进口与国产二甲双胍片生物等效性及药代动力学比较

二甲双胍(metformin)是一种治疗非胰岛素依赖型糖尿病(2型糖尿病)的降糖药。国内临床实验证明,每日口服0．5g或0．85g二甲双胍2次能有效的控制血糖。与硫脲类降糖药相比,二甲双胍不增加体重,且耐受性好。但进口和国产二甲双胍片两者价格悬殊。为了评价二甲双胍片的生物利用度,为其临床应用提供参考,作者等对两种二甲双胍片的药学指标进行比较,现将结果报道如下。     

SLC22A1 rs628031基因多态性与二甲双胍不良反应的关系

目的本研究旨在观察SLC22A1 rs628031基因多态性与二甲双胍不良反应之间的关系。方法前瞻性研究93例接受单用二甲双胍口服降糖治疗的初诊2型糖尿病患者。从患者外周血白细胞中提取DNA,应用单碱基延伸法进行基因分型,并分析基因多态性与不同剂量二甲双胍不良反应的关系。结果 rs628031基因多态性与二甲双胍不良反应的发生,差异无统计学意义(P=0.062)。在药物剂量亚组分析中,rs628031 GA/AA基因型的患者接受单用高剂量二甲双胍口服降糖治疗后,发生不良反应的比率明显增高(85.7%vs.14.3%,P=0.015),但是,在低剂量组中,组间比较差异无统计学意义(P=0.605)。结论本研究结果提示SLC22A1 rs628031基因多态性与高剂量二甲双胍的不良反应发生有关。     

二甲双胍对糖耐量减低患者血压的影响

高胰岛素血症、胰岛素抵抗与高血压的关系目前已成为一个研究热点，以往的研究多见于噻唑烷二酮类药物对2型糖尿病患者血压的影响，而二甲双胍对糖耐量减低(IGT)患者血压影响的报道国内鲜见。为此，我们观察了使用二甲双胍对IGT患者进行干预过程中的血压变化，现报告如下。     

SIRT1基因多态性对血糖控制不佳的2型糖尿病患者接受利拉鲁肽联合二甲双胍治疗效果的影响

目的 本研究旨在探讨SIRT1基因多态性对血糖控制不佳的2型糖尿病患者接受利拉鲁肽联合二甲双胍治疗临床疗效的影响.方法 研究纳入接受2型糖尿病治疗血糖控制不佳患者216例,采用利拉鲁肽联合二甲双胍治疗方案,26周后评价临床疗效,分析患者SIRT1基因多态性与疗效之间的关系.结果 216例患者接受26周利拉鲁肽联合二甲双...     

二甲双胍对急性单核细胞白血病细胞株THP-1增殖、分化和凋亡的影响

目的:探讨二甲双胍(metformin)对体外培养的急性单核细胞白血病细胞株THP-1细胞增殖、分化和凋亡的影响,并分析其可能的作用机制。方法:用不同浓度的二甲双胍分别对THP-1细胞进行体外干预,24 h、48 h后用CCK-8法检测细胞的增殖情况;20 mmol/L二甲双胍干预24 h后用Annexin V/7-AAD双标记法分析细胞凋亡情况;流式细胞术检测细胞表面分化抗原CD11b、CD14的变化;实时定量PCR检测BCL-XL、BAX、BIM、Caspase-3mRNA表达的变化。结果:CCK-8法检测显示二甲双胍对THP-1细胞增殖具有显著的抑制作用,且作用呈时间和剂量依赖性;20 mmol/L二甲双胍干预THP-1细胞24 h后,流式细胞术检测结果显示CD11b、CD14阳性细胞率无明显变化(P0.05);Annexin V/7-AAD标记的流式细胞术检测显示,实验组和对照组早期凋亡细胞比例分别为(2.02±0.85)%和(4.46±1.33)%,晚期凋亡细胞比例分别为(1.43±0.83)%和(3.31±0.59)%,在实验组明显高于对照组(P0.05);20 mmol/L二甲双胍诱导THP-1细胞过程中BCL-XL、BIM表达无明显变化,BAX、Caspase-3表达显著增加(P0.01)。结论:二甲双胍能有效抑制THP-1细胞增殖并促进细胞凋亡,但对THP-1细胞分化无明显影响,其促进凋亡机制可能与上调BAX及Caspase-3基因有关。     

SLC22A1、SLC22A4基因多态性与2型糖尿病患者二甲双胍疗效的相关性

目的探讨甘肃地区2型糖尿病(T2DM)患者SLC22A1 rs628031与SLC22A4 rs272893位点基因多态性与二甲双胍疗效的相关性。方法以300例T2DM患者与300例健康对照者为研究对象,用PCR-限制性片段长度多态性(PCR-RFLP)的方法检测2个基因多态性位点突变在甘肃汉族人群中的分布频率。选取其中新诊断的T2DM患者105例,接受每日口服500 mg二甲双胍的治疗,随访90 d;根据基因型分组,分析空腹血糖(FPG)、餐后2 h血糖(2h PPG)及糖化血红蛋白(Hb A1c)变化情况与各基因型的关系。结果 SLC22A1 rs628031与SLC22A4 rs272893在T2DM患者和健康对照者之间的分布频率差异均无统计学意义(P均0.05)。SLC22A1 rs628031 AG型与AA型、GG型与AA型FPG、Hb A1c治疗前后变化幅度差异均有统计学意义(P均0.05)。SLC22A4 rs272893基因多态性中GG型与AA型FPG治疗前后变化幅度差异有统计学意义(P0.05)。结论 SLC22A1rs628031和SLC22A4 rs272893基因多态性位点突变与2型糖尿病患者二甲双胍的疗效存在一定的关联。     

二甲双胍的临床应用

二甲双胍为目前国内外常用的双胍类降糖药。在临床上除主要用于降血糖外，还用于治疗多囊卵巢综合征（PCOS）。     

口服二甲双胍致过敏性休克1例

1病历摘要 男，64岁。因多尿、多饮、多食伴消瘦1个月于2008—02—20入院。空腹血糖9．0mmol／L，餐后2h血糖12．5mmol／L，诊断为2型糖尿病，给予二甲双胍口服以降血糖治疗（O．25g／次，3次／d），此期间未用任何其他药物。晚上第1次用药后0．5h感周身乏力不适，休息一会儿即缓解，未在意；次晨再次服用此药后约0．5h，患者自觉周身瘙痒、胸闷、呼吸困难，继之出现意识不清，二便失禁。立即急诊来院。既往曾有青霉素过敏史。     

二甲双胍对2型糖尿病胰岛素抵抗的影响

目的：观察二甲双胍对2型糖尿病患者胰岛素抵抗（1R）的影响。方法：40例2型糖尿病患者给予二甲双胍治疗12周。测定治疗前后血清胰岛素水平，计算稳态模型（Homa—model）的胰岛素抵抗指数（Homa—lit）β细胞功能（Homa—β）的变化。结果：二甲双胍治疗后与用药前相比，空腹胰岛素水平略有降低，馒头餐后胰岛素水平明显降低，IR明显降低，β细胞功能明显改善。结论：二甲双胍能有效降低1R和改善β细胞功能。     

Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics

The goal of this study was to determine the effects of genetic variation in the organic cation transporter 1, OCT1, on the pharmacokinetics of the antidiabetic drug, metformin. Twenty healthy volunteers with known OCT1 genotype agreed to participate in the study. Each subject received two oral doses of metformin followed by collection of blood and urine samples. OCT1 genotypes had a significant (P<0.05) effect on metformin pharmacokinetics, with a higher area under the plasma concentration-time curve (AUC), higher maximal plasma concentration (Cmax), and lower oral volume of distribution (V/F) in the individuals carrying a reduced function OCT1 allele (R61C, G401S, 420del, or G465R). The effect of OCT1 on metformin pharmacokinetics in mice was less than in humans possibly reflecting species differences in hepatic expression level of the transporter. Our studies suggest that OCT1 genotype is a determinant of metformin pharmacokinetics.     

Safety,tolerability, and pharmacokinetics of single and multiple topical ophthalmic administration of imatinib mesylate in healthy subjects

For the long‐term efficacy of dry eye disease treatment, relieving underlying inflammation is necessary. Imatinib mesylate is a novel ophthalmic formulation of imatinib mesylate, which is expected to alleviate inflammation by inhibiting the discoidin domain receptor 1 activity. This study aims to evaluate the safety and pharmacokinetics of imatinib mesylate in healthy subjects. A randomized, double‐blind, placebo‐controlled study was conducted. In a single ascending dose, 16 subjects received a single eye drop of imatinib mesylate 0.1%, 0.3%, or matching placebo. In the multiple ascending dose (MAD), subjects received multiple eye drops of imatinib mesylate 0.1%, 0.3%, or matching placebo once daily for 7 days. Safety and tolerability were assessed by ophthalmic examination, including the visual analog scale (VAS) to monitor the burning sensation in the eyes. A total of four treatment‐emergent adverse events (TEAEs) occurred during the study. All TEAEs were mildly severe with no serious cases. VAS results in the 0.1% MAD group exhibited highest score of two points, whereas it was less than one point in others. Insignificant difference between the imatinib mesylate and placebo groups in the VAS results was seen. After a single dose administration of imatinib mesylate 0.1%, all plasma concentrations were below the lower limit of quantification. The peak plasma concentrations of imatinib were less than 0.54 µg/L in all groups. In conclusion, a single and multiple topical ophthalmic administration of imatinib mesylate was well‐tolerated in healthy subjects. Because there was minimal systemic exposure to imatinib, the adverse effect in the body seems to be insignificant.     

Effect of eslicarbazepine acetate on the pharmacokinetics of digoxin in healthy subjects

Eslicarbazepine acetate (ESL) is a new-generation voltage-gated sodium channel blocker, which has been demonstrated to be effective and well tolerated in the treatment of epilepsy. The primary objective of this study was to investigate the effect of ESL on the pharmacokinetics of digoxin. This study was a randomized, double-blind, placebo-controlled, two-way crossover study of 12 healthy subjects (six men and six women). The study included two 8-day treatment periods with a washout of ≥10 days. In each period, subjects received either ESL 1200 mg once-daily or placebo, concomitantly with a loading oral dose of digoxin 0.5 mg on days 1 and 2, followed by a once-daily maintenance dose of 0.25 mg on days 3–8. Maximum serum digoxin plasma concentrations ( C _max) were reached ( t _max) at 0.5–2.0 h post-dose (median = 1.0 h) and at 0.5–4.0 h post-dose (median = 1.0 h) with Reference (digoxin plus placebo) and Test (digoxin plus ESL) treatments, respectively. The Test/Reference digoxin geometric mean ratios and 90% confidence intervals (90% CI) were 0.96 and 0.90–1.03 for the area under the plasma concentration–time curve over the dosing interval (AUC_0–24) and 0.85 and 0.68–1.07 for C _max. The 90% CI was within the bioequivalence range (0.80–1.25) for AUC_0–24, thus demonstrating bioequivalence. The 90% CI was outside the 0.80–1.25 range for digoxin C _max, but it appeared to be caused by a higher variability in digoxin C _max following co-administration of digoxin with placebo than with ESL. Co-administration of ESL and digoxin was well tolerated. Concomitant administration of ESL has no clinically relevant effect in the systemic exposure to digoxin.     

Evaluation of the safety and pharmacokinetics of a fast-acting recombinant FVIIa analogue, NN1731, in healthy male subjects

Summary.  Background:  NN1731 is a recombinant activated factor VII (rFVIIa) analog with enhanced activity. Objectives:  This clinical trial aimed to assess the safety and pharmacokinetics of single doses of NN1731 in healthy male subjects. Methods : This was a randomized, placebo-controlled dose - escalation trial with four dose tiers (NN1731 5 – 30 μg kg⁻¹). Eight subjects were randomized to either NN1731 ( n  =   6) or placebo ( n  =   2) in each tier. Results:  No thromboembolic or serious adverse events were reported and no antibody formation towards NN1731 was detected. NN1731 was demonstrated to be pharmacologically active based on coagulation-related parameters (prothrombin fragment 1+2, activated partial thromboplastin time and prothrombin time). There were five mild/moderate adverse events in three subjects. The FVIIa activity of NN1731 after ascending single-dose administration of NN1731 fits well with a two-compartment model, indicating a bi-exponential decline with a rapid initial distribution of approximately 73% FVIIa activity (half-life   =   20 min), followed by a less rapid terminal elimination phase eliminating the remaining 27% (half-life   =   3 h). Dose proportionality in healthy male subjects at the dose levels investigated (5 – 30 μg kg⁻¹) was supported by the FVIIa activity data. Conclusions:  Based on the results of this trial, NN1731 appears safe and well tolerated in healthy subjects at doses up to 30 μg kg⁻¹. No immunogenic or thromboembolic events were reported. The pharmacokinetic profile of NN1731 as measured by FVIIa activity appears to follow two-compartment pharmacokinetics characterized by an initial rapid distribution phase followed by a less rapid elimination phase.