Effects of trimethoprim and sulphonamide preparations on the pituitary-thyroid axis of rodents.

The effects on pituitary-thyroid function of the commonly prescribed anti-bacterial preparations co-trimoxazole and co-trifamole, and their component drugs, have been studied in the rat and compared to the changes caused by propylthiouracil. Co-trimoxazole and co-trifamole, in doses 20-fold in excess of a pharmacological dose administered for 10 days, produced marked changes in hormone levels consistent with blocking of hyperplastic goitre formation, were also demonstrated. Propylthiouracil produced less marked changes of thyroid hormone levels but higher levels of thyroid-stimulating hormone. Pharmacological doses of co-trimoxazole and co-trifamole and sulphamoxole, the sulphonamide component of co-trifamole, caused significant changes in thyroid hormone levels consistent with anti-thyroidal activity. In contrast, there was no evidence that trimethoprim, which is common to both preparations, or sulphamethoxazole, the sulphonamide component of co-trimoxazole, had an anti-thyroidal action, indeed, serum thyroxine levels were significantly increased at pharmacological dosage. We have concluded that the new commonly prescribed combination preparations retain the goitrogenic properties of the earlier sulphonamides.

Synergism between trimethoprim and sulfonamide in urine: does it exist?

In a randomized, crossover, multiple dose study, ten healthy volunteers received the recommended dosages of cotrimoxazole (80 mg trimethoprim and 400 mg sulfamethoxazole) and co-tri-famole (80 mg trimethoprim and 400 mg sulfamoxole) for five days each. Urinary levels of trimethoprim and each sulfonamide were measured daily for five days. The urinary ratios of trimethoprim and sulfonamide for both formulations were consistently lower than those considered optimal for synergy. Concentration of trimethoprim in the urine from both preparations was found to be greatly in excess of the MIC for trimethoprim-sensitive urinary pathogens (approximately 2 microgram/ml). The sulfonamide levels achieved were not consistently in excess of their MIC (approximately 200 microgram/ml) for either preparation.

In vitro studies with combinations of sulfamoxole and trimethoprim (co-trifamole).

Chequerboard studies with sulfamoxole and trimethoprim against urinary pathogens showed that the combination was never antagonistic but usually showed little or no synergistic effect. An exception was with the inherently sulphonamide-resistant Strep. faecalis in which marked synergism (F.I.C. Index less than 0.3) was shown with all strains tested. This synergism is thought to be clinically relevant. Experiments were undertaken with a new in vitro test system to establish whether the combination of sulfamoxole with trimethoprim will prevent the emergence of bacterial resistance. Using concentrations of the drugs attained in the blood during treatment, it was shown that trimethoprim monotherapy was likely to result in the emergence of trimethoprim-resistant pathogens, whereas treatment with sulfamoxole and trimethoprim resulted in the elimination of the test bacteria without the emergence of resistance. Using urinary concentrations of drugs, the "urinary' pathogen was shown to be eliminated by trimethoprim alone or in combination with sulfamoxole, without the emergence of resistant bacteria. This would not necessarily preclude the emergence of resistant bacteria in commensal sites exposed to lesser, sun-inhibitory drug concentrations.

Use of p-benzoquinone for the spectrophotometric determination of certain sulphonamides.

A simple spectrophotometric method for the determination of 15 sulphonamides in bulk and in dosage forms is described. The method is based on the interaction of p-benzoquinone with sulphonamides in 0.1 M hydrochloric acid. The resulting chromophore is measured at 500 nm. The effects of different variables on colour development were established. Beer's law was obeyed in a concentration range of 10-50 micrograms ml-1. Results from the analysis of different sulphonamide tablets and ophthalmic solutions marketed locally were in good agreement with that of a reference method. Correlations between A1cm(1%) and certain physical parameters such as pKa values, characteristic volume Vx, and molecular connectivity indices 1X and 1Xv were determined by linear regression equations. A poor correlation was found between A1cm(1%) and bulkiness parameters but a highly significant negative correlation was obtained with apparent pKa values.

Oral bioavailability of sulphamethoxydiazine, sulphathiazole and sulphamoxole in dwarf goats.

To get a better insight into the oral bioavailability of sulphonamides in ruminants, sulphamethoxydiazine (pKa 7.0), sulphathiazole (pKa 7.2), and sulphamoxole (pKa 7.4) were administered to dwarf goats (n = 5). The drugs were given at 2-week intervals by the intravenous or intraruminal route at a dose of 100 mg per kg body weight. After IV injection, the mean half-life (t1/2 beta in h +/- SEM) was 0.80 +/- 0.10 h, 2.35 +/- 0.38 h, and 3.36 +/- 1.25 h, for sulphathiazole, sulphamoxole, and sulphamethoxydiazine, respectively and the mean distribution volume (Vd beta) was 0.23 +/- 0.05 l/kg, 0.23 +/- 0.04 l/kg, and 0.33 +/- 0.02 l/kg. After intraruminal administration, the mean bioavailability varied from 86.0 +/- 11.8% for sulphamethoxydiazine to 46.6 +/- 4.3% for sulphamoxole, and 52.6 +/- 7.2% for sulphathiazole. The elimination half-life was significantly prolonged, probably due to a low rate of drug absorption from the gastrointestinal tract. In contrast to chloramphenicol, the sulphonamides studied were stable when incubated in rumen fluid at 39 degrees C.

Dispersion of sulfamoxole in tissues of poultry.

The blood levels and tissue dispersion of sulfamoxole in poultry has been investigated. The clinical importance and public health hazards on the basis of the results obtained has been discussed.

Synthesis, characterization, microbiological evaluation, genotoxicity and synergism tests of new nano silver complexes with sulfamoxole: X-ray diffraction of [Ag2(SMX)2]·DMSO.

The synthesis and microbiological evaluation of two new Ag(I) complexes with sulfamoxole (SMX), [Ag2(SMX)2]·H2O and [Ag4(SCN)3(SMX)]·H2O are described. Both were characterized by elemental analysis, thermogravimetry, powder and single crystal X-ray diffraction, NMR, Raman and experimental and theoretical IR spectroscopies. Their antibacterial and antifungal properties were evaluated by agar and broth dilution assays, respectively. In addition, synergism tests for Pseudomonas aeruginosa were performed, and genotoxicity studies were carried out employing the Allium cepa test. Both complexes displayed good activity against Escherichia coli, Staphylococcus aureus, P. aeruginosa, and 10 fungi strains, with lower minimum inhibitory concentrations (MICs) than that of free SMX in all cases. The nanometrical crystallite particle size determined from XRPD, DLS and TEM might explain the good microbiological activity in spite of the low solubility of both complexes. The fractional inhibitory concentration (FIC) calculated from the P. aeruginosa test data indicated that the activity of the complexes is not due to synergism of the free components in the concentration ratios studied. Moreover, none of the complexes displayed cytotoxic effects on onions in the concentration range tested, and chromosome aberrations were not observed.

[On the development of oral preparations of the combination sulfamoxole/trimethoprim (CN 3123) (author's transl)]. / Zur Entwicklung von oralen Darreichungsformen der Kombination Sulfamoxol/trimethoprim (CN 3123)

Within the broad range of activities in pharmaceutical research, the technological development and analytical evaluation of a new drug formulation represent only one step. The pharmaceutical development of three oral formulations of a combination product containing N1-(4,5-dimethyl-2-oxazolyl)-sulfanilamide (sulfamoxole) and 2,4-diamino-5-(3,4,5-trimethoxy-benzyl)-pyrimidine (trimethoprim) in a 5:1 ratio (investigational drug CN 3123; Nevin; Supristol), which was based on the physico-chemical characteristics of the 2 active substances, is presented. The various chemical and physical tests conducted with the drug formulations are described. The pharmaceutical or in-vitro availabilities (dissolution rate) of the active ingredients were determined by way of release-rate profiles, both of the active ingredients alone and in their final formulations. Also presented are the results of plasma level determinations following oral administration of film-coated tablets and a suspension. Finally, preliminary results of extensive stability tests with the three drug formulations are discussed.

Plasma levels of trimethoprim and sulfonamide after administration of trimethoprim-sulfamethoxazole and trimethoprim-sulfamoxole.

In a cross-over study with ten healthy volunteers, the plasma levels of trimethoprim (TMP) and sulfonamides were compared using orally given trimethoprim-sulfamethoxazole (TMP-SMX: Septra) and trimethoprim-sulfamoxole (TMP-SMO: Supristol) in recommended doses. The dosage schedule for TMP-SMX was 2 tablets every 12 h for nine doses, and for TMP-SMO it was 2 tablets as in the first dose, followed by 1 tablet every 12 h for eight more doses. Serial plasma levels of TMP and sulfonamides after the first dose of each of the two products showed no significant differences. However, after the ninth dose of each product, the paired t test revealed significantly higher levels of TMP and sulfonamides after TMP-SMX as compared with TMP-SMO.