Nisoldipine CC and Lisinopril Alone or in Combination for Treatment of Mild to Moderate Systemic Hypertension

The efficacy and safety of nisoldipine CC and lisinopril were compared in 278 patients with mild to moderate systemic hypertension in a double-blind, placebo run-in trial. Patients were randomized to nisoldipine CC or lisinopril for 8 weeks to achieve a trough sitting diastolic blood pressure (BP) ≤90 mmHg. Responders were maintained on their optimal dose for a further 8 weeks. Nonresponders were switched to combination therapy and treated for 8 weeks. Twenty-four-hour ambulatory BP monitoring (ABPM) was carried out during placebo and monotherapy. The responder rate of 73.8% with nisoldipine CC after 8 weeks was greater than 56.1% with lisinopril (p = 0.007). The responder rate with combination therapy was 61%. ABPM showed that both nisoldipine CC and lisinopril produced constant blood pressure lowering effects over the 24-hour period and maintained circadian rhythm. Adverse effects were more frequent with nisoldipine CC (headache and peripheral edema) than with lisinopril (cough) monotherapy. Nisoldipine CC monotherapy was at least as effective as lisinopril monotherapy in the management of mild to moderate hypertension. Both agents were well tolerated. Combination therapy with nisoldipine CC and lisinopril was effective and well tolerated in patients with blood pressure not controlled by monotherapy alone. This revised version was published online in July 2006 with corrections to the Cover Date.     

Comparison of the pharmacokinetics of fosinoprilat with enalaprilat and lisinopril in patients with congestive heart failure and chronic renal insufficiency

AIMS: To compare the serum pharmacokinetics of fosinoprilat with enalaprilat and lisinopril after 1 and 10 days of dosing with fosinopril, enalapril and lisinopril. METHODS: Patients with congestive heart failure (CHF, NYHA Class II-IV) and chronic renal insufficiency (creatinine clearance lisinopril in two parallel-group studies. In the first study 24 patients were treated with 10 mg fosinopril (n=12 patients) or 2.5 mg enalapril (n=12) every morning for 10 consecutive days. In the second study 31 patients were treated with 10 mg fosinopril (n=16 patients) or 5 mg lisinopril (n=15) every morning for 10 consecutive days. Samples of blood were collected for determination of pharmacokinetic parameters. The area under the curve (AUC) between the first and last days of treatment and the accumulation index (AI) were the primary outcome measures. RESULTS: All three angiotensin converting enzyme (ACE) inhibitors exhibited a significant increase in AUC between the first and last days of treatment in both studies. The difference between the AI for fosinoprilat (1.41) and enalaprilat (1.96) was statistically significant (95% CI: 1.05, 1.84). Similarly, the difference between the AI for fosinoprilat (1.21) and lisinopril (2.76) was statistically significant (95% CI: 1.85, 2.69). All three ACE inhibitors completely inhibited serum ACE for 24 h. All treatments were well tolerated. CONCLUSIONS: Fosinoprilat exhibits significantly less accumulation than enalaprilat or lisinopril in patients with CHF and renal insufficiency, most probably because fosinoprilat is eliminated by both the kidney and liver, and increased hepatic elimination can compensate for reduced renal clearance in patients with kidney dysfunction.     

高效液相色谱荧光法测定健康人血浆中赖诺普利浓度

目的:建立测定血浆中赖诺普利浓度的方法,为临床血药浓度的测定提供快速、有效的分析手段.方法:高效液相色谱法荧光法,采用HypersilODS柱,流动相为20mmol/LKH2P04缓冲液(pH=3.0)-甲醇(35:65,V/V),流速为1.0mL/min;血浆样品经固相萃取后与荧光试剂(荧光胺)发生衍生化反应,进样量为20μL;荧光检测器的激发波长为383 nm,发射波长为477 nm.结果:赖诺普利浓度在2～200 ng/mL范围内线性关系良好(r=0.997 8),平均绝对回收率为68.55%(n=15),日内与日间精密度均小于3%,最低检测限为1 ng/mL;内源性物质不干扰测定.结论:高效液相色谱荧光法工作曲线稳定,灵敏度高,操作步骤简单,可以用于赖诺普利的药动学和药效学研究及临床血药浓度的监测.     

Captopril modulates hormone receptor concentration and inhibits proliferation of human mammary ductal carcinoma cells in culture

The present study evaluated the effect of the angiotensin converting enzyme (ACE) inhibitor captopril on estrogen (ER) and progesterone (PR) receptor concentration and on proliferation in two lines of human mammary ductal carcinoma cells in culture: T-47D (ER+/PR+) and Hs578T (ER–/PR–). The incorporation of [³H]thymidine, validated by cell count, served as an index of proliferation. Compared to control cells, T-47D cells incubated for 48 hrs in 1, 2, or 5 mM captopril (but not in 0.5 mM) exhibited a reduction in ER from 130 ± 6 to 32 ± 32 fmol/mg cytosolic protein, and an increase in PR from 1780 ± 120 to 2740 ± 400 fmol/mg protein (p < 0.05). Western analysis confirmed these drug-induced changes in the concentration of immunoreactive receptor proteins. Captopril also induced the appearance of low but detectable PR in the Hs578T cells at concentrations as low as 50 µM. Captopril inhibited the incorporation of [³H]thymidine by both cell types during a 48 hr incubation, although Hs578T cells were 2–3 times more resistant than were T–47D cells. This cytostatic effect of captopril was not due to cytotoxicity as indicated by ⁵¹Cr release, and was not accompanied by significant changes in cell cycle distribution as determined by flow cytometry. The incorporation of [³H]uridine (RNA synthesis) and [¹⁴C]alanine (protein synthesis) also were inhibited by captopril, suggesting a general antimetabolic effect of the drug in the ductal carcinoma cells. These are novel actions of a common antihypertensive agent. In contrast, the nonthiol ACE inhibitor lisinopril, and penicillamine, a thiol compound with virtually no ACE inhibitory activity, had no effect on any of these endpoints.     

The new trials: AIRE,ISIS-4, and GISSI-3. Is the dossier on ACE inhibitors and myocardial infarction now complete?

Summary Recent studies have strengthened the arguments for the use of angiotensin-converting enzyme (ACE) inhibitors in the early postinfarct period. Those with clinically detectable heart failure, and hence at highest risk, will benefit most, as shown in the AIRE study, but those at lower risk with left ventricular dysfunction still have some benefit, theoretically through ventricular remodeling. In patients in the very early stages of acute myocardial infarction, three trials have shown discordant results. In CONSENSUS-II, intravenous enalaprilat followed by oral enalapril gave no benefit, rather causing excess hypotension and a possible increase in mortality. In ISIS-4 and GISSI-3, mortality improved by 0.46% and 0.8%, respectively, with risk reductions of 9% and 11%. Added transdermal nitrate in GISSI-3 gave a total reduction of 17%. In view of the risk of hypotension (20% in ISIS-4, compared with placebo 10%), very early ACE inhibition will probably only be used for selected patients. Logically, one target group would be those seen 7–24 hours after the onset of symptoms, particularly 7–12 hours, at which time captopril alone gave a reduction of 14.5% in risk. These mortality differences compare favorably with those recently found when comparing tPA and streptokinase in the GUSTO study.     

赖诺普利片人体药动学及生物等效性研究

目的:评价国产和进口赖诺普利片的生物等效性。方法:18名男性健康志愿者随机交叉单剂量口服20mg 国产和进口赖诺普利片,采用 HPLC 测定血浆中药物浓度,通过方差分析和双向单侧 t 检验比较2种片剂药-时曲线下面积(AUC_(0-60))。结果:2种制剂的 t_(max) 分别为(6.00±0.00)h 和(6.11±0.47)h,C_(max)为(110.37±23.35)ng·mL~(-1)和(109.18±26.06)ng·mL~(-1),2种制剂 t_(1/2)分别为(16.20±2.10)h 和(16.50±2.28)h,药时曲线下面积(AUC_(0→60)分别为(1531.73±239.08)μg·mL~(-1)·h 和(1535.39±170.93)μg·mL~(-1)·h。结论:2种赖诺普利片生物等效,相对生物利用度为(99.8±10.7)%。     

液相色谱-质谱法测定人血浆中复方赖诺普利及其人体药动学研究

目的:研究液相色谱-质谱法测定人血浆中的复方赖诺普利,并分析高蛋白高脂肪食物对其药动学的影响。方法:采用随机双周期交叉设计,12名健康受试者(男女各半)随机分为2组,Ⅰ组空腹服复方赖诺普利片1片(每片含赖诺普利10．0 mg,氢氯噻嗪12．5 mg),Ⅱ组进食后服复方赖诺普利片1片,交叉间隔为1 wk。结果:空腹和进食单剂量口服受试制剂:赖诺普利的tmax分别为(7．3±s 1．2)和(7．5±1．0)h;cmax分别为(42±7)和(33±10)μg·L-1;t1／2分别为(13．7±2．0)和(12．5±2．2)h; MRT分别为(20±3)和(19．9±2．5)h;AUC0～72分别为(545±147)和(493±125)μg·h·L-1。氢氯噻嗪的tmax分别为(2．8±0．7)和(4．6±1．1)h;cmax分别为(82±23)和(77±13)μg·L-1;t1/2分别为(8．6±1．8)和(8．4±1．7)h;MRT分别为(10．4±2．0)和(11．6±1．6)h;AUC0～48分别为(680±281)和(684±83)μg·h·L-1。结论:该方法选择性强、灵敏度高、操作简便,适用于复方赖诺普利制剂的临床药动学研究;进食高脂肪、高蛋白的食物会影响赖诺普利的达峰浓度和氢氯噻嗪的达峰时间。     

EFFECT OF LISNOPRIL,AN ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITOR ON SPERMATOGENESIS IN RATS

The role of ACE inhibitors (Lisinopril) in reproductive function remains controversial. Some benefits seem to be derivable even in non-hypertensive males with low doses. This study was done using rat model to establish this fact. Male rats were divided into different groups to receive different doses of lisinopril. A control group received no drugs. The mean arterial pressure fell the most with 5 mg of lisinopril. The greatest increase in sperm count and motility was recorded for this same group. This response was dose dependent, falling as the drug dose fell. Lisinopril appeared to, in a dose dependent manner, improve sperm count and motility. In low doses, there is no significant change in arterial pressure. Infertile males with poor quality semen could benefit from a low dose of ACE inhibition. Where they are also hypertensive, ACE inhibition would be an appropriate first line treatment.