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.

Plasma propranolol before, during, and after cardiopulmonary bypass.

We evaluated changes in propranolol plasma levels before, during, and after cardiopulmonary bypass (CPB). Two groups of patients were studied, all of whom had been on long-term propranolol and had received their last oral dose 10 to 15 hr before surgery. Approximately 100 min before CPB began group 1 patients (n = 7) received 0.1 mg/kg propranolol intravenously while group II patients (n = 7) received a placebo. Before CPB the plasma propranolol levels fell in accordance with published descriptions for nonsurgical patients receiving oral and intravenous propranolol. Thereafter, the changes in the plasma levels were much the same in both groups. With the onset of CPB, the plasma levels decreased by approximately 50%. There was an insignificant fall in plasma levels during CPB, but the most interesting observation was made after : in each patient, the plasma levels obtained 5, 60, 120, and 240 min after CPB were higher than the last level during CPB. Mean plasma levels did not decline in either group during the 4-hr period. Although the reason for the sustained rise in the propranolol levels after CPB is not known, we suggest that it is due to the redistribution of propranolol from the lungs of the plasma coupled with reduction in hepatic elimination.

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.

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.

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)

Inaccuracy of pulmonary capillary wedge pressure when compared to left atrial pressure in the early postsurgical period.

Simultaneous measurements of pulmonary capillary wedge pressure (PCWP) and left atrial pressure (LAP) were obtained before and after cardiopulmonary bypass and for a period of 16 hours postoperatively in 20 consecutive patients undergoing electric cardiac operations. In contrast to several previous reports that PCWP accurately reflects left-sided hemodynamics, we found that the PCWP significantly exceeded the LAP in the early postbypass period and was most significantly in error at 4, 8, and 12 hours after operation (p less than .02) (95% confidence limit). The magnitude of this discrepancy differed in individual patients; however, it was consistent for each patient for the time period studied and independent of the procedure performed. The disparity between PCWP and LAP may be due to an increase in lung interstitial water as a result of hemodilution, or it may be related to the differing effects of afterload reducing agents on the pulmonary versus the systemic circulation. We conclude from these data that LAP more accurately reflects left ventricular filling and performance in the early postoperative period and should be used instead of PCWP to monitor the hemodynamics of postsurgical patients.

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.

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.

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.

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.

Comparison of dopamine and dobutamine following coronary artery bypass grafting.

A prospective, randomized comparison of the hemodynamic effects of dopamine and dobutamine was performed in 20 patients following coronary artery bypass grafting. Approximately 6 hours postoperatively, when patients were hemodynamically stable, either dopamine or dobutamine was administered at 2.5, 5.0, and 7.5 micrograms per kilogram of body weight per minute. At 5.0 micrograms/kg, both drugs increased cardiac index without changing heart rate, mean arterial pressure, pulmonary capillary wedge pressure, or peripheral vascular resistance. At 7.5 microgram/kg, dobutamine caused a further increase in cardiac index without changing the other variables. In contrast, increasing dopamine from 5.0 to 7.5 micrograms/kg/min caused significant increases in mean arterial pressure, pulmonary capillary wedge pressure, and pulmonary vascular resistance but no further increase in cardiac index. We conclude that dobutamine is preferable to dopamine in patients following coronary artery bypass grafting, since it produces consistent, dose-related increases in cardiac index without increases in heart rate, mean arterial pressure, pulmonary capillary wedge pressure, or pulmonary vascular resistance.

Platelet loss during experimental cardiopulmonary bypass and its prevention with prostacyclin.

Prostacyclin (PGI2), a newly discovered short-acting prostaglandin that inhibits platelet aggregation, was evaluated as an agent for prevention of cardiopulmonary bypass-induced thrombocytopenia. Ten adult, splenectomized greyhounds were divided into three treatment groups prior to beginning 120 minutes of partial cardiopulmonary bypass. Group 1 animals received 300 units of heparin per kilogram of body weight, Group 2 animals received 300 units of heparin per kilogram plus PGI2, 1.5 micrograms per minute, and Group 3 animals received 300 units of heparin per kilogram plus PGI2 3.0 micrograms per minute. Bypass and PGI2 infusion were started simultaneously. Mean platelet counts of each group at 5 minutes were approximately 40% of prebypass levels. Additional platelet loss was seen in Groups 1 and 2 at 30, 60, and 120 minutes. However in Group 3, platelet counts at 30 and 60 minutes were essentially unchanged from prebypass levels. At 30, 60, and 120 minutes of cardiopulmonary bypass, the differences between Groups 1 and 3, and 2 and 3 are highly significant (p less than 0.01). We conclude that PGI2 is an effective agent for preserving platelet levels during experimental cardiopulmonary bypass. Furthermore, it is possible that platelet loss during cardiopulmonary bypass may be caused, in part, by an imbalance between PGI2 and thromboxane A2, which results in excessive platelet adhesion and aggregation.

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.

The effects of antacid and propantheline on the absorption of oral ranitidine.

The effects of propantheline bromide and an aluminum hydroxide/magnesium hydroxide suspension on absorption of ranitidine were evaluated in 12 healthy volunteers according to a Latin square design. Ranitidine 150 mg was administered alone, with 30 ml antacid or preceded by 15 mg propantheline. Ten serum samples were obtained over 12 hours during each treatment period for measurement of ranitidine concentration. The antacid had no significant effect on ranitidine absorption, but propantheline increased the relative bioavailability of ranitidine by 22%. In addition, there was a trend, although not statistically significant, for propantheline to increase the maximum ranitidine serum concentration and the time to maximum serum concentration. Ranitidine can be administered concomitantly with the evaluated doses of antacid and propantheline without a clinically significant alteration in its absorption.

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.

Diuresis with continuous infusion of furosemide after cardiac surgery.

We prospectively evaluated the diuretic effect of furosemide administered by bolus injection and by continuous infusion in 18 cardiac surgery patients. Nine patients were randomly assigned to receive 0.3 mg/kg of furosemide as a bolus injection at time 0 and again 6 hours later (nine patients) or 0.05 mg/kg per hour of furosemide as a constant infusion for 12 hours (nine patients). There were no significant differences between groups with respect to age, weight, creatinine clearance, changes in serum sodium and potassium levels, total urinary concentrations of sodium and potassium, or total urine volume for 12 hours. Diuresis during continuous infusion of furosemide was less variable from hour to hour than after bolus injection of furosemide and was sustained throughout the infusion period. Although the continuous infusion of furosemide will not provide the rapid and vigorous diuresis that is necessary in some clinical situations, it may be useful whenever a gentle, sustained diuresis is desired.

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.

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)

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.

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.