Publication: Rectal Artemisinins for Malaria : A Review of Efficacy and Safety from Individual Patient Data in Clinical Studies
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Date
2008
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1471-2334 (Electronic)
1471-2334 (Linking)
Published
2008
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BACKGROUND: Rectal administration of artemisinin derivatives has potential for early treatment for severe malaria in remote settings where injectable antimalarial therapy may not be feasible. Preparations available include artesunate, artemisinin, artemether and dihydroartemisinin. However each may have different pharmacokinetic properties and more information is needed to determine optimal dose and comparative efficacy with each another and with conventional parenteral treatments for severe malaria. METHODS: Individual patient data from 1167 patients in 15 clinical trials of rectal artemisinin derivative therapy (artesunate, artemisinin and artemether) were pooled in order to compare the rapidity of clearance of Plasmodium falciparum parasitaemia and the incidence of reported adverse events with each treatment. Data from patients who received comparator treatment (parenteral artemisinin derivative or quinine) were also included. Primary endpoints included percentage reductions in parasitaemia at 12 and 24 hours. A parasite reduction of >90% at 24 hours was defined as parasitological success. RESULTS: Artemisinin and artesunate treatment cleared parasites more rapidly than parenteral quinine during the first 24 hours of treatment. A single higher dose of rectal artesunate treatment was five times more likely to achieve >90% parasite reductions at 24 hours than were multiple lower doses of rectal artesunate, or a single lower dose administration of rectal artemether. CONCLUSION: Artemisinin and artesunate suppositories rapidly eliminate parasites and appear to be safe. There are less data on artemether and dihydroartemisinin suppositories. The more rapid parasite clearance of single high-dose regimens suggests that achieving immediate high drug concentrations may be the optimal strategy.
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Publication Pre-Referral Rectal Artesunate to Prevent Death and Disability in Severe Malaria : A Placebo-Controlled Trial(2009-02-14)BACKGROUND: Most malaria deaths occur in rural areas. Rapid progression from illness to death can be interrupted by prompt, effective medication. Antimalarial treatment cannot rescue terminally ill patients but could be effective if given earlier. If patients who cannot be treated orally are several hours from facilities for injections, rectal artesunate can be given before referral and acts rapidly on parasites. We investigated whether this intervention reduced mortality and permanent disability. METHODS: In Bangladesh, Ghana, and Tanzania, patients with suspected severe malaria who could not be treated orally were allocated randomly to a single artesunate (n=8954) or placebo (n=8872) suppository by taking the next numbered box, then referred to clinics at which injections could be given. Those with antimalarial injections or negative blood smears before randomisation were excluded, leaving 12 068 patients (6072 artesunate, 5996 placebo) for analysis. Primary endpoints were mortality, assessed 7-30 days later, and permanent disability, reassessed periodically. All investigators were masked to group assignment. Analysis was by intention to treat. This study is registered in all three countries, numbers ISRCTN83979018, 46343627, and 76987662. RESULTS: Mortality was 154 of 6072 artesunate versus 177 of 5996 placebo (2.5%vs 3.0%, p=0.1). Two versus 13 (0.03%vs 0.22%, p=0.0020) were permanently disabled; total dead or disabled: 156 versus 190 (2.6%vs 3.2%, p=0.0484). There was no reduction in early mortality (56 vs 51 deaths within 6 h; median 2 h). In patients reaching clinic within 6 h (median 3 h), pre-referral artesunate had no significant effect on death after 6 h or permanent disability (71/4450 [1.6%] vs 82/4426 [1.9%], risk ratio 0.86 [95% CI 0.63-1.18], p=0.35). In patients still not in clinic after more than 6 h, however, half were still not there after more than 15 h, and pre-referral rectal artesunate significantly reduced death or permanent disability (29/1566 [1.9%] vs 57/1519 [3.8%], risk ratio 0.49 [95% CI 0.32-0.77], p=0.0013). INTERPRETATION: If patients with severe malaria cannot be treated orally and access to injections will take several hours, a single inexpensive artesunate suppository at the time of referral substantially reduces the risk of death or permanent disability. FUNDING: UNICEF/UNDP/World Bank Special Programme for Research and Training in Tropical Diseases (WHO/TDR); WHO Global Malaria Programme (WHO/GMP); Sall Family Foundation; the European Union (QLRT-2000-01430); the UK Medical Research Council; USAID; Irish Aid; the Karolinska Institute; and the University of Oxford Clinical Trial Service Unit (CTSU).Publication The Use of Placebo in a Trial of Rectal Artesunate as Initial Treatment for Severe Malaria Patients En Route to Referral Clinics : Ethical Issues(2010)Placebo-controlled trials are controversial when individuals might be denied existing beneficial medical interventions. In the case of malaria, most patients die in rural villages without healthcare facilities. An artesunate suppository that can be given by minimally skilled persons might be of value when patients suddenly become too ill for oral treatment but are several hours from a facility that can give injectable treatment for severe disease. In such situations, by default, no treatment is (or can be) given until the patient reaches a facility, making the placebo control design clinically relevant; alternative bioequivalence designs at the facility would misrepresent reality and risk incorrect conclusions. We describe the ethical issues underpinning a placebo-controlled trial in severe malaria. To protect patients and minimise risk, all patients were referred immediately to hospital so that each had a higher chance of prompt treatment through participation. There was no difference between artesunate and placebo in patients who reached clinic rapidly; among those who could not, a single artesunate suppository significantly reduced death or permanent disability, a finding of direct and indirect benefit to patients in participating villages and elsewhere.Publication Impact of Malaria Control on the Demand for ACTs(World Bank, Washington, DC, 2008-06)As planning for malaria shifts from control to elimination and eventual eradication, policymakers are faced with decisions about resource allocation, and best approaches for financing malaria control interventions. At the operational level, these decisions will determine the relative emphasis on different tools such as insecticide treated nets (ITNs), indoor residual spraying (IRS) and artemisinin-based combinations (ACTs) in various local settings. At a global level, these decisions will guide the appropriate role of global financing mechanisms such as the Affordable Medicines Facility for Malaria (AMFm) in the malaria elimination effort. Previous papers have separately examined the cost-effectiveness of individual tools like IRS and ITNs and financing mechanisms such as the AMFm. Here we look at the cost-effectiveness of AMFm at different transmission intensities and levels of malaria control. We find that deaths averted as a result of AMFm are maximized when other control measures such as ITNs are simultaneously applied. Although policymakers have to tradeoff between investments in AMFm and malaria prevention tools, our results indicate strong synergies that get stronger as malaria control is amplified.Publication Intensifying the Fight Against Malaria : The World Bank's Booster Program for Malaria Control in Africa(Washington, DC : World Bank, 2009)This document describes the purpose and context of the Booster Program, its first three years of operation and the proposed design of phase two of the program. Phase two seeks to build on the successes of and lessons learned from phase one and to enable the World Bank to play its expected role in scaling up and sustaining malaria control interventions to reach the new ambitious but achievable global goal set by the Roll Back Malaria (RBM) Partnership, of eliminating malaria as a major public health problem in Africa by 2015. The Bank has subscribed fully to this agenda, as illustrated by statements made by senior management in several public forums.Publication Strengthening Malaria Service Delivery through Supportive Supervision and Community Mobilization in an Endemic Indian Setting : An Evaluation of Nested Delivery Models(World Bank, Washington, DC, 2014-06)Malaria continues to be a prominent global public health challenge, in part because of the slow population adoption of recommended preventive and curative behaviors. This paper tests the effectiveness of two service delivery models designed to promote recommended behaviors, including prompt treatment seeking for febrile illness, in Odisha India. The tested modules include supportive supervision of community health workers and community mobilization promoting appropriate health seeking. Program effects were identified through a randomized cluster trial comprising 120 villages from two purposively chosen malaria-endemic districts. Significant improvements were measured in the reported utilization of bed nets in both intervention arms vis-Ã -vis the control. Although overall rates of treatment seeking were equal across the study arms, treatment seeking from community health workers was higher in both intervention arms and care seeking from trained providers also increased with a substitution away from untrained providers. Further, fever cases in both treatments were more likely to have received timely medical treatment (within 24 hours) from a skilled provider. The study arm with supportive supervision was particularly effective in shifting care seeking to community health workers and ensuring prompt diagnosis and treatment. A community-based intervention combining the supportive supervision of community health workers with intensive community mobilization can be effective in shifting care seeking and increasing preventive behavior, and thus may be used to strengthen the national malaria control program.
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