Biswas S
Malaria Research Centre (Indian Council of Medical Research), 22 Sham Nath Marg, Delhi - 110054, India.
J Postgrad Med. 2004 Jan-Mar;50(1):17-20.
Antifolate antimalarials like sulfadoxine-pyrimethamine are used as second-line treatment for Plasmodium falciparum malaria patients who fail to respond to chloroquine. The efficacy of the sulfa-pyrimethamine combination in the treatment is also compromised by the development of resistance in the parasite. Resistance to these drugs has been shown to encode with point mutations in dihydrofolate reductase and dihydropteroate synthetase genes.
An experimental study.
Forty clinical isolates collected from different geographical locations in India were used to assess the relationships between resistance to sulfadoxine-pyrimethamine (SP) and mutations in P. falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS). In vitro drug susceptibility and mutation-specific polymerase chain reaction (PCR) assays were also done.
It was observed that a number of isolates possessed mutant genotypes and showed low sensitivity to SP in vitro. Of the 40 clinical isolates studied, 87.5% had DHFR and 15% had DHPS gene mutations. As observed from PCR results, 55( (22/40) presented double mutation of DHFR Arg-59 and Asn-108 and 32.5 % (13/40) had single mutant type allele of Asn-108. Of the 40 isolates, 10 % (4/40) presented doubly mutated forms of DHPS Phe-436 and Thr-613 and single mutant type allele Gly-581 was detected in 5 % (2/40) isolates. Parasites carrying double or single mutant forms of DHFR/DHPS showed elevated minimum inhibitory concentration (MIC) values of both pyrimethamine (760-6754 nM; r=0.69) and sulfadoxine (108 - 540 micro M; r=0.87) when compared to sensitive and resistant strains.
Though there was a correlation between molecular techniques and in vitro drug sensitivity profiles, the relevance of these findings to the clinical efficacy of SP combination drugs needs to be established by controlled clinical trials.
像磺胺多辛 - 乙胺嘧啶这样的抗叶酸抗疟药被用作对氯喹无反应的恶性疟原虫疟疾患者的二线治疗药物。寄生虫产生的耐药性也削弱了磺胺 - 乙胺嘧啶组合在治疗中的疗效。已表明对这些药物的耐药性与二氢叶酸还原酶和二氢蝶酸合酶基因中的点突变有关。
一项实验研究。
从印度不同地理位置收集的40株临床分离株用于评估对磺胺多辛 - 乙胺嘧啶（SP）的耐药性与恶性疟原虫二氢叶酸还原酶（DHFR）和二氢蝶酸合酶（DHPS）突变之间的关系。还进行了体外药物敏感性和突变特异性聚合酶链反应（PCR）测定。
观察到许多分离株具有突变基因型，并且在体外对SP表现出低敏感性。在所研究的40株临床分离株中，87.5% 有DHFR基因突变，15% 有DHPS基因突变。从PCR结果观察到，55%（22/40）呈现DHFR的Arg - 59和Asn - 108双突变，32.5%（13/40）具有Asn - 108单突变型等位基因。在40株分离株中，10%（4/40）呈现DHPS的Phe - 436和Thr - 613双突变形式，5%（2/40）的分离株中检测到单突变型等位基因Gly - 581。与敏感和耐药菌株相比，携带DHFR/DHPS双突变或单突变形式的寄生虫对乙胺嘧啶（760 - 6754 nM；r = 0.69）和磺胺多辛（108 - 540 μM；r = 0.87）的最低抑菌浓度（MIC）值均升高。
虽然分子技术与体外药物敏感性谱之间存在相关性，但这些发现与SP联合药物临床疗效的相关性需要通过对照临床试验来确定。
