Chronopharmacology of enalapril in hypertensive patients

The pharmacokinetics and pharmacodynamics of enalapril, an angiotensin converting enzyme inhibitor, are reported to vary with the time of administration. The present study was undertaken to examine whether the effect of enalapril on plasma bradykinin (BK), substance P and prostaglandin E₂ (PGE₂), which are likely to be involved in the mechanism of enalaprilinduced cough, might also be affected by its time of administration. Enalapril 5 mg or placebo was given orally at 10:00 h (day trial) or 22:00 h (night trial) to 12 patients with essential hypertension. Serum concentrations of total drug (enalapril + enalaprilat, its active metabolite) during the day and night trials did not differ significantly at any time. However, serum enalaprilat tended to be higher and its maximum concentration greater in the day trial than in the night trial. Blood pressure 24 h after administration of enalapril was reduced at 22:00 h, but not at 10:00 h. Plasma BK tended to increase following enalapril administration at 10:00 h, but not at 22:00 h. Remarkable increases in plasma BK were observed in two patients in the day trial and one of them also complained of cough. However, no such increase in plasma BK or subsequent adverse effect were recorded in the night trial. Plasma substance P and PGE₂ did not change significantly following enalapril administration either in the day or night trial. The results suggest that the response of BK to enalapril is affected by the time of administration. In patients who complain of cough during treatment with enalapril during the daytime, this adverse effect might be dminished or eliminated by a switch to night-time administration.     

Antihypertensive efficacy of manidipine and enalapril in hypertensive diabetic patients

Recent studies showed that in diabetic hypertensive patients, administration of angiotensin-converting enzyme (ACE)-inhibitors or calcium antagonists can effectively lower blood pressure (BP) and prevent diabetes-related cardiovascular complications with no adverse metabolic effects. We sought to assess the antihypertensive and metabolic effects of the new dihydropyridine calcium antagonist manidipine (M) in patients with diabetes mellitus and essential hypertension as compared with the ACE inhibitor enalapril (E). After 3 weeks of placebo, 101 (62 men; age range, 34-72 years) hypertensives with type II diabetes mellitus were randomized to M 10-20 mg or E 10-20 mg, od, for 24 weeks. At the end of the placebo period and the active-treatment phase, BP was measured with a mercury sphygmomanometer (office, O) and over the 24 h by ambulatory (A) monitoring. ABP recordings were analyzed to obtain 24-h, day (6 a.m. to midnight), and night (midnight to 6 a.m.) average systolic (S) and diastolic (D) BP and heart rate (HR) values. Homogeneity of the antihypertensive effect over the 24 h was assessed by the smoothness index [SI: i.e., the ratio between the average of the 24 hourly BP changes after treatment and the corresponding standard deviation (the higher the SI, the more uniform is the BP control by treatment over the 24 h]. The O SBP and DBP were significantly (p < 0.01) and similarly reduced by M (16 +/- 10 and 13 +/- 6 mm Hg, n = 49) and E (15 +/- 10 and 13 +/- 6 mm Hg, n = 45). The percentage of patients whose O DBP was reduced < or = 85 mm Hg (i.e., the value indicated to be the optimal DBP goal in diabetic hypertensives) was similar for M (37%) and E (40%). The reduction of 24-h BP also was similar between M (n = 38) and E (n = 38) for both drugs (systolic, 6 +/- 11 and 8 +/- 10 mm Hg; diastolic, 5 +/- 8 and 5 +/- 7; NS, M vs. E). The antihypertensive effect was distributed in a similar homogeneous fashion throughout the dosing interval, as shown by the similar SI values (M, 0.6 +/- 1.2 for SBP and 0.6 +/- 0.9 for DBP; E, 0.6 +/- 0.8 for SBP and 0.5 +/- 0.7 for DBP; NS, M vs. E). O and A HR were unchanged by either treatment. Markers of glucose and lipid metabolism and renal function were not significantly modified by treatment both with M and with E. In the diabetic hypertensives, M was as effective and metabolically neutral as the ACE-inhibitor E.     

Captopril: pharmacokinetics, antihypertensive and biological effects in hypertensive patients

The kinetics of captopril plasma levels and of the drug-induced plasma converting enzyme activity (PCEA), plasma renin activity (PRA) and diastolic blood pressure (DBP) modifications were studied over 24 h after oral administration of captopril, 1 mg/kg, to ten hypertensive patients. Free unchanged captopril pharmacokinetic parameters were: t1/2, alpha: 0.45 +/- 0.06 h; tmax: 0.98 +/- 0.13 h; Cmax: 1.31 +/- 0.20 mg l-1; t1/2,z: 0.66 +/- 0.13 h; V: 0.614 +/- 0.104 1 kg-1 and CLtot: 0.690 +/- 0.082 l h-1 kg-1. At 6 h captopril was no longer detectable in plasma. The onset of PCEA inhibition and of DBP decrease closely followed the rise of captopril's plasma levels, while that of PRA increase was delayed. In contrast, while captopril rapidly disappeared from plasma, its biological and antihypertensive effects were long-lasting. The lack of correlation between the relative bioavailability of captopril and the induced reduction in DBP (evaluated by the corresponding AUCs) suggests that free unchanged captopril plasma monitoring is not an adequate indicator of hypertensive patients' potential responsiveness to captopril's blood pressure lowering effects.     

Cost of switching hypertensive patients from enalapril maleate to lisinopril.

The costs and potential savings associated with switching patients in a hypertension clinic from enalapril maleate to lisinopril were analyzed. Patients taking enalapril were randomized to receive lisinopril or to continue taking enalapril. For the 47 patients randomized, data were collected for 25 patients switched to an equal milligram dosage of lisinopril and for 21 patients who continued to receive a constant dosage of enalapril. To maintain blood pressure control, it was necessary to double the dosage of lisinopril in five patients (20%) and have it in one patient (4%), while the enalapril dosage was doubled in two patients (9.5%). The total direct cost of switching patients to lisinopril was $66.33 per patient. The annual drug cost savings per patient for switching to lisinopril would be $52.08, $46.80, and $120.24 for therapy with one 5-, 10-, and 20-mg tablet per day, respectively. A patient would have to receive 15, 17, or 7 months of therapy with 5-, 10-, or 20-mg tablets of lisinopril, respectively, before a net cost savings would be realized. In the evaluation of a less expensive therapeutic alternative, the total cost of switching must be considered.     

The effects of methylamphetamine on mood and appetite in depressed patients: a placebo-controlled study

Methylamphetamine given intravenously as a single 15 mg dose led to a pronounced elevation of mood in 7 out of 21 depressed patients compared to a control injection of sterile water administered on another occasion in random order under double-blind conditions. All 7 responders experienced an increase of VAS self-ratings of hunger in contrast to what has been observed in normal subjects who show a decrease in hunger after amphetamine. The implications of these findings are discussed in the light of monoamine theories of depression and appetite control.     

Captopril improves cerebrovascular structure and function in old hypertensive rats

We examined the effects of an angiotensin-converting enzyme inhibitor (ACEI), captopril, on cerebral arterioles in young and old spontaneously hypertensive rats (SHR). Animals were anesthetized with sodium pentobarbitone (60 mg kg(-1) day(-1)). We measured cerebral blood flow (CBF, arbitrary units) and cerebral arteriolar internal diameter (ID, mum) prior to and during stepwise hypotension (SH) in 6- (WKY-6) and 15-month-old (WKY-15) Wistar Kyoto rats and in age-matched SHR that were untreated (SHR-6 and SHR-15) or treated for 3 months with captopril (SHR-6C, 105+/-2 mg kg(-1) day(-1) and SHR-15C, 94+/-1 mg kg(-1) day(-1)). ID and cross-sectional area of the vessel wall (CSA) were measured in deactivated (EDTA) cerebral arterioles during a second SH. Captopril decreased the lower limit of CBF autoregulation (61+/-6 in SHR-6C and 51+/-2 in SHR-15C vs 52+/-6 in WKY-6 and 62+/-7 in WKY-15 and 83+/-14 mmHg in SHR-6 and 120+/-19 mmHg in SHR-15; P<0.05) and CSA (510+/-21 in SHR-6C and 585+/-25 in SHR-15C vs 529+/-12 in WKY-6 and 549+/-20 in WKY-15 and 644+/-38 mmHg in SHR-6 and 704+/-38 mmHg in SHR-15; P<0.05). Captopril increased cerebral arteriolar external diameter of SHR (105+/-5 in SHR-6C and 94+/-4 in SHR-15C vs 125+/-8 in WKY-6 and 108+/-3 in WKY-15 and 83+/-2 mmHg in SHR-6 and 80+/-2 mmHg in SHR-15 for a pial arteriolar pressure step of 35-39 mmHg; P<0.05). Captopril attenuated increases in cerebral arteriolar distensibility in young SHR. Thus, ACEIs attenuate eutrophic and hypertrophic inward remodeling of cerebral arterioles in young and old SHR, thus decreasing the lower limit of CBF autoregulation.     

Antihypertensive effect of single doses of enalapril in hypertensive patients treated with bendrofluazide.

This study was designed to investigate the validity of the then current recommendations for initiation of therapy with enalapril in hypertensive patients on treatment with a diuretic. Enalapril in single doses of 10 and 20 mg was given to 13 hypertensive patients on treatment with bendrofluazide 5 mg daily in a randomised, crossover, placebo controlled study. The mean maximal reduction in blood pressure was similar with both doses (35/20 mmHg supine, 38/20 mmHg standing), occurred on average within 6 h of tablet ingestion, and was not accompanied by any significant change in heart rate. Three patients experienced symptomatic hypotension. In one patient this was incapacitating after 10 mg and precluded exposure to 20 mg. This study shows that in hypertensive patients receiving treatment with diuretics, the addition of enalapril should be undertaken with caution. An optimal starting dose of enalapril in such patients remains to be confirmed.     

Haemodynamic effects of enalapril,a new converting enzyme inhibitor,in hypertensive patients

Summary The haemodynamic effects of enalapril (EN), a new, long-acting, nonsulphhydryl converting enzyme inhibitor, were evaluated by non-invasive methods in 10 adult patients with mild to moderate essential hypertension (EH). Patients were randomly assigned, double blind to 2 treatment groups (EN 20 mg o.d. or 10 mg b.d.) for 4 weeks, and were crossed over to the other dosage regimen after a 2-week washout period. Measurements included mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), limb blood flow (LBF), plasma aldosterone (ALD), plasma renin activity (PRA) and systolic time intervals (STI). Both regimens (b.d. and o.d.) significantly reduced MAP (15.3% and 16.3%, respectively), total peripheral resistance (20.3% and 21.8%, respectively), limb vascular resistance (24.1% and 24.9%) and ALD (33.5% and 36.9%) and increased CO (7.8% and 8.7%), LBF (10.9% and 11.6%) and PRA (10.4% and 9.5%). No significant change was observed in HR or STI. EN 20 mg o.d. or 10 mg b.d. reduced arterial pressure to a similar extent through a fall in total peripheral resistance. An increase in CO was also observed.     

Left ventricular changes after chronic therapy with enalapril maleate in moderate to severe hypertensive patients

A randomized double-blind trial was carried out to determine the relationship of the changes in blood pressure and heart rate with changes in echocardiographic left ventricular indices in moderate to severe hypertensive patients with established left ventricular hypertrophy who were being treated chronically with enalapril or hydrochlorothiazide plus propranolol for 26 weeks. After a 2-week period on placebo, drug dosages in the two groups were adjusted to individual needs until blood pressure was normalized (diastolic less than 90 mmHg). Patients in Group I received 10 to 40 mg enalapril/day; those in Group II received 50 mg hydrochlorothiazide plus 80 to 240 mg propranolol/day. Echocardiographic measurements were made at the end of the placebo and 26-week active treatment periods. Significant correlations were observed between the changes in four pairs of variables in each group. In the 8 patients receiving enalapril, there were negative correlations between interventricular septal thickness and supine systolic blood pressure, erect and supine heart rates, and a positive correlation between relative wall thickness and erect diastolic blood pressure. In the 7 patients on hydrochlorothiazide plus propranolol, there were negative correlations between relative wall thickness and erect and supine heart rate, and positive correlations between left ventricular mass and erect diastolic blood pressure, and the percentage change in internal diameter of the left ventricle and supine systolic blood pressure. Possible explanations for and implications of these regional changes are discussed.     

Left ventricular changes after chronic therapy with enalapril maleate in moderate to severe hypertensive patients

Summary

A randomized double-blind trial was carried out to determine the relationship of the changes in blood pressure and heart rate with changes in echocardiographic left ventricular indices in moderate to severe hypertensive patients with established left ventricular hypertrophy who were being treated chronically with enalapril or hydrochlorothiazide plus propranolol for 26 weeks. After a 2-week period on placebo, drug dosages in the two groups were adjusted to individual needs until blood pressure was normalized (diastolic <90 mmHg). Patients in Group I received 10 to 40?mg enalapril/day; those in Group II received 50?mg hydrochlorothiazide plus 80 to 240?mg propranolol/day. Echocardiographic measurements were made at the end of the placebo and 26-week active treatment periods. Significant correlations were observed between the changes in four pairs of variables in each group. In the 8 patients receiving enalapril, there were negative correlations between interventricular septal thickness and supine systolic blood pressure, erect and supine heart rates, and a positive correlation between relative wall thickness and erect diastolic blood pressure. In the 7 patients on hydrochlorothiazide plus propranolol, there were negative correlations between relative wall thickness and erect and supine heart rate, and positive correlations between left ventricular mass and erect diastolic blood pressure, and the percentage change in internal diameter of the left ventricle and supine systolic blood pressure. Possible explanations for and implications of these regional changes are discussed.     

Effects of repeated caffeine administration on cognition and mood

The effects of repeated caffeine administration on cognitive and mood tasks were investigated in a double-blind study of 32 young healthy adults who were randomly assigned to one of the four treatment conditions: 0, 200, 400, or 600 mg of caffeine. Subjects were tested over six alternate days; on each test day they completed various tasks after drug administration. In general, caffeine produced no significant effects on cognitive performance; the exception is that the highest dose (600 mg) reduced the speed of completion of additions relative to the other doses. Also, post-hoc analysis showed that the highest dose impaired performance of the lower caffeine users more than higher users. Mood assessment showed individuals were sensitive to the effects of caffeine but the effect did not interact with cognitive performance. The present data suggest that tolerance to the cognitive effects of caffeine does not develop with continued caffeine administration, given the limitations that the individuals tested were young healthy adults and the testing took place only over 2 weeks.     

Antidepressant therapy can improve adherence to antiretroviral regimens among HIV-infected and depressed patients

Several strategies have been introduced to manage nonadherence to highly active antiretroviral therapy (HAART). Treatment with antidepressants may improve self-reported adherence. In this brief report, a small sample of HIV-depressed patients (n = 9) were treated for a 6-month period with antidepressants improving self-reported adherence based on the HAART scale (poor, good, satisfactory, and optimal). Before the antidepressant treatment, adherence was reported as "good" by 3 patients and "satisfactory" by 6 patients. After antidepressant therapy, adherence to antiretroviral regimes was statistically higher in HIV-depressed on treatment than in HIV-depressed patients not treated with antidepressants (P < 0.0001). We used chi2 test with a significance level at P < 0.05. Treating depression in HIV-infected patients may serve to improve adherence to HAART.     

Combination therapy with lercanidipine and enalapril reduced central blood pressure augmentation in hypertensive patients with metabolic syndrome

Arterial stiffness and blood pressure (BP) augmentation are independent predictors of cardiovascular events. In a randomized, open, parallel group study we compared the effect on these parameters of combination therapy with an ACE-inhibitor plus calcium channel blocker or thiazide diuretic in 76 hypertensive patients with metabolic syndrome uncontrolled by ACE-inhibitor monotherapy.After 4 weeks run-in with enalapril (ENA, 20 mg), patients were randomized to a combination therapy with lercanidipine (LER, 10–20 mg) or hydrochlorothiazide (HCT, 12.5–25 mg) for 24 weeks. Aortic stiffness (carotid to femoral pulse wave velocity, PWV), central BP values and augmentation (augmentation index, AIx) were measured by applanation tonometry.The two groups showed similar office and central BP after run-in. Office (ENA/LER: from 149.1 ± 4.9/94.5 ± 1.5 to 131.7 ± 8.1/82.2 ± 5.3; ENA/HCT: from 150.3 ± 4.7/94.7 ± 2.1 to 133.1 ± 7.1/82.8 ± 5.3 mm Hg) and central BP (ENA/LER 127.4 ± 17.1/85.2 ± 12.1 to 120.5 ± 13.5/80.0 ± 9.5 mm Hg; ENA/HCT 121.6 ± 13.4/79.3 ± 9.5 mm Hg) were similarly reduced after 24 weeks. PWV was comparable after run-in and not differently reduced by the two treatments (ENA/LER from 8.6 ± 1.5 to 8.1 ± 1.3 m/s, p < 0.05; ENA/HCT from 8.5 ± 1.2 to 8.2 ± 1.0 m/s, p < 0.05). Finally, both combinations reduced AIx, but its reduction was significantly greater (p < 0.05) in ENA/LER (from 26.8 ± 10.9 to 20.6 ± 9.1%) than in ENA/HCT arm (from 28.2 ± 9.0 to 24.7 ± 8.7%).In conclusion, the combination with LER caused a similar PWV reduction as compared to HCT, but a greater reduction in AIx in hypertensive patients with metabolic syndrome not controlled by ENA alone. These results indicate a positive effect of the combination of ENA/LER on central BP augmentation, suggesting a potential additive role for cardiovascular protection.     

The effects of high-dose and low-dose tryptophan depletion on mood and cognitive functions of remitted depressed patients

It has frequently been demonstrated that acute tryptophan depletion (ATD) induces a transient depressed mood in some patients who are in remission from depression. However, the effects of ATD on cognitive processes in remitted depressed patients have not been investigated. The aim of the present study was to investigate the effects of different extents of depletion on mood and cognitive tasks involving neutral and emotional stimuli. Twenty patients in remission or in partial remission from depression received ATD in a double-blind, crossover design. Mood was assessed at both sessions before, at +6.5 h and +24 h after depletion. Cognitive assessment in both sessions started at +4.75 h, and also before and after the whole procedure. The ATD mixtures induced the expected reductions of plasma tryptophan levels. High-dose ATD induced a depressive response in a subsample of patients and impaired the processing of positive information independent of mood change. Attention for neutral stimuli (Stroop interference) improved in a dose-dependent manner. ATD may affect mood and cognition via different pathways: one implicated in mood regulation and the processing of emotional information, and one for the processing of neutral information. The first pathway may be more important for discriminating vulnerability to impaired serotonin function. The comparison of the effects of high-dose and low-dose ATD is useful for those studies aiming to investigate the relationships among 5-HT, mood and cognition.