Biomedical subjects
Publications and source records attributed to D A Sica.
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Perindopril erbumine is a once-daily angiotensin-converting enzyme (ACE) inhibitor that effectively lowers systolic and diastolic blood pressure (BP) in patients with mild-to-moderate hypertension. Converted from the prodrug ester perindopril, the active diacid perindoprilat is distributed rapidly and extensively, primarily to tissues with high ACE activity. Its ability to lower BP is comparable to or better than that of other antihypertensive agents, both of its own class and other classes, and its trough-peak ratio is consistently between 75% and 100%, translating into 24 hours of true efficacy per dose. First-dose hypotension caused by an initial acute BP depression occurs less frequently with perindopril than with other ACE inhibitors, an advantage in volume-contracted patients and those whose BP is angiotensin II dependent, such as patients with congestive heart failure. A missed-dose study showed that most of the antihypertensive effect of perindopril remains for 24 to 48 hours after dosing, a characteristic that confers protection to patients who miss a dose. Perindopril improves the distensibility and compliance of large and small arteries, which are compromised in hypertension, and can effect vascular remodeling by a mechanism independent of BP lowering. The clinical implications of these effects are being investigated in large trials. Perindopril is well tolerated in the elderly, and combination therapy with a diuretic was shown to yield significant additional BP reduction. Perindoprilat is cleared renally; dosage should be adjusted in patients with renal impairment.
The treatment of hypertension has become increasingly refined during the past decade. Although a variety of antihypertensive medication classes exist, drugs that interrupt the renin-angiotensin axis have gained a favored position in the treatment of hypertension and its attendant end-organ complications. In this regard, two drug classes, angiotensin converting enzyme inhibitors and angiotensin receptor blockers, are most commonly used. Angiotensin receptor blockers have proven highly effective in the management of hypertension. This class is fairly heterogeneous with individual class members having somewhat distinctive pharmacologic properties. Eprosartan is a recent entry into this class. This compound compares favorably to others in this class relative to blood pressure reduction. In addition, preliminary studies indicate that this compound may uniquely interrupt the sympathetic nervous system and thereby preferentially reduce systolic blood pressure.
BACKGROUND: Eprosartan is a new nonphenyl angiotensin II receptor blocker, which has been approved for the treatment of hypertension. Although the drug has a relatively short plasma half-life of 5 to 9 h, clinical studies have suggested that its antihypertensive effect persists for 24 h. METHODS: We assessed both the changes in 24-h and trough blood pressure (BP) (last 4 h of the ambulatory BP while the patient was awake) of eprosartan at doses of 600 and 1,200 mg once daily in a randomized, double-blind, placebo-controlled trial. Ambulatory BP was monitored at placebo baseline and after 8 weeks of double-blind therapy. RESULTS: Two hundred patients randomized in the study with 177 patients completing the trial. The 24-h change in BP from baseline was 0.2/0.1 +/- 1.4/1.0 mm Hg, -7.9/ -5.4 +/- 1.0 mm Hg (P < .0001), and -7.4/-5.0 +/- 0.9 mm Hg (P < .0001) in the placebo, 600-mg eprosartan, and 1,200-mg eprosartan groups, respectively. Changes in trough ambulatory BP showed significant reductions of -6.3/-4.1 +/- 1.6/1.1 mm Hg and -7.7/-5.5 +/- 1.5/1.0 mm Hg for 600 mg of eprosartan and 1,200 mg of eprosartan, respectively. CONCLUSIONS: These data demonstrate that eprosartan at doses of 600 or 1200 mg significantly reduced BP throughout an entire 24-h dosing period. There were no differences between the 600- and 1,200-mg dose; thus, 600 mg once daily should be the only dose used in the treatment of hypertension with eprosartan.
BACKGROUND: The aim of this study was to assess potential differences in the 24-h antihypertensive response to treatment with the controlled-onset, extended-release (COER) calcium antagonist, verapamil in men versus women and older versus younger patients with hypertension. METHODS: Meta-analyses were performed of three prospective randomized, double-blind, placebo-controlled trials with COER-verapamil in patients with mid-stage I to stage III essential hypertension. The trials were conducted at medical clinics in the US and Canada in patients with a mean office diastolic blood pressure (BP) of 95 to 115 mm Hg on 2 consecutive weeks and a mean daytime diastolic BP >90 mm Hg. Patients were randomized to treatment with 180 to 540 mg/day of COER-verapamil (N = 273) or placebo (N = 125). Changes from baseline in ambulatory BP and heart rate after COER-verapamil were compared in men versus women and in older versus younger patients. RESULTS: Treatment with COER-verapamil caused significant reductions in 24-h and early-morning systolic and diastolic BP in all of the subpopulations as compared with placebo (P < .001). COER-verapamil induced a greater reduction in both 24-h systolic (-15.1 v -10.0 mm Hg; P < .001) and diastolic (-10.4 v -8.2 mm Hg; P = .003) BP in women compared with men. Older patients showed a greater mean reduction in 24-h diastolic BP (-10.2 v -8.2 mm Hg; P < .05) and heart rate (-5.7 v -4.4 beats/min; P < .05) compared with younger patients. Side effects were similar in all of the COER-verapamil treatment groups. CONCLUSIONS: Both gender and age were significant determinants of the response to COER-verapamil. The antihypertensive effect of verapamil is greater in women than in men and in older patients compared with younger patients.
The Heart Outcomes Prevention Evaluation study was a landmark study employing the angiotensin-converting enzyme inhibitor ramipril in a patient population pre-destined for vascular events. This study found that a 10 mg dose of ramipril in comparison with placebo reduced the incidence of death, myocardial infarction, stroke, and death from cardiovascular causes by 22%. This improvement in outcome was viewed as a direct consequence of ramipril, although the fact that blood pressure was reduced with ramipril has cast some considerable doubt on this supposition. Whether the observed findings in this study are a 'class effect' for all angiotensin-converting enzyme inhibitors is unclear. To its credit, ramipril is the first angiotensin-converting enzyme inhibitor shown to prevent ischemic events in high-risk patients without discernible left ventricular dysfunction. Other similar trials are underway, which are studying similar populations to those included in this landmark study and should resolve the question of whether the cardioprotective effects of angiotensin-converting enzyme inhibitors are a 'class effect'.
Blacks demonstrate a higher response rate to diuretic therapy for hypertension than do whites. This study examined the pharmacokinetic (PK), pharmacodynamic, and neurohumoral effects of hydrochlorothiazide (HCTZ) administration in a matched group of 9 black and 9 white hypertensive patients (mean +/- SD for black and white). After a 4-week washout period and 7-day control diet, subjects received a single dose of HCTZ (25 mg at 8 AM) with serial blood and urine collections for 36 hours. After HCTZ sodium excretion increased comparably in both groups (blacks: 122 +/- 42 pre to 265 +/- 49 mEq/24 hours post; whites: 117 +/- 29 pre to 255 beta 39 mEq/24 hrs post). Potassium excretion tended to be higher at baseline and was significantly higher following HCTZ in whites (blacks: 45 beta 20 pre to 66 beta 13 mEq at 24 hours post; blacks: 57 +/- 9 pre to 86 +/- 14 mEq at 24 hours post) with most of the post-dosing difference being observed in the hours 0 to 12 after HCTZ. There were no between group PK differences for urinary HCTZ. Aldosterone excretion followed a normal circadian pattern in the whites but did not show this pattern in the blacks. Aldosterone excretion (0 to 12 hours) was generally lower post-dosing in blacks. In conclusion, whereas the PK and single-dose natriuretic response for HCTZ were not racially distinct, potassium excretion was notably less in blacks. Aldosterone excretion was also lower in blacks and without its normal circadian pattern which may, in part, explain their altered potassium excretion pattern.
OBJECTIVE: Determine if increased intra-abdominal pressure (IAP) alone can cause systemic hypertension in a chronic canine model. DESIGN: Evaluate effects of increase in IAP with progressive inflation and deflation of an intra-abdominal balloon on systemic blood pressure in experimental and control animals. SUBJECTS: Male dogs weighing 15-25 kg underwent placement of an intra-abdominal balloon which was progressively inflated on a weekly basis in the experimental animals (5) over 4 weeks to 25 mmHg above baseline and kept there for an additional 2 weeks before gradual deflation over 2 weeks. Control animals (5) had the balloon placed but not inflated. Pain was controlled with osmotic analgesic pumps. MEASUREMENTS: The animals were anesthetized, blood pressure (BP) measured and blood drawn for plasma renin activity (PRA), aldosterone, atrial naturetic peptide (ANP), catecholamines, and serum sodium (Na). A right heart catheter was inserted for measuring cardiac output (CO) and pulmonary artery occlusion pressure (PAOP) at baseline, week 5 (maximal IAP) and week 7 (after balloon deflation). The animals were weighed and urinary bladder pressures recorded weekly before and after abdominal balloon inflation. RESULTS: Systolic (122+/-3 to 155+/-5 mmHg, P<0.05) and diastolic (82+/-4 mmHg to 107+/-7 mmHg, P<0.05) BP rose at 5 weeks at 25 mmHg IAP>baseline and returned to control with balloon deflation. Both systolic and diastolic BP rose (P<0.05) above control animals BP at 15 mmHg IAP at 2 weeks and remained elevated until abdominal decompression, at week 7. There were no significant changes in net animal weight, PRA, aldosterone, ANF, catecholamines, Na, CO or PAOP. CONCLUSION: Increased IAP from progressively inflating an intra-abdominal balloon in dogs was associated with significant increases in systolic and diastolic BP that resolved with balloon deflation. Increased IAP may be a cause for systemic hypertension in central obesity and pre-eclampsia.
BACKGROUND: Omapatrilat, a vasopeptidase inhibitor, preserves natriuretic peptides and inhibits the renin angiotensin aldosterone system by simultaneously inhibiting neutral endopeptidase and angiotensin-converting enzyme. METHODS: Oral omapatrilat, 10 mg/d, was administered for 8 to 9 days to three groups of eight subjects with varying degrees of renal function (CLCR values, normal > or = 80; mild to moderate impairment < 80 to > or = 30; severe impairment < 30 mL/min/1.73 mL2) and to six subjects undergoing maintenance hemodialysis. Omapatrilat and its metabolites (phenylmercaptopropionic acid, S-methylomapatrilat, S-methylphenylmercaptopropionic acid, and cyclic S-oxide-omapatrilat) were quantified in plasma by a validated liquid chromatography/mass spectrometry method. The model, Cmax or AUC(0-T) = intercept + slope x CLCR, was tested for a possible linear correlation between Cmax (peak plasma concentrations) or AUC(0-T) (area under plasma concentration versus time curve) and CLCR. RESULTS: For omapatrilat and its inactive metabolites, phenylmercaptopropionic acid, S-methylomapatrilat, and S-methylphenylmercaptopropionic acid, the median times to peak plasma concentrations (tmax) were 1.5 to 2, 2 to 3, 2.5 to 3.5, and 7 to 10 hours, respectively, and were independent of renal function. After Cmax attainment, plasma concentrations declined rapidly to about 10% of Cmax values. Cyclic S-oxide-omapatrilat, a potentially active metabolite, was undetectable at all sampling time points. Hemodialysis did not decrease circulating levels of omapatrilat. There was minimal accumulation of omapatrilat and phenylmercaptopropionic acid and moderate accumulation of the S-methylated metabolites. For omapatrilat and S-methylphenylmercaptopropionic acid, neither Cmax nor AUC(0-T) was CLCR dependent. However, AUC(0-T) for phenylmercaptopropionic acid and both the Cmax and AUC(0-T) for S-methylomapatrilat were CLCR dependent. CONCLUSIONS: The pharmacokinetics of omapatrilat, the only clinically relevant active compound studied, was independent of CLCR. For patients with reduced renal function, adjusting initial omapatrilat dose is not suggested. Hemodialysis did not significantly contribute to the clearance of omapatrilat. The long-term pharmacodynamic response to omapatrilat will dictate dose-adjustment needs.
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The sympathetic nervous system is intimately involved in both the origin and the perpetuation of the hypertensive state, although there is some debate as to its precise contribution to the long-term hypertensive condition. Catecholamines are leading candidates to be both the pressor mechanism that initiates the rise in blood pressure and the trophic mechanism that maintains hypertension by vascular hypertrophy. Although the relationship between sympathetic nervous system and systolic blood pressure would seem intuitive, the multiple interactive pathways between these two pathways still needs to be more completely clarified, particularly as relates to interplay with the renin-angiotensin axis. Along this line of reasoning, a number of studies have examined the interplay between ACE inhibitors or angiotensin-receptor antagonists and alterations in sympathetic nervous system activity. Recent data support a role for one of the angiotensin-receptor antagonists, eprosartan, in having a potent inhibitory effect on pre-synaptic type-1 angiotensin receptors (AT(1) -receptors) involved in the enhancement of sympathetic nervous system activity. This may provide an explanation for the differential effect on systolic blood pressure exhibited by this compound.
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Adolescents in low-socioeconomic-status environments are more susceptible to illnesses, such as hypertension and cardiovascular diseases. This study examined the influence of both neighborhood- and family-level socioeconomic status (SES) on blood pressure (BP) reactivity in a healthy sample of 76 black adolescents. It was hypothesized that a higher level of parental education and/or income would reduce the elevated BP reactivity associated with living in poorer neighborhoods. Census-derived data were obtained using each participant's address. Neighborhood level of SES was based on percentage of households below the poverty line, female-headed households, owner-occupied housing, percentage vacant housing, and average number of persons per household. Family level of SES was based on self-reported level of parental education and annual family income. Adolescents participated in a competitive video game to establish their BP reactivity scores. As predicted, adolescents who lived in poorer neighborhoods had lower diastolic BPs if their parents were more (versus less) educated (P<0.05; 7+/-8 versus 13+/-6 mm Hg). Adolescents who lived in poorer neighborhoods also had significantly lower diastolic BP reactivity (P<0.05) if their family had a higher (versus lower) annual income (7+/-7 versus 12+/-8 mm Hg). These data are the first to demonstrate the buffering effect of family SES on the negative health consequences of living in low-SES neighborhoods in healthy black adolescents.
The pharmacokinetics and pharmacodynamics of losartan and its active metabolite, E-3174, were studied in 8 stable, hypertensive continuous ambulatory peritoneal dialysis (CAPD) patients. Following a 1-week washout period, subjects received 100 mg of losartan orally for 7 days. On Days 1 and 7, hemodynamic and hormonal responses were determined, as were PK parameters on Day 7. Peritoneal equilibration testing was performed pre-Day 1 and on Day 7. AUC0-24 and t1/2 for losartan and E-3174 were 95 +/- 49.9 micrograms.min/mL and 176 +/- 82.1 micrograms.min/mL and 172.5 +/- 86.7 minutes and 628 +/- 575 minutes, respectively. These values are similar to those of normal subjects and subjects on hemodialysis. Peritoneal clearance of losartan and E-3174 was negligible. All subjects demonstrated a substantial reduction in blood pressure with at least a 10 mmHg drop in diastolic BP. Plasma renin activity (PRA) values increased, but aldosterone, endothelin, norepinephrine, and epinephrine values did not change following 7 days of losartan. Losartan was well tolerated in all study subjects.
The effective treatment of hypertension is an extremely important consideration in patients with end-stage renal disease (ESRD). Virtually any drug class--with the possible exception of diuretics--can be used to treat hypertension in the patient with ESRD. Despite there being such a wide range of treatment options, drugs which interrupt the renin-angiotensin axis are generally suggested as agents of choice in this population, even though the evidence in support of their preferential use is quite scanty. ACE inhibitors, and more recently angiotensin antagonists, are the 2 drug classes most commonly employed to alter renin-angiotensin axis activity and therefore produce blood pressure control. ACE inhibitor use in patients with ESRD can sometimes prove an exacting proposition. ACE inhibitors are variably dialysed, with compounds such as catopril, enalapril, lisinopril and perindopril undergoing substantial cross-dialyser clearance during a standard dialysis session. This phenomenon makes the selection of a dose and the timing of administration for an ACE inhibitor a complex issue in patients with ESRD. Furthermore, ACE inhibitors are recognised as having a range of nonpressor effects that are pertinent to patients with ESRD. Such effects include their ability to decrease thirst drive and to decrease erythropoiesis. In addition, ACE inhibitors have a unique adverse effect profile. As is the case with their use in patients without renal failure, use of ACE inhibitors in patients with ESRD can be accompanied by cough and less frequently by angioneurotic oedema. In the ESRD population, ACE inhibitor use is also accompanied by so-called anaphylactoid dialyser reactions. Angiotensin antagonists are similar to ACE inhibitors in their mechanism of blood pressure lowering. Angiotensin antagonists are not dialysable and therefore can be distinguished from a number of the ACE inhibitors. In addition, the adverse effect profile for angiotensin antagonists is remarkably bland, with cough and angioneurotic oedema rarely, if ever, occurring. In patients with ESRD, angiotensin antagonists are also not associated with the anaphylactoid dialyser reactions which occur with ACE inhibitors. The nonpressor effects of angiotensin antagonists--such as an influence on thirst drive and erythropoiesis--have not been explored in nearly the depth, as they have been with ACE inhibitors. Although ACE inhibitors have not been compared directly to angiotensin antagonists in patients with ESRD, angiotensin antagonists possess a number of pharmacokinetic and adverse effect characteristics, which would favour their use in this population.
BACKGROUND: Losartan is a selective angiotensin AT1 receptor antagonist currently employed in the management of essential hypertension. This compound is in common use in populations with renal failure and end-stage renal disease (ESRD). OBJECTIVE: To investigate the pharmacokinetics and pharmacodynamics of losartan in patients with ESRD in order to establish administration guidelines. METHODS: Patients were administered losartan 100 mg/day for 7 days, and after the seventh and final dose pharmacokinetic parameters were determined for both losartan and its active metabolite E-3174. During the study, the haemodialytic clearances of losartan and E-3174 were measured during a standard 4-hour dialysis session. Neurohumoral and biochemical changes were assessed during losartan administration. RESULTS: The pharmacokinetics of losartan and E-3174 in haemodialysis patients did not alter to a clinically significant level. Losartan administration was accompanied by a decline in plasma aldosterone level as well as by an increase in plasma renin activity. Losartan administration resulted in a decline in plasma uric acid level, despite the fact that the study participants had no residual renal function. Losartan and E-3174 were not dialysable. CONCLUSIONS: The pharmacokinetics of losartan and E-3174 are minimally altered in ESRD; thus, dosage adjustment is not required in the presence of advanced dialysis-dependent renal failure. In addition, postdialysis supplementation is not required for losartan because of the negligible dialysability of losartan and E-3174.
This review discusses important issues related to the use of angiotensin-converting enzyme inhibitors (ACEIs). ACEIs have been shown in clinical trials to slow progressive renal, cardiac, and vascular disease. The Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends ACEIs as alternative first-line therapy in patients with essential hypertension (HTN), congestive heart failure, and in hypertensive diabetics who also have renal disease. Many of the therapeutic benefits derived from ACEIs are thought to be class effects. There are certain distinctive pharmacokinetic and pharmacodynamic features for some of the ACEIs such as differences in absorption, protein binding, half-life, and metabolic disposition. In appropriate doses, they all lower blood pressure similarly. In the treatment of HTN and hypertensive renal disease, a class effect appears to be applicable when selecting an agent. It is less likely that ACEIs are interchangeable in the treatment of congestive heart failure because maximal cardioprotective tissue effect rather than blood pressure normalization is the goal. In addition, for some agents clinical trials that demonstrate decreased morbidity or mortality are currently lacking.
Research suggests that females seek out, prefer, and are more receptive to emotional support (encouragement), and that males seek out, prefer, and are more receptive to instrumental support (problem-solving). Thus, we hypothesized that boys would show lower blood pressure (BP) reactivity in response to instrumental than emotional or no support, and that girls would show lower BP reactivity in response to emotional than instrumental or no support. Forty-eight healthy African-American adolescents (50% males) participated in a role play conflict task and were randomized to receive either emotional, instrumental, or no support (presence only) from a confederate. Boys showed lower systolic blood pressure (SBP) reactivity in the instrumental than in the emotional or no support conditions and lower recovery SBP as compared to boys in the emotional or no support conditions. A similar pattern of results was demonstrated for diastolic blood pressure (DBP) reactivity. Girls, however, did not demonstrate lower BP reactivity in response to emotional as compared to instrumental support. These findings suggest that instrumental and emotional support differentially influence cardiovascular (CV) reactivity in African-American boys versus girls.