Pharmacokinetics and Safety of Olmesartan Medoxomil in Combination with Glibenclamide in Healthy Volunteers

Objective. To investigate the pharmacokinetic interactions, safety, and tolerability of the combination of olmesartan medoxomil with glibenclamide. Methods. In an open, three-way crossover, phase I trial, 18 healthy adults entered three randomly ordered, seven-day treatment periods. The three treatments comprised once daily administration of () olmesartan 20 mg, () olmesartan 20 mg plus glibenclamide 3.5 mg, or () glibenclamide 3.5 mg. Results. The combination of olmesartan with glibenclamide did not influence the bioequivalence of the area under the plasma-concentration time curve at steady state during one dosing interval 0 to τ = 24 hours (AUC_ss,τ) or the maximum steady-state concentration (C_ss,max) of both substances. Mean AUC_ss,τ values for olmesartan were 2594.8 ng h/ml for olmesartan alone and 2443.7 ng h/ml in combination with glibenclamide; the corresponding C_ss,max values were 479.3 ng/ml and 462.7 ng/ml, respectively. For glibenclamide, the mean AUC_ss,τ values were 525.7 ng·h/ml for monotherapy and 518.7 ng·h/ml for its combination with olmesartan. The median time to reach C_ss,max (t_max) for glibenclamide was shifted from 2.0 h to 1.0 h when combined with olmesartan, whereas the median t_max values for olmesartan remained unchanged at 1.5 h. During combined treatment with olmesartan plus glibenclamide, no adverse event occurred, and the medications were well tolerated. Conclusion. With the exception of a slight shift of t_max values for glibenclamide, the concomitant administration of olmesartan medoxomil with glibenclamide had no significant effects on the steady-state pharmacokinetics of either agent. This provides the pharmacokinetic rationale for clinical studies to test the combination therapy of patients with hypertension and type-2 diabetes mellitus with both compounds.     

Pemphigus vulgaris precipitated by glibenclamide therapy

Pemphigus vulgaris (PV) is a rare but potentially fatal autoimmune bullous disorder which frequently affects the oral mucosa. Although the essential cause of PV is unclear, its onset has occasionally been associated with drug therapy, in particular penicillamine. The patient described in this paper was a 78-year-old diabetic man who developed oral lesions of PV following institution of glibenclamide therapy.     

A prospective study of the effect of 12 months treatment on serum lipids and apolipoproteins A-I and B in type 2 (non-insulin-dependent) diabetes

Summary Serum high density lipoprotein cholesterol, total cholesterol, triglyceride and apolipoproteins A-I and B were studied at diagnosis and after 12 months conventional treatment in a group of Type 2 (non-insulin-dependent) diabetic patients. No significant deleterious effect on serum lipids and apolipoproteins was seen in any of the subgroups during the treatment period, although in the overall group there was a significant increase in serum total cholesterol in females. Serum high density lipoprotein cholesterol increased significantly in obese males treated with calorie restriction alone. There was a significant increase in serum apolipoprotein A-I in obese females treated with calorie restriction and metformin and in non-obese females treated with carbohydrate restriction and glibenclamide.     

On the Mechanism of Inhibition of KATP Channels by Glibenclamide in Rat Ventricular Myocytes

Glibenclamide Block of K_ATP Channels. Introduction: The mechanism by which glibenclamide inhibits K_ATP channel activity has been examined in membrane patches from isolated rat ventricular cells. Methods and Results: Inside-out patches were exposed to zero, or low, [ATP] to activate K_ATP channels. Glibenclamide did not affect single channel conductance, but reversibly reduced channel open probability from either side of the membrane. Internal (cytoplasmic) glibenclamide inhibited with half-maximal inhibitory [glibenclamide] = 6 μM, Hill coefficient = 0.35. Complete channel inhibition was not observed, even at 300 μM [glibenclamide]. The response to step increases of internal [glibenclamide] could be resolved into two phases of channel inhibition (t_{1/2, fast}, < 1 sec, t_{1/2, slow}= 10.5 ± 0.9 sec, n = 8). Step decrease of [glibenclamide] caused a single resolvable phase of reactivation (t_1/2= 20.4 ± 0.7 sec, n = 16). Channel inhibition by internal glibenclamide could be relieved by ADP, but only in the presence of Mg²⁺.
Conclusion: Glibenclamide can inhibit K_ATP channels from either side of the membrane, with block from one side being competitive with block from the other. Internal MgADP antagonizes the blocking action of glibenclamide. Glibenclamide inhibition of cardiac K_ATP channels differs quantitatively and qualitatively from the inhibition of pancreatic K_ATP channels.     

Transient Effect of the Combination of Insulin and Sulfonylurea (Glibenclamide) on Glycemic Control in Non-Insulin Dependent Diabetics Poorly Controlled with Insulin Alone

ABSTRACT In a double-blind cross-over study we compared the effects of insulin plus glibenclamide, 5 mg twice daily, with insulin plus placebo during 8-week periods on metabolic parameters in 13 non-insulin dependent diabetic (NIDDM) patients poorly controlled with insulin alone. The combination therapy improved diabetic control as assessed by fasting blood glucose (p<0.001), 24-hour urinary glucose (p<0.01) and glycohemoglobin (HbA₁) concentrations (p<0.05 at week 12). The effect tended to cease with time. Significantly higher C-peptide values were found during combination treatment than during insulin-placebo (p<0.01) and the changes in fasting C-peptide concentrations correlated positively with the changes in HbA₁ concentrations (r=0.56, p<0.05). There was no difference in glucagon concentrations, insulin binding to erythrocytes or insulin sensitivity between the two study periods. Neither did the combination therapy influence blood lipids significantly. The present study shows that the combination of insulin and glibenclamide may be of limited value in the treatment of NIDDM patients poorly controlled with insulin alone. However, thus far the long-term results are uncertain. In the absence of significant effects on insulin binding and insulin sensitivity, the improved diabetic control seems to be explained, at least partly, by glibenclamide-induced stimulation of insulin secretion.     

尼可地尔对大鼠心肌缺血再灌注损伤保护作用的实验研究

目的　确定尼可地尔 (nicorandil,NIC)对大鼠在体缺血再灌注 (IR)心肌是否具有保护作用。方法　建立在体大鼠心脏缺血再灌注模型。 64只大鼠随机分成 4组 :假手术组、IR组、NIC +IR组、GL+NIC +IR组。分别测定各组的心肌梗死范围、血清肌酸激酶 (CK)浓度和梗死部位心肌细胞ATP含量。结果　缺血后CK含量升高 ,局部ATP浓度下降 ;NIC可显著缩小心梗范围、降低CK浓度、减少梗死部位心肌细胞ATP的消耗 (P <0 .0 5 ) ;格列苯脲 (glibenclamide ,GL)可明显减弱NIC的上述作用 (P <0 .0 5 )。结论　NIC对在体缺血心肌有明显的保护作用 ,其机制可能与激活心肌细胞膜KATP通道有关。     

Improved effect of glibenclamide on administration before breakfast

Summary In an attempt to assess whether intake of glibenclamide before meals would improve its therapeutic capacity, the present investigation compared the effect of glibenclamide 2.5mg t.i.d. given before and together with meals. In addition, these effects were compared with that of glibenclamide given as a single morning dose of 7.5mg. The subjects studied were six Type 2 diabetics not previously exposed to sulphonylurea drugs. Irrespective of dosage and mode of administration, addition of glibenclamide to a standardized breakfast, lunch and dinner enhanced plasma IRI concentrations and reduced blood glucose concentrations as compared to administration of meals without the drug. The different modes of glibenclamide administration did not differ significantly with respect to IRI responses. However, the blood glucose reduction after breakfast was significantly greater when glibenclaimde 2.5mg had been given before the meal than when 2.5 or 7.5mg were given with the meal; a similar, but non-significant tendency was observed after lunch; no consistent difference was seen after dinner. Food intake did not affect glibenclamide kinetics. It appears that administration of glibenclamide 2.5mg before breakfast improved glucose utilization following the breakfast load, due to earlier attainment of an effective concentration of glibenclamide.     

Metformin-glibenclamide versus metformin plus rosiglitazone in patients with type 2 diabetes inadequately controlled on metformin monotherapy

AIM: This double-blind study evaluated the efficacy and safety of metformin-glibenclamide tablets vs. metformin plus rosiglitazone therapy in patients with type 2 diabetes inadequately controlled on metformin monotherapy. SUBJECTS AND METHODS: After an open-label, metformin lead-in phase, 318 patients were randomly assigned to treatment based on metformin-glibenclamide 500/2.5 mg tablets (initial daily dose 1000/5 mg) or metformin 500 mg plus rosiglitazone 4 mg (initial daily dose 1000-2000 mg + 4 mg, depending on previous treatment) for 24 weeks. Doses were titrated to achieve the therapeutic glycaemic target. The primary efficacy variable was the change in HbA1C. RESULTS: At week 24, metformin-glibenclamide tablets resulted in significantly greater reductions in HbA1C (-1.5%) and fasting plasma glucose [-2.6 mmol/l (-46 mg/dl)] than metformin plus rosiglitazone [-1.1%, p < 0.001; -2 mmol/l (-36 mg/dl), p = 0.03]. More patients receiving metformin-glibenclamide attained HbA1C <7.0% than did those in the metformin plus rosiglitazone group (60 vs. 47%) and had fasting plasma glucose levels <7 mmol/l (<126 mg/dl) by week 24 (34 vs. 25%). Both treatments were well tolerated. Frequency of adverse gastrointestinal events was comparable between groups. Four per cent of patients receiving metformin-glibenclamide withdrew because of symptomatic hypoglycaemia contrasted with 3% of patients receiving metformin plus rosiglitazone who withdrew because of persistent hyperglycaemia. Hypoglycaemic events were mild or moderate in intensity and were easily self-managed. CONCLUSIONS: Metformin-glibenclamide tablets resulted in significantly greater reductions in HbA1C and fasting plasma glucose compared with metformin plus rosiglitazone in patients with type 2 diabetes inadequately controlled on metformin monotherapy.     

Hyperlipidemic mice present enhanced catabolism and higher mitochondrial ATP-sensitive K+ channel activity

BACKGROUND & AIMS: Changes in mitochondrial energy metabolism promoted by uncoupling proteins (UCPs) are often found in metabolic disorders. We have recently shown that hypertriglyceridemic (HTG) mice present higher mitochondrial resting respiration unrelated to UCPs. Here, we disclose the underlying mechanism and consequences, in tissue and whole body metabolism, of this mitochondrial response to hyperlipidemia. METHODS: Oxidative metabolism and its response to mitochondrial adenosine triphosphate (ATP)-sensitive K+ channel (mitoK(ATP)) agonists and antagonists were measured in isolated mitochondria, livers, and mice. RESULTS: Mitochondria isolated from the livers of HTG mice presented enhanced respiratory rates compared with those from wild-type mice. Changes in oxygen consumption were sensitive to adenosine triphosphate (ATP), diazoxide, and 5-hydroxydecanoate, indicating they are attributable to mitochondrial ATP-sensitive K+ channel (mitoK(ATP)) activity. Indeed, mitochondria from HTG mice presented enhanced swelling in the presence of K+ ions, sensitive to mitoK(ATP) agonists and antagonists. Furthermore, mitochondrial binding to fluorescent glibenclamide indicates that HTG mice expressed higher quantities of mitoK(ATP). The higher content and activity of liver mitoK(ATP) resulted in a faster metabolic state, as evidenced by increased liver oxygen consumption and higher body CO(2) release and temperature in these mice. In agreement with higher metabolic rates, food ingestion was significantly larger in HTG mice, without enhanced weight gain. CONCLUSIONS: These results show that primary hyperlipidemia leads to an elevation in liver mitoK(ATP) activity, which may represent a regulated adaptation to oxidize excess fatty acids in HTG mice. Furthermore, our data indicate that mitoK(ATP), in addition to UCPs, may be involved in the control of energy metabolism and body weight.     

Beta-cell response to metformin-glibenclamide combination tablets (Glucovance) in patients with type 2 diabetes

This exploratory double-blind, randomised, 20-week study evaluated the mechanism of action of metformin-glibenclamide combination tablets (Glucovance) vs. metformin and glibenclamide in 50 type 2 diabetes patients inadequately controlled by diet and exercise. A glycaemic target of HbA1C 7.0% was used. Final HbA(1C), fasting glucose and post-oral glucose tolerance test (OGTT) glucose were similar between groups, although average doses of metformin and glibenclamide from combination tablets (708 and 3.5 mg) were lower than monotherapy doses (1500 and 6.6 mg). Second-phase insulin during a hyperglycaemic clamp increased by 93% with combination tablets, 36% with metformin and 46% with glibenclamide. The insulin response post-OGTT was more rapid with the combination tablets vs. glibenclamide. First-phase insulin responses improved modestly in all groups, possibly due to reduced glucotoxicity. Changes in insulin sensitivity were minor. Larger beta-cell responses between combination tablets and glibenclamide may reflect more rapid glibenclamide absorption.