The purpose of this study was to describe the characteristics and findings of antimalarial drug efficacy studies conducted in Ethiopia and to use the findings to formulate recommendations for antimalarial drug efficacy monitoring and use of evidence to inform antimalarial treatment policy for the Ethiopian setting. This study reviewed 44 antimalarial efficacy studies conducted in Ethiopia from 1974 to 2011. The analysis of results indicated that chloroquine as the first-line antimalarial drug for the treatment of malaria due to Plasmodium falciparum had a 22% therapeutic failure in 1985. Chloroquine was replaced with sulfadoxine-pyrimethamine in 1998, more than 12 years later, when its therapeutic failure had reached 65%. Sulfadoxinepyrimethamine at the time of its introduction had a treatment failure of 7.7%; it was replaced after seven years in 2004 by artemether-lumefantrine; by then its treatment failure had reached 36%. The WHO recommends the replacement of a first-line antimalarial drug when more than 10% of treatment failure is reported. The replacement drug should have a therapeutic efficacy of more than 95%; while the change itself should be completed within two years. The prolonged delay to replace failing antimalarial drugs in Ethiopia seems to have been influenced mainly by the lack of systematic antimalarial drug efficacy data collection and pragmatic use of the data and evidence gathered.Almost eight years after its introduction, isolated studies show that the efficacy of artemether-lumefantrine has decreased from 99% in 2003 to around 96.3% in 2008. Though this decrease is not statistically significant (chi-square 1.5; P=0.22) and has not reached the threshold of 10%, it is plausible that its efficacy may drop further. This is mainly due to regulatory provisions in the country that allow marketing of oral artemisinin mono-therapies that are not recommended for malaria treatment, use of less effective antimalarial combination drugs in the neighboring countries and widespread drug quality problems. The situation calls for and this study recommends the establishment of stringent drug efficacy monitoring and early warning system and alignment of the antimalarial drug regulatory practices with recommendations of the WHO. / Health Studies / D. Litt. et Phil. (Health Studies)

The purpose of this study was to describe the characteristics and findings of antimalarial drug efficacy studies conducted in Ethiopia and to use the findings to formulate recommendations for antimalarial drug efficacy monitoring and use of evidence to inform antimalarial treatment policy for the Ethiopian setting. This study reviewed 44 antimalarial efficacy studies conducted in Ethiopia from 1974 to 2011. The analysis of results indicated that chloroquine as the first-line antimalarial drug for the treatment of malaria due to Plasmodium falciparum had a 22% therapeutic failure in 1985. Chloroquine was replaced with sulfadoxine-pyrimethamine in 1998, more than 12 years later, when its therapeutic failure had reached 65%. Sulfadoxinepyrimethamine at the time of its introduction had a treatment failure of 7.7%; it was replaced after seven years in 2004 by artemether-lumefantrine; by then its treatment failure had reached 36%. The WHO recommends the replacement of a first-line antimalarial drug when more than 10% of treatment failure is reported. The replacement drug should have a therapeutic efficacy of more than 95%; while the change itself should be completed within two years. The prolonged delay to replace failing antimalarial drugs in Ethiopia seems to have been influenced mainly by the lack of systematic antimalarial drug efficacy data collection and pragmatic use of the data and evidence gathered.Almost eight years after its introduction, isolated studies show that the efficacy of artemether-lumefantrine has decreased from 99% in 2003 to around 96.3% in 2008. Though this decrease is not statistically significant (chi-square 1.5; P=0.22) and has not reached the threshold of 10%, it is plausible that its efficacy may drop further. This is mainly due to regulatory provisions in the country that allow marketing of oral artemisinin mono-therapies that are not recommended for malaria treatment, use of less effective antimalarial combination drugs in the neighboring countries and widespread drug quality problems. The situation calls for and this study recommends the establishment of stringent drug efficacy monitoring and early warning system and alignment of the antimalarial drug regulatory practices with recommendations of the WHO. / Health Studies / D. Litt. et Phil. (Health Studies)

Yes / The identification and quantification of functional cytochromes P450 (CYPs) in biological samples is proving important for robust analyses of drug efficacy and metabolic disposition. In this study, a novel CYP activity-based probe was rationally designed and synthesised, demonstrating selective binding of CYP isoforms. The dependence of probe binding upon the presence of NADPH permits the selective detection of functionally active CYP. This allows the detection and analysis of these enzymes using biochemical and proteomic methodologies and approaches. / Engineering and Physical Sciences Research Council (EPSRC) and Yorkshire Cancer Research

Nous avons développé un nouveau test de prédiction de l’efficacité de thérapies anti-cancéreuses. Ce concept se base sur la détermination d’une signature moléculaire tumorale par RT-qPCR. Cette signature est issue d’un algorithme de normalisation innovant de comparaison des données d’expression relative des cibles de la tumeur avec celles de tissus de référence. Cette normalisation offre à chaque cible de la signature un rang et un score spécifique permettant de hiérarchiser les voies pro-tumorales afin de trouver la ou les cibles dominantes responsables du développement de la tumeur. La signature comprend des cibles donnant des informations générales sur le statut et l’hétérogénéité de la tumeur, sur l’angiogenèse et la lymphangiogenèse, sur le microenvironnement tumoral et enfin sur l’activité migratoire. Une validation préclinique dans les modèles du cancer colorectal, de la prostate et du glioblastome, a montré que le test est prédictif de l’efficacité thérapeutique. / We developed a new tool for prediction of cancer treatment efficacy. Our process is based on the determination of the molecular signature which is intended to provide a clinician’s decision tool helping to select which tumor signaling pathway(s) has/have to be targeted for best therapeutic effect. This signature representing a scoring obtained by RT-qPCR through a sequential normalization process of the expression level of target genes in the tumor compared to cancer type-specific references. These genes were selected because of a good knowledge of related biological functions, a correlation between expression level and aggressiveness of the tumor, the existence of a therapeutic arsenal already in clinical use. This signature is validated in a preclinical model of colorectal cancer and prostate cancer and glioblastoma. The results obtained show that the test we developed allows to identify the most important signaling pathway implicated in the disease and to choose the best drug.

No description available.