Toxicity of Quaternary Mixture of Formulated Glyphosate and Phenols on Providencia vermicola Dehydrogenase Activity

Aims: To assess the toxicity of glyphosate (as an active ingredient in drysate), three phenols (2,4-dichlorophenol, 4-chlorophenols and phenol) and quaternary mixtures of glyphosate, 2,4-dichlorophenol, 4-chlorophenol and phenol on the dehydrogenase activity (DHA) of P. vermicola. Study Design: The glyphosate, 2,4-dichlorophenol, 4-chlorophenol and phenol mixture ratios (%) were designed as: 25%:25%:25%:25%; 30%:20%:20%:30%, 40%:10%:10%: 40%; 50%:5%:30%:15% and 20%:20%:10%:50% for the respective mixtures in the concentration range of 0-1000 mg/L. Place and Duration of Study: Silver Press Laboratory, Owerri Nigeria between July, 2016 and August, 2019. Methodology:A laboratory scale study was carried on four toxicants using dehydrogenase inhibition test. The inhibition of dehydrogenase activity of the isolate by toxicant was calculated relative to the control. The percentage inhibition data generated was fitted into a logistic dose response model and Weibulleum to obtain their respective IC50. Results:The results revealed that the median inhibitory concentrations (IC50) of the mixtures on the Providencia vermicola were 247.17 ±10.20, 163.44 ± 8.18, 251.33 ± 45.25, 267.30 ± 8.76 and 178.93 ± 45.53 mg/L, respectively. Toxicity index (TI) model was used to evaluate the joint action toxicity of the mixtures on the test organism and was 60 % antagonistic. Conclusion: Thus, these synergistic and additive interactions of formulated glyphosate with the intermediates of 2,4-D was possible against the dehydrogenase activity of Providenciavermicola an important plant growth promoting bacterium. The dynamics of the toxic effects thus would depend on the concentration of the compounds.

Coumarin-Chalcone Hybrids as Inhibitors of MAO-B: Biological Activity and In Silico Studies

Fourteen coumarin-derived compounds modified at the C3 carbon of coumarin with an α,β-unsaturated ketone were synthesized. These compounds may be designated as chalcocoumarins (3-cinnamoyl-2H-chromen-2-ones). Both chalcones and coumarins are recognized scaffolds in medicinal chemistry, showing diverse biological and pharmacological properties among which neuroprotective activities and multiple enzyme inhibition, including mitochondrial enzyme systems, stand out. The evaluation of monoamine oxidase B (MAO-B) inhibitors has aroused considerable interest as therapeutic agents for neurodegenerative diseases such as Parkinson’s. Of the fourteen chalcocumarins evaluated here against MAO-B, ChC4 showed the strongest activity in vitro, with IC50 = 0.76 ± 0.08 µM. Computational docking, molecular dynamics and MM/GBSA studies, confirm that ChC4 binds very stably to the active rMAO-B site, explaining the experimental inhibition data.

Emetine Is Not Ipecac: Considerations for Its Use as Treatment for SARS-CoV2

Emetine is a potent antiviral that acts on many viruses in the low-nM range, with several studies in animals and humans demonstrating antiviral activity. Historically, emetine was used to treat patients with Spanish influenza, in the last stages of the pandemic in the early 1900s. Some of these patients were “black” with cyanosis. Emetine rapidly reversed the cyanosis and other symptoms of this disease in 12–24 h. However, emetine also has been shown to have anti-inflammatory properties and it appears it is these anti-inflammatory properties that were responsible for the effects seen in patients with Spanish influenza. Emetine, in the past, has also been used in 10s to 100s of millions of people at a dose of ~60 mg daily to treat amoebiasis. Based on viral inhibition data we can calculate a likely SARS-CoV2 antiviral dose of ~1/10th the amoebiasis dose, which should dramatically reduce the risk of any side effects. While there are no anti-inflammatory dose response data available, based on the potential mode of action, the anti-inflammatory actions may also occur at low doses. This paper also examines the toxicity of emetine seen in clinical practice and that seen in the laboratory, and discusses the methods of administration aimed at reducing side effects if higher doses were found to be necessary. While emetine is a “pure drug” as it is extracted from ipecac, some of the differences between emetine and ipecac are also discussed.

Transmural and rate-dependent profiling of drug-induced arrhythmogenic risks through in silico simulations of multichannel pharmacology

BackgroundIn vitro hERG blockade assays alone provide insufficient information to accurately discriminate “safe” from “dangerous” drugs. Recent studies have suggested that the integration of multiple ion channel inhibition data can improve the prediction of drug-induced arrhythmogenic risks. In this study, using a family of cardiac cell models representing electrophysiological heterogeneities across the ventricular wall, we quantitatively evaluated transmural and rate-dependent properties of drug-induced arrhythmogenicity through computer simulations of multichannel pharmacology.Methods and ResultsRate-dependent drug effects of multiple ion channel inhibition on cardiac electrophysiology at their effective free therapeutic plasma concentrations (EFTPCs) were investigated using a group of in silico cell models (Purkinje (P) cells, endocardial (Endo) cells, mid-myocardial (M) cells and epicardial (Epi) cells). We found that (1) M cells are much more sensitive than the other cell types to drug-induced arrhythmias and can develop early afterdepolarization (EAD) in response to bepridil, dofetilide, sotalol, terfenadine, cisapride or ranolazine. (2) Most drug-induced adverse effects, such as pronounced action potential prolongations or EADs, occur at slower pacing rates. (3) Although most drug-induced EADs occur in M cells, the application of quinidine at its EFTPC can cause EADs in all four cell types. (4) The underlying ionic mechanism of drug-induced EADs differs across different cell types; while INaL is the major depolarizing current during the generation of EAD in P cells, ICaL is mostly predominant in other cell types. (5) Drug-induced AP alternans with larger beat-to-beat variations occur at high pacing rates in mostly P cells, while the application of bepridil can cause alternating EAD patterns at slower pacing rates in M cells.ConclusionsIn silico analysis of transmural and rate-dependent properties using multichannel inhibition data can be useful to accurately predict drug-induced arrhythmogenic risks and can also provide mechanistic insights into drug-induced adverse events related to cardiac arrhythmias.Author summaryIn vitro hERG blockade assays alone provide insufficient information to accurately discriminate “safe” from “dangerous” drugs, and computer simulation of ventricular action potential using multichannel inhibition data could be a useful tool to evaluate drug-induced arrhythmogenic risks. Our study suggested that the profiling of drug-induced transmural heterogeneities in cellular electrophysiology at all physiological pacing frequencies can be essential for the comprehensive evaluation of drug safety, and for the quantitative investigation into ionic mechanisms underlying drug-specific arrhythmogenic events. These in silico models and approaches may contribute to the ongoing construction of a comprehensive paradigm for the evaluation of drug-induced arrhythmogenic risks, potentially increase the success rate and accelerate the process of novel drug development.

In vitro Antichlamydial Activity of 1,2,3,5-Tetrasubstituted Pyrrole Derivatives

Background: Chlamydia is a group of bacterial pathogens distributed worldwide that can lead to serious reproductive and other health problems. The rise of antibiotic-resistant pathogens promotes the development of novel antichlamydial agents. The aim of this study is to assess in vitro antichlamydial activity of our previously synthesized 1,2,3,5- tetrasubstituted pyrroles. Methods: The derivatives were screened for their antichlamydial activity against three Chlamydia strains by calculating IC50 values using concentration-response inhibition data between 1 and 32 μM. The action of the compounds on Chlamydia elementary body (EB) infectivity and the impact of the chemicals’ administration time on their antichlamydial effect were evaluated to reveal the inhibitory mechanism. Results: Some of the compounds moderately inhibited the Chlamydia strains. Compound 10 exhibited the strongest inhibitory activity, with IC50 values from 4.34 to 5.83 μM. These pyrrole derivatives inhibited Chlamydia infection by reducing EB infectivity during the early stage and disturbing Chlamydia growth by targeting the early-to-middle stage prior to 12 h of the chlamydial life cycle. Conclusion: Our findings highlight the potential of 1,2,3,5-tetrasubstituted pyrrole derivatives as promising lead molecules for the development of antichlamydial agents.

Estimation of fractions metabolized by hepatic CYP enzymes using a concept of inter-system extrapolation factors (ISEFs) – a comparison with the chemical inhibition method

Background:For estimation of fractions metabolized (fm) by different hepatic recombinant human CYP enzymes (rhCYP), calculation of inter-system extrapolation factors (ISEFs) has been proposed.Methods:ISEF values for CYP1A2, CYP2C19 and CYP3A4/5 were measured. A CYP2C9 ISEF was taken from a previous report. Using a set of compounds, fractions metabolized by CYP enzymes (fm,CYP) values calculated with the ISEFs based on rhCYP data were compared with those from the chemical inhibition data. Oral pharmacokinetics (PK) profiles of midazolam were simulated using the physiologically based pharmacokinetics (PBPK) model with the CYP3A ISEF. For other CYPs, theResults:-Conclusions:The rhCYP data with the measured ISEFs provided reasonable calculation of fm,CYP3A4 values, showing slight over-estimation compared to chemical inhibition.