Inhibition of primary and secondary nucleation alongwith disruption of amyloid fibrils and alleviation of associated cytotoxicity: A biophysical insight of a novel property of Chlorpropamide (an anti-diabetic drug).

Aggregation of physiologically synthesized soluble proteins to insoluble, cytotoxic fibrils is a pre-requisite for pathogenesis of amyloid associated disorders including Alzheimer's disease, non-systemic amyloidosis, Parkinson's disease, etc. Considerable advancement has been made to understand the mechanism behind aggregation process but till date we have no efficient cure and preventive therapy for associated diseases. Strategies to prevent protein aggregation are nevertheless many which have been proved promisingly successful in vitro. One of those is repurposing already approved drugs that saves time and money too and has been employed in this study. Here, for the first time we are reporting the effectiveness of an anti-diabetic drug chlorpropamide (CHL) under dosage conditions, a novel property to inhibit aggregation in human lysozyme (HL) in vitro. Spectroscopic (Turbidity, RLS, ThT, DLS, ANS) and microscopic (CLSM) results demonstrates that CHL has the potency to suppress aggregation in HL up to 70 %. CHL is shown to affect the elongation of fibrils with IC50 value of 88.5 µM as clear from the kinetics results, may be by interacting near/with aggregation prone regions of HL. Hemolytic assay also revealed the reduced cytotoxicity in the presence of CHL. Disruption of amyloid fibrils and inhibition of secondary nucleation in the presence of CHL was also evidenced by ThT, CD and CLSM results with reduced cytotoxicity as confirmed by hemolytic assay. We also performed preliminary studies on α-synuclein fibrillation inhibition and surprisingly found that CHL is not just inhibiting the fibrillation but also stabilizing the protein in its native state. These findings insinuate that CHL (anti-diabetic) possess multiple roles and can be a promising drug for developing therapeutic against non-systemic amyloidosis, Parkinson's disease and other amyloid associated disorders.

La mortalidad entre las sulfonilureas / Mortality among the sulphonylureas

Fundamento: Las sulfonilureas (SU) son una opción terapéutica en segunda intención (cuando la metformina [MET] no se puede utilizar), o en el segundo nivel, en asociación con MET. Sin embargo, estos antidiabéticos orales (ADO) están asociados con un alto riesgo de eventos cardiovasculares (ECV) en comparación con otros ADO. La sensibilidad tisular y el riesgo de hipoglucemia son distintos según la SU, por ello esta revisión en forma de metaanálisis intenta evaluar si la mortalidad y el riesgo cardiovascular son diferentes según la molécula. Métodos: Para ello se buscó en Medline y en Embase, hasta el 11 de junio de 2014, estudios controlados que evaluaran el riesgo de muerte por cualquier causa (MCC), de muerte cardiovascular (MCV), o por infarto agudo de miocardio (IAM) entre al menos 2 SU. Se examinaron las diferencias entre el riesgo de ECV y SU utilizando modelos de efectos aleatorios con comparación directa por pares en una red de metaanálisis que incorporara datos directos e indirectos. Resultados: En 18 estudios evaluados, con un total de 167.327 pacientes, 14.970 murieron (9%); 841 (4%) de 19.334 que utilizaban gliclazida, 5.482 (11%) de 49.389 con glimepirida, 2.106 (15%) de 14.464 con glipizida; 5.296 (7%) de 77.169 con glibenclamida; 1.066 (17%) de 6.187 con tolbutamida y, por último, 179 (23%) de 784 con clorpropamida. Hubo una baja inconsistencia en la red de metaanálisis referente a la MCC y al riesgo relativo (RR) de muerte en relación con glibenclamida, que fue de 0,65 (IC 95% 0,53-0,79) para gliclazida, de 0,83 (IC 95% 0,68-1,00) para glimepirida, de 0,98 (IC 95% 0,80-1,19) para glipizida, de 1,13 (IC 95% 0,90-1·,42) para tolbutamida, y de 1,34 (IC 95% 0,98-1,86) para clorpropamida. Parecidas asociaciones se dieron en la MCV, de tal manera que el RR en comparación con glibenclamida fue de 0,60 (IC 95% 0,45-0,84) para gliclazida; de 0,79 (IC 95% 0,57-1,11) para glimepirida, de 1,01 (IC 95% 0,72-1,43) para glipizida, de 1,11 (IC 95%0,79-1,55) para tolbutamida, y de 1,45 (IC 95% 0,88-2,44) para clorpropamida. Conclusión: Concluyen que gliclazida y glimepirida se asociaron con un menor riesgo de MCC y MCV en comparación con glibenclamida. Con ello, se aconseja que los médicos consideren las diferencias en el riesgo de mortalidad entre las SU para seleccionar cuál deben prescribir (AU)

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Cotargeting MAPK and PI3K signaling with concurrent radiotherapy as a strategy for the treatment of pancreatic cancer.

There is an urgent need for the development of novel therapies to treat pancreatic cancer, which is among the most lethal of all cancers. KRAS-activating mutations, which are found in more than 90% of pancreatic adenocarcinomas, drive tumor dependency on the Ras/MAPK and Akt signaling pathways. Radiation is currently being explored as a component of the standard treatment regimen for pancreatic cancer. This study's purpose was to test the hypothesis that MAP kinase kinase (MEK or MAP2K) inhibitors will offer clear therapeutic benefit when integrated into radiotherapy treatment regimens for treatment of this disease. We explored the activation of the mitogen-activated protein kinase (MAPK) and Akt pathways in response to radiation in multiple pancreatic tumor cell lines. Small molecule inhibitors of MEK (PD0325901) and Akt (API-2) were subsequently evaluated for their radiosensitizing potential alone and in combination. In vivo efficacy was tested in subcutaneous MIA-PaCa2 xenografts. Phosphorylated levels of extracellular signal-regulated kinase (ERK)-1/2 and Akt were found to increase in response to radiation treatment in our pancreatic tumor cell line panel. MEK inhibitor-induced radiosensitization was observed in vitro and in vivo. The further addition of an Akt inhibitor to the MEK inhibitor/radiation regimen resulted in enhanced therapeutic gain as determined by increased radiosensitization and tumor cell death. In conclusion, MEK inhibition results in growth arrest, apoptosis, and radiosensitization of multiple preclinical pancreatic tumor models, and the effects can be enhanced by combination with an Akt inhibitor. These results provide rationale for further testing of a treatment regimen in pancreatic cancer that combines MEK inhibition with radiation, optimally in conjunction with Akt inhibition.

Ameliorative effects of Cnidoscolus aconitifolius on alloxan toxicity in Wistar rats.

BACKGROUND: Diabetes has been associated with several complications occasioned by oxidative stress. Thus, in treatment of the condition, these complications must also be taken into consideration. This study evaluates the effect of Cnidoscolus aconitifolius complications of diabetes induced by alloxan, on haematology and sperm morphometry using the Wistar rats. METHODS: Diabetes was induced in 25 rats using alloxan. The diabetic rats were then divided into five groups B-F consisting of five rats per group. Groups C-E were administered with 100 mg/kg, 500 mg/kg and 1000 mg/kg of ethanolic leaves extract of Cnidoscolus aconitifolius, respectively, for four weeks post treatment with alloxan, while group F received Chlorpropamide (Diabenes®, Pfizer). The diabetic rats in group B were not treated while group A served as the non diabetic control. RESULT: Following treatment with alloxan, there was anaemia, thrombocytopenia and leucopenia, while the sperm count, motility and live/dead ratio were significantly reduced. Sperm morphological abnormalities and erythrocyte osmotic fragility also increased significantly. Following treatment of alloxan treated-rats with the extract, there were significant increases in the PCV, RBC, Hb, WBC, MCV and the platelet values. Erythrocyte osmotic fragility, sperm count, motility and live/dead ratio also improved significantly. CONCLUSION: Cnidoscolus aconitifolius extract was found to ameliorate the effects of alloxan induced diabetes on the haematology but not on the abnormal sperm morphometry in rats.

Antidiabetic properties of ethanolic extract of Cnidoscolus aconitifolius on alloxan induced diabetes mellitus in rats.

This research was designed to investigate the antidiabetic properties of ethanolic extract of Cnidoscolus aconitifolius in alloxan-induced diabetes mellitus in Wistar male albino rats. Thirty male albino rats were used. Diabetes mellitus was induced in five of the six groups (B-F) by a single intra-peritoneal injection at the dose of 100mg/kg after normal fasting blood glucose had been determined. Group A served as the positive control while groups C-E received 100mg/kg, 500mg/kg and 1000mg/kg of Cnidoscolus aconitifolius extract respectively. Group B did not received any treatment while group F received chlorpropamide, a standard drug used in the treatment of diabetes mellitus. Blood glucose and body weights were monitored weekly for four weeks. Plasma lipids and electrolytes such as Total cholesterol, Triglyceride, Low Density Lipoproteins (LDL), High Density Lipoproteins (HDL), Creatinine and Blood Urea Nitrogen (BUN) were determined after four weeks of treatment with Cnidoscolus aconitifolius extract. The results show significant reduction (P<0.001) in the blood glucose in group C (100mg/kg of Cnidoscolus aconitifolius) when compared with diabetic control (Alloxan only) and other treatment groups. There was gradual increase in weight of all treatment groups compared with the diabetic control, which had progressive weight loss. Plasma cholesterol levels also significantly reduced (P<0.001) in rats treated with 1,000mg/kg Cnidoscolus aconitifolius extract. From this study, Cnidoscolus aconitifolius extract was found to considerably reduce blood glucose and plasma cholesterol levels and progressively increase weight gain in diabetic treated rats confirming its traditional use for the treatment of diabetes.

Chlorpropamide treatment restores the reduced carrageenan-induced paw edema and pleural exudate volume in diabetic rats.

OBJECTIVE AND DESIGN: Knowing that hyperglycemia is a hallmark of vascular dysfunction in diabetes and that neonatal streptozotocin-induced diabetic rats (n-STZ) present reduced inflammatory response, we decided to evaluate the effect of chlorpropamide-lowered blood glucose levels on carrageenan-induced rat paw edema and pleural exudate in n-STZ. MATERIALS: Diabetes was induced by STZ injection (160 mg/kg, ip) in neonates (2-day-old) Wistar rats. TREATMENT: n-STZ diabetic rats were treated with chlorpropamide (200mg/kg, 15d, by gavage) 8 weeks after STZ injection. METHODS: Carrageenan-induced paw edema and pleural exudate volumes were assessed concomitantly with peripheral and exudate leukocyte count. We also evaluated the expression of inducible nitric oxide synthase (iNOS) in lungs of all experimental groups. RESULTS: Chlorpropamide treatment improved glucose tolerance, beta-cell function (assessed by HOMA-beta), corrected paw edema, and pleural exudate volume in n-STZ. Neither leukocyte count nor iNOS expression were affected by diabetes or by chlorpropamide treatment. CONCLUSION: Chlorpropamide treatment by restoring beta-cell function, reducing blood sugar levels, and improving glucose tolerance might be contributing to the correction of the reduced inflammatory response tested as paw edema and pleural exudate in n-STZ diabetic rats.

Effect of Nigerian meals on the pharmacokinetics of chlorpropamide in type II diabetic patients.

Food-drug interactions are best evaluated on an individual drug basis, in a group of subjects in a population at risk. This is due to their complex nature, which is a function of type and size of meal, the physical and chemical form of the drug and the time lapse between food intake and drug administration. This work was aimed at investigating the effect of three different Nigerian meals, which are regularly consumed by the three major tribes in Nigeria, on the pharmacokinetics of chlorpropamide, a drug commonly used to treat Type II diabetes in this country. Meal A (maize flour meal) was composed of 81% carbohydrate, 3% protein and 11% fat; meal B (cassava flour meal) was composed of 76% carbohydrate, 3% protein and 15% fat; while meal C (browned yam flour meal) was composed of 85% carbohydrate, 2% protein and 8% fat. The effects of the three meals were investigated by administering each of the meals alone, without the medicinal drug (Treatment I); in Treatment II each meal was administered 30 min following the administration of 250 mg chlorpropamide; in Treatment III the drug was administered together with each of the standard meals. Analysis of the plasma levels of chlorpropamide was performed by high performance liquid chromatography (HPLC). Ingestion of the meal alone (Treatment I) resulted in a significant difference in postprandial plasma glucose levels. The time to maximum plasma chlorpropamide concentration was significantly increased in Treatment III (P < 0.05), while all pharmacokinetic parameters and plasma glucose levels were not significantly altered in Treatment II. Analysis of the results demonstrated a better glycaemic response with meals A and C compared with meal B.

The effect of deinsuring chlorpropamide on the prescribing of oral antihyperglycemics for Nova Scotia Seniors' Pharmacare beneficiaries.

On behalf of the Nova Scotia Seniors' Pharmacare Program, the Drug Evaluation Alliance of Nova Scotia developed a multicomponent intervention plan to facilitate the removal of chlorpropamide as an insured benefit. Chlorpropamide has caused serious hypoglycemia in seniors to a greater extent than some other agents. Pharmacy administrative claims were used to compute monthly use rates for insulin and each oral antihyperglycemic drug from January 1, 2000-December 30, 2002, in an intervention cohort (patients receiving chlorpropamide) and a control cohort (patients receiving an antihyperglycemic agent other than chlorpropamide). Initially, 630 patients were receiving chlorpropamide therapy. By the time chlorpropamide was deinsured, only 10% of the treatment cohort continued receiving chlorpropamide; shortly after deinsurance, no beneficiaries continued receiving the drug. The antihyperglycemics with the greatest increase in prescription were glyburide and gliclazide. The deinsuring of chlorpropamide and the educational strategies that accompanied it resulted in the selection of more appropriate antihyperglycemics for Nova Scotia seniors.

The advantages and disadvantages of a 'herbal' medicine in a patient with diabetes mellitus: a case report.

BACKGROUND: Patient-initiated alternative treatments in the management of chronic conditions are common and increasing in the United Kingdom. To date, there have been no reports of herbal medicine use alone in the management of diabetes mellitus. We report here the case of a man who attained excellent glycaemic control using a 'herbal' medicine and reveal how important it was to identify the products of active constituents. CASE REPORT: A 48-year-old man attending our clinic in Tooting, South London with known Type 2 diabetes, with evidence of both micro- and macro-vascular diabetes-related complications, was poorly controlled despite a drug regimen consisting of oral metformin and twice daily insulin. He went to India for at least 1 year and on returning to the clinic had excellent glycaemic control off all diabetic medication. While away he had started himself on a regimen of three different 'herbal' balls. Samples of blood were found to contain chlorpropamide in a therapeutic concentration; chlorpropamide was also found in one of the balls. He has been counselled on the potential risks associated with chlorpropamide and his treatment reverted to a more conventional treatment regimen. CONCLUSIONS: General practitioners and hospital physicians should be alert to those patients returning from abroad on effective 'herbal' medications that these may in fact contain an active ingredient.

Hypoglycemic effect of Sclerocarya birrea [(A. Rich.) Hochst.] [Anacardiaceae] stem-bark aqueous extract in rats.

This study was undertaken to evaluate the hypoglycemic effect of Sclerocarya birrea [(A. Rich.) Hochst.] subspecies caffra (Sond.) Kokwaro [family: Anacardiaceae] stem-bark aqueous extract in normal (normoglycemic) and in streptozotocin (STZ)-treated, diabetic Wistar rats. In one set of experiments, graded doses of S. birrea stem-bark aqueous extract (SB, 100-800 mg/kg p.o.) were separately administered to groups of fasted normal and fasted diabetic rats. In another set of experiments, a single dose of the plant aqueous extract (SB, 800 mg/kg p.o.) was used. The hypoglycemic effect of this single dose (SB, 800 mg/kg p.o.) of S. birrea stem-bark aqueous extract was compared with that of chlorpropamide (250 mg/kg p.o.) in both fasted normal and fasted diabetic rats. Following acute treatment, relatively moderate to high doses of S. birrea stem-bark extract (SB, 100-800 mg/kg p.o.) produced dose-dependent, significant reductions (P < 0.05-0.001) in the blood glucose concentrations of both fasted normal and fasted diabetic rats. Chlorpropamide (250 mg/kg p.o.) also produced significant reductions (P < 0.05-0.001) in the blood glucose concentrations of the fasted normal and fasted diabetic rats. Administrations of the single dose of S. birrea stem-bark aqueous extract (SB, 800 mg/kg p.o.) significantly reduced (P 0.01 < 0.001) the blood glucose levels of both fasted normal (normoglycemic) and fasted STZ-treated, diabetic rats. The results of this experimental animal study indicate that aqueous extract of Sclerocarya birrea possesses hypoglycemic activity, and thus lend credence to the suggested folkloric use of the plant in the management and/or control of adult-onset, type-2 diabetes mellitus in some African communities.

Coefficient of failure: a methodology for examining longitudinal beta-cell function in Type 2 diabetes.

AIMS: We describe a new method, the determination of the coefficient of failure, which allows the assessment of beta-cell failure from any index of glycaemia. Previous methods using glycaemic thresholds and calculating time-to-failure have systematic deficiencies relating to bias, reproducibility and statistical power. Analyses using threshold methodologies and conventional survival analysis have an intrinsic disadvantage in that they use categorical data and thus make no allowance for near-failure, or progression towards failure. In contrast, the coefficient of failure includes all data in the analysis and takes into account improvement of glycaemia as well as deterioration of glycaemia. METHODS: We describe the use of a 'coefficient of failure' defined as the slope of the least-squares regression line of a glycaemic index vs. time calculated for each individual patient on constant monotherapy. We exemplify the method using HbA1c levels from data from patients on chlorpropamide (n = 64) or glibenclamide (n = 65) monotherapy in the Oxford cohort of the UKPDS. RESULTS: Chlorpropamide-treated patients showed a mean coefficient of failure of 0.34 HbA(1c)%/year (0.44%/year sd) and glibenclamide-treated patients 0.50 HbA(1c)%/year (0.50%/year sd) (P = 0.046; unpaired two-tailed t-test). Kolmogorov-Smirnov testing demonstrated that the coefficients did not differ significantly from a normal distribution (chlorpropamide P = 0.12; glibenclamide P = 0.13). CONCLUSIONS: The coefficient of failure gives an estimate of beta-cell failure using any index of glycaemia. The coefficient is not constrained by predetermined glycaemic thresholds for failure and it allows the rate of decline in beta-cell function to be determined on any therapy or combination of therapies.

Differences in pharmacotherapy and in glucose control of type 2 diabetes patients in two neighbouring towns: a longitudinal population-based study.

AIM: To compare prescribing, dosage and blood glucose levels in patients with type 2 diabetes in two communities with differences in anti-hyperglycaemic drug utilization. METHODS: A retrospective longitudinal (1984-1994) population-based study in two neighbour towns in southern Sweden. The mean prescribed daily dose was expressed as a fraction of the Defined Daily Dose (DDD) for each drug. RESULTS: In town A, prescribing of oral agents and insulin was predominantly made by one specialized diabetes clinician, while in town B it was spread among several different general practitioners and one specialist. Altogether 44 636 medical visits by 2348 patients were identified. In each town, about 40% of the patients were treated without anti-hyperglycaemic drugs, about 40% with oral agents and about 20% with insulin. However, there were pronounced between-town differences in dosage and glucose control. The mean prescribed daily dose of sulphonylurea monotherapy decreased gradually from approximately 0.7 to approximately 0.5 DDD in town B but remained approximately 0.8 DDD in town A. The proportion of patients on both sulphonylurea and metformin increased substantially in town A but not in town B. In these patients, the mean prescribed daily dose of sulphonylurea exceeded 1.0 DDD in both towns, although it decreased with time in town B. The mean prescribed daily dose of insulin increased from 1.05 to 1.2 DDD in town A but remained virtually unchanged at 0.95 DDD in town B. The mean fasting blood glucose was lower in town A than in town B both overall (7.7 vs. 8.8 mmol/l), in those treated without any anti-hyperglycaemic drugs (7.2 vs. 8.1 mmol/l), in those on sulphonylurea monotherapy (8.3 vs. 9.7 mmol/l) and in those treated with insulin (8.1 vs. 10.2 mmol/l). CONCLUSIONS: Glucose control in routine care was better when most patients were treated by a diabetes specialist and were exposed to more intense pharmacotherapy.

The effect of oral hypoglycaemic agents on dyslipidaemia in Nigerian patients with newly diagnosed non-insulin dependent diabetes mellitus--a prospective study.

Thirty-five patients with non-insulin dependent diabetes (NIDDM) were treated and followed up for 24 weeks. Six of whom were managed with diet and/or metformin, nine received glibenclamide, twelve had a combination of metformin and glibenclamide, while the remaining eight patients received metformin and/or some other type of sulphonylurea (chlorpropamide or glipizide). By an analysis of variance, the different drug regimes showed equivalent glycaemic controlling effects, but the influence on dyslipidaemia was variable within the treatment groups, while these changes were insignificant between the groups. It is thus concluded that commonly used oral hypoglycaemic agents do not adversely affect plasma lipid levels in Nigerian patients with NIDDM.

Sensitivity to sulphonylureas in patients with hepatocyte nuclear factor-1alpha gene mutations: evidence for pharmacogenetics in diabetes.

INTRODUCTION: Maturity-onset diabetes of the young (MODY) is characterized by autosomal dominantly inherited, early-onset, non-insulin-dependent diabetes. Mutations in the hepatocyte nuclear factor (HNF)-1alpha gene are the commonest cause of MODY. Individual patients with HNF-1alpha mutations have been reported as being unusually sensitive to the hypoglycaemic effects of sulphonylurea therapy. We report three patients, attending a single clinic, with HNF-1alpha mutations that show marked hypersensitivity to sulphonylureas. CASE REPORTS: In cases 1 and 2 there were marked changes in HbA1c on cessation (4.4% and 5.8%, respectively) and reintroduction (5.0% and 2.6%) of sulphonylureas. Case 3 had severe hypoglycaemic symptoms on the introduction of sulphonylureas despite poor glycaemic control and was shown with a test dose of 2.5 mg glibenclamide to have symptomatic hypoglycaemia (blood glucose 2 mmol/l) after 4 h despite eating. CONCLUSIONS: HNF-1alpha MODY diabetic subjects are more sensitive to sulphonylureas than Type 2 diabetic subjects and this is seen in different families, with different mutations and may continue up to 13 years from diagnosis. This is an example of pharmacogenetics, with the underlying aetiological genetic defect altering the pharmacological response to treatment. The present cases suggest that in HNF-1alpha MODY patients: (i) sulphonylureas can dramatically improve glycaemic control and should be considered as initial treatment for patients with poor glycaemic control on an appropriate diet; (ii) hypoglycaemia may complicate the introduction of sulphonylureas and therefore very low doses of short acting sulphonylureas should be used initially; and (iii) cessation of sulphonylureas should be undertaken cautiously as there may be marked deterioration in glycaemic control.

Efficacy of indapamide in central diabetes insipidus.

BACKGROUND: Central diabetes insipidus (CDI) results from deficient vasopressin (antidiuretic hormone) secretion and causes polydipsia and polyuria. Desmopressin, a synthetic analog of vasopressin, is the drug of choice in the treatment of CDI, but in mild cases, there are alternative drugs that can be used, including chlorpropamide, carbamazepine, and thiazides. METHODS: In this study, we investigated the efficacy of treatment with indapamide, which is an antihypertensive diuretic oral agent, in 20 consecutive patients with CDI. The diagnosis of CDI was established by water-deprivation and vasopressin tests. Before the study, serum and urinary osmolality, daily urinary volume, and serum electrolyte levels were measured in all 20 patients. Indapamide (2.5 mg/d) was administered for 10 days, and then the investigations were performed again; for purposes of comparison, 250 mg/d of chlorpropamide was also administered to 11 of the 20 patients who had been given indapamide. RESULTS: Indapamide revealed a 40.56% +/- 9.70% (mean +/- SD) (range, 19.6%-55.0%) reduction in 24-hour urinary volume and an increase in urinary osmolality, as well as a decrease in serum osmolality, and was as effective as chlorpropamide (P<.05) in the treatment of CDI. CONCLUSION: Because of its low cost and lack of significant adverse effects, indapamide may be a suitable, easy-to-use alternative oral agent for some patients with CDI.

United Kingdom prospective diabetes study (UKPDS): what now or so what?

The UKPDS was a 20-year study involving 23 centres in the United Kingdom. More than 5000 patients with Type 2 diabetes were recruited. The aim of the study was to determine the impact of intensive blood glucose control on 21 predetermined clinical endpoints using, in the care of blood glucose control, sulphonylureas or insulin therapy or, in the overweight patient, treatment with metformin. In addition, the study investigated the impact of intensive blood pressure control on macro- and microvascular complications of diabetes and compared captopril treatment with atenolol. UKPDS found that improved control of blood glucose or blood pressure reduced the risk of major diabetic eye disease by one quarter, serious deterioration of vision by nearly one half, early kidney damage by one third, strokes by one third, and death from diabetes-related causes by one third. Blood glucose control had little or no effect on macrovascular events. There was no evidence of a major detrimental effect of the drugs or insulin on survival or outcome other than the expected risk of hypoglycaemia. Metformin appeared to be the drug of choice in obese diabetic patients. The targets of glucose and blood pressure control were often achieved by using several drugs. Many patients at the end of the studies were on four or five drugs for blood glucose and blood pressure treatment. The results and implications of the study are discussed. It is proposed that the results of UKPDS herald a new era of more focused therapy of Type 2 diabetes.

The antihyperglycamic effect of Telfaria occidentalis in mice.

The hypoglycemic effect of Telfaria occidentalis was studied in mice. The effect of the aqueous extract of the leaves on blood glucose level were assessed in normoglycaemic, glucose induced hyperglycaemic and streptozotocin (STZ) induced diabetic mice. The aqueous extract given orally in 1 g/kg did not alter the blood glucose level in normoglycaemic mice. In glucose-induced hyperglycemia, antidiabetic activity was seen when the extract and glucose were administered simultaneously and when the extract was giving to the mice 60 minutes before glucose. In STZ-induced diabetic mice, a reduction in the blood glucose level was seen from day two of the administration of the extract. The hypoglycemic effect of the aqueous extract was compared with that of an oral dose of chlorpropamide (200 mg/kg) under the same conditions. The results of this study indicate that the aqueous extract of the leaves of Telfaria occidentalis possess hypoglycaemic activity.

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.

BACKGROUND: Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial. METHODS: 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group, the aim was the best achievable FPG with diet alone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy. FINDINGS: Over 10 years, haemoglobin A1c (HbA1c) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group--an 11% reduction. There was no difference in HbA1c among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg). INTERPRETATION: Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes.(ABSTRACT TRUNCATED)