Artemether–lumefantrine and artesunate–amodiaquine are used as first-line artemisinin-based combination therapies (ACTs) in west Africa. Pyronaridine–artesunate and dihydroartemisinin–piperaquine are ...potentially useful for diversification of ACTs in this region, but further safety and efficacy data are required on malaria retreatment.
We did a randomised, multicentre, open-label, longitudinal, controlled phase 3b/4 clinical trial at seven tertiary centres in Burkina Faso, Guinea, and Mali. Eligible participants for first malaria episode and all retreatment episodes were adults and children aged 6 months and older with microscopically confirmed Plasmodium spp malaria (>0 to <200 000 parasites per μL of blood) and fever or history of fever in the previous 24 h. Individuals with severe or complicated malaria, an alanine aminotransferase concentration of more than twice the upper limit of normal, or a QTc greater than 450 ms were excluded. Using a randomisation list for each site, masked using sealed envelopes, participants were assigned to either pyronaridine–artesunate or dihydroartemisinin–piperaquine versus either artesunate–amodiaquine or artemether–lumefantrine. Block sizes were two or four if two treatments were allocated, and three or six if three treatments were allocated. Microscopists doing the parasitological assessments were masked to treatment allocation. All treatments were once-daily or twice-daily tablets or granules given orally and dosed by bodyweight over 3 days at the study centre. Patients were followed up as outpatients up to day 42, receiving clinical assessments on days 0, 1, 2, 3, 7, 14, 21, 28, 35, and 42. Two primary outcomes were compared for non-inferiority: the 2-year incidence rate of all microscopically confirmed, complicated and uncomplicated malaria episodes in patients in the intention-to-treat population (ITT; non-inferiority margin 20%); and adequate clinical and parasitological response (ACPR) in uncomplicated malaria across all episodes (unadjusted and PCR-adjusted for Plasmodium falciparum and unadjusted for other Plasmodium spp) in the per-protocol population on days 28 and 42 (non-inferiority margin 5%). Safety was assessed in all participants who received one dose of study drug. This study is registered at the Pan African Clinical Trials Registry (PACTR201105000286876).
Between Oct 24, 2011, and Feb 1, 2016, we assigned 4710 eligible participants to the different treatment strategies: 1342 to pyronaridine–artesunate, 967 to artemether–lumefantrine, 1061 to artesunate–amodiaquine, and 1340 to dihydroartemisinin–piperaquine. The 2-year malaria incidence rate in the ITT population was non-inferior for pyronaridine–artesunate versus artemether–lumefantrine (1·77, 95% CI 1·63–1·93 vs 1·87, 1·72–2·03; rate ratio RR 1·05, 95% CI 0·94–1·17); and versus artesunate–amodiaquine (1·39, 95% CI 1·22–1·59 vs 1·35, 1·18–1·54; RR 0·97, 0·87–1·07). Similarly, this endpoint was non-inferior for dihydroartemisinin–piperaquine versus artemether–lumefantrine (1·16, 95% CI 1·01–1·34 vs 1·42 1·25–1·62; RR 1·22, 95% CI 1·06–1·41) and versus artesunate–amodiaquine (1·35, 1·21–1·51 vs 1·68, 1·51–1·88; RR 1·25, 1·02–1·50). For uncomplicated P falciparum malaria, PCR-adjusted ACPR was greater than 99·5% at day 28 and greater than 98·6% at day 42 for all ACTs; unadjusted ACPR was higher for pyronaridine–artesunate versus comparators at day 28 (96·9% vs 82·3% for artemether–lumefantrine and 95·6% vs 89·0% for artesunate–amodiaquine) and for dihydroartemisinin-piperaquine versus comparators (99·5% vs 81·6% for artemether–lumefantrine and 99·0% vs 89·0% for artesunate–amodiaquine). For non-falciparum species, unadjusted ACPR was greater than 98% for all study drugs at day 28 and at day 42 was greater than 83% except for artemether–lumefantrine against Plasmodium ovale (in ten 62·5% of 16 patients) and against Plasmodium malariae (in nine 75·0% of 12 patients). Nine deaths occurred during the study, none of which were related to the study treatment. Mostly mild transient elevations in transaminases occurred with pyronaridine–artesunate versus comparators, and mild QTcF prolongation with dihydroartemisinin-piperaquine versus comparators.
Pyronaridine–artesunate and dihydroartemisinin–piperaquine treatment and retreatment of malaria were well tolerated with efficacy that was non-inferior to first-line ACTs. Greater access to these efficacious treatments in west Africa is justified.
The European and Developing Countries Clinical Trial Partnership, Medicines for Malaria Venture (Geneva, Switzerland), the UK Medical Research Council, the Swedish International Development Cooperation Agency, German Ministry for Education and Research, University Claude Bernard (Lyon, France), University of Science, Techniques and Technologies of Bamako (Bamako, Mali), the Centre National de Recherche et de Formation sur le Paludisme (Burkina Faso), Institut de Recherche en Sciences de la Santé (Bobo-Dioulasso, Burkina Faso), and Centre National de Formation et de Recherche en Santé Rurale (Republic of Guinea).
A recent randomized controlled trial, the WANECAM (West African Network for Clinical Trials of Antimalarial Drugs) trial, conducted at seven centers in West Africa, found that ...artemether-lumefantrine, artesunate-amodiaquine, pyronaridine-artesunate, and dihydroartemisinin-piperaquine all displayed good efficacy. However, artemether-lumefantrine was associated with a shorter interval between clinical episodes than the other regimens. In a further comparison of these therapies, we identified cases of persisting submicroscopic parasitemia by quantitative PCR (qPCR) at 72 h posttreatment among WANECAM participants from 5 sites in Mali and Burkina Faso, and we compared treatment outcomes for this group to those with complete parasite clearance by 72 h. Among 552 evaluable patients, 17.7% had qPCR-detectable parasitemia at 72 h during their first treatment episode. This proportion varied among sites, reflecting differences in malaria transmission intensity, but did not differ among pooled drug treatment groups. However, patients who received artemether-lumefantrine and were qPCR positive at 72 h were significantly more likely to have microscopically detectable recurrent Plasmodium falciparum parasitemia by day 42 than those receiving other regimens and experienced, on average, a shorter interval before the next clinical episode. Haplotypes of
and
were also evaluated in persisting parasites. These data identify a possible threat to the parasitological efficacy of artemether-lumefantrine in West Africa, over a decade since it was first introduced on a large scale.
Chloroquine was used for malaria treatment until resistant Plasmodium falciparum was identified. Because 4-aminoquinolines with modified side chains, such as AQ-13, are active against resistant ...parasites, we compared AQ-13 against artemether plus lumefantrine for treatment of uncomplicated P falciparum malaria.
We did a randomised, non-inferiority trial. We screened men (≥18 years) with uncomplicated malaria in Missira (northeast Mali) and Bamako (capital of Mali) for eligibility (≥2000 asexual P falciparum parasites per μL of blood). Eligible participants were randomly assigned to either the artemether plus lumefantrine group or AQ-13 group by permuting blocks of four with a random number generator. Physicians and others caring for the participants were masked, except for participants who received treatment and the research pharmacist who implemented the randomisation and provided treatment. Participants received either 80 mg of oral artemether and 480 mg of oral lumefantrine twice daily for 3 days or 638·50 mg of AQ-13 base (two oral capsules) on days 1 and 2, and 319·25 mg base (one oral capsule) on day 3. Participants were monitored for parasite clearance (50 μL blood samples twice daily at 12 h intervals until two consecutive negative samples were obtained) and interviewed for adverse events (once every day) as inpatients during week 1. During the 5-week outpatient follow-up, participants were examined for adverse events and recurrent infection twice per week. All participants were included in the intention-to-treat analysis and per-protocol analysis, except for those who dropped out in the per-protocol analysis. The composite primary outcome was clearance of asexual parasites and fever by day 7, and absence of recrudescent infection by parasites with the same molecular markers from days 8 to 42 (defined as cure). Non-inferiority was considered established if the proportion of patients who were cured was higher for artemether plus lumefantrine than for AQ-13 and the upper limit of the 95% CI was less than the non-inferiority margin of 15%. This trial is registered at ClinicalTrials.gov, number NCT01614964.
Between Aug 6 and Nov 18, 2013, and between Sept 18 and Nov 20, 2015, 66 Malian men with uncomplicated malaria were enrolled. 33 participants were randomly assigned to each group. There were no serious adverse events (grade 2–4) and asexual parasites were cleared by day 7 in both groups. 453 less-severe adverse events (≤grade 1) were reported: 214 in the combination group and 239 in the AQ-13 group. Two participants withdrew from the AQ-13 group after parasite clearance and three were lost to follow-up. In the artemether plus lumefantrine group, two participants had late treatment failures (same markers as original isolates). On the basis of the per-protocol analysis, the AQ-13 and artemether plus lumefantrine groups had similar proportions cured (28 100% of 28 vs 31 93·9% of 33; p=0·50) and AQ-13 was not inferior to artemether plus lumefantrine (difference −6·1%, 95% CI −14·7 to 2·4). Proportions cured were also similar between the groups in the intention-to-treat analysis (28 of 33, 84·8% for AQ-13 vs 31 of 33, 93·9% for artemether and lumefantrine; p=0·43) but the upper bound of the 95% CI exceeded the 15% non-inferiority margin (difference 9·1%, 95% CI −5·6 to 23·8).
The per-protocol analysis suggested non-inferiority of AQ-13 to artemether plus lumefantrine. By contrast, the intention-to-treat analysis, which included two participants who withdrew and three who were lost to follow-up from the AQ-13 group, did not meet the criterion for non-inferiority of AQ-13, although there were no AQ-13 treatment failures. Studies with more participants (and non-immune participants) are needed to decide whether widespread use of modified 4-aminoquinolones should be recommended.
US Food and Drug Administration Orphan Product Development, National Institutes of Health, US Centers for Disease Control and Prevention, Burroughs-Wellcome Fund, US State Department, and WHO.
Bee sting venom is generally well tolerated. However, some rare cases of massive stings can lead to anaphylactic shock and even renal failure. This observation is the illustration of a case of acute ...kidney injury secondary to bee stings in a 64-year-old black african subject.
A 64-year-old man without a known medical history was referred to the emergency department of the Fousseyni Daou hospital in Kayes (Mali) for disturbed consciousness 4 hours after massive stings from a bee swarm. Renal failure with serum creatinine level at 752,2 µmol/L was documented on day 3 in a context of total anuria. The patient was transferred to a nephrology unit and biology confirmed renal failure associated with intravascular haemolysis and rhabdomyolysis. The kidneys were of normal size and well differentiated. The diagnosis of severe acute kidney injury due to massive envenomation induced by bee venom was evoked. The evolution was favourable, with normalization of renal function at D26 after 5 sessions of haemodialysis in parallel with transfusions of packed red blood cells.
A massive bee attack should be considered a medical emergency because of the organic damage it can inflict. The renal prognosis depends on the number of stings, and especially on the delay and the quality of the treatment. Early initiation of dialysis treatment reduces mortality.
Introduction: Multiple myeloma (MM) is a monoclonal proliferation of mature plasma cells. It usually occurs in people over 50 years of age with a peak in frequency at 65 years of age and less than 2% ...of patients are under 40 years of age. Case presentation: This case report is of a 38 year old black African woman with chronic kidney disease stage 5D. The IR was of glomerular origin (hypertension for 2 years, proteinuria at 4 g/24 hours, oedematous syndrome). Serum protein electrophoresis showed a beta peak at 29.7 g/l and urine protein immunoelectrophoresis showed a kappa/lambda ratio of 8.4. The myelogram showed a rich marrow with 51% plasma cells. Radiography showed multiple cystic images at the upper 1/3 of the left humeral shaft. Renal histology showed minimal glomerular damage. The diagnostic profile of IgG kappa light chain MM with CRAB criteria complicated by chronic glomerulonephritis with unorganised monoclonal immunoglobulin deposits was suggested. Management consisted of chemotherapy with bortezomib and dexamethasone for 4 cycles. The evolution under chronic dialysis was favourable after 1 year. Conclusion: MM in young adults (defined as 19-40 years of age) is rare, but it does exist. In young patients, this condition is initially not considered in the differential diagnosis and the occurrence of IR has a strong prognostic impact. Survival seems to be better in young adults than in elderly patients, which needs to be proven by a longer follow-up.
Bee sting venom is generally well tolerated. However, some rare cases of massive stings can lead to anaphylactic shock and even renal failure. This observation is the illustration of a case of acute ...kidney injury secondary to bee stings in a 64-year-old black african subject.
A 64-year-old man without a known medical history was referred to the emergency department of the Fousseyni Daou hospital in Kayes (Mali) for disturbed consciousness 4 hours after massive stings from a bee swarm. Renal failure with serum creatinine level at 752,2 μmol/L was documented on day 3 in a context of total anuria. The patient was transferred to a nephrology unit and biology confirmed renal failure associated with intravascular haemolysis and rhabdomyolysis. The kidneys were of normal size and well differentiated. The diagnosis of severe acute kidney injury due to massive envenomation induced by bee venom was evoked. The evolution was favourable, with normalization of renal function at D26 after 5 sessions of haemodialysis in parallel with transfusions of packed red blood cells.
A massive bee attack should be considered a medical emergency because of the organic damage it can inflict. The renal prognosis depends on the number of stings, and especially on the delay and the quality of the treatment. Early initiation of dialysis treatment reduces mortality.
This is a prospective study of two cases of hypospadias in identical twins with the same location and the same symptomatology at Mali Gavardo Hospital. Hypospadias corresponds to hypoplasia of the ...tissues forming the ventral surface of the penis responsible for an ectopic abruption of the urethra. Its aetiology is multifactorial, the surgical management is adapted according to the anatomical location.the Mathieu urethroplasty technique was used in both patients, urine drainage was performed with 8fr silicone catheter for 5 days. Post-operative follow-up was marked by a skin fistula in one case on the fourth day with spontaneous closure on day 8. Material Methodology: This was a prospective study of two cases of hypospadias in identical twins at the Mali Gavardo Hospital. The following parameters were studied: age, reasons for consultation, physical examination, complementary examinations, surgical treatment and post-operative follow-up. Conclusion: Hypospadias is a congenital malformation in males, the frequency of which is increasing throughout the world, and should be treated from an early age. In our context, the presence of the same anatomical form and the same location in both twins is still very rare in the literature, hence the need to share our experience with others. The Mathieu technique remains the reference technique for the management of hypospadias.
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