Glibenclamide treatment in a Cantú syndrome patient with a pathogenic ABCC9 gain‐of‐function variant: Initial experience

Cantú syndrome (CS), characterized by hypertrichosis, distinctive facial features, and complex cardiovascular abnormalities, is caused by pathogenic variants in ABCC9 and KCNJ8 genes. These genes encode gain‐of‐function mutations in the regulatory (SUR2) and pore‐forming (Kir6.1) subunits of K_ATP channels, respectively, suggesting that channel‐blocking sulfonylureas could be a viable therapy. Here we report a neonate with CS, carrying a heterozygous ABCC9 variant (c.3347G>A, p.Arg1116His), born prematurely at 32 weeks gestation. Initial echocardiogram revealed a large patent ductus arteriosus (PDA), and high pulmonary pressures with enlarged right ventricle. He initially received surfactant and continuous positive airway pressure ventilation and was invasively ventilated for 4 weeks, until PDA ligation. After surgery, he still had ongoing bilevel positive airway pressure (BiPAP) requirement, but was subsequently weaned to nocturnal BiPAP. He was treated for pulmonary hypertension with Sildenafil, but failed to make further clinical improvement. A therapeutic glibenclamide trial was commenced in week 11 (initial dose of 0.05 mg^–1 kg^–1 day^–1 in two divided doses). After 1 week of treatment, he began to tolerate time off BiPAP when awake, and edema improved. Glibenclamide was well tolerated, and the dose was slowly increased to 0.15 mg^?1 kg^?1day^?1 over the next 12 weeks. Mild transient hypoglycemia was observed, but there was no cardiovascular dysfunction. Confirmation of therapeutic benefit will require studies of more CS patients but, based on this limited experience, consideration should be given to glibenclamide as CS therapy, although problems associated with prematurity, and complications of hypoglycemia, might limit outcome in critically ill neonates with CS.     

胰岛素-磺脲类药与胰岛素治疗2型糖尿病继发性磺脲类药失效的研究

目的：对比研究胰岛素加磺脲类药联合(INS／SU)或单用胰岛素(INS)二种疗法治疗继发性SU失效的疗效,并通过体外试验探讨INS加SU治疗的机理。方法：54例继发SU失效的2型糖尿病患者随机分二组,分别给INS加SU及INS治疗共3个月,测定2型糖尿病患者脂肪细胞与优降糖孵育后INS受体结合位点。结果：(1)治疗3个月时两组的血糖、糖化血红蛋白(HbAIc)得到较好控制。(2)两组治疗前后血脂无明显改变。(3)INS组较INS加SU组体重增加显著、血INS水平明显升高。(4)优降糖孵育后的脂肪细胞INS结合位点增多,与INS特异结合率提高。结论：(1)INS加SU与INS均可有效地治疗继发性SU失效的病人。(2)INS加SU联合治疗与单用INS治疗比较,其引起的血INS水平升高、体重增加程度均较低。(3)SU通过影响靶细胞INS受体等胰外作用．而增强INS的作用效应。     

Behaviour of glibenclamide on repeated administration to diabetic patients

Summary Six maturity onset diabetic patients took glibenclamide 5 mg by mouth, every morning 10 min before a standard breakfast. Serum levels of immunoreactive glibenclamide, glucose and immunoreactive insulin were measured repeatedly on the first and 15th days of treatment. Measured glibenclamide blood levels were in close agreement with an analogue computer simulation of data obtained from healthy volunteers: there was no accumulation of drug in the blood, but there was strong evidence for the existence of a slowly equilibrating deep compartment. Considerable insulin release and correction of the breakfast-induced hyperglycaemia were observed immediately after administration of the drug, as well as 5 h later, at lunch time. The clinical significance of blood levels of glibenclamide, as well as the correlation of pharmacokinetics with pharmacodynamics, are discussed in the light of these results.Glossary of symbols IR- immuno-reactive - GLI glibenclamide - IRI immuno-reactive insulin - GLU glucose - AK 1 values obtained with patient AK on the first day of treatment - AK 15 values obtained with patient AK on the 15th day of treatment - b serum level - b_max maximal serum level - t time after dose - t_max time of maximal serum level - G gastro-intestinal system - B central compartment (blood) - T peripheral compartment (tissue) - E excreta - M,N coefficients of the equation of a bi-exponential decay curve - µ, v exponents of the equation of a bi-exponential decay curve - e base of natural logarithms - K_BG K_EB K_TB K_BT first order rate constants (e. g. K_BG means: into B, from G) - K_BG first order rate constants - etc. not corrected for the volume of distribution     

盐酸埃他卡林对[~3H]格列本脲与动脉平滑肌K_(ATP)结合和解离动力学过程的影响以及与核苷酸的交互作用

目的　研究盐酸埃他卡林 (Iptakalimhydrochloride,Ipt)对 [3 H]格列本脲 (glibenclamide,Gli)与大鼠血管平滑肌ATP敏感性钾通道 (ATP sensitivepotassiumchannel,KATP)的硫脲受体(Sulfonylureareceptor,SUR2B)结合和解离动力学过程的影响 ,并比较其作用特点与核苷酸类物质的异同点及它们之间的交互效应。方法　KATP拮抗剂 [3 H]Gli与大鼠去内皮主动脉平滑肌特异性结合与解离的动力学试验。结果　 (1 )在浓度为 1 0pmol·L-1 ～ 0 5mmol·L-1 范围内 ,Ipt不能取代SUR2B与 [3 H]Gli2 0 0 3 0 616收稿 ,2 0 0 3 112 5修回 国家新药研究与发展重点项目 ,No 9690 10 10 1;国家“863”计划重大专项 ,No 2 0 0 2AA2Z3 13 7作者简介 :何华美 ,男 ,3 6岁 ,博士 ,副教授。研究方向 :心血管药理学。E mail:longchaoliang @sohu .com ;汪　海 ,男 ,40岁 ,研究员 ,博士生导师。研究方向 :心血管药理和新药。通讯作者。Tel :86 10 6693 2 65 1,Fax:86 10 682 1165 6,E mail:wh @nic.bmi.ac .cn之间的特异性结合。Ipt 1 0 0 μmol·L-1 调节 [3 H]Gli与SUR2B特异性结合的动力学过程的特征为抑制其结合动力学过程 ,使其结合速率减慢 ,结合幅度降低 ;促进其解离动力学过程 ,使其解离速率加快 ,解离幅度增加。 (2 )ATP     

格列吡嗪控释片治疗继发性磺脲类降糖药失效2型糖尿病的疗效

目的 :观察格列吡嗪控释片治疗继发性磺脲类降糖药失效 2型糖尿病的疗效。方法 :选取继发性磺脲类降糖药失效的 2型糖尿病患者 6 4例 ,随机分为 2组 ,各 32例。治疗组予格列吡嗪控释片治疗 ,对照组予格列吡嗪速效片治疗 ,观察 8wk(治疗组分成 4wk剂量调整期 ,4wk维持期 )。治疗前后行 2次口服糖耐量试验 (OGTT)和胰岛素释放试验 ,计算胰岛素释放指数 (IRG)和胰岛素敏感指数 (ISI) ;比较 2组治疗前后血糖 ,血胰岛素 ,IRG ,ISI和临床疗效。结果 :与治疗前比较 ,治疗组治疗后血糖水平下降 ,ISI增高 ,P <0 .0 1;但胰岛素水平及IRG与服药前无显著性差异。对照组各指标治疗前后均无显著性差异。治疗组总有效率 (5 6 .2 % )显著高于对照组 (9.3% ) ,P <0 .0 1,且无明显不良反应发生。结论 :格列吡嗪控释片可改善继发性磺脲类降糖药失效的 2型糖尿病患者胰岛素敏感性及血糖控制 ,可作为继发性磺脲类降糖药失效患者的治疗药物     

Canagliflozin,a sodium glucose co-transporter 2 inhibitor,reduces post-meal glucose excursion in patients with type 2 diabetes by a non-renal mechanism: results of a randomized trial

Objective

Canagliflozin is a sodium glucose co-transporter 2 inhibitor approved for treating patients with type 2 diabetes. This study evaluated renal and non-renal effects of canagliflozin on postprandial plasma glucose (PG) excursion in patients with type 2 diabetes inadequately controlled with metformin.

Materials/Methods

Patients (N = 37) were randomized to a four-period crossover study with 3-day inpatient stays in each period and 2-week wash-outs between periods. Patients received Treatments (A) placebo/placebo, (B) canagliflozin 300 mg/placebo, (C) canagliflozin 300 mg/canagliflozin 300 mg, or (D) canagliflozin 300 mg/canagliflozin 150 mg on Day 2/Day 3 in one of four treatment sequences (similar urinary glucose excretion [UGE] expected for Treatments B–D). A mixed-meal tolerance test (MMTT) was given 20 minutes post-dose on Day 3 of each period.

Results

A single dose of canagliflozin 300 mg reduced both fasting and postprandial PG compared with placebo, with generally similar effects on fasting PG and UGE observed for Treatments B–D. An additional dose of canagliflozin 300 mg (Treatment C), but not 150 mg (Treatment D), prior to the MMTT on Day 3 provided greater postprandial PG reduction versus placebo (difference in incremental glucose AUC_0–2h, − 7.5% for B vs A; − 18.5% for C vs A; − 12.0% [P = 0.012] for C vs B), leading to modestly greater reductions in total glucose AUC_0–2h with Treatment C versus Treatment B or D. Canagliflozin was generally well tolerated.

Conclusions

These findings suggest that a non-renal mechanism (ie, beyond UGE) contributes to glucose lowering for canagliflozin 300 mg, but not 150 mg.     

Roles of sulfonylurea receptor 1 and multidrug resistance protein 1 in modulating insulin secretion in human insulinoma

BACKGROUND:Sulfonylurea receptor 1(SUR1)and multidrug resistance protein 1(MRP1)are two prominent members of multidrug resistance proteins associated with insulin secretion. The aims of this study were to investigate their expression in insulinomas and their sole and synergistic effects in modulating abnormal insulin secretion. METHODS:Fasting glucose,insulin and C-peptide were measured in 11 insulinoma patients and 11 healthy controls. Prolonged oral glucose tolerance tests were performed in 6 insulinoma p...     

磺脲类药物继发性失效患者短期胰岛素泵强化治疗的临床观察

目的观察胰岛素泵（胰岛素皮下连续脉冲式输注，CSII）对磺脲类药物继发性失效的2型糖尿病患者强化治疗的效果。方法将78例磺脲类药物继发性失效的2型糖尿病患者随机分为常规多次皮下注射（MS10组（42例）和CSII组（36例）进行强化胰岛素治疗。结果CSII组患者血糖达标时间，平均住院的天数和胰岛素的用量明显少于MSII组；CSII组的血糖波动幅度较MSII组明显降低。低血糖的发生风险在两组患者间差异没有显著性。结论对于磺脲类药物继发性失效的2型糖尿病患者，CSII强化治疗较MSII治疗具有更多的优点，可能是最合适的胰岛素治疗方案。