Parviz Mojaverian

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.

Effects of Gender, Posture, and Age on Gastric Residence Time of an Indigestible Solid: Pharmaceutical Considerations

We have recently reported the effect of varying food composition on the gastric residence time (GRT) of an indigestible solid, the Heidelberg capsule (HC). The purpose of the present evaluation was to evaluate the reproducibility and the effect of gender, posture, and age on the GRT of the HC. The reproducibility in measurement of the GRT of the Heidelberg capsule was evaluated in two trials separated by 1 week. Mean GRT values obtained in nine healthy men on day 1 were not statistically different from those on day 8 (3.5 ± 0.6 vs 3.5 ± 0.7 hr, P > 0.05). To evaluate the influence of gender on the GRT of the HC, 12 healthy male volunteers and 12 age (±3 years)- and race-matched female counterparts entered into a randomized study. Each subject was served a standardized 500-kcal breakfast 30 min prior to oral ingestion of the HC. The mean (± SD) ambulatory GRT in the males was significantly faster than in the females (3.4 ± 0.6 vs 4.6 ± 1.2 hr, P < 0.01). Influence of posture on the GRT of HC was examined in the same 12 men in a two-way, randomized, crossover study. The mean GRT for volunteers in the supine state was not statistically different from that in the upright, ambulatory state (3.4 ± 0.8 vs 3.5 ± 0.7 hr, P > 0.05). The effect of age on the GRT of the HC was evaluated in 12 healthy elderly males (>65 years) with no prior gastrointestinal complications. The mean value of the GRT 30 min after a 500-kcal breakfast was significantly prolonged compared to that of the young male volunteers (4.5 ± 1.1 vs 3.4 ± 0.6 hr, P < 0.02). A larger GRT is consistent with the results of gastric emptying of a digestible solid in the elderly, reported by other investigators. In summary, the data indicate that even when the hormonal changes due to the menstrual cycle are normalized, women emptied their stomach slower than men, regardless of weight, height, or body surface area. In addition, the GRT of an indigestible capsule was prolonged in the elderly, especially in subjects >70 years old.

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.

Gastrointestinal transit of a solid indigestible capsule as measured by radiotelemetry and dual gamma scintigraphy

The objectives of the present study were to evaluate gastric and small bowel transit times of an indigestible solid matrix and to characterize the specific changes in intraluminal pH as a function of transit time through the gastrointestinal tract. Particular attention was paid to the lag time at the ileocecal junction. A Heidelberg capsule (HC), labeled with 10 µCi Indium-111, was given orally to six healthy male subjects 15 min after oral ingestion of 100 µCi of 99mTc-sulfur colloid as a liquid fatty meal (4 ml/kg). Intraluminal pH was monitored continuously via the HC. Gastric and small bowel transit of the radionuclides was monitored via external scintigraphy at 0.5-hr intervals. Gastric residence times (GRT) of the HC ranged from 2.8 to 4.8 hr, with a mean (±SD) of 3.6 ± 0.8 hr. These values were independent of the individuals weight, height, or body surface area. Small bowel transit times of the HC ranged from 2.8 to >5.5 hr, which were consistent with the reported values of 3 to 5 hr. The lag times of the HC at ileocecal junction ranged from 0.8 to >2.5 hr. The presence of the lag times at the ileocecal junction in all subjects confirmed that it acts as a valve or sphincter. Mouth-to-cecum transit times of the HC occurred within 9.0 hr in 50% of the subjects. In general, following a sharp rise upon pyloric passage of HC the pH dropped slightly but then increased linearly throughout the small intestine. The mean duodenal pH was 5.8 ± 0.8 and the pH at the ileocecal junction ranged from 6.5 to 8.5, with a mean of 7.3 ± 0.7. Passage through the ileocecal junction was associated with a 0.5- to 1.0-unit rise in pH in three subjects who exhibited passage of the HC into the large bowel within the study period. The present data may have implications in the designing of more effective dosage forms with specific delivery to proximal or distal small bowel regions.

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.

Application of Radiotelemetric Technique in Evaluating Diclofenac Sodium Absorption After Oral Administration of Various Dosage Forms in Healthy Volunteers

A radiotelemetric technique with the Heidelberg capsule (HC) was used to improve the quality of data generated in a bioavailability study involving an enteric-coated (EC) formulation. Further, changes in plasma levels of the drug from other dosage forms were related to changes in the pH environment as determined by the HC. Eight healthy male subjects received the following treatments, 15 min after a light breakfast, according to a randomized, four-way crossover design: (A) HC and 75 mg of a diclofenac sodium aqueous buffered solution; (B) HC and one 75-mg Voltaren EC tablet; (C) HC and one 100-mg Voltaren slow-release (SR) tablet; and (D) HC alone. Each treatment was separated by a 1-week washout period. Two additional subjects subsequently received Treatment B only. Multiple peaks were observed in the drug plasma level–time profiles for the buffered aqueous solution which, in all cases, occurred before gastric emptying of the HC. The multiple peaks were not observed for the Voltaren SR tablet, but a variable absorption lag time occurred which coincided with the gastric residence time of the SR tablet. For the EC tablet the variability of individual plasma level–time profiles was drastically reduced when the time after dosing was adjusted to coincide with gastric emptying of the HC. Finally, the lag time between gastric emptying of the EC tablet and the onset of drug absorption was consistently at 1 hr for all subjects. This lag time was longer than the in vitro disintegration or dissolution times measured under USP conditions.

Elevation in analgetic effect and plasma levels of morphine by desipramine in rats

Abstract Pretreatment of rats with desipramine (30 mg/kg, s.c.) enhanced both peak intensity and duration of morphine sulfate (5 mg/kg s.c.) analgesia as determined by measurement of tail flick latency. Morphine concentrations in plasma were also significantly elevated after desipramine. Increased narcotic analgetic responses following desipramine pretreatment appear related to higher circulating levels of unmetabolized morphine.

An optimized fluoroenzymatic assay for the determination of angiotensin converting enzyme inhibitors in biological fluids

An easy, analytically sound fluoroenzymatic assay for angiotensin converting enzyme (ACE) inhibitors is described. Drug samples and standards are extracted with methanol and evaporated to dryness. Drug residues are then incubated with the substrate N-benzyloxycarbonyl-phenyllanyl-l-histidyl-leucine and human plasma ACE at 37 degrees C, pH 7.65, for 1 h. Fluorescence of the o-phthaldialdehyde derivatized product is measured at wavelengths of 365 nm (excitation) and 490 nm (emission). A computer program converts fluorescence to percent of ACE activity inhibited and correlates this percent inhibition with drug concentration. The ester prodrug enalapril (MK-421) was measurable at levels of a 1 ng ml(-1) in serum after base hydrolysis to enalaprilat. Lowest reliable detection limits for enalaprilat (MK-422) and lisinopril (MK-521) in serum were 0.7 ng ml(-1). This method is easily adapted to most other ACE inhibitors, is well suited to automation and avoids the use of radioactivity.

Cimetidine versus famotidine: the effect on the pharmacokinetics of theophylline in rats

SummaryThe 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 a n d 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 a n d analyzed for theophylline concentration by HPLC. Concomitant famotidine administration did not alter any of the pharmacokinetic parameters of theophylline (AUC0-∞; 38.1±8.7 vs. 38.8±6.3 μg.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<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. 1 3 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.

The Effect of Amiodarone on Theophylline Pharmacokinetics in the Rat

Amiodarone is an investigational antiarrhythmic agent which has been implicated in reducing the activity of the hepatic mixed-function oxidase system. To evaluate this effect further, two groups of six male Sprague–Dawley rats each received theophylline (6 mg/kg, iv) preceded by either normal saline or amiodarone HC1 (100 mg/kg, iv). Blood samples were obtained serially for a period of 6 hr and the sera were assayed for theophylline by high-pressure liquid chromatography (HPLC). In rats pretreated with amiodarone, a significant 45% reduction in the mean (± SD) systemic clearance [0.057 (0.010) vs 0.031 (0.004) liter/hr/kg, P < 0.001] and a greater than 100% increase in the mean elimination half-life [2.03 (0.46) vs 4.29 (0.71) hr, P < 0.001] of theophylline were observed. These data demonstrate an acute inhibitory effect of amiodarone on the hepatic microsomal enzyme system.