No description available.

No / The structure of C16H10N4O4[HCl,1.5CH3OH], Mr = 406.80, has been determined from X-ray diffraction data. The crystals are monoclinic, space group C2/c, with eight molecules per unit cell and a = 21.482(4), b = 7.131(1), c = 24.495(5) A ° , b = 111.01(3) , crystal density Dc = 1.546 g/cm3. The material was difficult to crystallize and crystals produced were found to be poor diffractors. Intensity data were measured at liquid nitrogen temperature using a weakly diffracting crystal typical of the batch. However the X-ray analysis has finally enabled the chemical constitution of this cryptolepine derivative, which was previously incorrectly assigned, to be unequivocally established. Direct methods were used to solve the structure which was refined by full-matrix least squares to a conventional R-index of 0.0798 for 2,861 reflections and 268 parameters. The 7,9-dinitrocryptolepine molecule is highly planar with a strong intramolecular hydrogen bond between N(10) in ring C and O(92) of a nitro group. There are a number of intermolecular hydrogen bonds involving the cryptolepine derivative the hydrochloride and both solvated methanols. One of the methanol solvate molecules (methanol 2) is unusually disordered with its C atom lying exactly on a crystallographic twofold axis. Consequently the methanol OH and H3 groups are at 0.5 occupancy and repeated by the twofold symmetry.

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)

Malaria remains an important cause of morbidity and mortality among children in sub-Saharan Africa despite recent reductions in malaria incidence in some parts of Africa. Current control tools face threats such as the emergence of drug resistant parasites and insecticide resistant mosquitoes. A malaria vaccine is needed to complement and/or replace existing tools in order to achieve better malaria control and eventually eliminate the disease. RTS,S/AS01E is the most clinically advanced pre-erythrocytic malaria vaccine candidate and is currently being tested in a phase III trial. The short-term efficacy of RTS,S/AS01E is known but the duration of protection is unknown. Furthermore, although RTS,S is protective, it is unclear which immunological assays predict efficacy: hence there are no known correlates of vaccine-induced protection against clinical malaria. In a randomized controlled trial, I assessed the efficacy of RTS,S/AS01E in children (5-17 months old) residing in Kilifi, Kenya, over 4 years of follow-up and determined the correlates of protection against clinical malaria. In order to examine the effect of variations in malaria exposure on vaccine efficacy, I developed an individual marker of malaria exposure calculated as distance-weighted prevalence of malaria infection within 1 km radius of every child. Over 4 years of follow-up, RTS,S/AS01E had an efficacy of 29.9% (95%CI: 10.3% to 45.3%, p=0.005) and 16.8% (95%CI: -8.6% to 36.3% p=0.18) against first and all malaria episodes, respectively (by intention to treat analysis). Vaccine efficacy waned over time and with increasing malaria exposure. RTS,S/AS01E efficacy was 43.6% (95% CI, 15.5 to 62.3) in the first year but was -0.4% (95% CI, -32.1 to 45.3) in the fourth year. Vaccine efficacy was 45.1% (95%CI 11.3% to 66.0%) among children with lower than average malaria exposure index, but 15.9% (95%CI -11.0 to 36.4%) among children with higher than average malaria exposure index. Despite waning in efficacy, RTS,S/AS01E averted 65 cases of malaria per 100 vaccinated children, with more cases averted among the children in the higher malaria-exposure cohort (78 cases per 100 vaccinated children) than those the low exposure cohort (62 cases per 100 vaccinated children). RTS,S/AS01E induced high titres of anti-CS protein antibodies and CD4+ T cell but not CD8+ T cell responses. Anti-CS antibody titres and the frequency of TNF-α producing CD4+ T cell responses were independently associated with protection from clinical malaria, and the combination of both anti-CS titers and TNF-α producing CD4+ T cell response satisfied the Prentice criteria for surrogate markers of protection. There was no association between avidity of RTS,S-induced anti-CS protein antibodies and protection from clinical malaria. Conclusions: RTS,S/AS01E efficacy against all episodes is 16.8% over the 4 years of follow-up. The vaccine efficacy wanes over time and with increasing malaria exposure. RTS,S/AS01E-induced TNF-α producing CD4 T cell and anti-CS protein antibody responses were independently associated with protection from clinical malaria. Anti-CS avidity did not predict protection from clinical malaria. Long-term follow-ups of malaria vaccine trials are essential in the evaluation of the longevity of vaccine efficacy.

El objetivo de esta investigación retrospectiva, fue determinar la asociación existente entre mutaciones puntuales en los genes dihidrofolato reductasa (Pfdhfr) y dihidropteroato sintasa (Pfdhps) de Plasmodium falciparum y la respuesta clínica en pacientes con diagnóstico de malaria no complicada causada por P. falciparum, admitidos en un estudio de eficacia in vivo de sulfadoxina-pirimetamina (SP) llevado a cabo en dos áreas de la región Loreto en 1999. Se tomaron muestras de sangre de 86 pacientes antes de administrarles SP, las que se analizaron usando PCR-anclado específico de alelo para estudiar a los codones S108N/T, N51I, C59R, I164L y C50R del gen Pfdhf y los codones A436G, A437G, K540E, A581G y A613S/T del gen Pfdhps, encontrándose que las infecciones causadas por parásitos con 3 mutaciones en Pfdhfr (108Asn/51Ile/164Leu) y 2 (581Gli/437Gli) ó 3 mutaciones en Pfdhps (581Gli/437Gli/540Glu) denominados el quíntuple mutante y el séxtuple mutante, respectivamente, se encontraban asociadas con la falla del tratamiento con SP. Además, se estableció que cuanto más alto era el número de mutaciones tanto en Pfdhfr como en Pfdhps, más alto era el riesgo de fallar al tratamiento con SP, según resultado del análisis de regresión logística empleado para asociar a estas dos variables. Este estudio contribuye en brindar evidencias científicas de la asociación existente entre las variables en la región Loreto contribuyendo a su validación y su futuro uso para estudios de vigilancia de fármaco resistencia a SP no solo en el Perú sino en general para los países de América del Sur que comparten territorio de la selva Amazónica. / -- The objective of this retrospective study was to determine the asociation between point mutations in dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) Plasmodium falciparum genes, and clinical outcome of patients with non complicated P.falciparum malaria diagnosis, admitted to a in vivo sulphadoxine-pirymethamine (SP) drug efficacy study conducted in 1999, in two areas of Loreto region. We used allelic specific-nested PCR to analize 86 blood samples collected before SP treatment, and study mutations at codons S108N/T, N51I, C59R, I164L and C50R in Pfdhfr and codons A436G, A437G, K540E, A581G y A613S/T in Pfdhps genes, and found that Infections caused by parasites harbouring 3 mutations in Pfdhfr (108Asn/51Ile/164Leu) and either 2 or 3 mutations in Pfdhps (581Gly/437Gly and 540Glu) called the quintuple and sextuple mutants, respectively, were associated to failure with SP treatment. Logistic regression analysis was used to look for association between the variables, helping to establish the higher the number of mutations in both Pfdhfr and Pfdhps genes, the higher the risk of treatment failures when using SP.The contribution of this study is to provide scientific evidences of the association between both variables in Loreto region supporting its validation and future application in surveillance studies for SP drug resistance, that can be conducted not only in Peru but also in South American countries that share the Amazon basin territory.

In the second part of the project, the immunology of PfMSP-133 was studied. During the invasion of merozoites, PfMSP--142 is processed into two fragments with molecular weight of 33kDa and 19kDa. The 19kDa fragment (PfMSP-119) originating from the carboxyl--terminal of PfMSP--142 is relatively more immuno-dominant in different malarial species such as P. falciparum, P. vivax and P. yoelii. In the past, only limited researches about PfMSP-1 33 were performed. Apart from its difficulty in expression, PfMSP-1 33 was also believed to be incapable of inducing protection. / Nevertheless, following the breakthrough of expressing recombinant PfMSP-1 33 in our laboratory, we have demonstrated in this study that recombinant MSP-133 can elicit antibodies with a titer up to a million. Also, we observed that MSP-133 can help MSP-119 to induce protective immunity and such effect is independent from the covalent linkage between these two proteins. Most importantly, our results show that recombinant PfMSP-133 can elicit the production of antibodies that can potentiate the inhibitory effect of anti-MSP-142 serum at high serum dilution. Results of this study give new insights in malarial vaccine development in terms of optimizing the use of adjuvant and immunization regimens. / The 42kDa carboxyl terminal fragment of Plasmodium falciparum Merozoite Surface Protein-1 (PfMSP--142) is one of the most promising candidate antigens in the development of malarial vaccine. In vivo experiments in the 1990's showed that Aotus monkeys immunized with PfMSP--142 were protected from malarial challenge. Later on, other experiments also demonstrated the possibility of using recombinant PfMSP-142 as candidate antigen for malarial vaccine. Previously, recombinant PfMSP-142 (Bvp42) was expressed with the baculovirus expression system and characterized in our laboratory. / The aim of the first part of this project is to improve the production of Bvp42. Experimental results have shown that the expression level of Bvp42 was increased under a BMN compatible baculovirus expression vector---pVL1393. Besides, a codon optimized MSP-142 nucleotide is constructed for the construction of a baculovirus carrying codon optimized MSP-142 gene and aimed for higher expression level. Unfortunately, no Bvp42 expression is observed in the transfection samples and the reason of this observation is unclear. Meanwhile, the purification of Bvp42 was also improved. Pretreatment of the hemolymph with Q--sepharose before affinity chromatography could enhance the purity of the final product. / Yuen, Sai-hang Don. / "July 2007." / Adviser: Walter K. K. Ho. / Source: Dissertation Abstracts International, Volume: 69-01, Section: B, page: 0220. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (p. 183-195). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Thesis (MPH.) --University of Limpopo, 2016 / Background: Malaria is one of the important communicable diseases transmitted by Anopheline mosquitos to humans and is endemic in 108 countries around the world. Most malaria epidemics in African highland countries are caused by Plasmodium Falciparum (P Falciparum) and people residing in highlands are said to be having low immunity to malaria and both children and adults are affected by the disease, whereas vivax malaria is common in lowlands African countries. The current study was undertaken with an aim to determine the spatial distribution of malarial cases during the period 2006 to 2015 in Mopani District of Limpopo Province, South Africa. Methods: Quantitative retrospective descriptive methodology was employed to review the malaria distribution in Mopani district. A total of 12 037 malaria cases were identified for the period of the study and the data was kept anonymously by not using the names of the patients. Ethical clearance was received from the Turfloop Research Committee of University of Limpopo in consideration of section 14, 15, 16, and 17 of National Health Act 61 of 2004. The data was exported to excel spreadsheet and cleaned before exported into SPSS 23.0 software which was used for data analysis. Results: The findings revealed that most malaria cases were found in 2006 and again in 2014 and 2015 respectively. Malaria cases were also seen to be seasonal and were very high during January, February, March and April. Malaria cases also hiked during the month of October. The results also show that most malaria cases were reported between the patients aged of 16 to 25 and 26 to 40 years. There were more males than females who were infected by malaria in Mopani district and the sub district which was found to be having high malaria cases is Greater Giyani with more than 50% of the population (51.1%); followed by Ba Phalaborwa (23.1%); then Greater Tzaneen 13.1%. Conclusion: Mopani district has halved its malaria transmission for the comparison years, however the slow reduction in numbers of deaths is still a cause for concern. Key words: Malaria prevalence, spatial distribution, case fatality rate, elimination.

Malaria is still an epidemic in many parts of the world-about 220 million people are still infected with malaria worldwide and about 700 thousand people die from this disease per year. Most of the drugs used to treat malaria work well if they are used as required and they contain the right amounts of the active ingredient; however, it is estimated that more than 10% of drugs traded worldwide are counterfeits including 38% to 53% of antimalarial tablets produced in China and India. Due to the lack of data covering the extent of counterfeit antimalarial drugs in Ghana, the purpose of this quantitative study was to determine the percentage of counterfeit antimalarial drugs sold in Ghana by assessing the amounts of the 2 most common antimalarial drugs, artemether (ATMT) and lumefantrine (LMFT) in drugs sold in Ghana retail outlets. These drugs were purchased from retail outlets in Ghana and analyses at the Mayo Clinic Pharmacology core lab (Rochester, MN). The quality of the drugs were characterized by comparing the actual amount of ATMT & LMFT in each tablet to the expected amount. Using explanatory theory along with dose response-response occupancy theory, the researcher addressed quantitative solutions to questions related to the percentage and distribution of counterfeit ATMT and LMFT tablets. The results revealed that overall 20% of the drugs are counterfeit; this is not dependent on the location or kind of outlet but rather depends on whether the tablets were imported or locally manufactured and whether the tablets had a pedigree scratch panel. This study provides a better understanding of how much antimalarial medication is counterfeit in Ghana, which will aid interventions to minimize the adverse effects of counterfeit antimalarial medication in Ghana

El objetivo de esta investigación retrospectiva, fue determinar la asociación existente entre mutaciones puntuales en los genes dihidrofolato reductasa (Pfdhfr) y dihidropteroato sintasa (Pfdhps) de Plasmodium falciparum y la respuesta clínica en pacientes con diagnóstico de malaria no complicada causada por P. falciparum, admitidos en un estudio de eficacia in vivo de sulfadoxina-pirimetamina (SP) llevado a cabo en dos áreas de la región Loreto en 1999. Se tomaron muestras de sangre de 86 pacientes antes de administrarles SP, las que se analizaron usando PCR-anclado específico de alelo para estudiar a los codones S108N/T, N51I, C59R, I164L y C50R del gen Pfdhf y los codones A436G, A437G, K540E, A581G y A613S/T del gen Pfdhps, encontrándose que las infecciones causadas por parásitos con 3 mutaciones en Pfdhfr (108Asn/51Ile/164Leu) y 2 (581Gli/437Gli) ó 3 mutaciones en Pfdhps (581Gli/437Gli/540Glu) denominados el quíntuple mutante y el séxtuple mutante, respectivamente, se encontraban asociadas con la falla del tratamiento con SP. Además, se estableció que cuanto más alto era el número de mutaciones tanto en Pfdhfr como en Pfdhps, más alto era el riesgo de fallar al tratamiento con SP, según resultado del análisis de regresión logística empleado para asociar a estas dos variables. Este estudio contribuye en brindar evidencias científicas de la asociación existente entre las variables en la región Loreto contribuyendo a su validación y su futuro uso para estudios de vigilancia de fármaco resistencia a SP no solo en el Perú sino en general para los países de América del Sur que comparten territorio de la selva Amazónica. / The objective of this retrospective study was to determine the asociation between point mutations in dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) Plasmodium falciparum genes, and clinical outcome of patients with non complicated P.falciparum malaria diagnosis, admitted to a in vivo sulphadoxine-pirymethamine (SP) drug efficacy study conducted in 1999, in two areas of Loreto region. We used allelic specific-nested PCR to analize 86 blood samples collected before SP treatment, and study mutations at codons S108N/T, N51I, C59R, I164L and C50R in Pfdhfr and codons A436G, A437G, K540E, A581G y A613S/T in Pfdhps genes, and found that Infections caused by parasites harbouring 3 mutations in Pfdhfr (108Asn/51Ile/164Leu) and either 2 or 3 mutations in Pfdhps (581Gly/437Gly and 540Glu) called the quintuple and sextuple mutants, respectively, were associated to failure with SP treatment. Logistic regression analysis was used to look for association between the variables, helping to establish the higher the number of mutations in both Pfdhfr and Pfdhps genes, the higher the risk of treatment failures when using SP.The contribution of this study is to provide scientific evidences of the association between both variables in Loreto region supporting its validation and future application in surveillance studies for SP drug resistance, that can be conducted not only in Peru but also in South American countries that share the Amazon basin territory.

Background The years 1985 to 1988 and 1997 to 2001, were periods of high morbidity and mortality due to malaria in KwaZulu-Natal, South Africa. One reason for the increased burden of disease was the emergence of drug resistant Plasmodium falciparum. The parasite was resistant initially to chloroquine and then to sulphadoxine-pyramethamine, the medication of choice for the treatment and prevention of malaria in different periods of time. The changing epidemiology of malaria in Mrica was exacerbated by policy makers not making timely and rational change to the failing malaria drug regimens to newer and effective ones. Purpose ofthe study This study was conducted to determine the impact of delayed introduction of sulphadoxine-pyramethamine (Fansidar®) and artemether-lumefantrine (Coartem®) as a first-line drugs for malaria in KwaZulu-Natal from 1985 to 1988 and 1997 to 2001 respectivel y, Study Design Observational, Analytic, Ecological Method The incidence of malaria in KwaZulu-Natal was compared during different phases of the period when chloroquine was the first line treatment. The baseline phase (1982 to 1984) was taken when chloroquine correctly should have been used and this was compared with the delayed phase (1985 to 1988), when it should have been replaced by of sulphadoxinepyramethamine. During the second period sulphadoxine-pyramethamine was the first line treatment of malaria, the baseline phase (1993 to 1996) when it correctly should have been used was compared to the delayed phase (1997 to 2001) of introduction of the alternate treatment of malaria with artemether-Iumefantrine. Ethical approval for this study was obtained from the Biomedical Research Ethics Committee, of the University of KwaZulu-Natal. Statistical Methods The relative association of malaria infection during the chloroquine baseline and change phases and the sulphadoxine-pyrametharnine baseline and change phases were compared with statistical significance at 0.05. Results The risk of malaria infection was 4.5 times (Incidence Risk Ratio = 4.5; 95% Confidence Interval: 4.1 to 5.0; P < 0.0001) higher in chloroquine change phase relative to the baseline phase. During the sulphadoxine-pyrametharnine period, the malaria risk was 3.5 times greater (Incidence Risk Ratio = 3.50; 95% Confidence Interval: 3.40- 3.60; p < 0.0001) in the change phase. In the chloroquine period, the malaria mortality risk was 9.1 times higher (95% Confidence Interval: 2.1 to 38.5; p=0.0003) and the case fatality rate was increased 1.3 times more (95% Confidence Interval: 1.0 to 1.7; p< 0.001) in the change period. The risk of death during the sulphadoxine-pyramethamine change phase was 4.8 times (95% Confidence Interval: 3.3 to 7.0; p<O.OOl) and case fatality rate of2 times (95% Confidence Interval: 1.5 to 2.7; p <0.001) relative to the baseline phase. Conclusions The dramatic change in the malaria epidemiology in Africa in recent times was exacerbated by delay in replacing first line failing antimalarial drugs. The establishment of sentinel sites for assessing drug resistance or failure and the application of World Health Organisation standards in drug resistance studies will go a long way to achieving the Roll Back Malaria target by 2010. / Thesis (MMed.)-University of KwaZulu-Natal, Durban, 2007.