A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for the degree of Master of Science in Medicine in Epidemiology and Biostatistics Johannesburg, 2002. / To systematically evaluate the efficacy of double dose of sulfadoxine-pyremithamine (SP/SP) treatment in pregnancy in malaria endemic areas. Methods - The relevant articles were retrieved by a computerized search of Medline, Cochrane Review, Pub Med and Google with the following key words, sulfadoxine-pyrimethamine, intermittent, pregnancy, Quasi- experimental studies and Randomised Control Trials. Three reviewers identified only 2 papers meeting the inclusion criteria set for the study. Systematic quantitative review was performed. / IT2018

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

This study focused on two active pharmaceutical ingredients (APIs) that are used to treat two of the most notorious diseases in Africa, i.e. human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) and malaria. It is well known that many African countries lack effective regulatory control over medicines and patients are subsequently at risk of receiving sub-standard treatments. This study set out to investigate how the modification of the crystal packing (i.e. polymorphism) of these APIs may impact on their quality, safety and efficacy. Efavirenz (an antiretroviral) and Pyrimethamine (an antimalarial) were selected as the two model APIs for investigation during this study. It was found that a novel amorphous form (Form A) of Efavirenz had been prepared during this study through quench cooling. Form A was extensively characterised and compared to the preferred crystalline Form I, with the aim of providing a means of distinguishing between these two Efavirenz forms. In contrast to popular belief (that amorphous form should have improved dissolution and solubility properties over the crystalline counterpart), the powder dissolution of Form A was significantly lower than that of Form I. Further investigation indicated that this was due to the occurrence of agglomeration and phase-mediated transformation. This observation had led to the belief that Form A had poor thermodynamic stability. The glass transition temperature and the crystallisation activation energy, required for the recrystallisation of Form A, were subsequently determined in an attempt to elucidate its thermodynamic stability. The glass transition temperature of Form A was found to be unfeasibly low, hence confirming its tendency towards agglomeration. The crystallisation activation energy of Form A was determined by non-isothermal determinations, using differential scanning calorimetry (DSC), hot stage microscopy (HSM) and capillary melting point (CMP) analysis. These studies not only elucidated the required activation energy for the conversion of Form A into Form I, but it also found that the results from CMP were similar to those of the universally accepted DSC technique, allowing for the proposal of CMP as a cost-effective alternative to DSC for the quantitative measurement of the crystallisation of Efavirenz. Isothermal studies revealed that Form A had a short half-life, which, together with its poor dissolution performance, exemplified why this form was unsuitable for pharmaceutical use. The Pyrimethamine study focused on recrystallisation as a means of modifying its crystal packing and on an evaluation of the effect that such crystal modification may have on its safety and manufacturability. Anhydrous Pyrimethamine was recrystallised, using methanol, acetone, n-propanol, ethanol, N,N-dimethylformamide and N,N-dimethylacetamide. Ethanol, acetone and n-propanol altered the crystal habit of Pyrimethamine, without any modification of its crystal lattice. The different habits exhibited clear differences in flowability and compressibility, which could in turn affect manufacturing and therefore the quality of the finished pharmaceutical product (FPP). These habits were subsequently extensively characterised by means of in-silico molecular modelling predictions. It was found that recrystallisation from methanol, N,N-dimethylformamide and N,N-dimethylacetamide had resulted in solvatomorphism. These solvatomorphs contained their respective solvents in concentrations exceeding the allowed residual solvent limits, as set by the International Conference on Harmonisation (ICH) guidelines. These undesirable solvatomorphs were also comprehensively characterised as a service to the pharmaceutical industry, in order to identify the distinct characteristics that distinguish these forms from the preferred non-toxic form, and to provide techniques for transforming the toxic forms into the non-toxic form. / PhD (Pharmaceutics), North-West University, Potchefstroom Campus, 2015

This study focused on two active pharmaceutical ingredients (APIs) that are used to treat two of the most notorious diseases in Africa, i.e. human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) and malaria. It is well known that many African countries lack effective regulatory control over medicines and patients are subsequently at risk of receiving sub-standard treatments. This study set out to investigate how the modification of the crystal packing (i.e. polymorphism) of these APIs may impact on their quality, safety and efficacy. Efavirenz (an antiretroviral) and Pyrimethamine (an antimalarial) were selected as the two model APIs for investigation during this study. It was found that a novel amorphous form (Form A) of Efavirenz had been prepared during this study through quench cooling. Form A was extensively characterised and compared to the preferred crystalline Form I, with the aim of providing a means of distinguishing between these two Efavirenz forms. In contrast to popular belief (that amorphous form should have improved dissolution and solubility properties over the crystalline counterpart), the powder dissolution of Form A was significantly lower than that of Form I. Further investigation indicated that this was due to the occurrence of agglomeration and phase-mediated transformation. This observation had led to the belief that Form A had poor thermodynamic stability. The glass transition temperature and the crystallisation activation energy, required for the recrystallisation of Form A, were subsequently determined in an attempt to elucidate its thermodynamic stability. The glass transition temperature of Form A was found to be unfeasibly low, hence confirming its tendency towards agglomeration. The crystallisation activation energy of Form A was determined by non-isothermal determinations, using differential scanning calorimetry (DSC), hot stage microscopy (HSM) and capillary melting point (CMP) analysis. These studies not only elucidated the required activation energy for the conversion of Form A into Form I, but it also found that the results from CMP were similar to those of the universally accepted DSC technique, allowing for the proposal of CMP as a cost-effective alternative to DSC for the quantitative measurement of the crystallisation of Efavirenz. Isothermal studies revealed that Form A had a short half-life, which, together with its poor dissolution performance, exemplified why this form was unsuitable for pharmaceutical use. The Pyrimethamine study focused on recrystallisation as a means of modifying its crystal packing and on an evaluation of the effect that such crystal modification may have on its safety and manufacturability. Anhydrous Pyrimethamine was recrystallised, using methanol, acetone, n-propanol, ethanol, N,N-dimethylformamide and N,N-dimethylacetamide. Ethanol, acetone and n-propanol altered the crystal habit of Pyrimethamine, without any modification of its crystal lattice. The different habits exhibited clear differences in flowability and compressibility, which could in turn affect manufacturing and therefore the quality of the finished pharmaceutical product (FPP). These habits were subsequently extensively characterised by means of in-silico molecular modelling predictions. It was found that recrystallisation from methanol, N,N-dimethylformamide and N,N-dimethylacetamide had resulted in solvatomorphism. These solvatomorphs contained their respective solvents in concentrations exceeding the allowed residual solvent limits, as set by the International Conference on Harmonisation (ICH) guidelines. These undesirable solvatomorphs were also comprehensively characterised as a service to the pharmaceutical industry, in order to identify the distinct characteristics that distinguish these forms from the preferred non-toxic form, and to provide techniques for transforming the toxic forms into the non-toxic form. / PhD (Pharmaceutics), North-West University, Potchefstroom Campus, 2015

No description available.

Thesis (Ph. D.)--University of Washington, 2004. / Vita. Includes bibliographical references (leaves 101-112).

Malaria infection is a major cause of morbidity and mortality in tropical countries, and particularly in Mozambique. Recently substantial resources have been used to reduce the burden of malaria in Mozambique. These include the distribution of insecticide treated bed-nets, indoor residual insecticide spraying, access to artemisinin-based combination treatment (ACT), and intermittent preventive treatment of pregnant women with sulfadoxine-pyrimetamine (SP-IPTp). The most important benefit of SP-IPTp in malaria endemic areas has been the increase in birth weight, thus increasing the probability of child survival. The SP-IPTp policy was based on evidence of its effectiveness in areas of high intensity malaria transmission. The effect of SP-IPTp has been less evident in the presence of high coverage with insecticide treated bed-nets. It is not know whether reducing the risk of malaria through effective vector control using indoor residual insecticide spraying and large-scale deployment of ACTs has a similar effect in reducing the impact of SP-IPTp on birth weight. At the same time, increasing resistance of SP could be compromising the effect of SP-IPTp on birth weight, as could co-infection with HIV. The aim of this study was to determine if the effect of SP-IPTp on reduction in risk of low birth weight is modified by Plasmodium falciparum malaria prevalence. This retrospective antenatal record review, analyzed 20867 antenatal records from 2005 to 2007 from public health facilities in Maputo and Gaza provinces, southern Mozambique. One or two doses of SP-IPTp does not have any effect on reducing the risk of low birth weight, while women who had at least three doses of SP-IPTp had a 15% lower risk of their babies being born with low birth weigh compared with fewer doses, (OR=0.85; 95% CI 0.73 – 1.00; p=0.053). The risk of babies being born with low birth weight was reduced by 28% when both malaria prevalence and dhfr / dhps mutation prevalence are low, (OR=0.72; 95% CI 0.51 – 1.00), but this effect was no longer significant with higher malaria prevalence and or mutation prevalence. SP-IPTp has an effect on reducing low birth weight with three or more doses, and in areas where malaria prevalence and mutation prevalence are low.  Copyright / Dissertation (MSc)--University of Pretoria, 2013. / Clinical Epidemiology / unrestricted

Thesis (Ph. D.)--University of Washington, 2001. / Vita. Includes bibliographical references (leaves 92-99).

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.