Steady-state pharmacokinetics of diltiazem and hydrochlorothiazide administered alone and in combination

Diltiazem and hydrochlorothiazide are widely used to treat cardiovascular disease, often in combination. The purpose of this investigation was to determine whether a drug–drug pharmacokinetic interaction exists between diltiazem and hydrochlorothiazide. In a randomized, crossover, open study, multiple doses of diltiazem (60 mg four times daily for 21 doses) and hydrochlorothiazide (25 mg twice daily for 11 doses) were administered alone and in combination on three separate occasions to 20 healthy male volunteers. Trough and serial blood samples were collected and plasma was assayed for diltiazem, hydrochlorothiazide, and diltiazem metabolites (desacetyldiltiazem and N-desmethyldiltiazem) using HPLC. Total urine was also collected and quantified for hydrochlorothiazide. Coadministered hydrochlorothiazide did not significantly (p >0.05) alter diltiazem (alone versus combination) steady-state maximum plasma concentration (C; 145 versus 158 ng mL⁻¹, respectively), time to maximum plasma concentration (t_max; 3.0 versus 2.8 h, respectively); area under the plasma concentration–time curve (AUC_ss; 688 versus 771 ng·h mL⁻¹), oral clearance (Cl_oral; 96.2 versus 88.0 L h⁻¹), or elimination half-life (t_1/2; 5.2 versus 5.2 h). Similarly, administration of diltiazem did not significantly (p >0.05) influence hydrochlorothiazide (alone versus combination) C (221 versus 288 ng mL⁻¹), t_max (1.8 versus 2.0 h), AUC_ss (1194 versus 1247 ng·h mL⁻¹), Cl_oral (22.4 versus 21.2 L h⁻¹); t_1/2 (9.8 versus 9.6 h), or renal Cl (15.5 versus 15.2 L h⁻¹). In conclusion, a clinically significant pharmacokinetic interaction between diltiazem and hydrochlorothiazide does not exist. © 1998 John Wiley & Sons, Ltd.     

Pharmacokinetics of a fixed combination of sotalol and hydrochlorothiazide in hypertensive patients with moderate renal insufficiency

Summary Decreased elimination of a combined formulation of Sotalol (160 mg) and hydrochlorothiazide (25 mg) was found in patients with moderate renal insufficiency. Very slight accumulation of sotalol and hydrochlorothiazide was observed, so it appears unnecessary to reduce the dosage in patients with a creatinine clearance of 30 ml/min or more.     

应用动态血压监测评价培哚普利治疗原发性高血压的降压疗效

目的：应用动态血压监测（ABPM）评估培哚普利（Perindopril）对轻、中度原发性高血压（EH）病人的24h降压效果。方法：轻、中度EH病人36例,服用2周安慰剂,坐位舒张压仍在95ˉ114mmHg者给与培哚普利4mg/d治疗8周。及治疗2、4、6、8周末测诊室血压,于服安慰剂末及治疗8周末应用ABPM。结果：培哚普利治疗8周,降压总有效率为83.3%;24h各时点血压均较治疗前显著下降（P＜0.01）不伴有心率及血压昼夜节律的改变;降低收缩压和舒张压的谷／峰值分别为80.6%和86.7%。结论：培哚普利能平稳、有效的控制EH病人24h血压,且病人总体耐受良好。     

氯沙坦钾氢氯噻嗪治疗轻、中度高血压疗效观察

目的评价氯沙坦钾氢氯噻嗪对轻、中度高血压患者的疗效和安全性。方法将66例轻、中度高血压患者采用随机、双盲、平行对照的方法分为对照1组、对照2组及治疗组各22例。对照1组予以吲达帕胺治疗,对照2组予以氯沙坦钾治疗,治疗组予以氯沙坦钾氢氯噻嗪治疗。比较3组降压效果,并观察不良反应。结果治疗组临床显效率和总有效率高于对照1、2组;3组治疗后血压低于治疗前,且治疗组低于对照1、2组,差异均有统计学意义(P<0.05)。治疗组治疗前、后动态血压监测显示,收缩压和舒张压的谷峰比值分别为72.9%和55.8%。结论氯沙坦钾氢氯噻嗪对轻、中度原发性高血压有较好协同作用,且作用平稳,安全性好。     

The influence of ibuprofen,diclofenac and sulindac on the blood pressure lowering effect of hydrochlorothiazide

Summary In an open triple crossover study in 8 patients with essential hypertension, the possibility has been investigated of whether the blood pressure lowering effect of hydrochlorothiazide 50 mg once daily was attenuated by co-administration for 4 weeks of ibuprofen 400 mg t.i.d., diclofenac 25 mg t.i.d. or sulindac 200 mg b.i.d. Only a slight, statistically non-significant change was found, with the exception of a significant increase in systolic blood pressure after 4 weeks treatment with ibuprofen. There was considerable variation in the blood pressure response during treatment with all three NSAIDs, with slight rises in blood pressure in 13 out of 24 periods. Body weight increased significantly on treatment both with ibuprofen and diclofenac, whereas the increase on sulindac was less and was transient. No significant change was found in various biochemical parameters, including plasma electrolytes, plasma renin activity (PRA), aldosterone, albumin and creatinine, in haematocrit or in the 24-h urinary excretion of sodium and potassium. The sole exception was a decrease in PRA during ibuprofen treatment. From these observations it is concluded that ibuprofen and diclofenac differ from sulindac in their interaction with the diuretic action of hydrochlorothiazide. It appears that all three NSAIDs can safely be combined with hydrochlorothiazide in hypertensive patients, but blood pressure should be monitored carefully when an NSAID are added.     

培哚普利和螺内酯对高血压大鼠心血管重构及纤溶的影响

目的：探讨血管紧张素转换酶抑制剂培哚普利（ perindopril ）和醛固酮受体拮抗剂螺内酯（ spironlactone ）对实验性高血压大鼠心脏、血管重构的逆转作用及纤溶系统的影响。方法腹主动脉缩窄法建立高血压动物模型,44只雄性Wistar 大鼠随机分为高血压模型组、培哚普利组（2 mg · kg^-1· d^-1,螺内酯组（20 mg· kg-1· d-1）和假手术组对照组。治疗12周后,各组分别应用超声检测心脏结构和功能,主动脉内径,壁厚,病理检测主动脉形态,测定纤溶酶原激活物抑制物-1（plasminogen activator inhibitor-1, PAI-1）,组织纤溶酶原激活剂（tissure plasminogen activator,t-PA）。结果心脏超声结果显示,螺内酯组和培哚普利组同高血压模型组比较,舒张末期室间隔厚度,左心室后壁厚度,相对室壁厚度,左心室质量,左心室内径,左心房内径明显下降（ P ＜0殮．05或＜0．01）;胸主动脉壁厚明显下降（ P ＜0．01）,病理检测胸主动脉内中膜厚度,胸主动脉内中膜厚度/内径明显下降（ P ＜0．01）。血浆PAI-1水平培哚普利组,螺内酯组同假手术组比较明显升高（ P ＜0．01）,2组同高血压组比较差异无统计学意义（ P ＞0．05）。 t-PA 4组差异无统计学意义（ P ＞0．05）。结论高血压导致心脏、血管重构,纤溶活性降低,培哚普利和螺内酯均能逆转心脏和血管重构,但对高血压导致的低纤溶状态未产生明显逆转作用。     

Safety and antihypertensive efficacy of carvedilol and atenolol alone and in combination with hydrochlorothiazide

Carvedilol has been shown to be effective and safe in patients with essential hypertension when given as monotherapy. In this double-blind, randomized, group-comparative study, 2 groups of 59 patients with mild to moderate essential hypertension [median supine systolic/diastolic blood pressure at baseline (SBP/DBP), 168/105 mm Hg] were treated with either 25 mg carvedilol once daily (o. d.) or 50 mg atenolol o. d. for 4 weeks. Responders at 4 weeks (DBP, < 90=" mmhg)=" terminated=" the=" study.=" nonresponders=" continued=" the=" study.=" hydrochlorothiazide=" (hctz)=" was=" added=" at=" 25=" mg=" o.=" d.=" for=" a=" further=" 6=" weeks.=" the=" median=" blood=" pressure=" decreased=" under=" monotherapy=" with=" carvedilol=">n = 59) from 167/105 at baseline to 155/94 mmHg after 4 weeks, and in the atenolol group (n=59) it decreased from 168/105 to 162/97 mmHg. The patients who received carvedilol in combination with HCTZ and were evaluated for efficacy (n = 38) showed a decrease in SBP/DBP from 156/97 at the end of monotherapy to 145/88 mmHg after 10 weeks; the combination of atenolol with HCTZ (n = 44) reduced BP from 162/97 to 147/88. Both carvedilol and atenolol were safe when given either alone or in combination with HCTZ. In conclusion, after long-term administration, 25 mg carvedilol o. d. and 50 mg atenolol o. d. significantly reduced both SBP and DBP over 24 h. The addition of HCTZ led to a further increase in antihypertensive efficacy. Combined treatment with carvedilol or atenolol and HCTZ was very well tolerated, without hypotensive events or relevant changes in objective safety parameters.     

The haemodynamic and humoral effects of treatment for one month with the angiotensin converting enzyme inhibitor perindopril in salt replete hypertensive patients

Summary We have studied the effects of treatment for one month with perindopril, 4 or 8 mg once daily, in seven hypertensive patients. Blood pressure was lowered from 164/93 mm Hg to 145/84 mm Hg by 4 mg of perindopril and after one month remained at 142/82 mm Hg. Neither postural hypotension nor tachycardia occurred.Inhibition of plasma angiotensin converting enzyme (ACE) lasting for over 24 h was achieved and there was a significant increase in plasma renin activity (PRA).Maximum plasma concentrations of the active metabolite of perindopril, S-9780, were detected four h after oral administration.After treatment for one month there was evidence of reduced sensitivity of plasma ACE to the action of the inhibitor. The plasma concentration of S-9780 required to produce 50% inhibition of plasma ACE rose from 2.4 ng · ml^–1 following the first dose to 5.5 ng · ml^–1 after one month.     

Effects of combined therapy with amiloride and hydrochlorothiazide on plasma and total body potassium,blood pressure,and the renin-angiotensin-aldosterone system in hypertensive patients

Summary After a run-in period of 8 weeks on a regimen of hydrochlorothiazide (HCT, median dosage 75 mg/day), patients with essential hypertension were randomly allocated to continued hydrochlorothiazide therapy (Group I) or additional treatment with amiloride (Group II, median dosage 15 mg/day, or 5 mg per 25 mg hydrochlorothiazide) for the following 12 weeks. Thereafter all the patients were changed to treatment with a fixed combination tablet containing 5 mg amiloride and 50 mg hydrochlorothiazide (Moduretic), keeping the thiazide dosage unchanged for an additional 12 weeks. In Group I patients there was no change in plasma potassium, total body potassium content or the renin-angiotensin-aldosterone system during the 12 weeks on HCT. When the treatment was changed to Moduretic, significant increases were found of 10% in plasma potassium and 3% in total body potassium content. No important stimulation of the renin-angiotensin-aldosterone system was found. In Group II patients addition of an average of 15 mg amiloride to the hydrochlorothiazide treatment led to significant increases in plasma potassium and total body potassium content of approximately 15% and 4%, respectively. There was also a significant increase in the plasma concentrations of renin, angiotensin II and aldosterone. Reducing the average dose of amiloride to 7.5 mg/day by use of Moduretic did not lead to decrease in plasma potassium or total body potassium content. Plasma concentrations of renin, angiotensin II, and aldosterone were decreased, but the individual changes varied markedly and no significant overall change was found.     

Further evidence that chronic perindopril treatment maintains neurohormonal suppression but does not lower blood pressure in chronic cardiac failure

Aims Previous studies in heart failure (CHF) after temporary diuretic withdrawal have suggested that perindopril is associated with no first dose hypotension in comparison with other ACE inhibitors (ACEI) or placebo. The aim of this study was to explore further the profile of perindopril during chronic dosing. Methods We report the effects of acute and chronic (8 weeks) treatment with the ACE inhibitor perindopril (Per, 2→4 mg daily) or placebo (P) in a double-blind parallel group study of 24 diuretic treated patients (17M; 67±8 years, 80±17 kg) with ischaemic cardiomyopathy (fractional shortening, 19±5%; radionuclide ejection fraction, 31±3%). Baseline biochemical, hormonal (ACE, Ang I, Ang II), isotopic renal function (GFR, ERPF, ECFV), pretreatment diuretic dose and heart failure scores were similar between groups. Concomitant cardiac treatments remained unchanged and diuretic withdrawal was not used to introduce treatment. Results There were no significant effects on electrolytes, liver function tests, serum or erythrocyte magnesium. There was no significant first dose fall in SBP over 6 h) (P, baseline 137±18; min 115±16 mmHg; Per, baseline 137±15; min 118±17 mmHg). Neither supine nor erect BP was significantly affected by chronic treatment (P, erect baseline 134±23/76±10 to 124±41/74±10 mmHg; Per, baseline 135±21/76±14 to 128±22/70±12 mmHg, P=NS). Active treatment was associated with significant ACE inhibition (P, baseline 47±17 to 43±17; Per baseline 49±15 to 14±7); aldosterone (P, baseline 337±179 to 375±306; Per, baseline 335±357 to 293±155 pg ml⁻¹ ) and Ang II suppression (P, baseline 9±9 to 20±39; Per baseline 10±9 to 3±3 pm ). Isotopic renal function was unaffected by either treatment. Conclusions At this dose (2–4 mg orally) chronic perindopril therapy has no significant effect on blood pressure or renal function. Sustained neurohormonal suppression of ACE and AII occurred without evidence of AII reactivation. A lack of effect on BP at these doses may make perindopril suitable for study in unstable patients with acute HF or useful in those patients where there are concerns over ACEI induced hypotension.     

赖诺普利/氢氯噻嗪复方片在中国健康志愿者中的药代动力学研究(英文)

本研究描述了赖诺普利/氢氯噻嗪复方片在中国健康人体内的药代动力学特征。9名受试对象分别服用高、中、低3种剂量的复方片剂,结果表明,两种药物的AUC和Cmax都随着剂量的增加显著增加,但3种剂量间AUC/Dose、Cmax/Dose和tmax无明显差别。赖诺普利和氢氯噻嗪在涉及剂量范围内呈线性代谢特征。8名健康受试者在多次服用赖诺普利/氢氯噻嗪复方片后,与第1次服药比较,达稳态后的赖诺普利的AUC、Cmax和Cmin有所增加,其中AUC和Cmax显著增加;氢氯噻嗪的AUC、Cmax、Cmin和tmax有所增加,其中AUC和Cmin显著增加。达稳态后,赖诺普利的波动指数(FI)为2.29,浓度较为平稳,而氢氯噻嗪的波动指数FI为4.09,浓度相对波动较大。     

培哚普利对老年原发性高血压患者血栓前状态的影响

目的通过对老年原发性高血压患者血栓前状态(PTS)分子标志物的测定,研究培哚普利对老年原发性高血压患者血栓前状态的影响。方法测定40例老年高血压患者应用培哚普利治疗(10~20 mg,Qd,服用8周)前后及20例与原发性高血压患者年龄、性别相配的正常老年人血浆纤维蛋白原(Fbg)、假性血友病因子(VWF)、p-选择素(P-sele)、D-二聚体(D-d im er)。结果培哚普利治疗后可使Fbg、VWF、P-sele、D-d im er显著降低,老年原发性高血压患者治疗前Fbg、VWF、P-sele、D-d im er显著高于正常老年人。结论老年高血压患者存在血栓前状态,培哚普利抗高血压治疗可改善其血栓前状态。     

复方赖诺普利片人体药动学考察

目的：研究复方赖诺普利片在健康人体内药动学特征。方法：单剂量：空腹口服复方赖诺普利片1片（每片复方赖诺普利片含赖诺普利10mg、氢氯噻嗪12．5mg）。多剂量：多次给药连续9d，每天服药1次．每次1片。采用LC-MS法测定血浆中赖诺普利、氢氯噻嗪的浓度，计算药动学参数．以考察复方赖诺普利片多剂量口服达稳态过程和稳态药动学特征。结果：单剂量口服受试制剂：赖诺普利的tmax为（7．3±1．2）h；Cmax为（42．5±6．8）μg·L^-1；t（1/2）为（8．6±1．8）h；MRT为（20．1±3．0）；AUC（0-72）为（545．1±147．4）ng·h·L^-1。氢氯噻嗪的tmax为（2．8±0．7）h；Cmax为（81．6±22．7）μg·L^-1；t（1/2）为（13．7±2．0）h；MRT为（10．4±2．0）；AUC（0-48）为（679．8±280．7）ng·h·L^-1。多剂量口服受试制剂：赖诺普利的AUCss为（576．9±124．4）ng·h·L^-1，Css-max为（47．7±13．2）μg·L^-1，Css-min为（6．2±1．8）μg·L^-1．Css-av为（24．0±5．2）μg·L^-1，DF为（1．71±0．24）．tmax为（7．3±1．1）h，t（1/2）为（13．1±2．7）h；氢氯噻嗪的AUCss为（731．4±224．9）ng·h·L^-1，Css-max为（101．0±31．6）μg·L^-1，Css-min为（8．4±3．8）μg·L^-1，Css-av为（30．5±9．4）μg·L^-1，DF为（3．1±1．2），tmax为（3．0±0．9）h，t（1/2）为（8．8±1．6）h。结论：复方赖诺普利片主要药动学参数单剂量和多剂量给药差异无显著性，复方赖诺普利片在人体内无蓄积。     

海捷亚对24h血压控制效果观察

目的　观察海捷亚 (氯沙坦 /氢氯噻嗪 )对高血压患者 2 4h血压的控制作用。方法　从心内科门诊及病房高血压患者中通过用 2 4h动态血压监测 ,观察 2 5例以血压超负荷为特征的原发性高血压患者。治疗开始前行 2 4h动态血压监测 ,服药之前当日记录门诊偶测血压。海捷亚每日晨服用 1片 ,服药第 1,2 ,4周分别记录门诊偶测血压 ,第 4周结束时再次行 2 4h动态血压监测。结果　所有患者服用海捷亚 1周后白天门诊偶测血压已开始降低 (P <0 0 5 ) ,第 2周后血压水平继续降低 ,第 4周结束时白天偶测血压值降低有非常显著性 (P <0 0 1)。第 4周动态血压监测与治疗前相比 ,白昼收缩压 (SBP) >14 0mmHg和舒张压 (DBP) >90mmHg读数的百分数 ,夜间SBP >12 0mmHg和DBP >80mmHg的读数百分数均明显下降 (P <0 0 5 )。第 4周的夜间血压下降百分率较治疗前升高(P <0 0 5 )。结论　海捷亚有快速、稳定的降压疗效 ,能明显减轻白昼及夜间血压超负荷 ,并对血压昼夜节律的恢复有调节作用     

培哚普利单用和与格列齐特联用治疗糖尿病肾病的临床疗效评价

目的：评价培哚普利（perindopril)单用和与格列齐特联用对治疗Ⅱ型糖尿病（DM）伴高血压合并糖尿病肾病（DN）病人的疗效及安全性。方法：61例病人，男34例，女27例。随机分为两组，培哚普利组31例，培哚普利4mg,1次／d；格列齐特80mg,2次／d。硝苯地平组30例，硝苯地平缓释片10mg,1次／d；格列齐特80mg,2次／d。以治疗3mon为统计界限。结果：两组治疗前后比较，收缩压、舒张压、空腹血糖（FPG）、糖化血红蛋白（GHb)明显降低（P＜0．05），培哚普利组尿微量白蛋白（UMA）显下降（P＜0．01），硝苯地平组UMA无明显变化（P＞0．05）。两组治疗后，收缩压、舒张压、空腹血糖（PLG）、糖化血红蛋白（GHb)比较无显性差异（P＞0．05）。培哚普利组尿微量蛋白（UMA）较硝苯地平组明显下降（P＜0．01）。两组治疗前后及治疗后比较，WBC、RBC、PLT、血清尿素、Cr及K^ 均无显变化（P＞0．05）。结论：培哚普利是治疗Ⅱ型DM伴高血压合并DN保护肾功能安全有效的药物；培哚普利和格列齐特联合应用效果更佳。     

缬沙坦对高血压病患者血压及微量白蛋白尿的影响

目的 观察缬沙坦（valsartan）对高血压病患者并伴持续微量白蛋白尿（MAU）血压水平及尿蛋白排泄率的影响。方法 60例高血压病伴MAU患者随机分为治疗组（缬沙坦80 mg/d）、对照组（倍他乐克,75 mg/d）治疗8周。结果 治疗后2组血压水平明显下降（P〈0.05）,治疗组UAER较治疗前明显降低（P〈0.05）,而对照组治疗后较治疗前无显著差别。结论 缬沙坦可更有效地降低高血压病患者的微量白蛋白尿,且其肾脏保护作用独立于其降血压作用。     

A comparative study of the pharmacokinetics and pharmacodynamics of atenolol,hydrochlorothiazide and amiloride in normal young and elderly subjects and elderly hypertensive patients

Summary Six normal young and six normal elderly volunteers and six elderly hypertensive patients took part in an acute and chronic dose study of a combination capsule containing atenolol (50 mg), hydrochlorothiazide (25 mg) and amiloride (2.5 mg) designed for the treatment of hypertension. No difference in any of the drug pharmacokinetic parameters could be detected between the hypertensives and the normal elderly subjects. The bio-availability and the 24-h blood concentrations of all three drugs, half-life of atenolol and amiloride and the peak concentration of hydrochlorothiazide was significantly greater in the elderly. The 24-h blood concentrations of atenolol and hydrochlorothiazide did not alter with chronic dosing, but amiloride concentrations were significantly higher at this time in all groups. A significant fall in the blood pressure was observed in the hypertensive group. Heart rate fell more in the normal and hypertensive elderly subjects than in the young. The combination has shown to be an effective and well tolerated antihypertensive in the elderly patient with a 24-h duration of action.     

The pharmacokinetics and pharmacodynamics of metoprolol after conventional and controlled-release administration in combination with hydrochlorothiazide in healthy volunteers

Summary We have studied a controlled-release formulation containing metoprolol 100 mg and hydrochlorothiazide 12.5 mg. We compared the pharmacokinetics of both substances and the pharmacodynamics of metoprolol with those of a conventional combination tablet.The controlled-release formulation gave less variable plasma metoprolol concentrations, C_max 138 nmol·l^–1 and C_min 74 nmol·l^–1, whereas for the conventional formulation the mean C_max of metoprolol was 629 nmol·l^–1 and the C_min 20 nmol·l^–1.Despite lower relative systemic availability (68%) for metoprolol from the controlled-release formulation and a smaller AUC, metoprolol from the controlled-release formulation produced a greater total effect, calculated as the area under the curve of the effect on exercise heart rate vs. time (303 vs. 259%·h; P<0.05).Hydrochlorothiazide was rapidly absorbed from both formulations and the plasma concentration profiles were almost superimposable.Controlled-release metoprolol with hydrochlorothiazide combines effective ₁-adrenoceptor blockade for 24 h without affecting the pharmacokinetics of hydrochlorothiazide.     

氟西汀对高血压伴抑郁状态患者血压的影响

目的：观察氟西汀对高血压伴抑郁状态患者降压作用的影响。方法：将原发性高血压伴抑郁状态的患者106例随机分为对照组及氟西汀组，对照组给予常规降压治疗，氟西汀组则在此基础上加用氟西汀，观察18个月，对收缩压、舒张压、平均动脉压的最终下降幅度进行评定。结果：同对照组相比，氟西汀组收缩压、舒张压及平均动脉压的最终下降幅度明显降低，差异有统计学意义。结论：氟西汀有助于原发性高血压伴抑郁症状患者血压的控制。