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.

Purpose: To compare the incidence of gastric and duodenal mucosal injury with twice-daily administration of PN100, twice-daily enteric-coated naproxen, and twice-daily naproxen with delayed-release lansoprazole once daily. Methods: A single-center, randomized, parallel-group study enrolled 60 male and female volunteers aged 40–65 years. After normal baseline endoscopy (EGD), subjects received 14 days' treatment with either: (a) twice-daily PN100 (immediate-release lansoprazole 15mg and enteric-coated (EC) naproxen 500mg in a combination tablet), (b) twice-daily EC naproxen 500mg, or (c) delayed-release lansoprazole 15mg capsule each morning and twice-daily naproxen 500mg. The endoscopist was blinded to treatment assignment. EGD was performed at baseline and on days 8 and 14. Gastric pH monitoring (24 hour) and pharmacokinetic sampling were performed on days 1 and 7. Mucosal injury was assessed by the Lanza scale and enumeration of erosions and/or ulcers. Results: After two weeks, no ulcers were present in subjects receiving PN100 whereas 11% of subjects receiving EC naproxen had gastric ulcers. Subjects who received naproxen twice-daily with delayed-release lansoprazole each morning had an ulcer rate of 5%. The cumulative median numbers of gastric erosions at days 8 and 14 were: 5 for PN100; 14 for naproxen and lansoprazole; and 21 for EC naproxen (p = 0.02, Kruskal-Wallis test among 3 treatment groups). No mucosal lesions meeting criteria for Lanza Grade 4 were present at day 14 in subjects receiving PN100, whereas 53% of subjects receiving EC naproxen and 30% of subjects receiving naproxen and lansoprazole met criteria for Lanza Grade 4 injury (≥25 erosions or hemorrhages or any ulcer). Gastric pH monitoring suggested the possibility of better nocturnal acid suppression with use of twice-daily PN100 than with once-daily delayed-release lansoprazole and twice-daily naproxen. Conclusions: A combination tablet containing lansoprazole and EC naproxen was associated with the lowest incidence of upper gastrointestinal mucosal injury when compared with either EC naproxen alone or with naproxen administered with a morning dose of delayed-release lansoprazole. If these results are confirmed, clinical use of this novel formulation would ensure adherence with gastroprotective therapy when recommended for use with an NSAID.

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.

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 signifcant 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.

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 Vβ/F, Vdss/F, TBC/F, t1/2β, and AUC0r 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 μg ṁ 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.

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.

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.

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.

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.