scholarly journals Low Selectivity Indices of Ivermectin and Macrocyclic Lactones on SARS-CoV-2 Replication In Vitro

COVID ◽  
2022 ◽  
Vol 2 (1) ◽  
pp. 60-75
Author(s):  
Christine Chable-Bessia ◽  
Charlotte Boullé ◽  
Aymeric Neyret ◽  
Jitendriya Swain ◽  
Mathilde Hénaut ◽  
...  

Ivermectin was first approved for human use as an endectocide in the 1980s. It remains one of the most important global health medicines in history and has recently been shown to exert in vitro activity against SARS-CoV-2. However, the macrocyclic lactone family of compounds has not previously been evaluated for activity against SARS-CoV-2. The present study aims at comparing their anti-viral activity in relevant human pulmonary cell lines in vitro. Here, in vitro antiviral activity of the avermectins (ivermectin and selamectin) and milbemycins (moxidectin and milbemycin oxime) were assessed against a clinical isolate from a CHU Montpellier patient infected with SARS-CoV-2 in 2020. Ivermectin, like the other macrocyclic lactones moxidectin, milbemycin oxime and selamectin, reduced SARS-CoV-2 replication in vitro (EC50 of 2–5 μM). Immunofluorescence assays with ivermectin and moxidectin showed a reduction in the number of infected and polynuclear cells, suggesting a drug action on viral cell fusion. However, cellular toxicity of the avermectins and milbemycins during infection showed a very low selectivity index of <10. Thus, none of these agents appears suitable for human use for its anti-SARS-CoV-2 activity per se, due to low selectivity index.

2019 ◽  
Author(s):  
Wouter van Mol ◽  
Nathalie De Wilde ◽  
Stijn Casaert ◽  
Zhenzhen Chen ◽  
Marieke Vanhecke ◽  
...  

Abstract Background Psoroptic mange is an important disease in beef cattle, and Belgian Blue cattle are particularly susceptible. Treatment failure of macrocyclic lactones against Psoroptes ovis has been reported, but clear evidence of in vivo resistance is still lacking. This study was conducted to investigate ML efficacy in 16 beef farms in Belgium and The Netherlands in vivo and in vitro.Methods On each farm a group of animals (n= 7-14) with clinical psoroptic mange was treated with two subcutaneous injections of a macrocyclic lactone with 7-10 days interval (15 farms) or a single injection with a long-acting macrocyclic lactone (1 farm). In vivo efficacy was assessed by the reduction in mite counts and clinical index (part of the body affected by lesions), the cure rate after the first treatment round and the number of treatment rounds needed to cure all animals. In vitro knock-down and mortality was evaluated in a contact test.Results Cure rates after the first treatment round varied from 0-80%. All farms needed two or more rounds of treatments to obtain full efficacy. Clinical index had a high variation and only started to reduce after the second treatment round. Only three farms were categorized as susceptible with a mean mite count reduction>95% and a lower limit of the uncertainty interval>90%. One farm had a mean reduction>95%, but its lower limit of the confidence interval was <90%. All other farms had mean reductions<95% and lower limits of their uncertainty intervals<90%. No correlation was found between in vitro lethal dose 50 and knock-down dose 50 values and any parameter of in vivo efficacy.Conclusion Unambiguous treatment failure was detected on 12/16 beef farms, confirming the presence of macrocyclic lactone resistance in Belgian Blue beef farms. In vitro parameters could not discriminate the farms based on their in vivo susceptibility. The mean reduction in mite counts and the lower limit of the confidence interval stood out as most useful parameter to identify acaricide resistance.


2020 ◽  
Author(s):  
Wouter van Mol ◽  
Nathalie De Wilde ◽  
Stijn Casaert ◽  
Zhenzhen Chen ◽  
Marieke Vanhecke ◽  
...  

Abstract Background Psoroptic mange is an important disease in Belgian Blue cattle. Treatment failure of macrocyclic lactones against Psoroptes ovis has been reported, but clear evidence of in vivo resistance is lacking. This study assessed the efficacy of macrocyclic lactone products on 16 beef farms in Belgium and the Netherlands in vivo and in vitro . Methods On each farm a group of animals ( n = 7–14) with psoroptic mange was treated with two subcutaneous injections of a macrocyclic lactone product with 7–10 days interval (15 farms) or a single injection with a long-acting macrocyclic lactone (1 farm). In vivo efficacy was assessed by the reduction in mite counts, clinical index (proportion of the body surface affected by lesions), the proportion of the animals with negative mite counts after the first treatment round and the number of treatment rounds needed to obtain zero mites counts in all animals. A mite population was categorized as sensitive when the mite count reduction after the first treatment round > 95% and the lower limit of the uncertainty interval > 90%. Resistance was detected when both parameters were below their threshold and suspected when one parameter was too low. In vitro knockdown and mortality were evaluated in a contact test. Results The proportion of the animals with negative mite counts after the first treatment round varied from 0 to 80%. All farms needed two or more treatments rounds to obtain zero mite counts on all animals. Clinical index only started to reduce after the second treatment round. Mite populations from three farms were categorized as sensitive, one as suspected resistant and 12 as resistant. No correlation was found between in vitro lethal dose 50 and knockdown dose 50 values and in vivo efficacy parameters. Conclusions Unambiguous treatment failure was detected on 12 out of 16 farms, confirming the presence of macrocyclic lactone resistance on Belgian Blue beef farms. In vitro parameters could not discriminate the farms based on their in vivo sensitivity. The mean reduction in mite counts and the lower limit of the confidence interval are proposed as parameters to identify acaricide resistance.


2020 ◽  
Author(s):  
Wouter van Mol ◽  
Nathalie De Wilde ◽  
Stijn Casaert ◽  
Zhenzhen Chen ◽  
Marieke Vanhecke ◽  
...  

Abstract Background Psoroptic mange is an important disease in beef cattle, and Belgian Blue cattle are particularly susceptible. Treatment failure of macrocyclic lactones against Psoroptes ovis has been reported, but clear evidence of in vivo resistance is still lacking. This study was conducted to investigate the efficacy of macrocyclic lactone products in 16 beef farms in Belgium and The Netherlands in vivo and in vitro . Methods On each farm a group of animals (n= 7-14) with psoroptic mange was treated with two subcutaneous injections of a macrocyclic lactone product with 7-10 days interval (15 farms) or a single injection with a long-acting macrocyclic lactone (1 farm). In vivo efficacy was assessed by the reduction in mite counts and clinical index (estimated proportion of the body surface affected by lesions), the proportion of the animals with negative mite counts after the first treatment round and the number of treatment rounds needed to obtain zero mites counts in all animals. A mite population from a given farm was categorized as sensitive when the mite count reduction after the first treatment round >95% and the lower limit of the uncertainty interval >90%. Resistance was detected when both parameters were below the threshold. Resistance was suspected when only one was below its threshold. In vitro knock-down and mortality was evaluated in a contact test. Results The proportion of the animals with negative mite counts after the first treatment round varied from 0-80%. All farms needed two or more rounds of treatments to obtain zero mite counts on all animals. Clinical index had a high variation and only started to reduce after the second treatment round. Mite populations from three farms were categorized as sensitive, one as suspected resistant and the other 12 as resistant. No correlation was found between in vitro lethal dose 50 and knock-down dose 50 values and any parameter of in vivo efficacy. Conclusions Unambiguous treatment failure was detected on 12/16 beef farms, confirming the presence of macrocyclic lactone resistance on Belgian Blue beef farms. In vitro parameters could not discriminate the farms based on their in vivo sensitivity. The mean reduction in mite counts and the lower limit of the confidence interval are proposed as most useful parameters to identify acaricide resistance.


1998 ◽  
Vol 42 (3) ◽  
pp. 682-686 ◽  
Author(s):  
Shaun R. Hawley ◽  
Patrick G. Bray ◽  
Mathirut Mungthin ◽  
Jill D. Atkinson ◽  
Paul M. O’Neill ◽  
...  

ABSTRACT We have investigated the contribution of drug accumulation and inhibition of heme polymerization to the in vitro activities of a series of antimalarial drugs. Only those compounds exhibiting structural relatedness to the quinolines inhibited heme polymerization. We could find no direct correlation between in vitro activity against chloroquine-susceptible or chloroquine-resistant isolates and either inhibition of heme polymerization or cellular drug accumulation for the drugs studied. However, in vitro activity against a chloroquine-susceptible isolate but not a chloroquine-resistant isolate showed a significant correlation with inhibition of heme polymerization when the activity was normalized for the extent of drug accumulation. The importance of these observations to the rational design of new quinoline-type drugs and the level of agreement of these conclusions with current views on quinoline drug action and resistance are discussed.


Planta Medica ◽  
2017 ◽  
Vol 83 (14/15) ◽  
pp. 1214-1226 ◽  
Author(s):  
Hippolyt Greve ◽  
Marcel Kaiser ◽  
Reto Brun ◽  
Thomas Schmidt

AbstractIn the course of our ongoing search for new natural products as leads against protozoal diseases, the dichloromethane extract of Indian frankincense, the oleo-gum-resin obtained from Boswellia serrata, showed in vitro activity against Plasmodium falciparum. Bioactivity-guided fractionation led to the isolation of eight diterpenes: (1S,3E,7E,11R)-verticilla-3,7,12(18)-triene (1), cembrene A (2), serratol (3), 1S,3E,7R,8R,11E-7,8-epoxy-cembra-3,11-dien-1-ol (4), incensole oxide (5), rel (1S,3R,7E,11S,12R)-1,12-epoxy-4-methylenecembr-7-ene-3, 11-diol (6), isoincensole oxide (7), and isodecaryiol (8). Furthermore, 10 triterpenes, namely, oleanolic acid (9), 11-keto-β-boswellic acid (10), 3-epi-neoilexonol (11), uvaol (12), β-boswellic aldehyde (13), 5α-tirucalla-8,24-dien-3α-ol (14), isoflindissone lactone (15), isoflindissol lactone (16), rel (8R,9S,20R)-tirucall-24-ene-3β,20-diol (17), and rel (3α,8R, 9S,20R,24S)-20,24-epoxytirucalla-3,25-diol (18) as well as the sesquiterpene β-bourbonene (19), the monoterpene carvacrol (20) and the phenyl propanoids methyleugenol (21), and p-methoxycinnamaldehyde (22) were isolated. All compounds were identified by mass spectrometry and nuclear magnetic resonance spectroscopic measurements. Compounds 6, 11, and 16–18 are described for the first time. Compounds 13 – 15 are isolated as natural products for the first time, compound 8 for the first time from a plant. Antiplasmodial IC50 values and cytotoxicity against L6 rat skeletal myoblasts were determined. Isoflindissone lactone (15) was the most active compound with an IC50 of 2.2 µM against P. falciparum and a selectivity index of 18.


Planta Medica ◽  
2012 ◽  
Vol 78 (05) ◽  
Author(s):  
A Husni ◽  
S Ross ◽  
O Dale ◽  
C Gemelli ◽  
G Ma ◽  
...  

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