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Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 6 uppsatser.

Le paludisme demeure un des principaux fardeaux de l'humanité en dépit d'une évolution générale favorable du nombre de cas de paludisme. Les travaux contenus dans cette thèse concernent le déploiement d'une combinaison antipaludique à base de dérivés de l'artémisinine en zone rurale à transmission modérée. Le choix du traitement à adopter doit reposer sur l'évidence, dont la forme la plus aboutie demeure la revue systématique et méta-analyse. Cependant, la présentation des résultats peut être améliorée dans le but de faciliter la prise de décision. En outre pour compléter cette preuve expérimentale, il est nécessaire d’étudier l’utilisation des médicaments en pratique courante, dans une approche de médecine factuelle et d’en effectuer le suivi sur plusieurs années concernant l'efficacité, tolérance, sensibilité in vitro, qualité de la prise en charge, épidémiologie du paludisme.Un programme pilote de prise en charge du paludisme intégré dans le système de santé publique a été mis en place au dispensaire de Mlomp, Sénégal à partir de l’année 2000 : un traitement avec la combinaison artésunate + amodiaquine après confirmation parasitologique (en lieu et place d'un traitement présomptif par mono-thérapie). Ces travaux d'accompagnement de la mise à l'échelle des nouvelles directives de prise en charge du paludisme ont permis d'apporter des éléments pour améliorer la qualité des soins ainsi que permettre une meilleure compréhension des obstacles à la mise en place de la nouvelle stratégie et ses effets sur la santé de la population. / Malaria remains a major health burden for mankind despite trends towards a decrease in the number of cases in most endemic areas. The research summarized in this thesis concerns the deployment of an artemisinin-containing antimalarial drug combination (ACT) in a rural district of moderately intense transmission. The choice of an adapted treatment must be evidence based. Systematic reviews and meta-analysis are considered the most robust form of evidence. However, visual displays should be improved in order to improve decision making.Furthermore, to complement evidence from clinical trials, drugs should be studied when used in real-life conditions and followed-up over time for their efficacy, safety, parasite susceptibility, quality of case management, malaria epidemiology.A pilot programme to change case management modalities was started in 2000 in Mlomp, Senegal. The programme was embedded in the public health system and aimed at replacing the previous policy (single-agent treatment on clinical grounds) with the new policy (ACT for parasitologically confirmed malaria). The work conducted to support the scaling-up of the new policy allows improving case management and provides elements towards a better understanding of obstacles to the deployment of the new strategy and its effects on the health of populations.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

Class of 2013 Abstract / Specific Aims: To determine if melanoma cells are more vulnerable to Amodiaquine (AQ) or Lumefantrine (LF)-based artemisinin combination therapy compared to artemisinin monotherapy. Methods: Tested anti-malarials in vitro for anti-melanoma activity, which contained 100,000 of the A375 human metastatic melanoma cells that were repeatedly treated independently three times. Main Results: Dihydroartemisinin (DHA) monotherapy induced significant cell death in melanoma cells. However, artemisinin combination therapy (ACT) did not enhance DHA-induced cell death. AQ protected against DHA-induced cell death causing morphological changes detected by electron microscopy. As for LF, it did not affect DHA-induced cell death. Conclusion: The results demonstrated that ACT does not display enhanced anti-melanoma activity compared to artemisinin monotherapy. It suggests that AQ may have anti-oxidant properties, but would need to be explored further in the context of anti-oxidant cyto-protection.

Malaria is a disease affecting millions of people in 109 malarious countries and territories, causing approximately one million deaths annually. In 2004 one of the parasites causing human malaria, Plasmodium falciparum, was among the leading global causes of death from a single infectious agent, especially in Africa (WHO, 2008:23). Treatment of this disease with single active pharmaceutical ingredients has led to the emergence of resistant P. falciparum parasites, resulting in the most severe form of this illness. Alarmingly, the poor quality of commercially available antimalarial products, especially in Africa, has increasingly been reported as a major cause of resistance to antimalarials. In Pakistan it was found that a P. falciparum epidemic that initially was attributed to drug resistance, was actually caused by substandard sulfadoxine/pyrimethamine products, causing a 50 times higher incidence of malaria in these areas than elsewhere (Leslie et al., 2009:1758). Other results indicated that up to 10% of sulfadoxine/pyrimethamine tablets, sampled in six African countries, failed the assay test, whilst up to 40% failed the USP dissolution test. Furthermore, the World Health Organization (WHO) reported that 20 - 90% of products failed quality requirements during 1999 and 2000 in seven African countries (WHO, 2003:263). Cases like these have raised the awareness of the vast number of inferior products that are being distributed. The subsequent need for establishing mechanisms to proactively detect substandard medicines, specifically antimalarials, easily and effectively had indirectly led to the origin of this study, long before it was formally undertaken. Testing monographs for pharmaceutical products are developed to formalise, or standardise, the regulation of pharmaceutical dosage forms. Problems have, however, been reported with regards to the inadequacy of existing antimalarial monographs in assuring quality medicines, fit for their intended use. The WHO had requested the Research Institute for Industrial Pharmacy, incorporating the Centre for Quality Assurance of Medicines (RIIP®/CENQAM®), both operating at the Potchefstroom Campus of the North–West University, to develop monographs for three immediate–release antimalaria dosage forms, namely amodiaquine tablets, sulfadoxine/pyrimethamine fixed–dose combination tablets and mefloquine tablets. The undertaking of these projects, to develop specifications for the quality control of these pharmaceutical products, formed the object of this research study. Data had been accumulated since 2000, as a result of continuous requests by the WHO to help solve problems that had been experienced with analytical test methods, especially from manufacturers. These requests either led to the refinement of existing methods, or to the development of new ones. The success with which these outcomes were implemented worldwide, finally led to the decision to publish these research findings under the umbrella of this project. The proud product is a comprehensive package of tests for three commercial antimalarial products, the outcomes of which are hoped to contribute towards the combat against resistance formation to these important disease fighters. / Thesis (Ph.D. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2011.

Malaria is a disease affecting millions of people in 109 malarious countries and territories, causing approximately one million deaths annually. In 2004 one of the parasites causing human malaria, Plasmodium falciparum, was among the leading global causes of death from a single infectious agent, especially in Africa (WHO, 2008:23). Treatment of this disease with single active pharmaceutical ingredients has led to the emergence of resistant P. falciparum parasites, resulting in the most severe form of this illness. Alarmingly, the poor quality of commercially available antimalarial products, especially in Africa, has increasingly been reported as a major cause of resistance to antimalarials. In Pakistan it was found that a P. falciparum epidemic that initially was attributed to drug resistance, was actually caused by substandard sulfadoxine/pyrimethamine products, causing a 50 times higher incidence of malaria in these areas than elsewhere (Leslie et al., 2009:1758). Other results indicated that up to 10% of sulfadoxine/pyrimethamine tablets, sampled in six African countries, failed the assay test, whilst up to 40% failed the USP dissolution test. Furthermore, the World Health Organization (WHO) reported that 20 - 90% of products failed quality requirements during 1999 and 2000 in seven African countries (WHO, 2003:263). Cases like these have raised the awareness of the vast number of inferior products that are being distributed. The subsequent need for establishing mechanisms to proactively detect substandard medicines, specifically antimalarials, easily and effectively had indirectly led to the origin of this study, long before it was formally undertaken. Testing monographs for pharmaceutical products are developed to formalise, or standardise, the regulation of pharmaceutical dosage forms. Problems have, however, been reported with regards to the inadequacy of existing antimalarial monographs in assuring quality medicines, fit for their intended use. The WHO had requested the Research Institute for Industrial Pharmacy, incorporating the Centre for Quality Assurance of Medicines (RIIP®/CENQAM®), both operating at the Potchefstroom Campus of the North–West University, to develop monographs for three immediate–release antimalaria dosage forms, namely amodiaquine tablets, sulfadoxine/pyrimethamine fixed–dose combination tablets and mefloquine tablets. The undertaking of these projects, to develop specifications for the quality control of these pharmaceutical products, formed the object of this research study. Data had been accumulated since 2000, as a result of continuous requests by the WHO to help solve problems that had been experienced with analytical test methods, especially from manufacturers. These requests either led to the refinement of existing methods, or to the development of new ones. The success with which these outcomes were implemented worldwide, finally led to the decision to publish these research findings under the umbrella of this project. The proud product is a comprehensive package of tests for three commercial antimalarial products, the outcomes of which are hoped to contribute towards the combat against resistance formation to these important disease fighters. / Thesis (Ph.D. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2011.

The World Health Organization estimates that about 10-30% of pharmaceuticals in the world are either substandard or counterfeit. The number is even higher in the developing countries. From a public health perspective, a key contributor to the development and proliferation drug resistant strains of infections, including tuberculosis (TB), malaria and other infections that are leading killers in resource limited settings is poor quality medicines. Most of the main causes are profit driven corruption in many pharmaceutical companies, the poor manufacture and quality control, and/or the inappropriate storage conditions. Poor quality drugs lead to loss of life, create morbidity, strain the financial structure of the health system and lead to long-term drug resistance that affects us all. The current technology for screening poor quality drugs can be divided into 2 categories: the high end, precise and high cost technologies (such as High Performance Liquid Chromatography) and lower cost and qualitative technologies (such as Thin-Layered Chromatography). The high-end methods can give a precise measurement of active pharmaceutical ingredient (API) concentration and the presence of impurities in the tablets, but require trained personnel, advanced machine and lab set up, not suitable for field testing where most of poor quality pharmaceuticals have been found. The lower cost techniques require little training and simple equipment to operate at a relatively inexpensive price, but only gives qualitative results. In addition, most of current methods do not look at the dissolution profile of the tablets simultaneously with the concentration of API. Therefore, we propose to develop an assay that can quantify the concentrations of multiple APIs simultaneously and measure dissolution rates. In order to address current gaps in knowledge, my research proposal has three main parts in the assay development: 1) Development of an fluorescent/luminescent assay for detection of counterfeit/substandard antimalarial using small-molecules-based methods and field testing in Ghana; 2) Development of a fluorescent assay for detection of water-soluble pharmaceuticals using SELEX; and 3) Design a detection platform using microfluidic chips for real time quantification of multiple active pharmaceutical ingredients. For proof-of-concept, an antimalarial drug (artesunate and amodiaquine) and antibacterial antibiotics (sulfamethoxazole and trimethoprim) are selected to demonstrate the probe development and test the chip performance. Overall, the assay will be rapid, robust, portable, inexpensive, multiplexed, quantitative, specific, and sensitive. At a big picture level, emphasizing drug quality and creating robust mechanisms of drug testing will improve health outcomes and enhance treatment efficacy in resource limited settings.