cgp-56697 and Vomiting

In endemic malarial areas, young children have high levels of malaria morbidity and mortality. The World Health Organization recommends oral artemisinin-based combination therapy (ACT) for treating uncomplicated malaria. Paediatric formulations of ACT have been developed to make it easier to treat children.. To evaluate evidence from trials on the efficacy, safety, tolerability, and acceptability of paediatric ACT formulations compared to tablet ACT formulations for uncomplicated P falciparum malaria in children up to 14 years old.. We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; Embase; the Latin American and Caribbean Health Science Information database (LILACS); ISI Web of Science; Google Scholar; Scopus; and the metaRegister of Controlled Trials (mRCT) to 11 December 2019.. We included randomised controlled clinical trials (RCTs) of paediatric versus non-paediatric formulated ACT in children aged 14 years or younger with acute uncomplicated malaria.. Two authors independently assessed eligibility and risk of bias, and carried out data extraction. We analyzed the primary outcomes of efficacy, safety and tolerability of paediatric versus non-paediatric ACT using risk ratios (RR) and 95% confidence intervals (CI). Secondary outcomes were: treatment failure on the last day of observation (day 42), fever clearance time, parasite clearance time, pharmacokinetics, and acceptability.. Three trials met the inclusion criteria. Two compared a paediatric dispersible tablet formulation against crushed tablets of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA-PQ), and one trial assessed artemether-lumefantrine formulated as powder for suspension compared with crushed tablets. The trials were carried out between 2006 and 2015 in sub-Saharan Africa (Benin, Mali, Mozambique, Tanzania, Kenya, Democratic Republic of the Congo, Burkina Faso, and The Gambia). In all three trials, the paediatric and control ACT achieved polymerase chain reaction (PCR)-adjusted treatment failure rates of < 10% on day 28 in the per-protocol (PP) population. For the comparison of dispersible versus crushed tablets, the two trials did not detect a difference for treatment failure by day 28 (PCR-adjusted PP population: RR 1.35, 95% CI 0.49 to 3.72; 1061 participants, 2 studies, low-certainty evidence). Similarly, for the comparison of suspension versus crushed tablet ACT, we did not detect any difference in treatment failure at day 28 (PCR-adjusted PP population: RR 1.64, 95% CI 0.55 to 4.87; 245 participants, 1 study). We did not detect any difference in serious adverse events for the comparison of dispersible versus crushed tablets (RR 1.05, 95% CI 0.38 to 2.88; 1197 participants, 2 studies, low-certainty evidence), or for the comparison of suspension versus crushed tablet ACT (RR 0.74, 95% CI 0.17 to 3.26; 267 participants, 1 study). In the dispersible ACT arms, drug-related adverse events occurred in 9% of children in the AL study and 34% of children in the DHA-PQ study. In the control arms, drug-related adverse events occurred in 12% of children in the AL study and in 42% of children in the DHA-PQ study. Drug-related adverse events were lower in the dispersible ACT arms (RR 0.78, 95% CI 0.62 to 0.99; 1197 participants, 2 studies, moderate-certainty evidence). There was no detected difference in the rate of drug-related adverse events for suspension ACT versus crushed tablet ACT (RR 0.66, 95% CI 0.33 to 1.32; 267 participants, 1 study). Drug-related vomiting appeared to be less common in the dispersible ACT arms (RR 0.75, 95% CI 0.56 to 1.01; 1197 participants, 2 studies, low-certainty evidence) and in the suspension ACT arm (RR 0.66, 95% CI 0.33 to 1.32; 267 participants, 1 study), but both analyses were underpowered. No study assessed acceptability.. Trials did not demonstrate a difference in efficacy between paediatric dispersible or suspension ACT when compared with the respective crushed tablet ACT for treating uncomplicated P falciparum malaria in children. However, the evidence is of low to moderate certainty due to limited power. There appeared to be fewer drug-related adverse events with dispersible ACT compared to crushed tablet ACT. None of the included studies assessed acceptability of paediatric ACT formulation.

Topics: Adolescent; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Bias; Child; Child, Preschool; Confidence Intervals; Drug Combinations; Humans; Infant; Malaria, Falciparum; Quinolines; Randomized Controlled Trials as Topic; Suspensions; Tablets; Treatment Failure; Vomiting

Late treatment failures after artemisinin-based combination therapies (ACTs) for falciparum malaria have increased in the Greater Mekong subregion in southeast Asia. Addition of amodiaquine to artemether-lumefantrine could provide an efficacious treatment for multidrug-resistant infections.. We conducted an open-label, randomised trial at five hospitals or health centres in three locations (western Cambodia, eastern Cambodia, and Vietnam). Eligible participants were male and female patients aged 2-65 years with uncomplicated Plasmodium falciparum malaria. Patients were randomly allocated (1:1 in blocks of eight to 12) to either artemether-lumefantrine alone (dosed according to WHO guidelines) or artemether-lumefantrine plus amodiaquine (10 mg base per kg/day), both given orally as six doses over 3 days. All received a single dose of primaquine (0·25 mg/kg) 24 h after the start of study treatment to limit transmission of the parasite. Parasites were genotyped, identifying artemisinin resistance. The primary outcome was Kaplan-Meier 42-day PCR-corrected efficacy against recrudescence of the original parasite, assessed by intent-to-treat. Safety was a secondary outcome. This completed trial is registered at ClinicalTrials.gov (NCT03355664).. Between March 18, 2018, and Jan 30, 2020, 310 patients received randomly allocated treatment; 154 received artemether-lumefantrine alone and 156 received artemether-lumefantrine plus amodiaquine. Parasites from 305 of these patients were genotyped. 42-day PCR-corrected treatment efficacy was noted in 151 (97%, 95% CI 92-99) of 156 patients with artemether-lumefantrine plus amodiaquine versus 146 (95%, 89-97) of 154 patients with artemether-lumefantrine alone; hazard ratio (HR) for recrudescence 0·6 (95% CI 0·2-1·9, p=0·38). Of the 13 recrudescences, 12 were in 174 (57%) of 305 infections with pfkelch13 mutations indicating artemisinin resistance, for which 42-day efficacy was noted in 89 (96%) of 93 infections with artemether-lumefantrine plus amodiaquine versus 73 (90%) of 81 infections with artemether-lumefantrine alone; HR for recrudescence 0·44 (95% CI 0·14-1·40, p=0·17). Artemether-lumefantrine plus amodiaquine was generally well tolerated, but the number of mild (grade 1-2) adverse events, mainly gastrointestinal, was greater in this group compared with artemether-lumefantrine alone (vomiting, 12 [8%] with artemether-lumefantrine plus amodiaquine vs three [2%] with artemether-lumefantrine alone, p=0·03; and nausea, 11 [7%] with artemether-lumefantrine plus amodiaquine vs three [2%] with artemether-lumefantrine alone, p=0·05). Early vomiting within 1 h of treatment, requiring retreatment, occurred in no patients of 154 with artemether-lumefantrine alone versus five (3%) of 156 with artemether-lumefantrine plus amodiaquine, p=0·06. Bradycardia (≤54 beats/min) of any grade was noted in 59 (38%) of 154 patients with artemether-lumefantrine alone and 95 (61%) of 156 with artemether-lumefantrine plus amodiaquine, p=0·0001.. Artemether-lumefantrine plus amodiaquine provides an alternative to artemether-lumefantrine alone as first-line treatment for multidrug-resistant P falciparum malaria in the Greater Mekong subregion, and could prolong the therapeutic lifetime of artemether-lumefantrine in malaria-endemic populations.. Bill & Melinda Gates Foundation, Wellcome Trust.

Topics: Amodiaquine; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Malaria; Malaria, Falciparum; Male; Plasmodium falciparum; Recurrence; Vomiting

The burden of Plasmodium vivax infections has been underappreciated, especially in southeast Asia where chloroquine resistant strains have emerged. Our aim was to compare the safety and efficacy of dihydroartemisinin-piperaquine with that of artemether-lumefantrine in patients with uncomplicated malaria caused by multidrug-resistant P falciparum and P vivax.. 774 patients in southern Papua, Indonesia, with slide-confirmed malaria were randomly assigned to receive either artemether-lumefantrine or dihydroartemisinin-piperaquine and followed up for at least 42 days. The primary endpoint was the overall cumulative risk of parasitological failure at day 42 with a modified intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, trial number 00157833.. Of the 754 evaluable patients enrolled, 466 had infections with P falciparum, 175 with P vivax, and 113 with a mixture of both species. The overall risk of failure at day 42 was 43% (95% CI 38-48) for artemether-lumefantrine and 19% (14-23) for dihydroartemisinin-piperaquine (hazard ratio=3.0, 95% CI 2.2-4.1, p<0.0001). After correcting for reinfections, the risk of recrudescence of P falciparum was 4.4% (2.6-6.2) with no difference between regimens. Recurrence of vivax occurred in 38% (33-44) of patients given artemether-lumefantrine compared with 10% (6.9-14.0) given dihydroartemisinin-piperaquine (p<0.0001). At the end of the study, patients receiving dihydroartemisinin-piperaquine were 2.0 times (1.2-3.6) less likely to be anaemic and 6.6 times (2.8-16) less likely to carry vivax gametocytes than were those given artemether-lumefantrine.. Both dihydroartemisinin-piperaquine and artemether-lumefantrine were safe and effective for the treatment of multidrug-resistant uncomplicated malaria. However, dihydroartemisinin-piperaquine provided greater post-treatment prophylaxis than did artemether-lumefantrine, reducing P falciparum reinfections and P vivax recurrences, the clinical public-health importance of which should not be ignored.

Topics: Adolescent; Adult; Anemia; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Diarrhea; Drug Administration Schedule; Drug Combinations; Drug Resistance, Multiple; Ethanolamines; Female; Fluorenes; Humans; Indonesia; Infant; Malaria, Falciparum; Malaria, Vivax; Male; Middle Aged; Prospective Studies; Quinolines; Recurrence; Sesquiterpenes; Treatment Outcome; Urticaria; Vomiting

Artemisinin combination therapies such as artemether-lumefantrine (AL) are effective for first-line treatment of uncomplicated acute Plasmodium falciparum malaria. However, the safety profile of AL in large populations has not been fully assessed. The objective of this study was to establish the safety of AL in public health facilities in Tanzania using the Cohort Event Monitoring (CEM) method.. Patients who presented to public health facilities in four regions of Tanzania who were prescribed AL were enrolled in a CEM study, a prospective, observational cohort study to establish a profile of adverse events (AEs) for the medicine when used in routine clinical practice. Pre- and post-treatment forms were used to record baseline information and new health events before and 7 days after treatment.. A total of 8040 patients were enrolled in the study, of whom 6147 were included in the analysis. Following treatment initiation, a total of 530 AEs were reported in 6% (383) of the patients. The most frequent post-treatment AEs were in alimentary system (42%), including vomiting, nausea, diarrhoea, abdominal pain and anorexia, followed by AEs in the neurological system (25%). Causality assessment of the events showed that 51.9% (275/530) were possibly related to AL. There was a significant difference in the frequency of AEs by age-group with an increase in the number of AEs as age increased (P < 0.001). There was no statistically significant difference in the frequency of the events between males and females (P = 0.504). The AE profile was consistent with the AEs reported in the product information and in other studies; no new adverse drug reactions were identified. The majority of the reported AEs were the same as the symptoms of malaria and therefore indistinguishable from the underlying disease.. The safety profile of AL for treatment of malaria continues to be favourable. CEM as a pharmacovigilance tool has proven to provide reliable safety data in a short period.

Topics: Adolescent; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Cohort Studies; Drug Combinations; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Ethanolamines; Female; Fluorenes; Health Facilities; Humans; Infant; Malaria; Male; Middle Aged; Nausea; Prospective Studies; Tanzania; Vomiting; Young Adult