Quinapril treatment curtails decline of global longitudinal strain and mechanical function in hypertensive rats.

BACKGROUND: Left ventricular (LV) global longitudinal strain (GLS) has been proposed as an early imaging biomarker of cardiac mechanical dysfunction. OBJECTIVE: To assess the impact of angiotensin-converting enzyme (ACE) inhibitor treatment of hypertensive heart disease on LV GLS and mechanical function. METHODS: The spontaneously hypertensive rat (SHR) model of hypertensive heart disease ( n  = 38) was studied. A subset of SHRs received quinapril (TSHR, n  = 16) from 3 months (mo). Wistar Kyoto rats (WKY, n  = 13) were used as controls. Tagged cardiac MRI was performed using a 4.7 T Varian preclinical scanner. RESULTS: The SHRs had significantly lower LV ejection fraction (EF) than the WKYs at 3 mo (53.0 ±â€Š1.7% vs. 69.6 ±â€Š2.1%, P  < 0.05), 14 mo (57.0 ±â€Š2.5% vs. 74.4 ±â€Š2.9%, P  < 0.05) and 24 mo (50.1 ±â€Š2.4% vs. 67.0 ±â€Š2.0%, P  < 0.01). At 24 mo, ACE inhibitor treatment was associated with significantly greater LV EF in TSHRs compared to untreated SHRs (64.2 ±â€Š3.4% vs. 50.1 ±â€Š2.4%, P  < 0.01). Peak GLS magnitude was significantly lower in SHRs compared with WKYs at 14 months (7.5% ±â€Š0.4% vs. 9.9 ±â€Š0.8%, P  < 0.05). At 24 months, Peak GLS magnitude was significantly lower in SHRs compared with both WKYs (6.5 ±â€Š0.4% vs. 9.7 ±â€Š1.0%, P  < 0.01) and TSHRs (6.5 ±â€Š0.4% vs. 9.6 ±â€Š0.6%, P  < 0.05). CONCLUSIONS: ACE inhibitor treatment curtails the decline in global longitudinal strain in hypertensive rats, with the treatment group exhibiting significantly greater LV EF and GLS magnitude at 24 mo compared with untreated SHRs.

Benefit and risk evaluation of quinapril hydrochloride.

INTRODUCTION: Angiotensin-converting enzyme (ACE) inhibitors are a mainstay of antihypertensive therapy. Quinapril hydrochloride, a less commonly used, and less-studied ACE inhibitor has been approved for its primary use in hypertension. Studies also indicate its off-label use for congestive heart failure and diabetic nephropathy. The ANDI and TREND trials have been pivotal in demonstrating the effectiveness of quinapril. AREAS COVERED: The authors conducted a review of the literature analyzing the clinical efficacy and safety profile of quinapril. This review discusses the development of quinapril, provides an updated summary of the indications and contraindications, and presents a comparison with other ACE inhibitors. EXPERT OPINION: Quinapril is a safe and well-tolerated antihypertensive medication with a favorable safety profile compared to other ACE inhibitors. However, a lack of ample recent clinical trials and post-marketing data investigating the efficacy of quinapril in large cohorts has resulted in limited use in clinical practice. Quinapril may be an effective antihypertensive option for elderly populations as well as those who cannot tolerate the side effects profiles of other ACE inhibitors and as an additional treatment option for patients with heart failure with preserved ejection fraction.

Identification of a Gut Commensal That Compromises the Blood Pressure-Lowering Effect of Ester Angiotensin-Converting Enzyme Inhibitors.

BACKGROUND: Despite the availability of various classes of antihypertensive medications, a large proportion of hypertensive individuals remain resistant to treatments. The reason for what contributes to low efficacy of antihypertensive medications in these individuals is elusive. The knowledge that gut microbiota is involved in pathophysiology of hypertension and drug metabolism led us to hypothesize that gut microbiota catabolize antihypertensive medications and compromised their blood pressure (BP)-lowering effects. METHODS AND RESULTS: To test this hypothesis, we examined the BP responses to a representative ACE (angiotensin-converting enzyme) inhibitor quinapril in spontaneously hypertensive rats (SHR) with or without antibiotics. BP-lowering effect of quinapril was more pronounced in the SHR+antibiotics, indicating that gut microbiota of SHR lowered the antihypertensive effect of quinapril. Depletion of gut microbiota in the SHR+antibiotics was associated with decreased gut microbial catabolism of quinapril as well as significant reduction in the bacterial genus Coprococcus. C. comes, an anaerobic species of Coprococcus, harbored esterase activity and catabolized the ester quinapril in vitro. Co-administration of quinapril with C. comes reduced the antihypertensive effect of quinapril in the SHR. Importantly, C. comes selectively reduced the antihypertensive effects of ester ramipril but not nonester lisinopril. CONCLUSIONS: Our study revealed a previously unrecognized mechanism by which human commensal C. comes catabolizes ester ACE inhibitors in the gut and lowers its antihypertensive effect.

Binder jetting 3D printing of challenging medicines: From low dose tablets to hydrophobic molecules.

Increasing access to additive manufacturing technologies utilising easily available desktop devices opened novel ways for formulation of personalized medicines. It is, however, challenging to propose a flexible and robust formulation platform which can be used for fabrication of tailored solid dosage forms composed of APIs with different properties (e.g., hydrophobicity) without extensive optimization. This manuscript presents a strategy for formulation of fast dissolving tablets using binder jetting (BJ) technology. The approach is demonstrated using two model APIs: hydrophilic quinapril hydrochloride (QHCl, logP = 1.4) and hydrophobic clotrimazole (CLO, logP = 5.4). The proposed printing method uses inexpensive, well known, and easily available FDA approved pharmaceutical excipients. The obtained model tablets had uniform content of the drug, excellent mechanical properties, and highly porous structure resulting in short disintegration time and fast dissolution rate. The tablets could be scaled and obtained in predesigned shapes and sizes. The proposed method may find its application in the early stages of drug development where high flexibility of the formulation is required and the amount of available API is limited.

Pulmonary adverse drug event data in hypertension with implications on COVID-19 morbidity.

Hypertension is a recognized comorbidity for COVID-19. The association of antihypertensive medications with outcomes in patients with hypertension is not fully described. However, angiotensin-converting enzyme 2 (ACE2), responsible for host entry of the novel coronavirus (SARS-CoV-2) leading to COVID-19, is postulated to be upregulated in patients taking angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs). Here, we evaluated the occurrence of pulmonary adverse drug events (ADEs) in patients with hypertension receiving ACEIs/ARBs to determine if disparities exist between individual drugs within the respective classes using data from the FDA Spontaneous Reporting Systems. For this purpose, we proposed the proportional reporting ratio to provide a statistical summary for the commonality of an ADE for a specific drug as compared to the entire database for drugs in the same or other classes. In addition, a statistical procedure, multiple logistic regression analysis, was employed to correct hidden confounders when causative covariates are underreported or untrusted to correct analyses of drug-ADE combinations. To date, analyses have been focused on drug classes rather than individual drugs which may have different ADE profiles depending on the underlying diseases present. A retrospective analysis of thirteen pulmonary ADEs showed significant differences associated with quinapril and trandolapril, compared to other ACEIs and ARBs. Specifically, quinapril and trandolapril were found to have a statistically significantly higher incidence of pulmonary ADEs compared with other ACEIs as well as ARBs (P < 0.0001) for group comparison (i.e., ACEIs vs. ARBs vs. quinapril vs. trandolapril) and (P ≤ 0.0007) for pairwise comparison (i.e., ACEIs vs. quinapril, ACEIs vs. trandolapril, ARBs vs. quinapril, or ARBs vs. trandolapril). This study suggests that specific members of the ACEI antihypertensive class (quinapril and trandolapril) have a significantly higher cluster of pulmonary ADEs.

Beneficial effect of combined spironolactone and quinapril treatment on thrombosis and hemostasis in 2K1C hypertensive rats.

A strong correlation between raised aldosterone levels and increased risk of thrombotic disorders has been provided. Clinical studies have demonstrated the benefits of the addition of the aldosterone receptor antagonist to the standard therapy with angiotensin-converting enzyme inhibitor in the reduction of cardiovascular events in patients. We suggest that the benefits of this dual renin-angiotensin-aldosterone system (RAAS) blockade may be related to the drug's effects on the hemostatic and oxidative balance. Thus, we investigated the effect of combined spironolactone (SPIRO) and quinapril (QUIN) administration on thrombosis, hemostasis and oxidative stress in hypertensive rats. A two-kidney, one-clip model of renovascular hypertension in Wistar rats was used. QUIN, SPIRO, or QUIN + SPIRO were administered for 10 days. Venous thrombosis was induced by vena cava ligation. Thrombus weight and incidences of thrombosis were assessed. Bleeding time, platelet adhesion, tissue factor (TF), tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1), thrombin activatable fibrynolysis inhibitor (TAFI), malonyl dialdehyde, and hydrogen peroxide plasma levels were assayed. Aortic expression of NADPH oxidase and superoxidase dismutase were measured. We observed significant RAAS activation associated with hypercoagulability and oxidative stress augmentation in renovascular hypertensive rats. Thrombosis was reduced only in rats treated with QUIN + SPIRO. In all groups, decreases in TF, PAI-1, and TAFI levels were observed, however in the QUIN + SPIRO group those changes were more pronounced. The inhibition of platelet adhesion was also stronger in rats treated with QUIN + SPIRO. The oxidative stress parameters were markedly reduced in rats treated with QUIN or SPIRO, although the most evident changes were observed in the QUIN + SPIRO group. Dual RAAS blockade with aldosterone receptor antagonist and angiotensin-converting enzyme inhibitor provides additional benefits for experimental thrombosis associated with the antiplatelet, anticoagulative, profibrinolytic, and antioxidative effects in renovascular hypertensive rats.

A novel electrochemiluminescence sensor coupled with capillary electrophoresis for simultaneous determination of quinapril hydrochloride and its metabolite quinaprilat hydrochloride in human plasma.

A novel electrochemiluminescence (ECL) sensor with composite consisted of silica-sol, Zinc oxide nanoparticles (ZnO NPs), polyvinylpyrrolidone (PVP) and tris(2, 2'-bipyridine) ruthenium (II) was constructed. A new method for simultaneous determination of quinapril hydrochloride (QHCl) and its metabolite quinaprilat hydrochloride (QTHCl) in human plasma was developed using the ECL sensor coupled with capillary electrophoresis (CE). ECL intensities of QHCl and QTHCl increased dramatically when the ECL sensor was used as working electrode. The running buffer contains 14mmol/L phosphate (pH 8.0) and 20% n-propyl alcohol. Under optimized experimental conditions, the linearity ranges of the method are 0.007-8.0µg/mL for QHCl and 0.009-8.3µg/mL for QTHCl. The detection limits of QHCl and QTHCl (S/N=3) are 3.6ng/mL and 3.9ng/mL, respectively. The method was applied for the simultaneous determination of QHCl and QTHCl in human plasma with satisfactory results.

Efficacy of Administration of an Angiotensin Converting Enzyme Inhibitor for Two Years on Autonomic and Peripheral Neuropathy in Patients with Diabetes Mellitus.

Aim. To evaluate the effect of quinapril on diabetic cardiovascular autonomic neuropathy (CAN) and peripheral neuropathy (DPN). Patients and Methods. Sixty-three consecutive patients with diabetes mellitus [43% males, 27 with type 1 DM, mean age 52 years (range 22-65)], definite DCAN [abnormal results in 2 cardiovascular autonomic reflex tests (CARTs)], and DPN were randomized to quinapril 20 mg/day (group A, n = 31) or placebo (group B, n = 32) for 2 years. Patients with hypertension or coronary heart disease were excluded. To detect DPN and DCAN, the Michigan Neuropathy Screening Instrument Questionnaire and Examination (MNSIQ and MNSIE), measurement of vibration perception threshold with biothesiometer (BIO), and CARTs [R-R variation during deep breathing [assessed by expiration/inspiration ratio (E/I), mean circular resultant (MCR), and standard deviation (SD)], Valsalva maneuver (Vals), 30 : 15 ratio, and orthostatic hypotension (OH)] were used. Results. In group A, E/I, MCR, and SD increased (p for all comparisons < 0.05). Other indices (Vals, 30 : 15, OH, MNSIQ, MNSIE, and BIO) did not change. In group B, all CART indices deteriorated, except Vals, which did not change. MNSIQ, MNSIE, and BIO did not change. Conclusions. Treatment with quinapril improves DCAN (mainly parasympathetic dysfunction). Improved autonomic balance may improve the long-term outcome of diabetic patients.

The Effect of Combined Treatment with the (Pro)Renin Receptor Blocker HRP and Quinapril in Type 1 Diabetic Rats.

BACKGROUND/AIMS: Diabetic nephropathy remains a major clinical problem. The effects of prorenin might be adverse, but the literature data are controversial. We compared the renal effects of the (pro)renin receptor ((P)RR) blockade and angiotensin converting enzyme (ACE) inhibition on the progression of diabetic nephropathy in rats. METHODS: Diabetes (DM) was induced by ip. streptozotocin administration in adult male Sprague-Dawley rats, followed by eight weeks of treatment with the (P)RR blocker "handle region" decoy peptide (HRP, 0,1 mg/kg/day) or with the ACE inhibitor Quinapril (Q, 50 mg/kg/day) and grouped as follows: 1. Control (n=10); 2. DM (n=8); 3. DM+HRP (n=6); 4. DM+Q (n=10); 5. DM+Q+HRP (n=10). Renal functional parameters, histology and gene expressions were evaluated. RESULTS: HRP reduced glomerulosclerosis and podocyte desmin expression, but did not affect proteinuria and tubular ERK(1/2) phosphorylation. Both Q and Q+HRP treatment reduced proteinuria, glomerular and tubular damage, tubular TGF-ß1 expression and ERK(1/2) phosphorylation to the same extent. CONCLUSION: The effects of HRP were partially beneficial on diabetic kidney lesions as HRP reduced damage but did not improve tubular damage and failed to reduce ERK(1/2) phosphorylation in rats. The combination of HRP with Quinapril had no additive effects over Quinapril monotherapy on the progression of diabetic nephropathy.

Rapid analysis of drug dissolution by paper spray ionization mass spectrometry.

With a great quantity of solid dosage tested by dissolution technology, developing a rapid and sensitive method to access the content of drug within dissolution media is highly desired by analysts and scientists. Traditionally, dissolution media is not compatible with mass spectrometry since the inorganic salts in the media might damage the mass spectrometer. Here, paper spray ionization mass spectrometry (PSI-MS), one of the ambient mass spectrometry technologies, is developed to characterize the content of drugs in dissolution media. The porous structure of paper can effectively retain salts from entering mass spectrometer. This makes the measurement of drug content within dissolution media by mass spectrometer possible. After the experimental parameters were optimized, calibration curves of model drugs - enalapril, quinapril and benazepril were established by using corresponding deuterated internal standards. PSI-MS was then deployed to characterize the content of enalapril from the dissolution testing of enalapril tablets. The results from PSI-MS are comparable to those from HPLC characterization. More importantly, the analysis time of 6 samples is shortened from 90min to 6min. Detection limit of enalapril maleate tablets by PSI-MS is 1/300 of LC. PSI-MS is rapid, sensitive and accurate in analyzing drug content from dissolution tests.

In vitro study on binding interaction of quinapril with bovine serum albumin (BSA) using multi-spectroscopic and molecular docking methods.

The binding interaction between quinapril (QNPL) and bovine serum albumin (BSA) in vitro has been investigated using UV absorption spectroscopy, steady-state fluorescence spectroscopic, synchronous fluorescence spectroscopy, 3D fluorescence spectroscopy, Fourier transform infrared spectroscopy, circular dichroism, and molecular docking methods for obtaining the binding information of QNPL with BSA. The experimental results confirm that the quenching mechanism of the intrinsic fluorescence of BSA induced by QNPL is static quenching based on the decrease in the quenching constants of BSA in the presence of QNPL with the increase in temperature and the quenching rates of BSA larger than 1010 L mol-1 s-1, indicating forming QNPL-BSA complex through the intermolecular binding interaction. The binding constant for the QNPL-BSA complex is in the order of 105 M-1, indicating there is stronger binding interaction of QNPL with BSA. The analysis of thermodynamic parameters together with molecular docking study reveal that the main binding forces in the binding process of QNPL with BSA are van der Waal's forces and hydrogen bonding interaction. And, the binding interaction of BSA with QNPL is an enthalpy-driven process. Based on Förster resonance energy transfer, the binding distance between QNPL and BSA is calculated to be 2.76 nm. The results of the competitive binding experiments and molecular docking confirm that QNPL binds to sub-domain IIA (site I) of BSA. It is confirmed there is a slight change in the conformation of BSA after binding QNPL, but BSA still retains its secondary structure α-helicity.

Quinapril decreases antifibrinolytic and prooxidative potential of propofol in arterial thrombosis in hypertensive rats.

Angiotensin converting enzyme inhibitors and propofol both exert hypotensive action and may affect hemostasis. We investigated the influence of quinapril and propofol on hemodynamics and hemostasis in renal-hypertensive rats with induced arterial thrombosis. Two-kidney, one clip hypertensive rats were treated with quinapril (3.0 mg/kg for 10 days), and then received propofol infusion (15 mg/kg/h) during ongoing arterial thrombosis. The hemodynamic and hemostatic parameters were assayed. Quinapril exerted a hypotensive effect increasing after propofol infusion. Quinapril showed an antithrombotic effect with the platelet adhesion reduction, fibrinolysis enhancement and oxidative stress reduction. Propofol did not influence thrombosis; however, it inhibited fibrinolysis and showed prooxidative action. The effect of propofol on fibrinolysis and oxidative stress was significantly lower in quinapril-pretreated rats. Mortality was increased among rats treated with both drugs together. Our study demonstrates that pretreatment with quinapril reduced the adverse effects of propofol on hemostasis. Unfortunately, co-administration of both drugs potentiated hypotension in rats, which corresponds to higher mortality.

Comparison of Stability-Indicating LC Methods Using Light Scattering and Photodiode Array Detection with Monolithic Column for Determination of Quinapril and Hydrochlorothiazide.

Rapid stability-indicating LC methods for simultaneous analysis of quinapril and hydrochlorothiazide were developed, validated and compared using evaporative light scattering detection (ELSD) and diode array detection (DAD). For the separation of quinapril, hydrochlorothiazide and its major degradation products, a monolithic column was used and the analytes were eluted within 7 min, applying gradient mobile phase in both methods. Quinapril was subjected to hydrolytic, oxidative, thermal, humidity and photolytic stress conditions. Degradation products were well resolved from main peaks and from each other, proving the stability-indicating power of the methods. The response with DAD was linear and the response with ELSD was fitted to a power function, for quinapril and hydrochlorothiazide concentrations of 20-160 and 12.5-100 µg mL(-1), respectively. DAD method achieved better precision than ELSD method, the LOQ of DAD was lower and the accuracy of the methods was similar. Quinapril degrade by hydrolysis and thermal stress, showing the formation of quinaprilat and quinapril diketopiperazine as degradants, which were identified by MS-MS. The methods were successfully applied to quantify quinapril and hydrochlorothiazide in commercial tablets. LC-DAD and LC-ELSD methods are suitable to assess the stability and routine analysis of quinapril and hydrochlorothiazide in pharmaceutical industry.

[Regulatory Adaptive Status in Assessment of Efficacy of Pharmacotherapy and Prognostication of Complications in Functional Class III Chronic Heart Failure].

OBJECTIVE: to elucidate significance of regulatory adaptive status (RAS) for assessment of effectiveness of medical treatment and prediction of cardiovascular complications in functional class (FC) III congestive heart failure (CHF). MATERIAL AND METHODS: We included into this study 100 patients with hypertensive disease (HD) or ischemic heart disease (IHD) and FC III CHF with compromised systolic left ventricular (LV) function. All patients were randomized into two groups. In addition to complex background therapy (quinapril, torasemide, spironolactone) patients of group 1 (n=56, age 57.5+/-21.7 years) were given metoprolol succinate (59.1+/-12.1 mg/day) and patients of group 2 (n=44, age 57.1+/-21.4 years) - ivabradine (12.1+/-4.6 mg/day). Examination at baseline and after 6 months included cardiorespiratory synchronism test (in order to quantitatively define RAS), echocardiography, treadmill test, six minute walk test. Cardiovascular complications (CVC) were registered during 12 months of study treatment. RESULTS: Both schemes of complex therapy equally improved structural and functional state of the myocardium, increased tolerance to physical exercise, reduced neurohumoral hyperactivation. Positive impact on RAS was more pronounced in ivabradine group. Clinical efficacy of therapy as well as number of hospitalizations because of CHF decompensation, ischemic strokes, and cardiovascular deaths did not differ substantially between groups. Initially low or unsatisfactory RAS was associated with higher incidence of CVC while initial unsatisfactory RAS was associated with elevated risk of sudden death. CONCLUSION: The data obtained reflect independent value of determination of RAS for assessment of efficacy of pharmacotherapy and prognosis of CVC in patients with FCIII CHF.

Application of quantitative NMR for purity determination of standard ACE inhibitors.

This study investigated the accuracy of the quantitative NMR method for purity determination of ACE inhibitors reference standards and the discovery of two pairs of new diastereoisomers. Six types of ACE inhibitors, imidapril hydrochloride, benazepril hydrochloride, lisinopril, enalapril maleate, quinapril hydrochloride, and captopril were quantificated and validated for the qNMR method by discussing factors that affect parameters of the qNMR experiment, internal standards, integration, pH-effect, and uncertainty. The results were compared with data obtained by the mass balance method. The study found that maleic acid influenced the quantification of captopril in deuteroxide because of a chemical reaction. The mixtures of the reaction products were isolated by HPLC and structurally elucidated by NMR as two pairs of new diastereoisomers, 1-[(2S,4R)-thio-2-methylpropionyl-5-d-ethanedicarboxylicacid]-L-proline and 1-[(2S,4S)-thio-2-methylpropionyl-5-d-ethanedicarboxylicacid]-L-proline. The results showed that the accuracy and precision of quantitative (1)H NMR spectroscopy satisfied the requirements for quantitative analysis of chemical reference standards and provided a simple, rapid, and reliable method for purity determination of ACE inhibitors systematically.

ß-blocker Therapy is Not Associated with Reductions in Angina or Cardiovascular Events After Coronary Artery Bypass Graft Surgery: Insights from the IMAGINE Trial.

PURPOSE: To evaluate whether ß-blockers were associated with a reduction in cardiovascular events or angina after Coronary Artery Bypass Graft (CABG) surgery, in otherwise stable low-risk patients during a mid-term follow-up. METHODS: We performed a post-hoc analysis of the IMAGINE (Ischemia Management with Accupril post-bypass Graft via Inhibition of angiotensin coNverting Enzyme) trial, which tested the effect of Quinapril in 2553 hemodynamically stable patients with left ventricular ejection fraction (LVEF) >40 %, after scheduled CABG. The association between ß-blocker therapy and the incidence of cardiovascular events (death, cardiac arrest, myocardial infarction, revascularizations, angina requiring hospitalization, stroke or hospitalization for heart failure) or angina that was documented to be due to underlying ischemia was tested with Cox regression and propensity adjusted analyses. RESULTS: In total, 1709 patients (76.5 %) were using a ß-blocker. Patients had excellent control of risk factors; with mean systolic blood pressure being 121 ± 14 mmHg, mean LDL cholesterol of 2.8 mmol/l, 59% of patients received statins and 92% of patients received antiplatelet therapy. During a median follow-up of 33 months, ß-blocker therapy was not associated with a reduction in cardiovascular events (hazard ratio 0.97; 95 % confidence interval 0.74-1.27), documented angina (hazard ratio 0.85; 95 % confidence interval 0.61-1.19) or any of the individual components of the combined endpoint. There were no relevant interactions for demographics, comorbidities or surgical characteristics. Propensity matched and time-dependent analyses revealed similar results. CONCLUSIONS: ß-blocker therapy after CABG is not associated with reductions in angina or cardiovascular events in low-risk patients with preserved LVEF, and may not be systematically indicated in such patients.

Design, synthesis and evaluation of novel 2-butyl-4-chloroimidazole derived peptidomimetics as Angiotensin Converting Enzyme (ACE) inhibitors.

A series of novel 2-butyl-4-chloro-1-methylimidazole derived peptidomimetics were designed, synthesized and evaluated for their Angiotensin Converting Enzyme (ACE) inhibitor activity. 2-Butyl-4-chloro-1-methylimidazole-5-carboxylic acid 2 obtained after oxidation of respective carboxaldehyde 1, was condensed with various amino acid methyl esters 3a-k to give imidazole-amino acid conjugates 4a-k in very good yields. Ester hydrolysis of 4a-k with aqueous LiOH gave the desired peptidomimetics 5a-k. Screening all the new compounds 4a-k and 5a-k using ACE inhibition assay, resulted five compounds 4i, 4k, 5e, 5h and 5i as potent ACE inhibitors with IC50 of 0.647, 0.531, 1.12, 0.657 and 0.100µM with minimal toxicity. Among them, 5i emerged as most active ACE inhibitor with greater potency than marketed drugs Lisinopril, Ramipril and relatively equipotent to Benazepril, Quinapril and Enalapril.

Effect of carboxylesterase 1 c.428G > A single nucleotide variation on the pharmacokinetics of quinapril and enalapril.

AIM: The aim of the present study was to investigate the effects of the carboxylesterase 1 (CES1) c.428G > A (p.G143E, rs71647871) single nucleotide variation (SNV) on the pharmacokinetics of quinapril and enalapril in a prospective genotype panel study in healthy volunteers. METHODS: In a fixed-order crossover study, 10 healthy volunteers with the CES1 c.428G/A genotype and 12 with the c.428G/G genotype ingested a single 10 mg dose of quinapril and enalapril with a washout period of at least 1 week. Plasma concentrations of quinapril and quinaprilat were measured for up to 24 h and those of enalapril and enalaprilat for up to 48 h. Their excretion into the urine was measured from 0 h to 12 h. RESULTS: The area under the plasma concentration-time curve from 0 h to infinity (AUC0-∞) of active enalaprilat was 20% lower in subjects with the CES1 c.428G/A genotype than in those with the c.428G/G genotype (95% confidence interval of geometric mean ratio 0.64, 1.00; P = 0.049). The amount of enalaprilat excreted into the urine was 35% smaller in subjects with the CES1 c.428G/A genotype than in those with the c.428G/G genotype (P = 0.044). The CES1 genotype had no significant effect on the enalaprilat to enalapril AUC0-∞ ratio or on any other pharmacokinetic or pharmacodynamic parameters of enalapril or enalaprilat. The CES1 genotype had no significant effect on the pharmacokinetic or pharmacodynamic parameters of quinapril. CONCLUSIONS: The CES1 c.428G > A SNV decreased enalaprilat concentrations, probably by reducing the hydrolysis of enalapril, but had no observable effect on the pharmacokinetics of quinapril.

[INFLUENCE OF QUINAPRIL IN COMBINATION WITH ANGIOLINE ON THE CONNECTIVE TISSUE COMPONENTS IN THE RATS SERUM WITH EXPERIMENTAL HYPERTENSION].

One of the most active inhibitors angiotensin-converting enzyme is quinapril that has a high affinity for tissue ACE, improves endothelial vasodilation, has a wide therapeutic range and beneficient influence on heart rate. A new biological active compound with antioxidant action that has endothelioprotective, cardioprotective, antiischemic action is angiolin. In experimental arterial hypertension in the animals blood serum the activity of collagenase, the content of free and protein connecting fractions of hydroxyproline and indicators that reflect the metabolism of glycosaminoglycans have been increased. Angiolin increases the activity of collagenase free and protein connecting fractions of hydroxyproline comparing to control. Concentration glycosoaminoglycan (GAG) also exceeds the standard data. Quinapril has similar to angiolin action directed effect to the connective tissue components, though losing as proteinconecting of hydroxiproline action. Cooperative application quinapril with angioline most effectively influence the metabolic processes stabilization in experimental animals.