Peter H. Vlasses

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.

Effect of food on the absorption of enteric-coated aspirin: correlation with gastric residence time.

The Heidelberg capsule is an indigestible indicator of gastrointestinal pH, which was used to evaluate the relationship between gastric residence time (GRT) and variability in aspirin absorption from enteric‐coated tablets. In a crossover study, eight healthy subjects (four men and four women) received an enteric‐coated aspirin (648 mg) together with a Heidelberg capsule while fasting or with food (breakfast, followed 4 hours later by lunch). Salicylic acid and salicyluric acid concentrations in plasma and urine were measured by HPLC. The mean (±SD) GRT was significantly delayed by food (0.8 ± 0.5 vs. 5.9 ± 3.3 hours; P < 0.005). The mean (±SD) lag time (TL) and time to peak concentration (expressed as salicylic acid equivalents) were markedly prolonged after the fed regimen (2.7 ± 0.8 vs. 8.9 ± 3.7 hours [P < 0.005] and 8.3 ± 2.9 vs. 13.8 ± 4.5 hours [P < 0.025]). For the combined data from the fasting and fed evaluations, an excellent correlation existed between TL and GRT of the capsule (TL = 1.0 GRT + 1.95; n = 16; r = 0.94; P < 0.0001). Women demonstrated greater delays in GRT and TL than did men. The delay in aspirin absorption from an enteric‐coated tablet is directly related to its GRT, which is gender related and greatly affected by food.

Captopril in severe treatment-resistant hypertension

Abstract The blood pressure of the majority of hypertensive patients can be controlled by sodium restriction and by one or at most two antihypertensive drugs. When the blood pressure does not respond, a widely recommended three-drug regimen is an oral diuretic, propranolol and hydralazine. 10 Our 16 patients had essential and renovascular hypertension and were refractory to all previous therapy. The majority had end-organ manifestations of severe hypertension such as left ventricular hypertrophy, renal impairment, retinopathy and neurologic sequelae. When they were placed on STT, their blood pressure remained uncontrolled (SDBP > 100 mm. Hg). Because of the resistance of their blood pressure to STT, all our patients were ultimately switched to captopril in an effort to achieve better control. According to the protocol, patients were hospitalized after stopping STT the night before. Captopril was started in a dose of 25 mg. and increased according to the response. After the first dose, no patient had a symptomatic hypotensive response though one patients SDBP did fall 6030 mm. Hg. The maximum response to the initial dose usually occurred by 30 minutes, rapid for an oral medication. This initial response was often greater than the response to subsequent doses, most likely due to the residual effects of STT. It is controversial as to whether the pretreatment PRA is a predictor of the response to captopril. 7, 12 In our study, it was not possible to determine PRA unifluenced by drugs on a controlled sodium intake because of the severity of the hypertension. PRA increased after captopril, a response consistent with interruption of negative feedback inhibition of renin release. 13 As a group, the patients blood pressure on captopril alone approximated that on STT, but no one was adequately controlled. The addition of a diuretic enhanced the effectiveness of captopril and in six of the 16 patients it resulted in satisfactory blood pressure control. Several of these patients who had hypertension in association with renal artery stenosis, howeve, manifested an upright tachycardia. Worsening of angina pectoris occurred in one man and he and another woman developed subendocardial myocardial infarctions; the role of the tachycardia in the precipitation of these events is unclear. Nonetheless, diuretic-induced volume depletion with blockade of the renin-angiotensin system by captopril may cause standing tachycardia, which may constitute a problem in patients with compromised coronary or cerebral circulation. In this regard, two of the eight patients in Group 2, though well controlled on captopril and diuretic, had propranolol added in small doses (40 mg./day) to control symptomatic standing tachycardia. In the other six patients in this group, blood pressure was normalized by this new three-drug regimen and the regimen was well tolerated. Two patients (Group 3) could not be controlled even with this regimen, and were considered treatment failures. It is of interest that propranolol produced additional blood pressure lowering in the presence of captopril, which supports a hypotensive action of propranolol not due wholly to blockade of renin release. 14 In general, captopril was well tolerated; a number of patients remarked how much better they felt on captopril as compared to their previous regimens, especially with regard to central side effects. Five patients manifested a maculopapular and pruritic rash, but in only one did discontinuation of captopril prove necessary. In three patients, the rash disappeared in 7 to 10 days with only a temporary reduction of captopril dosage. Two men developed a loss of taste which similarly resolved despite continuation of captopril. No other adverse effects have been noted in our patients. Renal function was maintained, as serum creatinine did not change during the study. Captopril-induced proteinuria has been reported since the start of our study, 15 but could not be documented retrospectively in our patients. However, continued surveillance of captoprils side effects, especially proteinuria, is necessary. In summary, in our three month trial, captopril appears to provide a useful and important alternative for the management of severe, refractory hypertension. Its mechanism of action seems to be ideal for such patients in whom the renin-angiotensin system appears to play an important role. Although alone it was insufficient to adequately control the blood pressure in our severely hypertensive patients, its combination with a diuretic or a diuretic and a beta-blocker often provided an effective and well-tolerated combination. Nevertheless, even with the latter three-drug combination, there were two treatment failures. Adverse effects such as skin rash, which occurred in 30% of our patients, and loss of taste, do not seem to seriously limit the use of the drug. The development of a sustained standing tachycardia when a diuretic is added to captopril may be harmful in some patients with a compromised cardiovascular system and requires careful consideration before treatment. Addition of low doses of beta-adrenergic blocking agents, if not contraindicated, will control these heart rate increases. The benefits and hazards of long-term captopril therapy in severe hypertension requires further assessment.

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.

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.

MECHANISM OF GASTRIC EMPTYING OF A NONDISINTEGRATING RADIOTELEMETRY CAPSULE IN MAN

We studied the mechanism of gastric emptying of a pH-sensitive radiotelemetry capsule with respect to phases of the interdigestive migrating motor complex (IMMC) in fasting normal volunteers and the effect of the Heidelberg capsule (HC) on the duration or timing of the IMMC phases. A manometric catheter with eight mounted solid-state strain gauges was passed transnasally and positioned fluoroscopically in the duodenum and jejunum in four normal, fasted male volunteers, in their right lateral position. The HC was administered orally following the establishment of one complete IMMC cycle (defined by the recording time between the end of two subsequent phase III activity fronts) and during the beginning of Phase I of the next cycle. The gastric residence time (GRT) of the HC was measured as the time of a gastric pH rise of ≥3.0 units. In three subjects, GRT of the HC lasted to within 5 min of the onset of the next duodenal phase III of the IMMC, while in the fourth subject, the HC passed during the second phase III activity front. There were no significant differences in the duration of each phase of duodenal IMMC in the presence or absence of the HC (Phase I, 54 ± 9.3 vs 31.6 ± 10.1; Phase II, 22 ± 8.1 vs 58.9 ± 32; Phase III, 5.3 ± 0.7 vs 4.2 ± 0.7 min; mean ± SE; P > 0.1 in all phases). In addition, the HC had no effect on motility index or patterns of contractions. The Heidelberg radiotelemetry device (7 × 20 mm) may be used as a noninvasive, nonradioactive means of measuring the activity of the IMMC and the presence of Phase III peak IMMC activity. Further, it permits detailed evaluation of the emptying patterns of solid dosage forms (i.e., enteric-coated tablet or controlled-release matrix) in humans under fasted or fed conditions.

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.

Angiotensin‐Converting Enzyme Inhibitors: Mechanistic Controversies

Many studies have investigated the mechanisms responsible for the therapeutic effects of the angiotensin converting enzyme inhibitors. Initially, the hemodynamic changes that occur with these agents were attributed solely to the inhibition of the renin‐angiotensin‐aldosterone system in plasma. Further research suggested other mechanisms were operable as a relationship was not always evident between hemodynamic changes and inhibition of the plasma renin‐angiotensin‐aldosterone system. A relationship between the pharmacodynamics of these agents and the inhibition of vascular and tissue renin‐angiotensin systems, however, has been observed. Mechanisms less likely to contribute to the actions of the angiotensin converting enzyme inhibitors are increases in bradykinin and prostaglandin concentrations, or inhibition in the renin‐angiotensin system within the central nervous system. Ancillary cardiovascular effects of angiotensin converting enzyme inhibitors offer possible new therapeutic gains. An understanding of these mechanistic controversies and newly‐defined cardiovascular actions of angiotensin converting enzyme inhibitors are important to clinicians using these agents.

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.

Double-blind comparison of captopril and enalapril in mild to moderate hypertension

To compare the antihypertensive and humoral effects of the angiotensin-converting enzyme inhibitors captopril and enalapril, 20 patients with essential hypertension, not receiving treatment for 2 weeks and consuming a prescribed sodium ion intake, were randomly assigned to two parallel, double-blind treatment groups with stratification based on race and untreated seated diastolic blood pressure. These groups received a placebo (day -1) followed by either captopril, 200 mg every 12 hours (n = 9), or enalapril maleate, 20 mg every 12 hours (n = 11), alone (days 1 to 14) and then with hydrochlorothiazide, 25 mg every 12 hours (days 16 to 28). Captopril and enalapril were coadministered alone (day 15) and with hydrochlorothiazide (day 29) to assess whether further decreases in blood pressure would occur. Captopril and enalapril alone caused comparable decreases (p less than 0.05) in the mean 12 hour time-averaged seated diastolic blood pressure from values on day -1 (placebo), on day 1 (11 and 9 mm Hg, respectively) and day 14 (8 and 7 mm Hg, respectively). The addition of hydrochlorothiazide further decreased (p less than 0.05) blood pressure in each group (7 and 8 mm Hg, respectively) from values on day 14. Combined use of captopril and enalapril did not result in further reduction. Coupled with the comparable changes observed in each treatment group in serum angiotensin-converting enzyme activity, plasma renin activity and plasma aldosterone concentration, these data support the view that captopril and enalapril have similar antihypertensive effects and mechanisms.