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.

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.

[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.

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.

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

Rhodium (II) trifluoracetate (TFARh), rhodium (II) trifluoracetate 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 µmg/kg (40-70 and 59 mg/kg, respectively), these coumpounds had no toxic effects up to 14 days. At ip doses of 10 µmol 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 µM significantly increased the number of dead cells in cultured Ehrlich tumor cells

Two-layer membrane model for iontophoretic drug transport through excised rat skin.

Iontophoretic and passive transport of an ionized drug (sulfisoxazole) across excised rat skin was studied using a two-chamber cell with four electrodes under successive experimental conditions: without electrical current (stage-I) and with electrical current (stage-II). Two iontophoretic/diffusion models, i.e. a one-layer membrane model and a two-layer membrane model, in which a difference in the electrical potential gradient was taken into account between the stratum corneum and epidermis/dermis layer, were constructed to describe the non-steady-state drug permeation process during ionotrophoresis. The observed iontophoretic lag-time was two times greater than the calculated value based on the one-layer membrane model. According to the two-layer membrane model, the calculated ionotophoretic lag-time agreed with the observed value. It was revealed by model adaptation to the observed data that the stratum corneum fraction of the electro-chemical potential difference across the whole skin caused by the iontophoresis was around 90%. This result was consistent with the observation that the direct current resistance of whole skin was seven times greater than that of stripped skin.

[An open randomized trial, Pediazole versus cefaclor in the treatment of acute otitis media in children]. / Etude randomisée ouverte, Pédiazole versus céfaclor dans le traitement des otites moyennes aiguës de l'enfant.

The combination of erythromycin ethylsuccinate and acetyl sulfafuroxazole (Pediazole = ES) is effective against Hemophilus influenzae, including beta-lactamase-producing strains, and against Streptococcus pneumoniae, including macrolide-resistant strains. In this study, mean daily dosage was 40-50 mg/kg for cefaclor and 50 mg/kg ES + 150 mg/kg sulfamide for Pediazole. Both products were given in three divided doses per day for ten days. Tolerance was evaluable in 106 children and effectiveness in 103 children including 52 in the ES group and 51 in the cefaclor group. Mean age was 23.5 months and both groups were comparable as concerns age, weight, previous ENT disease, and severity of the otitis media. Tolerance was satisfactory in both groups. Clinical results were as follows: failures before or at completion of the course, 5/52 in the ES group versus 13/51 in the cefaclor for the treatment of children with acute otitis media.

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.

Malaria prophylaxis with proguanil and sulfisoxazole in children living in a malaria endemic area.

The effects of three separate antimalarial prophylactic regimens (proguanil, sulfisoxazole, and proguanil plus sulfisoxazole) and of vitamins in a control group were compared in a study population of 380 children living in a malaria endemic area along the Thai-Burmese border. The subjects, aged 5-16 years, were matched for age, weight, and presence of splenomegaly, then randomly assigned to one of the four groups. All medications were administered daily by the investigators and malaria smears were performed on a weekly basis. Among 99 subjects taking proguanil plus sulfisoxazole for a total of 1464 man-weeks, there was only one case of falciparum and no vivax malaria. Statistically, this regimen proved superior to each of the other groups against both Plasmodium falciparum and P. vivax. The data show that proguanil alone, as a causal or suppressive prophylatic, has poor efficacy against P. falciparum. Side-effects were infrequent and generally mild, except for two subjects whose sulfisoxazole prophylaxis was discontinued because of urticarial rash.

The effect of verbal commitment and treatment choice on medication compliance in a pediatric setting.

This experiment examined the manner in which verbal commitment and treatment choice affect medication compliance in a pediatric setting. Parents (N = 89) of children suffering from an inner ear infection (otitis media) were asked or not asked for a verbal promise to give their child all prescribed antibiotic medication (commitment manipulation) and allowed or not allowed to choose between two equally appropriate antibiotics as the treatment for their child (choice manipulation). Self-reports at follow-up visits, which were supported by urinalysis results, indicated that obtaining a verbal commitment significantly increased medication compliance. Verbal commitment also nonsignificantly increased the likelihood of a resolved infection at follow-up. Providing the parent with a choice of treatments had no effect on compliance or health outcome.

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.

Erythromycin-sulfisoxazole vs amoxicillin in the treatment of acute otitis media in children. A double-blind, multiple-dose comparative study.

A fixed combination of erythromycin ethylsuccinate and sulfisoxazole acetyl (erythromycin-sulfa) was compared with amoxicillin for the treatment of acute otitis media (AOM) in children. Of 145 patients studied, 76 boys and 69 girls were compliant and were evaluated for drug efficacy (72 amoxicillin, 73 erythromycin-sulfa). Based on otoscopic and tympanometric results, cure rates at ten to 14 days for AOM due to all organisms were 83% (63/72) for amoxicillin and 89% (65/73) for erythromycin-sulfa; for Haemophilus species (including mixed infections), they were 84% for amoxicillin (26/31) and 83% for erythromycin-sulfa (20/14). Cure rates for ampicillin-resistant Haemophilus were 1/1 for amoxicillin and 7/8 (88%) for erythromycin-sulfa; one patient (12%) had persistent AOM at day 10. Of the patients with AOM due to Streptococcus pneumoniae, 82% (29/35) in the amoxicillin-treated group and 98% (39/40) in the erythromycin-sulfa-treated group were cured. Patients with S pneumoniae as the initial infecting organism who were treated with amoxicillin had significantly more clinical recurrences then their erythromycin-sulfa-treated counterparts, 66% (8/12) vs 33% (3/9). There was no difference between treatment groups in recurrence rates for patients with Haemophilus as the initial infecting organism. On the treatment day indicated, the following number of patients had middle ear effusion: by days 10 to 14, 38% (27/72) amoxicillin-treated patients and 48% (35/73) erythromycin-sulfa-treated patients; by day 28, 10% (7/71) amoxicillin-treated patients and 16% (11/70) erythromycin-sulfa-treated patients. There were no significant differences in adverse reactions. The erythromycin-sulfa combination is safe and effective treatment for AOM, including ampicillin-resistant Haemophilus.

Treatment of urinary tract infections with varying regimens of sulfisoxazole.

Four therapeutic regimens of sulfisoxazole were compared and contrasted with the antibody-coated bacteria test in patients with acute urinary tract infections. Of 158 college coeds who entered the study 146 completed the randomly assigned regimen. All 146 patients received 2 gm. sulfisoxazole initially and 1 gm. 4 times daily for 3 days in 44 patients (group 1), 7 days in 51 (group 2), 14 days in 29 (group 3) and 21 days in 22 (group 4). The presumptive sites of infection by the antibody-coated bacteria test were kidney (positive test) in 43 per cent of the patients and bladder (negative test) in 51.3 per cent. There was no correlation between the results of the antibody-coated bacteria test with either the presenting symptoms or the therapeutic responses. The bacteriologic cure rates at 2 days after therapy were 100 per cent in all groups and at 4 weeks after therapy they were 88.6 per cent in group 1, 86.3 per cent in group 2, 86.2 per cent in group 3 and 91 per cent in group 4. A 3-day course of sulfisoxazole was as effective as the longer regimens.