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 (AUC_0–∞) 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 AUC_0–∞ 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.     

The Effects of Oral Atenolol or Enalapril Premedication on Blood Loss and Hypotensive Anesthesia in Orthognathic Surgery

Purpose

The aim of this study was to evaluate the effects of premedication with oral atenolol or enalapril, in combination with remifentanil under sevoflurane anesthesia, on intraoperative blood loss by achieving adequate deliberate hypotension (DH) during orthognathic surgery. Furthermore, we investigated the impact thereof on the amount of nitroglycerin (NTG) administered as an adjuvant agent.

Materials and Methods

Seventy-three patients undergoing orthognathic surgery were randomly allocated into one of three groups: an angiotensin converting enzyme inhibitor group (Group A, n=24) with enalapril 10 mg, a β blocker group (Group B, n=24) with atenolol 25 mg, or a control group (Group C, n=25) with placebo. All patients were premedicated orally 1 h before the induction of anesthesia. NTG was the only adjuvant agent used to achieve DH when mean arterial blood pressure (MAP) was not controlled, despite the administration of the maximum remifentanil dose (0.3 µg kg^-1min^-1) with sevoflurane.

Results

Seventy-two patients completed the study. Blood loss was significantly reduced in Group A, compared to Group C (adjusted p=0.045). Over the target range of MAP percentage during DH was significantly higher in Group C than in Groups A and B (adjusted p-values=0.007 and 0.006, respectively). The total amount of NTG administered was significantly less in Group A than Group C (adjusted p=0.015).

Conclusion

Premedication with enalapril (10 mg) combined with remifentanil under sevoflurane anesthesia attenuated blood loss and achieved satisfactory DH during orthognathic surgery. Furthermore, the amount of NTG was reduced during the surgery.     

Post‐renal transplant erythrocytosis: A case report

PTE is defined as hematocrit >51% or hemoglobin >17 g/dL after renal transplantation. Risk factors include native kidneys with adequate erythropoiesis pretransplant, smoking, renal artery stenosis, and cyclosporine treatment. We report the case of a 14‐yr‐old female kidney transplant patient, with triple therapy immunosuppression and stable graft function who developed PTE at 12 months post‐transplant with hemoglobin 17.3 g/dL, hematocrit 54.2%, stable graft function, and normotensive with normal cardiac echocardiogram and erythropoietin levels. The only risk factor found was tobacco use. As she had no spontaneous improvement, enalapril treatment was started at 19 months post‐transplant with a hemoglobin level of 17.5 g/dL and hematocrit 53%; by 23 months post‐transplant, hemoglobin lowered to 15 g/dL and hematocrit to 44.5% and continued to be in normal range thereafter. PTE is a rare condition in childhood and can be successfully treated with enalapril.     

Benefits of delapril in hypertensive patients along the cardiovascular continuum

Angiotensin-converting enzyme inhibitors (ACEIs) are the first-line therapy for the treatment of hypertension. However, not all ACEIs are equal. Delapril is a nonsulfhydryl ACEI with unique properties. Delapril has a high lipophilicity and weak bradykinin potentiating action. As a result, delapril has a more potent inhibition capacity of vascular wall angiotensin-converting enzyme activity and a lower incidence of cough than enalapril or captopril. With regard to efficacy, delapril has a long-lasting antihypertensive effect with a trough/peak ratio that is in the upper range of different ACEIs and a positively high smoothness index. Thus, delapril effectively and smoothly reduces blood pressure over 24 h. Moreover, the benefits of delapril are not limited to hypertensive patients, but also in those with microalbuminuria, left ventricular hypertrophy, myocardial infarction or heart failure; delapril appears to be effective and well tolerated.     

Effects of Enalapril Maleate on Plasma Level of Inactive Renin in Renovascular Hypertension

Changes in plasma levels of active and inactive renin after the treatment with enalapril maleate (MK-421), a new angiotensin converting enzyme inhibitor, were studied in five patients with renovascular hypertension(RVH) due to unilateral renal artery stenosis. The dosage was increased when the blood pressure (BP) was not normalized for more than 3 days. Blood sampling was performed before, and 5 hours and 24 hours after the first administration, and on the 3rd day with each dosage. Active and inactive renin concentrations (ARC and IRC) showed a reciprocal change in 4 cases, 5 hours after the first dose. In the chronic treatment, ARC and IRC before the morning dose did not change apparently until the BP was normalized, when both ARC and IRC were evidently increased. It was suspected that a conversion from inactive to active renin may occur in the patients with RVH, when the active renin secretion is stimulated suddenly by the first dose of MK-421. The chronically diminished perfusion pressure in the kidney may stimulate the secretion of inactive renin, but the decrease in endogenous angiotensin II may not.     

Effect of Enalapril Treatment on the Heart of Normal Rats

Previous experiments showed that enalapril (EN) treatment as well as enalaprilic acid, when added to the perfusion bath, diminish the inotropic response of the papillary muscles to isoproterenol (ISO). The main objective of this study was to evaluate, in normal rats, the effect of EN on basal contractility and inotropic response to ISO on the whole perfused ventricles (Langendorff preparation). Blood pressure (BP), increase in body weight (IBW), ventricular weight/body weight ratio (R) and concentration of ventricular proteins and DNA were also analyzed. Five groups were studied: EN10: 5 mg/kg/day, 10 days; EN21(L): 5mg/kg/day, 21 days; EN21(H): 15 mg/kg/day, 21 days. C10 and C21 were untreated controls. Cardiac contractility was evaluated by the maximal developed pressure, maximal rate of rise of pressure and maximal velocity of relaxation; no changes were found due to EN treatments either on basal conditions or on ISO stimulation. Significant differences (p<0.05 vs C21) were: lower BP and R in EN21(L) and EN21(H), slower IBW in EN21(H), decreased ventricular DNA in EN21(H). In conclusion, daily treatment for ten or twenty one days with enalapril does not change either basal cardiac contractile performance or inotropic response to ISO in the Langendorff preparation. Longterm treatment with EN seems to modify nuclear processes involved in cardiomyocite DNA content     

Hemodynamic effects of celiprolol at rest and during exercise; A comparison with enalapril

Summary The antihypertensive effects of once-daily administration of celiprolol 400 mg were compared with those of once-daily enalapril 20 mg in 20 mild to moderate essential hypertensives in a single-blind study in which the subjects were randomized to 2 weeks' treatment with either drug, preceded by 2 weeks of placebo administration.Supine and standing systolic blood pressure (SBP), diastolic pressure (DBP), and heart rate (HR) were measured at rest and during exercise (exercise bicycle with increasing work loads up to 100 watts) at the end of either period, 20 to 24 hr after drug or placebo administration.Compared to placebo, both celiprolol and enalapril reduced resting supine and standing SBP and DBP to a marked and similar extent; resting HR was unaffected by enalapril, while celiprolol produced modest reductions.During exercise, however, celiprolol significantly attenuated rises in SBP and HR, while enalapril did not.Indexes of cardiac function at rest obtained by echocardiography and systolic time intervals were unaffected by either drug.Thus, despite similar reductions by both drugs in resting blood pressures, celiprolol produced better antihypertensive effects during exercise than enalapril.     

Enalapril does not alter renal function in normotensive,normoalbuminuric, hyperfiltering Type 1 (insulin-dependent) diabetic children

Summary Using a prospective randomised double-blind crossover design, the effect of the angiotensin converting enzyme inhibitor enalapril compared to a placebo was studied in 18 normotensive, normoalbuminuric Type 1 (insulin-dependent) diabetic children. Each patient had a high normal or clearly elevated glomerular filtration rate (145 ml· min^–1· 1.73 m² or higher) in the 6 months prior to the study. Enalapril, 0.5 mg·kg^–1· day^–1, was given for 4 weeks followed by placebo for 4 weeks, or vice versa. At the end of each period, glomerular filtration rate, renal plasma flow, blood pressure, plasma renin activity, and converting enzyme activity were determined. Enalapril caused significant reduction (p=<0.001) in blood pressure and converting enzyme activity and a rise in plasma renin activity. A slight but not significant rise in glomerular filtration rate and renal plasma flow without change in filtration fraction was observed. These data suggest that the renin angiotensin system is not involved in the glomerular hyperfiltration of Type 1 diabetes, and can be interpreted as showing no evidence for the presence of intraglomerular hypertension in these patients.Recipient of the Schering Award of the Canadian Society of Clinical Investigation during the period of this research     

Angiotensin converting enzyme inhibitors: Comparative structure,pharmacokinetics, and pharmacodynamics

Summary Angiotensin converting enzyme (ACE) inhibitors are a novel class of antihypertensive and anticongestive heart failure agents with wide patient and physician acceptability. By blocking the formation of angiotensin II in blood and tissues, all ACE inhibitors significantly lower systemic vascular resistance, lower blood pressure, and improve cardiac function, while maintaining or enhancing perfusion of vital organs: kidneys, brain, and heart. Captopril is the first oral ACE inhibitor with an active sulfhydryl group. Enalapril and lisinopril are potent nonsulfhydryl inhibitors of ACE characterized by weak chelating properties. The side effects of skin rashes, pruritis, taste abnormalities, oral ulcers, pemphigus, and blood dyscrasias have been considered to be strongly characteristic of penicillaminelike drugs, including the sulfhydryl ACE inhibitors. The class effects of cough, angioedema, hyperkalemia, nonoliguric functional renal insufficiency, and hypotension can occur with equal frequency with all ACE inhibitors. It is unclear whether the many yet investigational ACE inhibitors would have distinct advantages over captopril, enalapril, lisinopril, and enalaprilat. This paper reviews the comparative structure and clinical pharmacology of the three commercially available but chemically different oral ACE inhibitors.     

Neurohormonal mechanisms and the role of angiotensin-converting enzyme (ACE) inhibitors in heart failure

Summary Clinical evidence accumulated over the past decade suggests that neurohormonal mechanisms significantly influence the pathogenesis and eventual outcome of congestive heart failure (CHF). Pharmacologic modulation of this neuroendocrine activity can, consequently, be expected to improve patient prognosis. Results of several recent clinical trials—the Studies of Left Ventricular Dysfunction (SOLVD), the second Veterans Administration Cooperative Vasodilator Heart Failure Trial (VHeFT-II), and the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)—provide substantial evidence that addition of the angiotensin-converting enzyme (ACE) inhibitor enalapril to conventional therapeutic regimens can significantly reduce mortality and improve prognosis in patients with all grades of heart failure. Moreover, data from all three trials confirm the involvement of neurohormonal systems in the development and progression of CHF and suggest that the beneficial effects of enalapril in heart failure may in part be due to the suppression of this neurohormonal activity. It is now apparent that some form of neurohormonal activation is present early in the course of the disease before the emergence of overt heart failure symptoms. On the basis of such findings, it would seem that early introduction of therapy targeted at neurohormonal influences may well become a central component of any future CHF treatment program.