Tesis sobre el tema "Antimalarial combinations"

Relief of the global malaria burden relies on the management and application of effective therapies. Unfortunately, the continuous development of resistance to therapies by the deadliest parasite strain, Plasmodium falciparum, has made the treatment and control of malaria much more difficult. Derivatives of the Chinese peroxidic antimalarial drug artemisinin primarily used in first-line combination therapy for treatment of P. falciparum malaria have proved to be highly effective. However, their use also is now compromised by the development of resistance by the parasite to the artemisinin derivative in the drug combination. This event emphasizes the need for ongoing development of new and effective drug combinations. This research aimed to identify efficacious combinations selected from a group of compounds known to induce oxidative stress by redox cycling combined with an artemisinin, which as an oxidant drug also induces oxidative stress but is unable to undergo redox cycling. Combination of the artemisinin with a redox-active compound is expected to both enhance and maintain oxidative stress within the parasite's proliferative environment. These combinations should be used together with a third drug with a completely different mode of action, such as a quinolone. Selected amino artemisinins and redox active phenothiazines, phenoxazines, thiosemicarbazones, and quinolone derivatives were screened for antimalarial activity and mammalian toxicity. These were found to be potently active (11 μM) to Chinese Hamster ovarian (CHO) cells. The compounds are thus highly selective for P. falciparum, as revealed by the selectivity indices (SI) of >270. The in vitro absorption, distribution, metabolism, and elimination (ADME) properties of the compounds were also determined through the application of specific assays. In vivo pharmacokinetic (PK) profiling was also carried out by intravenous and oral administration of the individual compounds to healthy C57BL/6 mice. Biological samples were analysed via liquid chromatography-tandem mass spectrometry (LC-MS/MS) bioanalytical methods, which were validated according to the fit-for purpose recommendations by the FDA. Evaluation of the in vitro and in vivo profiles thereby facilitated the identification of suitable combination candidates. The phenoxazine and phenothiazine derivatives were identified as the best potential redox partners and were each investigated in combination with the amino-artemisinin artemisone through fixed ratio isobole analysis. A substantial synergistic interaction was observed. Overall, the investigation enabled the identification of drug combinations that are potently active in vitro. This synergistic interaction strongly supports the redox cycling rationale for identifying new antimalarial therapies and further suggests that such combinations in chemotherapy may delay the onset of resistance to the new agents. The results strongly encourage further investigation of the in vivo pharmacokinetic and pharmacodynamic (PK/PD) relationships of these combinations in the humanized murine model of P. falciparum

Antimalarial drug resistance is a major cause of the increasing burden due to P. falciparum malaria. Artemisinin-based combination therapies (ACTs) are now recognised to be the ideal choice for the first-line treatment of uncomplicated malaria, in order to achieve two beneficial outcomes: improvement of treatment efficacy and delay in the development of drug resistance. However uncertainties remain about the current and future benefits, risks and costs of ACTs and in particular how these outcomes are affected by differences in malaria epidemiology, health care settings, human behaviour and implementation strategies. This thesis seeks to address these uncertainties by creating a comprehensive, dynamic, bio- economic model of malaria transmission and the spread of drug resistance, which incorporates vector factors, human immunity, human behaviour, drug characteristics and costs. Central to the model is a biological model, developed in collaboration with a mathematician, which outputs the proportion of drug resistant infections and the incidence of new and recrudescent infections. Parasite biomass is also tracked in order for human "infectiousness" to be measured and fed-back into the model. Sub-models are used to calculate severe malaria, deaths, costs and cost-effectiveness. Data were obtained to develop and populate the model. This included a community drug usage survey in Cambodia, which was undertaken in order to document the adherence and coverage rates to ACT following the implementation of locally blister-packaged ACT. Coverage was found to be extremely low, and the use of artemisinin derivatives on their own was widespread. However, both of these outcomes were improved by interventions to increase coverage, particularly village malaria volunteers. Application of the model in a low transmission setting suggests that with a 10-year time-frame, switching from monotherapy to an ACT is very cost-effective and results in overall cost savings in a range of scenarios. High coverage rates with an ACT are required to delay the spread of drug resistance if resistance has already arisen to one of the partner drugs. Running the model with data from Cambodia suggests that even in settings with low coverage, the change will be cost-effective and significant benefits are gained from the implementation of the specific delivery interventions. Strategies for optimising the implementation of ACTs are discussed in light of the findings.

Despite the success of recent global malaria control efforts, which. have halved global malaria mortality since 2000, malaria is still one of the world's most deadly diseases causing an estimated half a million deaths, mostly among African children, and around a quarter of billion clinical episodes every year as reported in 2014 1. Drug resistance is one of the most important challenges to malaria elimination. To contain drug resistance, many efforts have been put forth including improvement of surveillance systems and mass treatment in order. to stop or slow down the transmission of the resistant strain. To find out whether a population-level treatment strategy can have any benefit in containing drug resistance, mathematical models are an appropriate approach to this problem and individual-based models allow us to have a better understanding of the effect of individual heterogeneities on the outcome. The first part of the thesis is about building and validating an individual based microsimulation. The model is implemented as an individual-based discrete-time event simulation model in C++. The behaviors and the state changes of human individuals are determined by relevant events and mathematical formulas. This integrated model combines components that reproduce the most important features of malaria transmission and epidemiology: the infectiousness of human populations; clinical model of acute illness; heterogeneities in individuals' age, biting-rate level, drug absorption, drug action, multiple parasite populations, and human immunity. To validate this individual-based model, two types of validation have been done. The model's parameters were obtained from field or clinical data were used directly in the model. For those parameters that cannot be obtained directly from literature review, sensitivity analysis has been done to find how variation in parameter values affects certain key features of malaria epidemiology .

Includes bibliographical references (p. 253-265)
This study seeks to use the techniques of cost-effectiveness analysis to evaluate, within the context of effective vector control, the change to artemisinin-based combination therapies (ACTs) as first line malaria treatment and to evaluate the relevance of using definitive diagnosis (as opposed to clinical diagnosis) as the basis for initiating malaria treatment, especially when using ACTs for treatment. The cost-effectiveness of ACTs was evaluated in two study sites (i.e. In Kwazulu Natal which switched from SP monotherapy to AL in 2001 and in Mpumalanga which changed from SP monotherapy to AS+SP in 2003) in South Africa. The economic evaluation of use of routine definitive diagnosis as part of malaria case management, using rapid diagnostic tests (ROTs), was undertaken at two districts (Namaacha and Matutuine), in southern Mozambique, where routine use of ROTs and treating malaria patients with an ACT (using artesunate + SP) were implemented at pilot level in 2003.

Introduction: In sub-Saharan Africa, HIV treatment is initiated with combination of antiretroviral medications comprising of a backbone of either stavudine or zidovudine plus lamivudine with a non-nucleoside reverse transcriptase inhibitor of either efavirenz or nevirapine. Efavirenz is highly efficacious, durable and well tolerated. The risk for toxicity of efavirenz is determined by several factors including single nucleotide polymorphisms in the hepatic enzymes responsible for its metabolism and concurrently administered medications such as antimalarials, which share common metabolic pathways. The aims of this dissertation are to assess the long-term effectiveness of efavirenz-based antiretroviral therapy and the impact of pharmogenomics and pharmacokinetic interactions of artemisinin-based antimalarial therapy on efavirenz exposure among Ghanaian HIV-infected patients. Methods: The effectiveness of efavirenz- compared with nevirapine-based antiretroviral therapy was assessed retrospectively in nearly 4000 patients starting treatment between 2004 and 2010. The main outcome measure was a composite of toxicity, disease progression and attrition, and CD4 count changes. A prospective pharmacokinetic study of artesunate and efavirenz was conducted among 22 HIV-infected and 21 controls. Plasma efavirenz and artesunate/ dihydroartemisinin concentrations were measured using validated and standardised methods. Genotyping for single nucleotide polymorphisms in CYP2B6 G516T, T983C; CYP2A6*9B, UGT2B7*735 and *802 as well as CAR rs2307424 were performed for 800 patients with real-time polymerase chain reaction with allelic discrimination. Results: Antiretroviral therapy was associated with robust CD4 increases. Efavirenz was comparable with nevirapine in composite outcomes but better tolerated. Artesunate was well tolerated when administered to HIV-infected patients on efavirenz. Single nucleotide polymorphisms in the CYP2B6 G516T and T983C were associated with increased plasma efavirenz concentrations. Conclusions/Recommendation: Among this Ghanaian cohort, both efavirenz and nevirapine-based antiretroviral therapy were effective. The better tolerability of efavirenz compared with nevirapine means it can be safely used as the preferred first line non-nucleoside reverse transcriptase inhibitor in sub-Saharan Africa.

Malaria afflicts 300-500 million people in the world and the mortality ranges from 1-2 million, children in Africa being the most susceptible. With a vaccine not being available against malaria and the front line drugs such as chloroquine and antifolates registering widespread parasite resistance, the challenge of malaria treatment is a formidable task. While, research to discover new drugs has become essential, it has also become necessary to identify therapeutic strategies in the short-term. One approach is to examine whether known drugs used for other applications can be used to treat malaria. A second strategy is to look for natural compounds for antimalarial activity either singly or in combination. Combination therapy has assumed considerable importance in the context of artemisinin derivatives being the sole, tested, efficacious antimalarials left in the basket. A combination therapy with artemisinin derivative may prevent recrudescence due to monotherapy, extend the life of the drug and perhaps bring down the cost of therapy as well. A primary requirement to embark on such studies is to assess the status of drug resistance to the front line drugs in use. In India, chloroquine is still used as the front line drug for malaria therapy. Although, there have been indications and sporadic reports on the development of chloroquine resistance in the country, there has not been a detailed molecular or clinical evaluation for resistance. Keeping all these considerations in mind, the objectives of the present study are as follows: 1. Evaluation of chloroquine resistance inP.falciparum isolates from patients using Pfcrt-mutation as marker. 2. Evaluation of the anti-tubercular drugs, rifampicin and isonicotinic acid hydrazide (INH) for antimalarial activity. 3. Evaluation of curcumin from turmeric singly and in combination with α,β- arteether for antimalarial acitivity. Chapter I deals with the review of literature pertaining to scenario of available antimalarials, efforts to discover new antimalarials based on new drug targets, mechanisms of drug resistance and strategies for combination therapies. Chapter II deals with an evaluation of Pfcrt mutation in clinical samples of P.falciparum malaria in India. After several false starts to find molecular markers to identify chloroquine resistance, mutations in the Pfcrt gene of P.falciparum, K76T mutation in particular, has been shown to correlate very well with chloroquine resistance in culture. A study of 109 P.falciparum – infected blood samples from different parts of India has revealed that close to 95% of the isolates carry the K76T mutation. This was shown on the basis of susceptibility to ApoI restriction digestion of the PCR product covering this region (264 nt) and DNA sequencing of the PCR product. Interestingly, the resistant haplotype in this region of 72-76 amino acids was found to be mostly SVMNT, except for 4 samples with CVIET haplotype. SVMNT has all along been considered to be of South American origin, where as CVIET is of South East Asian/African origin. Subsequent studies by another group in the country has also shown that the Pfcrt - K76T mutation is seen at least in 85% of the cases and in addition to the dominant SVMNT haplotype, newer haplotypes are also seen. The present study has also included an analysis of N86Y mutation in the Pfmdr1 gene based on susceptibility to Afl III restriction enzyme digestion and DNA sequencing of the PCR product (603 nt). Pfmdr1 mutations have been extensively studied in literature for possible correlation to CQR. The net conclusion is that it does not contribute directly to CQR but may have an indirect correlation. It has been shown in Mali that there is very good correlation between Pfcrt - K76T mutation and Pfmdr1 - N86Y mutation in the P.falciparum isolates. However, in the present study with Indian isolates only around 30% of the samples were found to carry the Pfmdr1 - N86Y mutation. While, further studies on the clinical relevance of the extensive Pfcrt mutation seen in the Indian isolates are needed, it is clear that the genetic change towards chloroquine resistance has already taken place in the Indian context. Chapter III is devoted to a study of the antimalarial effects of the anti-tubercular drugs, rifampicin and INH. This is on the basis that rifampicin is an inhibitor of prokaryotic and mitochondrial/chloroplast RNA polymerase. P.falciparum harbors the apicoplast, a remnant of chloroplast with a 35kb DNA. It is known that the β, β’- subunits of the apicoplast RNA polymerase are coded by the apicoplast DNA. There is a report that rifampicin is a slow acting antimalarial in cases of P.vivax -nfection. INH is known to act by inhibiting the enoyl-ACP reductase and β - hydroxy ACP synthase in M.tuberculosis. While, M.tuberculosis is known to manifest Fab I and Fab II pathways of fatty acid biosynthesis, it has recently been shown that P.falciparum manifests the FabII (discrete enzymes) pathway. Thus, it was considered possible that INH may also inhibit the fatty acid biosynthetic pathway of P.falciparum leading to inhibition of phospohlipid and membrane biosynthesis. Studies were, therefore, carried out with rifampicin, INH and the combination on the survival of P.falciparum in culture and P.berghei in mice. With P.falciparum, growth was followed by measuring3[H]-Hypoxanthine incorporation and slide detection of parasites using Giemsa stain. The results indicate that while, rifampicin inhibits P.falciparum growth with an IC50 around 25nM, and INH fails to show any effect even at 200µM concentration. The combination of rifampicin (25nM) and INH (100µM) shows enhanced killing effect. In view of these results, studies were undertaken in mice infected with P.berghei. After 72 hr infection, the mice were orally fed with rifampicin (500 µg/40 g body weight) or INH (1 mg/40 g body weight) or a combination of the two orally for 5 days, starting on day 3. Apart from parasite clearance in blood, protection against mortality is a good index, since all the infected mice die in about 7-8 days. The results indicate that rifampicin leads to around 50% protection and INH treatment gives around 10% protection. However, the combination gives around 83% protection with complete clearance of the parasite in blood. Short- term treatment of infected mice with drugs and an assay of rpoB/C transcription in the parasite using appropriate PCR primers reveal a striking inhibition in combination treatment. Again, when such parasites were put into short-term culture and32P- incorporation into phospholipids was measured, there was striking inhibition with combination treatment. Thus, the results indicate that a combination of rifampicin and INH has potent antimalarial activity in P.berghei-infected mice. The results are dramatic in this case when compared to the results obtained with P.falciparum culture. It is not clear whether the differences are due to differences in action in vitro vs in vivo or due to differences in susceptibility between P.falciparum and P. berghei to the treatment provided. Chapter IV deals with the antimalarial activity of curcumin (diferuloyl methane) from turmeric singly or in combination with artemesinin or its derivative. Curcumin is reported to have a wide variety of biochemical effects and its anti-cancer activity is under serious investigation. There is an earlier report that curcumin shows antimalarial activity against chloroquine-sensitive P.falciparum. In the present study, curcumin was tested against a chloroquine-resistant culture of P.facliparum and it inhibits growth with an IC50 of 5-8 µM. When P.berghei-infected mice were orally fed with curcumin for 5 days, there was delay in the development of parasitemia, with about 30% of the animals protected against mortality by day 28. For reasons mentioned earlier curcumin was tested in combination with artemisinin/derivative in P.falciparum culture and P.berghei in mice. The results indicate that artemisinin and curcumin have an additive inhibitory effect on P.falciparum growth, based on a detailed analysis of the isobolograms. In terms of the mechanism of action, curcumin treatment leads to accumulation of45Ca in the parasite cytoplasm. It also has a striking inhibitory effect on32P-incorporation into parasite proteins and phospholipids, suggesting an interference with phosphorylation mechanisms. None of these effects are seen under artemisinin treatment, which has been reported to specifically inhibit PfATP6 (Ca ATPase) in P.falciparum. In view of the possible different modes of action of artemisinin and curcumin, the combination was tested in P.berghei-infected mice. The infected mice received a single injection of α,β-arteether and 3 oral doses of curcumin (5mg/30g body weight). Curcumin treatment was found to dramatically delay the onset of parasitemia seen in animals treated with α,β-arteether alone due to recrudescence. In particular, a combination with a single injection of α,β-arteether (750µg or 1.5mg/30g body weight) followed by 3 oral doses of curcumin leads to complete prevention of recrudescence and 100% protection against mortality. Several combinations with artemisinin derivative are under investigation and they all suffer from toxic side effects, pharmacokinetic mismatch, known resistance to the combining partner and high cost. It is felt that this artemisinin derivative curcumin combination could prove superior in view of the fact that no resistance is known to curcumin and is safe even at very high doses used in the human. Both the drugs are eliminated fast and curcumin is a cheap chemical and available in plenty from natural source (turmeric). In view of these positive attributes, a clinical trial with this combination is recommended. 121

Malaria accounts for 198 million cases worldwide; with a high mortality rate. 584000 deaths were reported in 2013. Malaria is a re-emerging disease globally due to drug resistance, parasite recrudescence and non-availability of a vaccine. Chloroquine, quinine and antifolates served as frontline antimalarial drugs for decades. Development of resistance to chloroquine and antifolates, and the decreased efficacy of mefloquine, and even quinine, in malaria-endemic regions, has led to artemisinin derivatives evolving as frontline drugs. Artemisinin is a potent antimalarial compound and clears around 104 parasites per cycle. Despite being a potent antimalarial, artemisinin derivatives suffer from poor pharmacokinetic properties and short half lives. This has led to the development of artemisinin-based combination therapies (ACTs) using a partner drug with a longer half-life. However, resistance to ACTs has been reported in the last few years, perhaps due to lack of adherence to prescribed regimens or suboptimal treatment and the use of counterfeit drugs. Therefore there is an urgent need to develop an alternative ACT which overcomes these limitations. This thesis entitled “Adjunct therapy with curcumin for the treatment of malaria: studies in a murine model” describes the antimalarial activity of curcumin and artemisinin and the adjunct role of curcumin in the prevention of parasite recrudescence and cerebral malaria. The thesis is divided into three chapters: The first chapter entitled “Introduction: Malaria and anti-malarial drugs” consists of a brief introduction of malaria, the parasite life cycle and currently known antimalarial drugs. During the course of infection, the Plasmodium undergoes sporogony in the mosquito, and merogony and schizogony in the human host. All these life cycle stages are briefly described with depictions. A major part of this chapter is dedicated to describe antimalarial compounds under the following headings 1. Quinoline derivatives 2. 4-aminoquinolines 3. Antifolates 4. Artemisinin derivatives 5. Antibiotics and 6. Curcumin. The second chapter is aimed at examining the ability of curcumin-arteether (a synthetic derivative of artemisinin) combination therapy in preventing parasite recrudescence in a murine model through immunomodulation employing various immunological, molecular biological, and biochemical techniques. The use of suboptimal doses of antimalarial drugs leads to recrudescence or relapse of malaria (reappearance of the parasite in blood after antimalarial regimen). In the present study we have addressed this issue by the use of curcumin as an adjunct molecule with α,β arteether (a synthetic derivative of artemisinin). We have studied recrudescence in a Swiss mice model. A suboptimal dose was standardized by the use of different doses of α,β arteether (AE) ranging from 250µg to 1500 µg. We found 750 µg to be a suboptimal dose and studied the adjunct nature of curcumin when animals were treated with AE suboptimal dose or AE+curcumin (AC) combination treatment and monitored the survival of animals. Our results clearly demonstrate that ~95% of animals treated with the suboptimal AE dose died of recrudescent malaria but there was almost 100% survival of AC-treated animals; these animals were under observation for at least 3 months. We have studied the effect of curcumin in a recrudescence model at the molecular level. Curcumin by itself has antimalarial activity, but only in combination with α,β arteether prevented recrudescence. Our results indicate that curcumin has immunomodulatory activity. Serum cytokine analysis and spleen mRNA analysis for proinflammatory and anti-inflammatory mediators indicate that AC treatment effectively reduced both mRNA and serum cytokine levels of IFNγ, TNFα, IL-12 and effectively increased both mRNA and serum levels IL-10 and antibodies of the IgG subclass. Using TLR2 and IL-10 knockout animals, we have conclusively demonstrated that TLR2 is involved in the production of IL-10, and IL-10 is required for the AC-mediated protection of animals during the recrudescence period. We conclude that curcumin is able to prevent parasite recrudescence essentially by switching the Th1 response to a Th2 response. The third chapter deals with the study the effect of areether-curcumin (AC) combination therapy in the prevention of Experimental Cerebral Malaria. Although malaria mortality rates have decreased by an impressive 47% between 2000 and 2013, it is still a major affliction of mankind (WHO 2014). Plasmodium falciparum infection causes human cerebral malaria (HCM). The mortality rate in HCM is unacceptably high (15–20%), despite the availability of artemisinin-based therapy. HCM is characterized by a rapid progression from headache, general malaise, and prostration to hemiparesis, ataxia, unrousable coma, and death. Paediatric HCM deaths are mostly due to respiratory arrest. Alternatively, death may be due to parasite-mediated injury to a sensitive location; a small lesion due to parasite in brain stem can cause sudden respiratory arrest. In HCM, cytoadherence of pRBCs in brain microvasculature has been implicated as a major contributing factor for CM pathology. The failure of a large number of adjunct therapies in HCM demands the development of new intervention strategies. An effective adjunct therapy is urgently needed. Experimental Cerebral Malaria (ECM) in mice manifests many of the neurological features of HCM. In this study, we have demonstrated the efficacy of curcumin and PLGA nanocurcumin in the treatment of Experimental Cerebral Malaria (ECM), using the Plasmodium berghei ANKA-infected mouse model (C57BL/6). Curcumin/PLGA nanocurcumin alone can prevent the onset of ECM. We have shown that curcumin/PLGA nanocurcumin can prevent CD8+ T cell, CXCR3+ CD8 T cell and parasite-infected RBC (pRBC) sequestration in the brain. These are also the essential parameters underlying HCM. We have also demonstrated that curcumin effectively inhibits T cell proliferation in spleen. We have explained the anti-inflammatory effects of curcumin by showing the inhibition of NF-B in both brain and spleen, which is a plausible explanation. But, curcumin/PLGA nanocurcumin treated animals died later due to build up of parasitemia in blood and subsequent anemia. Moreover, a combination therapy with arteether and curcumin given even after the onset of neurological symptoms can completely cure and protect the animals against mortality. We have tested AC-combination after the onset of symptoms to mimic patient conditions in HCM, since the murine regimens reported were not successful in the treatment of HCM. Our results clearly demonstrate that AC treatment even after the onset of symptoms ensures 100% survival. Since the bioavailability of curcumin is reported to be poor, we have also tested the efficacy of PLGA nanocurcumin and find that it is superior to native curcumin in terms of therapeutic effects. It is concluded that curcumin would be an ideal adjunct drug to be used with the artemisinin derivatives to treat malaria, including cerebral malaria.

Effective case management of malaria is hampered by the spread of parasite resistance to nonartemisinin antimalarials. To counteract the impact of drug resistance, the World Health Organization (WHO) has endorsed artemisinin-based combination therapy (ACT) as the first-line treatment for uncomplicated Plasmodium falciparum malaria. Currently recommended ACTs are artemether-lumefantrine, artesunate plus amodiaquine, artesunate plus mefloquine, artesunate plus sulfadoxine-pyrimethamine and dihydroartemisinin-piperaquine. This study sought to review evidence of the efficacy and safety of different non-artemisinin antimalarials in combination with artesunate, artemether or dihydroartemisinin for the treatment of uncomplicated P. falciparum malaria in non-pregnant adults and children. The search for randomized controlled trials (RCTs) was conducted in the Cochrane Central Register for Controlled Trials (CENTRAL), MEDLINE, EMBASE and in ClinicalTrials.gov in January 2009. The eligibility and the methodological quality of trials were assessed and data were extracted, using standard forms. Data were captured and analyzed in Review Manager Software, versions 4.2 and 5.0. The outcomes assessed were: treatment failure, fever and parasite clearance time, calculating the relative risk (RR) and a weighted mean difference (WMD) with a 95% confidence interval and p-values, indicating statistical significance at 0.05. Thirty-seven trials with 6862 participants were included. Artesunate combined with amodiaquine had a statistically significant lower risk of treatment failure compared to the combination of artesunate with sulfadoxine-pyrimethamine (RR=0.57, 95% CI [0.33, 0.97], p=0.04, seven trials, N=1341). In addition, treatment with artesunate plus mefloquine was significantly associated with a lower risk of treatment failure compared to artesunate plus azithromycin (RR=0.04, 95% CI [0.00, 0.64], p=0.02, one trial, N=54). There was no significant difference when either mefloquine or atovaquone-proguanil were combination partners with artesunate (RR=2.6, 95% CI [0.93; 7.24], p=0.07, one trial, N=1066). When artesunate was combined with chloroquine, primaquine or azithromycin and compared with artesunate monotherapy, there was no statistically significant difference in the risk of unadjusted treatment failure. Each of these comparisons had one trial each. Artesunate plus chloroquine was quicker at clearing fever compared to artesunate plus sulfadoxinepyrimethamine (WMD= -7.20, 95% CI [-12.53, -1.87], one trial, N=132). Few trials adequately reported adverse events. There was no significant difference observed in the risk of adverse events between artesunate plus amodiaquine compared with artesunate monotherapy, however, adverse events were significantly less in artesunate plus amodiaquine compared to artesunate plus methylene-blue. Artesunate plus amodiaquine on the other hand had significantly more adverse events reported compared to artesunate plus sulfadoxine-pyrimethamine. The findings of this study support the implementation of artemisinin-based combination therapy for the treatment of uncomplicated malaria. Most crucially, this review found a greater advantage of combining amodiaquine with artesunate compared to sulfadoxine-pyrimethamine. The efficacy of artesunate plus mefloquine was superior to that of artesunate plus azithromycin. Furthermore, the combination of artemisinins with chloroquine, primaquine and azithromycin has shown very low efficacy and these combination therapies should not be recommended. The reporting of efficacy was not standardized as many trials did not differentiate between re-infections and recrudescences. Adverse events were also not adequately reported.
Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2011.