RESULTS: The pharmacophore modelling mode of 5RE6 displayed two Hydrogen Bond Acceptors (HBA) and one Hydrophobic (HY) interaction. Besides, the pharmacophore model of 5REX showed two HBA and two HY interactions. Finally, the pharmacophore model of 5RFZ showed three HBA and one HY interaction. Based on ligand-based approach, 20 Schiff-based vanillin derivatives, showed strong MPro inhibition activity. This was due to their good alignment and common features to PDB-5RE6. Similarly, monolaurin and tetrodotoxin displayed some significant activity against SARS-CoV-2. From structure-based approach, vanillin derivatives (1) to (12) displayed some potent MPro inhibition against SARS-CoV-2. Favipiravir, chloroquine and hydroxychloroquine also showed some significant MPro inhibition.
METHODS: A randomized controlled trial was conducted in 3 district hospitals in Sabah, Malaysia to compare the efficacy of AL against chloroquine (CQ) for uncomplicated knowlesi malaria. Participants were included if they weighed >10 kg, had a parasitemia count <20000/μL, and had a negative rapid diagnostic test result for Plasmodium falciparum histidine-rich protein 2. Diagnosis was confirmed by means of polymerase chain reaction. Patients were block randomized to AL (total target dose, 12 mg/kg for artemether and 60 mg/kg for lumefantrine) or CQ (25 mg/kg). The primary outcome was parasite clearance at 24 hours in a modified intention-to-treat analysis.
RESULTS: From November 2014 to January 2016, a total of 123 patients (including 18 children) were enrolled. At 24 hours after treatment 76% of patients administered AL (95% confidence interval [CI], 63%-86%; 44 of 58) were aparasitemic, compared with 60% administered CQ (47%-72%; 39 of 65; risk ratio, 1.3 [95% CI, 1.0-1.6]; P = .06). Overall parasite clearance was shorter after AL than after CQ (median, 18 vs 24 hours, respectively; P = .02), with all patients aparasitemic by 48 hours. By day 42 there were no treatment failures. The risk of anemia during follow-up was similar between arms. Patients treated with AL would require lower bed occupancy than those treated with CQ (2414 vs 2800 days per 1000 patients; incidence rate ratio, 0.86 [95% CI, .82-.91]; P < .001). There were no serious adverse events.
CONCLUSIONS: AL is highly efficacious for treating uncomplicated knowlesi malaria; its excellent tolerability and rapid therapeutic response allow earlier hospital discharge, and support its use as a first-line artemisinin-combination treatment policy for all Plasmodium species in Malaysia.
CLINICAL TRIALS REGISTRATION: NCT02001012.
Methods: Streptomyces strains' growth curves, namely SUK 12 and SUK 48, were measured and P. falciparum 3D7 IC50 values were calculated. Metabolomics analysis was conducted on both strains' mid-exponential and stationary phase extracts.
Results: The most successful antiplasmodial activity of SUK 12 and SUK 48 extracts shown to be at the stationary phase with IC50 values of 0.8168 ng/mL and 0.1963 ng/mL, respectively. In contrast, the IC50 value of chloroquine diphosphate (CQ) for antiplasmodial activity was 0.2812 ng/mL. The univariate analysis revealed that 854 metabolites and 14, 44 and three metabolites showed significant differences in terms of strain, fermentation phase, and their interactions. Orthogonal partial least square-discriminant analysis and S-loading plot putatively identified pavettine, aurantioclavine, and 4-butyldiphenylmethane as significant outliers from the stationary phase of SUK 48. For potential isolation, metabolomics approach may be used as a preliminary approach to rapidly track and identify the presence of antimalarial metabolites before any isolation and purification can be done.
Materials and Methods: This study was conducted using the livers of 18 mice fixed in 10% neutral-buffered formalin. A completely randomized design with a unidirectional pattern comprising six treatments was used in this study, with each treatment consisting of three replications. Treatment 0 was the negative control group infected with P. berghei, treatment 1 was the positive control group infected with P. berghei followed by chloroquine administration at a dose of 5 mg/kg BW, and treatments 2, 3, 4, and 5 were groups infected with P. berghei and administered Malacca leaf ethanolic extracts at doses of 100, 300, 600, and 1200 mg/kg BW, respectively. The extracts were administered orally using a gastric tube for 4 consecutive days. Mice were sacrificed on the 7th day and livers were collected for histopathological examination.
Results: Histopathological examination of the livers of mice infected with P. berghei demonstrated the presence of hemosiderin, hydropic degeneration, fat degeneration, necrosis, and megalocytosis. However, all these histopathological changes were reduced in the livers of P. berghei-infected mice treated with various doses of Malacca leaf ethanolic extract. The differences between the treatments were found be statistically significant (p<0.05).
Conclusion: Ethanolic extract of Malacca leaves has the potential to protect against liver damage in mice infected with P. berghei. The dose of 600 mg/kg BW was found to be the most effective compared with the doses of 100, 300, and 1200 mg/kg BW.
Methods: The clinical information of the patient was collected. Microscopy of blood smear was conducted after Giemsa staining. Genomic DNA was extracted from blood, and PCR was conducted to amplify rDNA. The PCR products were sequenced and analyzed with BLAST
Results: The patient returned from a one-week tour in a tropical rain forest in Malaysia. The first disease attack occurred in Guangzhou on Oct. 16, 2014, with fever, shivering and sweating. The patient was initially diagnosed as malaria and hospitalized on Oct. 26, 2014. Microscopic observation revealed typical forms of P. knowlesi in blood smear. The red blood cells became enlarged, with big trophozoites appearing as a ring with dual cores and dark brown malaria pigment. The trophozoites were slightly bigger and thicker than P. falciparum. The schizont had 6-8 merozoites, with obvious brown malaria pigment. PCR resulted in a specific band of 1 099 bp. BLAST analysis showed that the sequence of the PCR product was 99% homologous to P. knowlesi (acession No. AM910985.1, L07560.1 and AY580317.1). The patient was diagnosed as P. knowlesi infection, and was then given an 8-day treatment with chloroquine and primaquine, together with dihydroartemisinin piperaquine phosphate tablet. The patient was discharged after recovery on Oct. 28, 2014.
Conclusion: According to the clinical symptoms, epidemiological history and laboratory test, the patient has been confirmed as P. knowlesi infection. It may also be the first active case of knowlesi malaria reported in China.
METHODS: We did this open-label, randomised controlled trial at three district hospitals in Sabah, Malaysia. Patients aged 1 year or older with uncomplicated P knowlesi malaria were randomly assigned, via computer-generated block randomisation (block sizes of 20), to receive oral artesunate-mefloquine (target dose 12 mg/kg artesunate and 25 mg/kg mefloquine) or chloroquine (target dose 25 mg/kg). Research nursing staff were aware of group allocation, but allocation was concealed from the microscopists responsible for determination of the primary endpoint, and study participants were not aware of drug allocation. The primary endpoint was parasite clearance at 24 h. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01708876.
FINDINGS: Between Oct 16, 2012, and Dec 13, 2014, we randomly assigned 252 patients to receive either artesunate-mefloquine (n=127) or chloroquine (n=125); 226 (90%) patients comprised the modified intention-to-treat population. 24 h after treatment, we recorded parasite clearance in 97 (84% [95% CI 76-91]) of 115 patients in the artesunate-mefloquine group versus 61 (55% [45-64]) of 111 patients in the chloroquine group (difference in proportion 29% [95% CI 18·0-40·8]; p<0·0001). Parasite clearance was faster in patients given artesunate-mefloquine than in those given chloroquine (18·0 h [range 6·0-48·0] vs 24·0 h [6·0-60·0]; p<0·0001), with faster clearance of ring stages in the artesunate-mefloquine group (mean time to 50% clearance of baseline parasites 8·6 h [95% CI 7·9-9·4] vs 13·8 h [12·1-15·4]; p<0·0001). Risk of anaemia within 28 days was lower in patients in the artesunate-mefloquine group (71 [62%; 95% CI 52·2-70·6]) than in those in the chloroquine group (83 [75%; 65·6-82·5]; p=0·035). Gametocytaemia as detected by PCR for pks25 was present in 44 (86%) of 51 patients in the artesunate-mefloquine group and 41 (84%) of 49 patients in the chloroquine group at baseline, and in three (6%) of 49 patients and two (4%) of 48 patients, respectively, at day 7. Fever clearance was faster in the artesunate-mefloquine group (mean 11·5 h [95% CI 8·3-14·6]) than in the chloroquine group (14·8 h [11·7-17·8]; p=0·034). Bed occupancy was 2426 days per 1000 patients in the artesunate-mefloquine group versus 2828 days per 1000 patients in the chloroquine group (incidence rate ratio 0·858 [95% CI 0·812-0·906]; p<0·0001). One (<1%) patient in the artesunate-mefloquine group had a serious neuropsychiatric event regarded as probably related to study drug.
INTERPRETATION: Artesunate-mefloquine is highly efficacious for treatment of uncomplicated P knowlesi malaria. The rapid therapeutic response of the drug offers significant advantages compared with chloroquine monotherapy and supports a unified treatment policy for artemisinin-based combination therapy for all Plasmodium species in co-endemic areas.
FUNDING: Malaysian Ministry of Health, Australian National Health and Medical Research Council, and Asia Pacific Malaria Elimination Network.