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P E Pool

Publications and source records attributed to P E Pool.

At least 19 recordsLinked to original sources
PubMed2000

Anomalies in the dosing of diltiazem.

From early research, investigators understood that the dose of diltiazem required for the treatment of hypertension (commonly 360 mg/day) was greater than that required for the treatment of angina (commonly 240 mg/day). Nonetheless, studies of recent prescribing practices show that the 240 and 180 mg capsule strengths constitute more than 70% of the diltiazem prescriptions for hypertension. Physicians became accustomed to the lower antianginal doses of diltiazem for 7 years before a hypertension indication was approved. Subsequently, these dosing levels were reinforced by the production of once-a-day formulations with highest capsule strengths of 240 mg and 300 mg. These strengths were dictated by the sheer bulk of the formulations, which limited how much diltiazem could be inserted into the #00 capsule, the largest capsule that can be comfortably administered. An examination of the combined data from the six randomized, blinded, and placebo-controlled trials submitted to the FDA for the original new drug applications of the three formulations of diltiazem available in the United States shows a clear linear dose-response relationship between diltiazem dose and blood pressure lowering through the 480-540 mg/day range. It also demonstrates that the 90-120 mg/day range is the "no-effect dose." These conclusions are supported by a MEDLINE review of all other studies of multilevel dosing of higher dose levels of diltiazem. The data support the conclusion that diltiazem is generally underdosed, but when properly dosed may be the single most potent antihypertensive overall.

Angina Pectoris↗
PubMed2000

Effects of intravenous dofetilide in patients with frequent premature ventricular contractions: a clinical trial.

BACKGROUND: Although suppression of premature ventricular contractions (PVCs) is not a predictor of mortality over the long term, the extent of PVC suppression is an important characteristic of any antiarrhythmic drug. HYPOTHESIS: This study was undertaken to determine whether intravenous (i.v.) dofetilide has the ability to suppress PVCs in patients who have frequent occurrences. METHODS: Subjects were men and women, aged 18 to 75 years, with > 30 PVCs/h on two consecutive 24-h Holter recordings while drug free, and > 50 PVCs/h during a 2-hour telemetric electrocardiogram. The study was randomized, double-blind, and placebo controlled. Subjects received a single-blind, i.v. infusion of placebo and were randomized (3:1) to receive a double-blind second infusion of placebo or an infusion of dofetilide (a 15-min loading infusion of 4 g/kg followed by a 60-min maintenance infusion of 3.5 g/kg, for a total dose of 7.5 g/kg). RESULTS: Dofetilide produced an 82.6% and placebo a 2.9% median reduction in PVCs. Drug responder rate, defined as 80% reduction in PVCs, was 50% in the dofetilide group and 0% in the placebo group. CONCLUSION: Intravenous dofetilide significantly reduced PVCs in patients who had > 30 PVCs/h at baseline, and it produced > or = 80% reduction in PVCs in 50% of all subjects.

Adult↗
PubMed2000

Does Chinese ethnicity affect the pharmacokinetics and pharmacodynamics of angiotensin-converting enzyme inhibitors?

Information from clinical and pharmacokinetic studies of angiotensin-converting enzyme inhibitors (ACEIs) has come from subjects who are mostly male and Caucasian, but the use of ACEIs extends to populations worldwide. Significant differences between Chinese in general and male Caucasians have been demonstrated in the pharmacokinetics/dynamics of other drug classes that could have implications for the use of ACEIs in the Chinese population. These include: significant Chinese/Caucasian genetic variation in the renin-angiotensin system based on an insertion/deletion (O/D) polymorphism of the ACE gene; the genetic determination of plasma ACE activity in the Chinese population; and genetic factors involving the disease substrate which may also influence the response to treatment. Oral and IV pharmacokinetic data from various studies of Chinese and Caucasian subjects are available for cilazapril, fosinopril, and perindopril, and pharmacodynamic data are available for eight different ACEIs. Based on these data, there are few differences among the pharmacokinetics of ACEIs between Chinese and Caucasians. Most ACEIs showed good blood pressure lowering efficacy in Chinese (benazepril, enalapril, fosinopril and spirapril), with perhaps less blood pressure lowering with cilazapril or a relatively shorter-term effect with cilazapril or perindopril compared to Caucasions. Chinese experience more cough from ACEIs (captopril and enalapril) than Caucasians. Data suggest that fosinopril may not induce cough in as many subjects as other ACEIs, and this seems to be true of Chinese as well. The mechanism, currently unknown, could involve fosinopril's dual elimination pathway (hepatic and renal). Pharmacokinetic data also support the use of fosinopril in congestive heart failure where elimination pathways may be impaired. In conclusion, ethnic differences between Chinese and Caucasians with respect to ACE and AGT gene polymorphism, which might be expected to differentially affect the action of ACEIs in these two ethnic groups, do not, in fact, have such an effect. Rather, differences among the ACEIs appear to be more important. Journal of Human Hypertension (2000) 14, 163-170.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Neurohormonal activation in the treatment of congestive heart failure: basis for new treatments?

Traditionally, the pathophysiology of heart failure was viewed as a derangement in hemodynamic factors. Impairment in cardiac function resulted in decreased cardiac output and end-organ hypoperfusion triggering compensatory increases in heart rate, blood pressure and cardiac contractility. While initially beneficial, these mechanisms placed additional stress on the failing heart. Unfortunately, pharmacologic therapies that restored hemodynamic balance failed to halt disease progression. The activation of neurohormonal responses, including those of the renin-angiotensin-aldosterone system, the sympathetic nervous system and the arginine vasopressin system, has been implicated in the progression of heart disease. In acute heart failure, their effects help to restore cardiovascular homeostasis. However, the chronic stimulation of these systems eventually leads to worsening left ventricular function. Drug treatments that activate neurohormonal systems may have long-term clinically deleterious outcomes, and therefore new pharmacological therapies for cardiovascular disease must take into account the interaction between neurohormonal activation and hemodynamic factors.

Benzimidazoles↗
PubMed1997

Effect of morning versus evening dosing of diltiazem on myocardial ischemia detected by ambulatory electrocardiographic monitoring in chronic stable angina pectoris. Dilacor XR Ambulatory Ischemia Study Group.

Myocardial ischemia occurs frequently during daily life and has a circadian pattern similar to that reported for myocardial infarction and sudden death. Because of the increased risk of myocardial ischemia in the morning hours, it has been suggested that the administration of anti-ischemic medication before bedtime may be more effective than the traditional morning dosing. This randomized, double-blind, placebo-controlled, crossover study evaluated the effects of 480-mg/day diltiazem (given either in the A.M. or the P.M.) on myocardial ischemia using ambulatory electrocardiographic monitoring in 68 patients with chronic stable angina and > or = 2 minutes of ischemia per 48 hours. During treatment with diltiazem, the duration and number of myocardial ischemic episodes were reduced by 45% (94 to 52 minutes, p <0.004) and by 40% (4.5 to 2.7 episodes, p <0.003), respectively. The duration and number of myocardial ischemic episodes during daytime (6 A.M. to 6 P.M.) hours were also reduced by 52% (74 to 36 minutes, p <0.002) and by 48% (3.1 to 1.6 episodes, p <0.001), respectively. There was no significant difference between A.M. and P.M. dosing. Morning ischemia (6 A.M. to noon), considered separately from daytime ischemia, was also significantly reduced by both A.M. and P.M. dosing regimens, with no difference between the regimens. The results of this study showed that both A.M. and P.M. dosing of long-acting diltiazem were equally effective in suppressing episodes of ambulatory myocardial ischemia at all times.

Analysis of Variance↗
PubMed1997

The clinical significance of neurohormonal activation.

Progressive heart disease after the onset of left ventricular dysfunction has typically been attributed to hemodynamic factors. As left ventricular function declines, decreased cardiac output and tissue hypoperfusion lead to compensatory increases in afterload, preload, and heart rate. The purpose of these compensatory responses is to increase cardiac output and maintain tissue perfusion; however, they may also create hemodynamic stress for the failing heart. However, this does not explain the progression of heart failure despite hemodynamic maintenance with pharmacologic therapy. Activation of neurohormonal systems that are essential for homeostasis in the normal heart plays a key role in the progression of heart failure. In acute heart failure, these systems have beneficial effects, but in chronic heart failure their activation produces deleterious effects by increasing the load on the left ventricle and promoting structural remodeling, which may further impair left ventricular function. The issue of neurohormonal activation is an important one in cardiovascular medicine, not only for patients with heart failure but also for patients with hypertension and ischemic heart disease when left ventricular dysfunction is present. As neurohormonal activation may play a pathogenic role in the long-term outcome of patients, interventions that have favorable hemodynamic but unfavorable neurohormonal effects can actually exacerbate cardiac disease and may increase cardiovascular morbidity and mortality. As neurohormonal activation appears to parallel the severity of heart failure, whether assessed according to symptoms or prognosis, an understanding of neurohormonal activation and its interaction with hemodynamic factors is essential for optimizing pharmacologic therapy for cardiovascular disease.

Age Factors↗
PubMed1996

Arbutamine vs. exercise stress testing in patients with coronary artery disease: evaluation by echocardiography and electrocardiography.

Arbutamine is a new beta-adrenergic agonist with potent chronotropic and inotropic properties developed to pharmacologically induce stress. A prospective trial was conducted in five centers with a total enrolment of 45 patients with angiographically documented coronary artery disease. The primary purpose of the trial was to compare the efficacy of arbutamine with symptom-limited exercise in provoking clinical (angina), electrocardiographic (> or = 0.1 mV ST depression) and echocardiographic (induced wall motion abnormality) evidence of transient stress-induced ischemia. The secondary purpose was to assess the safety of arbutamine in patients with coronary artery disease. Ischemia was induced at a lower heart rate, systolic blood pressure and pressure-rate product during arbutamine infusion than during exercise. Using angina and/or electrocardiographic evidence of ischemia, arbutamine was more sensitive than exercise in detecting myocardial ischemia (77 vs. 58%, P = 0.021). Using echocardiography, the sensitivity for inducing wall motion abnormalities was 88% with arbutamine and 79% with exercise (P = not significant). Echocardiography in combination with angina and/or electrocardiographic evidence increased the sensitivity to 94% using arbutamine and to 88% with exercise. For the patients with multivessel disease, the sensitivity was 97% and 91%, respectively. No serious adverse events, either cardiac or noncardiac, were associated with arbutamine, and no patient had prolonged ischemia. Although exercise is the preferred method of stress for patients who are able to exercise adequately, arbutamine is at least as sensitive as exercise for the diagnosis of myocardial ischemia, and appears to be a safe and effective alternative to exercise testing in patients unable to exercise adequately.

Adrenergic beta-Agonists↗
PubMed1995

Stress testing with closed-loop arbutamine as an alternative to exercise. The International Arbutamine Study Group.

OBJECTIVES: This study compared exercise and pharmacologic stress testing using arbutamine delivered by a closed-loop device for the detection of coronary artery disease. BACKGROUND: Arbutamine, an agent designed to simulate exercise, has been developed in conjunction with a closed-loop delivery device that modulates the rate of administration on the basis of physiologic feedback. METHODS: Two hundred ten patients (180 men, 30 women) with symptoms and angiographic evidence of coronary artery disease were studied. Ischemia was categorized in three ways: 1) the presence of angina; 2) the occurrence of > or = 0.1-mV horizontal or downsloping ST segment depression or elevation at 60 ms after the J point; or 3) the presence of either condition 1 or 2. RESULTS: In the 210 patients, the mean increase in heart rate and systolic blood pressure evoked by arbutamine and exercise was 51 and 53 beats/min (p = NS) and 36 and 44 mm Hg (p < 0.0001), respectively. Arbutamine detected ischemia more often than exercise with each of the three ischemic end points. Sensitivity for detecting ischemia by either angina or ST segment change was 84% (95% confidence interval ¿ change was 84% (95% confidence interval [CI] 79% to 89%) for arbutamine and 75% (95% CI 69% to 81%) for exercise testing (p = 0.014). For angina alone, sensitivity was 73% (95% CI 67% to 79%) for arbutamine and 64% (95% CI 57% to 71%) for exercise (p = 0.026). For ST segment change alone, sensitivity was 47% (95% CI 40% to 54%) for arbutamine and 44% (95% CI 37% to 51%) for exercise (p = 0.426). Cardiac events occurred in five patients (1.8%) within 24 h of the arbutamine test. CONCLUSIONS: In detecting documented coronary artery disease, the sensitivity of arbutamine testing was equal to that of exercise for the electrocardiographic end point of ST segment change alone. Arbutamine testing was significantly superior to exercise testing for either ST change or angina or for angina alone.

Aged↗
PubMed1994

Conversion from immediate-release to extended-release diltiazem in angina pectoris.

This multicenter, open-label, single crossover study examined 195 patients taking an immediate-release diltiazem tablet as chronic stable angina therapy to determine if apparently logical methods of converting them to an extended-release, once-daily formulation were effective. Patients were converted from the immediate-release (Phase I) to an extended-release (Phase II) formulation of diltiazem on a mg-for-mg basis or, when a similar dose was not available, to the next higher 120 mg dose. Weekly angina occurrences and nitroglycerin use, exercise testing at the end of each phase, and ambulatory electrocardiographic monitoring (AEM) during the week prior to the exercise study were evaluated. There was a statistically significant decrease in angina frequency and nitroglycerin consumption during Phase II. In the exercise studies, there was an insignificant increase in time to 1 mm ST-segment depression and total exercise time associated with a statistically significantly lower end-exercise blood pressure and heart rate in Phase II. In those patients who had ischemia during either phase on AEM, total ischemic duration and ischemic episodes were insignificantly lower in Phase II. All observations were similar in the subgroup of patients who were converted mg-for-mg. Adverse reactions were equal. Thus, in converting patients from an immediate- to an extended-release diltiazem formulation for the treatment of symptomatic coronary artery disease, it is reasonable to convert directly to the same or, if not available, the next higher available dose of the extended-release preparation.

Aged↗
PubMed1993

Amlodipine once a day in stable angina: double-blind crossover comparison with placebo.

Although calcium antagonists form a mainstay of therapy in patients with angina pectoris, the currently available agents have significant limitations. Nifedipine, diltiazem, and verapamil are all high-clearance agents with significant hepatic extraction and rapid clearance, leading to limited and short-lived bioavailability necessitating frequent daily administration. In contrast, amlodipine, a dihydropyridine calcium antagonist, has a long half-life of 35-50 h (compared with 3 to 4 h elimination half-life of diltiazem, verapamil, and nifedipine). After oral doses, the relative bioavailability of amlodipine is high (64%) and absorption is smooth, with peak plasma levels being achieved 6-12 h postdose. Bioavailability is not affected by the consumption of food. In common with other dihydropyridine calcium antagonists, amlodipine is eliminated mainly by metabolism. None of the metabolites of amlodipine has significant calcium antagonist effects in humans. In contrast to verapamil or diltiazem, amlodipine has no effect on sinus or atrioventricular node and little or no effect on the resting heart rate. Amlodipine does not have any appreciable negative inotropic effect with the relevant clinical dose. Other clinical studies have shown amlodipine to be effective when used once-daily in chronic stable angina and vasospastic angina. Comparative studies indicate that the antianginal efficacy of amlodipine is comparable to the beta blocker nadolol and the benzothiazepine calcium antagonist diltiazem. Amlodipine has also been found to provide improved antianginal effects when combined to treatment with beta blockers and/or long-acting nitrates. Treatment with amlodipine either as monotherapy or combined with other antianginal therapy for up to 26 weeks shows that efficacy is maintained, with no evidence of tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1991

Metabolic consequences of treating hypertension.

Reduction of morbidity and mortality has been the aim of drug treatment for hypertension since its beginning in the 1950s. Its efficacy has been tested in many trials. An outstanding result of these trials has been their clear success in preventing stroke and stroke-related deaths and in decreasing the incidence of congestive heart failure (CHF) and renal disease. A similar success has not been achieved in reducing coronary heart disease endpoints. Diuretics and beta-blockers played a central role in these studies; however, their adverse effects on lipid metabolism have been cited as a possible explanation for the failure of antihypertensive therapy to affect coronary heart disease (CHD). Recently, the extent and significance of these lipid changes has been put into perspective, and new insights into the role of carbohydrate metabolism and insulin resistance in hypertension have emerged. The same drugs which adversely affect lipid metabolism also adversely affect carbohydrate metabolism, and more is becoming known about these mechanisms and their role in hypertension and its sequelae. Other classes of antihypertensive drugs such as the calcium antagonists, angiotensin converting enzyme (ACE) inhibitors, and alpha 1-antagonists do not share these adverse effects. It has become increasingly clear that effective antihypertensive therapy includes both the lowering of blood pressure and containment of the abnormalities that accompany the hypertensive state.

Adrenergic beta-Antagonists↗
PubMed1990

Efficacy of encainide in supraventricular arrhythmias.

This review summarizes the data from all the studies conducted in the United States and Europe that have evaluated the efficacy of encainide in patients with a variety of supraventricular arrhythmias. Using clinical criteria of efficacy, encainide was found to be effective or partially effective in 77% of patients evaluated by electrophysiologic means. Similar levels of efficacy were observed in patients with AV as well as AV nodal reentry arrhythmias. Patients with other forms of supraventricular arrhythmias in smaller series also experienced comparable degrees of efficacy. Encainide was discontinued because of intolerance by 8% of the patients in these studies: 6% because of side effects and 2% because of proarrhythmia.

Anilides↗
PubMed1990

Antihypertensive monotherapy with tablet (prompt-release) diltiazem: multicenter controlled trials.

The tablet formulation of diltiazem has been available for the treatment of angina pectoris but has not been comprehensively evaluated in hypertension. This study's aim was to evaluate the efficacy, dose-response characteristics, and duration of action of tablet (prompt-release) diltiazem in mild to moderate hypertension. Three placebo-controlled trials were designed. The first (trial #1) evaluated the dose response of 120, 240, and 360 mg/day (q12h regimen) of diltiazem in parallel fixed-dose fashion using hourly blood pressures. The second (trial #2) evaluated a q12h titration from 240 to 360 mg/day, which could be switched to q8h. The third (trial #3) evaluated a q8h titration from 180 to 270 to 360 mg/day, followed by conversion to a q12h regimen. The goal was a supine diastolic blood pressure of less than 90 mmHg and 10 mmHg less than baseline. With doses of diltiazem increasing from 120 to 240 to 360 mg/day, there was a progressive decrease in the average mean arterial pressure, describing a dose response with 120 mg/day as the ineffective dose. The peak effect for each dose regimen was found at 6 hours, with significant reductions lasting over 10 hours in the 240 mg/day and 360 mg/day groups. Peak plasma concentrations occurred at 3 hours. The residual effect at the trough of the 240 mg/day and 360 mg/day doses was 48% and 53% of the peak effect, respectively. When titration was carried out on a q8h regimen, both systolic and diastolic blood pressures were significantly decreased. When the regimen was switched from q8h to q12h, the effect was not maintained.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Sustained-release diltiazem: duration of antihypertensive effect.

The antihypertensive activity of a sustained-release preparation of diltiazem (given each 12 hours) was assessed in 96 patients with supine diastolic blood pressure (BP) between 95 and 110 mm Hg in a multicenter, randomized, double-blind, placebo run-in, parallel-group trial comparing optimally titrated doses of diltiazem and placebo. The aim was to assess the onset of action as well as the extent and variability of BP control of this formulation during the 12-hour interval. Diltiazem was titrated from 120 mg bid to 180 mg bid as necessary to lower BP. At baseline, on the first day of titration, and at the end of 8 weeks, BP was evaluated at 0, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours after dosing. The onset of action was within 2 hours, and the effect was maintained throughout the 12-hour period. Mean BP for the diltiazem group at baseline was 154/101 mm Hg. At week 8, BP was 148/93 mm Hg at hour "0" (P less than .02 and P = .0001 for systolic and diastolic BP vs. placebo), 139/84 mm Hg at the nadir at hour 5 (P = .0001), and 149/91 mm Hg at the end of the 12-hour period (P less than .02 and P = .0001 for systolic and diastolic BP). Diltiazem was significantly more effective than placebo (P = .0001) with 50% of patients controlled to a diastolic pressure of less than 90 mm Hg at 7 of the 10 evaluation points, including the evaluation point of 12 hours post-dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1989

Effects of encainide on the function of implanted pacemakers.

The effect of encainide on chronic pacing thresholds was evaluated in 10 patients, age 64-89, who were exposed to weekly increased encainide dosing (25 mg TID, 50 mg TID, 75 mg TID). Median pacing threshold (mujoules) increased modestly at each period compared to placebo and returned rapidly to baseline after discontinuation. (table; see text) No patient experienced a pacing-related clinical event. One patient had a large threshold increase (566%), but no failure to capture on 24-hour ECG, and one patient whose threshold increased minimally had clinically insignificant capture failure, the longest event being 3 beats. No other failure to capture was noted. Thus, encainide, like a number of other antiarrhythmic drugs, appears to affect pacing thresholds. At the highest dose of 225 mg/day (75 mg TID, which exceeds the generally recommended dose of 50 mg TID), but not at lower doses, some patients may experience loss of capture that does not appear related to the change in threshold energy required. Increases in the duration of the paced QRS induced by encainide did not predict increases in threshold. Therefore, when higher doses of encainide are required in patients with pacemakers, clinical observation and ambulatory electrocardiographic monitoring should be carried out.

Aged↗
PubMed1988

Treatment of ectopic atrial arrhythmias and premature atrial complexes in adults with encainide.

Few studies of the antiarrhythmic effects of encainide have included patients with primary atrial tachycardias and premature atrial contractions (PACs). In this review, 11 patients with primary atrial tachycardia and 10 patients with symptomatic PACs were abstracted from all studies known to have been performed. These patients had been shown to be highly resistant to prior antiarrhythmic treatments. Intravenous encainide terminated a primary atrial tachycardia in 4 of 4 patients, 3 of whom had an incessant arrhythmia, and oral encainide was effective or partially effective in 6 of 10 patients treated for an average of 2.9 years with a mean dosage of 156 mg/day. Intravenous encainide was effective or partially effective in 8 of 10 patients with symptomatic PACs, and oral encainide was effective or partially effective in 6 of 9 patients treated for an average of 1.8 years with a mean dosage of 114 mg/day. The median number of PACs per hour on Holter recording was reduced from a baseline rate of 1,139/hour to 166/hour at 3 to 5 months of treatment (p = 0.001). Adverse effects were modest. The mechanism of action of encainide in these arrhythmias appears to be depression of ectopic pacemaker activity.

Adolescent↗
PubMed1988

Metabolic effects of antihypertensive therapy with a calcium antagonist.

The effect of diuretics to increase serum glucose, low-density lipoprotein cholesterol and triglycerides, as well as the adverse changes in triglycerides and high-density lipoprotein cholesterol produced by nonselective beta blockers, have been largely ignored in the treatment of hypertension. However, a number of trials have shown that reductions in serum lipids can alter cardiovascular mortality. Calcium antagonists have become major drugs in the treatment of hypertension, and some data suggest that calcium antagonists may increase serum glucose levels. Significantly less data on lipid effects have been published. Lipid and glucose effects were examined in an 8-week antihypertensive study using a sustained-release preparation of diltiazem titrated from 240 to 360 mg/day in a twice-daily regimen in a randomized, double-blind, placebo-controlled parallel trial in 96 patients. Average supine blood pressure at week 8 was 156/98 mm Hg, standing blood pressure with placebo 152/100 mm Hg, and with diltiazem 147/91 and 144/93 mm Hg. There were no statistically significant changes in serum lipids or glucose in the diltiazem or placebo group or between the groups. Mean values (mg/dl) at baseline and week 8 in the diltiazem group were, respectively, for cholesterol 215 and 218, high-density lipoprotein cholesterol 50 and 51, low-density lipoprotein cholesterol 128 and 133, triglycerides 169 and 175, and glucose 113 and 110. Thus, this large and placebo-controlled study shows that diltiazem is among the antihypertensives with no adverse long-term lipid or glucose effects.

Blood Glucose↗