abnormal Involuntary Movements with Blood Glucose, Lipid Levels in Chronic Schizophrenics

OBJECTS: It has been reported that the incidence of tardive dyskinesia(TD), the remarkable abnormal involuntary movement, was higher in the schizophrenics with high blood sugar levels and that TD had been improved by small amount of insulin-injection for 90 days. And also it was generally known that the blood lipids were higher in the schizophrenics with tardive dyskinesia. Thus, we tried to replicate the correlations of abnormal involuntary movements with blood sugar levels and blood lipids in chronic schizophrenics treated with antipsychotics. METHODS: Thirty-eight male schizophrenic inpatients who were stable in clinical state with medications, were included. The patients who had been already diagnosed as diabetes mellitus(DM), organic brain disorder, substance-related disorder, physical illness were excluded and also we excluded female patients to remove the hormonal effect on TD. Eleven patients who ranked higher(above five) in the Abnormal Involuntary Movement Scale(AIMS) were assigned into 2 groups, a dibenese group and a placebo group. Diabinese or placebos were administrated for 3 weeks with antipsychotics and AIMS was rechecked. RESULTS: There were no correlations between the total AIMS scores and blood sugar and lipids levels in all subjects. The means of total and subscale scores(objective, face, and extremity) of AIMS did not reveal statistical significances between diabinese and placebo groups. However(total, jaw, face, upper arm, and objective feeling), were statistically higher in the diabinese group than those in the placebo group. And correlations of total cholesterol(TC) with fast blood sugar(FBS), weight with body mass index(BMI) and waist, total glycerol (TG) with BMI were statistically significant. CONCLUSION: In this study, there were statistical significances in the changes in ratings of AIMS scores between the diabinese group and the placebo group. Application of oral hypoglycemic agent might be a way of improving abnormal involuntary movements in schizophrenics with abnormal involuntary movements or TD. Althogugh it was not certain that there were correlations of abnormal involuntary movement with blood sugar and lipids, correlations of TC/TG with AIMS, of FBS with AIMS cautiously suggest that the regular check of HbA1C, waist, and weight are recommended for schizophrenics.

Agentes antidiabéticos orales / Oral antidiabetical agents

El presente artículo describe los diferentes agentes antidiabéticos orales utilizados con frecuencia en casos de diabetes mellitus Tipo II. Se detalla su acción terapéutica, modos de acción y efectos colaterales y adversos

Tratamiento de liquen plano con griseofulvina / Treatment of lichen planus with griseofulvin

Presentamos un paciente de sexo masculino, de 15 años de edad, con diagnóstico clínico e histopatológico de liquen plano. Fue tratado con griseofulvina 500 mg/día y fenoxifenadina 120 mg/día con mejoría tanto subjetiva como objetiva al cabo del mes de tratamiento. Se confirma la griseofulvina como alternativa terapéutica para el liquen plano

Effect of ATP-dependent K+ channel openers and blockers on serum concentration of aldosterone in rats

There are many reports for involvement of ATP-sensitive potassium channels in pancreatic, cardiac and vascular smooth muscle cells. This study examined the effect of single doses of K+ channel openers; diazoxide, minoxidil and K+ channel blockers; chlorpropamide, glibenclamide on serum concentration of aldosterone in male rats. Blood samples were obtained 60 minutes after drug treatment and serum aldosterone level was determined by RIA. The basal serum aldosterone was 659.32 +/- 71.48 pg/ml and after diazoxide or minoxidil administration increased to 1188.53 +/- 99.45 pg/ml and 1392.69 +/- 177.83 pg/ml, respectively. Chlorpropamide or glibenclamide treatment did not produce any change in basal serum aldosterone concentration, but in early streptozotocin-induced diabetic rats decreased serum aldosterone level significantly [P<0.001]. Pretreatment with glibenclamide blocked aldosterone response to diazoxide but did not affect aldosterone response to exogenous ACTH to the same extent. Effect of diazoxide in insulin-treated rats was approximately similar to that of normal rats. Comparison of blood glucose concentration determined in normal, insulin treated and diabetic rats after different drug administration showed that there is no correlation between blood glucose level and the responses observed in serum hormone concentration. The results indicate that regulatory processes involved in the secretion of aldosterone are responsive to drugs affecting glibenclamide-sensitive K+ channels

New synthesis method of chlorpropamid

The chlorpropamid (1) is an antidiabetic drug synthetized from chlorobenzene (2) in five steps through intermediates p-clorobenzenesulfonyl chloride (3), calcium p-chlorobenzene sulfonyl cyanamide (6), p-clorobenzenesulfonyl cyanamide (7), p-clorobenzenesulfonyl urea (8) and then the compound 8 was condensated with n-propylamine. The product have melting point, Rf, IR spectral data that suitable with to the chlopropamid extracted from Novopropamid tablet of Canada.

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.

Simultaneous high performance liquid chromatography determination of three sulfonylureas in plasma

A high-performance liquid chromatographic [HPLC] method has been developed for the simultaneous analysis of three frequently used sulfonylureas [chlorpropamide, glipizide and glibenclamide] by using a reversed phase C-8 column with a mobile phase consisting of 0.1% Ortho- phosphoric acid pH 2.7: isopropanol: acetonitrile, [45:25:30] operated at ambient temperature, with analysis time less than ten minutes. The eluted drugs were monitored by UV at 235nm. The extraction was performed by using dichloromethane after the plasma sample was mixed with the buffer [0.1% orthophosphoric acid].The overall recoveries and relative standard deviations were [93.7 +/- 5.3]% for chlorpropamide, [91.5 +/- 4.9]% for glipizide and [95 +/- 2.8]% for glibenclamide. The response was linear in the range [0.1 -100mg/ml] for chlorpropamide, glipizide, and glibenclamide, with r' > 0.999 for all drugs. Detection limits were 2ng/ml plasma for chlorpropamide, 15ng/ml plasma for glipizide and 7ng/ml plasma for glibenclamide, measured at a Signal/ Noise [S/N] of 3. No interference from administered drugs [barbiturates, b-blockers, Tranquillizer, Antihypertensive, Histamine antagonist, Antidepressant, anti emetic, and anticonvulsant] or endogenous constituents were observed

Simultaneous high performance liquid chromatography determination of three sulfonylureas in plasma

A high-performance liquid chromatographic [HPLC] method has been developed for the simultaneous analysis of three frequently used sulfonylureas [chlorpropamide, glipizide and glibenclamide] by using a reversed phase C-8 column with a mobile phase consisting of 0.1% Ortho-phosphoric acid pH 2.7: isopropanol: acetonitrile, [45:25:30] operated at ambient temperature, with analysis time less than ten minutes. The eluted drugs were monitored by UV at 235nm. The extraction was performed by using dichloromethane after the plasma sample was mixed with the buffer [0.1% orthophosphoric acid].The overall recoveries and relative standard deviations were [93.7 +/- 5.3]% for chlorpropamide, [91.5 +/- 4.9]% for glipizide and [95 +/- 2.8]% for glibenclamide. The response was linear in the range [0.1 -100mg/ml] for chlorpropamide, glipizide, and glibenclamide, with r > 0.999 for all drugs. Detection limits were 2ng/ml plasma for chlorpropamide, 15ng/ml plasma for glipizide and 7ng/ml plasma for glibenclamide, measured at a Signal/ Noise [S/N] of 3. No interference from administered drugs [barbiturates, b-blockers, Tranquillizer, Antihypertensive, Histamine antagonist, Antidepressant, anti emetic, and anticonvulsant] or endogenous constituents were observed

Experiencia clínica con un inhibidor de la alfa glucosidasa (acarbosa) en el tratamiento de la diabetes no insulinodependiente: estudio multicéntrico / Multicentric study on the effect of an alpha glucosidase inhibitor in the treatment of non insulin dependent diabetes

Diabetic patients received acarbose, 150 mg/day durign four weeks and this dose was increased to 300 mg/day durign 3 months. Afterwards, patients were followed for a period of 12 weeks without acarbose. Fasting and post-prandial blood glucose and glycosilated hemoglobin were measured sequentially durign the study. Results: Eighty five patients were recruited for the study but 64 complied with the treatment protocol. The age of these patients was 56 ñ 8.8 years old, their diabetes duration was 7.8 ñ 8.8 years and their body mass index was 27.6 ñ 3.6 kg/m². During acarbose treatment, glycosilated hemoglobin decreased from 8.36 ñ 1.33 to 7.71 + 1.7 percent (p < 0.001), fasting blood glucose decreased from 173 ñ 48 to 159 ñ 59 mg/dl (p < 0.03) and post-prandial blood glucose decreased from 254 ñ 80 to 241 ñ mg/dl (NS). After discontinuing acarbose glycosilated hemoglobin and blood glucose levels returned to basal levels. Body weight and blood pressure did not change during the treatment period. Fifty nine patients bad gastrointestinal symptoms (meteorism, flatulence and abdominal distention) that were mild in 59 percent and moderate in 39 percent. Episodes of hypoglycemia were not observed. Conclusions: Acarbose, associated to sylphonylureas is an effective drug to reduce blood glucose and glycosilated hemoglobin levels in patients with non insulin dependent diabetes

Rol de magnesio en la eficacia de fármacos hipoglicemiantes / Role of magnesium in the efficacy of hypoglycemic agents

El objetivo de este trabajo fue el de demostrar que la deficiencia de magnesio inhibe el uso de glucosa, estimulada por la insulina, basal y exógena, e hipoglicemiantes orales. Se utilizaron 21 ratas albinas (250-300 g) a las cuales se les extrajo el músculo sóleo, para incubación en medio Ringer-Krebs, con presencia o ausencia de magnesio y con una cantidad conocida de glucosa (6 x 10 a la menos 3 mol?L). El dosaje de las muestras obtenidas de los medios se realizó antes y después de la incubación, con una prueba de glucosa enzimática, realizándose las lecturas en espectrofotómetro. El estudio se dividió en tres etapas: en la primera, se vió la interacción con calcio y magnesio; en la segunda, la interacción con insulina a una concentración de 1mU/L; y en la tercera, la interacción con hipoglicemiantes orales: clorpropamida y glibenclamida. Observamos mayor utilización de glucosa por parte del músculo en los medios que contenían tanto calcio como magnesio, que en los que no tenían magnesio pero sí calcio, esto se vió tanto con la insulina basal como exógena. En la interacción con sulfonilúreas existió una disminución del uso de glucosa en el medio sin magnesio; siendo mayor ésta conla sulfonlúrea de primera generación que con la de segunda generación. Estos resultados nos sugieren que los niveles de utilización tisular de glucosa basal y estimulada por la hipoglicemiantes son dependientes de la concentración de magnesio, encontrándose disminuida en situaciones de hipomagnesemia.

Effect of Ocimum sanctum and chlorpropamide on pancreatic islets of diabetic rats

Ocimum sanctum is well known medicinal herb, highly available around the Indo-Pak Subcontinent and widely been used in many aliments. Its antimicrobial, antitusstive, hypolycaemic and hypochoglestrolaemic properties are familiar. In this study its hypoglycaemic property has been further explored and effect on pancreas was examined histologically. A total of 47 diabetic rats were treated in different groups with Ocimum sanctum, chlorpropamide and in combination for 15 days. Then the weight of the pancreas was measured and found significant increase in chlorpropamide treated group and in combined group. Beta cells increased significantly in Ocimum sanctum treated group and in combined treated group. Alpha cells reduced significantly [p <0.05] in combined group only. This experiment suggests the proliferation of B cells per islet

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.

Effect of bed time intermediate acting insulin in NIDDM subjects refractory to a combination of sulphonylureas and biguanides.

The effect of a single dose of intermediate acting (Lente) insulin given subcutaneously at 9.00 P.M. in 22 NIDDM subjects refractory to a combination of Sulphonylureas and Biguanides was analysed. Euglycemia was achieved and maintained during the study period of three months with a mean insulin requirement of 14.22 +/- 5.98 units/day. Plasma FFA, Total cholesterol, triglyceride and VLDL-cholesterol also showed significant reduction. The level of FFA modulates hepatic glucose production, which in turn correlates positively with the fasting blood glucose. The therapeutic modality of bed time Lente Insulin based on physiological principles is an effective way of achieving glycemic control in NIDDM subjects who have become non-responsive to oral hypoglycemic agents.