Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In 1982, the fixed combination of pyrimethamine and sulfadoxine (Fansidar) became available in the United States, and was recommended for use in travelers at risk of acquiring chloroquine-resistant Plasmodium falciparum. Prior to that time, no reports of severe cutaneous reactions had appeared in the medical literature despite widespread use for more than 8 years in both Europe and malarious areas of the developing world. In the fall of 1984, the Centers for Disease Control received reports of 4 cases of toxic epidermal necrolysis (including 3 fatalities) among Americans who had used pyrimethamine-sulfadoxine (PYR/SDX) for the prevention of malaria. Subsequent investigation into severe cutaneous reactions associated with the use of this drug by American travelers detected 24 cases of erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis. Twenty-three of the 24 patients concurrently used chloroquine. Seven patients died. No risk factors in the development of these reactions other than the use of PYR/SDX could be identified. Among American travelers, we estimate that these reactions occur in 1 per 5,000-8,000 users, and that fatal reactions occur in 1 per 11,000-25,000 users. This higher than expected incidence necessitates that the use of PYR/SDX for the prevention of malaria be reconsidered. In the United States it is now recommended that the routine weekly use of the drug be reserved for those travelers at highest risk of acquiring chloroquine-resistant P. falciparum, when alternate prophylactic regimens are not deemed appropriate.
 ...
PMID:Severe cutaneous reactions among American travelers using pyrimethamine-sulfadoxine (Fansidar) for malaria prophylaxis. 293 35

The efficacy in vivo of a 3-day oral regimen of quinine (30 mg/kg/day) was assessed in 34 children with falciparum malaria in an area of northern Nigeria with previously documented low-grade parasite resistance to chloroquine and sulphadoxine-pyrimethamine (SDX/PYR). By day 4, all 34 children were free of parasites. Mean parasite clearance time and fever clearance time were 2.7 and 1.7 days, respectively. However, on day 14, 5 (14.7%) children were again parasitaemic and 4 of them were clinically ill. They were again treated successfully with a standard course of oral chloroquine. No adverse drug effects were recorded. Of the 34 children, 9 parasite isolates were successfully cultured in vitro. EC50 and EC99 were 14.0 and 126.0 pmol per well respectively, indicating decreased parasite sensitivity but no resistance in vitro. In conclusion, the 3-day course of quinine was found to be an effective alternative to standard chloroquine treatment in the study area.
 ...
PMID:Efficacy of a 3-day oral regimen of quinine in an area of northern Nigeria with low-grade resistance of Plasmodium falciparum to chloroquine and sulphadoxine-pyrimethamine. 756 54

Resistance of Plasmodium falciparum to antifolate chemotherapy is a significant problem where combinations such as Fansidar (pyrimethamine-sulfadoxine; PYR-SDX) are used in the treatment of chloroquine-resistant malaria. Antifolate resistance has been associated with variant sequences of dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS), the targets of PYR and SDX respectively. However, while the nature and distribution of mutations in the dhfr gene are well established, this is not yet the case for dhps. We have thus examined by DNA sequence analysis 141 field samples from several geographical regions with differing Fansidar usage (West and East Africa, the Middle East and Viet Nam) to establish a database of the frequency and repertoire of dhps mutations, which were found in 60% of the samples. We have also simultaneously determined from all samples their dhfr sequences, to better understand the relationship of both types of mutation to Fansidar resistance. Whilst the distribution of mutations was quite different across the regions surveyed, it broadly mirrored our understanding of relative Fansidar usage. In samples taken from individual patients before and after drug treatment, we found an association between the more highly mutated forms of dhps and/or dhfr and parasites that were not cleared by antifolate therapy. We also report a novel mutation in a Pakistani sample at position 16 of DHFR (A16S) that is combined with the familiar C59R mutation, but is wild-type at position 108. This is the first observation in a field sample of a mutant dhfr allele where the 108 codon is unchanged.
 ...
PMID:Resistance to antifolates in Plasmodium falciparum monitored by sequence analysis of dihydropteroate synthetase and dihydrofolate reductase alleles in a large number of field samples of diverse origins. 936 63

The 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.
 ...
PMID:Utilization of exogenous folate in the human malaria parasite Plasmodium falciparum and its critical role in antifolate drug synergy. 1038 65

Dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr) alleles were typed in 67 Malaysian Plasmodium falciparum isolates. The isolates were collected from two geographically distinct locations: 51 from Sabah, Malaysian Borneo, where sulfadoxine/pyrimethamine (SDX/PYR) is used to treat uncomplicated malaria and 16 from Peninsular Malaysia where in vivo resistance to SDX/PYR has been reported. A total of seven dhps alleles were identified with no significant difference in allele frequency between the 2 populations. Two of the dhps alleles described here have not been previously reported. Four dhfr alleles were detected in 67 P. falciparum isolates. Eighty-seven percent of the isolates from the Peninsula, where clinical SDX/PYR failure has been reported, had dhfr alleles with triple point mutations while all of the isolates from Sabah had dhfr alleles with 2 or less point mutations. The difference in dhfr allele frequency between the two populations was highly significant. There was no correlation between in vitro PYR response and accumulation of dhfr point mutations.
 ...
PMID:Short report: differences in dihydrofolate reductase but not dihydropteroate synthase alleles in Plasmodium falciparum isolates from geographically distinct areas in Malaysia. 1142 58

We have studied resistance to sulfadoxine-pyrimethamine (S/P) in the rodent malaria parasite Plasmodium chabaudi. A stable S/P-resistant mutant, AS(50S/P), was selected by drug treatment of a clone, AS(PYR), already resistant to pyrimethamine. The sequences of the P. chabaudi dhfr and dhps genes were obtained and found to be identical in AS(50S/P) and AS(PYR), showing that resistance to S/P in AS(50S/P) was not due to additional mutations in either gene. AS(50S/P) was crossed with a drug-sensitive clone, AJ, and 16 independent recombinant progeny were obtained. These clones were phenotyped for their susceptibility to S/P and to sulfadoxine and pyrimethamine separately. Pyrimethamine resistance was invariably associated with S/P resistance, but no correlation was found between resistance to S/P and resistance to sulfadoxine. Quantitative trait locus analysis of the progeny with 31 chromosome-specific markers showed that mutant P. chabaudi dhfr, or one or more genes closely linked to it, was a major determinant of S/P resistance. In addition, the inheritance of genes on chromosomes 5 and 13 from the sensitive parent appeared to contribute to the level of resistance observed. These results demonstrate that the S/P resistance of the AS(50S/P) mutant of P. chabaudi does not involve mutation in dhps and is not due simply to a combination of two genes determining resistance to pyrimethamine and sulfadoxine separately.
 ...
PMID:Sulfadoxine-pyrimethamine resistance in the rodent malaria parasite Plasmodium chabaudi. 1212 22

A technique that can distinguish and quantify genetically different malaria parasite clones in a mixed infection reliably and with speed and accuracy would be very useful for researchers. Many current methods of genotyping and quantification fall down on a number of aspects relating to their ease of use, sensitivity, cost, reproducibility and, not least, accuracy. Here we report the development and validation of a method that offers several advantages in terms of cost, speed and accuracy over conventional PCR or antibody-based methods. Using real-time quantitative PCR (RTQ-PCR) with allele-specific primers, we have accurately quantified the relative proportions of clones present in laboratory prepared ring-stage mixtures of two genetically distinct clones of the rodent malaria parasite Plasmodium chabaudi chabaudi. Accurate and reproducible measurement of the amount of genomic DNA representing each clone in a mixture was achieved over 100-fold range, corresponding to 0.074% parasitised erythrocytes at the lower end. To demonstrate the potential utility of this method, we include an example of the type of application it could be used for. In this case, we studied the growth rate dynamics of mixed-clone infections of P. chabaudi using an avirulent/virulent clone combination (AS (PYR) and AJ) or two clones with similar growth rate profiles (AQ and AJ). The modification of the technique described here should enable researchers to quickly extract accurate and reliable data from in-depth studies covering broad areas of interest, such as analyses of clone-specific responses to drugs, vaccines or other selection pressures in malaria or other parasite species that also contain highly polymorphic DNA sequences.
 ...
PMID:Real-time quantitative PCR for analysis of genetically mixed infections of malaria parasites: technique validation and applications. 1451 7

Markers of Plasmodium falciparum resistance to chloroquine (CQ) and pyrimethamine-sulfadoxine (PYR-SDX) are widespread in areas where malaria is endemic. In an area where the use PYR-SDX is negligible, the Ashanti Region of Ghana, West Africa, adult individuals were enrolled in an analysis of CQ- and PYR-SDX-associated molecular resistance markers in 2001 (n = 177) and 2003 (n = 180). Parasite prevalence, as assessed by PCR assays, were 56.5 and 48.8% in 2001 and 2003, respectively. A high frequency of CQ, PYR, and SDX resistance markers was observed, whereby, as a weak trend, the frequency was higher in 2003. The quintuple combination of three pfdhfr mutations and two pfdhps mutations has previously been recognized to be the most important determinant of PYR-SDX resistance. Approximately 60% of parasite carriers harbored fourfold mutated parasites, indicative of a considerable risk for a switch to high-level PYR-SDX resistance in an area where the rate of PYR-SDX use is low. Among the factors contributing to the high frequency of PYR-SDX resistance-associated mutations are background use of PYR-SDX, past use of PYR for malaria prophylaxis, cross-resistance of trimethoprim with PYR, and the sufficient biological fitness of resistant parasites in the absence of drug pressure.
 ...
PMID:High prevalence of markers for sulfadoxine and pyrimethamine resistance in Plasmodium falciparum in the absence of drug pressure in the Ashanti region of Ghana. 1572 9

Antimalarial drug resistance in endemic malaria zones is first detected in vitro; when it reaches a certain threshold, it becomes perceptible and is expressed in therapeutic failure among subjects only slightly or not at all immune. This work conducted in northern Abidjan (Cote d'Ivoire) studied children with uncomplicated malaria, who were followed for 14 days (during the year 2000) in accordance with the WHO protocol for surveillance of antimalarial drug resistance. Concomitantly, the Plasmodium falciparum isolates were cultured in the presence of variable concentrations of chloroquine, pyrimethamine and quinine during in vitro chemosensitivity tests. The RPMI 1640 used as medium for the pyrimethamine did not contain PABA (para-amino benzoic acid) or folic acid. In all, 114 in vitro tests were completed, 33 to chloroquine, 32 to pyrimethamine, and 49 to quinine. Therapeutic efficacy was tested in 65 patients: 33 to chloroquine and 32 to sulfadoxine-pyrimethamine (SP). The results found 36% of the isolates were chloroquine-resistant (CQ-R) and 33% of the patients treated with chloroquine did not respond adequately (therapeutic failure, TF). The 12 CQ-R isolates corresponded to 11 TF subjects and 1 patient with adequate clinical and parasitological response. The concordance between the two tests was good (kappa=0.93). For pyrimethamine, 37.5% of the isolates were resistant (PYR-R), and 37.5% of patients responded adequately to SP. The 12 PYR-R isolates were from 12 TF subjects, so that kappa=1.0, when pyrimethamine resistance is defined as IC50 > 2,000 nM. Because of the elevated rate of chloroquine resistance, the national antimalaria program has recommended since July 2003 that amodiaquine be used as a first-line drug, to replace chloroquine. The relatively elevated number of TF with SP are a source of concern, because it is used in Yopougon (Abidjan). Additional studies to assess the prevalence of resistance to this combination in other areas of Abidjan city (Cote d' Ivoire) would be useful.
 ...
PMID:[Limits of the efficacy of chloroquine and sulfadoxine-pyrimethamine in Northern Abidjan (Cote d'Ivoire): Combined in vivo and in vitro studies]. 1574 69

Nested PCR and restriction analysis were used to detect mutations at codon 76 of Plasmodium falciparum chloroquine resistance transporter gene (pfcrt) and codon 59 of dihydrofolate reductase gene (dhfr) that indicate chloroquine (CQ) and pyrimethamine-sulfadoxine (PYR-SDX) resistance respectively. P. falciparum isolates from malaria-endemic area of Jazan showed CQ resistance rate (89.5%), the highest percentage of chloroquine resistance ever recorded in Saudi Arabia. One the other hand, 10.5% of isolates showed a PYR-SDX resistant allele as a first reported in the kingdom. The use of molecular markers as additional tools to map areas of chloroquine resistance was expected to contribute in the development of new strategies for therapeutic intervention towards malaria in Saudi Arabia.
 ...
PMID:Detection of drug resistance markers for chloroquine and pyrimethamine-sulfadoxine in Jazan area, Saudi Arabia using PCR and restriction digestion. 1758 May 65


1 2 Next >>