Adsorption and Release of Sulfamethizole from Mesoporous Silica Nanoparticles Functionalised with Triethylenetetramine.

Mesoporous silica nanoparticles (MSN) were synthesised and functionalised with triethylenetetramine (MSN-TETA). The samples were fully characterised (transmission electron microscopy, small angle X-ray scattering, Fourier transform infrared spectroscopy, thermogravimetric analysis, zeta potential and nitrogen adsorption/desorption isotherms) and used as carriers for the adsorption of the antimicrobial drug sulphamethizole (SMZ). SMZ loading, quantified by UV-Vis spectroscopy, was higher on MSN-TETA (345.8 mg g-1) compared with bare MSN (215.4 mg g-1) even in the presence of a lower surface area (671 vs. 942 m2 g-1). The kinetics of SMZ adsorption on MSN and MSN-TETA followed a pseudo-second-order model. The adsorption isotherm is described better by a Langmuir model rather than a Temkin or Freundlich model. Release kinetics showed a burst release of SMZ from bare MSN samples (k1 = 136 h-1) in contrast to a slower release found with MSN-TETA (k1 = 3.04 h-1), suggesting attractive intermolecular interactions slow down SMZ release from MSN-TETA. In summary, the MSN surface area did not influence SMZ adsorption and release. On the contrary, the design of an effective drug delivery system must consider the intermolecular interactions between the adsorbent and the adsorbate.

Gastric emptying after pylorus-preserving gastrectomy in comparison with conventional subtotal gastrectomy for early gastric carcinoma.

It is well known that surgical intervention on the stomach will greatly alter gastric function and gastric emptying. In this study, we evaluated the difference in postoperative gastric remnant emptying following pylorus-preserving gastrectomy (PPG) and conventional subtotal gastrectomy (CDG) using sulfamethizole capsule food. The subjects comprised 18 patients who underwent PPG and 23 who underwent CDG for early gastric carcinoma. While delayed gastric emptying was observed early after PPG, 1 year after PPG it was markedly accelerated compared with that measured in the early postoperative period. However, it was slower than that in the CDG patients. On the other hand, rapid gastric emptying was observed early after CDG and did not change with time. These findings stress that although PPG results in stasis in the early postoperative period, it seems to prevent unduly rapid 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.

Urine flow dependence of renal clearance and interrelation of renal reabsorption and physicochemical properties of drugs.

A physiologically based model is presented for the analysis of the reabsorption kinetics of drugs in the renal tubules. The two reabsorption parameters, AR(I) X Pe and sigma, expressing the permeability of a drug through lipoidal membranes and the reflection coefficient, respectively, are obtained on the basis of this model using the results of clearance experiments in rats. These two reabsorption parameters are compared among four drugs, sulfanilamide, sulfamethizole, theophylline, and ethanol. Urine flow dependence of the percentage of reabsorbed drugs is reasonably expressed by the model. Moreover, the percentage of reabsorbed drugs which are highly reflected at the membranes is affected by the change of the glomerular filtration rate. In contrast, the percentage of reabsorbed drugs, such as ethanol, having a small reflection coefficient is not sensitive to the glomerular filtration rate. A good linear relationship is obtained between AR(I) X Pe and the n-octanol/water partition coefficient. The reflection coefficient is related to the molecular weight of the compound. The reflection coefficient of ethanol is small because of its low molecular weight, whereas the reflection coefficient is almost unity when the molecular weight is higher than 170. Accordingly, this physiological model approach can be acceptable to the reabsorption kinetics of drugs in the renal tubules.

Absorption of anticancer drugs through bladder epithelium.

Fundamental and clinical evaluations of ten anticancer drugs were performed. The required qualities of an anticancer drug ideal for bladder instillation therapy are thought to be as follows: (1) a high sensitivity for bladder tumor cells; (2) a pKa which provides a high percentage of nonionized molecules in a pH 6-7 solution; (3) a log P in the range from -0.4 to -1.2 or from -7.5 to -8.0; and (4) a molecular weight over 200.

Multiple cobinding of two ligands to serum albumin: a stoichiometric description of binding equilibria.

Binding equilibria for simultaneous binding of several molecules of two anionic ligands, sulfamethizole/warfarin in one series and sulfamethizole/diflunisal in another, to human serum albumin were studied by equilibrium dialysis. It was found that Klotz's stepwise binding equilibrium concept, extended to cover interaction of two ligands with one carrier, could be used for a quantitative description of binding equilibria. Reciprocity of ligand effects was established at all levels. Heterotropic anticooperativity was present among these pairs of ligands. The experiments were supplemented with observations of albumin binding equilibria for traces of warfarin in the presence of varying amount of oleate, up to 6 mol/mol albumin, by measuring dialysis rates for unbound warfarin. Binding of warfarin to albumin is enhanced upon binding of oleate up to 4 mol/mol albumin, and decreases at higher oleate concentrations. Using stoichiometric (stepwise) binding constants for oleate previously published by Ashbrook et al. [(1975) J. Biol. Chem. 250, 2333-2338], the reverse effect, of warfarin on binding of oleate, was calculated. Simultaneous binding of these ligands to albumin could be described according to the stoichiometric principles as used above for sulfamethizole/warfarin and sulfamethizole/diflunisal.

The pharmacokinetics and serum and urine bactericidal activity of ciprofloxacin.

Ciprofloxacin is an investigational quinolone agent possessing an impressive antibacterial spectrum. Its pharmacokinetics were studied in six volunteers after 250-mg and 500-mg single oral doses, and its bactericidal activity compared to that of trimethoprim-sulfamethoxazole given to the same volunteers. Mean peak serum levels were 1.45 micrograms/mL and 2.46 micrograms/mL for 250-mg and 500-mg doses, and time to peak was 1 and 1.3 hours. The 12-hour levels were 0.12 micrograms and 0.22 microgram. Half-life (T1/2)alpha were 0.32 and 0.43 with T1/2 beta were 3.97 and 4.15 and volume of distribution (area) were 80L and 90L, respectively. Area under the concentration curve (AUC) was 5.65 h X micrograms/mL and 10.37h X micrograms/mL. Serum clearance was 23L for both doses. Approximately 49% of the 250-mg dose and 43% of the 500-mg dose was recovered in the urine. Bactericidal levels were determined against clinical isolates. Sera at 1.5 hours after the 500-mg dose averaged bactericidal levels of 1:20 or better for an Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and beta-lactamase producing Haemophilus influenzae and Branhamella catarrhalis. Urinary bactericidal levels at eight to 12 hours were greater than or equal to 1:157 for E coli, K pneumoniae, gentamicin-piperacillin resistant P aeruginosa, Staphylococcus aureus, and 1:20 for Streptococcus faecalis. Serum bactericidal levels were superior, and urine bactericidal levels were superior or equal to the bactericidal levels obtained with trimethoprim-sulfamethoxazole.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of nephrotoxic compounds on active uptake of drugs in isolated renal tubules in rabbits.

The uptake of sulfonamides and phenolsulfonphthalein (PSP) was examined in vitro using isolated renal proximal tubule suspension, and the effects of nephrotoxic compounds on the uptake of sulfamethizole (SMZ) were studied. The uptake of SMZ and PSP was energy dependent and was inhibited competitively by iodopyracet (IP), which is transported actively by the p-aminohippurate mechanism. The uptake of sulfamethoxazole was also reduced by IP but that of sulfanilamide was negligible. The present results correspond well with those of in vitro experiments reported previously. Nephrotoxic compounds, mercuric chloride, neomycin, viomycin and kanamycin, decreased the uptake of SMZ non-competitively. The inhibitory action of the three antibiotics corresponds with in vivo potency, suggesting that this renal tubule preparation may provide a simple method for predicting the nephrotoxicity of drugs.

Quantitative investigation on renal handling of drugs in rabbits, dogs, and humans.

A renal clearance method based on a computer analysis after administration of a single dose of drug was developed for measuring the renal handling of several drugs in rabbits, dogs, and humans. Secretion and reabsorption of sulfamethizole, sulfanilamide, cephalexin, and ampicillin in the nephron were analyzed quantitatively using the plasma concentration and the urinary excretion rate of the drugs. The validity of the proposed model was demonstrated. It appears that tubular secretion of sulfamethizole, cephalexin, and ampicillin depend on the active transport system which is described by Michaelis-Menten kinetics; the tubular reabsorption of these drugs is expressed by first-order kinetics. The maximum velocity of renal secretion per unit weight of these drugs was much higher in rabbits than in dogs or humans. Reabsorption showed similar values in dogs and humans. These findings suggest that an analysis of the renal handling of drugs in dogs might provide useful information when considering the appropriate therapeutic dose in humans.

Simplified method for estimating volume of distribution at steady state.

Current methods for measuring the volume of distribution at steady state (Vdss) require extrapolation of the plasma concentration curve from time zero to infinity (AUC0-infinity). A new method for measuring Vdss is described. This method saves time since it requires following the plasma concentration curve only until a steady state is reached. The Vdss of sulfamethizole was measured simultaneously by the new method (2 hr) and by established methods (7 hr) in six dogs. There was not significant difference between the results obtained by the two methods.

Mutual displacement interactions in the binding of two drugs to human serum albumin by frontal affinity chromatography.

A continuous frontal analysis chromatographic method was developed for studying the simultaneous binding of two drugs or ligands with an immobilized macromolecule. The usefulness of this method was demonstrated in the interactions of sulphamethizole and salicylic acid with human serum albumin (HSA). The mutual inhibitory effect on the binding of one drug of the presence of the other was directly shown to be due to displacement of the bound drug from HSA by the other. On the basis of a double-reciprocal plot analysis, these two drugs are interpreted as competing for the same primary binding sites.

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.

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.

Pharmacokinetics in the elderly.

The pharmacokinetics of sulphamethizole, paracetamol and phenylbutazone were investigated and compared in young and geriatric subjects. The rate and extent of absorption of the drugs did not appear to be affected by increasing subject age. However, the mean half-lives for sulphamethizole and paracetamol were significantly increased in the geriatric subjects. A number of correlations are presented between the elimination rate constants of the drugs and certain subject parameters and variables. The elimination of phenylbutazone was found not to be influenced significantly by subject age. The apparent volumes of distribution of the three drugs were not age-dependent.