METHODS: Malaysian adults presenting with uncomplicated P. knowlesi infections received six doses of artemether (1.7 mg/kg) plus lumefantrine (10 mg/kg) over 3 days. Venous blood and dried blood spot (DBS) samples were taken at predetermined time-points over 28 days. Plasma and DBS artemether, dihydroartemisinin, lumefantrine and desbutyl-lumefantrine were measured using liquid chromatography-mass spectrometry. Multi-compartmental population pharmacokinetic models were developed using plasma with or without DBS drug concentrations.
RESULTS: Forty-one participants (mean age 45 years, 66% males) were recruited. Artemether-lumefantrine treatment was well tolerated and parasite clearance was prompt. Plasma and DBS lumefantrine concentrations were in close agreement and were used together in pharmacokinetic modelling, but only plasma concentrations of the other analytes were used because of poor correlation with DBS levels. The areas under the concentration-time curve (AUC0-∞ ) for artemether, dihydroartemisinin and lumefantrine (medians 1626, 1881 and 625 098 μg.h/L, respectively) were similar to those reported in previous pharmacokinetic studies in adults and children. There was evidence of auto-induction of artemether metabolism (mean increase in clearance relative to bioavailability 25.2% for each subsequent dose). The lumefantrine terminal elimination half-life (median 9.5 days) was longer than reported in healthy volunteers and adults with falciparum malaria.
CONCLUSION: The disposition of artemether, dihydroartemisinin and lumefantrine in knowlesi malaria largely parallels that in other human malarias. DBS lumefantrine concentrations can be used in pharmacokinetic studies but DBS technology is currently unreliable for the other analytes.
METHODS: A total of 3002 blood samples on filter paper were collected from 555 inhabitants of 8 longhouses with recently reported knowlesi malaria cases in the Betong Division of Sarawak, Malaysian Borneo. Each longhouse was visited bimonthly for a total of 10 times during a 21-month study period (Jan 2014-Oct 2015). DNA extracted from blood spots were examined by a nested PCR assay for Plasmodium and positive samples were then examined by nested PCR assays for Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, Plasmodium knowlesi, Plasmodium cynomolgi and Plasmodium inui. Blood films of samples positive by PCR were also examined by microscopy.
RESULTS: Genus-specific PCR assay detected Plasmodium DNA in 9 out of 3002 samples. Species-specific PCR identified 7 P. knowlesi and one P. vivax. Malaria parasites were observed in 5 thick blood films of the PCR positive samples. No parasites were observed in blood films from one knowlesi-, one vivax- and the genus-positive samples. Only one of 7 P. knowlesi-infected individual was febrile and had sought medical treatment at Betong Hospital the day after sampling. The 6 knowlesi-, one vivax- and one Plasmodium-infected individuals were afebrile and did not seek any medical treatment.
CONCLUSIONS: Asymptomatic human P. knowlesi and P. vivax malaria infections, but not P. cynomolgi and P. inui infections, are occurring within communities affected with malaria.
OBJECTIVES: To assess the effects of favipiravir compared to no treatment, supportive treatment, or other experimental antiviral treatment in people with acute COVID-19.
SEARCH METHODS: We searched the Cochrane COVID-19 Study Register, MEDLINE, Embase, the World Health Organization (WHO) COVID-19 Global literature on coronavirus disease, and three other databases, up to 18 July 2023.
SELECTION CRITERIA: We searched for RCTs evaluating the efficacy of favipiravir in treating people with COVID-19.
DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures for data collection and analysis. We used the GRADE approach to assess the certainty of evidence for each outcome.
MAIN RESULTS: We included 25 trials that randomized 5750 adults (most under 60 years of age). The trials were conducted in Bahrain, Brazil, China, India, Iran, Kuwait, Malaysia, Mexico, Russia, Saudi Arabia, Thailand, the UK, and the USA. Most participants were hospitalized with mild to moderate disease (89%). Twenty-two of the 25 trials investigated the role of favipiravir compared to placebo or standard of care, whilst lopinavir/ritonavir was the comparator in two trials, and umifenovir in one trial. Most trials (24 of 25) initiated favipiravir at 1600 mg or 1800 mg twice daily for the first day, followed by 600 mg to 800 mg twice a day. The duration of treatment varied from five to 14 days. We do not know whether favipiravir reduces all-cause mortality at 28 to 30 days, or in-hospital (risk ratio (RR) 0.84, 95% confidence interval (CI) 0.49 to 1.46; 11 trials, 3459 participants; very low-certainty evidence). We do not know if favipiravir reduces the progression to invasive mechanical ventilation (RR 0.86, 95% CI 0.68 to 1.09; 8 trials, 1383 participants; very low-certainty evidence). Favipiravir may make little to no difference in the need for admission to hospital (if ambulatory) (RR 1.04, 95% CI 0.44 to 2.46; 4 trials, 670 participants; low-certainty evidence). We do not know if favipiravir reduces the time to clinical improvement (defined as time to a 2-point reduction in patients' admission status on the WHO's ordinal scale) (hazard ratio (HR) 1.13, 95% CI 0.69 to 1.83; 4 trials, 721 participants; very low-certainty evidence). Favipiravir may make little to no difference to the progression to oxygen therapy (RR 1.20, 95% CI 0.83 to 1.75; 2 trials, 543 participants; low-certainty evidence). Favipiravir may lead to an overall increased incidence of adverse events (RR 1.27, 95% CI 1.05 to 1.54; 18 trials, 4699 participants; low-certainty evidence), but may result in little to no difference inserious adverse eventsattributable to the drug (RR 1.04, 95% CI 0.76 to 1.42; 12 trials, 3317 participants; low-certainty evidence).
AUTHORS' CONCLUSIONS: The low- to very low-certainty evidence means that we do not know whether favipiravir is efficacious in people with COVID-19 illness, irrespective of severity or admission status. Treatment with favipiravir may result in an overall increase in the incidence of adverse events but may not result in serious adverse events.
METHODS: Sensitive and specific nested polymerase chain reaction was used to identify all Plasmodium species present in (1) blood samples obtained from 960 patients with malaria who were hospitalized in Sarawak, Malaysian Borneo, during 2001-2006; (2) 54 P. malariae archival blood films from 15 districts in Sabah, Malaysian Borneo (during 2003-2005), and 4 districts in Pahang, Peninsular Malaysia (during 2004-2005); and (3) 4 patients whose suspected cause of death was P. knowlesi malaria. For the 4 latter cases, available clinical and laboratory data were reviewed.
RESULTS: P. knowlesi DNA was detected in 266 (27.7%) of 960 of the samples from Sarawak hospitals, 41 (83.7%) of 49 from Sabah, and all 5 from Pahang. Only P. knowlesi DNA was detected in archival blood films from the 4 patients who died. All were hyperparasitemic and developed marked hepatorenal dysfunction.
CONCLUSIONS: Human infection with P. knowlesi, commonly misidentified as the more benign P. malariae, are widely distributed across Malaysian Borneo and extend to Peninsular Malaysia. Because P. knowlesi replicates every 24 h, rapid diagnosis and prompt effective treatment are essential. In the absence of a specific routine diagnostic test for P. knowlesi malaria, we recommend that patients who reside in or have traveled to Southeast Asia and who have received a "P. malariae" hyperparasitemia diagnosis by microscopy receive intensive management as appropriate for severe falciparum malaria.
METHODS: Using the recently completed genome sequences from P. malariae, P. ovale and P. knowlesi, a set of 33 candidate cell surface and secreted blood-stage antigens was selected and expressed in a recombinant form using a mammalian expression system. These proteins were added to an existing panel of antigens from P. falciparum and P. vivax and the immunoreactivity of IgG, IgM and IgA immunoglobulins from individuals diagnosed with infections to each of the five different Plasmodium species was evaluated by ELISA. Logistic regression modelling was used to quantify the ability of the responses to determine prior exposure to the different Plasmodium species.
RESULTS: Using sera from European travellers with diagnosed Plasmodium infections, antigens showing species-specific immunoreactivity were identified to select a panel of 22 proteins from five Plasmodium species for serological profiling. The immunoreactivity to the antigens in the panel of sera taken from travellers and individuals living in malaria-endemic regions with diagnosed infections showed moderate power to predict infections by each species, including P. ovale, P. malariae and P. knowlesi. Using a larger set of patient samples and logistic regression modelling it was shown that exposure to P. knowlesi could be accurately detected (AUC = 91%) using an antigen panel consisting of the P. knowlesi orthologues of MSP10, P12 and P38.
CONCLUSIONS: Using the recent availability of genome sequences to all human-infective Plasmodium spp. parasites and a method of expressing Plasmodium proteins in a secreted functional form, an antigen panel has been compiled that will be useful to determine exposure to these parasites.
METHODS: Plasmodium knowlesi, P. cynomolgi, P. coatneyi, P. inui and P. fieldi, were detected using nested PCR assays in DNA samples from 276 wild-caught long-tailed macaques. These samples had been derived from macaques captured at seven locations, two each in the Philippines (n = 68) and Indonesia (n = 70), and one each in Cambodia (n = 54), Singapore (n = 40) and Laos (n = 44). The results were compared with previous studies of malaria parasites in long-tailed macaques from other locations in Southeast Asia. Fisher exact test and Chi square test were used to examine the geographic bias of the distribution of Plasmodium species in the macaque populations.
RESULTS: Out of 276 samples tested, 177 were Plasmodium-positive, with P. cynomolgi being the most common and widely distributed among all long-tailed macaque populations (53.3 %) and occurring in all populations examined, followed by P. coatneyi (20.4 %), P. inui (12.3 %), P. fieldi (3.4 %) and P. knowlesi (0.4 %). One P. knowlesi infection was detected in a macaque from Laos, representing the first documented case of P. knowlesi in wildlife in Laos. Chi square test showed three of the five parasites (P. knowlesi, P. coatneyi, P. cynomolgi) with significant bias in prevalence towards macaques from Malaysian Borneo, Cambodia, and Southern Sumatra, respectively.
CONCLUSIONS: The prevalence of malaria parasites, including those that are transmissible to humans, varied among all sampled regional populations of long-tailed macaques in Southeast Asia. The new discovery of P. knowlesi infection in Laos, and the high prevalence of P. cynomolgi infections in wild macaques in general, indicate the strong need of public advocacy in related countries.
MATERIALS & METHODS: F-BC-MTX-LPHNPs were fabricated using self-assembled nano-precipitation technique. Fructose was conjugated on the surface of the particles. The in vitro cytotoxicity, sub-cellular localization and apoptotic activity of F-BC-MTX-LPHNPs were evaluated against MCF-7 breast cancer cells. The antitumor potential of F-BC-MTX-LPHNPs was further studied.
RESULTS & CONCLUSION: Outcomes suggested that F-BC-MTX-LPHNPs induced the highest apoptosis index (0.89) against MCF-7 cells. Following 30 days of treatment, the residual tumor progression was assessed to be approximately 32%, in animals treated with F-BC-MTX-LPHNPs. F-BC-MTX-LPHNPs are competent to selectively convey the chemotherapeutic agent to the breast cancers. Beta carotene ameliorated MTX-induced hepatic and renal toxicity.