Effects of Hydrochlorothiazide on the Pharmacokinetics,Pharmacodynamics, and Tolerability of Canagliflozin,a Sodium Glucose Co-transporter 2 Inhibitor,in Healthy Participants

Background

Many patients with type 2 diabetes mellitus (T2DM) also have hypertension, which is commonly treated with thiazide diuretics, including hydrochlorothiazide (HCTZ). Canagliflozin, a sodium glucose cotransporter 2 inhibitor developed for the treatment of T2DM, lowers plasma glucose by inhibiting renal glucose reabsorption, thereby increasing urinary glucose excretion and mild osmotic diuresis. Because patients with T2DM are likely to receive concurrent canagliflozin and HCTZ, potential interactions were evaluated.

Objective

This study evaluated the effects of HCTZ on the pharmacokinetic and pharmacodynamic properties and tolerability of canagliflozin in healthy participants.

Methods

This Phase I, single-center, open-label, fixed-sequence, 2-period study was conducted in healthy participants. During period 1, participants received canagliflozin 300 mg once daily for 7 days, followed by a 14-day washout period. During period 2, participants received HCTZ 25 mg once daily for 28 days, followed by canagliflozin 300 mg + HCTZ 25 mg once daily for 7 days. Blood samples were taken before and several times after administration on day 7 of period 1 and on days 28 and 35 of period 2 for canagliflozin and HCTZ pharmacokinetic analyses using LC-MS/MS. Blood and urine samples were collected for up to 24 hours after canagliflozin administration on day 1 of period 1 and day 35 of period 2 for pharmacodynamic glucose assessment. Tolerability was also evaluated.

Results

Thirty participants were enrolled (16 men, 14 women; all white; mean age, 43.7 years). Canagliflozin AUC during a dosing interval (T) at steady state (AUC_τ,ss) and C_max at steady state (C_max,ss) were increased when canagliflozin was coadministered with HCTZ, with geometric mean ratios (90% CI) of 1.12 (1.08–1.17) and 1.15 (1.06–1.25), respectively. AUC_τ,ss and C_max,ss for HCTZ were similar with and without canagliflozin coadministration. The 24-hour mean renal threshold for glucose and mean plasma glucose were comparable for canagliflozin alone and coadministered with HCTZ. The change in 24-hour urine volume from baseline was −0.1 L with canagliflozin alone and 0.4 L with HCTZ alone and with canagliflozin + HCTZ. The overall incidence of adverse events (AEs) was higher with canagliflozin + HCTZ (69%) than with canagliflozin (47%) or HCTZ (50%) alone; most AEs were of mild severity. Overall, minimal changes in serum electrolytes (eg, sodium, potassium) were observed after coadministration of canagliflozin + HCTZ compared with individual treatments.

Conclusions

Adding canagliflozin treatment to healthy participants on HCTZ treatment had no notable pharmacokinetic or pharmacodynamic effects; canagliflozin coadministered with HCTZ was generally well tolerated, with no unexpected tolerability concerns. ClinicalTrials.gov identifier: NCT01294631.     

Pharmacokinetic Interaction Between Rosuvastatin and Metformin in Healthy Korean Male Volunteers: A Randomized,Open-label, 3-period,Crossover, Multiple-dose Study

Purpose

Rosuvastatin is indicated for hypercholesterolemia or dyslipidemia and metformin mainly for type 2 diabetes. These 2 drugs are frequently prescribed in combination due to the high comorbidity of the 2 diseases. However the nature of pharmacokinetic interaction between the 2 drugs has not been previously investigated. The purpose of our study was to investigate the pharmacokinetic interaction between rosuvastatin and metformin in healthy Korean male volunteers.

Methods

This was a randomized, open-label, 6-sequence, 3-period, crossover, multiple-dose study. Eligible subjects, aged 20 to 50 years and within 20% of the ideal body weight, received 1 of the following 3 treatments for each period once daily for 5 consecutive days with a 10-day washout period between the treatments: monoadministration of rosuvastatin 10 mg tablet, monoadministration of metformin 750 mg tablet, and coadministration of rosuvastatin 10 mg tablet with metformin 750 mg tablet. Blood samples were collected up to 72 hours after the last dose and pharmacokinetic parameters for rosuvastatin and metformin were compared between combination and monotherapy. Adverse events were investigated and evaluated based on subject interviews and physical examinations.

Findings

Among the 36 enrolled subjects, 31 completed the study. The coadministration of rosuvastatin with metformin produced a significant pharmacokinetic interaction in rosuvastatin C_ss,max, with the 90% CI for the geometric mean ratio (coadministration:monoadministration) being 110.27% to 136.39% (P = 0.0029), whereas no significant interaction was observed in rosuvastatin AUC_tau, yielding the 90% CI of 104.41% to 118.95%. When metformin was coadministered with rosuvastatin, no significant pharmacokinetic interaction was observed for C_ss,max and AUC_tau of metformin, yielding the 90% CIs of the geometric mean ratio for coadministration to monoadministration as 87.38% to 102.54% and 86.70% to 99.08%, respectively. Overall, 19 mild and 1 moderate adverse events occurred in 12 subjects, with no significant differences in the incidence among the 3 treatments.

Implications

Although the C_ss,max of rosuvastatin was significantly influenced by coadministration with metformin, the degree of interaction seen was considered clinically insignificant, with no significant interaction observed in the other pharmacokinetic measures between the 2 drugs. These results imply that drug effects of rosuvastatin and metformin will also not be significantly influenced by coadministration of the 2 drugs. All treatments were well tolerated and no serious adverse events occurred. ClinicalTrials.gov identifier: NCT01526317.     

Pharmacokinetics and Safety of Subcutaneous Pasireotide and Intramuscular Pasireotide Long-acting Release in Chinese Male Healthy Volunteers: A Phase I,Single-center,Open-label,Randomized Study

Purpose

The purpose of this study was to assess the pharmacokinetic (PK) properties and safety of single and multiple doses of subcutaneous (SC) pasireotide and a single-dose intramuscular (IM) long-acting release (LAR) formulation of pasireotide in Chinese healthy volunteers (HVs) versus the PK properties in Western HVs (pooled from previous PK studies).

Methods

In this phase I, single-center, open-label study, 45 Chinese male HVs were evenly randomized to 1 to 9 treatment sequences: each volunteer received a single dose of 300, 600, or 900 μg of pasireotide SC on day 1, followed by administration of the same dose BID from day 15 to the morning of day 19, and then a single IM dose of 20, 40, or 60 mg of pasireotide LAR on day 33. The PK parameters were assessed with noncompartmental analysis. Statistical comparison of PK parameters, including AUC, C_max, and CL/F from both formulations, was made for Chinese versus Western male HVs. The safety profile was also assessed. Metabolic parameters, including blood glucose, insulin, and glucagon, and measures that reflect the effects of pasireotide LAR on relatively long-term glucose control, lipid metabolism, and systemic concentrations of pancreatic enzymes and thyrotropin were evaluated.

Findings

Of the 45 randomized HVs, 42 completed the study per protocol, 1 withdrew his informed consent for personal reasons, and 2 prematurely discontinued the study because of adverse events (AEs). Concentration-time and safety profiles of both formulations were similar to those reported in Western HVs. Mean geometric mean ratios (GMRs) of Chinese versus Western HVs ranged from 0.79 to 1.42. For most primary PK parameters, 90% CIs for GMRs were within a predefined ethnic insensitivity interval (90% CI, 0.70–1.43). After considering age and weight as covariates in the statistical model, the GMRs and 90% CIs for other PK parameters were within the predefined interval (C_max in single-dose SC administration) or significantly decreased (C_min,ss in multiple BID SC doses and first peak C_max in the single-dose LAR formulation). No serious AEs were reported. Both formulations were well tolerated; pasireotide SC caused transient changes in glucose metabolism. Owing to the differential binding affinity to the somatostatin receptor subtypes, pasireotide LAR elicited a concentration-dependent increase of fasting blood glucose, substantial reduction in triglyceride, and a mild decrease in cholesterol. The most frequently reported AEs after single-dose and multiple-dose pasireotide SC were injection site reaction, nausea, dizziness, and diarrhea; most HVs developed diarrhea with single-dose pasireotide LAR.

Implications

The pasireotide formulations had similar PK and safety profiles between Chinese and Western male HVs. Thus, no ethnic sensitivity was found for pasireotide SC or LAR.     

流式细胞仪分选侧群细胞条件的探索与优化

目的探讨不同浓度的荧光染料(Hoechst 33342)和抑制剂维拉帕米(verapamil)对流式细胞仪分选侧群(SP)细胞的影响。方法实验分为Hoechst 33342组(Hoechst 33342浓度分别为2.5、5.0和7.5μg/mL)和抑制组(Hoechst 33342+verapamil,verapamil浓度分别为50、100和150μmol/L),用流式细胞仪分选人肺腺癌细胞系A549中SP细胞,摸索Hoechst 33342和verapamil的最佳浓度,并用本实验室构建的一株肿瘤细胞系K1进行验证。结果在verapamil和Hoechst 33342浓度分别为150μmol/L和7.5μg/mL时,A549细胞染色充分,SP细胞亚群与非SP(non-SP)细胞亚群分群明显,SP细胞约为2.2%。K1细胞在verapamil为50μmol/L和Hoechst 33342为5μg/mL时,SP细胞亚群与non-SP细胞亚群分群明显,SP细胞亚群可被verapamil抑制,其比例约为1.3%。分选后的SP细胞和non-SP细胞可进一步扩增培养。结论 Hoechst 33342和verapamil可影响肿瘤细胞中SP细胞分选效率。     

盐城市盐都区高危人群梅毒抗体检测结果分析

目的：了解盐城市盐都区高危人群梅毒感染状况,为预防和干预提供科学依据。方法采用 ELISA 法检测 TP 抗体,TP 抗体阳性者用梅毒螺旋体抗体明胶颗粒凝集试验（TPPA）进行复检,确认阳性者再作梅毒快速血浆反应素试验（RPR）。结果高危人群梅毒抗体阳性率为14.30％,梅毒感染者中 RPR 阳性率为58.18％;不同人群、不同年龄组性别梅毒抗体阳性率经统计学分析差异有统计学意义（P ＜0.05）。结论盐都区高危人群梅毒感染率高,性病门诊就诊者、劳教收容人员感染率均高于艾滋病自愿咨询检测（VCT）者;21～40岁女性感染率明显高于男性。应加强高危人群监测,开展宣传教育和行为干预,从而有效遏制梅毒在人群中的传播。     

新疆汉族与维吾尔族HBV耐药变异类型与基因型研究

目的探讨新疆地区慢性乙型肝炎患者乙型肝炎病毒(HBV)耐药变异类型与基因型的关系。方法应用聚合酶链反应(PCR)对245例HBV DNA阳性标本进行HBV基因分型。采用基因芯片技术对HBV拉米夫定及阿德福韦酯相关耐药基因突变位点(包括180、204、181、236位点)进行检测。结果 245例慢性乙型肝炎患者检出HBV基因型B型40例、C型137例、C/D混合型48例、其它型别20例,在不同性别及年龄间的分布差异无统计学意义(χ2=1.791,P=0.617;χ2=14.214,P=0.115),而在不同民族间的分布差异有统计学意义(χ2=83.076,P=0.000)。HBV在180、204、181、236位点的突变检出率分别为33.8%、76.8%、66.9%、45.0%,差异有统计学意义(P0.05);HBV常见变异类型的基因型构成差异无统计学意义(χ2=14.969,P=0.454),但C型HBV在各变异类型中所占的比例均最高。结论 HBV基因型在不同民族间的分布不同;HBV常见耐药位点的突变情况不同;HBV基因型在常见变异类型中的分布相同。     

压疮危险人群居家护理管理

目的：运用全程化的护理模式对居家的压疮危险人群进行管理,降低居家压疮危险人群压疮发生率。方法：建立压疮危险人群居家护理管理小组,进行相关培训,明确人员职责及运行模式,把本院出院及门诊就诊患者压疮危险人群纳入统一管理,进行相关护理干预,创建开放的压疮护理网络服务微信平台,为专科护士、社区护士、压疮危险人群居家护理者提供压疮预防、护理的相关资讯。结果：培训前、后参训人员的基本理论及基本操作技能考核成绩明显提高（P<0.01）;居家压疮危险人群压疮发生率明显降低（P<0.01）。结论：通过压疮危险人群居家护理管理可明显降低其压疮发生率。     

日本血吸虫中间宿主钉螺的种群遗传变异研究

以采自中国湖北、江苏、四川省三地现场钉螺和饲养在泰国玛希伦大学实验室的菲律宾钉螺为研究种群,用水平淀粉凝胶电泳方法研究各种群间的遗传变异.实验共观察7个酶中的14个等位点,并以杂合子、多态位点百分比和每位点平均等位基因数衡量遗传变异,结果表明中国大陆钉螺种群的变异程度较高.湖北省钉螺与菲律宾钉螺间的遗传距离最大,为0.44,湖北省与江苏省钉螺间遗传距离最小,为0.03.以UPGMA相似性聚类分析而构建的分校图谱显示中国大陆钉螺存在多亚种.