Comparative study of interactions between 4-biphenylacetic acid and sulfamethizole, and between fenbufen and sulfamethizole in rats.
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Adverse pregnancy outcome in users of sulfamethizole during pregnancy: a population-based observational study.
OBJECTIVE: To estimate the risk of adverse birth and neonatal outcome, and miscarriage in women who used sulfamethizole during pregnancy. METHODS: The association between use of sulfamethizole and adverse birth and neonatal outcome was investigated in a case-control and a cohort study in Denmark. We used data from the Prescription Database, the Birth Registry and the Hospital Discharge Registry in North Jutland County to study any association between sulfamethizole use and first recorded miscarriage. The cohort analysis included 3484 women who received a prescription for sulfamethizole from 30 days before conception to date of delivery, and 60175 women who did not use a sulphonamide-containing drug during pregnancy or 30 days before conception. The case-control analysis included 3347 women who had a miscarriage, of whom 90 had taken sulfamethizole, and 22599 primiparous controls who had a live birth. RESULTS: Among women who received prescriptions for sulfamethizole, adjusted odds ratios and 95% confidence intervals for adverse birth outcome were: malformation 1.17 (0.95-1.43); low birth weight 0.69 (0.49-0.98); pre-term birth 1.12 (0.97-1.30); stillbirth 1.02 (0.61-1.68); neonatal jaundice 1.14 (0.38-3.46); and for receiving a prescription for sulfamethizole within 1 week before miscarriage 1.66 (0.92-2.99). CONCLUSIONS: We found no increased risk of congenital malformation, stillbirth or pre-term birth, and no association between use of sulfamethizole late in pregnancy and risk of neonatal jaundice. There was an increased risk of miscarriage after exposure to sulfamethizole during the week before miscarriage, but further studies are needed to evaluate whether this increased risk is causal.
Abnormalities, Drug-Induced↗
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.
Female↗
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.
Adult↗
Improvement of water solubility of sulfamethizole through its complexation with beta- and hydroxypropyl-beta-cyclodextrin. Characterization of the interaction in solution and in solid state.
The aim of this study was to increase the solubility of sulfamethizole in water by complexing it with beta-cyclodextrin (BCD) and hydroxypropyl-beta-cyclodextrin (HPBCD). The interaction of sulfamethizole with the cyclodextrins was evaluated by the solubility, 1H NMR spectrometry and molecular modelling. The stability constants calculated from the phase solubility method increase in order HPBCD<BCD. From the NMR studies could be concluded that the sulfamethizole:cyclodextrin mole ratio was 1:1 (mol/mol) in the BCD complex and 2:3 (mol/mol) in the HPBCD complex. In both cases the sulfamethizole moiety included in the cyclodextrin was the thiadiazole group. MM2 calculations, either in vacuum or in the presence of a solvent, support this structure. Solid inclusion complexes of sulfamethizole with BCD and HPBCD were obtained by freeze drying 1:1 (mol/mol) solutions in aqueous ammonium hydroxide. Host-guest interactions were studied in the solid state by powder X-ray diffractometry and differential scanning calorimetry. The dissolution rates of sulfamethizole increased by the complexation with BCD or HPBCD.
2-Hydroxypropyl-beta-cyclodextrin↗
[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.
Gastric Emptying↗
Studies on drug-milk freeze-dried formulations. I: Bioavailability of sulfamethizole and dicumarol formulations.
In this study, solid dispersion formulations of dicumarol (3,3'-methylenebis[4-hydroxycoumarin]) and sulfamethizole (N'-(5-methyl-1,3, 4-thiadiazol-2-yl)sulfanilamide) in defatted milk were prepared by freeze-drying. X-ray crystallographic data showed that both drugs were dispersed in the formulations in an amorphous state. Bioequivalency comparisons between freeze-dried formulations, after regeneration with water, and control capsules containing the pure drug substances were studied in four male volunteers. Determination of the plasma dicumarol levels indicated superiority of the dicumarol-milk formulation. Statistically significant differences were found between area under the curve, maximum plasma concentration, and apparent elimination rates. Analysis of the urine sulfamethizole data revealed that the two formulations exhibit statistically equivalent rates and extents of excretion of unchanged sulfamethizole. The binding of both drugs to casein and their solubility in the presence of casein were measured in vitro. The presence of casein caused an increase in the solubility of dicumarol, while it had no effect on the solubility of sulfamethizole. Normal protein binding cannot be responsible for the effects noted. Extrapolation of the in vitro data to the in vivo situation was attempted. Drug-milk freeze-dried formulations are promising for the enhancement of the bioavailability of sparingly water soluble drugs.
Adult↗
Effects of sulfamethizole and amdinocillin against Escherichia coli strains (with various susceptibilities) in an ascending urinary tract infection mouse model.
Resistance to antibiotics used for the treatment of urinary tract infections (UTIs) is increasing worldwide. The impact of in vitro resistance on clinical outcome in UTIs requires further study, since most studies of both humans and animals have evaluated only the efficacy of antibiotics toward bacteria susceptible in vitro. We were interested in evaluating the relationship between the in vitro antibacterial effect and the in vivo efficacy after antibiotic treatment. We simulated a natural ascending UTI by use of the ascending UTI mouse model and used Escherichia coli strains with various susceptibilities to amdinocillin (mecillinam) and sulfamethizole. Mice were treated for 3 days with antibiotic doses approximating human urinary tract concentrations after a standard oral dose. For a susceptible strain (MIC, 0.5 micro g/ml) and a resistant strain (MIC, 128 micro g/ml), respectively, there were significant reductions in bacterial counts in the urine, bladder, and kidneys after treatment with amdinocillin, whereas for a strain for which the MIC was 16 micro g/ml, there was a significant reduction in bacterial counts in the kidneys only (P < 0.05). Treatment with sulfamethizole resulted in a significant reduction in bacterial counts in all samples from a susceptible strain (MIC, 128 micro g/ml) and a resistant strain (MIC, 512 micro g/ml). Infection with a sulII gene-positive strain (MIC, >2,048 micro g/ml) could not be treated with sulfamethizole, as no effect could be demonstrated in the urine, bladder, or kidneys. For amdinocillin, there was no clear-cut relationship between the in vitro susceptibility and the in vivo outcome, while for sulfamethizole, we found a relationship between the MIC for the strain and the effect in the urinary tract.
Amdinocillin↗
Measurement of sulfamethizole clearance rate by nonthrombogenic constant blood-withdrawal system.
A method for the measurement of the total body clearance rate (CR) of drugs is described. It involves a single intravenous injection of a known quantity of the drug (D) and automatic integration of the plasma concentration curve, using a portable, nonthrombogenic, constant blood-withdrawal system. When blood withdrawal is carried out until the concentration of the drug in the plasma approaches zero, the concentration of the drug in the collected pool, the integrated concentration (ICT) multiplied by the time of collection (T) yields the integral of the concentration curve: (see article). The method was tested by measuring the clearance rate of sulfamethizole in five dogs by the established constant infusion method. At three plasma levels (25, 75, and 200 mg/liter), the plasma concentration had no significant effect on the clearance rate. The clearance rate of sulfamethizole was subsequently measured in the same dogs by the new single-injection constant withdrawal method. Multiple blood samples were collected at 15-min intervals simultaneously with the constant withdrawal of blood. There was no significant difference between the clearance rate of sulfamethizole measured by the two methods. The initial peak mean concentration of the drug from the time of injection (t = 0) to the time of the first blood sampling (t = 15 min) was calculated from the difference between (see article) obtained by the constant withdrawal method and that obtained from the results of the multiple blood withdrawals by the trapezoidal rule. The integrated concentration IC15 was significantly higher than its estimation by the semilogarithmic linear regression method.
Animals↗
Double blind comparison of short and medium term sulfonamides, sulfamethizole and sulfamethoxazole, in uncomplicated acute urinary tract infections.
Sulfamethizole and sulfamethoxazole were compared in a prospective, randomized, double blind study on uncomplicated, acute urinary tract infections. 59 patients were evaluable for therapeutic effect of sulfamethizole and 53 for sulfamethoxazole. The cure rates were 91.5 and 92.5% respectively for sulfamethizole and sulfamethoxazole. The rates of side effects were the same in the two groups, 5.4% and 4.2%. Also instances where the infecting bacteria were sulfonamide-resistant were cured.
Acute Disease↗
Sulfamethizole-induced inhibition of diphenlhydantoin, tolbutamide, and warfarin metabolism.
The influence of sulfamethizole on the metabolism of diphenylhydatoin (DPH) tolbutamide, and warefarian is examined. In 8 patients DPH means half-life (T/2) increased from 11.8 plus or minus 3.6 hr to 19.6 plus or minus 5.2 hr and mean metabolic clearance rate (MCR) decreased from 43.7 plus or minus 16,8 to 28.1 plus or minus 9.1 ml/min durus or minus 1.2 to 9.2 plus or minus 1.2 hr MCR decrease from 17.0 plus or minus 5.4 to 10.5 plus or minus 1.2 ml/min. In 2 patients warfarin T/2 increased fron an average of 64.7 to 92.7 hr and MCR decreased from 1.65 ml/min to 1.05 ml/min. In 4 patients on long-term DPH treatment after 1 wk on sulfamethizole inhibits hepatic metabolism of DPH, tolbutamide, and warfarin.
Depression, Chemical↗
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.
Adult↗
Nitrofurantoin, sulfamethizole and cephalexin urinary concentration in unequally functioning pyelonephritic kidneys.
Nitrofurantoin, sulfamethizole and cephalexin peak urinary drug concentrations were studied in patients and non-human primates with unequally functioning pyelonephritic kidneys. The peak urinary drug concentration of the poorly functioning kidney in comparison to the better kidney was greater than its percentage relative blood flow or creatinine clearance but variable in its relationship to creatinine concentration, osmolality and sodium concentration. Although for each unit of creatinine clearance the poorly functioning kidney had a higher peak urinary drug concentration than the better functioning kidney, for each kidney the peak urinary drug concentration seemed to be directly proportional to the creatinine clearance, the drug dosage and the renal mechanisms of drug excretion. Nitrofurantoin in the usual recommended dosage did not reach minimal inhibitory urinary drug concentration below a unilateral creatinine clearance of 20 ml. per minute. Whereas, sulfamethizole and cephalexin reached peak urinary drug concentrations greater than the minimal inhibitory concentration at the lowest studied unilateral creatinine clearance of 4 and 11 ml. per minute, respectively.
Adolescent↗
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.
Adult↗
Inhibition of bioluminescence in Photobacterium phosphoreum by sulfamethizole and its stimulation by thymine.
In bioluminescent bacteria very few agents have been reported that can selectively inhibit the luminescence. In sensitivity tests with Photobacterium phosphoreum, using 55 different antibiotics, it was found that sulfamethizole, an inhibitor of dihydropteroate synthetase and the formation of folic acid, inhibited bioluminescence more than growth. Likewise, in mutants requiring thymine for growth, the luminescence per cell was much less in a medium low in thymine. In neither case could the decreased specific luminescence be attributed to a decrease in the cellular level of luciferase or aldehyde factor; the involvement of additional but unidentified factors in the regulation of in vivo bioluminescence is postulated.
FMN Reductase↗
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.
Animals↗
Kinetic studies on drug disposition in rabbits. III. Effect of tolbutamide on renal excretion of sulfamethizole.
The effect of tolbutamide (TB) on the urinary excretion of sulfamethizole (SMZ) under constant infusion of SMZ at 100 mg/h was studied. Intravenous administration of TB (50 mg/kg) caused a decrease in the urinary excretion rate of SMZ but an increase in the unbound concentration of SMZ in plasma. The total concentration of SMZ in plasma decreased rapidly after TB injection and then increased gradually to a level higher than the control. The slope of the terminal phase of the unbound concentration of TB in plasma in the presence of SMZ was significantly smaller than that of TB alone. The analysis using the perfusion limited model showed that the elimination kinetics of SMZ in the presence of TB could be described by the mutual displacement of plasma protein binding of both drugs and the competitive inhibition of the tubular secretion of SMZ by the unbound concentration of TB in renal vein. Further the inhibitor constant was in good agreement with that for the in vitro uptake by renal cortex slices.
Animals↗
Effect of iodopyracet on renal excretion of sulfamethizole in rabbits.
To predict quantitatively drug interaction kinetics from the single-drug clearance studies, we examined the effect of iodopyracet (IOD) on sulfamethizole (SMZ) excretion in rabbits. Even though the decline of systemic IOD plasma concentration was linear, the renal clearance of SMZ decreased significantly in the presence of IOD. The results could be described by a perfusion model incorporated with the competitive inhibition for tubular secretion. For IOD with a high extraction ratio, it was suggested that a heavy load of the drug was supplied to the sites of secretion and caused the saturation of transport systems, even though the renal excretion kinetics were apparently linear in respect to the systemic circulation. These facts indicated that a linear relationship between the concentrations in the systemic circulation and at the sites of tubular secretion can not always be presumed. Consequently, SMZ-IOD interaction study stressed the importance of the drug concentrations at the sites of interaction for quantitative elucidation of drug-drug interactions.
Animals↗