微粉化及包合技术对格列本脲溶出度的影响

 目的考察微粉化及包合技术对格列本脲溶出度的影响。方法用球磨机制备了微粉化物，用研磨法制备了格列本脲-β-环糊精包合物，并通过DSC和XRD研究包合物的性质；测定了微粉化物及包合物的溶出速率，并考察了两者的稳定性。结果溶出速率的大小依次为微粉化物＞包合物＞原料药，DSC和XRD的结果表明形成了包合物；微粉化物及包合物均有良好的稳定性。结论微粉化及包合技术能显著提高格列本脲的溶出度。     

格列喹酮治疗非胰岛素依赖型糖尿病35例

格列喹酮——一种新的第二代磺脲类口服降糖药物,治疗35例非胰岛素依赖型糖尿病患者作临床前瞻性研究,该药是降糖药中唯一不受肾功能影响的药物。以格列本脲作为对照药物。格列喹酮平均剂量94±30mg/d,分1-3次口服,共服药4-4.5mo。研究结果表明格列喹酮降糖作用肯定,其疗效与格列本脲相当,并有改善周围组织胰岛素敏感性的作用,无明显毒副作用。该药是一种安全、有效的口服降糖药物,值得临床推广使用。     

The effects of metformin and glibenclamide on glucose metabolism, counter-regulatory hormones and cardiovascular responses in women with Type 2 diabetes during exercise of moderate intensity.

AIMS: To compare the effects of metformin and glibenclamide on cardiovascular, metabolic and hormonal parameters during exercise of moderate intensity performed in the postprandial state, in women with Type 2 diabetes. METHODS: Ten patients treated with metformin, 10 with glibenclamide and 10 control subjects (C) exercised on a bicycle ergometer at 50% of oxygen uptake (VO(2)) peak for 45 min. Cardiovascular, blood metabolic and hormonal parameters were determined at times -60 min (fasting), 0, +15, +30, +45 min (exercise) and at +60, +90 min (recovery). Thirty minutes prior to exercise, participants consumed a standard breakfast. Patients with diabetes took metformin or glibenclamide before the meal. RESULTS: Systolic and diastolic blood pressure and plasma glucose were higher in both diabetic groups, for the whole experiment. Blood glucose did not change during exercise in the three groups and increased at recovery only in the control group. Plasma glucagon concentrations at the end of exercise and recovery, and plasma lactate concentrations at recovery were higher in the metformin group. Insulin, noradrenaline, growth hormone, cortisol and free fatty acid responses were similar in all three groups. CONCLUSIONS: Our results suggest that the usual dose of glibenclamide and metformin can be taken safely before postprandial exercise of moderate intensity without affecting cardiovascular, metabolic and hormonal responses. However, after exercise, glibenclamide and metformin prevent the normal rise in blood glucose and metformin delays the fall in plasma lactate concentrations.     

HPLC-MS测定人血浆中格列本脲的浓度及不同剂量格列本脲的药物动力学

目的建立血浆中灵敏的格列本脲HPLC-MS测定法,研究不同剂量格列本脲片在正常人体的药物动力学。方法以格列美脲为内标,血浆样品经乙醚萃取后,经MACHEREY-NAGEL C18柱分离,采用质谱检测器检测,18名健康受试者采用随机交叉,单剂量口服格列本脲片2.5 mg或10 mg后测定其血药浓度,研究不同剂量格列本脲的药物动力学。结果格列本脲与内标分离度好,内源性杂质不干扰测定。在0.51-852μg·L^-1格列本脲浓度与峰面积比的线性关系良好,最小可定量浓度为0.51μg·L^-1,回收率为100.68%-108.7%,日内RSD为2.1%-3.4%;日间RSD为1.9%-4.9%。单次服用格列本脲片2.5 mg或10 mg后AUC0→48分别为（533.5±247.0）h·μg·L^-1和（1 982.9±893.1）h·μg·L^-1,Cmax分别为（94.1±19.1）μg·L^-1和（349.6±82.9）μg·L^-1,tmax分别为（1.90±0.40）h和（1.9±0.4）h,t1/2为（10.2±4.4）h和（9.4±1.8）h。结论HPLC-MS方法简单,准确度高,灵敏度好,可用于小剂量格列本脲在人体内药物动力学研究。单次给予格列本脲2.5 mg·次^-1或10 mg·次^-1,其人体内的药物动力学规律无明显改变。     

中药降糖制剂中非法掺入的化学降糖药物成分的检测

目的 建立能够同时检查中药制剂中可能非法添加的10种化学降糖药物成分(盐酸二甲双胍、盐酸苯乙双胍、甲苯磺丁脲、格列吡嗪、格列齐特、罗格列酮、吡格列酮、格列本脲、格列美脲、格列喹酮)的HPLC.方法 采用Thermo-ODS 色谱柱 (4.6 mm ×25 0mm,5 μm),0.01 mol·L-1的醋酸铵溶液(A)-甲醇(B)梯度洗脱,紫外230 nm检测,流速为1.0 mL·min-1.结果 在选定的色谱条件下,10种化学降糖药物有很好的分离.结论 该法灵敏准确,有助于降糖中药制剂的质量检验监督.     

Hormonal and metabolic effects of chlorpropamide,glibenclamide and placebo in a cross-over study in diabetics not controlled by diet alone

Summary Twenty diabetic patients, whose hyperglycaemia had been shown to fail to respond to at least one month's dietary treatment, completed a crossover study in order to: 1) compare the effectiveness of two sulphonylureas, chlorpropamide and glibenclamide, and 2) study the effects of sulphonylureas on insulin secretion and on biochemical indices of glucose intolerance. Fasting blood glucose fell on active treatment from 10.7±0.6 (mean ± SEM) to 6.6±0.7 mmol/l and rose again to 10.6±0.7 after 4 months placebo. A second period of 4 months sulphonylurea therapy resulted in a comparable fall in blood glucose (to 6.9±0.7 mmol/l) and a similar relapse was seen after the second placebo period (to 10.5±0.9 mmol/l). Glucose tolerance and associated insulin secretion improved markedly on active treatment, with ketone bodies, non-esterified fatty acids, and glycerol falling to within the reference range. Sulphonylurea therapy was associated with a small but significant increase in the fasting insulin level. These effects were nearly all reversed 4 months after withdrawal of the sulphonylureas. No marked changes were found in growth hormone, lactate, pyruvate, lactate/pyruvate ratio or fasting cholesterol, triglycerides and lipoproteins. On a weight basis, glibenclamide was 26 times more potent than chlorpropamide and, in the doses used in this study, their biochemical effects were indistinguishable. The effects of these two sulphonylureas seem most likely to be mediated by a direct stimulation of insulin secretion by the B-cell.     

Beta-cytotrophic action of glibenclamide on the pancreas of diabetic patients

Summary Observations on the beta-cytotrophic action of glibenclamide are reported in three cases of maturity-onset diabetes treated with insulin and glibenclamide and in whom autopsy was carried out after death due to causes other than diabetes. Since histological examination revealed the presence of large numbers of giant islets, of islets with irregular and not clearly defined outlines, the unusual shape and arrangement of individual cells within the islets and the presence of -granules in the newly formed islets, it is thought that these were signs of the regeneration of pancreatic islets. The possibility is discussed that these newly formed islets originate both from the exocrine pancreatic tissue and from the epithelium of secondary pancreatic ducts.

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Zusammenfassung Es werden Beobachtungen über den beta-zytotropen Effekt von Glibenclamid bei drei Fällen von mit Insulin und Glibenclamid behandeltem Erwachsenen-Diabetes beschrieben, bei welchen nach dem Tod infolge nichtdiabetischer Ursache eine Obduktion vorgenommen wurde. Da die histologische Untersuchung eine grosse Anzahl von Rieseninseln, Inseln mit unregelmässigen und nicht klar erkennbaren Grenzen, mit einzelnen Zellen von ungewöhnlicher Form und Anordnung innerhalb der Inseln und mit beta-Granulation in den neugeformten Inseln zeigte, wird angenommen, dass es sich um Zeichen der Regeneration pankreatischer Inseln handelt. Es wird die Möglichkeit diskutiert, dass diese neugeformten Inseln sowohl aus dem exokrinen Pankreasgewebe als auch aus dem Epithel der sekundären Pankreasgänge hervorgehen.

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Resumen Se exponen algunas observaciones sobre la acción betacitotrófica de la glibenclamida, referente a tres casos de diabetes en edad madura tratados con sulfanilurea y con insulina, los cuales fueron sometidos a comprobación autópsica tras defunción debida a causas ajenas. Puesto que el examen histológico puso en evidencia la presencia de un gran número de islas gigantes, de islas con contornos irregulares y no claramente definidos, con forma y disposición infrecuente de las diversas células en el inerior de las islas, de gránulos en esas islas neoformadas, se opina que dichos indicios sean la expresión de la regeneración de las islas pancreáticas. Se aduce le posibilidad de que esas islas neoformadas tengan origen tanto en el tejido pancrático exócrino como en el epitelio de los dúctulos pancreáticos secundarios.

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Résumé On fait quelques observations sur l'action bêta-cytotrophique de la glibenclamide concernant trois cas de diabète de l'âge mûr traités avec sulfanilurée et insuline et pour lesquels on a effectué un examen nécroscopique après le décès provoqué par d'autres causes. L'examen histologique ayant mis en évidence la présence d'un grand nombre d'îlots géants, d'îlots avec des contours irréguliers et pas clairement définis, d'une forme et arrangement insolites des différentes céllules à l'intérieur des îlots, de granules dans ces îlots de formation toute récente, on a cru que ces signes étaient le résultat d'une régénération des îlots pancréatiques. On a également discuté la possibilité que ces îlots de formation récente originent du tissu pancréatique exocrine aussi bien que de l'épithélium des canaux pancréatiques secondaires.

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Riassunto Vengono riferite alcune osservazioni sull'azione beta-citotrofica della glibenclamide, riguardanti tre casi di diabete dell'età matura trattati con la sulfanilurea e con l'insulina e nei quali venne eseguito, dopo il decesso intervenuto per altre cause, riscontro autoptico. Poiché l'esame istologico ha evidenziato la presenza di un gran numero di isole giganti, di isole con contorni irregolari e non chiaramente definiti, di forma e disposizione non usuali delle singole cellule all'interno delle isole, di granuli in queste isole neoformate, si è pensato che tali segni siano espressione di rigenerazione delle isole pancreatiche. Viene discussa la possibilità che queste isole neoformate si originino sia dal tessuto pancreatico esocrino che dall'epitelio dei dotti pancreatici secondarî.

     

(Pro-)Insulin Biosynthesis and Release of Newly Synthesized (Pro-)Insulin from Isolated Islets of Rat Pancreas in the Presence of Amino Acids and Sulphonylureas+,++

Abstract. The influence of arginine, lysine, tolbutamide and glibenclamide on (pro-)insulin biosynthesis and release of newly synthesized (pro-)insulin was studied in isolated islets of rat pancreas. Islets were incubated with ³H-leucine and glucose in the presence and absence of the test agents. Proinsulin and insulin of islets and incubation media were separated by gel filtration on Sephadex G 50. Estimations were carried out for radioactivity and immunoreactivity for insulin. All four test substances were able to enhance insulin release whereas no stimulation of leucine incorporation into (pro-)insulin was found. Arginine and tolbutamide even markedly reduced (pro-)insulin synthesis. Conversion of proinsulin to insulin was not affected by any of the test agents. For studying the influence of the 4 substances on secretion of newly synthesized (pro-)insulin two experimental models were used: 1) Labelling of the islets in the presence of the test agents, followed by uniform stimulation with glucose alone in the presence or absence of Ca⁺⁺. 2) Addition of the 4 test substances after uniform prelabelling of the islets. 1) Presence of arginine and sulfonylureas during labelling resulted in a significantly enhanced relative fractional release of newly synthesized (pro-)insulin, although the bulk of secreted hormone appeared to stem from the storage pool also under these conditions. The enhanced fractional release was persistent also during the postlabelling period when the islets had been labelled in the presence of arginine or glibenclamide. On the other hand, a decreased release of newly synthesized (pro-)insulin was observed during the postlabelling period in islets labelled in the presence of tolbutamide. Lysine was without significant effects in both periods. Omission of calcium ions during the postlabelling period inhibited the release of both immunoreactive and radioactive hormone. 2) When amino acids or sulphonylureas were added after prelabelling no signifcant changes were found in the specific radioactivity of released (pro-)insulin or in the fractional release of newly synthesized hormone. Enhanced release of fresh granules from the beta cell might explain the increased fractional release of newly synthesized (pro-) insulin when labelling is carried out in the presence of arginine and sulphonylureas, especially glibenclamide.     

Verapamil prevents stretch-induced shortening of atrial effective refractory period in langendorff-perfused rabbit heart

INTRODUCTION: Atrial dilation and rapid pacing reduce atrial effective refractory periods (AERPs), thereby increasing the susceptibility to sustained atrial fibrillation (AF) in Langendorff-perfused rabbit hearts. It is unclear whether similar pathophysiologic mechanisms are operative in short-term electrophysiologic changes caused by dilation and rapid pacing. Therefore, we analyzed whether both forms of short-term electrophysiologic changes are similarly affected by pharmacologic interventions acting on different potential mechanisms underlying these changes. METHODS AND RESULTS: Thirty Langendorff-perfused rabbit hearts underwent a protocol with stepwise increase of intra-atrial pressure from 0 to 12 cm H2O followed by 10 minutes of rapid pacing at 4 cm H2O. The protocol was repeated after addition of glibenclamide (10 micromol/L, n = 7), cariporide (1 micromol/L, n = 7), or verapamil (1 micromol/L, n = 9). In the basal state, increase of intra-atrial pressure from 0 to 12 cm H2O decreased AERPs from 85 +/- 11 to 55 +/- 9 msec (P < 0.01), rapid pacing at low intra-atrial pressure (4 cmH2O) decreased AERP to a similar extent, from 81 +/- 11 to 60 +/- 10 (P < 0.01). At higher intra-atrial pressure, decrease of AERP was more pronounced (10 cm H2O: 37 +/- 2 msec) (n = 7). Addition of verapamil decreased basal AERP from 86 +/- 10 msec to 68 +/- 11 msec (P < 0.05). Short-term electrophysiologic changes due to atrial dilation were abolished; changes due to rapid pacing were reduced but still present. Glibenclamide and cariporide had no significant effect. CONCLUSION: Langendorff-perfused rabbit heart is a suitable model for studying short-term electrophysiologic changes due to both rapid pacing and atrial dilation. AERPs are shortened to a similar extent by both mechanisms, whereas a combination of the two leads to more pronounced AERP reduction. Calcium overload plays a crucial role in short-term electrophysiologic changes caused by atrial dilation, whereas atrial ischemia or acidosis has no significant impact.