格列齐特治疗非胰岛素依赖型糖尿病106例的近期疗效

应用国产格列齐特治疗非胰岛素依赖型糖尿病106例,并以格列本脲(优降糖)作对照药物。治疗3mo后,初诊断27例均有效(100％);已用其他磺酰脲药物79例(包括失效33例),改用格列齐特后有效68例(86％)。有效病例的空腹和餐后2h血糖、24h尿糖、糖基化血红蛋白(HbA_1)均明显降低。初诊断组经治疗后甘油三酯也明显降低。格列齐特不良反应轻微,是一种安全、可靠的药物。     

High affinity hippocampal [3H]-glibenclamide binding sites are preserved in Alzheimer's disease

Summary ATP-sensitive K⁺ channels were examined in sections of the hippocampus from patients with Alzheimer's disease and age-matched control subjects by means of quantitative autoradiography. ATP-sensitive K⁺ channels were labelled with the sulfonylurea, [³H]-glibenclamide, which is a potent blocker of these channels. The density of cells in the subiculum and the activity of choline acetyltransferase were determined in the same hippocampal tissue samples. In the hippocampal formation of control subjects, the density of high affinity [³H]-glibenclamide binding sites ranged from 17.6±0.9 pmoles/g in the presubiculum to 11.6±0.6 pmoles/g in the parvopyramidal layer of the presubiculum. There was no difference between Alzheimer patients and controls in the level of high affinity [³H]-glibenclamide binding in any hippocampal region although there was a marked loss of subicular cells (reduced by 29% compared to controls) and a reduction in choline acetyltransferase activity (reduced by 60% compared to controls). The results suggest that ATP-sensitive K⁺ channels are associated with elements in the hippocampus which are preserved in Alzheimer's disease.     

Serum glibenclamide in diabetic patients,and influence of food on the kinetics and effects of glibenclamide

Summary The steady state concentrations of glibenclamide in serum were measured radioimmunologically in 37 diabetic patients after administration for at least a year. No other antidiabetic drugs had been given. The interindividual variation in glibenclamide concentrations was extremely large (0 to 1520 nmol/l), greatly exceeding the variation in dosage (2.5–25 mg daily). There was no relation between dose and serum concentration of glibenclamide. Only four (9%) patients had fasting blood glucose concentrations below 5.5 mmol/l, and fewer than half had values below 8 mmol/l. In most cases, therefore, the therapy was inadequate. Single-dose kinetics of glibenclamide was assessed in healthy volunteers. Food intake did not influence the bioavailability of a 5 mg dose of glibenclamide. There was no insulin increase in response to glibenclamide unless a meal was also given, and this increase was not significant until 1 h after administration of drug and meal, when the mean serum concentration of glibenclamide had reached 100nmol/l. Even in the fasting state, however, there was a progressive fall in blood glucose after glibenclamide administration, significant within 45 min and with a nadir at 2–2 1/2 h.     

国产格列本脲片的溶出度对比分析

目的：采用药物溶出度测定仪考察2009年国家评价性抽验计划中16个企业生产的298批次格列本脲片的溶出曲线,比较产品的内在质量差异,分析现行溶出度方法的质量可控性。方法：按照中国药典2005年版溶出度测定法测定单点溶出度,以及分别按照日本橙皮书、美国FDA药品审评部门仿制药办公室公布的溶出度试验条件、英国药典（BP）2008版中格列本脲片溶出度测定法测定溶出曲线。结果：本次2009年国家评价性抽检的16个生产企业共298批样品,按中国药典2005年版二部进行检验,均符合规定;对这16个生产企业的格列本脲片进行溶出曲线评价,1个生产企业的格列本脲片批间重复性较好,大部分样品批间的溶出曲线存在较大差异,个别企业片间溶出曲线有较大的差异,反映出产品内在质量的稳定性和均一性较差。结论：用单点溶出度控制药物学溶出行为,对很多产品而言不能全面准确地反映产品的溶出性能与内在质量,特别是不能反映出产品之间的质量差异。     

Combination of glibenclamide–metformin HCl for the treatment of type 2 diabetes mellitus

Introduction: Combination of glibenclamide (glyburide in the U.S.) and metformin hydrochloride simultaneously addresses two different but complimentary mechanisms to improve glycemic control in type 2 diabetes.

Areas covered: The pharmacokinetics, efficacy, and side effect profile of the oral combination of glibenclamide–metformin are reviewed.

Expert opinion: Those patients, uncontrolled with single oral agent sulfonylurea or metformin alone, benefit from combination glibenclamide–metformin. There is improvement in fasting plasma glucose, HbA_1C, and post-prandial glucose control, and patients are more likely to achieve a HbA_1C < 7%. Initiation should be started at the lowest doses and titrated to get the desired effect. Combination therapy allows for reduced pill burden while treating a multifactorial disease by two different mechanisms. Practitioners should be cognizant of risks of hypoglycemia and the theoretical potential for lactic acidosis in the elderly and those with renal impairment. We caution the use of glibenclamide–metformin in patients at risk for cardiovascular disease. Therapy should be individualized, but overall, combination of glibenclamide–metformin should be considered in patients, without renal or cardiovascular impairment, who are not controlled on monotherapy alone. Alternatively, practitioners may want to weigh the efficacy and safety of available dipeptidyl-peptidase-4 inhibitor–metformin combinations to those of glibenclamide–metformin when considering combination therapy.     

格列本脲致低血糖反应的文献分析

目的探讨格列本脲致低血糖反应发生的情况并分析相关因素,为临床合理用药提供参考。方法对格列本脲致的742例低血糖反应文献进行分类统计与分析。结果男女比例为1.1:1,老年人占88.0%,39.6%的病例存在不合理用药行为,14.6%单独用药,43.9%联合用药,临床表现以低血糖昏迷为主(62.7%),93.5%病例治愈,48例转归不良(死亡41例)。结论格列本脲可引起较为严重的低血糖反应,甚至可致死亡,使用时须慎重考虑年龄、用法用量等相关因素,做到合理用药,减少低血糖反应的发生。     

Regulation of vascular nitric oxide in vitro and in vivo; a new role for endogenous hydrogen sulphide?

BACKGROUND AND PURPOSE: The aim of these experiments was to evaluate the significance of the chemical reaction between hydrogen sulphide (H2S) and nitric oxide (NO) for the control of vascular tone. EXPERIMENTAL APPROACH: The effect of sodium hydrosulphide (NaHS; H2S donor) and a range of NO donors, such as sodium nitroprusside (SNP), either alone or together, was determined using phenylephrine (PE)-precontracted rat aortic rings and on the blood pressure of anaesthetised rats. KEY RESULTS:Mixing NaHS with NO donors inhibited the vasorelaxant effect of NO both in vitro and in vivo. Low concentrations of NaHS or H2S gas in solution reversed the relaxant effect of acetylcholine (ACh, 400 nM) and histamine (100 microM) but not isoprenaline (400 nM). The effect of NaHS on the ACh response was antagonized by CuSO(4) (200 nM) but was unaffected by glibenclamide (10 microM). In contrast, high concentrations of NaHS (200-1600 microM) relaxed aortic rings directly, an effect reduced by glibenclamide but unaffected by CuSO4. Intravenous infusion of a low concentration of NaHS (10 micromol kg(-1) min(-1)) into the anaesthetized rat significantly increased mean arterial blood pressure. L-NAME (25 mg kg(-1), i.v.) pretreatment reduced this effect. CONCLUSIONS AND IMPLICATIONS: These results suggest that H2S and NO react together to form a molecule (possibly a nitrosothiol) which exhibits little or no vasorelaxant activity either in vitro or in vivo. We propose that a crucial, and hitherto unappreciated, role of H2S in the vascular system is the regulation of the availability of NO.     

Comparison of the pharmacokinetics of glipizide and glibenclamide in man

Summary Four subjects received 5 mg¹⁴C-glipizide orally, 3 subjects 1 mg intravenously and 2 subjects 5 mg¹⁴C-glibenclamide orally. Plasma levels of radioactivity, and urinary and faecal excretion were measured. For both drugs the disappearance of radioactivity from plasma followed complex kinetics and the apparent half-lives increased steadily with time. The two sulfonylureas were extensively metabolized and were excreted in the urine as hydroxylated or conjugated metabolites. The effects of both drugs on blood glucose and immunoreactive insulin were comparable. The findings are compared with other published results.     

Accumulation of dopamine in mouse pancreatic B-cells following injection of L-DOPA. Localization to secretory granules and inhibition of insulin secretion

Summary Accumulation and subcellular localization of dopamine (DA) in pancreatic B-cells and its effects on insulin secretion were investigated in mice following a single injection of L-3,4-dihydroxyphenyl-alanine (L-DOPA). Electron microscopic autoradiography showed that³H-DA formed from administered³H-DOPA was present over B-cells as well as over other types of islet cells. Pretreatment of the animals with a decarboxylase inhibitor greatly reduced the number of autoradiographic grains. In the B-cells the³H-DA-grains were associated with the secretory granules. The location of the label may suggest an incorporation in the periphery of the -granule, rather than in the dense core, supposed to contain insulin. Accumulation of DA in the B-cells following L-DOPA administration was found to inhibit partially the insulin secretory response to different insulin secretagogues (glucose, glibenclamide and L-isopropylnoradrenaline (L-IPNA)). Treatment with monoamine oxidase inhibitor + L-DOPA induced an almost total suppression of L-IPNA-stimulated insulin secretion, whereas glucose-induced insulin release was still only partially inhibited. Pretreatment with a decarboxylase inhibitor abolished the effects of L-DOPA. It is suggested that intracellularly accumulated DA in the B-cell exerts an inhibitory action on insulin releasing mechanisms induced by different secretagogues and that this action might involve interference with a calcium translocation process at the level of the secretory granule.This work was supported by the Swedish Medical Research Council (Project Nos. 14X-4286, 04P-4289 and 12X-537) and Vera and Carl J. Michaelsens donationsfond. The skilful technical assistance of Mrs. Lena Kvist, Mr. Peter Okmark and Mrs. Gunnel Bokhede is gratefully acknowledged