Exposure?response modelling for empagliflozin,a sodium glucose cotransporter 2 (SGLT2) inhibitor,in patients with type 2 diabetes

Aims

To provide model-based clinical development decision support including dose selection guidance for empagliflozin, an orally administered sodium glucose cotransporter 2 inhibitor, through developed exposure−response (E−R) models for efficacy and tolerability in patients with type 2 diabetes mellitus (T2DM).

Methods

Five randomized, placebo-controlled, multiple oral dose studies of empagliflozin in patients with T2DM (n = 974; 1–100 mg once daily, duration ≤12 weeks) were used to develop E−R models for efficacy (glycosylated haemoglobin [HbA_1c], fasting plasma glucose [FPG] and urinary glucose excretion). Two studies (n = 748, 12 weeks) were used to evaluate tolerability E−R.

Results

The efficacy model predicted maximal decreases in FPG and HbA_1c of 16% and 0.6%, respectively, assuming a baseline FPG concentration of 8 mm (144 mg dl⁻¹) and 10–25 mg every day empagliflozin targeted 80–90% of these maximums. Increases in exposure had no effect on incidence rates of hypoglycaemia (n = 4), urinary tract infection (n = 17) or genital/vulvovaginal-related (n = 16) events, although low prevalence rates may have precluded more accurate evaluation.

Conclusions

E−R analyses indicated that 10 and 25 mg once daily empagliflozin doses achieved near maximal glucose lowering efficacy.     

Synthesis of isotope‐labeled HSP90 inhibitor: [13CD3] and [14C]‐TAK‐459

[¹³CD₃]‐TAK‐459 (1A), an HSP90 inhibitor, was synthesized from [¹³CD₃]‐sodium methoxide in three steps in an overall yield of 29%. The key intermediate [¹³CD₃]‐2‐methoxy‐6‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)pyridine was synthesized in two steps from 2,6‐dibromopyridine and stable isotope‐labeled sodium methoxide. [¹⁴C]‐TAK‐459 (1B) was synthesized from [¹⁴C(U)]‐guanidine hydrochloride in five steps in an overall radiochemical yield of 5.4%. The key intermediate, [¹⁴C]‐(R)‐2‐amino‐7‐(2‐bromo‐4‐fluorophenyl)‐4‐methyl‐7,8‐dihydropyrido[4,3‐d]pyrimidin‐5(6H)‐one, was prepared by microwave‐assisted condensation.     

Retinoic acid remodels extracellular matrix (ECM) of cultured human fetal palate mesenchymal cells (hFPMCs) through down-regulation of TGF-β/Smad signaling

The regulation of extracellular matrix (ECM) by retinoic acid (RA) is interesting in light of the fact that the ECM plays an essential role in morphogenesis and palatal shelf elevation. In the current study, we explored the effect of RA overexposure on ECM and the probable mechanisms in cultured human fetal palate mesenchymal cells (hFPMCs). RA dose-dependently inhibited cell proliferation and mRNA and protein levels of ECM components fibronectin, tenascin C and fibrillin-2. Zymography revealed that MMP-2 activity was suppressed by RA. Further analysis revealed that mRNA levels of MMP2 and TIMP2 were decreased, while the MMP2/TIMP2 mRNA ratio was increased, which might facilitate the ECM degradation. Because of the pivotal role of TGF-β/Smad pathway in palatogenesis we therefore checked the effect of RA on TGF-β/Smad signaling. The results indicated RA treatment increased Smad7 expression and decreased the levels of TGF-β1, TGF-β3, TGF-β type II receptor (TβRII) and phosphorylated Smad2 and Smad3. Activation of the Smad pathways by either exogenous TGF-β3 or recombinant adenoviruses for Smad3 attenuated RA-induced inhibition of cell proliferation and ECM components and rescued the RA-altered MMP2/TIMP2 mRNA ratio. In conclusion, these findings suggested that RA overexposure inhibited cell proliferation and disrupted the ECM network through down-regulation of TGF-β/Smad pathway.     

沃泰西汀的作用机制与临床应用状况

沃泰西汀是一种新型抗抑郁药,其作用机制主要与抑制5－羟色胺的再摄取、增强中枢神经系统5－羟色胺的活性有关,主要用于治疗抑郁症,其安全性和耐受性较好。本文对沃泰西汀的临床药理学、临床评价和安全性等进行介绍。     

泮托拉唑联合生长抑素治疗不明原因消化道出血的疗效

目的观察单用泮托拉唑（PPI）及联用生长抑素治疗不明原因消化道出血的疗效。方法将92例不明原因消化道出血患者,均分为单用PPI组和联合用药组。PPI组予泮托拉唑40mg加0.9%Na Cl溶液100ml静滴,2次/d;联合组在使用PPI基础上加用生长抑素250μg首剂缓慢静推,然后3mg加36ml 0.9%Na Cl溶液微泵静脉持续泵入,250μg/h。两组均观察48h。观察期间所有患者均不使用其他止血药物。分别对两组患者治疗24h及48h后止血率进行比较,同时对比72h内仍有间断或持续性出血,进一步行介入或手术治疗的患者例数。结果联合组24h及48h止血率分别为89.1%和95.7%,单药组24h及48h止血率分别为71.7%和82.6%,两组比较差异有统计学意义（P〈0.05）。单药组最终需要接受急诊介入及手术例数比例为17.4%,联合组最终需要接受急诊介入及手术例数比例为4.3%,两组比较差异有统计学意义（P〈0.05）。结论使用PPI联合生长抑素与单独用PPI相比,在治疗不明原因消化道出血中更有效。     

四环鸟嘌呤型磷酸二酯酶抑制剂TCG-33的合成

目的合成一种活性很高的磷酸二酯酶的四环鸟嘌呤型抑制剂TCG-33。方法以6-氨基尿嘧啶为起始原料,经硅醚化、甲基化、脱保护3步反应首先合成了6-氨基-3-甲基尿嘧啶,再经亚硝化、还原、缩合、加氢、酰胺化、关环氯代、取代、关环8步反应得到目标产物。结果与结论报道了TCG-33的全合成,采用1H-NMR、ESI-MS对相关中间体和最终产物的结构进行了鉴定,并对关键步骤的反应过程进行了详细讨论。     

我院质子泵抑制剂用药分析及合理使用探讨

目的：通过专项点评了解我院质子泵抑制剂的使用情况,指导临床合理用药。方法：随机抽取2013年7-12月份归档病历共202份,对该类药物的适应证、用法用量、药物相互作用、不良反应等进行专项点评和综合分析。结果：202份病历中,应用质子泵抑制剂的有78份,使用率为38.61%;其中使用合理的病历40份,不合理的病历38份。结论：我院质子泵抑制剂的使用在用药指征、剂型选择、给药途径、药物相互作用等方面尚存在颇多不合理的地方,亟待改进。     

门诊质子泵抑制剂应用分析及合理性评价

目的 分析门诊质子泵抑制剂的应用现状及合理用药情况,为临床用药提供参考.方法 采用回顾性调查方法,对该院2012年1～12月门诊患者质子泵抑制剂的应用分布、用药金额、用药频度、药物利用指数、日均费用、用药合理性等情况进行分析.结果 使用频度前3位的是兰索拉唑肠溶片、奥美拉唑肠溶片、雷贝拉唑肠溶片;用药金额前3位的是泮托拉唑注射剂、兰索拉唑肠溶片、雷贝拉唑肠溶片;药物利用指数大多接近1;处方合格率为96.05%,不合理的主要原因为无指征用药.结论 该院门诊应用质子泵抑制剂的合理性有待提高.     

质子泵抑制剂与硫糖铝对危重患者呼吸机相关性肺炎影响的研究

目的探讨降低呼吸机相关性肺炎（VAP）发生率的方法。方法选取符合人选标准的接受气管插管机械通气的患者为研究对象,将患者随机分为研究组和对照组,两组患者的常规治疗方法相同,研究组应用硫糖铝混悬液2g,3次／d鼻饲;对照组应用泮托拉唑40mg,2次／d静脉滴注。记录急性上消化道出血（AUGIB）和VAP的发生情况。结果两组患者轻中度AUGIB（黑便和咖啡色胃液）的发生率比较,差异无统计学意义（P〉O．05）：对照组VAP的发生率明显高于研究组（P〈0．05）。结论对于有轻中度应激性溃疡风险的患者,应用硫糖铝在较好预防AUBIG发生的同时可明显降低发生VAP的风险。