PubMed Health⌕ Search

Biomedical subjects

W Neumann

Publications and source records attributed to W Neumann.

At least 37 records · Page 2Linked to original sources
PubMed1976

[Pharmacological investigations with the combination sulfamoxole/trimethoprim, a new broadspectrum chemotherapeutic agent (author's transl)].

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.

Animals↗
PubMed1976

[Toxicological investigations of the combination sulfamoxole/trimethoprim, a new broad-spectrum chemotherapeutic (author's transl)].

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.

Animals↗
PubMed1976

[Investigations on the effect of the combination sulfamoxole/trimethoprim on fertility and fetal development in rats and rabbits (author's tranls)].

The chemotherapeutically active combination of N1-(4,5-dimethyl-2-oxazolyl)-sulfanilamide (sulfamoxole) and 2,4-diamino-5-(3,4,5-trimethoxy-benzyl)-pyrimidine (trimethoprim) in a dose ratio of 5:1 (CN 3123, Nevin, Supristol) was investigated, with respect to teratogenicity, effects on fertility and reproduction and influence on peri- and post-natal development. Experiments with the combination and partly with the single substances were done on Sprague-Dawly and Wistar rats and on rabbits (New Zealand White). With regard to the known effects of trimethoprim in this field--fetal malformations typical of those caused by folic acid antagonists--it was to clarify whether or not potentiation phenomena or new toxic effects occur with the combination. The results were as follows: 1. CN 3123 is teratogenically and fetotoxically active when given in very high doses to pregnant rats and rabbits during the critical phase of organogenesis (day 8-15 of pregnancy in rats, day 8-14 in rabbits). There were malformations, decrease in the number of pups and an increase in the number of absorption sites. Litter size and litter weight were reduced. The malformations observed were cleft palates, rarely cleft lips, micrognathies and shortening of limbs. Doses up to 180 mg/kg CN 3123, corresponding to more than tenfold the daily maintenance dose in man, were without any effects on all parameters observed. Toxic effects were observed in Sprague-Dawley rats at a dose level of 420 mg/kg and in Wistar rats with 600 mg/kg, corresponding to the effects seen following 100 mg/kg of trimethoprim alone. Sulfamoxole in the corresponding dose of 500 mg/kg caused no embryotoxic effects in the rat. In rabbits 600 mg/kg CN 3123 induced no malformations but increased fetal loss. Therefore it can be concluded, that the teratogenic and fetotoxic effects seen with high doses of CN 3123 are due to the amount of trimethoprim in the combination. The observed effects with the combination are quantitatively related to those seen with trimethoprim. 2. CN 3123 in high doses which are teratogenic also provoked a reduction of growth of the animals. Food consumption and weight gain were reduced in dams with 420 and 600 mg/kg CN 3123. In this dose range the pup weights and the weight gain of the offspring of dams with continued dosing during lactation were also reduced. Variation rate including retardations was increased. The depressing effect of CN 3123 in high doses on food consumption and weight gain is known from long-term toxicological studies previously described [7]. 3. CN 3123 even with high doses has no effects on the fertility of male and female rats. The number of corpora lutea and implantations and also the pregnancy rate were unaffected when either the female or the male rats used for mating had been treated. There was also no influence on mating activity of the male animals treated. 4. According to the results of the fertility study with treatment of the male rats for a period of ten weeks or more there were no signs of mutagenic effects due to CN 3123.

Abnormalities, Drug-Induced↗
PubMed1975

[Pharmacological and toxicological properties of the saluretic xipamide (4-chloro-5-sulfamoyl-2',6'-salicyloxylidide)].

Xipamide (4-chloro-5-sulfamoyl-2',6'-salicyloxylidide, Aquaphor), a new compound is a derivate of salicylic acid with marked sodium and water excreting potency. Its effect is dosage dependent. Dosages as low as 0.001 mg/kg p.o. in rats and 0.04 mg/kg p.o. in dogs lead to a statistically significant increase of sodium and water excretion. Potassium excretion was less affected and showed to be rather constant in a dosage range between 0.01 and 10.0 mg/kg. In rats a maximum of sodium and water excretion could be reached by a dose of 200 mg/kg duration of action in rats was approximately 10 h. In dogs a statistically significant sodium and chloride excretion could be detected after oral application of 0.04 mg/kg. Xipamide increased diuresis started with an oral dose of 0.1 mg/kg. Intravenous application of xipamide in a dose of 0.2 mg/kg in dogs accompanied by permanent infusion of 5 per cent mannit solution clearly showed the diuretic profile of the substance: increased diuresis started within 40 min. A peak was reached within 40-60 min post injectionem. Then excretion decreased slowly. Even 120 min post injectionem a diuretic action could be detected. Diuresis and sodium excretion could be demonstrated in rats with experimentally predamaged kidneys and with steroid dependent sodium retention. As could be demonstrated in hypertensive rats xipamide had a hypotensive effect, normotensive rats were not affected. In animal studies xipamide was excellently tolerated. The therapeutic range of the substance was high in single doses as well as when the drug administered over 6 weeks.

Animals↗