Clinical pharmacology of dilevalol (II). The pharmacokinetic, pharmacodynamic, and tolerance studies of dilevalol during repeated administration in healthy subjects

Dilevalol (50 mg) was given orally twice daily for eight days in six healthy subjects. All parameters were obtained following 1st (on day 1) and 15th (on day 8) dosages. Blood samples for plasma drug concentrations were taken for a 12-hour (after 1st dosage) or a 24-hour (after 15th dosage) post-drug period. Blood pressure (BP) as well as heart rate (HR) at supine position, during 50 degrees tilting and during a submaximal exercise were measured after each dosage. The mean time to maximum concentration (tmax) was faster, and the mean area under the plasma concentration-time curve (AUC) was greater after 15th dosage than following 1st dosage. No significant differences were observed in the maximum plasma concentration (Cmax), the distribution half-life (t 1/2 alpha) or the elimination half-life (t 1/2 beta) between the two dosages. BP at supine position as well as during 50 degrees tilting decreased significantly after each dosage, and did not differ between 1st and 15th dosages. Postural changes in BP or HR during 50 degrees tilting were not induced following 1st or 15th dosage. The suppressing effects (%R) on an increase in HR during a submaximal exercise were significantly larger after 15th dosage than after 1st dosage. A significant correlation was observed between plasma dilevalol concentration and %R in HR. These data indicate that the hypotensive effect of dilevalol is not altered during the repeated administration of the drug for 8 days. However, the beta-blocking activity of dilevalol might be enhanced during the repeated dosages, which is, in part, attributed to dosage-dependent elevation in plasma drug concentrations.     

Clinical pharmacology of dilevalol (I). Comparison of the pharmacokinetic and pharmacodynamic properties of dilevalol and labetalol after a single oral administration in healthy subjects

Dilevalol (25 mg----50 mg----100 mg) or labetalol (100 mg) was given orally in six healthy subjects. The study was carried out on four occasions with a week interval. Blood samples for plasma drug concentrations were taken for a 24-hour post-drug period. Blood pressure (BP) as well as heart rate (HR) at supine position, during 50 degrees tilting and during a submaximal exercise were measured after each treatment. The mean maximum plasma concentration (Cmax) as well as the mean area under the plasma concentration-time curve (AUC) increased in a dose-dependent manner after dilevalol. These parameters after dilevalol 100 mg were significantly lower than after labetalol 100 mg. No significant differences were observed in the time to maximum concentration (tmax), the distribution half-life (t1/2 alpha) or the elimination half-life (t1/2 beta) between dilevalol and labetalol. There were no significant differences in BP at supine position or during 50 degrees tilting among the dosages. Postural changes in HR during 50 degrees tilting was significantly smaller after dilevalol 100 mg than following labetalol 100 mg. The suppressing effect of dilevalol 100 mg on an increase in HR during a submaximal exercise was significantly greater than during labetalol 100 mg. These data indicate that although plasma drug concentrations are lower after dilevalol than following labetalol, the beta-blocking activity of dilevalol is more potent than labetalol.     

Clinical pharmacology of dilevalol (i.v.). Influence of hepatic and renal functions on the disposition of dilevalol and atenolol in hypertensive subjects

Dilevalol (100 mg) or atenolol (50 mg) was given orally in 13 subjects with essential hypertension. Two trials were done by a single-blind, crossover design with an interval of 6 days. Blood samples for drug concentrations were taken for a period of 24 hours after dosage. A retained percentage of indocyanine green dye at 15 minute (ICG R15) reflecting hepatic function and a creatinine clearance (CLCR) reflecting renal function were determined in each subject during observation period. A significant correlation was observed between the ICG R15 and the area under the plasma concentration-time curve (AUC) of dilevalol, while there was no significant correlation between the CLCR and any pharmacokinetic parameter of the agent. In contrast to dilevalol, significant correlations were observed between the CLCR and AUC or elimination half-life of atenolol. However, there was no significant correlation between the ICG R15 and any pharmacokinetic parameter of atenolol. These data indicate that the disposition of dilevalol is influenced by hepatic rather than by renal function while that of atenolol is altered by renal function.     

Effect of oral dilevalol on forearm circulation in essential hypertension.

In 7 patients with untreated mild essential hypertension, a single 200-mg dilevalol dose was administered orally. Blood pressure (BP, left brachial artery catheter), heart rate (HR), and left and right forearm blood flows were measured and left and right forearm vascular resistances were calculated before and for approximately 3 h after drug administration. Dilevalol administration was followed by a sustained reduction in BP, little change in HR, and a similar pronounced and sustained increase in left and right forearm blood flows and reduction in left and right forearm vascular resistances. At the end of the observation period, the changes in left forearm circulation were unaffected by left brachial artery infusion of saline but markedly reduced by left brachial artery infusion of propranolol at doses that had no effect on BP, HR, and contralateral forearm vasodilatation. Thus, at an oral dose exerting an antihypertensive effect, dilevalol induces a marked and persistent vasodilation due largely to the beta-adrenoceptor agonism of the drug.     

Pressor responses to hyperventilation in elderly subjects differentiate essential from secondary hypertension

We evaluated pressor responses to the hyperventilation test in elderly normotensive (n=43, mean age 82 ± 5 years) and elderly hypertensive subjects (n=45 with essential hypertension, mean age 82 ± 2 years, and n=49 with secondary hypertension, mean age 82 ± 3 years). Hyperventilation did not change blood pressure (BP) in normotensive and secondary hypertensive subjects, whereas it decreased BP in essential hypertensives. Hierarchical cluster analysis based on BP responses to hyperventilation disclosed three groups of subjects in each population: group 1 exhibited a reduction in BP (essential hypertensives: 76%), group 2 no change (normotensives: 70%, secondary hypertensives: 76%), and group 3 an increase (normotensives: 19%, essential hypertensives: 13%, secondary hypertensives: 14%). Ambulatory BP monitoring found significant differences in pressor daytime profiles of hypertensive patients according to pressor responses to hyperventilation showing wide fluctuations in group 1 and 3 patients. Interestingly, the peak ambulatory SBP values correlated to the pre-hyperventilation SBP values in group 1, and to the hyperventilation peak SBP values in group 3. In conclusion: 1) Aging decreases reactivity to respiratory alkalosis in elderly normotensives; 2) hyperventilation induces significant pressor changes frequently in essential hypertension, but rarely in secondary hypertension; 3) the significant pressor responses to hyperventilation reflect the daytime pressor profiles predicting the highest daily fluctuations of BP values.     

脉君安片联合缬沙坦治疗中老年原发性高血压的临床研究

目的 探讨脉君安片联合缬沙坦胶囊治疗中老年原发性高血压的临床疗效.方法 选择2021年2月—2021年6月在天津市红桥医院治疗的102例原发性高血压老年患者,根据用药的差别分为对照组和治疗组,每组各51例.对照组口服缬沙坦胶囊,80 mg/次,1次/d;治疗组在对照组基础上口服脉君安片,1.5 g/次.3次/d.两组患...     

动态血压变异性与老年原发性高血压左室肥厚的关系

目的探讨动态血压各参数的变异性与老年高血压左室肥厚的关系。方法采用动态血压、超声心动图检查142例年龄大于65岁的原发性高血压患者,其中81例无左室肥厚,61例有左室肥厚, 对两组动态血压参数进行组间比较及昼夜间比较,并对各参数与左室质量指数(LVMI)进行相关性分析。结果①昼、夜收缩压水平、脉压与LVMI呈强相关,左室肥厚组的收缩压、舒张压水平及脉压明显高于无左室肥厚组；②两组之间血压变异无差异；③所有患者收缩压变异大于舒张压变异,收缩压变异白昼大于夜间,而昼夜间舒张压变异、脉压水平改变不明显。结论老年高血压患者左室肥厚与血压变异相关性较小,主要与收缩压水平与脉压水平相关,老年高血压患者24h舒张压变异与脉压水平处于相对恒定的水平,脉压可能是预测老年高血压性左室肥厚的一个简便易行的指标。     

Comparison of the renal effects of dilevalol and carteolol in patients with mild to moderate essential hypertension

Summary The effects of 6 weeks of treatment with dilevalol 100 mg once daily, or carteolol 10 mg once daily, on renal blood flow (RBF), glomerular filtration rate (GFR) and total renal vascular resistance (TRR) were studied in 10 patients with mild-to-moderate essential hypertension in a randomised cross-over experiment.Both drugs lowered the systolic and diastolic blood pressures to a similar extent without altering the heart rate. Carteolol non-significantly decreased RBF by 9.2% and GFR by 12.3% without altering. TRR, whereas dilevalol produced a significant reduction in TRR by 13.2% (p<0.05), a non-significant decrease in RBF by 4.6% and no change in GFR.Neither drug changed plasma osmotic pressure, serum total protein concentration, electrolytes or plasma aldosterone concentration. Plasma renin activity tended to be lower in the dilevalol phase as compared to the carteolol phase.The results suggest that dilevalol may cause a greater decrease in TRR and less reduction in GFR when compared to carteolol in patients with mild-to-moderate essential hypertension. The difference in the renal effects might be due to the difference in the potency of vasodilatory properties of both drugs at the doses applied.     

原发性高血压患者血压变异性的临床研究

目的 探讨原发性高血压病(EH)血压变异性(BPV)的临床意义.方法 对45例EH患者和40例健康者(对照组)进行24h动态血压监测(ABPM),以测得的各时间段血压标准差(SD)作为BPV指标.结果 EH组血压变异性明显大于对照组,Ⅱ、Ⅲ期EH患者血压变异性明显大于Ⅰ期EH患者;EH患者血压变异性随血压水平的增加而逐...     

Evaluation of labetalol in elderly patients with essential hypertension

Labetalol was evaluated in a multicenter, placebo-controlled study of elderly patients (greater than or equal to 60 years) with mild to moderate essential hypertension. After a placebo-washout period, doses were titrated from 100 mg BID to a maximum of 400 mg BID over a 6-week period. Once blood pressure control (standing diastolic blood pressure [SDBP] less than 90 mm Hg and greater than or equal to 10 mm Hg reduction from baseline) was achieved or the maximum allowable dosage had been given, the dosage remained the same until the end of the study. The titration phase was followed by a 4-week maintenance period. Blood pressure control was achieved in 37/54 (69%) of the patients who were treated with labetalol compared with 21/58 (36%) of the patients who received placebo (P less than .001). Twenty-nine (78%) of those controlled on labetalol responded to doses of 200 mg or less BID, and there was no significant difference between groups with respect to orthostatic blood pressure changes. Adverse experiences were generally mild and occurred with similar frequency in the labetalol and placebo groups; six patients who received labetalol and five who received placebo withdrew from the study due to adverse experiences, but in only one case (labetalol) was the adverse experience considered drug-related. In summary, labetalol effectively and safely lowered diastolic blood pressure in the elderly without producing significant orthostatic changes.     

贝那普利联合氨氯地平治疗原发性高血压的临床研究

目的对贝那普利联合氨氯地平治疗原发性高血压进行研究。方法选择2013年8月~2015年8月入住我院的资料完整的原发性高血压患者160例患者作为研究对象,将其治疗方法不同随机分为观察组和对照组,每组各80例。两组均采取非药物治疗措施,对照组口服贝那普利,观察组联合氨氯地平治疗,治疗2个月后评价两组的临床疗效及两组患者治疗前后SBP、DBP的变化情况,并对比分析两组治疗4周后、治疗8周后的24 h ABPVs、24 h ABPVd的变化情况。结果观察组总有效率为95%,对照组总有效率为75%,两组临床总有效率比较,差异有统计学意义(P0.05),治疗2个月后,两组的SBP、DBP水平均分别较治疗前显著降低,其中,观察组治疗后SBP(120.28±20.22)mm Hg,DBP(83.20±11.23)mm Hg,分别与对照组比较,观察组治疗后的SBP、DBP水平显著低于对照组,差异具有显著性(P0.05),观察组治疗8周后的24h ABPVs、24h ABPVd分别显著低于对照组,差异具有显著性(P0.05)。结论贝那普利联合氨氯地平治疗原发性高血压临床疗效显著提高,降压效果显著,有效降低高血压患者的血压变异性,有效协助降压,维持血压稳定,值得推广和应用。     

Enalapril in essential hypertension: a comparative study with propranolol. Enalapril in Hypertension Study Group (UK).

We report the first comparative study on enalapril maleate, a new angiotensin converting enzyme inhibitor, in patients with uncomplicated mild to moderate essential hypertension. Fifty-four patients were randomly assigned to treatment with enalapril or propranolol for 16 weeks following a placebo run-in-phase. The study was double-blind. Enalapril and propranolol both reduced blood pressure, though the changes were significantly treated with enalapril were normotensive at the end of the study. Enalapril treatment was associated with a significant reduction in weight. Both drugs raised plasma potassium and urea. No haematological abnormalities occurred with enalapril and there were no reports of rash, taste disturbance or proteinuria. At the end of the trial the mean daily dose of enalapril was 20 mg and that of propranolol was 180 mg.     

硝苯地平联合贝那普利治疗老年高血压的临床研究

目的探讨硝苯地平联合贝那普利治疗老年高血压的临床疗效。方法选取2015年4月—2015年12月在天津市河西区康复医院就诊的老年高血压患者86例,随机分为对照组和治疗组,每组各43例。对照组患者口服盐酸贝那普利片,10 mg/次,1次/d,根据血压情况剂量加至20~40 mg/d。治疗组患者在对照组的基础上口服硝苯地平控释片,30 mg/次,1次/d。两组患者均连续治疗6周。观察并比较两组患者临床疗效、内皮舒张功能、内皮分泌功能和动脉血压变化。结果治疗后,对照组的总有效率为79.07%,显著低于治疗组的93.02%,两组总有效率比较差异有统计学意义(P0.05)。治疗后,两组患者24 h平均舒张压(24 h DBP)、24 h平均收缩压(24 h SBP)、白天平均舒张压(d DBP)、白天平均收缩压(d SBP)、晚上平均舒张压(n DBP)、晚上平均收缩压(n SBP)和收缩压的昼夜变异率(BPF)均显著下降(P0.05);且治疗组患者动脉血压改善优于对照组(P0.05)。治疗后,两组患者肱动脉内径变化率(FMD)均显著升高(P0.05);且治疗后治疗组患者FMD显著高于对照组(P0.05)。治疗后,两组患者血清NO水平显著上升,内皮素(ET)和神经肽Y(NPY)水平显著下降,同组比较差异具有统计学意义(P0.05);且治疗组患者NO、ET和NPY水平显著优于对照组,两组比较差异具有统计学意义(P0.05)。结论硝苯地平控释片联合贝那普利治疗老年高血压,可以降低血压变异性,改善血管内皮功能,具有一定的临床推广应用价值。     

氢氯噻嗪联合缬沙坦治疗老年高血压的临床研究

目的 探讨氢氯噻嗪联合缬沙坦治疗老年高血压的临床疗效。方法 2011年7月—2014年6月上海交通大学医学院附属新华医院收治的老年原发性高血压患者96例,随机分为对照组（48例）和治疗组（48例）,对照组口服缬沙坦胶囊80 mg/d。治疗组口服氢氯噻嗪片12.5 mg/d,其他同对照组。两组均持续治疗2个月。治疗后,评价两组的临床疗效,同时比较两组治疗前后收缩压（SBP）、收缩压变异度（SBPV）、舒张压（DBP）、舒张压变异度（DBPV）、血压晨峰（MBPS）的控制率、一氧化氮、内皮素的变化。结果 治疗组和对照组的总有效率分别为97.92%、83.33%,两组比较差异有统计学意义（P<0.05）。治疗后,两组患者平均SBP、SBPV、DBP、DBPV、内皮素均较治疗前显著降低,一氧化氮水平显著升高,同组治疗前后差异有统计学意义（P<0.05）,且治疗后治疗组这些观察指标的改善程度优于对照组,两组比较差异有统计学意义（P<0.05）。治疗组MBPS控制率为93.75%,对照组为81.25%,两组比较差异有统计学意义（P<0.05）。结论 氢氯噻嗪联合缬沙坦治疗老年高血压具有较好的临床疗效,可显著降低患者血压和血压昼夜变异度,可能与调节内皮一氧化氮和内皮素水平有关。     

Intravenous dilevalol in the treatment of severe hypertension

Dilevalol, the stereoisomer of labetalol, was given in repeated incremental intravenous bolus injections to 10 patients with severe hypertension requiring urgent blood pressure lowering. The mean cumulative dose of dilevalol was 445 +/- 165 mg. Blood pressure was reduced from 201 +/- 33/131 +/- 13 to 150 +/- 12/109 +/- 7 mm Hg (p less than 0.01) and heart rate did not change significantly. In only one patient was the study discontinued because of side effects (nausea and dizziness). There were no other clinically significant adverse reactions and no change was observed in electrocardiogram or routine biochemical and hematologic tests. Five of these patients, who achieved diastolic blood pressure of less than or equal to 105 mm Hg, participated in a subsequent outpatient phase of the study with combination of oral dilevalol with hydrochlorothiazide. Of these only one achieved good blood pressure control. We concluded that in such severely hypertensive patients intravenous dilevalol was safe and effective for the short-term lowering of blood pressure. However, long-term outpatient maintenance with this drug needs further evaluation.     

心可舒片联合缬沙坦治疗原发性高血压的临床研究

目的探究心可舒片联合缬沙坦胶囊治疗原发性高血压的临床疗效。方法选择2016年5月—2018年6月南通市第一人民医院收治的158例原发性高血压患者,全部原发性高血压患者分为对照组和治疗组,每组各79例。对照组口服缬沙坦胶囊,80mg/次,1次/d。治疗组在对照组基础上口服心可舒片,1.24g/次,3次/d。两组均连续治疗12周。观察两组的临床疗效,比较两组的血压、血脂水平、血清因子水平。结果治疗后,对照组和治疗组的总有效率分别为86.08%、96.20%,两组比较差异有统计学意义(P0.05)。治疗后,两组24 h平均收缩压(24 h mSBP)、24 h平均舒张压(24 h mDBP)均较治疗前显著下降,同组治疗前后比较差异有统计学意义(P0.05);且治疗组24 h mSBP、24 h mDBP明显低于对照组,两组比较差异有统计学意义(P0.05)。治疗后,治疗组总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL-C)水平均显著降低,治疗前后比较差异有统计学意义(P0.05);且治疗组TC、TG、LDL-C水平均明显低于对照组,两组比较差异有统计学意义(P0.05)。治疗后,两组单核细胞趋化蛋白-1(MCP-1)、内皮素-1(ET-1)水平均显著下降,一氧化氮(NO)水平显著上升,同组治疗前后比较差异有统计学意义(P0.05);且治疗后治疗组MCP-1、ET-1、NO水平均明显优于对照组,两组比较差异有统计学意义(P0.05)。结论心可舒片联合缬沙坦胶囊治疗原发性高血压具有较好的临床疗效,能改善患者的血压血脂水平,降低炎症反应,促进血管内皮功能的恢复,具有一定的临床推广应用价值。     

A double-blind comparative study of ketanserin with atenolol in essential hypertension

Sixty patients, with mild to moderate essential hypertension, were considered for a double-blind trial comparing the effects of ketanserin and atenolol. After 2 weeks of placebo, a group of 30 patients was given ketanserin 20 mg twice daily for 15 days and 40 mg twice daily for the subsequent 45 days, while the second group (30 patients) was given atenolol for 60 days at the dose of 100 mg once daily. Blood pressure and pulse rate in the supine and standing positions were evaluated every 15 days. After the beginning of treatment with ketanserin, there was a gradual but highly significant decrease of the diastolic and systolic blood pressure values. No important side-effects or significant alterations in the biochemical parameters considered were observed during treatment with ketanserin.     

A pharmacokinetic study of intramuscular (i.m.) parecoxib sodium in normal subjects

A single-center, double-blind, placebo-controlled, randomized study was conducted to determine the pharmacokinetics, safety, and tolerability of single, rising intramuscular (i.m.) doses and the single maximum tolerated dose of parecoxib sodium, a prodrug of the novel COX-2 selective anti-inflammatory analgesic drug valdecoxib, in 56 healthy male volunteers, ages 18 to 45 years inclusive. Cohorts of up to 6 subjects in each dose schedule were administered either parecoxib sodium (1 mg, 2 mg, 5 mg, 10 mg, 20 mg, or 40 mg) or matching placebo. Following i.m. administration, serial blood samples for measurement of plasma concentrations of parecoxib, valdecoxib, and valdecoxib metabolite (M1) were collected at predetermined intervals (from 15 minutes prior to dose and through 96 hours postdose). Urine collections were obtained for drug assay (from -12 to 0 hours, 0 to 12 hours, and 12 to 24 hours postdose). After i.m. administration, peak plasma concentrations of parecoxib were reached within 15 minutes and then declined rapidly as prodrug was converted to the active moiety, valdecoxib. Change in plasma concentrations of valdecoxib, which declined more slowly (t(1/2) = 5.4-9.9 hours), reflected transformation to several metabolites, one of which was the minor active metabolite M1. As measured by the AUC(0-infinity), Cmax, and XU(0-24) of valdecoxib, parecoxib sodium demonstrated dose proportionality when administered in the range of 1 mg to 40 mg of parecoxib. All single i.m. doses up to the maximum of 40 mg of parecoxib, as well as concentrations of up to 20 mg/ml, were well tolerated.     

Clinical pharmacology of predisintegrated ibuprofen 800 mg tablets: an endoscopic and pharmacokinetic study

Thirty-five healthy adults were randomized to receive either: (1) ibuprofen 800 mg tablets; (2) ibuprofen 800 mg aqueous suspension; (3) ibuprofen 800 mg orange juice suspension; or (3) 325 mg aspirin tablets. All treatments were tid for 7 days. Pharmacokinetic sampling was conducted on days 1, 4 and 8. Gastroduodenoscopy was performed on days 1 and 8. Side effects and safety laboratory tests were monitored throughout the study. On day 8 the aspirin group showed significantly more gastric irritation than all of the ibuprofen groups (P less than .005). Both ibuprofen suspension groups showed more gastric irritation than the ibuprofen tablet group (P less than .1). The duodenal scores did not differ among the treatment groups. The aspirin group experienced a higher rate of tinnitus and abdominal pain. The rate and extent of absorption of the ibuprofen suspensions were significantly less than that of the tablets. These data suggest that the taking of ibuprofen as an extemporaneous suspension is therapeutically inferior to ibuprofen tablets and therefore should be discouraged.