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PubMed1987

Decreased hepatic elimination of pyrimethamine during malaria infection. Studies in the isolated perfused rat liver.

The elimination of the antimalarial drug pyrimethamine was studied in isolated liver preparations from young rats (80-100 g) infected with merozoites of Plasmodium berghei two weeks earlier. Perfusate half-life of pyrimethamine was increased in livers from M.I. rats (t1/2 beta control group = 56 +/- 11 min vs M.I. group = 101 +/- 12, P less than 0.01), reflecting a decrease in hepatic clearance (3.6 +/- 1.1 ml/min vs 1.9 +/- 0.5 ml/min, P less than 0.01). There was no significant difference in volume of distribution between livers from M.I. and control groups. Intrahepatic concentration of unchanged drug at 3 hr was 4-5-fold greater in livers from infected rats (control group = 4725 +/- 2287 ng/ml vs M.I. group = 22,324 +/- 6824 ng/ml), while liver: perfusate concentration ratios were not significantly different (control group = 30.8 +/- 24.1 vs M.I. group = 35.6 +/- 20.3). We conclude that the hepatic elimination of pyrimethamine is substantially impaired in the malaria-infected rat.

Animals↗

PubMed1983

Suppression of mitogenic lectin-induced blast transformation of human peripheral blood mononuclear cells by pyrimethamine.

The anti-malarial drug pyrimethamine suppresses in vitro mitogenic lectin-induced blast transformation by human peripheral blood mononuclear cells (MNC) when the drug is added to cells (1 X 10(-5) M/culture). Sulphadoxine, a second widely used anti-malarial drug has no suppressive effect on the MNC. MNC responsiveness in the mixed leucocyte reaction and cellular viability are not altered by either pyrimethamine or sulphadoxine. In addition, no significant suppression is found when serum obtained from individuals on pyrimethamine-sulphadoxine chemoprophylaxis is added to MNC in the assays. The data, however, do not totally rule out any clinically significant suppressive effect by the anti-malarial drugs on human cellular immune responses.

Antigens, Surface↗

PubMed1984

Concomitant resistance to pyrimethamine and cycloguanil of chloroquine-resistant falciparum malaria from East Africa: an in vitro study of 12 isolates.

The susceptibility of 12 isolates of Plasmodium falciparum to chloroquine, pyrimethamine and cycloguanil was studied in vitro after adaptation of the isolates to continuous culture by a 48-hour single-step multiplication inhibition assay. All of seven isolates imported from Tanzania since 1981 proved chloroquine resistant and six of these had an IC50 above 0.64 X 10(-6)M suggesting RII-RIII resistance. All chloroquine-resistant isolates were concomitantly resistant to pyrimethamine (IC50 above 10(-6)M). All chloroquine and pyrimethamine-resistant strains had IC50 values for cycloguanil of at least 0.6 X 10(-6)M which is higher than the Malayan (Camp.) strain studied in vitro and known to be proguanil/cycloguanil-resistant in vivo. Cycloguanil is the active metabolite of proguanil, and this result makes it doubtful whether proguanil would be a more effective prophylactic than chloroquine in East Africa, and whether any advantage over chloroquine alone would be derived from a combination of the two.

Africa, Eastern↗

PubMed1985

Susceptibility of Plasmodium falciparum in The Gambia to pyrimethamine, Maloprim and chloroquine.

A five-year malaria chemoprophylaxis study has begun with Maloprim in children aged three months to five years and pregnant women in a population of 13,000 in the area of Farafenni, The Gambia. Sensitivity of Plasmodium falciparum to pyrimethamine, Maloprim and chloroquine was assessed in vivo and in vitro in rural Gambian villages before drug intervention. 569 children aged one to seven years inclusive were sampled at the end of the wet season of 1982; 46% had positive blood films. All afebrile children were treated with a single dose of one of the antimalarials under study. Febrile children were treated with chloroquine. 109 infected children were retested 7 to 10 days after treatment and none showed asexual parasitaemia. 83 micro in vitro tests were successfully performed from fingerprick blood samples and the results confirmed the in vivo study. Pyrimethamine in combination with dapsone, in the proportion present in Maloprim, i.e., 1:8, showed a synergistic effect, the mean effective dose of pyrimethamine being reduced 13 times at the 50% inhibitory level.

Antimalarials↗

PubMed1985

Simultaneous determination of pyrimethamine and sulphadoxine in human plasma by high-performance liquid chromatography.

Pyrimethamine was extracted as a base, and sulphadoxine simultaneous as an ion pair with tetrabutyl-ammonium into methylene chloride. After re-extraction into an acidic aqueous phase separation of the drugs was performed by reversed-phase high performance liquid chromatography using Nucleosil C-18 as the support and acetonitrile-phosphate buffer pH 5.5 (28 + 72) as the mobile phase with tetrabutyl-ammonium as counter ion. Photometric detection at 240 nm was used for both substances. The within-day precision of the method was 5 to 10% for pyrimethamine within 50 to 1000 nmol/l (13 to 250 ng/ml) and for sulphadoxine 3 to 6% within 50 to 1000 mumol/l (16 to 310 micrograms/ml) in plasma. The method is suitable for simultaneous determination of plasma levels of pyrimethamine and sulphadoxine after therapeutic doses of Fansidar.

Chromatography, High Pressure Liquid↗

PubMedDate not supplied

Standard and reduced doses of sulfadoxine-pyrimethamine for treatment of Plasmodium falciparum in Tanzania, with determination of drug concentrations and susceptibility in vitro.

88 asymptomatic Tanzanian schoolchildren with Plasmodium falciparum parasitaemia were given all, half or quarter of the recommended standard therapeutic dose of sulfadoxine-pyrimethamine (Fansidar). All children cleared the parasites by day 3 and all remained negative during 28-42 days of follow-up. All 32 successful in vitro micro-tests showed full sensitivity. High performance liquid chromatographic methods were applied for drug determinations. Using 100 microliter capillary blood dried on filter paper for sulfadoxine determination the inter-individual variation during follow-up of the standard dose group was 2-4 fold and the median half life was 8.9 d. Sulfadoxine concentrations in the half and quarter dose groups were roughly proportional to those in the standard dose group. The median whole blood to plasma concentration ratio for sulfadoxine was 0.72 and the correlation coefficient 0.95. There was only a weak correlation (r=0.46) between plasma concentrations of sulfadoxine and pyrimethamine. The uniform efficacy of sulfadoxine-pyrimethamine in vivo, even when reduced doses were used, makes this combination a good alternative for treatment of P. falciparum in Tanzania.

Adolescent↗

PubMedDate not supplied

Plasma concentrations of sulfadoxine-pyrimethamine and of mefloquine during regular long term malaria prophylaxis.

The plasma concentrations of sulfadoxine, pyrimethamine, mefloquine and its major metabolite were determined in 18 healthy male volunteers who had regularly taken either 500 mg of sulfadoxine and 25 mg of pyrimethamine (Fansidar) weekly or 250 mg mefloquine regularly every 14 d during 6 months for malaria prophylaxis. The mean trough concentrations of sulfadoxine, pyrimethamine and mefloquine were 194, 0.28 and 1.48 mumol/litre and the mean half lives were 7.7, 4.2 and 25 d respectively. The variation in area under the curve for the 3 drugs was only 2-3 fold. The findings do not indicate that drug accumulation or induction of metabolism occurred during long-term usage.

Adult↗

PubMedDate not supplied

Treatment of Plasmodium falciparum malaria with pyrimethamine-sulfadoxine: selective pressure for resistance is a function of long elimination half-life.

In an area of continuing transmission of Plasmodium falciparum on the Kenya coast, children treated with pyrimethamine-sulfadoxine experienced rapid parasite clearance, although a high proportion became reinfected within a short time. The frequency of pyrimethamine resistance in vitro in new infections was higher during the elimination phase of drug from a previous treatment. In infections which occurred at times when predicted residual drug concentrations were no longer inhibitory, incidence of pyrimethamine resistance was no different from the natural or background frequency. These results are discussed in terms of the selective pressure for resistance which is exerted by drugs with long elimination half-lives and a consideration of possible ways by which the problem might be addressed.

Animals↗

PubMed1989

Point mutations in the dihydrofolate reductase-thymidylate synthase gene as the molecular basis for pyrimethamine resistance in Plasmodium falciparum.

The dihydrofolate reductase-thymidylate synthase (DHFR-TS) bifunctional complex from pyrimethamine-sensitive (3D7) and drug-resistant (HB3 and 7G8) clones from Plasmodium falciparum was purified to homogeneity. A modified sequence of purification steps with a 10-formylfolate affinity column at its center, allows the isolation of the enzyme complex with a 10-fold higher yield than previously reported, irrespective of the pyrimethamine resistance of the parasites. Titration of the homogenous DHFR-TS complex with the inhibitor revealed a 500-fold lower affinity of the enzyme from clone 7G8 for the drug than found with the enzyme from clone 3D7. Direct comparison of the homogenous enzyme preparations on SDS-PAGE revealed no difference in the molecular mass of the DHFR-TS from the 3 clones, nor could a reproducible difference be detected in the peptide patterns obtained after digesting the DHFR-TS complex with various proteases. The amplification of segments from the DHFR-TS coding region of the 3 clones and 7 isolates of P. falciparum by polymerase chain reaction resulted in fragments of the predicted length without any size heterogeneity. The DNA sequence of the DHFR coding region from FCR-3, 3D7, HB3 and 7G8 differs in a total of 4 nucleotides. One point mutation changes amino acid residue 108 from threonine (FCR-3) or serine (3D7) to asparagine (HB3 and 7G8). The presence of asparagine-108 appears to be the molecular basis of pyrimethamine resistance of HB3 and 7G8. The degree of resistance is associated with a point mutation affecting the codon for amino acid 51 in 7G8.

Animals↗

PubMed1990

Detection of pyrimethamine resistance in Plasmodium falciparum by mutation-specific polymerase chain reaction.

The point mutation at nucleotide 323 within the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum, which distinguishes pyrimethamine-sensitive from drug-resistant isolates, can be discriminated by the polymerase chain reaction using mutation-specific primers. The technique makes use of the principle that short oligonucleotides with a perfect match at their 3' ends, complementary to the mutation to be detected, will initiate the polymerization by Taq polymerase far more efficiently than primers with a single mismatch in this position. The Asn-108 codon was detected using a primer of 17 nucleotides with an adenosine at its 3' end, the Thr-108 codon with a 14-mer primer ending with a cytosine and the Ser-108 codon with a 16-mer containing guanidine at the critical 3' end. By selecting appropriate counterprimers, the size of the amplification products is either indicative of pyrimethamine-resistant parasites of the 7G8 type, or of pyrimethamine-sensitive parasites of the FCR-3 type or 3D7 type. The fragments obtained can be easily separated in a single lane after agarose gel electrophoresis. Coded P. falciparum DNA samples were typed unambiguously using these primers as were reconstituted parasitized blood samples stored as high salt lysates. Sensitivity, speed and specificity make this assay a realistic alternative to in vitro drug testing to monitor the resistance of P. falciparum to inhibitors of the dihydrofolate reductase.

Animals↗

PubMed1984

Intranuclear structures in pyrimethamine-resistant isolates of the malaria parasite Plasmodium falciparum.

The ultrastructure of the malaria parasite Plasmodium falciparum is well known, both from natural infections and from culture material ( Aikawa , 1977, Langreth et al., 1978). It is noteworthy that all of these studies were done with pyrimethamine-sensitive strains, e.g. FCR-3/Gambia. Except for spindle microtubules during schizogony, no intranuclear structures have been described in any of the asexual erythrocytic stages. In the course of isolating clones from the pyrimethamine-resistant strain Honduras I/CDC (V.K. Bhasin and W. Trager , in print) and checking by electron microscopy for the presence or absence of knobs, we noticed intranuclear structures that might be correlated with pyrimethamine resistance. For comparison, we then examined the multi-drug-resistant strain Indochina 1. We present here a first report on these structures as a basis for further studies.

Animals↗

PubMed1993

Simultaneous determination of dapsone, monoacetyldapsone and pyrimethamine in whole blood and plasma by high-performance liquid chromatography.

A sensitive, selective and rapid reversed-phase high-performance liquid chromatographic method was developed for the simultaneous analysis of dapsone, monoacetyldapsone and pyrimethamine in human whole blood and plasma. The procedure involved extraction of the compounds and the internal standard, monopropionyldapsone, with tert.-butylmethyl ether under alkaline conditions. A newly marketed column, Supelcosil LC-ABZ (Supelco, 15 cm x 4.6 mm I.D.), was employed. The mobile phase, consisting of acetonitrile-methanol-phosphate buffer (2:1:7, v/v/v), was delivered at a flow-rate of 1.2 ml/min, and ultraviolet absorbance was monitored at 286 nm. The limit of determination using a 150-microliters sample was 10 ng/ml (40 nM) for dapsone and pyrimethamine and 8 ng/ml (28 nM) for monoacetyldapsone. Given that only a small amount of blood is required in this method, it could now be applied in studies involving blood level monitoring and pharmacokinetics in children on Maloprim (dapsone-pyrimethamine) prophylaxis in malaria endemic areas.

Anti-Infective Agents↗

PubMedDate not supplied

Plasmodium yoelii: activity of azithromycin in combination with pyrimethamine or sulfadoxine against blood and sporozoite induced infections in Swiss mice.

The efficacy of pyrimethamine or sulfadoxine administered in combination with azithromycin was examined in a rodent malaria model. Outbred Swiss mice infected with blood stage parasites were treated from day 0 to day 3 and efficacy of different regimens was monitored in terms of the curative response and the delay time to reach 2% parasitaemia (2% DT). Administration of azithromycin alone at 60 mg/kg/day produced curative response while lower doses showed marginally delayed 2% DT. A marked potentiation in activities of pyrimethamine (100-fold) or sulfadoxine (10-fold) was observed when administered at non-curative doses of 0.1 mg/kg/day in combination with azithromycin (30 mg/kg/day) against blood stage parasites. A combination of 10 mg/kg/day azithromycin with 0.3 mg/kg/day sulfadoxine was also curative. Likewise in the causal prophylactic test, a combination regimen comprising 1/16th and 1/3rd the individual curative doses of pyrimethamine and azithromycin, respectively, prevented the development of patent infection after Plasmodium yoelii sporozoite challenge. Our results suggest that a combination of azithromycin with the second line treatment regimen of fansidar may enhance the therapeutic efficacy of the latter and also provide better prophylaxis against Plasmodium falciparum malaria.

Animals↗

PubMed2004

Patterns of resistance and DHFR/DHPS genotypes of Plasmodium falciparum in rural Tanzania prior to the adoption of sulfadoxine-pyrimethamine as first-line treatment.

A study was carried out to assess the patterns of resistance and occurrence of DHFR/DHPS genotypes of Plasmodium falciparum prior to the adoption of sulfadoxine-pyrimethamine (SP) as first-line treatment for uncomplicated malaria in Tanzania. Children under five years (n = 117) with clinical, uncomplicated malaria were randomly allocated to standard treatments of either chloroquine (CQ) (25 mg/kg) or SP (25 mg sulfadoxine and 1.25 mg pyrimethamine/kg). Patients were monitored for 28 days. Clinical recovery was achieved in 98% (n = 58) and 90% (n = 59) of the patients in the SP and CQ groups, respectively. Parasitologically, 14% of the patients in the SP group and 51% in the CQ group exhibited RII/RIII resistance. When relating pre-treatment blood drug levels to treatment outcome and the degree of parasite resistance to the number of mutations, no relationships could be detected. There was an overall significant increase in haemoglobin levels from day 0 to day 28 in both patient groups. Sulfadoxine-pyrimethamine produced an acceptable clinical response but the high degree of parasitological resistance (RII/RIII) observed two years prior to the introduction of the drug as first-line treatment is of concern, especially considering the long half-lives of sulfadoxine and pyrimethamine.

Animals↗

PubMed2000

In vivo sensitivity of Plasmodium falciparum to chloroquine and sulfadoxine-pyrimethamine among schoolchildren in rural Uganda: a comparison between 1995 and 1998.

Sensitivity of Plasmodium falciparum to chloroquine and sulfadoxine-pyrimethamine was tested among asymptomatic school children in 1995 and 1998 using a modified in vivo test with examination for parasitaemia on day 0, 2 and 7. Sensitivity (S/RI) to chloroquine in 'urban' areas was found in 42% in 1995 and 62% in 1998 with resistance at the RII/RIII level observed in 58 and 38%, respectively (P<0.01). In 'rural' areas, sensitivity to chloroquine was 76% in 1995 and 72% in 1998 (P=0.6) with resistance at the RII/RIII level observed in 24 and 18%, respectively (P=0.4). Sensitivity to sulfadoxine-pyrimethamine was found in 98 and 99% in 1995 and 1998, respectively. The apparent improvement in sensitivity to chloroquine in 'urban' areas might be due to a different school being included in the two studies. It is concluded that the pattern of sensitivity of P. falciparum to chloroquine and sulfadoxine-pyrimethamine has not changed over a period of 2.5 year.

Animals↗

PubMed1997

In vivo sensitivity of Plasmodium falciparum to chloroquine and sulfadoxine-pyrimethamine in school children in Hoima district, western Uganda.

In vivo testing of Plasmodium falciparum sensitivity to chloroquine and sulfadoxine-pyrimethamine was carried out among asymptomatic school children from seven schools in four sub-counties in Hoima District in western Uganda. Seven hundred and twenty five children were screened, 487 (67%) had parasitaemia and 307 met the inclusion criteria. Full sensitivity to chloroquine in urban areas was found in 42%. Chloroquine resistance at RII level was observed in 46% (33-58%) and RIII level in 13% (0-24%) In rural areas, however, full sensitivity to chloroquine was found in 76% (70-84%). Resistance at RII and RIII level was found in 18 and 6% respectively. Full sensitivity to sulfadoxine-pyrimethamine was found in 98% and only 2% resistant at RII level. The relatively high proportion of chloroquine resistance at RII and RIII levels in urban areas could be attributed to easy access to chloroquine as well as frequent and probably inadequate use of chloroquine. Chloroquine can still be used as first line antimalarial drug in the area. Sulfadoxine-pyrimethamine should be the second line drug for cases not responding to chloroquine.

Antimalarials↗

PubMedDate not supplied

Current absence of pyrimethamine resistance of Plasmodium falciparum in Madagascar.

Reported are (i) the in vitro sensitivities to pyrimethamine of 58 primary Plasmodium falciparum isolates collected from the foothill and coastal areas in Madagascar, and (ii) the results of the amplification of the dhfr gene followed by restriction enzyme digestion of codon 108. Testing took place between March 1999 and February 2000 and all the isolates were sensitive to pyrimethamine. The 50% inhibitory concentration (IC50) ranged from 0.1 nM to 242.9 nM (mean IC50 = 30.5 nM, median IC50 = 4.8 nM, 95% confidence interval 17.6-43.4 nM). None of the 58 isolates yielded digestion products after polymerase chain reaction product treatment with BsrI or ScrFI. The results indicate the absence of the dhfr encoding Asn108 and Thr108 among tested clinical isolates. The sensitivity of P. falciparum to pyrimethamine-based antimalarial drugs in Madagascar is discussed.

Animals↗

PubMed2001

Plasmodium falciparum cross-resistance between trimethoprim and pyrimethamine.

Trimethoprim-sulfamethoxazole has been recommended as part of the standard package of care for people with HIV and AIDS in Africa. A similar antifolate combination, sulfadoxine-pyrimethamine, is now the first-line antimalarial drug in several of the African countries with the highest rates of HIV infection. We present evidence of Plasmodium falciparum cross-resistance between trimethoprim and pyrimethamine at the molecular level. The impact of trimethoprim-sulfamethoxazole on the efficacy of sulfadoxine-pyrimethamine needs to be assessed urgently, and alternative antimalarial treatment should be considered for people on trimethoprim-sulfamethoxazole prophylaxis.

Africa↗