Comparative Toxicological, Chemotherapeutic and Pharmacokinetic Studies with Sulphormethoxine and other Sulphonamides in Animals and Man

Böhni, E.; Fust, B.; Rieder, Josef; Schaerer, K; Havas, László

doi:10.1159/000220630

Cited by 46 publications

(16 citation statements)

References 14 publications

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“…In contrast, the addition of 11 nM folic acid increased the IC 50 SDX value ≈ 60‐fold to over 1.3 μM (Fig. 1b) and, at 23 nM folic acid or higher, the values moved rapidly off the scale of the normal assay range and became difficult to measure reliably, approaching the solubility limits of SDX for aqueous solutions that lie in the mM range (Bohni et al ., 1969; Kapoor, 1988). This phenomenon, qualitatively consistent with earlier studies (Chulay et al ., 1984), was seen for other parasite lines exhibiting the folate effect and indicates a fundamental difference in the mode of action of the two antagonists.…”

Section: Resultsmentioning

confidence: 96%

“…The degree of exposure of the parasites will depend upon the precise levels attained in a given patient and the half‐lives of elimination for each drug. The latter show considerable patient variation (Bohni et al ., 1969; Weidekamm et al ., 1982); in one such study, t 1/2 values for PYR varied from 46 to 150 h (mean 96 h) and from 113 to 226 h (mean 184 h) for SDX (Weidekamm et al ., 1982). To better correlate drug levels and their decay with our inhibition curves in Fig.…”

Section: Resultsmentioning

confidence: 99%

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Utilization of exogenous folate in the human malaria parasite Plasmodium falciparum and its critical role in antifolate drug synergy

Wang

Brobey

Horii

et al. 1999

Molecular Microbiology

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SummaryThe antifolate combination pyrimethamine/sulphadoxine (PYR /SDX; Fansidar) is frequently used to combat chloroquine-resistant malaria. Its success depends upon pronounced synergy between the two components, which target dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS) in the folate pathway. This synergy permits clearance of parasites resistant to either drug alone, but its molecular basis is still unexplained. Plasmodium falciparum can use exogenous folate, which is normally present in vivo, bypassing SDX inhibition of DHPS and, apparently, precluding synergy under these conditions. However, we have measured parasite inhibition by SDX/PYR combinations in assays in which folate levels are strictly controlled. In parasites that use exogenous folate efficiently, SDX inhibition can be restored by levels of PYR significantly lower than those required to inhibit DHFR. Isobolograms show that the degree of synergy between PYR and SDX is highly dependent upon prevailing folate concentrations and are indicative of PYR acting to block folate uptake and/or utilization. No significant synergy was observed at physiological drug levels when PYR / SDX acted on purified DHFR, whether wild type or mutant. We conclude that the primary basis for antifolate synergy in these organisms arises from PYR targeting a site (or sites) in addition to DHFR, which restores DHPS as a relevant target for SDX.

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Utilization of exogenous folate in the human malaria parasite Plasmodium falciparum and its critical role in antifolate drug synergy

Wang

Brobey

Horii

et al. 1999

Molecular Microbiology

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“…Sulfadimethoxine (SDM), a sulfonamide synthetic antibacterial drug (Bohni et al, 1969), is reported to inhibit thyroid hormone synthesis resulting in thyroid growth stimulation through elevation of serum TSH. In rats initiated with DHPN, not only adenomas but also carcinomas, which frequently invade the capsule, are found at high incidences within 8-12 weeks of SDM treatment (Mitsumori et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Sequential Analysis of Development of Invasive Thyroid Follicular Cell Carcinomas in Inflamed Capsular Regions of Rats Treated with Sulfadimethoxine after N-bis(2-hydroxypropyl)nitrosamine-initiation

et al. 2004

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A 2-stage thyroid follicular carcinogenesis model in rats initiated with N-bis(2-hydroxypropyl)nitrosamine (DHPN) is widely used to detect modifying effects of chemicals on thyroid carcinogenesis. A number of goitrogens are known to strongly promote carcinogenesis, and the carcinomas often originate adjacent to the thyroid capsule and show invasive growth into the capsule or adjacent tissues. To clarify mechanisms of progression to invasive carcinomas, we sequentially evaluated histopathological and immunohistochemical characteristics of thyroids in male F344 rats treated with sulfadimethoxine (SDM, 0.1% in drinking water) for 0-10 weeks beginning 1 week after DHPN initiation (2800 mg/kg body weight, single s.c. injection). In DHPN-SDM-treated rats, multiple focal hyperplasias and adenomas developed in thyroid follicular parenchyma at weeks 4 to 6. Apart from the proliferative lesions, capsular thickening with inflammatory cell infiltration, mainly consisting of macrophages, and migration of follicular epithelium into the capsule were also observed. Focal hyperplasias/adenomas adjacent to the capsule progressively developed to invasive carcinomas at weeks 6 to 10. In thyroid parenchyma, malignant lesions were seldom observed. With SDM-treatment alone, although no neoplastic lesions were observed, capsular thickening with inflammation and epithelial migration resulted in intracapsular residual follicles. Intracapsular residual follicular cells as well as invasive and intrathyroidal carcinoma cells generally showed increased cell proliferative activity, coincidental with cytoplasmic/nuclear positivity for β-catenin. These results suggested that β-catenin activation related to capsular inflammation may play a role in development of invasive carcinomas but is insufficient for tumor formation by itself. Whether this is associated with mutations in the β-catenin gene remains to be clarified.

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“…This may explain the delay in response to therapy and the early occurrence of the relapses after the cessation of therapy. In contrast, the early efficacy of sulfadiazine could be related to its longer half-life in mice (11 h) and a large diffusion in tissues (3).…”

mentioning

confidence: 97%

In vivo assessment of antimicrobial agents against Toxoplasma gondii by quantification of parasites in the blood, lungs, and brain of infected mice

Piketty

Derouin

Rouveix

et al. 1990

Antimicrob Agents Chemother

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The in vivo effects of antimicrobial agents against Toxoplasma gondii were evaluated in mice that were infected intraperitoneally with 104 tachyzoites of the RH strain by determination of survival rates and study of the kinetics of growth of T. gondi in infected mice. At various intervals after infection, subcultures of serial dilutions of blood, lung, and brain homogenates were performed in fibroblast tissue cultures for determination of parasitic loads. Pyrimethamine (18.5 mg/kg per day), sulfadiazine (375 mg/kg per day), and clindamycin (300 mg/kg per day) were administered for 10 days from day 1 or day 4 after infection. Untreated control mice died within 9 days and showed early and predominant lung involvement. All mice treated with sulfadiazine administered from day 1 survived and were apparently healthy; parasitic loads decreased early after treatment, but a relapse was observed 5 days after the cessation of therapy. When pyrimethamine was administered from day 1, 7 of 11 mice died within 25 days; by determination of parasitic loads, the effect of pyrimethamine was only demonstrable from day 6, and a relapse was constantly observed after the cessation of therapy. When pyrimethamine and sulfadiazine were administered in combination, 100% of mice survived; when therapy was started at day 1, parasites remained undetectable; in mice treated from day 4, parasites were eradicated by day 8 but infection relapsed 8 days after the cessation of therapy. All mice treated with clindamycin from day 1 or day 4 died within 10 days, but parasitemia was always undetectable. These results indicate that study of the kinetics of parasitic loads in blood and organs may provide additional information on the effect of antimicrobial agents against T. gondii in regard to the evolution of the infection and may represent a reliable basis for the determination of therapeutic regimens in humans.In vivo experimental studies of Toxoplasma gondii are usually performed in mice that are either acutely infected by intraperitoneal injection of tachyzoites or chronically infected by peroral ingestion or intraperitoneal injection of cysts. Another alternative, which better fits with the pathophysiology of toxoplasmosis in immunocompromised human patients, is to induce a reactivation in chronically infected mice by depleting the CD4+ lymphocyte subpopulation (19), administering anti-gamma interferon (18), or creating a model of intracerebral infection by local injection of tachyzoites (11,12). Assessment of the efficacy of antimicrobial agents is based on the comparative study of mean survival times of untreated and treated mice, enumeration of brain cysts, and in some cases, histologic examination of organs and subinoculation to mice of dilutions of organ homogenates. The survival rate is an important parameter which can be determined easily but which is poorly informative regarding the mode of drug action. Since additional histological studies and mice subinoculations are time-consuming and may not be applied for extensive studies, we propos...

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Comparative Toxicological, Chemotherapeutic and Pharmacokinetic Studies with Sulphormethoxine and other Sulphonamides in Animals and Man

Cited by 46 publications

References 14 publications

Utilization of exogenous folate in the human malaria parasite Plasmodium falciparum and its critical role in antifolate drug synergy

Utilization of exogenous folate in the human malaria parasite Plasmodium falciparum and its critical role in antifolate drug synergy

Sequential Analysis of Development of Invasive Thyroid Follicular Cell Carcinomas in Inflamed Capsular Regions of Rats Treated with Sulfadimethoxine after N-bis(2-hydroxypropyl)nitrosamine-initiation

In vivo assessment of antimicrobial agents against Toxoplasma gondii by quantification of parasites in the blood, lungs, and brain of infected mice

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