A Head-to-Head Comparison of Four Artemisinin-Based Combinations for Treating Uncomplicated Malaria in African Children: A Randomized Trial

BackgroundArtemisinin-based combination therapies (ACTs) are the mainstay for the management of uncomplicated malaria cases. However, up-to-date data able to assist sub-Saharan African countries formulating appropriate antimalarial drug policies are scarce.Methods and findingsBetween 9 July 2007 and 19 June 2009, a randomized, non-inferiority (10% difference threshold in efficacy at day 28) clinical trial was carried out at 12 sites in seven sub-Saharan African countries. Each site compared three of four ACTs, namely amodiaquine-artesunate (ASAQ), dihydroartemisinin-piperaquine (DHAPQ), artemether-lumefantrine (AL), or chlorproguanil-dapsone-artesunate (CD+A). Overall, 4,116 children 6-59 mo old with uncomplicated Plasmodium falciparum malaria were treated (1,226 with AL, 1,002 with ASAQ, 413 with CD+A, and 1,475 with DHAPQ), actively followed up until day 28, and then passively followed up for the next 6 mo. At day 28, for the PCR-adjusted efficacy, non-inferiority was established for three pair-wise comparisons: DHAPQ (97.3%) versus AL (95.5%) (odds ratio [OR]: 0.59, 95% CI: 0.37-0.94); DHAPQ (97.6%) versus ASAQ (96.8%) (OR: 0.74, 95% CI: 0.41-1.34), and ASAQ (97.1%) versus AL (94.4%) (OR: 0.50, 95% CI: 0.28-0.92). For the PCR-unadjusted efficacy, AL was significantly less efficacious than DHAPQ (72.7% versus 89.5%) (OR: 0.27, 95% CI: 0.21-0.34) and ASAQ (66.2% versus 80.4%) (OR: 0.40, 95% CI: 0.30-0.53), while DHAPQ (92.2%) had higher efficacy than ASAQ (80.8%) but non-inferiority could not be excluded (OR: 0.35, 95% CI: 0.26-0.48). CD+A was significantly less efficacious than the other three treatments. Day 63 results were similar to those observed at day 28.ConclusionsThis large head-to-head comparison of most currently available ACTs in sub-Saharan Africa showed that AL, ASAQ, and DHAPQ had excellent efficacy, up to day 63 post-treatment. The risk of recurrent infections was significantly lower for DHAPQ, followed by ASAQ and then AL, supporting the recent recommendation of considering DHAPQ as a valid option for the treatment of uncomplicated P. falciparum malaria.Trial registrationClinicalTrials.gov NCT00393679; Pan African Clinical Trials Registry PACTR200901000091175

Evaluation of the Concentrations of Some Heavy Metals (Pb, Cd and Cr) and Long Term Exposure Due to Daily Consumption of Ready-to-Eat Foods Sold at Petrol Station’s Atmospheric Conditions (AF) in Calabar Metropolis

Background: Heavy metals contamination has been reported at petrol station environments. There is a possibility of contamination foods around petrol stations. Objectives: In this study, the concentrations of Pb, Cd and Cr, long term exposure and daily consumption of ready-to-eat food foods sold at Petrol station’s Atmospheric conditions (AF) in Calabar Metropolis was evaluated. Methods: Foods samples, including such prepared ready-to-eat foods were collected at the point of sale at the fuel stations in Calabar Nigeria, about 7:00am in the morning before they were opened for sale (and exposed to the environment of the filling stations). These were labelled “Before”. At about 2:00pm to 3:00pm same day, the same ready-to-eat food samples were collected again at the same spots, for a duration of 3 months. Results: In this study, the levels of Pb, Cd and Cr were determined in some ready-to-eat foods that are sold around the filling station environments in Calabar metropolis. The results obtained showed that the levels of Pb and Cd were significantly (p<0.05) increased in garri, afang soup, melon soup, white rice, beans, stew and meat pie, while the level of and Cr was significantly (p<0.05) increased in afang soup, melon soup, white rice, beans, stew and meat pie after 6 hours of exposure to petrol station’s atmospheric conditions. Conclusion: From this study, it may be concluded that exposure of ready-to-eat foods at the filling station’s atmospheric conditions may cause heavy metal contamination to the foods, particularly Pb, Cd and Cr

Investigating the potential of thiazolyl carbohydrazides derivatives as anti-Candida albicans agents: An intuition from molecular modelling, pharmacokinetic evaluation, and molecular docking analysis

With increasing incidences of antifungal resistance, biofilm formation, and its predilection for vulnerable populations, Candida albicans have been reported to cause a wide range of infections, from superficial skin irritations to life-threatening systemic diseases. Therefore, understanding and addressing the infections associated with Candida albicans has become an urgent imperative in the realm of global healthcare. As a result, this study employed DFT calculations at the DFT/ωB97XD/6–311++G (2d, 2p) level to optimize the geometric properties of two compounds: (Z)-N'-(4-(4-bromophenyl)-3-(4-fluorophenyl)thiazol-2(3H)-ylidene)-2-(thiophen-2-yl)thiazole-5-carbohydrazide (4-FBC) and (Z)-N'-(4-(4-bromophenyl)-3-(2-fluorophenyl)thiazol-2(3H)-ylidene)-2-(thiophen-2-yl)thiazole-5-carbohydrazide(2-FBC). Significantly, employing spectral analysis techniques such as FT-IR and NMR, the compounds were characterized and identified. Additionally, the compounds (4-FBC and 2-FBC) exhibited comparable reactivity and stability, with more promising reactivity potential in water than in the gas phase. The analysis of Molecular Electrostatic Potential (MESP) and the density of States (DOS) shed light on the electrical characteristics and intermolecular interactions occurring during chemical processes. Furthermore, the natural bond orbital (NBO) analysis provided insights into second-order perturbation energies and the presence of intense intermolecular interactions, as evident in the order of their increasing concentrated intermolecular interaction as thus: 4-FBC_gas (668.34 kcal/mol) > 4-FBC _water (563.98 kcal/mol) and 2-FBC _gas (978.64 Kcal/mol) > 2-FBC_water (696.46 Kcal/mol). The pharmacokinetics study indicated favorable intestinal absorption, low distribution, and cytotoxicity profiles, although 4-FBC required further optimization due to slower clearance, potential enzyme interactions, and immunotoxicity concerns. In addition, molecular docking analysis revealed robust binding affinities and the presence of significant conventional hydrogen bonds. The optimal binding positions (best pose) for the 4-FBC and 2-FBC complexes were determined to have binding affinities of -8.7, -8.4, -8.3 kcal/mol, and -8.6, -8.5, -8.3 kcal/mol, respectively, when interacting with 4YDE, 3DRA, and 1EAG. These findings provide strong evidence supporting the potential pharmacological suitability of 4-FBC and 2-FBC compounds as effective choices for inhibiting and treating Candida albicans

Unraveling the impact of polar solvation on the molecular geometry, spectroscopy (FT-IR, UV, NMR), reactivity (ELF, NBO, HOMO-LUMO) and antiviral inhibitory potential of Cissampeline by molecular docking approach

Cissampeline, a highly promising natural substance derived from medicinal plants of the Cissampelos genus, has recently garnered significant interest due to its potent antiviral properties against a broad spectrum of viral infections. In this comprehensive study, we employed gd3bj-B3LYP/def2svp level of theory to investigate the impact of polar solvation on the molecular structure, dynamical stability, spectroscopy, nature of bonding, and antiviral inhibitory potential of Cissampeline. Our results demonstrated excellent agreement between the theoretically characterized structure and the experimentally determined one. Interestingly, we observed that in the absence of a solvent environment, the gas phase exhibited shorter bond angles compared to when different solvents were utilized, indicating reduced solvent interactions. Regarding solvation dynamics, we found that the total energy of the structure, when optimized in different solvents, followed the order DMSO > MeOH > Water > Gas, with corresponding total final energies of 1736.599 > 867.932 > 837.760 > 413.989 kcal/mol, respectively. Furthermore, NBO analysis revealed the strength of electron delocalization, with the order of perturbation energies being DMSO > MeOH > H2O > Gas phase, measured at 626.07 > 241.40 > 238.65 > 72.93 kcal/mol, respectively. Particularly noteworthy was the σ-σ* transition in the DMSO solvent phase, displaying the highest perturbation energy of 626.07 kcal/mol. FMO analysis provided insights into the energy levels of the studied species, with values of 4.5432 eV for Gas, 4.5250 eV for MeOH, 4.5247 eV for H2O, and 4.5242 eV for DMSO, respectively. Regarding the interaction of Cissampeline with amino acid residues, we found that the ligand exhibited the highest binding affinity with 3MX2 at -7.7 kcal/mol, followed by CMPL + 3T5N at -7.3 kcal/mol, and CMPL + 3MX5 at -6.0 kcal/mol. In comparison, the standard drug RIBAV only displayed successful interaction with 3MX2, showing the least binding affinity at -5.8 kcal/mol. This study showed highlights the remarkable potential of Cissampeline as an effective antiviral agent and sheds light on the importance of considering solvation effects in molecular investigations

Evaluation of the therapeutic potentials of extract fractions of Vernonia calvoana on streptozotocin-induced diabetic rats: approach through in silico, in vitro and in vivo studies

Abstract Background Diabetes is a serious metabolic disorder and many medicinal plants are used in traditional medicine to manage it. This study aimed to evaluate the therapeutic effects of Vernonia calvoana (V. calvoana) extract fractions on streptozotocin-induced diabetic rat models. In this study, we first investigated the binding affinity of ligands from extracts of V. calvoana crystal structure proteins using a molecular docking approach. Furthermore, the in silico predictions were validated by in vitro and in vivo biochemical evaluations to ascertain the efficacy of these extract fractions. The in vitro antioxidant activity of the fractions was evaluated using DPPH, FRAP, SOD, and LPx scavenging. For biological activity, extract fractions of V. calvoana and metformin (400 mg and 500 mg/kg body weight, respectively) were administered to diabetic rats for 21 days after induction and confirmation of diabetes. Results The radical scavenger activities of the fractions showed a good dose-dependent reaction activity. A significant reduction in hyperglycemia, hyperlipidemia, nephrotoxicity, and hepatotoxicity was observed in all experimental treated groups. Improved hematological and histopathological changes were also observed. Conclusion The In silico analyses revealed that all the compounds from extract fractions of V. calvoana have varying binding affinity for PFK and lipoprotein lipase, with some showing higher affinity than the standard drug, further validating the biological activity of the plant. The results of this study indicated that V. calvoana extracts might have potential value in treating complications arising from diabetes mellitus

A Head-to-Head Comparison of Four Artemisinin-Based Combinations for Treating Uncomplicated Malaria in African Children: A Randomized Trial

BACKGROUND: Artemisinin-based combination therapies (ACTs) are the mainstay for the management of uncomplicated malaria cases. However, up-to-date data able to assist sub-Saharan African countries formulating appropriate antimalarial drug policies are scarce. METHODS AND FINDINGS: Between 9 July 2007 and 19 June 2009, a randomized, non-inferiority (10% difference threshold in efficacy at day 28) clinical trial was carried out at 12 sites in seven sub-Saharan African countries. Each site compared three of four ACTs, namely amodiaquine-artesunate (ASAQ), dihydroartemisinin-piperaquine (DHAPQ), artemether-lumefantrine (AL), or chlorproguanil-dapsone-artesunate (CD+A). Overall, 4,116 children 6-59 mo old with uncomplicated Plasmodium falciparum malaria were treated (1,226 with AL, 1,002 with ASAQ, 413 with CD+A, and 1,475 with DHAPQ), actively followed up until day 28, and then passively followed up for the next 6 mo. At day 28, for the PCR-adjusted efficacy, non-inferiority was established for three pair-wise comparisons: DHAPQ (97.3%) versus AL (95.5%) (odds ratio [OR]: 0.59, 95% CI: 0.37-0.94); DHAPQ (97.6%) versus ASAQ (96.8%) (OR: 0.74, 95% CI: 0.41-1.34), and ASAQ (97.1%) versus AL (94.4%) (OR: 0.50, 95% CI: 0.28-0.92). For the PCR-unadjusted efficacy, AL was significantly less efficacious than DHAPQ (72.7% versus 89.5%) (OR: 0.27, 95% CI: 0.21-0.34) and ASAQ (66.2% versus 80.4%) (OR: 0.40, 95% CI: 0.30-0.53), while DHAPQ (92.2%) had higher efficacy than ASAQ (80.8%) but non-inferiority could not be excluded (OR: 0.35, 95% CI: 0.26-0.48). CD+A was significantly less efficacious than the other three treatments. Day 63 results were similar to those observed at day 28. CONCLUSIONS: This large head-to-head comparison of most currently available ACTs in sub-Saharan Africa showed that AL, ASAQ, and DHAPQ had excellent efficacy, up to day 63 post-treatment. The risk of recurrent infections was significantly lower for DHAPQ, followed by ASAQ and then AL, supporting the recent recommendation of considering DHAPQ as a valid option for the treatment of uncomplicated P. falciparum malaria. TRIAL REGISTRATION: ClinicalTrials.gov NCT00393679; Pan African Clinical Trials Registry PACTR2009010000911750status: publishe