Influence of beta-adrenoceptor antagonists on the pharmacokinetics of rizatriptan, a 5-HT1B/1D agonist: differential effects of propranolol, nadolol and metoprolol.

AIMS: Patients with migraine may receive the 5-HT1B/1D agonist, rizatriptan (5 or 10 mg), to control acute attacks. Patients with frequent attacks may also receive propranolol or other beta-adrenoceptor antagonists for migraine prophylaxis. The present studies investigated the potential for pharmacokinetic or pharmacodynamic interaction between beta-adrenoceptor blockers and rizatriptan. METHODS: Four double-blind, placebo-controlled, randomized crossover investigations were performed in a total of 51 healthy subjects. A single 10 mg dose of rizatriptan was administered after 7 days' administration of propranolol (60 and 120 mg twice daily), nadolol (80 mg twice daily), metoprolol (100 mg twice daily) or placebo. Rizatriptan pharmacokinetics were assessed. In vitro incubations of rizatriptan and sumatriptan with various beta-adrenoceptor blockers were performed in human S9 fraction. Production of the indole-acetic acid-MAO-A metabolite of each triptan was measured. RESULTS: Administration of rizatriptan during propranolol treatment (120 mg twice daily for 7.5 days) increased the AUC(0, infinity) for rizatriptan by approximately 67% and the Cmax by approximately 75%. A reduction in the dose of propranolol (60 mg twice daily) and/or the incorporation of a delay (1 or 2 h) between propranolol and rizatriptan administration did not produce a statistically significant change in the effect of propranolol on rizatriptan pharmacokinetics. Administration of rizatriptan together with nadolol (80 mg twice daily) or metoprolol (100 mg twice daily) for 7 days did not significantly alter the pharmacokinetics of rizatriptan. No untoward adverse experiences attributable to the pharmacokinetic interaction between propranolol and rizatriptan were observed, and no subjects developed serious clinical, laboratory, or other significant adverse experiences during coadministration of rizatriptan with any of the beta-adrenoceptor blockers. In vitro incubations showed that propranolol, but not other beta-adrenoceptor blockers significantly inhibited the production of the indole-acetic acid metabolite of rizatriptan and sumatriptan. CONCLUSIONS: These results suggest that propranolol increases plasma concentrations of rizatriptan by inhibiting monoamine oxidase-A. When prescribing rizatriptan to migraine patients receiving propranolol for prophylaxis, the 5 mg dose of rizatriptan is recommended. Administration with other beta-adrenoceptor blockers does not require consideration of a dose adjustment.

Association of body mass, gender and race with heart failure primarily due to hypertension.

OBJECTIVES: This study was performed to determine the association between clinical characteristics, particularly body mass and race, and the likelihood of hypertension as the primary etiology for heart failure (HTNCM). BACKGROUND: Although held to be important in the development of heart failure, the clinical characteristics predictive of HTNCM have not been well delineated. METHODS: The study analysis was conducted using 680 patients from the University of North Carolina Heart Failure Database. This data set is racially diverse (44% African-American) and contains data concerning baseline clinical characteristics and cardiac function in patients with and without HTNCM. Logistic regression techniques determined independent predictors of HTNCM among the entire study population as well as the subgroup of study patients with hypertension. RESULTS: Hypertension was present in 51% of the study patients but was the primary etiology of heart failure in only 25%. Body mass, race, gender and baseline systolic blood pressure were identified as significant independent predictors of the likelihood of HTNCM (all p < 0.001). These characteristics were predictors in the total study population and also in the subgroup of study patients with hypertension. CONCLUSIONS: Hypertension remains a common etiologic factor for the development of heart failure but was the primary cause of heart failure in a minority of study patients. However, the presence of increased body mass, female gender, African-American ethnic origin or elevated baseline systolic blood pressure significantly increased the likelihood of HTNCM.

A discriminant analysis extension to mixed models.

Discriminant analysis is commonly used to classify an observation into one of two (or more) populations on the basis of correlated measurements. Classical discriminant analysis approaches require complete data for all observations. Our extension enables the use of all available longitudinal data, regardless of completeness. Traditionally a linear discriminant function assumes a common unstructured covariance matrix for both populations, which may be taken from a multivariate model. Here, we can model the correlated measurements and use a structured covariance in the discriminant function. We illustrate cases in which the estimated covariance structure is either compound symmetric, heterogeneous compound symmetric or heterogeneous autoregressive. Thus a structured covariance is incorporated into the discrimination process in contrast to standard discriminant analysis methodology. Simulations are performed to obtain a true measure of the effect of structure on the error rate. In addition, the usual multivariate expected value structure is altered. The impact on the discrimination process is contrasted when using the multivariate and random-effects covariance structures and expected values. The random-effects covariance structure leads to an improvement in the error rate in small samples. To illustrate the procedure we consider repeated measurements data from a clinical trial comparing two active treatments; the goal is to determine if the treatment could be unblinded based on repeated anxiety score measurements.

Clinical predictors of worsening heart failure during withdrawal from digoxin therapy.

Previous work provides limited information concerning predictors of clinical deterioration after digoxin withdrawal. We investigated the association between selected baseline clinical characteristics and symptomatic deterioration in two similarly designed trials: Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin (PROVED) and Randomized Assessment of Digoxin and Inhibitors of Angiotensin-Converting Enzyme (RADIANCE). Cox proportional-hazards analysis found the following independent predictors of worsening during follow-up in the combined PROVED and RADIANCE patients: heart failure score, left ventricular ejection fraction, cardiothoracic ratio, use of an angiotensin-converting enzyme inhibitor, use of digoxin, and age. When these factors, except for digoxin use, were tested in the subgroup of patients withdrawn from digoxin, they all were significant independent predictors of worsening heart failure. In contrast, only use of angiotensin-converting enzyme inhibitor predicted deterioration in patients who continued digoxin. Patients with more congestive symptoms, worse ventricular function, greater cardiac enlargement, or who were not taking an angiotensin-converting enzyme inhibitor were significantly more likely to worsen early after digoxin discontinuation than patients without these characteristics.

Patients with mild heart failure worsen during withdrawal from digoxin therapy.

OBJECTIVES: We investigated whether patients with mild heart failure due to left ventricular systolic dysfunction were at risk of worsening during digoxin withdrawal. BACKGROUND: Deterioration during digoxin withdrawal is often believed to be restricted to patients with moderate to severe clinical evidence of heart failure. To test this hypothesis, we studied the outcome of patients categorized by treatment assignment and a clinical signs and symptoms heart failure score in two rigorously designed clinical heart failure trials: the Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin (PROVED) and the Randomized Assessment of Digoxin and Inhibitors of Angiotensin-Converting Enzyme (RADIANCE) trial. METHODS: Potential differences in treatment failure, left ventricular ejection fraction and exercise capacity were evaluated in three groups of patients: those with mild heart failure (score < or = 2) who were withdrawn from digoxin (Dig WD Mild); those with moderate heart failure (score > 2) who were withdrawn from digoxin (Dig WD Moderate); and patients who continued receiving digoxin regardless of heart failure score (Dig Cont). RESULTS: Heart failure score at randomization did not predict outcome during follow-up in Dig Cont-group patients. Dig WD Mild-group patients were at increased risk of treatment failure and had deterioration of exercise capacity and left ventricular ejection fraction compared with that in Dig Cont-group patients (all p < 0.01). Patients in the Dig WD Moderate group were significantly more likely to experience treatment failure than patients in either the Dig WD Mild or Dig Cont group (both p < 0.05). CONCLUSIONS: Patients with systolic left ventricular dysfunction were at risk of clinical deterioration after digoxin withdrawal despite mild clinical evidence of congestive heart failure.

Relation between gender, etiology and survival in patients with symptomatic heart failure.

OBJECTIVES: This study investigated the relation between gender, etiology and survival in patients with symptomatic heart failure. BACKGROUND: Previous work provides conflicting results concerning the relation between gender, clinical characteristics and survival in patients with heart failure. METHODS: We examined the relation of these factors in 557 patients (380 men, 177 women) who had symptomatic heart failure, predominantly nonischemic in origin (68%) and typically associated with severe left ventricular dysfunction. RESULTS: Follow-up data were available in 99% of patients (mean follow-up period 2.4 years, range 1 day to 10 years) after study entry, and 201 patients reached the primary study end point of all-cause mortality. By life-table analysis, women were significantly less likely to reach this primary end point than men (p < 0.001). A significant association was found between female gender and better survival (p < 0.001), which depended on the primary etiology of heart failure (p = 0.008 for the gender-etiology interaction) but not on baseline ventricular function. Women survived longer than men when heart failure was due to nonischemic causes (men vs. women: relative risk [RR] 2.36, 95% confidence interval [CI] 1.59 to 3.51, p < 0.001). In contrast, outcome appeared similar when heart failure was due to ischemic heart disease (men vs. women: RR 0.85, 95% CI 0.45 to 1.61, p = 0.651). CONCLUSIONS: Women with heart failure due to nonischemic causes had significantly better survival than men with or without coronary disease as their primary cause of heart failure.

Absence of a pharmacokinetic interaction between losartan and hydrochlorothiazide.

To support the use of a combination of losartan, a highly specific and selective AT1 angiotensin II receptor antagonist, and hydrochlorothiazide for treatment of hypertension, a pharmacokinetic drug interaction study was conducted. In this open-label, randomized, three-period, crossover study, patients with mild to moderate hypertension received a 12.5-mg tablet of hydrochlorothiazide, a 50-mg losartan tablet, or a combination tablet of 12.5 mg of hydrochlorothiazide and 50 mg of losartan for 7 days. Twelve patients (age range, 35-55 years; mean age, 44 years) were allocated to treatment. Drug interactions were evaluated by comparing the 24-hour area under the concentration-time curve (AUC24) for losartan and its active metabolite, E-3174, when losartan (50 mg) was given alone or in combination with 12.5 mg hydrochlorothiazide. The urinary recovery over the 24-hour period of hydrochlorothiazide was compared for hydrochlorothiazide (12.5 mg) given alone or in combination with 50 mg losartan. A clinically significant interaction was defined as a treatment difference of more than 35%. There was no evidence of a clinically significant effect of hydrochlorothiazide on the pharmacokinetics of losartan or E-3174, as the geometric mean AUC24 ratio (90% confidence interval [CI]) was 1.02 (0.95, 1.09) for losartan and 1.02 (0.96, 1.09) for E-3174. Based on urinary recovery over a 24-hour period of hydrochlorothiazide, losartan did not affect the pharmacokinetics of hydrochlorothiazide, as the geometric mean ratio of urinary hydrochlorothiazide recovery (90% CI) was 0.898 (0.79, 1.20). There was a minor (17%) decrease in the AUC24 of hydrochlorothiazide after administration of the combination tablet. Coadministration of hydrochlorothiazide and losartan was well tolerated.

Losartan does not affect the pharmacokinetics and pharmacodynamics of warfarin.

Losartan, on orally active, nonpeptide angiotensin II receptor antagonist is being developed as a therapeutic agent for the treatment of hypertension and heart failure. Many patients requiring anticoagulant therapy with warfarin also may have hypertension or heart failure, and thus, are potential candidates for losartan therapy. This study was designed to investigate whether losartan at likely dosage levels would alter the anticoagulant response to warfarin. In a two-period, placebo-controlled, randomized, crossover study, ten healthy male subjects received a single oral dose of 30 mg warfarin sodium on the seventh day of a 13-day treatment with losartan, 100 mg daily by mouth, or placebo. Multiple plasma samples were collected over a 6-day period after both warfarin doses for the measurements of R- and S-warfarin concentrations and prothrombin times. The pharmacokinetics of R- and S-warfarin were comparable in the absence and presence of losartan (no significant effects of losartan on area under the curve, Cmax, or tmax). Losartan also had no significant effect on the anticoagulant effect of warfarin, as assessed by the area under the prothrombin time versus time curve and the maximum response for prothrombin time. The lack of pharmacokinetic or pharmacodynamic interaction between warfarin and losartan observed in this investigation suggests that a clinically important interaction between these drugs is unlikely to occur in patients requiring concomitant administration of both drugs.

Novel oral medication delivery system for famotidine.

A famotidine wafer that rapidly disperses on the tongue without water is a novel alternative to other histamine2 (H2)-antagonist dosage forms. Benefits associated with such a dosage form include convenience and potentially improved compliance for patients who dislike or have difficulty taking tablets and capsules. This report describes the research of three studies on the famotidine wafer dosage form. In the first trial, the bioequivalence and tolerability of the new 40-mg famotidine wafer and the marketed 40-mg famotidine tablet were studied in a 2-period crossover study (n = 18). The two formulations were bioequivalent as assessed by area under the plasma concentration versus time curve and maximum plasma concentration of famotidine. The plasma concentration of famotidine associated with 50% inhibition of pentagastrin stimulated gastric acid secretion (EC50; 10 ng/mL) was attained on average within 0.5 hours post-dose for the wafer and tablet. In a second trial, the tolerability of the famotidine 20-mg and 40-mg wafers or placebo given twice daily (bid) for 14 days were evaluated (n = 192). Both wafer strengths were well and equally tolerated. In a third trial of 450 subjects, the 40-mg wafer was preferred over tablets by 75% of the subjects, when they were asked to consider the method of administration and flavor. When used as an alternative to tablets and other conventional dosage forms, the wafers have the potential therapeutic benefit of improved compliance. It is concluded that similar systemic exposure, excellent tolerability, palatability, and preference make the famotidine wafer a clinically acceptable and convenient dosage from for patients on H2-antagonist therapy.