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The susceptibility to pyrimethamine and proguanil of a strain of Plasmodium falciparum from Thailand was assessed by using blood from the same patient cultured by two different techniques. Irrespective of the technique used, the strain of P. falciparum appeared more sensitive to proguanil than to pyrimethamine.
Recurrent isosporiasis in an immunocompetent host is reported. The patient suffered from chronic intermittent diarrhea for over a decade. Multiple short-term administrations of trimethoprim-sulfamethoxazole followed by pyrimethamine, or albendazole combined with tinidazole could not control the relapses. However, treatment with pyrimethamine, 25 mg/d for 20 weeks, was successful.
In this international, noncomparative, randomized phase II trial, we evaluated the effectiveness and tolerance of atovaquone suspension (1500 mg orally twice daily) plus either pyrimethamine (75 mg per day after a 200-mg loading dose) or sulfadiazine (1500 mg 4 times daily) as treatment for acute disease (for 6 weeks) and as maintenance therapy (for 42 weeks) for toxoplasmic encephalitis (TE) in patients infected with human immunodeficiency virus. Twenty-one (75%) of 28 patients receiving pyrimethamine (95% lower confidence interval [CI], 58%) and 9 (82%) of 11 patients receiving sulfadiazine (95% lower CI, 53%) responded to treatment for acute disease. Of 20 patients in the maintenance phase, only 1 experienced relapse. Eleven (28%) of 40 eligible patients discontinued treatment as a result of adverse events, 9 because of nausea and vomiting or intolerance of the taste of the atovaquone suspension. Although gastrointestinal side effects were frequent, atovaquone-containing regimens are otherwise well tolerated and safe and may be useful for patients intolerant of standard regimens for toxoplasmic encephalitis.
The role of the sickle cell hemoglobin type as a determinant of treatment outcome with sulfadoxine-pyrimethamine was retrospectively studied in young children with uncomplicated falciparum malaria who lived in an area with intense perennial malaria transmission. Between 1993 and 1997, 2795 treatments involving 813 children were monitored. Sickle cell trait (HbAS) was present in 17.7% of the children. Two-and-a-half percent of the children experienced early clinical treatment failure by day 2-3, and 17.3% of the children were parasitemic on day 7. Treatments in HbAS children were less likely than those in HbAA children to result in persistence of parasitemia by day 3 (relative risk [RR], 0.66; 95% confidence interval [CI], 0.47-0.93; P=.02) or in parasitologic treatment failure on day 7 (RR, 0.51; 95% CI, 0.36-0.71; P<.0001). These results suggest that the HbAS phenotype should be included among factors that determine sulfadoxine-pyrimethamine treatment outcome.
The effectiveness of chloroquine or sulfadoxine-pyrimethamine administered with artesunate for treating uncomplicated falciparum malaria was assessed in 2 Vietnamese provinces where the sensitivity of parasites in vitro to conventional therapies had increased with the removal of drug pressure. In the province of Dac Lac, where potential malaria exposure begins at birth, 57 subjects (mean age, 9.6 years) were randomized to receive artesunate-chloroquine (group 1) or artesunate-sulfadoxine-pyrimethamine (group 2). In the province of Binh Phuoc, 66 nonimmune workers and their relatives (mean age, 24.2 years) were similarly randomized. By day 28 of follow-up, >96% of Dac Lac patients and <52% of Binh Phuoc patients in group 1 and group 2 had an in vivo response that demonstrated sensitivity to therapy. PCR-confirmed cure rates paralleled in vivo results among patients in Binh Phuoc, but PCR results identified 9 (15.7%) of the Dac Lac patients as having experienced asymptomatic, submicroscopic recrudescences. In Dac Lac, pfcrt K76T was near fixation, but infection with parasites with this mutation predicted recrudescence among group 1 patients in Binh Phuoc. Common pfdhfr mutations did not predict outcome in group 2. The successful reintroduction of conventional therapies in combination with artesunate depends on epidemiological and/or parasitological factors.
BACKGROUND: The target enzyme of pyrimethamine is dihydrofolate reductase (DHFR), but little is known about allelic variants of dhfr in Plasmodium vivax populations. Still less is known about associations between specific alleles and the failure of sulfadoxine/pyrimethamine (S/P) to clear the erythrocytic stages of P. vivax in vivo. METHODS: We studied P. vivax dhfr mutations in 24 patients who received S/P therapy in Papua or Central Java, Indonesia, and we measured the resistance of the alleles in vitro in a dhfr yeast expression assay. RESULTS: Fourteen (58%) of 24 patients had an inadequate therapeutic response. Two of 6 alleles that were identified were novel. One allele that expressed 4 point mutations (57L+58R+61M+117T) correlated with a high risk of therapeutic failure. The 9 patients infected by P. vivax carrying this allele proved 23 times more likely to experience early therapeutic failure, compared with patients infected by P. vivax carrying other alleles (P=.003; 95% confidence interval, 2-450). This allele also conferred high levels of pyrimethamine resistance in vitro. The experimental antifolate WR99210 inhibited the allele in this system. CONCLUSIONS: The present study identified a strong correlation between specific mutations in P. vivax dhfr and S/P treatment failure. Our results suggest that WR99210 could provide effective therapy for S/P-resistant P. vivax.
BACKGROUND: The altered immune response of persons with human immunodeficiency virus (HIV) infection could result in increased rates of antimalarial treatment failure. We investigated the influence of HIV infection on the response to sulfadoxine-pyrimethamine treatment. METHODS: Febrile adults with Plasmodium falciparum parasitemia were treated with sulfadoxine-pyrimethamine and were monitored for 28 days. HIV status and CD4 cell count were determined at study enrollment. RESULTS: Of the adults enrolled in the study, 508 attended all follow-up visits, including 130 HIV-uninfected adults, 256 HIV-infected adults with a high CD4 cell count (> or =200 cells/ micro L), and 122 HIV-infected adults with a low CD4 cell count (<200 cells/ micro L). The hazard of treatment failure at day 28 of follow-up was significantly higher for HIV-infected adults with a low CD4 cell count (20.5%) than for HIV-uninfected adults (7.7%). Anemia (hemoglobin level, <110 g/L) modified the effect of HIV status on treatment failure. When we controlled for fever and parasite density, the hazard of treatment failure for HIV-infected adults with a low CD4 cell count and anemia was 3.4 times higher than that for HIV-uninfected adults (adjusted hazard ratio, 3.38; 95% confidence interval, 1.56-7.34). CONCLUSIONS: HIV-infected persons with a low CD4 cell count and anemia have an increased risk of antimalarial treatment failure. The response to malaria treatment in HIV-infected persons must be carefully monitored. Proven measures for the control and prevention of malaria must be incorporated into the basic package of services provided by HIV/acquired immunodeficiency syndrome care and treatment programs in malarious areas.
Trimethoprim and pyrimethamine, inhibitors of dihydrofolate reductase (DHFR), cause folate deficiency in some patients. We investigated impairment of intestinal folate absorption by these drugs. By use of the in vivo intestinal-loop methods in rats, absorption of [3H] folic acid was significantly decreased in the presence of either drug. Kinetic studies using the influx chamber method demonstrated a pattern of competitive inhibition of folate transport. [3H] folic acid absorption from jejunal loops was determined 3-16 h after IV administration of methotrexate; this treatment abolished DHFR activity in the small intestine. In rats pretreated with methotrexate, luminal disappearance and systemic absorption of folic acid were significantly enhanced with respect to controls. Trimethoprim and pyrimethamine are weak competitive inhibitors of intestinal folate transport and folate absorption inhibition occurs at the site of membrane transport and appears to be unrelated to concurrent inhibition of DHFR activity in enterocytes.
Drug resistance is contributing to increasing mortality from malaria worldwide. For assessment of the role of resistance-conferring parasite mutations on treatment responses to sulfadoxine-pyrimethamine (SP) and transmission potential, 120 subjects with uncomplicated falciparum malaria from Buenaventura, Colombia, were treated with SP and followed for 21 days in the period February 1999 to May 2000. Exposures of interest were mutations in Plasmodium falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthase that confer resistance to pyrimethamine and sulfadoxine, respectively. Although SP was highly efficacious (96.7%), the presence together of DHFR mutations at codons 108 and 51 was associated with longer parasite clearance time (relative hazard = 0.24, p = 0.019) more so than the 108 mutation alone (relative hazard = 0.45, p = 0.188). This association remained after controlling for potential confounders. Infections with these mutations were also associated with the presence of gametocytes, the sexual form of the parasite responsible for transmission, 14 and 21 days after treatment (p = 0.016 and p = 0.048, respectively). Higher gametocytemia is probably due to DHFR mutations prolonging parasite survival under drug pressure, resulting in longer parasite clearance time and allowing asexual parasites to differentiate into gametocytes. These results suggest that even when SP efficacy is high, DHFR mutations that are insufficient to cause therapeutic failure may nevertheless increase malaria transmission and promote the spread of drug resistance.
Pyrimethamine, 25 mg thrice weekly, was evaluated as primary prophylaxis for toxoplasmic encephalitis (TE) in a double-blind, randomized clinical trial in patients with human immunodeficiency virus (HIV) disease, absolute CD4 lymphocyte count of < 200/microL (or prior AIDS-defining opportunistic infection), and the presence of serum IgG to Toxoplasma gondii. Leucovorin was coadministered only for hematologic toxicity. There was a significantly higher death rate among patients receiving pyrimethamine (relative risk [RR], 2.5; 95% confidence interval [CI], 1.3-4.8; P = .006), even after adjusting for factors predictive of survival. The TE event rate was low in both treatment groups (not significant). Only 1 of 218 patients taking trimethoprim-sulfamethoxazole but 7 of 117 taking aerosolized pentamidine for prophylaxis against Pneumocystis carinii pneumonia developed TE (adjusted RR for the trimethoprim-sulfamethoxazole group, 0.16; 95% CI, 0.01-1.79; P = .14). Thus, for HIV-infected patients receiving trimethoprim-sulfamethoxazole, additional prophylaxis for TE appears unnecessary.
A nonfatal case of accidental prolonged overdosage of pyrimethamine (10 times the usual dose for 10 days) in a seven-week-old infant treated for congenital toxoplasmosis is presented. The drug was identified and quantitated in plasma and urine using an HPLC technique with diode-array detection. Initial plasma concentration of pyrimethamine was 6.22 micrograms/mL. Results are discussed in light of the existing literature.
Malaria parasites (Plasmodium falciparum) provide an excellent system in which to study the genomic effects of strong selection in a recombining eukaryote because the rapid spread of resistance to multiple drugs during the last the past 50 years has been well documented, the full genome sequence and a microsatellite map are now available, and haplotype data can be easily generated. We examined microsatellite variation around the dihydrofolate reductase (dhfr) gene on chromosome 4 of P. falciparum. Point mutations in dhfr are known to be responsible for resistance to the antimalarial drug pyrimethamine, and resistance to this drug has spread rapidly in Southeast (SE) Asia after its introduction in 1970s. We genotyped 33 microsatellite markers distributed across chromosome 4 in 61 parasites from a location on the Thailand/Myanmar border. We observed minimal microsatellite length variation in a 12-kb (0.7-cM) region flanking the dhfr gene and diminished variation for approximately 100 kb (6 cM), indicative of a single origin of resistant alleles. Furthermore, we found the same or similar microsatellite haplotypes flanked resistant dhfr alleles sampled from 11 parasite populations in five SE Asian countries indicating recent invasion of a single lineage of resistant dhfr alleles in locations 2000 km apart. Three features of these data are of especially interest. (1). Pyrimethamine resistance is generally assumed to have evolved multiple times because the genetic basis is simple and resistance can be selected easily in the laboratory. Yet our data clearly indicate a single origin of resistant dhfr alleles sampled over a large region of SE Asia. (2). The wide valley ( approximately 6 cM) of reduced variation around dhfr provides "proof-of-principle" that genome-wide association may be an effective way to locate genes under strong recent selection. (3). The width of the selective valley is consistent with predictions based on independent measures of recombination, mutation, and selection intensity, suggesting that we have reasonable estimates of these parameters. We conclude that scanning the malaria parasite genome for evidence of recent selection may prove an extremely effective way to locate genes underlying recently evolved traits such as drug resistance, as well as providing an opportunity to study the dynamics of selective events that have occurred recently or are currently in progress.
OBJECTIVE: To investigate the efficacy and safety of three regimens for primary prophylaxis of Pneumocystis carinii pneumonia (PCP) and toxoplasmic encephalitis (TE) and to evaluate their effect on survival in patients with HIV infection. DESIGN: Randomized, open label, prospective trial. SETTING: A single Infectious Diseases Department in Italy. PATIENTS: HIV-infected patients (n = 197) with a CD4 count < 200 x 10(6)/l and without previous PCP or TE. INTERVENTIONS: Patients were randomly assigned to receive (1) aerosolized pentamidine (AP; 300 mg monthly), (2) cotrimoxazole (CTX; 160 mg trimethoprim and 800 mg sulfamethoxazole every other day), or (3) dapsone-pyrimethamine (DP; 100 mg weekly dapsone and 25 mg biweekly pyrimethamine). MAIN OUTCOME MEASURES: PCP, TE, death, and drug-limiting toxicity. Considering difference in PCP occurrence the trial was interrupted on June 1992. Observation was prolonged until June 1994 for TE and survival. RESULTS: Intention-to-treat analysis yielded PCP rates of 10.2 per 100 person-years in the AP, 2.0 in the CTX, and 32.1 in the DP group [adjusted relative risk of DP versus CTX: 17.5; 95% confidence interval (CI), 2.2-139.6; P = 0.007]. TE rates in patients with positive Toxoplasma serology were 25.6 per 100 person-years in the AP, 8.9 in the CTX and 9.4 in the DP group. In 'on treatment' analysis, no episode of TE developed in the DP group, and rates were 34.7 per 100 person-years in the AP and 2.5 in the CTX group (AP versus CTX: P = 0.01; AP versus DP: P = 0.004). The adjusted risk of mortality for the DP group was 2.8 times that of the CTX group in the first part of the study (95% CI, 1.1-7.3; P = 0.037), and 1.8 times (95% CI, 1.1-2.9; P = 0.02) in the prolonged follow-up. No significant difference in the occurrence of serious adverse reactions was observed between the three treatment groups. CONCLUSIONS: Intermittent CTX was more effective than low-dose DP and showed a slight but not significant advantage on AP for primary PCP prophylaxis. DP was associated with a shorter survival. Both CTX and DP resulted in a significant reduction in the risk of TE.
Pyrimethamine is used for the treatment of toxoplasmosis and the prophylaxis of malaria. Among the well-documented side effects are megaloblastic anemia, leukopenia, thrombopenia, rash, vomiting, and diarrhea. Hyperpigmentation is a very rare side effect. In some patients, associated HIV infection makes it difficult to distinguish the reasons for the etiology. We herein describe an HIV-negative patient who developed hyperpigmentation after pyrimethamine use.
1. The multiple-dose kinetics of dapsone (DDS), its major metabolite monoacetyldapsone (MADDS) and pyrimethamine (PYR) were studied in six healthy adult male volunteers following weekly administration of Maloprim (100 mg DDS plus 12.5 mg PYR). 2. After the last maintenance dose of Maloprim, the following kinetic parameters (mean values) were determined for DDS and PYR, respectively: maximum plasma concentration (Cmax) = 1,134 and 116 ng ml-1; elimination half-life (t1/2) = 23 and 105 h; plasma clearance (CL) = 37.6 and 15.9 ml h-1 kg-1 and apparent volume of distribution (Vss) = 1.20 and 2.29 l kg-1. The mean t1/2 of MADDS was 22 h. 3. The mean whole blood to plasma (B/P) and erythrocyte to plasma (E/P) concentration ratios for DDS were 1.04 and 1.09, respectively. MADDS had a B/P ratio of 0.69 and an E/P ratio of 0.33. The B/P and E/P ratios for PYR were 0.98 and 0.54, respectively. 4. The drug combination was assessed in vitro by measuring inhibition of re-invasion of two Plasmodium falciparum isolates grown in the presence of volunteers' sera. The chloroquine (CQ)- and PYR-sensitive FC-27 isolate was completely inhibited by the sera but the drug combination was ineffective against the CQ- and PYR-resistant K1 strain. The in vitro findings suggest that Maloprim may not be effective against strains of P. falciparum with a high level of resistance to pyrimethamine.
BACKGROUND AND OBJECTIVE: Malaria is a disease of major public health importance in Kenya killing 26,000 children under 5 years of age annually. This paper seeks to assess the quality of sulphadoxine-pyrimethamine (SP) and amodiaquine (AQ) products available over-the-counter to communities in Kenya as most malaria fevers are self-medicated using drugs from the informal retail sector. METHODS: A retail audit of 880 retail outlets was carried in 2002 in four districts in Kenya, in which antimalarial drug stocks and their primary wholesale sources were noted. In addition, the expiry dates on audited products and the basic storage conditions were recorded on a proforma. The most commonly stocked SP and AQ products were then sampled from the top 10 wholesalers in each district and samples subjected to standard United States Pharmacopoeia (USP) tests of content and dissolution. RESULTS AND DISCUSSION: SP and AQ were the most frequently stocked antimalarial drugs, accounting for approximately 75% of all the antimalarial drugs stocked in the four districts. Of 116 SP and AQ samples analysed, 47 (40.5%) did not meet the USP specifications for content and/or dissolution. Overall, approximately 45.3% of SP and 33.0% of AQ samples were found to be sub-standard. Of the sub-standard SP products, 55.2% were suspensions while 61.1% of the substandard AQ products were tablets. Most SP failures were because of the pyrimethamine component. CONCLUSION: There is a need to strengthen post-marketing surveillance systems to protect patients from being treated with sub-standard and counterfeit antimalarial drugs in Kenya.
Dihydrofolate reductase activity of 0.2 nmole of dihydrofolate reduced/min/mg protein was detected in crude extracts of unsporulated oocysts of Eimeria tenella. The enzyme was purified by a combination of affinity and ion-exchange chromatography. Its molecular weight was estimated as 240,000 daltons. An anticoccidial drug pyrimethamine is a potent inhibitor of the activity of E. tenella dihydrofolate reductase (Ki = 3 nM), but it is less effective an inhibitor of dihydrofolate reductase from chicken liver. This difference may explain the in vivo therapeutic action of pyrimethamine against Coccidia.
Placental sequestration of Plasmodium falciparum in pregnancy may impair the usefulness of molecular markers of sulfadoxine-pyrimethamine resistance. In 300 infected, delivering women, the concordance of PCR-restriction fragment length polymorphism-derived parasite resistance alleles in matched samples from placenta and circulation was 83 to 98%. Sulfadoxine-pyrimethamine resistance typing in peripheral blood is reasonably representative of P. falciparum infecting pregnant women.