The aim of this Cochrane Review was to find out whether the antimalarial drug artesunate is effective and safe in treating simple cases of an important type of malaria (Plasmodium falciparum).We collected and analyzed all relevant studies to answer this question and found 10 studies.
Pyronaridine-artesunate is effective in the treatment of uncomplicated falciparum malaria.Pyronaridine-artesunate is generally safe, but blood tests in some people who receive it show liver damage.It doesn’t seem to last or make people sick.
The World Health Organization (WHO) recommends the use of drug combinations called artemisinin combination therapies (ACTs) to treat malaria.Pyronaridine-artesunate is a new ACT.New ACTs are needed to treat malaria resistant to currently available ACTs and to help prevent malaria from becoming more resistant to treatment.
We compared artesunate with other ACTs to assess its efficacy against Plasmodium falciparum, and compared artesunate and pyrrolidine alone with other drugs to assess their safety.
We included five studies in the treatment effect analysis.Four studies compared pyrrolidine-artesunate with artemether-phenylfluorenol in adults and children of all ages in Africa and Asia.One study compared artesunate with artesunate amodiaquine in African adults and older children, and one study compared artesunate in African and Asian adults and older children With Mefloquine Plus Artesunate.We included five additional studies in our drug safety analysis.
Pyronaridine-artesunate is effective in treating uncomplicated P. falciparum and may be at least as good or better than existing ACT (low-to-moderate-quality evidence).Pyronaridine-artesunate increases the risk of mild liver injury on blood tests (moderate to high-quality evidence).We found no evidence that any such liver damage was severe or irreversible.We don’t know how artesunate affects people who already have liver damage.
We found two trials specifically recruiting children under the age of 12, with a total of 732 participants.When only data from these trials were included, we found no differences in therapeutic efficacy or safety between pyrrolidine-artesunate and artemether-phenylfluorenol.
We identified seven additional studies that provided observational data on the safety of pyrrolidine.Data from these studies allowed us to increase the population for which safety was assessed.Observational data did not suggest a plethora of important adverse effects.
Pyronaridine-artesunate was effective against uncomplicated P. falciparum; achieved a PCR-adjusted treatment failure rate of less than 5% on days 28 and 42; and likely was at least as good or better than other marketed ACTs.
Pyronaridine-artesunate increases the risk of episodes of abnormal ALT elevations.Observational data did not suggest a plethora of clinically important adverse effects.
The World Health Organization (WHO) recommends artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated Plasmodium falciparum malaria.Concerns about artemisinin resistance have led to a global initiative to develop new partner medicines to protect artemisinin derivatives in ACT.Pyronaridine-artesunate is a novel ACT.
To evaluate the efficacy of artesunate compared with alternative ACT in patients with uncomplicated falciparum malaria, and to evaluate the safety of artesunate and other pinaridine treatments compared to alternative treatments.
We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; Medical Lines; Stationed; and Lilac.We also searched ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform, and the ISRCTN registry for ongoing or recently completed trials.The date of the last search was October 27, 2021.
For efficacy analysis, we included randomised controlled trials (RCTs) of artesunate in the treatment of uncomplicated falciparum malaria.For safety analysis, we included RCTs of pyrrolidine alone or in combination with any other antimalarial drug.In addition to these analyses, we conducted a separate systematic review summarizing safety data from any nonrandomized study (NRS) in patients receiving pyrrolidine (NRS Safety Review).
Two review authors independently extracted all data and assessed the certainty of evidence.We performed a meta-analysis of the data to calculate the hazard ratio (RR) for treatment failure between comparisons, and the safety outcomes between and between comparisons.
We included 10 relevant RCTs.Seven RCTs were co-funded by Shin Poong Pharmaceuticals and three were funded by government agencies.
For efficacy analyses, we identified five RCTs with 5711 participants.These included 4465 participants from 13 locations in Africa and 1246 participants from 5 locations in Asia.The analysis included 541 children under 5 years of age.Overall, the polymerase chain reaction (PCR)-adjusted treatment failure rate for pyrrolidine-artesunate was less than 5%.We evaluated pyronaridine-artesunate with the following.
• Artemether-phenylfluorenol.Artesunate may perform better for PCR adjustment failure at day 28 (RR 0.59, 95% confidence interval (CI) 0.26 to 1.31; 4 RCTs, 3068 participants, low-quality evidence); for day 28 for unadjusted failure at day 42 (RR 0.27, 95% CI 0.13 to 0.58; 4 RCTs, 3149 participants, low-quality evidence); for unadjusted failure at day 42 (RR 0.61, 95% CI 0.46 to 0.82; 4 RCTs, 3080 participants, low-quality evidence).There was probably little difference between groups for failure to adjust for PCR at day 42 (RR 0.86, 95% CI 0.49 to 1.51; 4 RCTs, 2575 participants, low-quality evidence).
• Artesunate-Amodiaquine.Artesunate may perform better at day 28 for PCR adjustment failure (RR 0.55, 95% CI 0.11 to 2.77; 1 RCT, 1245 participants, low-quality evidence); unadjusted failure at day 28 Likely to perform better (RR 0.49, 95% CI 0.30 to 0.81; 1 RCT, 1257 participants, moderate-quality evidence); likely to have little or no effect on PCR adjustment failure at day 42 (RR 0.98, 95 % CI 0.20 to 4.83; 1 RCT, 1091 participants, low-quality evidence); and probably had little effect on unadjusted failure at day 42 (RR 0.98, 95% CI 0.78 to 1.23; 1 RCT, 1235 participants, moderate-quality evidence).
• Mefloquine plus artesunate.Artesunate may perform better for PCR-adjusted failures at day 28 (RR 0.37, 95% CI 0.13 to 1.05; 1 RCT, 1117 participants, low-quality evidence); unadjusted failures at day 28 Likely to perform better (RR 0.36, 95% CI 0.17 to 0.78; 1 RCT, 1120 participants, moderate-quality evidence); likely to have little or no effect on unadjusted failure at day 42 (RR 0.84, 95 % CI 0.54 to 1.31; 1 RCT, 1059 participants, low-quality evidence); but may result in a higher rate of PCR adjustment failure at day 42 (RR 1.80, 95% CI 0.90 to 3.57; 1 RCT, 1037 participants, low-quality evidence).
For the RCT safety analysis, we identified eight RCTs, one by study site, comparing artesunate with other antimalarial drugs.Artesunate was associated with elevated liver enzymes compared with other antimalarial drugs: alanine aminotransferase (ALT) (RR 3.59, 95% CI 1.76 to 7.33; 8 RCTS, 6669 participants, high quality evidence) and aspartate aminotransferase (AST) (RR 2.22, 95% CI 1.12 to 4.41; 8 RCTs, 6669 participants, moderate-quality evidence).Bilirubin did not show this effect (RR 1.03, 95% CI 0.49 to 2.18; 7 RCTs, 6384 participants, moderate-quality evidence).There was one reported case of elevated ALT with elevated bilirubin.No studies reported serious drug-induced liver injury.Artesunate electrocardiogram (ECG) abnormalities are less common than with other antimalarial drugs.We found no other security issues.
A review of the safety of NRS allowed us to increase the population for which safety was assessed.We included 7 studies with 9546 participants: 5 single-arm observational studies, 1 cohort event monitoring study, and 1 dose-escalation study.All studies provided data on the frequency of adverse events, and a small number of participants experienced serious adverse events and adverse reactions related to pyrrolidine: serious adverse events averaged 0.37%; drug-related 9.0%.In two studies reporting elevations in liver enzymes, a small proportion of participants (2.4% and 14.1%, respectively) experienced elevations in ALT, AST, or bilirubin on day 7; however, these were small increases, Back to normal on day 42.
Post time: Jul-13-2022