Discovery and Development of Artemisinin and Related Compounds / 中草药·英文版

Artemisinin is isolated from the plant Artemisia annua, sweet wormwood, an herb employed in traditional Chinese medicine. Prof. You-you Tu discovered artemisinin in the 1960s, so she was awarded the 2015 Nobel Prize in Physiology or Medicine. Artemisinin and its semi-synthetic derivatives are a group of drugs that possess the most rapid action of all current drugs against Plasmodium falciparum malaria. In this review, the author investigated history on discovery of artemisinin, ethnopharmacology of Artemisia plants, chemistry and pharmacological activities of the relative compounds, and introduced Tu and other Chinese and world scientists' contribution, development of artemisinin and the related compounds and registered and marketed artemisinin drugs in China, UK, and USA. The author also recalled the studies on the mechanism of action of artemisinins and artemisinin combination therapies and summed up the resistance issues. In Current Recommendations and the Global Plan for Insecticide Resistance Management in Malaria Vectors (GPIRM), that the WHO prevents the development and manages the spread of insecticide resistance is summarized in the technical basis for coordinated action against insecticide resistance: preserving the effectiveness of modern malaria vector control. Prof. Tu re-emphasized the artemisinin resistant on five principles to the WHO. She called on the world's scientists to pay attention to the study of drug resistance, and hopes scientists to contribute to break resistance of artemisinins.

In vitro sensitivity pattern of chloroquine and artemisinin in Plasmodium falciparum.

Artemisinin (ART) and its derivatives form the mainstay of antimalarial therapy. Emergence of resistance to them poses a potential threat to future malaria control and elimination on a global level. It is important to know the mechanism of action of drug and development of drug resistance. We put forwards probable correlation between the mode of action of chloroquine (CQ) and ART. Modified trophozoite maturation inhibition assay, WHO Mark III assay and molecular marker study for CQ resistance at K76T codon in Plasmodium falciparum CQ-resistant transporter gene were carried out on cultured P. falciparum. On comparing trophozoite and schizont growth for both CQ-sensitive (MRC-2) and CQ-resistant (RKL-9) culture isolates, it was observed that the clearance of trophozoites and schizonts was similar with both drugs. The experiment supports that CQ interferes with heme detoxification pathway in food vacuoles of parasite, and this may be correlated as one of the plausible mechanisms of ART.

Drug resistance in malaria.

Antimalarial chemotherapy is an important component of all malaria control programmes throughout the world. This is especially so in light of the fact that there are no antimalarial vaccines which are available for clinical use at present. Emergence and spread of malaria parasites which are resistant to many of the available antimalarials today is, therefore, a major cause for concern. Till date, resistance to all groups of antimalarials excluding artemisinin has been reported. In recent years, in vitro resistance to even artemisinin has been described. While resistance to antibacterial agents has come to prominence as a clinical problem in recent years, antiparasitic resistance in general and antimalarial resistance in particular has not received much attention, especially in the Indian scenario. The present review deals with commonly used antimalarial drugs and the mechanisms of resistance to them. Various methods of detecting antimalarial resistance and avoiding the same have also been dealt with. Newer parasite targets which can be used in developing newer antimalarial agents and antimalarials obtained from plants have also been mentioned.

Sequence analysis of coding DNA fragments of pfcrt and pfmdr-1 genes in Plasmodium falciparum isolates from Odisha, India

The global emergence and spread of malaria parasites resistant to antimalarial drugs is the major problem in malaria control. The genetic basis of the parasite's resistance to the antimalarial drug chloroquine (CQ) is well-documented, allowing for the analysis of field isolates of malaria parasites to address evolutionary questions concerning the origin and spread of CQ-resistance. Here, we present DNA sequence analyses of both the second exon of the Plasmodium falciparum CQ-resistance transporter (pfcrt) gene and the 5' end of the P. falciparum multidrug-resistance 1 (pfmdr-1) gene in 40 P. falciparum field isolates collected from eight different localities of Odisha, India. First, we genotyped the samples for the pfcrt K76T and pfmdr-1 N86Y mutations in these two genes, which are the mutations primarily implicated in CQ-resistance. We further analyzed amino acid changes in codons 72-76 of the pfcrt haplotypes. Interestingly, both the K76T and N86Y mutations were found to co-exist in 32 out of the total 40 isolates, which were of either the CVIET or SVMNT haplotype, while the remaining eight isolates were of the CVMNK haplotype. In total, eight nonsynonymous single nucleotide polymorphisms (SNPs) were observed, six in the pfcrt gene and two in the pfmdr-1 gene. One poorly studied SNP in the pfcrt gene (A97T) was found at a high frequency in many P. falciparum samples. Using population genetics to analyze these two gene fragments, we revealed comparatively higher nucleotide diversity in the pfcrt gene than in the pfmdr-1 gene. Furthermore, linkage disequilibrium was found to be tight between closely spaced SNPs of the pfcrt gene. Finally, both the pfcrt and the pfmdr-1 genes were found to evolve under the standard neutral model of molecular evolution.

Evaluación de la eficacia de la cloroquina para eltratamiento de la malaria por Plasmodium vivax enYacuiba, Tarija, Bolivia / Evaluation of the chloroquine efficacy for the treatment of malaria by Plasmodium vivax in Yacuiba, Tarija, Bolivia

Se realizó una evaluación in vivo de la eficacia de la cloroquina para el tratamiento de la malaria por Plasmodium vivax, en elsitio centinela de Palmar Chico, Municipio de Yacuiba, Provincia Gran Chaco, Departamento de Tarija al Sur de Bolivia. Fueronincluidos en el estudio 61 pacientes entre 5 y 59 años de edad que presentaban monoinfección por P. vivax. Todos los pacientesrecibieron una dosis total de cloroquina de 25 mg/Kg en 3 días (10mg/Kg el primer día; 7,5 mg/Kg el segundo y tercer días).De acuerdo al protocolo estandarizado de la OPS/OMS, todos los pacientes fueron seguidos por 28 días (controles clínicos yparasitológicos). Se completó el seguimiento de 60 pacientes, ninguno de los pacientes tuvo recurrencias de la parasitemia opresentó manifestaciones clínicas después del tercer día de tratamiento. Este estudio mostró 100% de sensibilidad de P. vivaxa la cloroquina, lo que justifica su permanencia en la política de medicamentos antimaláricos como la droga más adecuada parael tratamiento de las infecciones por P. vivax en el Sur de Bolivia.

We carried out an evaluation in vivoof the chloroquine efficacy for the treatment of malaria by Plasmodium vivax, in the sentinelsite of Palmar Chico, Municipality of Yacuiba, Province Gran Chaco, Department of Tarija to the South of Bolivia. Sixty one patientsaged between 5 and 59 years that presented monoinfection by P. vivaxwere included in the study. All patient received undersupervision a total dose of chloroquine 25mg/kg over three days (10mg/kg on the first day; 7.5 mg/kg on the second and thirddays). According the standardized protocol of the PAHO/WHO, all patients were followed-up for 28 days (clinical and parasitologicalcontrols). Sixty patients completed the follow-up, none of the patients had recurrences of parasitemia or presented clinicalmanifestations after third day of treatment. This study showed 100% of sensibility from P. vivax to chloroquine, what justifies theirpermanency in the antimalarial drug policy as the most adequate drug for the treatment of the P. vivax infections in the South of Bolivia.