Pharmacodynamic evaluation of clopidogrel plus PA32540: the Spaced PA32540 With Clopidogrel Interaction Gauging (SPACING) study.

PA32540 combines 325 mg enteric-coated (EC) aspirin (ASA) with 40 mg immediate-release omeprazole; its influence on the antiplatelet effect of clopidogrel (C) is unknown. In this randomized, open-label study, subjects (n = 30) were treated with (i) 300 mg C + 325 mg ECASA followed by 75 mg C + 325 mg ECASA on days 2-7, (ii) 300 mg C + PA32540 followed by 75 mg C + PA32540 on days 2-7, or (iii) PA32540 in the morning + 300 mg C 10 h later on day 1 and PA32540 in the morning + 75 mg C 10 h later on days 2-7. We analyzed the noninferiority of PA32540 relative to ECASA, as defined by the upper bound of the 95% confidence interval ≤10% for the difference in least-square means of platelet inhibition between the treatments. As compared to ECASA+C, synchronous treatment of PA32540+C was not noninferior, whereas the spacing strategy of PA32540+C was noninferior. Spacing the administration of PA32540 and clopidogrel lessens the interaction observed with synchronous administration; PA32540 administration with clopidogrel may be associated with a different antiplatelet profile.

Clinical trial: evaluation of gastric acid suppression with three doses of immediate-release esomeprazole in the fixed-dose combination of PN 400 (naproxen/esomeprazole magnesium) compared with naproxen 500 mg and enteric-coated esomeprazole 20 mg: a randomized, open-label, Phase I study in healthy volunteers.

BACKGROUND: PN 400 is a fixed-dose combination formulated to provide sequential delivery of immediate-release (IR) esomeprazole and enteric-coated (EC) naproxen. AIM: To evaluate gastric acid suppression with three doses of esomeprazole in PN 400 compared with EC esomeprazole 20 mg. METHODS: In this Phase I, randomized, open-label study, 28 healthy adults received PN 400 b.d. (naproxen 500 mg plus esomeprazole 10, 20 and 30 mg) and non-EC naproxen 500 mg b.d. plus EC esomeprazole 20 mg o.d., each for 9 days in a crossover fashion. The primary endpoint was percentage of time on day 9 that intragastric pH was >4.0; secondary endpoints included pharmacokinetics and safety. RESULTS: Day 9 percentage of time where intragastric pH was >4.0 was 76.5%, 71.4%, 40.9% and 56.9% [corrected] for PN 400 containing 30, 20 and 10 mg esomeprazole, and naproxen plus esomeprazole 20 mg respectively. This was significantly greater for PN 400 containing 30 and 20 mg esomeprazole vs. naproxen plus esomeprazole 20 mg (95% CI: 13.0-26.0 and 7.8-20.7 respectively). The pharmacokinetics of PN 400 were consistent with its formulation. No serious adverse events occurred. CONCLUSION: PN 400 containing 20 mg esomeprazole was the lowest dose to achieve gastric acid suppression comparable to EC esomeprazole 20 mg and was selected for further evaluation.

Results of a national survey on anticoagulation for PTCA.

In order to assess the current practice patterns in the United States for anticoagulation during PTCA, a survey was sent to the ACC membership. A total of 377 surveys from physicians performing PTCA were tabulated; 5 (1.3%) respondents performed < 20 PTCAs/year, 128 (34.0%) performed 20-75 PTCAs/year, 141 (37.4%) performed 75-150 PTCAs/year, 98 (26.0%) performed > 150 PTCAs/year and 5 (1.3%) did not report their volume. Seventy-eight (20.7%) were at university hospitals 153 (40.6%) were at other teaching hospitals, 142 (37.7%) were at non-teaching hospitals and 4 (1.1%) did not report their institutional affiliation. A total of 76.8% of respondents routinely started with a 10,000 U bolus of heparin, while only 3.2% of respondents used only a weight-adjusted heparin bolus. Fifty-nine percent of respondents routinely used intra-procedure heparin infusions, usually 1000 U/hr. Anticoagulation monitoring was used by 92.6% of respondents during PTCA, almost always activated clotting times (ACTs). Of the 335 physicians who used ACTs to guide heparin therapy during PTCA, 59.1% used the Hemochron device, 16.7% used the HemoTec device, and 24.2% did not know which machine they used. Lower volume operators and operators at non-teaching hospitals were more likely not to know the type of ACT machine used. Post-procedure heparin infusions (usually titrated to an aPTT > 2 x control) were used by 70.3% of respondents. Lower volume operators were more likely to use post-procedure heparin infusions. Thus, heparin therapy for PTCA continues to be largely empiric, although the vast majority of cardiologists surveyed use ACT-guided heparin therapy for the procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

Healthcare resource and lost labour costs of migraine headache in the US.

Migraine headache is responsible for significantly more healthcare resource and lost labour costs than previously reported. Costs associated with migraine were assessed via a survey conducted in 940 patients, 70% of whom responded. All met the International Headache Society's diagnostic criteria for migraine and had participated in one of two multicentre, single-dose, parallel-group, randomised, placebo-controlled clinical trials designed to assess the efficacy of an anti-migraine compound. Migraine frequency and costs, in terms of healthcare resource utilisation and lost labour (decreased productivity and missed workdays), were assessed. Over 90% of respondents visited a clinic and nearly 50% presented to an emergency room for treatment of migraine-related symptoms at least once in the year prior to the survey. These 648 respondents used an estimated $US529 199 per year in healthcare services. 89% of employed respondents reported that job performance was adversely affected by migraine and over 50% of them missed at least two days of work per month. Depending on the estimates used for migraine prevalence and using 1986 estimates of median earnings for the US work force, the extrapolated costs to employers ranged from $US5.6 billion to $US17.2 billion dollars annually due to decreased productivity and missed work days. The cost of migraine is not fully appreciated by the medical community or by society.

Health-related quality of life among patients undergoing percutaneous transluminal coronary angioplasty.

A randomized clinical trial was recently conducted to investigate whether a new antiplatelet agent could prevent restenosis in patients who had undergone percutaneous transluminal coronary artery angioplasty (PTCA). Approximately 1,200 patients were enrolled at 13 separate clinical sites. To assess the impact of this intervention on health-related quality of life, a patient questionnaire for telephone administration was developed. This questionnaire focused attention on several specific dimensions likely to be important in this patient population: physical well-being, perceived health, emotional well-being, home management, work, recreation, and social and sexual functioning. This paper describes the instrument that was used in this trial and reports on its psychometric [corrected] properties based on completed interviews with approximately 500 patients at study entry and 1 month after PTCA.

Pharmacokinetics and pharmacodynamics of labetalol in elderly and young hypertensive patients following single and multiple doses.

Several physiologic changes accompany the aging process and may alter the pharmacokinetics and pharmacodynamics of drugs given to elderly patients. The primary purpose of the present investigation was to compare the pharmacokinetics of labetalol in young and elderly hypertensive patients. Limited data regarding the pharmacodynamics of labetalol in each of these age groups were also evaluated. Ten young (age 32-48 yrs) and nine elderly (age 60-68 yrs) patients with essential hypertension were evaluated after the first and last doses of a 15-day regimen of labetalol. The young group received 200 mg orally at 9:00 P.M. and 9:00 A.M.; the elderly group received 200 mg once daily at 9:00 P.M. No significant differences in the mean (SD) apparent oral clearance of the drug existed between groups after the first [4.8 (1.9) and 4.3 (1.2) L/hr/kg] and final [4.4 (2.2) and 3.4 (1.0) L/hr/kg] doses of labetalol. No changes in any pharmacokinetic values for labetalol were detected as a function of age. Changes in standing blood pressure and heart rate after the first and last doses were generally similar between the young and elderly hypertensives. Labetalol was effective and well tolerated in both groups.

Attenuation of the hemodynamic responses to endotracheal intubation with preinduction intravenous labetalol.

Endotracheal intubation following anesthesia induction frequently produces hypertension and tachycardia. This study evaluated the efficacy of preinduction IV labetalol for attenuating the hemodynamic responses to intubation following thiopental and succinylcholine induction of anesthesia. Two hours after diazepam (10 mg by mouth), 60 patients were randomized in a double-blind manner and received IV saline or labetalol at doses of 0.25, 0.5, 0.75, or 1 mg/kg in a parallel design study. Five minutes later, thiopental (4 mg/kg) and succinylcholine (1 mg/kg) were administered, and the trachea was intubated in 2 minutes. Nitrous oxide (70%) anesthesia was maintained for 10 minutes. Hemodynamic parameters were grouped and analyzed for significance (p less than 0.05) by two-way repeated measures analysis of variance and t-test with Bonferroni adjustments. Baseline group demographics and hemodynamics were comparable. All doses of labetalol significantly attenuated the rate-pressure product increase immediately postintubation versus placebo. There was a dose-dependent attenuation of the increases in heart rate and the systolic, diastolic, and mean blood pressures versus placebo following intubation. IV labetalol at doses up to 0.75 mg/kg offers an effective pharmacologic means of attenuating preoperative hemodynamic responses to endotracheal intubation.

Hemodynamic effects of labetalol in young and older adult hypertensives.

Twenty young (45 years or younger) and 20 older (55 years or older) adult patients with mild hypertension were enrolled in this study to compare the hemodynamic effects of labetalol versus placebo in two age groups. Ten patients in each group were randomly assigned to receive either a single oral dose of labetalol (200 mg) or placebo. Hemodynamic parameters were recorded immediately before and two hours after ingestion. Labetalol was more effective than placebo in significantly lowering systolic blood pressure (-11 versus + 5 mm Hg, -23 versus + 4 mm Hg), diastolic blood pressure (-9 versus + 2 mm Hg, -12 versus + 5 mm Hg), and total systemic resistance (-259 versus + 42 dynes-sec cm-5, -390 versus + 74 dynes-sec cm-5) in young and older hypertensive subjects, respectively. There was no significant changes in heart rate, stroke volume index, or cardiac index in either age group. These data indicate that labetalol lowers blood pressure in young an older hypertensives primarily by reducing peripheral resistance and that the antihypertensive effect may be somewhat greater in older patients.

Interindividual and intraindividual variability in labetalol pharmacokinetics.

The between-subject and within-subject variability in the pharmacokinetics of labetalol at steady state were determined. Sixteen nonobese normal volunteers (mean age, 27 years) received five different formulations of labetalol orally on five different occasions every 12 hours for five doses. A 7-day washout separated each administration phase. Plasma concentration-time data for labetalol were obtained over the 24-hour period after the fifth dose in each phase. Labetalol concentrations in plasma were measured using high-performance liquid chromatography (HPLC). Pharmacokinetic parameters for each subject after each study phase were estimated. The mean V beta/F, Vdss/F, TBC/F, t1/2 beta, and AUC tau 0 for each subject ranged between 18.1 and 161.9 L/kg, 7.1 and 53.9 L/kg, 1.3 and 5.72 L/hr/kg, 6.9 and 11.0 hours, and 154 and 520 micrograms.hr/L, respectively, indicating large interindividual variability. Considerable intraindividual variability in each of the pharmacokinetic parameters was also observed. These data indicate that a larger number of subjects will be required to detect "significant" differences in the disposition of labetalol.

Labetalol blunts morning pressor surge in systolic hypertension.

Twenty-four-hour ambulatory blood pressure, including the acceleration phase, and left ventricular mass were evaluated in 16 patients with isolated systolic hypertension (standing blood pressure greater than or equal to 160 mm Hg systolic and less than or equal to 95 mm Hg diastolic). After a 4-week, single-blind, placebo period, each patient underwent 24-hour ambulatory blood pressure monitoring and echocardiography. Labetalol therapy was then initiated at 100 mg twice a day in a single-blind manner and increased weekly by 100 mg twice a day until blood pressure control was obtained or a maximum dosage of 400 mg twice a day was reached. Blood pressure control was achieved at a mean daily dose of 363 +/- 46 mg of labetalol. Measurements were repeated at the end of an 8-week maintenance phase. Labetalol therapy significantly reduced the mean 24-hour systolic ambulatory blood pressure from 154 +/- 8 (mean +/- SEM) mm Hg at baseline to 142 +/- 6 mm Hg (p greater than 0.01) and controlled the early morning surge in systolic ambulatory blood pressure. Minor reductions in diastolic blood pressure and heart rate were statistically but not clinically significant. Left ventricular mass was not changed. Labetalol monotherapy provides effective 24-hour control of systolic blood pressure, including the acceleration phase, in patients with isolated systolic hypertension.

Labetalol in the treatment of hypertension in elderly and younger patients.

The efficacy and safety of labetalol therapy were evaluated in 20 patients 60 years and older with isolated systolic or diastolic hypertension and 19 patients aged younger than 60 years with diastolic hypertension. After a two-week placebo washout period, labetalol was titrated for up to four weeks (100-400 mg bid) until blood pressure control was achieved (standing systolic less than 160 mm Hg or greater than or equal to 10% reduction from baseline, and standing diastolic less than 90 mm Hg or a decrease of 10 mm Hg from baseline). Mean decreases in standing systolic and diastolic blood pressure from baseline were statistically significant for both age groups (greater than or equal to 60 years, -23/-13; less than 60 years, -18/-12, P less than .01). Control criteria were met in 18 (90%) older and 15 (79%) younger patients who then entered a four-week maintenance period. Sixteen (80%) of the older patients and six (32%) of the younger patients maintained blood pressure control on 200 mg or less of labetalol bid (P less than .05). Three patients, two of whom withdrew from the study, were judged to have experienced adverse events that were drug related. It was concluded that labetalol was effective and well-tolerated antihypertensive therapy in both elderly and younger patients. In addition, significantly less medication was required to achieve blood pressure control in the elderly.

Comparison in young and elderly patients of pharmacodynamics and disposition of labetalol in systemic hypertension.

Pharmacodynamics and pharmacokinetics of labetalol, a combined alpha- and beta-adrenoceptor antagonist drug, were studied in elderly and young hypertensive patients. After receiving intravenous labetalol, elderly patients had a greater maximal mean decrease in systolic blood pressure (BP) (39 +/- 8 vs 25 +/- 13 mm Hg, p less than 0.02); however, maximal decrease in diastolic BP was similar in elderly (18 +/- 10 mm Hg) and young (17 +/- 6 mm Hg) patients. After receiving oral labetalol, elderly patients had a greater maximal decrease in standing systolic BP (41 +/- 16 vs 16 +/- 14 mm Hg, p less than 0.001) and similar decreases in standing diastolic BP (21 +/- 7 vs 17 +/- 9 mm Hg). Sitting maximal BP decreases after oral labetalol treatment were similar in elderly and young patients (12 +/- 16 vs 17 +/- 7 mm Hg systolic and 24 +/- 6 vs 12 +/- 7 diastolic). The decrease in heart rate was greater in young patients after intravenous labetalol administration. To evaluate labetalol pharmacodynamics, a linear model was used. Slope of labetalol concentration vs systolic BP for elderly vs young patients was 0.928 +/- 1.05 vs 0.326 +/- 0.490 ng/ml X mm Hg-1 (difference not significant). The slope of labetalol concentration vs heart rate for elderly vs young patients was 0.176 +/- 0.063 vs 0.406 +/- 0.303 ng/ml X beats/min-1 (p less than 0.05), with 2 elderly patients showing no decrease in heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

The disposition and dynamics of labetalol in patients on dialysis.

The disposition of labetalol was assessed in 16 patients on dialysis after intravenous dosing with 0.7 to 1.0 mg/kg during an interdialytic period and just before hemodialysis (n = 8) and during continuous ambulatory peritoneal dialysis (CAPD) (n = 8). The plasma concentration time data exhibited triexponential decay in all patients. The terminal t 1/2 of labetalol was 12.90 +/- 4.68 hours, the total body clearance was 1198.2 +/- 249.4 ml/min, and the AUC was 921.4 +/- 175.2 ng hr/ml during the interdialytic period. No significant changes were observed in these parameters after dosing with labetalol just before dialysis. The hemodialysis clearance of labetalol was 30.67 +/- 5.49 ml/min, and only 0.189 +/- 0.042 mg of labetalol was removed by hemodialysis. The terminal t 1/2 averaged 13.05 +/- 6.32 hours during CAPD. Steady-state volume of distribution, total body clearance (Clp), and CAPD clearance were 10.39 +/- 2.77 L/kg, 1397.2 +/- 372.3 ml/min, and 1.94 +/- 0.65 ml/min, respectively. The fraction of the dose recovered in the CAPD dialysate during the 72-hour study period was 0.14% +/- 0.09%. The decay of the antihypertensive effect of labetalol was gradual and paralleled the decline in the log plasma concentration. There was a significant correlation between labetalol plasma concentration and the fall in supine diastolic and mean blood pressure after the interdialytic dose and during CAPD. Although labetalol is removed by dialysis, dialysis does not significantly enhance Clp.

Comparative tolerability of labetalol versus propranolol, atenolol, pindolol, metoprolol, and nadolol.

The side-effect profile of labetalol was assessed in 34 patients with mild to moderate essential hypertension who had previously experienced side effects during beta-blocker therapy. The most frequently reported beta-blocker side effects were fatigue, impotence, cold extremities, and depression. After discontinuing their previous beta-blocker for 4 weeks, labetalol was titrated (100-400 mg b.i.d.) to achieve blood pressure control. Twenty-seven of 34 patients did not have a recurrence of a beta-blocker related side effect while receiving labetalol. The most common new side effect with labetalol was dizziness (3 patients). As judged by the attending physician and the patient, labetalol was better tolerated than conventional beta-blocker therapy in 30 of 34 patients (88%). Twenty-four of 34 patients (71%) preferred labetalol over previous therapy. Labetalol controlled blood pressure in 30 of 34 patients (88%). At equal antihypertensive doses, some side effects common to beta-blockers are seen less frequently with labetalol.

Postmarketing comparison of labetalol and propranolol in hypertensive patients.

A survey was conducted to compare the safety and effectiveness of labetalol and propranolol under routine conditions of clinical use. Patients received either labetalol (n = 805) or propranolol (n = 135) twice daily, according to package insert instructions, for six weeks. Every two weeks the patients were evaluated and weight, heart rate, blood pressure, dose, and adverse symptoms were recorded. Both treatment groups experienced a significant decline in blood pressure at six weeks; blood pressure decreased by 24/15 mmHg in the labetalol patients and by 20/14 mmHg in the propranolol patients. Heart rate decreased significantly in both groups, but the drop in the propranolol group was greater than in the labetalol group. Significantly more propranolol-treated patients reported fatigue (15.2% versus 6.3%), impotence (9.0% versus 3.2%), bad dreams (2.3% versus 0.3%), and cold extremities (2.3% versus 0%). Dizziness was reported more frequently by the labetalol group (9.1% versus 3.8%). Overall, both drugs were safe and effective in treating hypertension, but complaints of beta-blocker-associated side effects were more frequent with propranolol.

Effects of histamine-2 receptor blockade on lidocaine kinetics.

The hypothesis that the H2-receptor blockers cimetidine and ranitidine have different effects on the disposition of lidocaine, a microsomally metabolized drug dependent on hepatic blood flow for elimination, was tested. Six normal men received lidocaine infusions (2 mg/kg over 10 minutes) and lidocaine levels were determined by HPLC. Lidocaine kinetics were studied in the untreated state (O) and in a double-blind, double-dummy design after 2 days of placebo (P), cimetidine (C, 300 mg every 6 hours by mouth), or ranitidine (R, 160 mg every 12 hours by mouth). Model-independent kinetics were estimated by the statistical moment theory. The steady-state volume of distribution was lower after cimetidine (means +/- SD: O, 156 +/- 39 L; P, 156 +/- 48 L; C, 123 +/- 20 L; and R, 174 +/- 38 L). A trend toward decreased lidocaine clearance after cimetidine was also noted (O, 1011 +/- 140 ml/min; P, 1087 +/- 227 ml/min; C, 886 +/- 214 ml/min; and R, 1143 +/- 225 ml/min). Elimination rate constants were of the same order in all four treatments. Only higher levels of alpha 1-acid glycoprotein appeared to limit the lidocaine steady-state volume of distribution. Cimetidine and ranitidine have distinctly different effects on lidocaine kinetics in normal subjects. The absence of ranitidine effects on the disposition of lidocaine, a high-extraction, high-clearance drug, suggests that H2-receptor blockade may not decrease hepatic blood flow, and that cimetidine impairs drug elimination only by inhibition of hepatic microsomal enzymes. Such interactions are not likely to occur with ranitidine.

Lack of effect of histamine H2-receptor antagonists on indocyanine green disposition measured by two methods.

Eleven healthy male volunteers were treated according to a randomized, crossover design with ranitidine (300 mg/day), cimetidine (1200 mg/day), or nothing for 48 hours. Ninety minutes after the 48-hour dose, each volunteer was given 0.5 mg/kg indocyanine green by iv bolus. Indocyanine green plasma concentrations were measured by the traditional spectrophotometric method at 800 nm and by HPLC simultaneously monitored at 214 and 656 nm. Neither histamine H2-receptor antagonist altered the disposition of indocyanine green. The mean (+/- S.D.) plasma clearance by the spectrophotometric method was 7.48 +/- 2.07 (control), 7.15 +/- 3.07 (ranitidine), and 6.88 +/- 1.35 ml/min/kg (cimetidine). The power to detect a 20 per cent change is 0.87. The spectrophotometric method generally produced a biexponential plasma concentration decay, whereas the HPLC method resulted in a monoexponential decay. Analysis of the 5- to 15-minute data by the conventional technique showed that although indocyanine green total plasma clearance was not significantly different for the two methods (P greater than 0.10), the volume of distribution was significantly greater (P less than 0.001) and the elimination rate constant was significantly smaller (P less than 0.001) for the spectrophotometric than the HPLC method. Although neither ranitidine nor cimetidine chronic administration alters indocyanine green disposition by either method, the absolute values of the pharmacokinetic parameters are dependent upon the analytical technique employed.

Cost savings from hetastarch use in place of albumin on a cardiothoracic surgery service.

The use of hetastarch in 38 cardiothoracic surgery patients was monitored prospectively to determine patient parameters that influence physicians' prescribing practices. Potential cost savings from substituting hetastarch for albumin were calculated and use of hetastarch, following introduction to the hospital, was monitored. Data were statistically analyzed, and no correlation was seen among operative procedure, type of admission (transfer or direct admission), or patient age. During the 2-month study period, $800 was saved on the cardiothoracic surgery unit by substituting hetastarch for 5% albumin. An additional $1,600 could have been saved if optimal amounts of hetastarch had been used. Substitution of hetastarch for 5% albumin on just one intensive care unit in this 283-bed hospital is projected to elicit annual cost savings of $14,000.