Roger K. Ferguson

Estimation of gastric residence time of the heidelberg capsule in humans: Effect of varying food composition

In animal and human studies, the gastric emptying of large (greater than 1 mm) indigestible solids is due to the activity of the interdigestive migrating myoelectric complex. The gastric residence time (GRT) of an orally administered, nondigestible, pH-sensitive, radiotelemetric device (Heidelberg capsule) was evaluated in three studies in healthy volunteers. In 6 subjects, the GRT of the Heidelberg capsule was compared with the half-emptying time (t1/2) of diethylenetriaminepentaacetic acid labeled with technetium 99m after a 4-ml/kg liquid fatty meal. The mean (+/-SD) GRT (4.3 +/- 1.4 h) was significantly (p less than 0.001) longer than the mean t1/2 (1.1 +/- 0.3 h); the GRT was prolonged compared with the t1/2 in each subject. In a randomized, crossover trial in 10 subjects, frequent feeding caused a dramatic prolongation in mean GRT of the capsule compared with the fasting state (greater than 14.5 vs. 0.5 h, p less than 0.005). In another crossover study in 6 subjects, the GRT of the capsule was evaluated after an overnight fast, a standard breakfast including solid food, and a liquid meal (i.e., 200 ml of diluted light cream). The mean GRT was 2.6 +/- 0.9 h after the liquid meal vs. 1.2 +/- 0.8 h after fasting (p less than 0.025). The mean GRT after the breakfast was 4.8 +/- 1.5 h, which was significantly greater than that after fasting (p less than 0.001) and after the liquid meal (p less than 0.01). These data suggest that the GRT of the Heidelberg capsule is a marker of the interdigestive migrating myoelectric complex in humans, the interdigestive migrating myoelectric complex can be markedly delayed by frequent feedings with solids, and the interdigestive migrating myoelectric complex is delayed by both liquid and solid meals.

Initial Evaluation of Transdermal Timolol: Serum Concentrations and β-Blockade

The serum concentrations and β-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 < 0.05 from pretreatment), and β-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 × −5.3: r = −0.92: p < 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.

A Comparative Pilot Study of Enalapril, A New Converting Enzyme Inhibitor, and Hydrochlorothiazide in Essential Hypertension

Abstract: Eight patients with essential hypertension completed a double‐blind, randomly allocated crossover comparison of either 5 or 10 mg enalapril maleate, 50 mg hydrochlorothiazide, or their combination administered once daily during sequential two‐week periods. Blood pressure, pulse rate, plasma renin activity, angiotensin‐converting enzyme activity, plasma aldosterone concentration, and urinary electrolytes were monitored for 24 hours after placebo and on days 1 and 14 of each treatment period. After two weeks of each treatment, only the combination of enalapril and hydrochlorothiazide significantly lowered the mean seated diastolic blood pressure (SDBP). Likewise, SDBP control (≤ 90 mm Hg) was achieved only after combination therapy; six of the eight patients were controlled by the combination for up to 24 hours. The initial SDBP response to combination therapy differed with the sequence of drug addition; however, by day 14 the responses were comparable, regardless of whether hydrochlorothiazide or enalapril was first given. Mean converting enzyme activity was suppressed by enalapril in all patients, though it did not always correlate with changes in SDBP or plasma aldosterone. Mean plasma renin activity increased, but the increase was significant only on the combination. There were no serious adverse effects.

Sulindac disposition when given once and twice daily

To investigate whether sulindac once daily in the evening might be equivalent to the currently recommended twice‐daily dose schedule in sustaining plasma concentrations of bioactive sulfide metabolite, 12 healthy subjects received, in a randomized crossover study, sulindac, 200 mg b.i.d. (at 9:00 A.M. and 9:00 P.M.) and 400 mg once daily (at 9:00 P.M.), each for 7 days. At steady state the area under the plasma concentration‐time curve (AUC) over 24 hr for sulfide metabolite was greater after once‐daily dosing (112 and 84μg · hr · ml−1, P < 0.05), while mean trough concentrations did not differ. The greater AUC seemed to be related to diurnal variation in metabolite cumulation. A circadian rhythm was apparent at steady state during twice‐daily dosing; the mean AUC and peak plasma concentration (Cmax) were greater between 9 A.M. and 9 P.M. than between 9 P.M. and 9 A.M. (50 and 34 μg · hr · ml−1; 6.85 and 4.23 μg/ml). Although Cmax values of sulfide were higher after morning doses of sulindac, it was apparent that much of the plasma sulfide after morning doses was actually derived from the previous evening dose. This may be a consequence of circadian rhythm in gallbladder emptying. While renal clearance of sulindac was related to urinary pH, diurnal changes in urinary acidity did not cause the fluctuations in plasma sulfide. Since once‐daily sulindac in the evening is as, if not more, effective than twice‐daily drug in sustaining plasma sulfide levels, further studies on the therapeutic efficacy of once‐daily dosing are warranted.

Amiodarone—benefits and risks in perspective

Amiodarone has recently emerged as an extraordinarily effective compound for the long-term prophylaxis of treatment-resistant supraventricular and ventricular tachyarrhythmias.‘-‘j Although the unique electrophysiologic actions of amiodarone were recognized in Europe over 10 years ago,7-s the drug has only recently attracted attention in the United States where its investigational use, particularly in the prevention of recurrent ventricular tachycardia and fibrillation, is rapidly growing. The results of initial studies in the U.S. have confirmed the European experience with regard to the drug’s clinical efficacy. Amiodarone causes marked suppression of complex ventricular ectopic activity and prevents the recurrence of ventricular tachycardia in 70% to 95% of patients, many of whom have experienced cardiac arrests despite treatment with two or more conventional antiarrhythmic agent.s.1-6 Comparable clinical efficacy has been shown in the management of supraventricular tachycardia, especially in association with the Wolff-ParkinsonWhite syndrome, and many investigators believe that the availability of amiodarone has considerably diminished the need for surgical treatment.” lo-l3 Beneficial responses have been maintained for up to 5 years in a few reported patients.5 Precisely how the antiarrhythmic effects of amiodarone are achieved is yet unclear. It appears, however, that its major cellular electrophysiologic effect is uniform prolongation of action potential duration with little effect on the rate of rise of the upstroke.14 In this respect, it is similar to bretylium tosylate and sotalol hydrochloride. Electrophysiologic studies in humans have disclosed that amiodarone increases the refractory periods of atria1 and ventricular myocardium, the AV node as well as accessory pathways.‘lv l5 It also significantly

Pharmacology of enantiomers and (-) p-OH metabolite of indacrinone.

Indacrinone, a racemic mixture, is a loop‐blocking diuretic with effects on uric acid elimination that differ from those of furosemide. A series of studies in healthy men was undertaken to characterize the pharmacologic activity of the positive (+) and negative (–) enantiomers (E) of indacrinone and its (–) p‐OH metabolite, (–) MET. All subjects were on sodium‐ and potassium‐controlled diet; each experiment was similar in design and included placebo and positive controls. Oral (–)E and (–)MET exerted dose‐related natriuretic and diuretic effects; intravenous doses of (–)E were more effective than (–)MET. The effects of (–)E and (–)MET on serum uric acid were the same as those reported with indacrinone. After (–)E, both (–)E and generated (–)MET appeared to contribute to the natriuresis. (+)E induced dose‐related decreases in serum uric acid up to 24 hr after dosage; at the higher doses of (+)E, the hypouricemic effects were of the order of those after 500 mg of probenecid. Thus, indacrinone is a novel loop diuretic with enantiomers and a (–)MET, each of which has a different pharmacologic profile.

Comparative Antihypertensive Effects of Enalapril Maleate and Hydrochlorothiazide, Alone and in Combination

Abstract: 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 < 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.

Clinical applications of angiotensin-converting enzyme inhibitors

Although only recently introduced, angiotensin-converting enzyme inhibitors have been utilized to treat a wide variety of clinical disorders. Their uses to date, approved by the Food and Drug Administration, have been in the treatment of refractory hypertension and congestive heart failure. However, they have been evaluated with mixed results in numerous other conditions in which the renin-angiotensin-aldosterone system may play a role. Their current status in the treatment of hypertension, congestive heart failure, and these other conditions is reviewed.

Characterization of Dexamethasone Binding in Normal and Uremic Human Serum

The purpose of this study was to examine the extent and linearity of dexamethasone binding over a wide concentration range in normal and uremic serum. Tritiated dexamethasone was added to both untreated and charcoal-treated pooled normal serum and to pooled uremic serum to produce concentrations similar to those attained therapeutically (10–1000 ng/mL). Protein binding was determined by equilibrium dialysis at 37°C. Dexamethasone serum binding was linear over the entire range of concentrations for each set of pooled serum. The mean (± SD) percent bound (mean ± SD) for dexamethasone was similar for untreated (75.1 ± 3.6 percent) and charcoal-treated (77.3 ± 3.5 percent) normal serum. Dexamethasone binding (69.2 ±1.8 percent, p<0.05) and serum albumin concentrations (39.9 vs. 55.1 mmol/L) were significantly less in uremic vs. normal serum, respectively. These results suggest that (1) the binding of dexamethasone is linear and occurs primarily to albumin, with little or no binding to corticosteroid-binding globulin; (2) endogenous cortisol does not compete with dexamethasone for protein binding sites; and (3) steroid pharmacokinetics may be altered in uremic patients due to the 24 percent higher free fraction of dexamethasone in this population.

Adrenocortical function after chronic inhalation of fluocortinbutyl and beclomethasone dipropionate

Fluocortinbutyl (FCB) is a C‐21 ester, topically active corticosteroid; no adrenal suppression has been noted after large doses. We compared safety and effects on adrenocortical function of orally inhaled FCB (40 mg/day), beclomethasone dipropionate (BDP) (2 mg/day), and placebo administered in four monitored divided doses for 4 wk by three groups of five healthy men. Circadian plasma Cortisol concentrations and daily urinary free cortisol excretion were determined before and after 3‐ and 4‐wk exposure. Although pretreatment mean area under the curve (μg · hr · dl−1) for plasma cortisol did not differ among groups, mean values after weeks 3 and 4 of treatment were lower (p < 0.05) in the BDP group (95.1 and 83) than in the FCB (155.8 and 153.7) and placebo (141 and 135.8) groups. Mean urinary Cortisol excretion after week 4 for the BDP group (29 μg) was less (p < 0.05) than in the FCB (59 μg) and the placebo (69 μg) groups. Slopes of individual regression lines noting time trends in plasma and urinary Cortisol in the BDP group were negative and less (p < 0.05) than those of the other groups. A cosyntropin test given intravenously after 4 wk of exposure resulted in similar plasma Cortisol responses among groups. No serious adverse effects were noted. Thus after long‐term high‐dose treatment BDP but not FCB suppressed basal adrenocortical function, but neither suppressed the adrenocortical response to cosyntropin.