Involvement of imidazoline and opioid receptors in the enhancement of clonidine-induced analgesia by sulfisoxazole.

Clonidine, an alpha2-adrenergic agonist, has been demonstrated to produce significant analgesia and potentiate morphine analgesia. Endothelin (ETA) receptor antagonists have also been found to potentiate the antinociceptive response to morphine. Clonidine and ET have been reported to have cardiovascular interactions involving the sympathetic nervous system, but it is not known whether ETA receptor antagonist affects clonidine analgesia. This study examined the influence of sulfisoxazole (ETA receptor antagonist) on clonidine analgesia. Male Swiss Webster mice were used to determine antinociceptive response of drugs by measuring tail-flick latency. The effect of clonidine (0.3, 1.0, and 3.0 mg/kg, i.p.) alone or in combination with sulfisoxazole (25, 75, and 225 mg/kg, p.o.) on analgesia and body temperature was determined. Clonidine produced a dose-dependent analgesia and hypothermia. Sulfisoxazole (25, 75, and 225 mg/kg), when administered with clonidine (0.3 mg/kg), significantly potentiated (31% increase in area under the curve (AUC)) the analgesic effect of clonidine. Yohimbine (alpha2-adrenergic receptor antagonist) did not affect analgesic effect of clonidine plus sulfisoxazole. Idazoxan (I1-imidazoline and alpha2-adrenergic receptor antagonist) reduced (47% decrease in AUC) the analgesic effect of clonidine plus sulfisoxazole. Treatment with naloxone reduced (46% decrease in AUC) the analgesic effect of clonidine plus sulfisoxazole. The effect of another ETA receptor antagonist, BMS-182874 (2, 10, and 50 microg, i.c.v.) was studied, and it was found that the dose of 10 microg significantly potentiated (26% increase in AUC) the analgesic effect of clonidine. These results indicate that sulfisoxazole, an ETA receptor antagonist, potentiates the analgesic effect of clonidine, which could be mediated through I1-imidazoline receptors and opioid receptors.

Simultaneous determination of N(1)-acetyl sulfisoxazole and its metabolites, and relative bioavailability compare to sulfisoxazole in rats.

N(1)-acetyl sulfisoxazole (N1AS), a dihydropteroate synthase inhibitor is known to be biotransformed primarily to sulfisoxazole, partly to N(4)-acetyl sulfisoxazole (N4AS), and likely also to diacetyl sulfisoxazole (DAS) and other compounds. Although its clinical use has been limited due to urolithiasis, some countries still use the drug in combination with trimethoprim in cattle. A liquid chromatographic method using ultraviolet detection was developed for the simultaneous determination of four substances for the first time. Four analytes and sulfamethoxazole (IS) were separated on a reversed-phase column with gradient elution of a mobile phase. Because DAS and N1AS in plasma were changed very quickly into N4AS and sulfisoxazole, respectively, and esterase inhibitors (sodium fluoride and eserine) could not prevent the transformation, sulfisoxazole and N4AS were monitored in rat plasma following a single oral administration of N1AS and sulfisoxazole in five rats. The relative bioavailability of N1AS to sulfisoxazole was about two, indicating that a half-dose of N1AS would be equivalent to a dose of sulfisoxazole to achieve the same systemic exposure to sulfisoxazole.

Sulfisoxazole chemoprophylaxis for frequent otitis media.

Sulfisoxazole, 75 mg/kg/d in two divided doses for 3 months, was administered in a double-blind placebo crossover study to 35 children aged 6 months to 5 years who had frequent recurring episodes of otitis media. There was a 40% reduction in the rate of otitis media among patients receiving sulfisoxazole compared with those receiving placebo (0.25 v 0.42 episode per patient-month) which did not depend on age, sex, season, or several other factors. Using a randomized order, among patients who received placebo first, there was a 64% reduction on sulfisoxazole therapy compared with placebo (0.20 v 0.56 episode per patient-month). In this subgroup, there was significant improvement in eustachian tube function according to serial tympanograms. In the patients who received sulfisoxazole first, the rate of acute otitis remained low on placebo (0.28 v 0.30 episode per patient-month), and tympanogram patterns continued to improve after discontinuation of the active drug. These differences suggest a carry-over effect from the benefits of chemoprophylaxis. There was no significant difference in the species or sensitivity patterns of bacteria isolated from patients receiving sulisoxazole or placebo. Sulfisoxazole chemoprophylaxis appears to be safe and effective in significantly reducing episodes of otitis media and improving tympanogram patterns.

Proguanil-sulphonamide for malaria prophylaxis.

There are few safe, effective chemoprophylactic regimens for preventing Plasmodium falciparum infection in south-east Asia. In two randomized placebo-controlled trials, combinations of proguanil and sulphonamide were tested for chemoprophylactic activity in schoolchildren, aged 6-15 years, living near the Thai-Burmese border. Proguanil at an equivalent adult dose of 200 mg/d was combined with sulphafurazole (= sulfisoxazole) at 25 mg/kg/d or sulphamethoxazole at 25 and 10 mg/kg/d. Combinations of daily proguanil/sulphafurazole and proguanil/sulphamethoxazole were equally effective (greater than 75%) against both falciparum and vivax malaria when the sulphonamide component was used at 25 mg/kg/d. Proguanil and sulphamethoxazole at 10 mg/kg/d was ineffective. Approximately 1% of the children had sulphonamide-related skin rashes which resolved when treatment stopped. Proguanil/sulphonamide is a possible alternative chemoprophylactic regimen in areas with multiple drug-resistant P. falciparum.

Saturable first-pass metabolism of sulfisoxazole N1-acetyl in rats.

Saturable metabolism of sulfisoxazole N1-acetyl in the rat during the initial pass of the drug from the intestinal lumen through the liver following oral administration of the drug (saturable first-pass metabolism) was investigated. The fraction of the total amount of drug recovered from the urine as the N4-conjugate fraction was apparent following the intravenous administration of sulfisoxazole acetyl or the oral administration of sulfisoxazole at the same dose levels.

Interpretation of plasma concentration-time curves after oral dosing.

The pharmacokinetic information obtained after oral administration is examined using the two-compartment model. Data were obtained by simulation and experimentally by administering sulfisoxazole by an exponential infusion to rabbits. When the absorption rate constant is allowed to approach alpha, a typical two-compartment oral absorption curve is obtained, which is described by a triexponential equation. However, if the absorption rate constant approaches E2 (the sum of the elimination rate constants out of the peripheral compartment), the data are adequately fit by a one-compartment model, with the calculated absorption rate equal to alpha. The relative error in using a one-compartment model to calculate absorption rate constants for two-compartment data is also evaluated.

Effect of sulfisoxazole on pharmacokinetics of free and plasma protein-bound bilirubin in experimental unconjugated hyperbilirubinemia.

The effect of sulfisoxazole on the time course of free (unbound) bilirubin concentrations in plasma was studied. Normal adult rats were made hyperbilirubinemic by continuous intravenous infusion of bilirubin. Sulfisoxazole was administered by either rapid intravenous injection or slow intravenous infusion, and the plasma concentrations of free and total (free plus bound) unconjugated bilirubin were determined as a function of time. Rapid injection of sulfisoxazole caused a rapid and pronounced decrease of total bilirubin concentrations in plasma but had only a transient effect on the concentration of free bilirubin. Slow infusion of sulfisoxazole caused a gradual and eventually pronounced decrease of total bilirubin concentrations in plasma but had no apparent effect on the concentration of free bilirubin at any time. These results are consistent with recently developed pharmacokinetic theory according to which the plasma clearance of total bilirubin should increase upon administration of a displacing agent while the plasma clearance of free bilirubin should remain unchanged. Bilirubin-induced encephalopathy caused by sulfisoxazole or other displacing agents may be due to very transient elevations of free bilirubin concentrations in plasma of infants with elevated plasma concentrations of total bilirubin and the consequent redistribution of the pigment to extravascular sites, including the brain.

Antitumor effects of rhodium (II) complexes on mice bearing Ehrlich tumors.

Rhodium (II) trifluoroacetate (TFARh), rhodium (II) trifluoroacetate adduct with sulfadiazine (TFARh.Sd) and rhodium (II) acetate adduct with sulfisoxazole (RhSx) were tested in mice for acute toxicity, antitumoral activity against Ehrlich ascites carcinoma and for viability of Ehrlich tumor cells in culture. At ip doses up to 60 mumol/kg (40-70 and 59 mg/kg, respectively), these compounds had no toxic effects up to 14 days. At ip doses of 10 mumol kg-1 day-1 for 5 days, TFARh and TFARh.Sd significantly increased the survival rate of mice bearing Ehrlich ascites cells (probability of survival to the end of 34th day, controls = 0.23, TFARh = 0.85, TFARh.Sd = 0.74). No significant effect was observed for RhSx. In vitro, these rhodium complexes at 40 microM significantly increased the number of dead cells in cultured Ehrlich tumor cells.

Antimicrobial treatment of otitis media: penicillins, cephalosporins, sulfonamides.

Otitis media continues to be one of the most common diagnoses made in the offices of family physicians, pediatricians, and otolaryngologists. The emergence of ampicillin resistant Hemophilus influenzae as an important etiologic agent for otitis media has altered the selection of a therapeutic antimicrobial drug. This article reviews the role of the penicillins, cephalosporins, and sulfonamides in the treatment of otitis media. Amoxicillin continues to be the drug chosen for the uncultured otitis media. Backup drugs for use in unresponsive cases include trimethoprim-sulfamethoxazole, erythromycin-sulfisoxazole, and cefaclor. The cost of the drug should be a factor in the selection when efficacy is equal.

Evidence that sulfisoxazole, an antibacterial sulfonamide, can adversely affect the development of Brugia pahangi in Aedes aegypti mosquitoes.

The average number of infective larvae recovered from Brugia pahangi-infected Aedes aegypti was approximately one-half that recovered from the controls after the former group of infected mosquitoes had ingested a 1.0% solution of sulfisoxazole diolamine (SXZ) in 10% sucrose-water for 4 consecutive days, beginning 4 days after infection. Most of the filarial larvae from the SXZ-treated mosquitoes were small and sluggish compared with those from the controls. There was no increased mortality of mosquitoes that ingested 1.0% SXZ in sugar-water for 4 days. Average filarial larval burdens were not decreased in mosquitoes that ingested a solution of 10(-6) M methotrexate (MTX), a potent dihydrofolate reductase inhibitor, in sugar-water for 4 days, beginning 4 days after infection. The distributional pattern of larval burdens in mosquitoes that ingested combined 1.0% SXZ and 10(-6) M MTX in sugar-water for 4 days closely resembled that seen in mosquitoes that had imbibed 1.0% SXZ only. Average filarial larval burdens were not decreased in mosquitoes with 4-day-old B. pahangi infections that fed upon jirds which received intraperitoneal injections of SXZ (2 g/kg) and MTX (1 mh/kh), alone and in combination, 1 hr previously. Survival of the mosquitoes that fed upon the drug-treated hosts was unaffected, as was the hatchability of their eggs and subsequent growth and development of the mosquito larvae.

Efficacy of oral antibiotics for the treatment of persistent otitis media with effusion.

We followed 137 children who were found to have persistent otitis media with effusion (POME) one month after the diagnosis of acute otitis media. Subjects were randomly assigned to either treatment with erythromycin ethylsuccinate and sulfisoxizole or to no treatment. Follow-up utilizing pneumatic otoscopy and tympanometry showed that treated patients were more likely to have normal findings, and less likely to develop acute otitis media during the month following treatment. These data indicate that children with POME one month following acute otitis media may benefit from an additional course of antibiotics.

Urine concentrations of chloramphenicol, tetracycline, and sulfisoxazole after oral administration to healthy adult dogs.

Chloramphenicol, tetracycline, and sulfisoxazole were administered (orally) in separate trials to clinically healthy adult dogs of both sexes at 8-hour intervals for five consecutive 8-hour test periods. All urine was collected from each dog during each test period and an aliquot from each period was assayed for antimicrobial activity. Daily doses of the antimicrobics were as follows: chloramphenicol 99 mg/kg of body weight, tetracycline 55 mg/kg, and sulfisoxazole 66 mg/kg. Mean 8-hour urine concentrations (+/- 1SD) for chloramphenicol were 124 +/- 40 micrograms/ml; for tetracycline, 138 +/- 65 micrograms/ml; and for sulfisoxazole, 1,466 +/- 832 micrograms/ml. The mean 8-hour percentages of the doses of drug eliminated in active form in the urine were 6.3 +/- 2.6% for chloramphenicol, 11.2 +/- 2.0% for tetracycline, and 68.5 +/- 2.1% for sulfisoxazole.

[Treatment of acute otitis media]. / Traitement des otites moyennes aiguës.

The treatment of acute otitis media (AOM) has three main aims: to relieve pain, to control fever and in case of suppurative AOM, to overcome the bacterial infection. The two former aims are best managed with salicylates or paracetamol. The local instillation of drops of an anaesthetic-antiseptic solution in the external canal is a useful adjuvant in painful congestive viral otitis. Antibiotherapy is only indicated in suppurative AOM. The most common organisms being Haemophilus influenzae and Streptococcus pneumoniae, amoxicillin is the first line treatment. However, in children who were treated for suppurative AOM in the previous months, amoxicillin/clavulanic acid or a second generation cephalosporin is preferable. Erythromycin-sulfonamide may also be used, particularly in children who are allergic to beta-lactamines. In case of failure of the first choice antibiotic treatment, it is necessary to perform a bacteriological study of the effusion which will determine the appropriate antibiotic to be used in second hand. The duration of the antibiotic treatment must be of 8 days in the absence of spontaneous perforation, and of 10 days in case of perforation. An examination of the tympanum at 10 days is recommended in infants under 6 months of age and in children with repeated AOM. A myringostomy is only indicated when a bacteriological evaluation is needed, mainly in infants under 6 months of age, in immuno-compromised children, and in case of failure of a first line antibiotic treatment.