瑞格列奈与迪沙片治疗新诊断2型糖尿病的疗效对比观察

比较对新诊断2型糖尿病患者应用瑞格列奈（11例）和迪沙片（10例）治疗4周后空腹血糖（FPG）、餐后2h血糖（2hPG）、晨3点血糖（3aPG）,空腹胰岛素（FIns）、餐后2h胰岛素（2hIns）,糖化白蛋白的值。结果显示,与迪沙片组相比,瑞格列奈组治疗后空腹血糖、餐后2h血糖的下降幅度更为明显,但低血糖的发生次数反而减少。     

Hypoglycaemic effects of the novel antidiabetic agent repaglinide in rats and dogs

1. Repaglinide, a novel compound with a nonsulphonylurea structure, is currently being clinically tested as a therapeutic agent. In the present study, the hypoglycaemic effects of repaglinide in rats and dogs were investigated.
2. Whereas the R-enantiomer, AG-EE 624 ZW, showed only weak hypoglycaemic activity, the S-enantiomer, repaglinide, turned out to be a potent hypoglycaemic compound in rats after oral as well as after intravenous administration. Only 50% of the dose of repaglinide was needed to be equieffective with the racemic mixture AG-EE 388 ZW. The corresponding ED₅₀ values calculated for the effects after 120 min p.a. (intravenous administration) were 3.4 μg kg⁻¹ (repaglinide) and 6 μg kg⁻¹ (AG-EE 388 ZW).
3. When compared to glimepiride or glibenclamide, repaglinide displayed a 18 to 25 times higher potency in fasted rats. The ED₅₀ values calculated for the effects after 120 min p.a. (oral administration) were 10 μg kg⁻¹ (repaglinide), 182 μg kg⁻¹ (glimepiride) and 255 μg kg⁻¹ (glibenclamide).
4. In glucose loaded rats (0.5, 1.0, 2.0 and 3.0 g kg⁻¹ glucose, p.o.) repaglinide exerted a very strong antihyperglycaemic activity which was even more pronounced than under normoglycaemic conditions. So for a reduction in blood glucose of 1 mmol l⁻¹, 10.3, 9.3, 7.0 8.4 and 7.2 μg kg⁻¹ repaglinide were needed after glucose loads of 0.0, 0.5, 1.0, 2.0 and 3.0 g kg⁻¹, respectively.
5. In beagle dogs repaglinide again showed a pronounced hypoglycaemic effect (ED₅₀ 28.3 μg kg⁻¹) which lasted for up to 24 h. However, insulin levels were only transiently increased.
6. The in vivo data presented are well supported by recently published in vitro findings. From its activity profile, repaglinide appears to be a promising new therapeutic agent.

     

Effects of Fluvastatin on the Pharmacokinetics of Repaglinide: Possible Role of CYP3A4 and P-glycoprotein Inhibition by Fluvastatin

The purpose of this study was to investigate the effects of fluvastatin on the pharmacokinetics of repaglinide in rats. The effect of fluvastatin on P-glycoprotein and CYP3A4 activity was evaluated. The pharmacokinetic parameters and blood glucose concentrations were also determined after oral and intravenous administration of repaglinide to rats in the presence and absence of fluvastatin. Fluvastatin inhibited CYP3A4 activity in a concentration-dependent manner with a 50% inhibition concentration(IC₅₀) of 4.1 µM and P-gp activity. Compared to the oral control group, fluvastatin significantly increased the AUC and the peak plasma level of repaglinide by 45.9% and 22.7%, respectively. Fluvastatin significantly decreased the total body clearance (TBC) of repaglinide compared to the control. Fluvastatin also significantly increased the absolute bioavailability (BA) of repaglinide by 46.1% compared to the control group. Moreover, the relative BA of repaglinide was 1.14- to 1.46-fold greater than that of the control. Compared to the i.v. control, fluvastatin significantly increased the AUC_0-∞ of i.v. administered repaglinide. The blood glucose concentrations showed significant differences compared to the oral controls. Fluvastatin enhanced the oral BA of repaglinide, which may be mainly attributable to the inhibition of the CYP3A4-mediated metabolism of repaglinide in the small intestine and/or liver, to the inhibition of the P-gp efflux transporter in the small intestine and/or to the reduction of TBC of repaglinide by fluvastatin. The study has raised the awareness of potential interactions during concomitant use of repaglinide with fluvastatin. Therefore, the concurrent use of repaglinide and fluvastatin may require close monitoring for potential drug interactions.     

Study on the interactions of pharmacokinetics and liver distributions between rosuvastatin and repaglinide in rats

In the present study,we aimed to investigate the interactions of pharmacokinetics and liver distributions between rosuvastatin and repaglinide in rats.Coadministration of repaglinide (0.5 mg/kg, 1 mg/kg and 2 mg/kg) for 7 d significantly increased the AUC_0–24 and C_max of rosuvastatin (P<0.01), but dramatically decreased the CL/F of rosuvastatin (P<0.01) after a single dose of rosuvastatin (10 mg/kg). There were no obviously changes in the parameters of T_max and t_1/2. Coadministration of repaglinide also decreased the liver distribution of rosuvastatin (P<0.01). Coadministration of rosuvastatin (20 mg/kg) for 7 days significantly increased the AUC_0–12 and C_max of repaglinide (P<0.05), and decreased the CL/F of repaglinide (P<0.01) after a single dose of repaglinide (1 mg/kg). The liver distribution of repaglinide was also decreased (P<0.01). Our animal study indicated that repaglinide could significantly affect the pharmacokinetics and liver distribution of rosuvastatin in rats and vice versa.     

瑞格列奈片有关物质的HPLC测定

目的：建立高效液相色谱法测定瑞格列奈片中有关物质的方法。方法：色谱柱为Agilent ZORBAX SB-Aq（150 mm×4.6mm，5μm），以磷酸盐缓冲液（取磷酸二氢钾4.0g，加水1000ml溶解后，用磷酸调节pH值至3.2）为流动相A，以流动相A-乙腈（30:70）为流动相B，进行梯度洗脱；流量为1.5mL?min-1，检测波长240nm，柱温为45℃。结果：各相邻杂质峰之间、杂质峰与主峰之间能有效分离且物料平衡。结论：该方法专属性好，灵敏度高，结果准确，可用于瑞格列奈片有关物质的测定。     

甘精胰岛素联合西格列汀对首诊2型糖尿病血糖波动炎症因子及低血糖事件的影响

目的 探讨甘精胰岛素联合西格列汀对首诊2型糖尿病（T2DM）患者血糖波动、炎症因子及低血糖事件的影响。方法 选择2017年6月至2018年10月在无锡市第三人民医院接受治疗的124例首诊T2DM患者为研究对象,采用随机数字表法分为对照组与观察组,每组62例。对照组给予甘精胰岛素联合瑞格列奈治疗,观察组给予甘精胰岛素联合西格列汀治疗。比较两组患者空腹血糖（FBG）、餐后2 h血糖（2 h PBG）、糖化血红蛋白（HbA1c）、日内血糖平均波动幅度（MAGE）、日内血糖波动次数（NGE）、肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）、C反应蛋白（CRP）、体质指数（BMI）,以及低血糖发生率和甘精胰岛素用量的差异。结果 观察组患者治疗后的MAGE为（2.53±1.19）mmol/L、NGE为（1.53±0.93）mmol/L,均低于对照组,差异有统计学意义（P<0.05）。两组患者治疗前与治疗后MAGE、NGE的差值进行比较,差异有统计学意义（P<0.05）。观察组患者治疗后的血清CRP水平为（2.76±1.03）mg/L、TNF-α为（19.83±8.41）ng/L、IL-6为（18.61±4.73）ng/L,均低于对照组,差异有统计学意义（P<0.05）。两组患者治疗前与治疗后血清CRP、TNF-α、IL-6差值进行比较,差异有统计学意义（P<0.05）。观察组患者治疗后的BMI为（23.24±2.83）kg/m²,对照组为（24.29±3.05）kg/m²,差异有统计学意义（P<0.05）。观察组患者低血糖发生率为1.60%、甘精胰岛素用量为（25.54±5.09）U/d,均低于对照组,差异有统计学意义（P<0.05）。结论 甘精胰岛素联合西格列汀能够减少血糖波动,减轻机体微炎症反应,减少低血糖发生率和甘精胰岛素用量。     

Clinical study of repaglinide efficacy and safety in type 2 diabetes mellitus patients with blood glucose levels inadequately controlled by sitagliptin

Aims/Introduction

The aim of the present study was to evaluate the long‐term efficacy and safety of adding repaglinide in patients with type 2 diabetes mellitus whose blood glucose levels were not sufficiently controlled by treatment with a dipeptidyl peptidase‐4 inhibitor, sitagliptin, in addition to diet and exercise therapies.

Materials and Methods

This was a multicenter, uncontrolled, dose‐titration study with a treatment period of 52 weeks. The primary end‐point was the change in glycated hemoglobin levels from baseline.

Results

The glycated hemoglobin level was 7.43 ± 0.57% (mean ± standard deviation) at baseline, and decreased to 6.93 ± 0.91% at the end of the study. The mean changes in glycated hemoglobin levels at 4 weeks and at the end of the study were −0.44 ± 0.28% and −0.50 ± 0.82%, respectively. The glycated hemoglobin‐lowering effect was maintained for 52 weeks. The rate of adverse events was 86.0% (86/100), and there were 352 adverse events. The rate of adverse drug reactions was 21.0% (21/100). Hypoglycemia was reported in 5.0% (5/100) of patients, but there was no incidence of ‘major hypoglycemia’.

Conclusions

Combination therapy with repaglinide and sitagliptin was considered effective for a long term without clinical safety problems in patients with type 2 diabetes mellitus.     

降糖舒片联合瑞格列奈治疗2型糖尿病的临床研究

目的观察降糖舒片联合瑞格列奈治疗2型糖尿病的临床效果。方法选择2017年2月—2018年8月在宝鸡文理学院医院治疗的2型糖尿病患者165例,随机分为对照组(82例)和治疗组(83例)。对照组患者餐前30min口服瑞格列奈片,初始剂量0.5 mg/次,3次/d,之后根据血糖水平调整用药剂量,最大剂量为4 mg/d。治疗组在对照组基础上口服降糖舒片,5片/次,3次/d。两组患者均连续治疗3个月。观察两组患者临床疗效,同时比较治疗前后两组患者糖化血红蛋白(HbA1c)、餐后2 h血糖(2 h PBG)、空腹血糖(FBG)、胰岛素抵抗指数(HOMA-IR)、胰高血糖素样肽-1(GLP-1)和空腹胰岛素(FINS)水平。结果治疗后,对照组临床有效率为78.05%,显著低于治疗组的93.98%,两组比较差异有统计学意义(P0.05)。治疗后,两组患者HbA1c、2 h PBG和FBG水平均显著下降(P0.05),且治疗组患者HbA1c、2 h PBG和FBG水平明显低于对照组(P0.05)。治疗后,两组患者HOMA-IR显著降低(P0.05),而GLP-1和FINS水平均显著升高(P0.05),且治疗组患者上述胰岛素指标水平明显好于对照组(P0.05)。结论降糖舒片联合瑞格列奈治疗2型糖尿病,可有效改善患者临床症状,降低血糖水平和胰岛素抵抗。     

西格列汀与瑞格列奈治疗初诊2型糖尿病的临床疗效对比

目的 比较西格列汀与瑞格列奈治疗初诊2型糖尿病（T2DM）的临床疗效。方法 回顾性分析104例初诊T2DM患者的临床资料,其中54例为西格列汀治疗（G组）,50例为瑞格列奈治疗（R组）。比较两组治疗前后空腹血糖（FPG）、餐后2 h血糖（2 hPG）、糖化血红蛋白（HbA1c）、总胆固醇（TC）、三酰甘油（TG）、高密度脂蛋白胆固醇（HDL-C）水平及糖化血红蛋白（HbA1c）达标率、体质指数（BMI）变化量和低血糖发生率。结果 两组治疗后的FPG、2hPG、HbA1c水平均明显低于治疗前,同组治疗前后比较差异有统计学意义（P<0.05）,但组间差异无统计学意义。两组治疗前后的TG、TC、HDL-C水平均无明显变化。两组HbA1c达标率无统计学意义,G组BMI变化量及低血糖发生率明显低于R组,组间差异有统计学意义（P<0.05）。结论 西格列汀与瑞格列奈治疗初诊T2DM患者均能有效降低血糖,对血脂无明显影响,但西格列汀在控制BMI和减少低血糖方面更有优势。     

二甲双胍与瑞格列奈治疗老年糖尿病患者疗效比较

探讨二甲双胍治疗老年糖尿病患者的疗效及安全性。方法：72例老年糖尿病患者随机分为观察组与对照组各36例。观察组采用二甲双胍片治疗,对照组给予瑞格列奈片,疗程均为8周。比较两组的疗效及安全性。结果：两组治疗后空腹、三餐后2h及晚10点时的血糖值均较前显著下降（P〈0．05）;观察组治疗后空腹血糖水平明显低于对照组（P〈0．05）,其他时间点血糖值与对照组比较差异无统计学意义（P〉0．05）。观察组治疗后HbAle水平明显低于治疗前（P〈0．05）,对照组治疗前后HbAlc水平差异无统计学意义（P〉0．05）。观察组药品不良反应发生率低于对照组,差异有统计学意义（P〈0．05）。结论：二甲双胍在治疗老年患者糖尿病治疗中效果显著,安全性高,值得进一步推广应用。