复方盐酸二甲双胍片的人体相对生物利用度

目的研究国产复方盐酸二甲双胍片(含盐酸二甲双胍和格列本脲)与盐酸二甲双胍片和格列本脲片的人体相对生物利用度。方法采用随机交叉、自身对照试验设计,18名健康男性志愿者单剂量口服复方盐酸二甲双胍片(含盐酸二甲双胍500 mg,格列本脲2.5 mg)或同时口服盐酸二甲双胍片500 mg和格列本脲片2.5 mg,在不同时间点取静脉血,盐酸二甲双胍血药浓度采用HPLC-UV测定,格列本脲血药浓度采用HPLC-MS测定。以方差分析对主要药动学参数进行差别检验,以双单侧t检验进行生物等效性判定。结果单剂量口服复方盐酸二甲双胍片(含盐酸二甲双胍500 mg,格列本脲2.5 mg)或同时服用盐酸二甲双胍片500 mg和格列本脲片2.5 mg后,盐酸二甲双胍的药动学参数:AUC0~24分别为(6 252.9±2 628.3)、(6 270.6±2 202.6)ng.h.mL-1,AUC0~∞分别为(6 764.4±2 895.2)、(7 195.1±4 153.1)ng.h.mL-1,Cmax分别为(1 082.4±348.2)、(1 111.0±343.3)ng.mL-1,tmax分别为(1.5±0.5)、(1.7±0.6)h。试验制剂中盐酸二甲双胍的相对生物利用度为99.72%±13.59%。格列本脲的药物动力学参数AUC0~36分别为(533.5±247.0)、(495.7±223.3)ng.h.mL-1,AUC0~∞分别为(578.8±263.8)、(525.4±253.5)ng.h.mL-1,Cmax分别为(94.1±19.1)和(87.39±20.72)ng.mL-1,tmax分别为(1.8±0.4)和(1.9±0.4)h。与参比制剂相比,试验制剂中格列本脲的相对生物利用度为103.83%±12.94%。方差分析结果表明试验制剂与参比制剂的主要药物动力学参数之间无明显差异,双单侧t检验结果表明试验制剂与参比制剂为生物等效制剂。结论复方盐酸二甲双胍片与同时口服相同剂量的盐酸二甲双胍片和格列本脲片生物等效。     

十味玉泉胶囊中添加格列苯脲的检测

目的 检测十味玉泉胶囊中添加的格列苯脲。方法采用TLC法和HPLC法。结果供试品中检出了格列苯脲。结论本方法简便、准确，为揭露在中成药中擅自添加化学药成分的违法行为提供实验依据。     

LC-MS-MS法研究消糖灵分散片中格列本脲人体生物等效性

目的:建立人血浆中格列本脲的LC-MS-MS测定方法,研究中成药消糖灵分散片中格列本脲在男性健康志愿者体内的药代动力学行为,评价其生物利用度和生物等效性。方法:20名健康成年男性志愿者采用随机分组自身交叉对照试验设计,单剂量口服参比制剂格列本脲片1片(2.5 mg)或试验制剂消糖灵分散片4片(每片含格列本脲0.7 mg)后,用LC-MS-MS联用法测定血浆中药物浓度。结果:试验制剂和参比制剂的主要药代动力学参数:Tm ax分别为(3.8±1.0)和(3.3±0.9)h;Cm ax分别为(84.09±21.90)和(97.30±20.99)μg/L;AUC(0-36)分别为(577.99±150.92)和(530.76±98.25)μg/L.h;T1/2分别为(6.2±1.6)和(6.6±1.8)h。以AUC(0-36)计算的试验制剂的相对生物利用度为(94.94±13.6)%。结论:建立的分析方法准确灵敏,测得的数据可靠,统计学分析表明两种制剂生物等效。     

吡那地尔对低氧低糖诱导神经细胞凋亡的抑制作用

目的　探讨ATP敏感性钾通道(K_ATP)开放剂吡那地尔(Pin)对低氧低糖再复氧诱导的大鼠皮质神经细胞凋亡的影响。方法　用电镜和流式细胞分析技术,检测原代培养的大鼠皮质神经细胞凋亡。结果　低氧低糖再复氧可诱导大鼠皮质神经细胞凋亡。Pin (10^-5,10^-6,10^-7mol·L^-1 ) 3个剂量组均能降低凋亡细胞百分率,以10^-5mol·L^-1 组效果最好。上述作用可被K_ATP特异性阻断剂格列苯脲(Gli)所拮抗。结论　Pin对低氧低糖再复氧诱导的大鼠皮质神经细胞凋亡有明显的抑制作用,提示KATP通道在调控细胞凋亡的过程中可能起着重要的作用。     

A placebo-controlled crossover study comparing the effects of nateglinide and glibenclamide on postprandial hyperglycaemia and hyperinsulinaemia in patients with type 2 diabetes

Aim:  This was a randomized, double blind, three period crossover study. The objective was to compare glucose, insulin and C-peptide 24 h profiles in patients with type 2 diabetes mellitus after dosing with nateglinide (given preprandially before three test meals), glibenclamide (administered once before breakfast) or placebo (given before three test meals).
Methods:  Fourteen patients underwent screening followed within 3 weeks by three treatment periods of 1 day, each separated by 7 days. Dosing followed a six-sequence balanced, two 3 × 3-replicated Latin square.
Results:  Mean peak serum insulin levels were lower after nateglinide (115 mU/l) than after glibenclamide (145 mU/l.h; p = 0.017) but higher than after placebo (79 mU/l; p = 0.001). However, peak insulin levels were reached earlier after nateglinide [mean time to peak ( t _max) 1.7 h] compared to glibenclamide (mean t _max 2.1 h, p = 0.06). Total insulin exposure over the day was higher after glibenclamide compared with that following nateglinide (1216 vs. 1067 mU/l.h; p = 0.009). Similar findings were seen with serum C-peptide. Despite this, mean peak plasma glucose concentrations were lower following nateglinide (11.4 mmol/l from a baseline of 8.3 mmol/l) compared with glibenclamide (13.2 mmol/l from a baseline of 8.5 mmol/l; p = 0.001) and placebo (14.0 mmol/l from a baseline of 8.0 mmol/L; p < 0.001).
Conclusions:  Nateglinide improves early prandial measures of insulin and glucose response to a standard meal, more so than glibenclamide, in people with type 2 diabetes.     

Comparison of the effects of glimepiride and glibenclamide on adipose tissue tumour necrosis factor-alpha mRNA expression and cellularity

Aim: The aim of this study was to compare the effects of glimepiride and glibenclamide on tumour necrosis factor (TNF)‐α expression and adipocyte cellularity in spontaneously diabetic, obese rats. Methods: Eight‐week‐old male Otsuka Long‐Evans Tokushima Fatty (OLETF) rats were randomized to receive glimepiride, glibenclamide or control treatment for 12 weeks, after which TNF‐α mRNA levels, adipose tissue cellularity and physiological parameters were measured. Results: TNF‐α mRNA expression in retroperitoneal fat tissue was significantly greater in the glibenclamide group (2.2 ± 1.1), compared with the control group (0.9 ± 0.4; p < 0.05) or the glimepiride group (0.9 ± 0.2; p < 0.01). The mean fat‐cell area in retroperitoneal fat tissue was increased at study endpoint in the glibenclamide group (13 764 ± 7036 µm²), compared with both the control and glimepiride groups (10 755 ± 6193 µm² and 11 317 ± 5646 µm² respectively; p < 0.05). Investigation of cellularity revealed a decrease in the frequency of small fat cells and an increase in the frequency of large fat cells in both the glibenclamide and glimepiride groups compared with the control group, with a greater increase in large fat cells in the glibenclamide group. At study endpoint, insulin and triglyceride values were significantly higher in the active treatment groups compared with the control group; however, insulin levels were significantly greater in glibenclamide‐treated animals compared with glimepiride‐treated animals. An oral glucose tolerance test performed at the end of the study showed that there were no significant differences among the three groups in terms of plasma glucose and insulin concentrations. Conclusions: This study suggests that although both glibenclamide and glimepiride may have a hypertrophisizing effect on fat cells in adipose tissues, this effect is greater with glibenclamide, leading to augmentation of TNF‐α mRNA expression and possible exacerbation of insulin resistance.     

Effects of the hypoglycaemic drugs repaglinide and glibenclamide on ATP-sensitive potassium-channels and cytosolic calcium levels in Β TC3 cells and rat pancreatic beta cells

Summary The present study demonstrates the action of the hypoglycaemic drugs repaglinide and glibenclamide in cultured newborn rat islet cells and mouse TC3 cells. In cell-attached membrane patches of newborn rat islet cells repaglinide (10 nmol/l) and glibenclamide (20 nmol/l) decrease the open probability of single ATP-sensitive K⁺-channels to approximately 10% of the activity prior to addition of the drugs in short-term experiments (<5 min). The influence of repaglinide and glibenclamide on the ATP-sensitive K⁺ current was studied using the whole-cell patch clamp configuration. A half-maximal steady-state inhibition of the ATP-sensitive K⁺ currents is observed at 89 pmol/l repaglinide and at 47 pmol/l glibenclamide in whole-cell experiments of longer duration (30 min). Applying digital Ca²⁺ imaging on single TC3 cells we found that repaglinide and glibenclamide induced a concentration-dependent increase in intracellular free Ca²⁺ concentration ([Ca²⁺]_i) with a half-maximal effect at 0.5 nmol/l for both drugs in long-term experiments (30 min). The rise in [Ca²⁺]_i results from Ca²⁺ entry through voltage-dependent L-type Ca²⁺-channels since it is inhibited by verapamil (10 mol/l). The effect of repaglinide and glibenclamide is partly reversible (80%).Abbreviations K⁺ _ATP-channel ATP-sensitive potassium channel - [Ca²⁺]_i intracellular free Ca²⁺ concentration - EGTA ethylene glycol-O,O-bis(2-aminoethyl]-N,N,N,N-tetraacetic acid - IC₅₀ apparent inhibitor constant - repaglinide ((S)-(+)-2-ethoxy-4-[2-((3-methyl-1-[2-(1-piperidinyl) phenyl]-butyl)amino)-2-oxoethyl) benzoic acid - NIDDM non-insulin-dependent diabetes mellitus - TC3 cells transgenic mouse insulinoma tumour cell line     

Glibenclamide blunts coronary flow reserve induced by adenosine and dipyridamole

Objective—A reduced coronary flow reserve is considered indicative of significant coronary stenosis. As experimental data suggest that adenosine and dipyridamole induce vasodilatation by opening of ATP‐sensitive potassium channels, we sought to determine the effect of glibenclamide, an antidiabetic blocker of ATP‐sensitive potassium channels, on adenosine‐ and dipyridamole‐induced coronary flow reserve.

Design—Coronary flow velocities were measured in 15 pigs using a Doppler flow wire. The effect of increasing glibenclamide concentrations (0.1–10?μM) on adenosine‐induced coronary flow reserve was examined in five animals. Ten pigs served as time controls. The time controls were subsequently treated by 3?μM glibenclamide (n?=?5) or corresponding vehicle (n?=?5) and the flow response to 0.56?mg/kg dipyridamole determined.

Results—Glibenclamide elicited a concentration‐dependent inhibition of adenosine‐induced coronary flow reserve, reaching significance at glibenclamide concentrations of 3 and 10?μM. The coronary flow reserve stimulated by dipyridamole was reduced significantly by 3?μM glibenclamide.

Conclusion—Glibenclamide blunts coronary flow reserve stimulated by adenosine and dipyridamole. This interaction may have clinical implications in diabetics undergoing adenosine‐ or dipyridamole‐dependent diagnostic procedures.     

Blockade of 5-HT2 receptors with sarpogrelate uncovers 5-HT7 receptors inhibiting the tachycardic sympathetic drive in pithed rats

Our group has previously shown in pithed rats that the cardiac sympathetic drive, which produces tachycardic responses, is inhibited by 5-HT via the activation of prejunctional 5-HT_1B/1D/5 receptors. Interestingly, when 5-HT₂ receptors are chronically blocked with sarpogrelate, the additional role of cardiac sympatho-inhibitory 5-HT_1F receptors is unmasked. Although 5-HT₂ receptors mediate tachycardia in rats, and the chronic blockade of 5-HT₂ receptors unmasked 5-HT₇ receptors mediating cardiac vagal inhibition, the role of 5-HT₇ receptors in the modulation of the cardiac sympathetic tone remains virtually unexplored. On this basis, male Wistar rats were pretreated during 14 days with sarpogrelate (a 5-HT₂ receptor antagonist) in drinking water (30 mg/kg/day; sarpogrelate-pretreated group) or equivalent volumes of drinking water (control group). Subsequently, the rats were pithed to produce increases in heart rate by either electrical preganglionic spinal (C₇-T₁) stimulation of the cardiac sympathetic drive or iv administration of exogenous noradrenaline. The iv continuous infusion of AS-19 (a 5-HT₇ receptor agonist; 10 µg/kg/min) (i) inhibited the tachycardic responses to sympathetic stimulation, but not those to exogenous noradrenaline only in sarpogrelate-pretreated rats. This inhibition was completely reversed by SB258719 (a selective 5-HT₇ receptor antagonist; 1 mg/kg, iv) or glibenclamide (an ATP-sensitive K⁺ channel blocker; 20 mg/kg, iv). These results suggest that chronic 5-HT₂ receptor blockade uncovers a cardiac sympatho-inhibitory mechanism mediated by 5-HT₇ receptors, involving a hyperpolarization due to the opening of ATP-sensitive K⁺ channels. Thus, these findings support the role of 5-HT₇ receptors in the modulation of the cardiac sympathetic neurotransmission.     

Triple Oral Antidiabetic Therapy

Our objective was to determine the efficacy of adding acarbose to the combination of metformin and a sulfonylurea in the treatment of type II diabetes mellitus. Acarbose was added to the treatment regimen of 11 type II diabetic patients who were not adequately controlled on the combination of a sulfonylurea and metformin. Glycosylated hemoglobin before and after the addition of acarbose was compared to assess the efficacy of this additional therapy. One patient did not tolerate acarbose therapy. Of the remaining ten patients, the mean improvement in glycosylated hemoglobin with the addition of acarbose was 1.4 percentage points, p = 0.01. Eight patients had improvements in glycosylated hemoglobin; mean improvement, 2.0 percentage points. Two patients’ glycohemoglobin values worsened. Thus, the addition of acarbose to the treatment regimen of type II diabetic patients presently on a combination of a sulfonylurea and metformin improves glycemic control.