Sulfamethizole capsules containing contrast medium for assessment of gastric emptying in functional dyspepsia patients.

The usefulness of sulfamethizole capsules containing contrast medium in gastric emptying tests for functional dyspepsia was evaluated in five healthy volunteers and nine patients with dysmotility-like symptoms. Each subject swallowed 15 capsules with a liquid, food, and at 0, 15, 30, 45, 60, 90, and 120 min, the capsule position and size were monitored fluoroscopically for 30 sec and radiograms were obtained. Blood sulfamethizole concentrations were also measured at the same time. Visualized capsule movement from the proximal to distal stomach up to 60 min was faster in the patients, whereas in the later digestion period, proximal stomach emptying in the patients was delayed significantly (P < 0.05), and the number of capsules remaining in the distal stomach at 120 min was significantly larger in the patients (P < 0.05). This test method was evaluated as being useful in monitoring solid emptying in normal and pathophysiologic conditions.

Sulfamethizole absorption test for the assessment of gastric emptying. Comparison with scintigraphic method.

BACKGROUND: To investigate whether the sulfamethizole absorption test can be applied for the assessment of gastric emptying, we measured comparatively plasma sulfamethizole concentration and gastric emptying as determined by scintigraphy in 15 subjects. METHODS: After the ingestion of a solid-liquid meal that contained sulfamethizole and radioisotope (technetium-99m-labeled diethylenetriaminepentaacetic acid), the plasma sulfamethizole concentrations were measured every 15 to 60 min up to 180 min. The initial emptying time (duration after ingestion until 10% reduction in radioactivity of the stomach) and the exponential curve in the cumulative reduction of radioactivity were used as indicators of gastric emptying. RESULTS: The initial emptying time was significantly correlated with the sulfamethizole concentration at 15 min after ingestion (r = -0.64, p < 0.05). A close correlation was observed between the rate of decrease in radioactivity and sulfamethizole concentration at 60 min after ingestion (r = 0.80, p < 0.001). CONCLUSIONS: The sulfamethizole absorption test can be used for the evaluation of gastric motility. Two points of measurement, 15 and 60 min after ingestion, are sufficient to demonstrate the initial and subsequent gastric emptying.

Sulfamethizole capsule method. A new method for assessing gastric emptying of solids.

We have developed a new method that is capable of assessing gastric emptying in humans. This method is based on the rapid absorption of sulfamethizole in the upper small intestine. Sulfamethizole capsules are gelatin capsules that are filled with a solid composed of egg albumin and sulfamethizole. After subjects ingested of 15 capsules with ham and bread, blood concentrations of sulfamethizole were measured and the areas under the sulfamethizole concentration-time curve (AUC) were calculated as an index of gastric emptying. After ingestion of 99mTc-labeled sulfamethizole capsules, there was a statistically significant correlation between the percentage of radioactivity remaining in the stomach at 120 min and AUC for 120 min (r = -0.82, P < 0.01). This method yielded a reliable value for gastric emptying of a solid meal as estimated by AUC. This method can be considered safe and is easily applicable to human subjects for assessment of gastric emptying.

Kinetic studies on drug disposition in rabbits. II. Dose dependent pharmacokinetics of sulfamethizole.

In order to evaluate dose-dependent sulfamethizole (SMZ) kinetics, 100, 300 and 1000 mg of SMZ was constantly infused over 5 min in rabbits and thereafter plasma and urine samples were collected at convenient intervals. When a dose of 100 mg was given, the time course of total plasma concentration followed a biexponential characteristic. For higher doses, plasma decay curves revealed a convex descending feature after the distribution phase. The respective unbound fraction in plasma (fp) at the total plasma concentrations of 200 and 100 micrograms/ml were 0.41 and 0.19. The corresponding total body clearances were 2.6 and 2.2 l/h, indicating that the drug elimination did not contribute to the convex-descending plasma curves. A physiologically based pharmacokinetic model was adapted to various tissue levels of SMZ. No saturable tissue binding was observed and the apparent volume of distribution of SMZ at steady state with a rabbit of 3.3 kg, Vss (1), calculated by tissue volumes and partition coefficients of tissue to unbound plasma was expressed as follows: Vss = 0.14 + 1.86fp. From this relationship, it was shown that the apparent volume of distribution of SMZ was significantly affected by the unbound fraction in plasma and the dose-dependent kinetics after intravenous administration was due to the decrease of the apparent volume of distribution with time. The tissue distribution study contributed significantly to the understanding of the dose-dependent drug kinetics.

Kinetic studies on drug disposition in rabbits. I. Renal excretion of iodopyracet and sulfamethizole.

In order to quantify the renal handling of iodopyracet (IOD) and sulfamethizole (SMZ), single-drug clearance studies in rabbits were performed under quasi-steady state conditions with stepwise increasing the infusion rate of IOD or SMZ. Although concentration dependence of plasma protein binding was observed for both drugs, the urinary excretion rate of IOD was proportional to its total plasma concentration at low total plasma concentrations of 0.05-0.8 mM. On the other hand, the relationship between urinary excretion rate and total plasma concentration of SMZ was a concave-ascending curve at low plasma concentrations and the renal clearance of SMZ was sensitive to changes in plasma protein binding. However, renal clearances referenced to unbound plasma concentration at total plasma concentrations of 0.05 mM for IOD and SMZ were 9.5 and 38 l/h, respectively. Those values were much greater than the effective plasma flow in rabbits. These facts indicated that the intrinsic clearances at the sites of tubular secretion were high and that the rates of secretion were fully or partially limited by the renal plasma flow. Furthermore it was suggested that unbound drug was liberated from plasma protein at the sites of tubular secretion. The data obtained at high plasma concentrations indicated that the tubular secretion of IOD had capacity limited characteristics and that the urinary excretion of SMZ involved tubular reabsorption as well as saturable tubular secretion. From the data obtained, a perfusion-limited pharmacokinetic model was constructed characterizing the excretory processes, namely, glomerular filtration, passive tubular reabsorption, saturable tubular secretion and reequilibrium between bound and unbound drugs in plasma. For both drugs, the estimates for bulk flow rate were reasonable values of effective renal plasma flow and the dissociation constants for tubular secretion agreed well with those for in vitro renal cortex accumulation, suggesting that the kinetic model based on physiological concepts was useful for the understanding of the drug elimination processes.

Drug binding properties of neonatal albumin.

Neonatal and adult albumin was isolated by gel chromatography on Sephacryl S-300, from adult and umbilical cord serum, respectively. Binding of monoacetyl-diamino-diphenyl sulfone, warfarin, sulfamethizole, and diazepam was studied by means of equilibrium dialysis and the binding data were analyzed by the method of several acceptable fitted curves. It was found that the binding affinity to neonatal albumin is less than to adult albumin for monoacetyl-diamino-diphenyl sulfone and warfarin. Sulfamethizole binding to the neonatal protein is similarly reduced when more than one molecule of the drug is bound per albumin molecule, and binding of the first sulfamethizole molecule is possibly reduced as well. Diazepam binds with equal affinity to the fetal and adult proteins. Among the two main albumin drug-binding functions, for warfarin and diazepam, the former is thus compromised in the newborn infant while the diazepam binding function is at the adult level.

[A new device for the gastric emptying test--a sulfamethizole capsule food method].

We have developed a simple but reliable method for assessing gastric emptying, a sulfamethizole capsule food method. The capsule food contains egg albumin and sulfamethizole. In saline or hydrochloride solution only a small amount of sulfamethizole, in sodium bicarbonate solution, however, a large amount of the drug was released from the capsule food. In this method, sulfamethizole concentrations in blood were measured in subjects after ingestion of 15 pieces of capsule food containing 1.0 g of sulfamethizole, and area under the curve of the blood concentrations was calculated as an index of gastric emptying. Gastric emptying of capsule food had a lag phase of 15 minutes, which was already reported in gastric emptying of radioisotope labeled solid food. Bread combined with the capsule food caused a delay in gastric emptying and a larger volume of the bread was associated with a longer gastric emptying time. In conclusion, our sulfamethizole capsule food method is useful in clinical practice to assess gastric emptying of solid food.

Quantitative investigation of renal handling of drugs in dogs with renal insufficiency.

A quantitative analytical method for studying renal handling of drugs in dogs with mild renal impairment is described. Renal damage was induced experimentally by pretreatment with mercuric chloride or neomycin. Analytical results of renal handling in those animals indicated a reduction in maximum transport of secretion, while the affinity of drugs to secretion site and reabsorption showed slight or no change. These results were consistent qualitatively with other renal function test values which demonstrated the state of glomerular or proximal renal tubular function. Evidence for the applicability of the proposed analytical method for quantitative validation of functional changes in the nephron in renally impaired animals, as well as the precise determination of the site of damage, was demonstrated. This work holds considerable promise for the study of dosage adjustments in patients with renal disease.

Antibacterial activity of nitroxoline and sulphamethizole alone and in combination in urinary tract infections.

In vitro studies on the antibacterial activity of nitroxoline and sulphamethizole, alone and in combination, were undertaken and minimal inhibitory concentrations (MICs) determined on a range of urinary pathogens. Eighty per cent of the strains tested were sensitive to less than or equal to 16 mg/l of nitroxoline, and all strains, including Pseudomonas aeruginosa and Streptococcus faecalis, were sensitive to less than or equal to 64 mg/l of nitroxoline. No synergism could be demonstrated with sulphamethizole, but the combination was antagonistic when tested against strains of Ps. aeruginosa and Strep. faecalis. An in vivo study on 10 volunteers showed excellent urinary levels of nitroxoline and sulphamethizole after an oral dose of 160 mg of each agent, and 6-hour urinary nitroxoline levels were greater than or equal to 64 mg/l in 9 of the 10 subjects, and sulphamethizole levels were greater than or equal to 64 mg/l in all 10 subjects. Laboratory findings suggest that nitroxoline and sulphamethizole are both suitable agents for use in urinary tract infections caused by organisms sensitive to these agents, but there appears to be litte advantage in using them in combination.

Bioavailability of sulfonamide suspensions I: Dissolution profiles of sulfamethizole using paddle method.

A comparative bioavailability study was performed using two commercially available, chemically equivalent brands of sulfamethizole suspension. One gram of each suspension was administered to 12 different subjects following a completely randomized crossover design. Serum levels and derived pharmacokinetic parameters were compared statistically. There were no significant differences in the extent of sulfamethizole absorption from the two suspensions as evidenced by the area under the serum level--time curves. Significant differences (p less than 0.05) in the mean serum levels at 0.5 and 0.75 hr and differences in Cmax and tmax indicated that the absorption rate differed for the two products. In vitro tests including particle-size analysis and dissolution studies were performed. The size--frequency distribution of particles in the suspensions was studied using a resistance particle counter. The dissolution characteristics of the two products were studied using the Food and Drug Administration's paddle method and the spin-filter apparatus. Suspension A had a significantly greater amount of drug dissolved at 15 and 30 min using either method. It also had a greater percentage of particles at the smaller size range, indicating that the greater dissolution rate may be related directly to the decreased particle size. A comparison of the in vivo and in vitro results demonstrated a definite rank-order correlation between the dissolution performance of the two suspensions and the in vivo parameters reflecting the absorption rate. Suspension A had a greater amount of drug dissolved at 15 and 30 min and resulted in higher serum levels at 0.5 and 0.75 hr, a higher Cmax, and a shorter tmax.

Effect of exercise on the serum level and urinary excretion of tetracycline, doxycycline and sulphamethizole.

The serum level and urinary excretion of sulphamethizole, tetracycline and doxycycline were studied in healthy volunteers subjected to intensive exercise and bed rest in a cross-over trial. Each group consisted of 7--8 subjects. The exercise or bed rest began 15 min before oral administration of the drug and was continued for the following 4 hours. During exercise serum drug concentration and the area under the serum concentration-time curve for each agent was significantly higher (p less than 0.05) than the corresponding values at rest. Exercise greatly suppressed the renal excretion of tetracycline and doxycycline, but the decrease alone appeared insufficient to account for the pronounced increase in serum drug concentration. Total drug excretion in urine was unchanged. Thus, it seemed most unlikely that overall absorption from the gastrointestinal tract had been altered by exercise. However, the rate of absorption appeared to be more rapid in the exercise than in the rest period. Marked haemoconcentration was not produced by the exercise. In addition to changes in absorption and elimination rates, alteration in the volume of distribution might contribute to the higher serum drug concentration during exercise. Therefore, the level of physical activity should be considered in the interpretation of pharmacokinetic data both in clinical practice and in pharmacokinetic studies.

Comparative bioavailabilities from truncated blood level curves.

The period of time after administration over which blood level measurements are required to obtain a reliable bioavailability comparison of two or more formulations of the same drug was considered by the analysis of bioavailability data taken from the literature. The drugs examined, selected to represent a range of absorption and elimination half-lives, were acetaminophen, aminosalicylic acid, chloramphenicol, chlordiazepoxide, digoxin, isoniazid, phenylbutazone, sulfamethizole, tetracycline, and warfarin. For most drugs, ratios of areas under the curve changed little between the end of the absorption period and the time when blood sampling was terminated. Reliable bioavailability comparisons among different brands of the drugs apparently could have been made by blood sampling over 24 hr or less.

Application of electrophoresis for separation of trimethoprim and sulphamethoxazole in combined therapy.

Determination of the concentration of each drug in the combination trimethoprim: sulphamethoxazole was performed in patient sera by separation of the drugs by electrophoresis in agarose-gel followed by microbiological assay. The electrophoretic method was equivalent to the methods used in the routine and showed good reproducibility,