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.

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.

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.

[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.

[Use of multicomponent ointments on a hydrophilic base in the treatment of suppurative wounds]. / Primenenie mnogokomponentnykh mazei na gidrofil'noi osnove pri lechenii gnoinykh ran.

The results of experimental and clinical studies on the development of multicomponent ointments on a hydrophilic base for local treatment of wounds at phase I of the inflammatory process have been analyzed. A pronounced therapeutic effect of the use of the remedies suggested (levosin, levomecol, dioxycole, sulphamecole, iodmetroxide) resulting from simultaneous dehydrating, antimicrobial, necrolytic and anesthetic effect, 2-fold shortening of the period of wound treatment and improvement of the results of treatment of the patients with different types of purulent surgical infection were noted.

Trimethoprim sulphamoxole in the treatment of chancroid. Comparison of two single dose treatment regimens with a five day regimen.

In a prospective blinded study, 135 men with genital ulcers culture positive for Haemophilus ducreyi, were randomized to one of three regimens. Two single dose regimens, either the combination of sulphamoxole 3200 mg/trimethoprim 640 mg or trimethoprim 700 mg alone were compared to a five day regimen of sulphamoxole 800 mg/trimethoprim 160 mg twice daily. All 31 treated with a five day regimen of trimethoprim sulphamoxole healed without further treatment. Of 27 patients treated with the single dose sulphamoxole/trimethoprim regimen, only 21 were cured and of 34 treated with trimethoprim alone, 25 responded. Antibacterial susceptibilities were performed on 31 H. ducreyi isolates. The laboratory susceptibility of these strains to trimethoprim correlated with the clinical response to the single agent. Trimethoprim alone in a dose of 700 mg or the combination of sulphamoxole (3200 mg) and trimethoprim (640 mg) is not satisfactory for the single dose treatment of genital ulcer disease. However, when prescribed for five days, sulphamoxole/trimethoprim is effective and compares favourably with other treatment regimens.

Bacteriostatic and bactericidal activity of two trimethoprim-sulfonamide combinations.

Sulfamoxole (SDMO) has the same half-life of elimination from human plasma as sulfamethoxazole. Its antibacterial properties, however, are often inferior to those of co-trimoxazole. Its less pronounced antibacterial effect, especially against gram-negative pathogens, also becomes evident in the combination with trimethoprim (TM). The inhibition zones are often smaller around discs containing the same amount of the components SDMO/TM as those with co-trimoxazole and the inhibitory concentrations needed are frequently 2-4 times higher, especially against gram-negative bacteria, such as Escherichia coli and Proteus vulgaris. Accordingly, the curative doses 50% of the new combination are 2-3 times higher than those of co-trimoxazole in experimental infections with E. coli and P. vulgaris in mice. The bactericidal action in human urine, collected after a course of treatment with the combination SDMO/TM in the planned lower dosage, is not only often retarded, but also frequently incomplete in comparison with that in urine after co-trimoxazole in standard dosage. Clinically, this might lead to increased development of resistance or to an increase of recurrent infections.

[Pharmacokinetic studies with the combination sulfamoxole/trimethoprim in animals and men (author's transl)]. / Pharmakokinetik der Kombination Sulfamoxol/Trimethoprim (CN 3123) bei Tier und Mensch

The pharmacokinetics of the 5:1 combination of N1-(4,5-dimethyl-2-oxazolyl)-sulfanilamide (sulfamoxole) and 2,4-diamino-5-(3,4,5-trimethoxy-benzyl)-pyrimidine (thrimethoprim) (CN 3123, Nevin, Supristol) corresponds to the well known data of the single substances. Investigations on blood level, concentration in plasma water and excretion via urine and bile were done on experimental animals and with therapeutic dosage (single and repeated administration) on men. There were no alterations of the kinetics of the single substances due to drug interaction during simultaneous administration, neither qualitatively nor quantitatively. The dosage schedule elaborated is as follows: dosage interval=12 h, ratio initial dose: maintenance dose=2:1. For adults this regimen with a maintenance dose of 400 mg sulfamoxole and 80 mg trimethoprim results in a steady state of the minimal concentrations immediately before the following dose. These minimal concentrations in plasma water exceed the minimal inhibitory concentrations determined in vitro for most pathogens by several times.

[Toxicological investigations of the combination sulfamoxole/trimethoprim, a new broad-spectrum chemotherapeutic (author's transl)]. / Toxikologische Untersuchungen der Kombination Sulfamoxol/Trimethoprim (CN 3123), eines neuen Breitbandchemotherapeutikums

The chemotherapeutically effective 5:1 combination N1-(4,5-dimethyl-2-oxazolyl)-sulfanilamide (sulfamoxole) and 2,4-diamino-5-(3,4,5-trimethoxy-benzyl)-pyrimidine (trimethoprim) (CN 3123, Nevin, Supristol) was investigated to determine any evidence of toxicological potentiation or new toxic signs. It was found that CN 3123 had a very low acute toxicity when administered orally to mice, rats and dogs (oral LD50: mouse greater than 12 000 mg/kg; rat greater than 14 000 mg/kg; dog greater than 1000 mg/kg body weight). The combination was also tolerated by rats and dogs in repeated doses administered over a period of 4 or 26 weeks, that greatly exceeded the therapeutic dose. The only change observed occurred in the thyroid, which in all doses administered exhibited a dose-related increase in weight accompanied by histological changes indicating an activation of thyroid function and a hypersecretion of basophilic thyrotropic cells in the anterior lobe of the pituitary. Six weeks after discontinuation of treatment this condition showed a tendency to reversibility or had already returned to normal. In dogs there was a dose-related increase in iodine uptake by the thyroid and a decrease in serum thyroxine over a period of 6 months under the highest dosage of CN 3123 administered. Whereas the thyroid changes observed under the combination could be reproduced with sulfamoxole, no effect on thyroid weight was observed in rats and dogs in the subacute toxicity phase of a comparative investigation with trimethoprim. Moreover, trimethoprim did not increase the effect of sulfamoxole on the thyroid gland. The effect of sulfamoxole on the thyroid is discussed in detail with a review of the literature. It can be characterized as species-specific for sulfonamides in mice, rats, rabbits and dogs but not in monkeys or in man and appears to be caused by the inhibition of the organic binding of iodine in the thyroid, whereby the predisposing factors must vary considerably from species to species. The thyroid hypertrophy observed is due to the activation of the regulatory cycle via the anterior lobe of the pituitary. The following systemic changes occurred after 600 mg CN 3123/kg, a lethal-toxic dosage and the highest administered in the study: reduced body weight, decreased food consumption leading to cachexia, slightly increased SGPT and alkaline phosphatase, slight thrombocyte depression, enlargement and increased fatty degeneration of the liver, occurrence of necrotic areas in the liver, hemosiderin accumulation in Kupffer's cells, and an increase of reticular cells in the spleen. The acute toxicity of CN 3123 and all major functional and histological changes under repeated administration were due exclusively to sulfamoxole. The combination sulfamoxole/trimethoprim gives no indication of toxicological potentiation or new toxic signs.

[Pharmacological investigations with the combination sulfamoxole/trimethoprim, a new broadspectrum chemotherapeutic agent (author's transl)]. / Pharmakologische Untersuchungen zur Verträglichkeit der Kombination Sulfamoxol/Trimethoprim (CN 3123), eines neuen Breitbandchemotherapeutikums

Investigations were conducted with the combination of N1-(4,5-dimethyl-2-oxazolyl)-sulfanilamide (sulfamoxole) and 2,4-diamino-5-(3,4,5-trimethoxy-benzyl)-pyrimidine (trimethoprim) (CN 3123, Nevin, Supristol) in a dose ratio of 5:1, with respect to pharmacological activity and possible side effects. The effects obtained with the combination CN 3123 were compared with those of the single substances. In a dose range comparable to that as used in clinical treatment, there were no effects on cardiovascular or respiratory functions, on functions of autonomic and central nervous system, on contractility of smooth muscles and on data of clinical chemistry such as urine and electrolyte excretion, blood sugar, blood coagulation and liver function tests. Doses which are 5 to 10 times higher than the initial dose or 10 to 20 times higher than the maintenance dose used in man caused an increase of urine and sodium excretion without influencing potassium and chloride output. There were no signs of sedation as alteration of motility or EEG patterns, but in mice and rats there was an increase in both duration and depth of anaesthesia caused by barbiturates or ether. Only in a dose range 30 to 40 times higher than the initial dose for man there were some slight alterations with respect to cardiovascular system and liver function tests. In vitro, with high concentrations of CN 3123 there was a weak, unspecific spasmolytic effect on the isolated ureter and an increase in the refractory period of the guinea pig atrium. There were no hints that the side effects seen with separate administration of high or very high doses of sulfamoxole or trimethoprim were increased or poteniated by their simultaneous administration. Slight side effects in animals were only observed with doses exceeding the tenfold of the doses for therapeutic use in men. Therefore, the therapeutic range of CN 3123 seems to be more than adequate.

Experiencia clinica y bacteriologica con co-tripanol (Sulfamoxol trimethoprim) en las infecciones bacterianas de los niños

En esta comunicacion, se informa sobre un trabajo prospectivo realizado en un grupo de cien niños con edades entre los dos a doce anos, portadores de diversos procesos infecciosos y asistidos en el Hospital del Niño de la ciudad de La Paz (Bolivia). La investigacion bacteriologica inicial permitio distinguir a dos grandes grupos: treinta y seis casos cuyo estudio de sensibilidad "in vitro" identifico resistencia a la combinacion: sulfamoxol/trimethoprim; otros sesenta y cuatro ninos se habilitaron para un esquema terapeutico con tal droga, administrada por via oral y en dosis menores a las convencionales. Por los resultados obtenidos, se comenta el beneficio demostrado por el Co-trifamol en una poblacion pediatrica, sugiriendo el desarrollo de investigaciones mas especificas, a fin de precisar la mayor sensibilidad y/o resistencia de ciertos germenes ante esta droga

Estudio comparativo del sulfamoxol trimetoprin y la hidroximetil nitrofurantoina en infeccion urinaria

Se realizo un estudio doble ciego en 60 pacientes utilizando el sulfamoxol trimetoprim y la hidroximetil-nitrofurantoina en el tratamiento de la infeccion urinaria. Habiendose encontrado una buena respuesta terapeutica con ambas drogas aunque algo mayor en el grupo que recibio sulfamoxol trimetoprin; asi mismo en este grupo no se informaron efectos colaterales que se hicieron evidentes con la nitrofurantoina. El germen mas frecuente fue la Ecoli en ambos grupos. Los parametros de eficacia laboratorial se hicieron evidentes al cabo del tercer dia de iniciado el tratamiento.