Malaria is a major cause of morbidity and mortality in many African countries and parts of Asia and South America.Novel approaches to combating the disease have emerged in recent years and several drug candidates are ...Malaria is a major cause of morbidity and mortality in many African countries and parts of Asia and South America.Novel approaches to combating the disease have emerged in recent years and several drug candidates are now being tested clinically.However,it is long before these novel drugs can hit the market,especially due to a scarcity of safety and efficacy data.To reduce the malaria burden,the Medicines for Malaria Venture(MMV)was established in 1999 to develop novel medicines through industry and academic partners’collaboration.However,no reviews were focused following various preclinical and clinical studies published since the MMV initiation(2000)to till date.We identify promising approaches in the global portfolio of antimalarial medicines,and highlight challenges and patient specific concerns of these novel molecules.We discuss different clinical studies focusing on the evaluation of novel drugs against malaria in different human trials over the past five years.The drugs KAE609 and DDD107498 are still being evaluated in Phase I trials and preclinical developmental studies.Both the safety and efficacy of novel compounds such as KAF156 and DSM265 need to be assessed further,especially for use in pregnant women.Synthetic non-artemisinin ozonides such as OZ277 raised concerns in terms of its insufficient efficacy against high parasitic loads.Aminoquinoline-based scaffolds such as ferroquine are promising but should be combined with good partner drugs for enhanced efficacy.AQ-13 induced electrocardiac events,which led to prolonged QTc intervals.Tafenoquine,the only new anti-relapse scaffold for patients with a glucose-6-phosphate dehydrogenase deficiency,has raised significant concerns due to its hemolytic activity.Other compounds,including methylene blue(potential transmission blocker)and fosmidomycin(DXP reductoisomerase inhibitor),are available but cannot be used in children.At this stage,we are unable to identify a single magic bullet against malaria.Future studies should focus on effective single-dose mol展开更多
Background::The elimination of Plasmodium vivax malaria requires 8-aminoquinolines,which are contraindicated in patients with glucose-6-phosphate dehydrogenase(G6PD)deficiency due to the risk of acute haemolytic anaem...Background::The elimination of Plasmodium vivax malaria requires 8-aminoquinolines,which are contraindicated in patients with glucose-6-phosphate dehydrogenase(G6PD)deficiency due to the risk of acute haemolytic anaemia.Several point-of-care devices have been developed to detect G6PD deficiency.The objective of the present study was to evaluate the performance of two of these devices against G6PD genotypes in Mauritania.Methods::Outpatients were screened for G6PD deficiency using CareStart?rapid diagnostic test(RDT)and CareStart?G6PD biosensor in Nouakchott,Mauritania,in 2019-2020.African-type and Mediterranean-type G6PD genotypes commonly observed in Africa were determined by polymerase chain reaction-restriction fragment length polymorphism and sequencing.Qualitative variables were compared using Fisher’s exact test.Results::Of 323 patients(74 males and 249 females),5 males and 2 homozygous females had the African-type A-genotype:A-(202)in 3 males and 2 females and G6PD A-(968)in 2 males.Among heterozygous females,13 carried G6PD A-(202),12 G6PD A-(968),and 3 G6PD A-(542)variants.None had the Mediterranean-type G6PD genotype.Eight had a positive G6PD RDT result,including all 7 hemizygous males and homozygous females with A-or A-A-(0.12 to 2.34 IU/g haemoglobin,according to G6PD biosensor),but RDT performed poorly(sensitivity,11.1%at the cutoff level of<30%)and yielded many false negative tests.Thirty-seven(50.0%)males and 141(56.6%)females were anaemic.The adjusted median values of G6PD activity were 5.72 and 5.34 IU/g haemoglobin in non-anaemic males(n=35)and non-anaemic males and females(n=130)with normal G6PD genotypes using G6PD biosensor,respectively.Based on the adjusted median of 5.34 IU/g haemoglobin,the performance of G6PD biosensor against genotyping was as follows:at 30%cut-off,the sensitivity and specificity were 85.7%and 91.7%,respectively,and at 80%cut-off,the sensitivity was 100%while the specificity was 64.9%.Conclusions::Although this pilot study supports the utility of biosensor to screen fo展开更多
文摘Malaria is a major cause of morbidity and mortality in many African countries and parts of Asia and South America.Novel approaches to combating the disease have emerged in recent years and several drug candidates are now being tested clinically.However,it is long before these novel drugs can hit the market,especially due to a scarcity of safety and efficacy data.To reduce the malaria burden,the Medicines for Malaria Venture(MMV)was established in 1999 to develop novel medicines through industry and academic partners’collaboration.However,no reviews were focused following various preclinical and clinical studies published since the MMV initiation(2000)to till date.We identify promising approaches in the global portfolio of antimalarial medicines,and highlight challenges and patient specific concerns of these novel molecules.We discuss different clinical studies focusing on the evaluation of novel drugs against malaria in different human trials over the past five years.The drugs KAE609 and DDD107498 are still being evaluated in Phase I trials and preclinical developmental studies.Both the safety and efficacy of novel compounds such as KAF156 and DSM265 need to be assessed further,especially for use in pregnant women.Synthetic non-artemisinin ozonides such as OZ277 raised concerns in terms of its insufficient efficacy against high parasitic loads.Aminoquinoline-based scaffolds such as ferroquine are promising but should be combined with good partner drugs for enhanced efficacy.AQ-13 induced electrocardiac events,which led to prolonged QTc intervals.Tafenoquine,the only new anti-relapse scaffold for patients with a glucose-6-phosphate dehydrogenase deficiency,has raised significant concerns due to its hemolytic activity.Other compounds,including methylene blue(potential transmission blocker)and fosmidomycin(DXP reductoisomerase inhibitor),are available but cannot be used in children.At this stage,we are unable to identify a single magic bullet against malaria.Future studies should focus on effective single-dose mol
文摘Background::The elimination of Plasmodium vivax malaria requires 8-aminoquinolines,which are contraindicated in patients with glucose-6-phosphate dehydrogenase(G6PD)deficiency due to the risk of acute haemolytic anaemia.Several point-of-care devices have been developed to detect G6PD deficiency.The objective of the present study was to evaluate the performance of two of these devices against G6PD genotypes in Mauritania.Methods::Outpatients were screened for G6PD deficiency using CareStart?rapid diagnostic test(RDT)and CareStart?G6PD biosensor in Nouakchott,Mauritania,in 2019-2020.African-type and Mediterranean-type G6PD genotypes commonly observed in Africa were determined by polymerase chain reaction-restriction fragment length polymorphism and sequencing.Qualitative variables were compared using Fisher’s exact test.Results::Of 323 patients(74 males and 249 females),5 males and 2 homozygous females had the African-type A-genotype:A-(202)in 3 males and 2 females and G6PD A-(968)in 2 males.Among heterozygous females,13 carried G6PD A-(202),12 G6PD A-(968),and 3 G6PD A-(542)variants.None had the Mediterranean-type G6PD genotype.Eight had a positive G6PD RDT result,including all 7 hemizygous males and homozygous females with A-or A-A-(0.12 to 2.34 IU/g haemoglobin,according to G6PD biosensor),but RDT performed poorly(sensitivity,11.1%at the cutoff level of<30%)and yielded many false negative tests.Thirty-seven(50.0%)males and 141(56.6%)females were anaemic.The adjusted median values of G6PD activity were 5.72 and 5.34 IU/g haemoglobin in non-anaemic males(n=35)and non-anaemic males and females(n=130)with normal G6PD genotypes using G6PD biosensor,respectively.Based on the adjusted median of 5.34 IU/g haemoglobin,the performance of G6PD biosensor against genotyping was as follows:at 30%cut-off,the sensitivity and specificity were 85.7%and 91.7%,respectively,and at 80%cut-off,the sensitivity was 100%while the specificity was 64.9%.Conclusions::Although this pilot study supports the utility of biosensor to screen fo
