坎地沙坦联合比索洛尔治疗对老年高血压患者左心室肥厚及心功能不全的影响

目的观察坎地沙坦联合比索洛尔治疗对老年高血压患者左心室肥厚及心功能不全的影响。方法将2011年7月-2012年8月收治的60岁以上的门诊或住院高血压患者117例随机分为对照组58例和试验组59例。对照组给予比索洛尔及苯磺酸左旋氨氯地平治疗,试验组给予坎地沙坦联合比索洛尔治疗。结果两组患者治疗3个月后的血压与治疗前比较均下降差异有统计学意义（P〈0.05）,两组患者治疗后的血压比较差异无统计学意义（P〉0.05）;两组患者治疗12个月后左心室舒张末期内径、室间隔舒张末期厚度、左心室后壁舒张末期厚度、心肌质量及左心室质量指数与治疗前后比较均下降,差异有统计学意义（P〈0.05）,射血分数与E/A升高,差异有统计学意义（P〈0.05）,且试验组结果优于对照组,差异有统计学意义。结论比索洛尔联合苯磺酸左旋氨氯地平或坎地沙坦均能有效控制老年高血压患者的血压及逆转左心室肥厚与心功能不全,但比索洛尔联合坎地沙坦的效果优于联合苯磺酸左旋氨氯地平。     

富马酸氯马斯汀联合盐酸奥洛他定治疗慢性荨麻疹临床观察

目的评价富马酸氯马斯汀联合盐酸奥洛他定治疗慢性荨麻疹的临床疗效及安全性。方法将入选的90例患者随机分成两组各45例,对照组口服富马酸氯马斯汀口服溶液10 mL 2次/d;治疗组在对照组基础上加用盐酸奥洛他定片5 mg,2次/d,疗程共8周。结果治疗结束后,治疗组有效率(90.48%)明显高于对照组(72.09%),差异有统计学意义(P<0.05)。治疗结束1个月后,治疗组复发率(15.79%)明显低于对照组(38.71%),差异有统计学意义(P<0.05)。且两组患者不良反应轻微。结论富马酸氯马斯汀联合盐酸奥洛他定治疗慢性荨麻疹安全、有效。     

Tolerability and Pharmacokinetics of Delayed-Release Dimethyl Fumarate Administered With and Without Aspirin in Healthy Volunteers

Background

Delayed-release dimethyl fumarate (DR-DMF) has cytoprotective and antiinflammatory properties and has recently been approved in the United States as an oral treatment for relapsing forms of multiple sclerosis. The most common adverse events associated with DR-DMF are flushing and gastrointestinal (GI) events, the incidences of which diminish over time.

Objective

The purpose of this study was to evaluate the tolerability and pharmacokinetic (PK) profile of DR-DMF with or without concomitant acetylsalicylic acid (aspirin), a cyclooxygenase inhibitor.

Methods

Healthy volunteers (N = 56) were randomized to receive different dosing regimens of DR-DMF or matching placebo with or without pretreatment with 325 mg aspirin for 4 days. Plasma levels of the active metabolite monomethyl fumarate were assessed on days 1 and 4. Flushing and GI events were assessed using patient-reported scales. Potential flushing mediators were explored.

Results

DR-DMF showed a safety, tolerability, and PK profile consistent with previous clinical experience, with no evidence of accumulation. Pretreatment with aspirin had no effect on the primary PK parameters, AUC_0–10h, or C_max. Flushing severity, assessed by 2 subject-reported rating scales, was generally mild and was rated highest at the start of treatment. Pretreatment with aspirin reduced flushing incidence and intensity without affecting GI events or the PK profile of DR-DMF. In some DR-DMF–treated individuals, plasma concentrations of a prostaglandin D₂ (PGD₂) metabolite were increased.

Conclusions

In healthy volunteers, DR-DMF was well tolerated over 4 days of dosing, with a PK profile consistent with that previously reported and no evidence of accumulation. Aspirin pretreatment reduced the incidence and intensity of flushing without affecting GI events or the DR-DMF PK profile. Elevated levels of PGD₂ in some DR-DMF–treated individuals suggest that flushing may be, at least in part, prostaglandin mediated. ClinicalTrials.gov identifier: ID: NCT01281111.     

Pharmacokinetics and Tolerability of Tenofovir Disoproxil Fumarate 300 mg Once Daily: An Open-Label,Single- and Multiple-Dose Study in Healthy Chinese Subjects

Background

Tenofovir disoproxil fumarate (TDF) has been approved worldwide for the treatment of adults with chronic hepatitis B and, in combination with other antiretroviral agents, HIV-1 infection. Although its use for the treatment of HIV has been approved by the Chinese State Food and Drug Administration, there are no data on the pharmacokinetic profile of TDF in Chinese individuals.

Objectives

This study aimed to investigate the pharmacokinetic properties and tolerability of TDF in healthy Chinese subjects.

Methods

This open-label, single- and multiple-dose study was conducted in healthy Chinese volunteers. Subjects received TDF 300 mg once daily, administered as a single dose (day 1) and multiple doses (days 4–10). Multiple plasma samples were collected over time, and the concentrations of TDF were determined using LC-MS/MS. Pharmacokinetic parameters were estimated using a noncompartmental model. Tolerability was determined using clinical evaluation and monitoring of adverse events (AEs).

Results

Fourteen volunteers were enrolled (7 men, 7 women; mean age, 24.6 years). TDF was rapidly absorbed; median T_max was 0.75 hour, and t_½ was ~21 hours with single dosing. The mean ratio of AUC_0–τ steady state/AUC_0–24 single dose was 1.55. The pharmacokinetic properties of TDF were consistent between the single dose and multiple doses, and between men and women. No serious AEs were reported, and there were no discontinuations due to AEs.

Conclusions

There was an accumulation of approximately 55% in tenofovir exposure in healthy Chinese between multiple dose and single dose. TDF exhibited a pharmacokinetic profile similar to that of healthy Western subjects in a historical comparison. TDF was generally well tolerated in these healthy Chinese subjects. ClinicalTrials.gov identifier: NCT01480622.     

富马酸二甲酯慢性毒性与致癌性研究

给４４０只Ｗｉｓｔａｒ大鼠喂饲含０、１２５、２５０、５００及１０００ｐｐｍ富马酸二甲酯（ＤＩＭＥＦＵ）的饲料２４个月。实验结果，各实验组与对照组相比，食物利用率、掺入量、生长、一般表现、列亡率及平均寿命均无显著性差异。血液学检查仅个别指标出现差别，但波动在正常范围。１０００ｐｐｍ组动物血清ＧＰＴ、ＧＯＴ及肝、肾脏器系数呈现持续性改变。病理组织学检查表明各组非肿瘤性及肿瘤性病变发生率与饲料中ＤＩＭＥ     

Decreased ciprofloxacin absorption with concomitant administration of ferrous fumarate

The effect of ferrous fumarate on the relative bioavailability of ciprofloxacin after a single 500 mg oral dose of ciprofloxacin was studied in eight healthy males. Blood samples were collected at regular intervals 0–24 h post-dose. Urine was collected during 24 h to determine the cumulative urine excretion of ciprofloxacin. Ciprofloxacin concentrations in serum and urine were determined by high pressure liquid chromatography. Mean area under the serum concentration—time curve decreased significantly (P<0.001) after ciprofloxacin was taken with 200 mg ferrous fumarate. The relative bioavailability was 30% when ciprofloxacin was given with ferrous fumarate. The maximum blood level decreased from 2.1±0.9 (control) to 0.6±0.2 mg/l (with ferrous fumarate). Further studies are needed to determine if chronic treatment with ferrous fumarate further decreases the relative bioavailability. For the moment administration of ciprofloxacin with ferrous fumarate should therefore be avoided.     

西替利嗪与酮替芬治疗儿童急性荨麻疹的比较

目的 比较西替利嗪与酮替芬治疗学龄期儿童急性荨麻疹的疗效和不良反应。方法 6-12岁急性荨麻疹病人98例，分别给予口服西替利嗪(49例，10mg，1次／d)及酮替芬(49例，2／3片，2次／d)，均用药7d；根据治疗前后病损总积分下降指数，分析疗效并观察比较不良反应。结果 治疗总有效率，西替利嗪组为95．8％，酮替芬组为85．7％，二组无显著差异；西替利嗪组仅有2例出现注意力或记忆力减退，酮替芬组则出现嗜睡l0例，口干5例，注意力或记忆力减退2例。结论 西替利嗪对学龄期儿童急性荨麻疹的疗效并不明显优于酮替芬，但其不良反应轻微。     

Improvement of bone mineral density and markers of proximal renal tubular function in chronic hepatitis B patients switched from tenofovir disoproxil fumarate to tenofovir alafenamide

Tenofovir alafenamide (TAF) is a novel prodrug that reduces tenofovir plasma levels by 90% compared to tenofovir disoproxil fumarate (TDF), resulting in decreased bone mineral density (BMD) loss and renal toxicity. We aimed to study changes in BMD and markers of renal function of chronic hepatitis B (CHB) patients previously treated with TDF who were switched to TAF in as early as 12 weeks. This was a prospective single‐arm open‐label study of 75 CHB patients treated with TDF 300 mg daily who were switched to TAF 25 mg daily and followed for 24 weeks. All patients had been treated with TDF for at least 12 months and had HBV DNA <21 IU/mL at the time of switch. BMD and markers of renal function were taken on the day of switch and repeated after 12 and 24 weeks of TAF treatment. Hip and spine bone mineral density significantly increased from baseline to week 12 (+12.9% and +2.4%, respectively, P < 0.01). There were significant decreases in urinary beta‐2‐microglobulin to creatinine and retinol‐binding protein to creatinine ratios by week 12 (P < 0.01 for both). Mean estimated glomerular filtration rate (GFR) did not change. Tubular reabsorption of phosphate was decreased at week 24 (P < 0.05). In conclusion, CHB patients previously treated with TDF experienced significant improvement in bone density and some markers of renal tubular function and as early as 12 weeks after switching to TAF. Bone density changes associated with TDF may not be entirely related to renal handling of phosphate.     

Assessment of the steady-state pharmacokinetic interaction between etravirine administered as two different formulations and tenofovir disoproxil fumarate in healthy volunteers

Objective

Two open‐label, randomized, cross‐over trials in healthy volunteers were conducted to investigate the pharmacokinetic interaction between etravirine and tenofovir disoproxil fumarate.

Methods

Etravirine was administered as either 800 mg twice a day (bid) (phase II formulation in Study 1) or 200 mg bid (phase III formulation in Study 2) for 8 days followed by a 12 h pharmacokinetic evaluation. After a minimum of 14 days washout, tenofovir disoproxil fumarate 300 mg once a day was administered for 16 days. Volunteers were randomized to receive co‐administration of etravirine with tenofovir disoproxil fumarate on either days 1–8 or days 9–16 followed by a 12 h pharmacokinetic evaluation for etravirine on day 8 or 16, respectively. Plasma and urine tenofovir concentrations were determined on days 8 and 16 over 24 h.

Results

The least square mean (LSM) ratio [90% confidence interval (CI)] for the area under the plasma concentration–time curve from 0 to 12 h (AUC_{12 h}) for etravirine co‐administered with tenofovir disoproxil fumarate vs. etravirine alone was 0.69 (0.61–0.79) and 0.81 (0.75–0.88) in Studies 1 and 2, respectively. The LSM ratio (90% CI) for the effect of etravirine on tenofovir AUC_{24 h} was 1.16 (1.09–1.23) in Study 1 and 1.15 (1.09–1.21) in Study 2.

Conclusions

These alterations are not considered clinically relevant for either drug and no dose adjustment is necessary when etravirine and tenofovir disoproxil fumarate are co‐administered.     

比索洛尔对充血性心力衰竭患者髓过氧化物酶和超敏C反应蛋白的影响

目的 探讨用β受体阻滞剂比索洛尔对充血性心力衰竭（CHF）患者心血管炎症标志物髓过氧化物酶（MPO）、超敏C反应蛋白（hs-CRP）水平以及心功能的影响.方法 按纽约心脏病协会（NYHA）分级标准,96例CHF患者分为Ⅱ～Ⅳ级,完全随机分为常规治疗组（地高辛＋血管紧张素转换酶抑制剂＋利尿剂,n=46）和比索洛尔组（比索洛尔＋常规治疗组药物,n=50）,所有受试者分别于治疗前和随访6个月后测定外周血中MPO、hs-CRP的水平并行心脏彩色多普勒超声检测心功能.结果 常规治疗组及比索洛尔组的CHF患者外周血中MPO、hs-CRP的水平治疗后较治疗前均有明显下降[（38.6±6.4）μg/L比（46.4±7.6）μg/L,（32.5±5.4）μg/L比（47.2±6.6）μg/L;（7.8±1.3）mg/L比（10.2±1.6）mg/L,（6.6±1.5）mg/L比（9.9±1.4）mg/L,P＜0.05],左心室射血分数[（45.3±7.1）%比（38.3±8.7）%;（48.4±6.6）%比（37.5±9.8）%]明显增加（P＜0.05）,心功能明显改善.但比索洛尔组较常规治疗组在心功能改善和MPO、hs-CRP的水平下降方面更明显,差异有统计学意义（P＜0.05）.结论 比索洛尔是一种高选择性β受体阻滞剂,能有效抑制CHF患者神经内分泌的过度激活,控制CHF患者的临床症状,改善预后.