We have investigated the plasma pharmacokinetics and mass fate in mice, of pyrimethamine administered as either the base or as the poorly soluble pamoate salt, in each case by the intraperitoneal (i.p.) and subcutaneous (s.c.) routes. Following the administration of pyrimethamine base (i.p. and s.c.) and pyrimethamine pamoate (i.p.), maximum measured plasma levels of pyrimethamine were attained within 1 h, before declining monoexponentially. There was no significant difference between these three groups in the clearance (0.29 +/- 0.05, 0.30 +/- 0.03, 0.26 +/- 0.05 ml min-1), elimination half-life (4.5 +/- 0.5, 4.8 +/- 0.8, 4.9 +/- 0.5 h) and AUC (19.4 +/- 4.4, 17.3 +/- 2.2, 21.1 +/- 4.4 micrograms.h ml-1). By contrast, after s.c. dosage of pyrimethamine pamoate, drug absorption was significantly delayed, maximum plasma levels being reached after 4 h, these levels being approximately one-third of those in the other three groups. Absorption was however complete, as the values for AUC and clearance were not significantly different from the other groups. The pattern of faecal and urinary elimination of 14C radioactivity was unaffected by either dose site or formulation of pyrimethamine. The majority of the dose (44.5-64.2 per cent) was eliminated in the faeces suggesting extensive biliary excretion. Localization of 14C radioactivity in the major organs was negligible in all groups. Following each dose, between 85 and 98 per cent of the dose was accounted for. These studies indicate that of the four treatment groups only pyrimethamine pamoate on s.c. administration demonstrates a sustained release action from the dose site.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Chloroquine sensitivity of Plasmodium falciparum in vivo in a savanna town in Cameroon.

Chloroquine-resistant Plasmodium falciparum has been reported in the Sahel and forest regions of Cameroon since 1985. In vivo response to chloroquine treatment (25 mg/kg) was assessed in 19 patients with malaria in the savanna North-West province. 58% of the cases showed RII resistance to chloroquine. RIII resistance was suspected in one patient. Only 35% of cases showed complete parasite clearance by day 5 of treatment. Chloroquine reduced parasite counts by at least 87% in all patients. Chloroquine resistance now seems to be well established and widespread in Cameroon. Its rapid spread and the prevalence of resistance suggest the existence of sustained drug pressure resulting in rapid selection of less sensitive strains. Unfortunately, similar pressure is also being exerted with quinine.

Adolescent↗

PubMedDate not supplied

The potential of desipramine to reverse chloroquine resistance of Plasmodium falciparum is reduced by its binding to plasma protein.

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Animals↗

PubMedDate not supplied

Glutathione S-transferase GSTM1 and GSTT1 genotypes in ovarian cancer: association with p53 expression and survival.

The objective of this study was to determine whether the association between GSTM1 null/GSTTI null and survival in ovarian cancer is mediated by the influence of these genes on p53 expression. In 81 women with pure invasive ovarian cancer, GSTM1 null and GSTT1 null genotypes were identified using polymerase chain reaction and p53 expression was assessed using immunohistochemistry. The association of these factors with survival was examined using Cox's proportional hazards regression models. Performance status (P < 0.001), operative stage (P = 0.004), residual disease (P = 0.001), histologic subtype (P = 0.05), tumor grade (P = 0.007), and the combined GSTMI null/GSTTl null genotype (P = 0.023) were all individually associated with survival. p53 expression was not associated with survival (P = 0.45). In a multivariate analysis, the effects of GSTM1 null/GSTT1 null on survival were lost when residual disease and tumor grade were included. The effects of p53 expression on survival were unchanged when residual disease, tumor grade, operative stage, and performance score were included. GSTM1 null/GSTT1null did not influence the effects of p53 expression on survival and vice versa. The GSTM1 null/GSTT1 null genotype was associated with response to primary chemotherapy (P = 0.007) but p53 expression was not. We conclude that the association of GSTM1 null/GSTTl null with survival appears to be mediated through different mechanisms to p53 expression in ovarian cancer and in addition, may be a better predictor of outcome.

Adult↗