scholarly journals Emetine, Ipecac, Ipecac Alkaloids and Analogues as Potential Antiviral Agents for Coronaviruses

2020 ◽  
Vol 13 (3) ◽  
pp. 51 ◽  
Author(s):  
Martin Bleasel ◽  
Gregory Peterson
Keyword(s):  
Side Effects ◽  
Treatment Options ◽  
Antiviral Agents ◽  
Effective Concentration ◽  
Potential Treatment ◽  
Optimal Method ◽  
Half Maximal Effective Concentration ◽  
Related Compounds ◽  
Old Drugs

The COVID-19 coronavirus is currently spreading around the globe with limited treatment options available. This article presents the rationale for potentially using old drugs (emetine, other ipecac alkaloids or analogues) that have been used to treat amoebiasis in the treatment of COVID-19. Emetine had amongst the lowest reported half-maximal effective concentration (EC50) from over 290 agents screened for the Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) coronaviruses. While EC50 concentrations of emetine are achievable in the blood, studies show that concentrations of emetine can be almost 300 times higher in the lungs. Furthermore, based on the relative EC50s of emetine towards the coronaviruses compared with Entamoeba histolytica, emetine could be much more effective as an anti-coronavirus agent than it is against amoebiasis. This paper also discusses the known side effects of emetine and related compounds, how those side effects can be managed, and the optimal method of administration for the potential treatment of COVID-19. Given the serious and immediate threat that the COVID-19 coronavirus poses, our long history with emetine and the likely ability of emetine to reach therapeutic concentrations within the lungs, ipecac, emetine, and other analogues should be considered as potential treatment options, especially if in vitro studies confirm viral sensitivity.

scholarly journals Primum non nocere – Are chloroquine and hydroxychloroquine safe prophylactic/treatment options for SARS-CoV-2 (covid-19)?

2020 ◽  
Vol 54 ◽  
pp. 68 ◽  
Author(s):  
Claudia Biguetti ◽  
Mauro Toledo Marrelli ◽  
Marco Brotto
Keyword(s):  
Clinical Trials ◽  
Side Effects ◽  
Animal Studies ◽  
Prophylactic Treatment ◽  
Randomized Clinical Trials ◽  
Treatment Options ◽  
Vulnerable Groups ◽  
Drug Effectiveness ◽  
Risk Balance

ABSTRACT Chloroquine (CQ) and its analog hydroxychloroquine (HCQ) were recently included in several clinical trials as potential prophylactic and therapeutic options for SARS-CoV-2 infection/covid-19. However, drug effectiveness in preventing, treating, or slowing the progression of the disease is still unknown. Despite some initial promising in vitro results, rigorous pre-clinical animal studies and randomized clinical trials have not been performed yet. On the other hand, while the potential effectiveness of CQ/HCQ is, at best, hypothetical, their side effects are factual and most worrisome, particularly when considering vulnerable groups of patients being treated with these drugs. In this comment, we briefly explain the possible mechanisms of action of CQ/HCQ for treating other diseases, possible actions against covid-19, and their potent side effects, in order to reinforce the necessity of evaluating the benefit-risk balance when widely prescribing these drugs for SARS-CoV-2 infection/covid-19. We conclude by strongly recommending against their indiscriminate use. DESCRIPTORS: Coronavirus Infections. Chloroquine, toxicity. Hydroxychloroquine, toxicity. Contraindications, Drug.

scholarly journals Preclinical Characterization and Human Microdose Pharmacokinetics of ITMN-8187, a Nonmacrocyclic Inhibitor of the Hepatitis C Virus NS3 Protease

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Ravi Rajagopalan ◽  
Lin Pan ◽  
Caralee Schaefer ◽  
John Nicholas ◽  
Sharlene Lim ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Oral Absorption ◽  
Antiviral Agents ◽  
Hcv Infection ◽  
Chimeric Mouse ◽  
Elimination Kinetics ◽  
Half Maximal Effective Concentration ◽  
Chronic Hcv

Abstract The current paradigm for the treatment of chronic hepatitis C virus (HCV) infection involves combinations of agents that act directly on steps of the HCV life cycle. Here we report the preclinical characteristics of ITMN-8187, a nonmacrocyclic inhibitor of the NS3/4A HCV protease. X-ray crystallographic studies of ITMN-8187 and simeprevir binding to NS3/4A protease demonstrated good agreement between structures. Low nanomolar biochemical potency was maintained against NS3/4A derived from HCV genotypes 1, 2b, 4, 5, and 6. In cell-based potency assays, half-maximal reduction of genotype 1a and 1b HCV replicon RNA was afforded by 11 and 4 nM doses of ITMN-8187, respectively. Combinations of ITMN-8187 with other directly acting antiviral agents in vitro displayed additive antiviral efficacy. A 30-mg/kg of body weight dose of ITMN-8187 administered for 4 days yielded significant viral load reductions through day 5 in a chimeric mouse model of HCV. A 3-mg/kg oral dose administered to rats, dogs, or monkeys yielded concentrations in plasma 16 h after dosing that exceeded the half-maximal effective concentration of ITMN-8187. Human microdose pharmacokinetics showed low intersubject variability and prolonged oral absorption with first-order elimination kinetics compatible with once-daily dosing. These preclinical characteristics compare favorably with those of other NS3/4A inhibitors approved for the treatment of chronic HCV infection.

scholarly journals In VitroEfficacy of Brincidofovir against Variola Virus

2014 ◽  
Vol 58 (9) ◽  
pp. 5570-5571 ◽  
Author(s):  
Victoria A. Olson ◽  
Scott K. Smith ◽  
Scott Foster ◽  
Yu Li ◽  
E. Randall Lanier ◽  
...  
Keyword(s):  
Animal Models ◽  
Effective Concentration ◽  
Variola Virus ◽  
Half Maximal Effective Concentration ◽  
Animal Rule ◽  
Virus Strains ◽  
Lipid Conjugate

ABSTRACTBrincidofovir (CMX001), a lipid conjugate of the acyclic nucleotide phosphonate cidofovir, is under development for smallpox treatment using “the Animal Rule,” established by the FDA in 2002. Brincidofovir reduces mortality caused by orthopoxvirus infection in animal models. Compared to cidofovir, brincidofovir has increased potency, is administered orally, and shows no evidence of nephrotoxicity. Here we report that the brincidofovir half-maximal effective concentration (EC50) against five variola virus strainsin vitroaveraged 0.11 μM and that brincidofovir was therefore nearly 100-fold more potent than cidofovir.

scholarly journals Amnestic Concentrations of Etomidate Modulate GABAA,slowSynaptic Inhibition in Hippocampus

2009 ◽  
Vol 111 (4) ◽  
pp. 766-773 ◽  
Author(s):  
Shuiping Dai ◽  
Misha Perouansky ◽  
Robert A. Pearce
Keyword(s):  
Time Constant ◽  
Hippocampal Slices ◽  
Effective Concentration ◽  
Detectable Effect ◽  
Gamma Aminobutyric Acid ◽  
Gaba A ◽  
Phasic Inhibition ◽  
Half Maximal Effective Concentration

Background Gamma-aminobutyric acid type A (GABA(A)) receptor-mediated inhibition in the central nervous system exists in two forms: phasic (inhibitory postsynaptic currents, IPSCs) and tonic (nonsynaptic). Phasic inhibition is further subdivided into fast (GABA(A,fast)) and slow (GABA(A,slow)) IPSCs. By virtue of its dendritic location and kinetics, GABA(A,slow) has been proposed to control synaptic plasticity and memory. Etomidate is a nonbarbiturate, intravenous anesthetic that selectively modulates GABA(A) receptors and produces amnesia at low doses in vivo. This study tested whether correspondingly low concentrations of etomidate in vitro alter GABA(A,fast) and GABA(A,slow) phasic inhibition. Methods Electrophysiological recordings were obtained from hippocampal slices prepared from postnatal day 3-8 mice and maintained in organotypic culture for 10-14 days. Etomidate was applied at concentrations corresponding to one-half to four times the half maximal effective concentration that impairs hippocampus-dependent learning and memory--i.e., 0.125-1.0 microm. Results Etomidate 0.25 microm (the half maximal effective concentration) doubled the time constant of decay of GABA(A,slow) IPSCs, but it had no detectable effect on GABA(A,fast) IPSCs. Higher concentrations of etomidate had stronger effects on both types of phasic inhibition: 0.5 and 1 microm etomidate prolonged the time constant of decay by 310% and 410% for GABA(A,slow) and by 25% and 78% for GABA(A,fast). Concentrations of etomidate up to 1 microm had no significant effects on the amplitudes of either GABA(A,fast) or GABA(A,slow) IPSCs. Conclusions At concentrations that impair hippocampus-dependent memory, etomidate modulates GABA(A,slow) more strongly than GABA(A,fast) IPSCs. Effects of etomidate on GABA(A,slow) IPSCs may contribute to etomidate-induced amnesia.

scholarly journals In vitro anti-motility and antispasmodic effects of Garcinia mangostana extracts in isolated chicken ileum preparation

2019 ◽  
Vol 10 (2) ◽  
pp. 1444-1447
Author(s):  
Michelle Ooi Yi Ching ◽  
Sasikala Chinnappan ◽  
Mogana Sundari Rajagopal
Keyword(s):  
Effective Concentration ◽  
Aqueous Extracts ◽  
Inhibitory Effects ◽  
Garcinia Mangostana ◽  
Response Curves ◽  
Half Maximal Effective Concentration ◽  
Set Up ◽  
Smooth Muscle Contractions ◽  
Significant Concentration

Garcinia mangostana pericarps have been traditionally used in Southeast Asia for a variety of medicinal conditions. The present study was carried out to determine the anti-motility and antispasmodic effects of methanolic and aqueous G. mangostana extracts (MEM and AEM) on isolated chicken ileum. Extracts were prepared from the pericarp of G. mangostana using maceration technique with methanol and distilled water. Isolated ileum preparations were set up for recording in Tyrode’s solution at 37°C. Dose-response curves were plotted using various doses of agonist as control such as acetylcholine (ACh) and histamine. Atropine, mepyramine and extracts were used as an antagonist. The results showed that methanolic and aqueous extracts possess significant concentration-dependent inhibitory effects (p<0.05) on agonist-induced contractions. The half maximal effective concentration (EC50) of extracts and standard antagonists were higher than the agonist alone. Both methanolic and aqueous extract of G. mangostana exerts anti-motility and antispasmodic effects on smooth muscle contractions. The study provides findings that support G. mangostana can be the potential treatment for diarrhoea and spasm.

scholarly journals Short Communication:In VitroEfficacy Testing of Praziquantel, Ivermectin, and Oxfendazole againstTaenia SoliumCysts

2012 ◽  
Vol 2012 ◽  
pp. 1-4 ◽  
Author(s):  
S. Cederberg ◽  
C. S. Sikasunge ◽  
Å. Andersson ◽  
M. V. Johansen
Keyword(s):  
Culture Media ◽  
Taenia Solium ◽  
Effective Concentration ◽  
Effect Measurement ◽  
Recommended Dose ◽  
Drug Of Choice ◽  
Porcine Cysticercosis ◽  
Half Maximal Effective Concentration ◽  
Brain Cysts

Oxfendazole is recommended as the drug of choice for treating porcine cysticercosis. The drug does not kill brain cysts and is not registered for use in pigs. Latest its safety in the recommended dose has been questioned. The aim of this study was to investigate two alternative anthelminthics. The efficacy of praziquantel and ivermectin was compared to oxfendazoleIn VitroonTaenia solium. Cysts ofT. soliumwere isolated from infected pork and incubated in culture media together with the drugs. The degree of evagination was used as effect measurement and determined after 6 hours. Praziquantel had a half maximal effective concentration (EC50) of value 0.006 ± 0.001 μg/mL. Ivermectin did not show any impact on the evagination in concentrations from 0.001 to 30 μg/mL and neither did oxfendazole in concentrations from 0.001 to 50 μg/mL.

scholarly journals Investigation of Fertilizing Capacity of Zebrafish (Danio rerio) Sperm Exposed to Heavy Metals

Dose-Response ◽  
2020 ◽  
Vol 18 (2) ◽  
pp. 155932582091959
Author(s):  
Flóra Kerekes ◽  
Tímea Kollár ◽  
Gyöngyi Gazsi ◽  
Eszter Kása ◽  
Béla Urbányi ◽  
...  
Keyword(s):  
Heavy Metals ◽  
Embryonic Development ◽  
Danio Rerio ◽  
Aquatic Environment ◽  
Fertilization Rate ◽  
Effective Concentration ◽  
Toxicological Studies ◽  
Half Maximal Effective Concentration ◽  
The Given

The objective of our study was to investigate the effects of heavy metals on the fertilizing capacity of exposed zebrafish sperm, on embryonic survival, and on occurrence of embryonic deformities following fertilization with exposed sperm. It is important to test heavy metals because they are well-known pollutants. Sperm of externally fertilizing species can get in contact with pollutants found in aquatic environment. Zebrafish sperm, despite its advantages, has seldom been used in in vitro toxicological studies and no reports are available regarding the fertilizing capacity of exposed sperm. Zebrafish sperm was stripped and exposed to concentrations of the tested heavy metals (Zn2+, Cd2+, Cr3+, Cu2+, Ni2+, Hg2+, As3+) for 30 or 120 minutes. Calculated half-maximal effective concentration (EC50) values do not differ significantly from those calculated for motility for any of the tested heavy metals, which means fertilization rate can indicate the toxicity of the given substance following exposure of sperm. Thus, its application as in vitro toxicological end point is reasonable. The survival of embryos and embryonic development have not been affected by the exposure of spermatozoa, which means all alterations in spermatozoa caused by heavy metals have been expressed before 24 hours post fertilization.

scholarly journals Distribution, Pathotypes, and Metalaxyl Sensitivity of Phytophthora sojae from Heilongjiang and Fujian Provinces in China

Plant Disease ◽  
2010 ◽  
Vol 94 (7) ◽  
pp. 881-884 ◽  
Author(s):  
Linkai Cui ◽  
Weixiao Yin ◽  
Qinghua Tang ◽  
Suomeng Dong ◽  
Xiaobo Zheng ◽  
...  
Keyword(s):  
Root Rot ◽  
Phytophthora Sojae ◽  
Effective Concentration ◽  
Effective Management ◽  
Population Status ◽  
The Past ◽  
Metalaxyl Sensitivity ◽  
Half Maximal Effective Concentration ◽  
Soybean Leaf

Phytophthora sojae causes root and stem rot, one of the most devastating diseases of soybean worldwide. In Heilongjiang and Fujian provinces in China, serious cases of Phytophthora stem and root rot have occurred and caused heavy losses in the past several years. To determine the current population status of this pathogen, we investigated the pathogen's distribution, pathotypes, and metalaxyl sensitivity in both provinces. P. sojae was baited and isolated from 258 soil samples in both provinces using the soybean leaf bait method. The pathotypes of all isolates were characterized on 13 differential soybean cultivars using the hypocotyl slit inoculation method, and the sensitivity of all isolates to metalaxyl was tested in vitro. In all, 75 isolates were recovered from 75 fields in 33 counties; of these, 31 counties were in Heilongjiang Province and 2 counties were in Fujian Province. Thirty-five new pathotypes were identified compared with the previously defined races. Less than 5% of the isolates were virulent to cultivars with individual Rps genes 1a, 1c, or 1k. No metalaxyl-resistant isolates were found; the half maximal effective concentration values of all isolates ranged from 0.04 to 0.22 μg ml–1. These results suggest that effective management of the disease in both provinces can be accomplished through the use of resistant cultivars with Rps genes 1a, 1c, or 1k and the fungicide metalaxyl.

scholarly journals Effect of selected nonsteroidal anti-inflammatory drugs on the viability of canine osteosarcoma cells of the D-17 line: in vitro studies

2019 ◽  
Vol 63 (3) ◽  
pp. 399-403 ◽  
Author(s):  
Dominik Poradowski ◽  
Bożena Obmińska-Mrukowicz
Keyword(s):  
Effective Concentration ◽  
Tolfenamic Acid ◽  
Osteosarcoma Cells ◽  
Anticancer Effect ◽  
Canine Osteosarcoma ◽  
Half Maximal Effective Concentration ◽  
Analysis Of Results ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

Abstract Introduction Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in veterinary medicine. They are used in pain control and in anti-inflammatory and antipyretic therapies. Some NSAIDs, e.g piroxicam, also have a documented anticancer effect. The objective of this study was to evaluate which of the commonly used NSAIDs (etodolac, flunixin, tolfenamic acid, carprofen, and ketoprofen) are cytotoxic to the D-17 cell line of canine osteosarcoma. Material and Methods The viability of the cells was evaluated using the MTT assay. Four independent repetitions were performed and the results are given as the average of these values; EC50 values (half maximal effective concentration) were also calculated. Results The analysis of results showed that carprofen and tolfenamic acid displayed the highest cytotoxicity. Other drugs either did not provide such effects or they were very poor. For carprofen, it was possible to determine an EC50 which fell within the limits of concentrations obtainable in canine serum after the administration of routinely used doses. Conclusion The results are promising but further studies should be conducted to confirm them, since this study is only preliminary. The possibility of introducing carprofen and tolfenamic acid into the routine treatment of osteosarcoma in dogs should be considered.

Erythromycin contracts rabbit colon myocytes via occupation of motilin receptors

1992 ◽  
Vol 262 (1) ◽  
pp. G50-G55 ◽  
Author(s):  
W. L. Hasler ◽  
A. Heldsinger ◽  
O. Y. Chung
Keyword(s):  
Dissociation Constant ◽  
Effective Concentration ◽  
Rabbit Colon ◽  
Colonic Motor ◽  
Half Maximal Effective Concentration ◽  
Gastroduodenal Motility ◽  
Maximal Binding ◽  
Motilin Receptor ◽  
Dissociation Constant Kd

Erythromycin stimulates gastroduodenal motility via action on motilin receptors. We evaluated erythromycin as a colonic muscle motilin agonist using in vitro rabbit colon studies. Isolated myocytes contracted to erythromycin with a half-maximal effective concentration of 2 pM and peak shortening of 22.4 +/- 2.5% at 1 nM, which was superimposable with the response to motilin. 125I-labeled motilin binding to colon muscle homogenates was saturable and specific with a dissociation constant (Kd) of 0.39 nM and maximal binding (Bmax) of 41 +/- 3 fmol/mg protein. Motilin displaced specifically bound 125I-motilin, with a Kd of 0.31 nM. Erythromycin displaced 125I-motilin but was less potent, with an inhibitory constant of 84.0 nM. Bmax values from displacement studies were similar to the Scatchard data. Motilin receptor protection from alkylation by N-ethylmaleimide preserved contraction to motilin and erythromycin but not acetylcholine or cholecystokinin, whereas protection with erythromycin preserved contraction to motilin but not other agonists. In conclusion, erythromycin binds to colon muscle motilin receptors present in densities similar to reported values for the upper gut. Furthermore, erythromycin contracts colonic myocytes via specific action on motilin receptors. Thus erythromycin may have colonic motor-stimulating properties by action on motilin receptors.

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