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Background: This was a randomized, double-blind, placebo-controlled, multicentre, parallel group, dose-ranging trial of ranitidine tablets for relief of episodic heartburn. Adult out-patients who reported heartburn relieved by antacids at least seven times per week were eligible., Methods: Patients who successfully completed a 1-week single-blind placebo run-in phase and who did not achieve adequate relief in more than 50% of heartburn episodes were randomized to a 1-week, double-blind treatment phase during which they received ranitidine doses of 25, 75 or 125 mg, or placebo., Results: Of 577 patients randomized, 566 had at least one evaluable heartburn episode and were included in the intention-to-treat analysis. All three ranitidine doses were statistically significantly superior to placebo in providing overall episodic heartburn relief for the first episode (P < 0.002), last episode (P

Background: Approximately 30% of adults in the USA suffer from heartburn or related symptoms monthly; more than 20% of these sufferers experience heartburn at least once per day. Although many rely on self-medication with antacids for the relief of their symptoms, treatments that decrease gastric volume as well as increase the pH of refluxed material should be more effective in relieving heartburn., Aim: To compare the safety and efficacy of low-dose regimens of ranitidine for the relief of heartburn., Methods: Adults with at least a 3-month history of heartburn were eligible for this randomized, double-blind, parallel group, multicentre dose-ranging study. Following a 1-week open-label run-in phase to document baseline heartburn frequency, subjects were randomized to receive treatment with one tablet of either ranitidine 75 mg (n = 491), ranitidine 25 mg (n = 504), or placebo (n = 494), to be taken as needed up to four times daily for 2 weeks for the relief of heartburn., Results: The ranitidine 75 mg regimen was clinically (> 10 percentage points) and statistically (P < 0.05) significantly more effective than placebo for all measured efficacy end-points in relieving heartburn and reducing antacid consumption. In addition, the ranitidine 75 mg regimen was superior to placebo in providing heartburn relief within 30 min of dosing that lasted for up to 12 h. Ranitidine 25 mg was observed to be statistically superior (P < 0.05) but not clinically different from placebo, as defined a priori, in providing heartburn relief. All treatments were well tolerated and adverse events occurred no more frequently with the ranitidine regimens than with placebo., Conclusions: Ranitidine 75 mg provides prompt relief of heartburn that lasts for up to 12 h and has a safety profile comparable to that of placebo.

Background: Ranitidine hydrochloride (Zantac) is one of the most extensively studied and widely used drugs of all time. This has provided an excellent opportunity to define its safety profile., Methods: Data from 189 controlled clinical trials in which more than 26,000 patients received daily doses of ranitidine for 4 weeks or more were reviewed. More than 80% of patients were treated with up to 300 mg ranitidine daily; the remaining patients received doses of up to 1200 mg daily. Eighty-seven trials were placebo controlled. Analyses of post-marketing surveillance and a database of all spontaneously reported adverse events were also evaluated., Results: Overall in the clinical trial programme adverse events were reported by 20% of those receiving ranitidine compared with 27% of those receiving placebo. The pattern of events was similar in all treatment groups with no evidence of dose-related toxicity in regimens encompassing an eightfold range of therapeutic doses. Similarly in a programme of studies designed to evaluate a dose of ranitidine of 75 mg for non-prescription (over-the-counter) use in the treatment of heartburn, ranitidine was not associated with an adverse event profile distinct from that of placebo. Analysis of spontaneously reported adverse event data allowed identification of rare idiosyncratic events., Conclusions: Review of data from a large population of controlled clinical trials with analyses of postmarketing surveillance studies and spontaneously reported adverse events confirmed the excellent safety profile of ranitidine.

Elevated aluminum concentrations have been implicated in several disease states in the elderly. We examined the effects of sucralfate, a basic aluminum salt of sucrose sulfate, and ranitidine, administered individually and in combination, on plasma and urine aluminum concentrations in the elderly in a prospective, randomized, three-arm crossover study. Subjects were 20 healthy volunteers over age 65 years, with no clinically significant comorbidities or recent use of aluminum-containing drugs or histamine (H)2-antagonists. The three regimens were ranitidine 300 mg at bedtime, sucralfate 1 g 4 times/day, and ranitidine 300 mg at bedtime plus sucralfate 1 g 4 times/day, administered for 4 weeks, with a washout period of at least 1 week between regimens. Plasma and urine aluminum concentrations were measured on days 0, 1, 7, 14, and 28 of each regimen. After 28 days, mean plasma aluminum concentrations were significantly higher in subjects receiving sucralfate alone (8.5 +/- 1.8 micrograms/L) and sucralfate plus ranitidine (5.1 +/- 1.3 micrograms/L) compared with those receiving ranitidine alone (2.4 +/- 0.7 micrograms/L). Urine aluminum concentrations were significantly higher in subjects receiving sucralfate alone (133.2 +/- 32.8 micrograms/g creatinine) and sucralfate plus ranitidine (148.1 +/- 51.9 micrograms/g creatinine) compared with those receiving ranitidine alone (11.0 +/- 3.7 micrograms/g creatinine). There was no significant difference in plasma or urine aluminum concentrations between subjects who received sucralfate alone versus those who received sucralfate plus ranitidine. Sucralfate 4 g/day in elderly subjects produces a significant increase in both plasma and urine aluminum concentrations, compared with ranitidine 300 mg/day. This increase most likely is secondary to gastrointestinal absorption of aluminum in the sucralfate formulation. The clinical relevance of this increase requires further evaluation.

Objective: This study evaluated the prevalence and resulting costs of ceftazidime dosing in excess of product labeling recommendations in elderly hospitalized patients. Ceftazidime is a beta-lactam antibiotic excreted via glomerular filtration. According to product labeling, ceftazidime dosing can frequently be decreased in the elderly because glomerular filtration declines with age., Methodology: A multicenter, retrospective utilization audit involving 11 US academic medical centers examined 221 medical records of patients 65 years of age or older receiving ceftazidime (any brand, any indication). The creatinine clearance of each patient was estimated using the Cockcroft-Gault formula., Results: Renal insufficiency, defined as an estimated creatinine clearance of less than 50 mL/min, was present in 111 of the patients (50 percent). Ceftazidime dosing in excess of product labeling recommendations was noted in 75 of those 111 (68 percent). The cost of excess ceftazidime dosing for those 75 patients (i.e., extra drug acquisition, preparation, administration) was $13,822.50., Conclusions: Although the dosage of ceftazidime required in a specific patient is based on many factors, ceftazidime is frequently overdosed in the elderly because renal function is not considered. Ceftazidime dose-adjustment in the elderly, based on the estimated creatinine clearance, can lead to cost savings. In the US, where hospital reimbursement by Medicare is based on diagnosis, institutions can realize direct cost savings.

The authors conducted a retrospective review of 21 United States trials of ranitidine in acid peptic diseases and compared the adverse events in elderly (> or = 65 years) and nonelderly (< 65 years) patients. Ranitidine dosages ranged from 150 mg/day to 300 mg twice daily for treatment periods of 4 to 52 weeks. Of the 4041 patients included in this review, 402 elderly and 2188 nonelderly patients received ranitidine and 245 elderly and 1206 nonelderly patients received placebo; 29%, 29%, 32%, and 26% of these patients, respectively, reported some type of adverse event. When only drug-related adverse events (as judged by the investigators under blinded conditions) were evaluated, these percentages dropped to 2%, 2%, and 1% and 2%, respectively. Gastrointestinal adverse events (e.g., nausea and diarrhea) and central nervous system adverse events (e.g., headache and dizziness) were the most common (0.7% and 0.8%, respectively), with comparable incidence rates in the elderly and nonelderly patients. The authors conclude that ranitidine is as safe in elderly patients as it is in nonelderly patients. No difference in the incidence of adverse events was found between older and younger patients who received ranitidine or placebo.

Labetalol and hydrochlorothiazide (HCTZ) were compared for their efficacy in controlling hypertension of blacks in a prospective, double-blind study. Sixty-one adult patients with mild to moderate hypertension (standing diastolic blood pressure greater than or equal to 95 mm Hg and less than or equal to 114 mm Hg) were randomly selected to receive either labetalol 100 mg twice daily (n = 30) or HCTZ 25 mg twice daily (n = 31). The study was divided into two phases: a 4-week placebo run-in phase, during which all previous antihypertensive medication was discontinued, and a 12-week drug treatment phase. Labetalol and HCTZ doses were titrated to 400 mg twice and 50 mg twice daily, respectively, during the first 6 weeks of the drug treatment phase for those patients not achieving blood pressure control (standing diastolic blood pressure less than 90 mm Hg and a decrease of 10 mm Hg from baseline) on initial dosages. By the end of the 12 weeks of drug administration, patients on labetalol experienced a mean decrease of 10 mm Hg in standing diastolic blood pressure compared to a mean decrease of 10.1 mm Hg in patients on HCTZ. No differences were observed between the two treatment groups in reductions of either standing blood pressure or heart rate. While 19 of 30 patients on labetalol (63%) achieved blood pressure control at some point during the study with a mean daily dose of 568 mg, 18 of 31 (58%) HCTZ-treated patients achieved control with a mean daily dose of 72 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

Labetalol was evaluated in a multicenter, placebo-controlled study of elderly patients (greater than or equal to 60 years) with mild to moderate essential hypertension. After a placebo-washout period, doses were titrated from 100 mg BID to a maximum of 400 mg BID over a 6-week period. Once blood pressure control (standing diastolic blood pressure [SDBP] less than 90 mm Hg and greater than or equal to 10 mm Hg reduction from baseline) was achieved or the maximum allowable dosage had been given, the dosage remained the same until the end of the study. The titration phase was followed by a 4-week maintenance period. Blood pressure control was achieved in 37/54 (69%) of the patients who were treated with labetalol compared with 21/58 (36%) of the patients who received placebo (P less than .001). Twenty-nine (78%) of those controlled on labetalol responded to doses of 200 mg or less BID, and there was no significant difference between groups with respect to orthostatic blood pressure changes. Adverse experiences were generally mild and occurred with similar frequency in the labetalol and placebo groups; six patients who received labetalol and five who received placebo withdrew from the study due to adverse experiences, but in only one case (labetalol) was the adverse experience considered drug-related. In summary, labetalol effectively and safely lowered diastolic blood pressure in the elderly without producing significant orthostatic changes.

The disposition of drugs in the elderly is particularly relevant with antiinfectives, because this population has an increased risk of infections. Renal function deteriorates with age, yet dosage guidelines for antibiotics that allow for this reduction remain to be established. Ceftazidime, a cephalosporin with enhanced antipseudomonal activity that is eliminated primarily by glomerular filtration, has been evaluated in the elderly. Herein, we review ceftazidime's pharmacokinetic profile and dosing considerations in this population. Several aspects of renal function deteriorate with the normal aging process, including a decreased glomerular filtration rate (GFR). Using serum creatinine concentrations as an estimate of the GFR in the elderly is unreliable; a more reliable way of estimating GFR is the use of inulin or 51Cr-editic acid clearance or calculation from formulas or nomograms based on age, weight, sex, and serum creatinine. From pharmacokinetic studies it was found that the elderly individual without renal disease generally has an increased elimination half-life and decreased clearance of ceftazidime compared with a young person. A positive correlation (r = 0.7-0.95) was shown between ceftazidime clearance and GFR, suggesting that estimates of GFR may be used to determine the ceftazidime dose. In several studies, the trough (after 12 hours) ceftazidime serum concentration exceeded by several fold its minimum inhibitory concentration required to inhibit 90% of organisms for most commonly encountered organisms; efficacy and safety were also confirmed with an every-12-hour regimen. A twice-daily dosage regimen for ceftazidime in elderly patients with normal renal function should be considered based on age-related decreases in renal function and drug elimination.

Purpose: This study compared the safety and efficacy of labetalol and enalapril as antihypertensive therapy for elderly patients., Patients and Methods: A randomized, open-label, parallel controlled trial was conducted. After completing a 4-week placebo phase, 79 elderly (65 years or older) patients with an average standing diastolic blood pressure (BP) 95 mm Hg or above and 114 mm Hg or less were randomized to receive a 12-week course of either labetalol or enalapril in an open-label design. The patients' BP and heart rate were evaluated biweekly by trained observers unaware of the treatment status, and drug dosage was titrated (up to 400 mg twice a day of labetalol or 40 mg daily of enalapril) to achieve a standing diastolic BP of less than 90 mm Hg and a decrease of 10 mm Hg from baseline. Patients underwent 24-hour ambulatory BP monitoring (ABPM) at the end of the placebo phase and again after 8 weeks of active treatment., Results: The treatment groups were comparable in their reduction of supine diastolic BP, with no significant differences between the two treatments. Labetalol demonstrated a significantly greater reduction (p less than 0.05) in standing diastolic BP at the end of the titration period compared to enalapril, but this difference was not significant by the end of the study period. Based on 24-hour ABPM readings, labetalol reduced mean 24-hour diastolic BP (p less than 0.05) and mean heart rate (p less than 0.05) more than enalapril. The labetalol-treated patients were significantly less often above their diastolic BP goal throughout the 24-hour ABPM period (p less than 0.01). The two treatments were equally well tolerated., Conclusions: The results indicate that labetalol and enalapril are equally effective in lowering supine diastolic BP in the elderly, but labetalol is more effective in lowering ambulatory BP and heart rate throughout the day.

Calcium antagonists have been shown to depress hepatic enzymes and accelerate hepatic blood flow. This study was designed to compare the effects of two calcium antagonists, isradipine and diltiazem, on antipyrine and indocyanine green (ICG) clearances in the elderly. Eighteen elderly subjects (aged 65 to 80 years) received either isradipine (5 mg every 12 hours), diltiazem (90 mg every 8 hours), or placebo (every 12 hours) for 4 days. On the third day after the study treatment, a 0.5 mg/kg dose of ICG was administered. Blood samples were obtained over 20 minutes for HPLC determination of ICG plasma concentrations. Ten minutes later, subjects ingested 1.2 gm antipyrine. Blood samples were obtained over 48 hours for HPLC determination of antipyrine plasma concentrations. Mean +/- SD antipyrine clearance after diltiazem (0.0258 +/- 0.0065 L/hr/kg) was significantly lower than that observed after isradipine (0.0334 +/- 0.0098 L/hr/kg) or placebo (0.0329 +/- 0.0082 L/hr/kg). Antipyrine clearance after isradipine was not significantly different from that after placebo. Mean +/- SD ICG clearances after diltiazem (9.17 +/- 1.35 ml/min/kg) or isradipine (9.57 +/- 1.82 ml/min/kg) were significantly higher than that observed after placebo (8.06 +/- 1.45 ml/min/kg). These findings suggest that diltiazem, but not isradipine, affects hepatic enzyme activity in the elderly. Both agents accelerate ICG clearance, a marker of hepatic blood flow.

The safety and efficacy of labetalol and hydrochlorothiazide (HCTZ) were compared in a group of 34 patients aged 65 years or older with mild to moderate essential hypertension. After a 4-week placebo run-in period, during which all previous antihypertensive medication was discontinued, patients were randomized to receive either labetalol (100 mg bid) or HCTZ (25 mg bid). The patients' blood pressure and heart rate were evaluated biweekly and drug dosage was titrated (up to 400 mg and 50 mg bid of labetalol and HCTZ, respectively) to achieve a standing diastolic blood pressure less than 90 mm Hg. Patients underwent 24-hour ambulatory blood pressure monitoring at the end of the placebo run-in period and again after the 6-week titration period. Both labetalol and HCTZ significantly (P less than .01) reduced standing systolic (-19.4 vs -27.7 mm Hg) and diastolic (-14.0 vs -15.2 mm Hg) blood pressures following 12 weeks of treatment. Both antihypertensives effectively controlled the 24-hour ambulatory blood pressure, however, the labetalol group experienced a significantly lower rate of rise in diastolic blood pressure (P = .02) and mean arterial pressure (P = .02) during the acceleration period (400-1200) compared to the HCTZ group. HCTZ caused significant decreases in serum potassium (P less than .01) and alkaline phosphatase (P less than .05) and increases in uric acid (P less than .01) and urea nitrogen (P = .07). These results indicate that labetalol may offer some unique advantages over thiazide diuretics that may be particularly important in the treatment of elderly patients with hypertension.

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.

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.

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.

The pharmacodynamic effects of single oral doses of atenolol (100 mg), labetalol (300 mg), and propranolol (80 mg) were compared with those of placebo in a randomized, double-blind, Latin square design in 12 patients with hypertension. Atenolol and propranolol both significantly reduced cardiac output (-0.55 vs. -0.31 L/min) and heart rate (-8.0 vs. -6.6 bpm), whereas labetalol had no effect on either parameter (-0.08 L/min; + 1.0 bpm). Labetalol significantly reduced vascular resistance (-339 dynes X cm/sec5), but atenolol and propranolol did not (147 vs. 62 dynes X cm/sec5). Only labetalol significantly reduced the systolic (-15.3 mm Hg), diastolic (-11.5 mm Hg), and mean blood pressures (-12.8 mm Hg). Atenolol significantly reduced only diastolic blood pressure (-5.20 mm Hg), whereas propranolol failed to lower these parameters significantly. These data indicate that the hemodynamic profile of labetalol differs from that of selective and nonselective beta-blockers. Labetalol lowered blood pressure primarily by reducing vascular resistance, whereas reductions in heart rate and cardiac output were the predominant effects of atenolol and propranolol.

Elderly and young hypertensive patients differ with regard to clinical and pathophysiologic profiles. In the elderly, hypertension is generally characterized by elevated peripheral vascular resistance and decreased cardiac output. To establish an individualized or patient-specific approach to their treatment, antihypertensive agents must be evaluated specifically in this subpopulation. Labetalol, an alpha- and beta-blocking agent, has been shown to lower blood pressure in young and elderly hypertensive patients primarily by reducing peripheral vascular resistance without compromising cardiac output. Examination of recent reports on the pharmacokinetics and pharmacodynamic effects, and on the efficacy and safety of labetalol in elderly persons with hypertension, leads us to conclude that the drug appears to be well suited for use in these patients.

A 25-year-old man with sickle cell disease and chronic renal insufficiency had tonic-clonic seizures treated with phenytoin. Serum phenytoin concentrations, total and free, measured by two homogeneous enzyme immunoassays (EMIT, CAC) were reported to be within the therapeutic range, yet the patient experienced seizures. Values on discharge exceeded the therapeutic range but were not associated with signs or symptoms of toxicity. Reanalysis of serum samples by a more specific, high performance liquid chromatographic (HPLC) method revealed the previous values were spurious, apparently due to phenytoin metabolite cross-reactivity. Values by fluorescence polarization immunoassay (TDX) correlated well with those by HPLC, as well as with the patient's clinical course.

The effects of labetalol, diltiazem and verapamil on antipyrine and indocyanine green clearance were evaluated in a placebo-controlled, repeated measures evaluation. Twelve healthy subjects received either labetalol (200 mg every 12 hours), diltiazem (90 mg. every 8 hours), verapamil (80 mg every 8 hours), or placebo (every 12 hours) for 4 days. On the morning of Day 3 immediately following their dose, the subjects assumed the supine position for 90 minutes, after which time a 0.5 mg/kg dose of indocyanine green was administered. Blood samples were obtained serially over a 20 minutes period for indocyanine green plasma concentration determinations by HPLC. Ten minutes later, subjects ingested a 1.2 Gm. dose of antipyrine and blood samples were obtained over a 48 hour period for antipyrine plasma concentration determinations by HPLC. A 2 week washout period separated treatment sequences. Mean (SD) antipyrine clearance (L/hr/kg) following diltiazem [0.028 (0.010)] and verapamil [0.030 (0.012)] treatment was significantly lower than that observed following placebo [0.039 (0.012)]. Antipyrine clearance following labetalol administration [0.033 (0.010)] was not significantly different from that observed following placebo, diltiazem or verapamil administration. No effects of these drugs on indocyanine green clearance could be detected.

Labetalol is an alpha 1- and beta-adrenergic antagonist currently used in the treatment of hypertension. Studies which have evaluated the effects of age on its pharmacokinetics have yielded conflicting results. The purpose of this study is to comprehensively re-evaluate the effect of age on the elimination of labetalol. Data were obtained from 4 single-dose and 3 multiple-dose studies of the pharmacokinetics of the drug. An analysis of covariance was performed on the single-dose data to determine whether the type of subject evaluated (normotensive vs hypertensive), type of assay methodology used and/or age were significant factors affecting labetalol clearance estimates. A similar covariance procedure was used for the multiple-dose data, to assess whether the type of subject, duration of treatment and/or age were significant variables affecting labetalol elimination. Subsequent to the analysis of covariance, linear regression and correlation analysis was used to evaluate the effects of age on labetalol clearance. A modest though significant relationship was observed between the apparent oral clearance of the drug and age; it appeared slightly stronger when clearance was normalised for bodyweight. No relationship was found following multiple doses of the drug. Hence, age does not appear to be a significant factor affecting the oral clearance of labetalol, particularly in individuals receiving the drug in the long term.

Prednisone is a glucocorticoid that must be converted in vivo to prednisolone for pharmacologic activity. We examined the effects of the H2-receptor antagonists cimetidine and ranitidine on the time course of plasma prednisolone concentrations after an oral dose of prednisone. Nine healthy men received each of three oral treatments in a double-blind, balanced, crossover manner: cimetidine (300 mg every 6 hours), ranitidine (150 mg twice a day), or placebo for 4 days, with prednisone (40 mg) taken also on day 4. Serial blood and urine samples were collected for 30 hours after prednisone dosing. Prednisone and prednisolone plasma and urine concentrations were analyzed by HPLC. No differences were found between treatments in the maximum prednisolone plasma concentration, t1/2, apparent volume of distribution, and AUC. Cimetidine reduced the mean (+/- SD) ratio of prednisone dose to the plasma prednisolone AUC (16.6 +/- 2.9 L/hr) below that ratio after ranitidine (19.2 +/- 4.2 L/hr) and placebo (19.3 +/- 2.8 L/hr), and resulted in the lowest fractional excretion of prednisolone in the urine (5.2% +/- 2.2%, 9.8% +/- 4.5%, and 12.4% +/- 4.9%, respectively). The minor alterations in prednisolone kinetics during concomitant cimetidine dosing are not likely to induce clinically significant alterations in steroid effect.

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.

Blood pressure and heart rate exhibit a circadian rhythm, with both rising rapidly during the morning hours and then decreasing throughout the day to a nadir around 3 AM. Current evidence suggests a possible link between cardiovascular events, such as myocardial infarction and sudden cardiac death, which have been shown to occur most frequently during the morning hours, and the rapid rise in blood pressure and heart rate during this same time period. We review data from ambulatory blood pressure studies to ascertain which antihypertensive agents provide the most satisfactory control of blood pressure and heart rate during the hours of 6 AM to 12 noon. Of the forms of drug therapy studied, labetalol, a combined alpha- and beta-blocker, and two calcium channel blockers, nifedipine and verapamil, appear to be the most effective in blunting the rise in arterial blood pressure during these critical morning hours.