HPLC Determination of Captopril in Human Plasma with Pre-column Derivation and Solid-phase Extraction and Studies on Its Pharmacokinetic and Relative Bioavailability

A new pre-column derivation HPLC method with solid-phase extraction to determine captopril in human plasma was established. Derivation products were extracted by a solid-phase extraction method after the reagent, p-a-dibromoacetophenone(p-BPB), was added in the plasma samples. The samples were analyzed in a VP-ODS column with UV-detector. The calibration curve of captopril was linear within the range of 5~1000 ngmL-1 with r=0.9987, the recovery of this method was 98.652.04%, within day and between day RSD were no more than 3.4% and 8.4% respectively. To study the pharmacokinetics and the relative bioavailability of captopril tablets, two formulations of captopril tablets were given to 18 healthy male volunteers according to a randomized 2-way cross-over design with a 1-week washout period. The respective AUC0~6 , Cmax and Tmax values of the two formulations were 424.5125.7 and 439.4113.3 mghL-1; 505.9244.6 and 504.8172.2 mgL-1; 0.6620.181 and 0.5280.176 h. Results from statistics analysis showed that there were no significant difference between the AUC0~6 , Cmax and Tmax values of the two formulations, The relative bioavailability of tablets I with respect to II was 96.114.6% from AUC0~6 measurement. Bioequivalance was observed between the two tablets.

The Effects of Captopril and Cicaprost on Changes of Cardiac Membrane Fluidity and Lipid Peroxidation

The main purpose of this study was to investigate the protective actions of captopril and cicaprost on changes of membrane fluidity of cultured neonatal rat myocardial cells exposed to anoxia and sugar deprivation.Lipid peroxidation level estimated by determining the thiobarbituric acid reactive substance(TBARS)content and lactate dehydrogenase(LDH)released in culture medium was also observed in order to examine other membrane-related changes due to anoxia.Membrane fluidity was monitored by measuring changes in the steady state fluorescence anisotropy(r_s)by fluorescence spectroscopy.The r_s value,TBARS level and LDH release were significantly increased after 3 h anoxia.Captopril(180 μmol/L),cicaprost(30 nmol/L)and indomethacin(1μmol/L)did not alter r_s, TBARS level and LDH activity of normal cultured neonatal rat myocardial cells.However,both captopril and cicaprost significantly prevented the increases of r_s,TBARS content and LDH release in those cells exposed to anoxia and sugar deprivation.lndomethacin abolished the actions of captopril on TBARS production and LDH release,but maintained its membrane fluidity protection.These results indicate that captopril and cicaprost protect membrane fluidity and lipid peroxidation changes in anoxia- injured myocardial cells.The action mechanism of captopril may be due,in part,to stimulation of prostacyclin synthesis and/or release.

Effect of captopril on myocardial energy metabolism in chronic pressure overload rats

Objective To investigate the effects of captopril on cardiac function and levels of energy-rich phosphates in pressure overload induced left ventricular hypertrophy rats. Methods One hundred and twenty SD rats were randomly divided into three groups： sham operation group （SH group, n=40）,coarctation of abdominal aorta group （CAA group, n=40） and captopril treatment lmg~ 100g1 ~ d-1） group （CAP group, n=40）. Left ventricular end-diastolic pressure （LVEDP）, left venh-icular mass index （LVMI）, levels of energy-rich phosphates and morphological changes of the myocardial mitochondria were compared at the 62 and 82 week after operation. Results At 62 week, in CAA group, LVMI and LVEDP were increased and _ dp/dtmax was decreased, while ATP and ADP were decreased and AMP was increased （P〈0.01）. These changes were much obvious at 8th week （P〈0.01）. Compared with those of CAA group, the parameters of heart function and energy-rich phosphates （ATP, ADP, AMP, TAN） in CAP group were improved significantly（P〈0.01） at the 6th and 8th week. In CAP group, the parameters of heart function and energy-rich phosphates （ADP, AMP, TAN） were much better at 8~ week than those at 6th week. The morphological change of mitochondria was less in CAP group than that in CAA group. Conclusion Captopril significantly improves myocardial energy metabolism in pressure overload rats and protects the function of myocardial mitochondria

BENEFICIAL EFFECTS OF CAPTOPRIL ON PROGNOSIS IN ELDERLY PATIENTS WITH ACUTE MYOCARDIAL INFARCTION

Objective. This study sought to investigate the effects of early and long-term intervention with an- giotensin-converting enzyme(ACE) inhibitor captopril on the elderly patients with acute myocardial in farc- tion(AMI), and observe its in-hospital and post-hospital outcomes during serial follow-up of 54 months. Methods. 631 elderly patients(60～75 years old) with AMI and without cardiogenic shock were hospi- talized within 72 hours of symptoms and were randomly allocated to captopril (n = 361;treatment group) and conventional treatment (n = 270; control group). The survival and cardiac events (congestive heart fail- ure, reinfarction, severe arrhythmias and cardiac death)of each group were determined during hospitaliza-tion and follow-up. Results. During hospitalization, the survival was higher in treatment group than in control group(p< 0. 0001 ). On the other hand, in treatment group lower mortality was true for patients with anterior my- ocardial infarction(p < 0. 001 ) or with anterior+inferior myocardial infarction (P= 0. 026 ), but not statis- tically significant in ones with inferior myocardial infarction (P= 0. 061 ). During follow-up, the occurrence of cardiac death, heart failure, reinfarction and severe arrhythmias were lower in treatment group (P = 0. 0001, P = 0. 05, P = 0. 0004 and P = 0. 027). So higher survival (P = 0. 005 ) and lower total cardiac events(p= 0. 0008) could be seen in treatment group over this period. Conclusions. Early and long-term treatment with captopril in the elderly patients with AMI has bene-ficial outcomes in both in-hospital and follow-up periods.

EFFECT OF CAPTOPRIL ON RENAL HEMODYNAMICS AND RENAL PROSTAGLANDINS IN EARLY TYPE Ⅱ DIABETIC PATIENTS WITH NORMO-OR MICROALBUMINURIA

In this study,we investigated the effect of captopril(CPT) on glomerular filtration rate(GFR),effective renal plasma flow(ERPF),filtration fraction(FF),urinary albumin excretion(UAE) and daily urinary excretion of thromboxane B2(TXB2) and 6-keto-prostaglandin F1a(6-keto-PGFla) in 29 normotensive non-insulin-dependent diabetes(NIDDM) patients without clinically discernible nephropathy.Before treatment,urinary excretion 6-keto-PGF1a was significantly increased(P<0.05) in 29 NIDDM patients compared with 25 health subjects matched for age and sex.The values of GFR and FF were significantly higher(P<0.01 and P<0.005,respectively) in NIDDM than in normal volunters,whereas ERPF was comparable in both groups.Meanwhile we observed that UAE of early NIDDM was increased before treatment.After CPT treatment,GFR,FF,UAE and urinary excretion of 6-keto-PGFla were significantly reduce(all P<0.005) compared with those of NIDDM before treatment. These data indicated that CPT is effective in lowering glomerular filtration pressure and ameliorating microalbuminuria in the normotensive early NIDDM.

COMPARATIVE EFFECTS OF LOSARTAN AND CAPTOPRIL ON VENTRICULAR REMODELING AND FUNCTION AFTER MYOCARDIAL INFARCTION IN THE RAT

Objective. To determine the effects of losartan and captopril treatment on ventricular remodeling and function after myocardial infarction in rats. Methods. Thirty-two rats with MI induced by coronary ligation after seven days were divided into four groups randomly and treated with captopril(2 g. liter-1, group A), losartan(10 mg. kg-1. d-1, group B), losartan(30 mg. kg-1. d-1,group C) and placebo (no drug, group D) for six weeks, respectively. Shamoperated rats(group E)served as controls. Echocardiography was performed at 1 and 7 weeks after MI, re- spectively. Results. Compared with the results before treatment,both LV end-diastolic internal diameter and volume decreased significantly and the thickened Posterior wall was reversed in group A, B and C; the peak early filling velocity decreased whereas the peak velocity was increased in these three groups. There are no significant difference among the three treated groups. However,LV end-diastolic internal diameter and the E/A were still increased,whereas the thickness of anterior wall and the peak velocity of LV outflow were decreased in group A,B,and C after treatment comparing with group E. Conclusion. Both angiotensin converting enzyme inhibitor and angiotensin II receptor antagonist can prevent the ventricular remodeling and improve the ventricular function.

Effect of captopril or verapamil on intracellular sodium in cultured vascular smooth muscle cells

The effects of captopril (Cap) and verapamil (Ver)alone and in combination on intracellular Na+ concentration ([Na+]i) in cultured aortic smooth muscle cells (ASMC) of rabbits was evaluated by a direct measurement of [Na+]i with fluorescent dye sodium-binding benzofuran isophthalate (SBFI) combined with digital image. [Na+]i in resting cells was found to be 11.9 ± 0. 7 mmol/L. Angiotensin II (Ang-II, 0.1-10μmol/L) induced an increase of [Na+]i in concentration-dependent manner. Ver (0.1-10μmol/L) inhibited Ang-II (1 μmol/L)-induced increase in [Na+]i, while Cap enhanced Ang-II-induced increase in [Na+]i at 10μmol/L but not at 0.1-1μmol/L. Ver (0.1-1μmol/L)abolished enhancement of Ang-II-induced increase in [Na+]i by Cap. Thus, the inhibition of Capenhanced [Na+]i by Ver may provide a new hypothesis for the underlying molecular mechanism of synergistic effect of the combination of Ca2+ antagonists and angiotensinconverting enzyme inhibitors in controlling blood pressure.

ABNORMAL LEFT VENTRICULAR SYSTOLIC AND DIASTOLIC FUNCTIONAL RESPONSE TO ISOMETRIC EXERCISE IN IDIOPATHIC DILATED CARDIOMY-OPATHY: BENEFICIAL EFFECT OF CAPTOPRIL

In 19 patients with idiopathic dilated cardiomyopathy and symptoms of congetive heart failure, left ventricular (LV) systolic performance and diastolic velocity profiles were assessed by two- dimensional echocardiography and pulsed wave Doppler at rest and during handgrip exercise before and ninety minutes after administration of captopril (mean dose 25 +12mg; range 12. 5─50mg). Although heart rate and blood pressure increased similarly during handgrip exercise before and after captopril treatment, both were lower with handgrip exercise during captopril treatment. The results from this study indicated that acute angiotensin converting enzyme inhibition with captopril reduces preload and afterload and ameliorates handgrip exercise-induced LV systolic and diastolic filling dysfunction in patients with congestive heart failure secondary to idiopathic dilated cardiomyopathy.

THE LONG TERM EFFECT OF CAPTOPRIL TREATMENT ON ENDOTHELIAL FUNCTION IN SPONTANEOUSLY HYPERTENSIVE RATS

The aim of this study is to elucidate the long term effect Of captopril treatment on the endothelial func-tion to release nitric Oxide (NO) in spontaneOusly hypertensive rats (SHR). The properties of endotheliumwere determined with a model of hindquarter perfusion in response to al adrenergic agonist, phenylephrine,at the age of 40 weeks of SHR which was administrated with captopril (100 mg/kg/day) from lntrauterineand withdrawn at 16 weeks of age. Furthermore, in the presence of N-nitro-L-arginine methyl ester(LNAME), or L-arginine, the responses to phenylephrine were studied. From the curve of perfusion pres-sure, the minimal, maximal perfusiOn pressure (PPmin,PPmax) and the maximal slOpe (slope),as well asthe 5O% of effective concentratiOn (EC,,) were obtained. The data show that in captopril treated SHR,PPmin, PPmax and slope were markedly lower, but EC50 higher than those of untreated SHR. The curveinduced by phenylephrine was significantly right shift compared with that of untreated SHR. Like WKY,the intensive reactivity to phenylephrine in the presence of LNAME was much lower than that of untreatedSHR. ln the presence of L-arginine, however, the right shift of curves was seen only in captopril treatedSHR and WKY rats, but not in control SHR. In conclusipn, endothelium does involve in the respnse ofresistant vessel to phenylephrine. The mechanism of enhanced reactivity In untreated SHR may be, at leastin part, due to the diminished capacity of producing No frpm endpthelium, and the effect pf sustained hy-potension of early captopril treatment might be relevant to the improved ability of endOthelium.

Spectrofluorimetric analysis of captopril based on its obstruction effect of the nanomaterial surface energy transfer between acridine orange and gold nanoparticles

A simple and sensitive method for detection of captopril was established based on its obstructive effect on nanomaterial sur- face energy transfer （NSET）. It was found that the acridine orange （AO） could be adsorbed onto the surface of citrated-gold nanoparticles （AuNPs） through electrostatic interaction. Incidentally, the fluorescence of AO was quenched owing to the dipole-dipole interaction of NSET between AO fluorophore and the AuNPs. However, captopril could obstruct the occurrence of NSET between AO and AuNPs effectively with the formation of Au-S covalent bonds between it and the AuNPs. Consequently, AO molecules were moved away from the surface of AuNPs leading to a decline of the energy transfer efficiency. Moreover, the fluorescence of AO could be gradually restored with the addition of captopril. Under the optimal conditions, the recovered fluorescence intensity correlated linearly with the concentration of captopril in the range of 400 nmol/L-2.0μmol/L with a detection limit of 71 μmol/L. Besides, the proposed method was successfully applied for the detection of captopril in troches with the recovery of 93%-102% and the RSD lower than 2.24%. The results were in good agreement with those obtained from the HPLC method,

Efficacy and safety of ACEI plus tanshinone for acute exacerbation of pulmonary heart disease: a meta-analysis

Acute exacerbation of pulmonary heart disease(AECPHD) is life-threatening. Conventional therapy plus angiotensinconverting enzyme inhibitors(ACEI) is not always practical. Recent trials have suggested the beneficial effects of the combination of ACEI and tanshinone on AECPHD. In the present study, we aimed to evaluate its efficacy and safety by meta-analysis systematically. The result indicated that combination of ACEI and tanshinone was more effective than ACEI monotherapy in AECPHD, as represented by treatment efficiency and mean pulmonary arterial pressure, PaCO_(2), and PaO_(2). However, the incidence of adverse events of combined therapy was higher than the control group, while the result of the analysis for adverse events was unstable. Further large-scale, multicenter, and rigorously designed randomized controlled trials(RCT) are needed to evaluate the efficacy and safety of combined therapy.

Long-term mortality in patients with myocardial infarction: impact of early treatment with captopril for 4 weeks

Objective In an earlier interim report of the Chinese Cardiac Study (CCS-1) trial, 15 000 patients up to 36 hours after the onset of suspected acute myocardial infarction (AMI) were randomized to receive either oral captopril or matching placebo for one month. Results showed that captopril was associated with a non-significant reduction in 4-week mortality (681 ［9.1%］ captopril-allocated vs 730 ［9.7%］ placebo-allocated deaths; 2P=0.19), but the long-term effects remained uncertain. The present study reports on the long-term effect of early captopril treatment on mortality and other major events in AMI patients of the earlier CCS-1 trial.Methods Long-term follow-up was carried out in those hospitals which had recruited more than 20 cases in the CCS-1 trial. 8000 patients with MI were thus selected for long-term follow-up. Data on 6749 patients (84.4%) were available. Results Patient characteristics were comparable between the treatment group (n=3391) and the placebo group (n=3358). Average follow-up time was 23.4±16.9 months; average age was 63.6±10.6 years, and 76.2% were male. At the end of the follow-up time, cardiac function of NYHA Ⅲ-Ⅳ was 9.0% in the treatment group and 9.8% in the placebo group; the reinfarction rate was 5.6% vs. 6.0%; total cardiovascular events were 32.9% vs. 34.3%. Total mortality was 11.9% (n=404) vs 13.8% (n=463), with a 13.8% reduction in the captopril group (P=0.03). Cardiovascular mortality was 10.0% vs. 11.8% (P=0.01), death due to heart failure was 4.1% vs. 5.5% (P=0.01). From the above results, it is estimated that early treatment with captopril can save 19 lives per 1000 patients treated; patients with systolic blood pressure (SBP)≥100 mm Hg at entry would have a long-term mortality 12.4% in the treatment group vs. 13.8% in the placebo group (P=0.04) and patients with a heart rate (HR)≥60/minute at entry would have a long term mortality 12.0% in captopril groups vs. 14.5% in the placebo group (P=0.01). Conclusion Early treatment with captopril during AMI for 4 weeks can significantly reduce long-term total mortality.