Comparative beta-blocking activities and effects on sodium excretion of sotalol and propranolol.
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Adrenergic beta-Antagonists↗
Biomedical subjects
R K Ferguson
Publications and source records attributed to R K Ferguson.
Comparative antihypertensive effects of enalapril maleate and hydrochlorothiazide, alone and in combination.
Enalapril maleate is an investigational oral prodrug whose hydrolyzed diacid metabolite is a potent angiotensin-converting enzyme inhibitor. Fourteen patients with mild to moderate hypertension were evaluated after receiving placebo, and two weeks of treatment with each of the following: enalapril maleate (20 mg b.i.d.), hydrochlorothiazide (25 mg b.i.d.), and the two in combination. In comparison to placebo, the magnitudes of the blood pressure reduction after enalapril and hydrochlorothiazide alone were comparable. The reduction in blood pressure following enalapril was evident throughout the 12-hour dosing interval. The combination of enalapril and hydrochlorothiazide resulted in a marked further reduction in blood pressure that was greater than that predicted from the responses to the individual drugs (P less than 0.05). Biochemical parameters confirmed inhibition of angiotensin-converting enzyme during enalapril treatment; serum angiotensin-converting enzyme activity proved an excellent monitor of compliance. Enalapril was generally well tolerated. Adverse effects included symptomatic hypotension in three patients when enalapril was first added to hydrochlorothiazide and hyperesthesia of the oral mucosa without a loss of taste in one patient on enalapril. Enalapril maleate alone and especially in combination with hydrochlorothiazide appears to be an effective, well-tolerated converting enzyme inhibitor with at least a 12-hour duration of action.
Adult↗
Methyldopa does not alter the disposition of digoxin.
To investigate whether methyldopa alters digoxin disposition, eight healthy subjects received methyldopa titrated to 250 mg t.i.d. or placebo in a double-blind, cross-over manner for 16 consecutive days, with 0.25 mg intravenous digoxin coadministered on day 5 and 0.25 mg oral digoxin on days 9 to 16. Digoxin concentrations in plasma and urine were measured by RIA. Although assay sensitivity did not allow an adequate assessment of serum AUC(0-infinity) after intravenous administration, mean digoxin AUC(0-24) was 10.2 +/- 3.5 and 10.0 +/- 1.8 ng/ml X hr with placebo and methyldopa, respectively (P greater than 0.05). Mean urinary excretion after digoxin with or without methyldopa treatment was 0.204 +/- 0.34 and 0.197 +/- 0.38 mg, respectively. The mean steady-state serum concentrations of oral digoxin (AUC(0-24)/zeta) with and without methyldopa were 0.65 +/- 0.2 and 0.62 +/- 0.3 ng/ml, respectively. These data revealed no significant differences (P greater than 0.05) for various parameters with power of greater than 0.8 to detect meaningful differences of approximately 30 per cent. Thus, methyldopa did not alter digoxin disposition in healthy subjects, and a pharmacokinetic interaction in patients is unlikely.
Administration, Oral↗
Academic-industrial clinical pharmacology: a working model.
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Animals↗
A dose-titration trial of guanadrel as step-two therapy in essential hypertension.
The efficacy and safety of low-dose guanadrel sulfate were evaluated in 20 patients with essential hypertension based on seated diastolic blood pressures (SDBP) ranging from 95 to 115 mm Hg despite a trial dosage of hydrochlorothiazide 50 mg/d for up to five weeks. These patients had been resistant to, or intolerant of, one or more step-two antihypertensive drugs in the past (i.e., methyldopa, beta-adrenergic blocking agents, clonidine, or prazosin). The majority of patients demonstrated a satisfactory response (SDBP 95 mm Hg or reduction in SDBP of 10 mm Hg) to guanadrel. Nine patients responded at a low dosage, 10 to 20 mg/d and remained free from adverse effects throughout the study (up to 12 weeks of treatment). Of the remaining 11 patients titrated to higher dosages of guanadrel (30 to 60 mg/d), three had no discernible response while six developed adverse effects. The results of the study suggest that guanadrel has an acceptable benefit-to-risk ratio only when used in low dosages (10 to 30 mg/d) and may be successfully employed as step-two antihypertensive therapy in patients resistant to, or intolerant of, other step-two agents.
Adult↗
Captopril: clinical pharmacology and benefit-to-risk ratio in hypertension and congestive heart failure.
Captopril, a competitive antagonist of angiotensin converting enzyme, has been marketed in the United States for the treatment of resistant hypertension. Despite extensive study, its exact mechanism of action remains unclear; decreased renin-angiotensin-aldosterone and sympathoadrenal system activity as well as increased bradykinin and prostaglandin E and F activity have been postulated. The drug decreases peripheral vascular resistance. Controlled trials in resistant hypertension of various etiologies and chronic congestive heart failure have demonstrated sustained effectiveness and therapeutic benefits. Side effects include skin rash, loss of taste, proteinuria, and leukopenia; higher doses and concomitant renal dysfunction appear to be predisposing factors. The benefit-to-risk ratio for captopril clearly justifies its use in resistant cases of hypertension and congestive heart failure, but further experience is needed to evaluate its use in milder forms of these diseases.
Captopril↗
Indacrinone: natriuretic and uricosuric effects of various ratios of its enantiomers in healthy men.
Indacrinone is an investigational loop-acting diuretic. To evaluate the natriuretic and uricosuric effects of varying ratios of its enantiomers, 10 healthy men, on a controlled Na+ (100 mEq) and K+ (80 mEq) diet, participated in a double-blind, randomized, balanced incomplete block, multiple-dose (one week) study of a fixed daily dose (10 mg) of (-) enantiomer combined with increasing doses (40, 90 and 140 mg) of (+) enantiomer versus 50 mg hydrochlorothiazide and placebo. On day 1, mean 24-h urinary Na+ increased (p less than 0.01) comparably (approximately 285 mEq) after each enantiomer combination and hydrochlorothiazide; however, the enantiomer combinations had marked uricosuric and hypouricemic effects that were enhanced with increased (+) enantiomer doses. By day 7, while enantiomer combinations and hydrochlorothiazide demonstrated comparable natriuretic activity, mean serum uric acid levels (mg/dl), in comparison to placebo, were increased (p less than 0.05) with hydrochlorothiazide but progressively decreased with increases in (+) enantiomer. Thus varying the ratio [(+, uricosuric): (-, natriuretic)] of the enantiomers of indacrinone caused natriuresis similar to hydrochlorothiazide, but had an opposite effect on serum uric acid.
Adult↗
Steady-state disposition of diflunisal: once- versus twice-daily administration.
To evaluate the steady-state bioequivalence of the nonsteroidal antiinflammatory analgesic agent, diflunisal, administered once versus twice daily, 13 healthy volunteers received diflunisal as follows: 1000 mg at 8:00 AM and 500 mg at 8:00 AM and 8:00 PM, each for 14 days in a randomized crossover study. The mean (+/- SD) steady-state peak plasma concentrations were significantly greater after once-daily dosing (186 +/- 25 micrograms/ml vs 150 +/- 37 micrograms/ml; p less than 0.01). The time to peak concentration was also longer after the single-dose regimen (2.5 +/- 0.8 vs 1.9 +/- 0.9 hr; p less than 0.05). The regimens were similar with respect to the mean 24-hour area under the plasma concentration-time curve at steady state (2839 +/- 612 vs 2782 +/- 778 micrograms.hr.ml-1), steady-state plasma concentrations (118 +/- 25 vs 116 +/- 32 micrograms/ml), trough plasma concentration (85 +/- 27 vs 92 +/- 28 micrograms/ml) as well as 24-hour urinary excretion (776 +/- 79 vs 771 +/- 89 mg) of diflunisal. Based on urinary recoveries, the bioequivalence ratio (once vs twice daily) was 1.01 +/- 0.08. These results indicate that diflunisal administered once daily might offer comparable therapeutic effects but be more convenient than a twice-daily regimen.
Adult↗
Acute hepatotoxicity after excessively high doses of carbamazepine on two occasions.
A 2 1/2-year-old child being treated with carbamazepine (CBZ) for a seizure disorder on two separate occasions experienced elevated CBZ serum concentrations (28 and 23.2 mg/L), severe liver damage (SGOT greater than 6000 IU, SGPT greater than 5000 IU), and central nervous system manifestations (coma, lethargy, seizures). During the first episode, the time course of CBZ concentrations exhibited a nonlinear decline and was accompanied by CBZ-10,11-epoxide concentrations that were elevated 4-fold compared to normal values. Cerebrospinal fluid concentrations of CBZ and CBZ-10,11-epoxide were also elevated, although their ratios to serum concentrations did not suggest enhanced permeability of the central nervous system to these substances. The concentrations of CBZ-10,11-epoxide but not CBZ were elevated for the duration of time that the patient was comatose, suggesting that this metabolite may contribute to the neurotoxic side effects observed with CBZ therapy.
Alanine Transaminase↗
Cimetidine versus famotidine: the effect on the pharmacokinetics of theophylline in rats.
The effects of cimetidine and a new, potent H2-antagonist, famotidine, on the single dose pharmacokinetics of theophylline were examined in rats. Male Sprague-Dawley rats (6 rats/group) received an i.v. dose of theophylline (6 mg/kg) alone and in conjunction with an i.v. dose of famotidine (10 mg/kg) or cimetidine (10 mg/kg). Venous blood samples were collected serially for seven hours after theophylline infusion and analyzed for theophylline concentration by HPLC. Concomitant famotidine administration did not alter any of the pharmacokinetic parameters of theophylline (AUC0- infinity; 38.1 +/- 8.7 vs. 38.8 +/- 6.3 micrograms.hr.ml-1), while cimetidine demonstrated a significant reduction in theophylline systemic clearance (0.11 +/- 0.02 vs. 0.16 +/- 0.02 L/hr/kg; p less than 0.001), a 40% prolongation of half-life (2.8 +/- 0.9 vs. 2.0 +/- 0.5 hr), with no change in the volume of distribution (0.39 +/- 0.1 vs. 0.41 +/- 0.13 L/kg). These results suggest that in contrast to cimetidine, famotidine, a non-imidazole H2-receptor antagonist, does not interfere with theophylline disposition in the rat.
Animals↗
Effects of captopril, diuretic, and their combination in low-renin essential hypertension.
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Adult↗
Wernicke-Korsakoff syndrome in head injury: a missed insult.
A survey of the use of thiamine in patients at risk from Wernicke-Korsakoff syndrome (WKS) in Scottish specialist neurosurgical units, and a 2-year retrospective study of 218 at-risk patients admitted to a regional neurosurgical unit with a head injury were undertaken. Although responses to the survey indicated otherwise, the study revealed that there was no consistent practice regarding thiamine administration. Overall, 20.6% of patients received thiamine, with an alcohol history being the only factor correlating with thiamine administration. Of known alcoholics and heavy drinkers, 56.1% and 26.2% respectively received thiamine as in-patients; 44.5% of patients received additional carbohydrate loads in the form of i.v. dextrose or parenteral nutrition, but only 28.9% of these received thiamine as well. Although the actual thiamine status of these patients was not known, given the difficulties of diagnosing WKS in the presence of a head injury, the conclusion is that written protocols are needed in units to ensure that head injury patients at risk of WKS receive appropriate thiamine treatment or prophylaxis.
Adolescent↗
Thiamine deficiency in head injury: a missed insult?
Practice regarding the use of thiamine in head-injured patients at risk of Wernicke-Korsakoff syndrome in Scottish neurosurgical units was surveyed by questionnaire and revealed no clear policy. A 2 year retrospective study of 218 admissions to one of these units of patients who had taken alcohol shortly before sustaining head injury is also described. The minority (20.6%) of the total had been given thiamine, with just over half (56.1%) of those categorized as alcoholic receiving this treatment. Additional carbohydrate loads, in the form of i.v. dextrose or parenteral nutrition, had been given to 44.5% of patients and only 28.9% of this group had also been given thiamine. The dose and duration of thiamine given was inadequate in most cases. It is suggested that failure to ensure that head injury patients at risk of Wernicke-Korsakoff syndrome receive appropriate thiamine prophylaxis represents a missed and treatable additional insult to the damaged brain.
Adolescent↗
Initial evaluation of transdermal timolol: serum concentrations and beta-blockade.
The serum concentrations and beta-blockade after dermal application of timolol ointment were evaluated in six healthy men (21-31 years old; 74-82 kg). Two patches (25 cm2) containing placebo and either 30 (n = 2) or 60 mg (n = 4) timolol base were randomly applied to the chest for 30 h. Serial serum concentrations of timolol were measured by a radioligand receptor assay. Bicycle ergometry, at a predetermined workload, was performed before and at 3, 8, 24, and 48 h after patch application; mean +/- SD heart rates (beats/min) at these times were 167 +/- 2, 158 +/- 7, 125 +/- 7, 120 +/- 5, and 150 +/- 5 (last 3 values: p less than 0.05 from pretreatment), and beta-blockade was evident in all subjects. Measurable serum concentrations in the therapeutic range were achieved in all subjects. The change in exercise-induced heart rate (y) was closely related to log timolol serum concentration (x) (y = -36 X - 5.3; r = -0.92; p less than 0.001). Based on the amount of timolol in the residual ointment, 50-60% of the original timolol dosage was delivered from the patch. Skin irritation under the patch compared with placebo was minimal. Further studies are warranted to assess the potential clinical utility of transdermal timolol.
Adult↗
The role of beta-blocking agents following myocardial infarction.
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Adrenergic beta-Antagonists↗
Enalapril, a nonsulfhydryl angiotensin-converting enzyme inhibitor.
The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage of enalapril maleate, a nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor, are reviewed. Enalapril is rapidly converted by ester hydrolysis to enalaprilat, a potent ACE inhibitor; enalapril itself is only a weak ACE inhibitor. Enalapril lowers peripheral vascular resistance without causing an increase in heart rate. In patients with congestive heart failure, enalapril has beneficial hemodynamic effects based on reduction of both cardiac preload and afterload. Approximately 60% of a dose of enalapril is absorbed after oral administration. Excretion of enalaprilat is primarily renal. Accumulation of enalaprilat occurs in patients with creatinine clearances less than 30 mL/min. Enalapril 10-40 mg per day orally has shown efficacy comparable to that of captopril in treating patients with mild, moderate, and severe hypertension, hypertension caused by renal-artery stenosis, and in congestive heart failure resistant to digitalis and diuretics. When given alone for hypertension, enalapril has efficacy comparable to that of thiazide diuretics and beta blockers. Side effects observed with enalapril have generally been minor. Captopril-associated side effects such as skin rash, loss of taste, and proteinuria have been observed in a small number of patients receiving enalapril to date; neutropenia less than 300/mm3 has been noted with captopril but not enalapril. The incidence of these side effects has been noted to be greatly decreased in patients on low doses of captopril. Enalapril appears to be similar in efficacy to captopril for treating hypertension and congestive heart failure. Whether enalapril is safer than low-dose captopril in patients at high risk for captopril-associated side effects will require further investigation.
Angiotensin-Converting Enzyme Inhibitors↗
Resolution of captopril-induced rash after substitution of enalapril.
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Angiotensin-Converting Enzyme Inhibitors↗
Effect of captopril and propranolol, alone and in combination, on the responses to isometric and dynamic exercise in normotensive and hypertensive men.
This study evaluated the effects of single doses of the angiotensin converting enzyme inhibitor captopril and the beta-adrenergic blocking agent propranolol, alone or in combination, on the blood pressure, heart rate and humoral responses to both isometric (handgrip) and dynamic (ergometric) exercise in normotensive and hypertensive men. Single oral doses of either placebo, captopril 50 mg, propranolol 80 mg, or the latter two in combination were administered to age-matched groups (n = 5) of normotensive and hypertensive men in a random, double-blind manner. Captopril alone was indistinguishable from placebo after both isometric and ergometric exercise. Propranolol suppressed heart rate after both types of exercise and tended to decrease systolic blood pressure only in the hypertensive group; combination with captopril did not alter these responses. These data suggest that in sodium-replete subjects undergoing short-term vigorous exercise, the renin-angiotensin system, as measured by captopril inhibition, is less important than the sympathoadrenal system, as measured by propranolol inhibition, in the reflex cardiovascular adjustments accompanying acute isometric and dynamic exercise in both normotensive and hypertensive men.
Adult↗