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1.
Medicina (Kaunas) ; 57(10)2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34684095

RESUMO

Urogenital schistosomiasis is caused by Schistosoma haematobium (S. haematobium) infection, which has been linked to the development of bladder cancer. In this study, three repurposing drugs, ivermectin, arteether and praziquantel, were screened to find the potent drug-repurposing candidate against the Schistosoma-associated bladder cancer (SABC) in humans by using computational methods. The biology of most glutathione S-transferases (GSTs) proteins and vascular endothelial growth factor (VEGF) is complex and multifaceted, according to recent evidence, and these proteins actively participate in many tumorigenic processes such as cell proliferation, cell survival and drug resistance. The VEGF and GSTs are now widely acknowledged as an important target for antitumor therapy. Thus, in this present study, ivermectin displayed promising inhibition of bladder cancer cells via targeting VEGF and GSTs signaling. Moreover, molecular docking and molecular dynamics (MD) simulation analysis revealed that ivermectin efficiently targeted the binding pockets of VEGF receptor proteins and possessed stable dynamics behavior at binding sites. Therefore, we proposed here that these compounds must be tested experimentally against VEGF and GST signaling in order to control SABC. Our study lies within the idea of discovering repurposing drugs as inhibitors against the different types of human cancers by targeting essential pathways in order to accelerate the drug development cycle.


Assuntos
Preparações Farmacêuticas , Neoplasias da Bexiga Urinária , Animais , Reposicionamento de Medicamentos , Humanos , Ivermectina/farmacologia , Simulação de Acoplamento Molecular , Schistosoma haematobium , Neoplasias da Bexiga Urinária/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular
2.
Viruses ; 13(10)2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34696514

RESUMO

Nuclear transport and vesicle trafficking are key cellular functions involved in the pathogenesis of RNA viruses. Among other pleiotropic effects on virus-infected host cells, ivermectin (IVM) inhibits nuclear transport mechanisms mediated by importins and atorvastatin (ATV) affects actin cytoskeleton-dependent trafficking controlled by Rho GTPases signaling. In this work, we first analyzed the response to infection in nasopharyngeal swabs from SARS-CoV-2-positive and -negative patients by assessing the gene expression of the respective host cell drug targets importins and Rho GTPases. COVID-19 patients showed alterations in KPNA3, KPNA5, KPNA7, KPNB1, RHOA, and CDC42 expression compared with non-COVID-19 patients. An in vitro model of infection with Poly(I:C), a synthetic analog of viral double-stranded RNA, triggered NF-κB activation, an effect that was halted by IVM and ATV treatment. Importin and Rho GTPases gene expression was also impaired by these drugs. Furthermore, through confocal microscopy, we analyzed the effects of IVM and ATV on nuclear to cytoplasmic importin α distribution, alone or in combination. Results showed a significant inhibition of importin α nuclear accumulation under IVM and ATV treatments. These findings confirm transcriptional alterations in importins and Rho GTPases upon SARS-CoV-2 infection and point to IVM and ATV as valid drugs to impair nuclear localization of importin α when used at clinically-relevant concentrations.


Assuntos
Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Atorvastatina/farmacologia , COVID-19/tratamento farmacológico , Ivermectina/farmacologia , SARS-CoV-2/efeitos dos fármacos , alfa Carioferinas/metabolismo , Células A549 , Citoesqueleto de Actina/efeitos dos fármacos , Animais , Antivirais/farmacologia , Linhagem Celular Tumoral , Chlorocebus aethiops , Reposicionamento de Medicamentos , Células HeLa , Humanos , NF-kappa B/metabolismo , Células Vero , Proteínas rho de Ligação ao GTP/metabolismo
3.
Trop Anim Health Prod ; 53(5): 460, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34542704

RESUMO

The chemical-based tick management method is gradually losing its clutch due to the establishment of resistant ticks. For development of region-specific tick management strategies, the present study was aimed to evaluate the comparative resistance profile of Rhipicephalus microplus isolates collected from seven districts of Uttar Pradesh, a northern state of India. Comparative analysis of the dose-response data using adult immersion test (AIT) against coumaphos, malathion, deltamethrin, ivermectin, and fipronil revealed that all the isolates were resistant to discriminating concentration of deltamethrin having LC50 of 295.12-436.52 ppm with a resistance ratio of 22.02-32.58. An emerging low level of ivermectin resistance (resistance ratio, RR50 = 1.03-2.26) with LC50 in the range of 22.39-48.98 ppm was found across the isolates. The coumaphos was highly effective against all except Amethi (AMT) isolate. Similarly, malathion was efficacious against most of the isolates except Pratapgarh (PRT) and Sultanpur (SUL) isolates showing LC50 of 5128.61 and 5623.41 ppm, respectively. All the isolates were responsive to fipronil. Comparative detoxifying enzymes profiles revealed a significant correlation between the increased activity of esterase and deltamethrin resistance. The GST activity was 51.2% correlated with RR50 of malathion while esterase activity was significantly correlated (68.9%) with RR50 of coumaphos. No correlation between the ivermectin resistance and enzyme activity was established. Multiple sequence analysis of S4-5 linker region of the sodium channel gene of all the isolates revealed a point mutation at 190th position (C190A) which is associated with deltamethrin resistance. The possible tick management strategies in this part of the country are discussed.


Assuntos
Acaricidas , Piretrinas , Rhipicephalus , Acaricidas/farmacologia , Animais , Cumafos , Índia , Resistência a Inseticidas , Ivermectina/farmacologia , Malation/farmacologia , Nitrilas , Pirazóis , Piretrinas/farmacologia
4.
Ticks Tick Borne Dis ; 12(6): 101818, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34537543

RESUMO

Rhipicephalus microplus is posing a serious threat to productive animal husbandry. Excessive use of synthetic chemicals in tick management has led to the development of resistant tick populations. Characterization of resistance to deltamethrin, cypermethrin, coumaphos and ivermectin in ticks is necessary to develop a suitable and sustainable control strategy. Based on adult immersion test and larval packet test, the resistance ratios (RR50) for adults and larvae of R. microplus populations from two Indian states ranged from 3.8 to 19.4 and 1.35-25.0 against deltamethrin, 0.061-26.3 and 0.22-19.2 against cypermethrin, and 0.2-9.5 and 0.01-3.1 against coumaphos, respectively, were recorded. Moreover, the RR50 for adults ranged from 0.212 to 3.87 against ivermectin. The RR50 for different acaricides was significantly (p<0.01) correlated with esterases, Glutathione S-transferase and monooxygenase activity. A point mutation at the 190th position of the domain II S4-5 linker region of the sodium channel gene in synthetic pyrethroids (SP) resistant populations was also detected. An antitick natural formulation prepared from the plant Azeratum conyzoides and containing two major compounds, Precocene-I (7­methoxy-2, 2-dimethyl 2H-chromene) and Precocene II (6, 7-dimethoxy-2, 2-dimethyl- 3-chromene), was developed and tested against the resistant ticks. The LC50 values of the natural formulation against the resistant populations were in the range of 4.31-5.33% irrespective of their RR50 values. Multi-acaricide resistant populations of R. microplus are established in India and the A. conyzoides based natural formulation can be used for its management.


Assuntos
Acaricidas/farmacologia , Ageratum/química , Rhipicephalus/efeitos dos fármacos , Animais , Cumafos/farmacologia , Resistência a Medicamentos , Feminino , Índia , Ivermectina/farmacologia , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Masculino , Nitrilas/farmacologia , Piretrinas/farmacologia , Rhipicephalus/crescimento & desenvolvimento
5.
Vet Parasitol ; 298: 109535, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34340009

RESUMO

The equine roundworm Parascaris univalens has developed resistance to the three anthelmintic substances most commonly used in horses. The mechanisms responsible for resistance are believed to be multi-genic, and transport proteins such as the P-glycoprotein (Pgp) family have been suggested to be involved in resistance in several parasites including P. univlaens. To facilitate further research into the mechanisms behind drug metabolism and resistance development in P. univalens we aimed to develop an in vitro model based on larvae. We developed a fast and easy protocol for hatching P. univalens larvae for in vitro studies, resulting in a hatching rate of 92 %. The expression of transport protein genes pgp-2, pgp-9, pgp-11.1, pgp-16.1 and major facilitator superfamily (MFS) genes PgR006_g137 and PgR015_g078 were studied in hatched larvae exposed to the anthelmintic drugs ivermecin (IVM) 10-9 M, pyrantel citrate (PYR) 10-6 M and thiabendazole (TBZ) 10-5 M for 24 h. In comparison, the expression of these transport protein genes was studied in the anterior end and intestinal tissues of adult worms in vitro exposed to IVM, TBZ and PYR, at the same concentrations as larvae, for 3 h, 10 h and 24 h. Larval exposure to sub-lethal doses of IVM for 24 h did not affect the expression levels of any of the investigated genes, however larvae exposed to PYR and TBZ for 24 h showed significantly increased expression of pgp-9. In vitro drug exposure of adult worms did not result in any significant increases in expression of transport protein genes. Comparisons of constitutive expression between larvae and adult worm tissues showed that pgp-9, pgp-11.1, pgp-16.1 and MFS gene PgR015_g078 were expressed at lower levels in larvae than in adult tissues, while pgp-2 and MFS gene PgR006_g137 had similar expression levels in larvae and adult worms. All investigated transport protein genes were expressed at higher rates in the intestine than in the anterior end of adult worms, except pgp-11.1 where the expression was similar between the two tissues. This high constitutive expression in the intestine suggests that this is an important site for xenobiotic efflux in P. univalens. Despite the fact that the results of this study show differences in expression of transport protein genes between larvae and adult tissues, we believe that the larval assay system described here will be an important tool for further research into the molecular mechanisms behind anthelmintic resistance development and for other in vitro studies.


Assuntos
Anti-Helmínticos , Ascaridoidea , Proteínas de Transporte , Regulação da Expressão Gênica , Animais , Anti-Helmínticos/farmacologia , Ascaridoidea/efeitos dos fármacos , Ascaridoidea/genética , Proteínas de Transporte/genética , Resistência a Medicamentos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Ivermectina/farmacologia , Larva/efeitos dos fármacos
6.
Vet Parasitol ; 298: 109538, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34364153

RESUMO

In the present study, an anthelmintic treatment regimen with reduced treatment frequency was evaluated in horses on two study sites in Belgium during three consecutive summer pasture seasons. Historically, the horses on both study sites were treated up to 6 times a year with ivermectin (IVM) or up to 4 times a year with moxidectin (MOX), and previous efficacy evaluations indicated a reduced egg reappearance period in some of the treated horses for both IVM (28 days) and MOX (42 days). In the present study, all horses were treated with IVM or MOX in the spring and in autumn. Faecal egg counts (FEC) were conducted every two weeks during the summer pasture season and whenever the individual FEC exceeded 250 eggs per gram of faeces, the specific horse was treated with pyrantel embonate. No increase in parasitic disease over the three-year period of the study was observed. The FEC data collected in the study as well as the age of the animals and local weather data were then imported into a cyathostomin life-cycle model, to evaluate long term effects of the newly applied treatment regimen on the selection pressure for anthelmintic resistance, and compare to the previous high frequency treatment regimen. The model simulations indicated that the whole-herd treatment regimen with at least 4 macrocyclic lactone treatments annually led 2-3 times faster resistance development than any of the alternative treatment regimens evaluated under the specific conditions of these two study sites. Further lowering the treatment frequency or applying even more selective treatments enhanced the delay in resistance development, but to a lesser extent.


Assuntos
Doenças dos Cavalos , Ivermectina , Macrolídeos , Animais , Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/farmacologia , Bélgica/epidemiologia , Resistência a Medicamentos/efeitos dos fármacos , Fezes/parasitologia , Doenças dos Cavalos/tratamento farmacológico , Doenças dos Cavalos/epidemiologia , Doenças dos Cavalos/prevenção & controle , Cavalos , Ivermectina/administração & dosagem , Ivermectina/farmacologia , Macrolídeos/administração & dosagem , Macrolídeos/farmacologia , Óvulo/efeitos dos fármacos , Contagem de Ovos de Parasitas/veterinária
7.
Biophys Chem ; 278: 106677, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34428682

RESUMO

The SARS-CoV-2 pandemic has accelerated the study of existing drugs. The mixture of homologs called ivermectin (avermectin-B1a [HB1a] + avermectin-B1b [HB1b]) has shown antiviral activity against SARS-CoV-2 in vitro. However, there are few reports on the behavior of each homolog. We investigated the interaction of each homolog with promising targets of interest associated with SARS-CoV-2 infection from a biophysical and computational-chemistry perspective using docking and molecular dynamics. We observed a differential behavior for each homolog, with an affinity of HB1b for viral structures, and of HB1a for host structures considered. The induced disturbances were differential and influenced by the hydrophobicity of each homolog and of the binding pockets. We present the first comparative analysis of the potential theoretical inhibitory effect of both avermectins on biomolecules associated with COVID-19, and suggest that ivermectin through its homologs, has a multiobjective behavior.


Assuntos
Antivirais/química , Proteases 3C de Coronavírus/antagonistas & inibidores , DNA Helicases/antagonistas & inibidores , Ivermectina/análogos & derivados , alfa Carioferinas/antagonistas & inibidores , beta Carioferinas/antagonistas & inibidores , Animais , Antivirais/farmacologia , Sítios de Ligação , COVID-19/tratamento farmacológico , COVID-19/virologia , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/metabolismo , DNA Helicases/química , DNA Helicases/metabolismo , Humanos , Ivermectina/química , Ivermectina/farmacologia , Cinética , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , SARS-CoV-2/química , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Termodinâmica , alfa Carioferinas/química , alfa Carioferinas/metabolismo , beta Carioferinas/química , beta Carioferinas/metabolismo
8.
Front Cell Infect Microbiol ; 11: 700502, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34395311

RESUMO

The recent COVID-19 pandemic has highlighted the urgency to develop effective antiviral therapies against the disease. Murine hepatitis virus (MHV) is a coronavirus that infects mice and shares some sequence identity to SARS-CoV-2. Both viruses belong to the Betacoronavirus genus, and MHV thus serves as a useful and safe surrogate model for SARS-CoV-2 infections. Clinical trials have indicated that remdesivir is a potentially promising antiviral drug against COVID-19. Using an in vitro model of MHV infection of RAW264.7 macrophages, the safety and efficacy of monotherapy of remdesivir, chloroquine, ivermectin, and doxycycline were investigated. Of the four drugs tested, remdesivir monotherapy exerted the strongest inhibition of live virus and viral RNA replication of about 2-log10 and 1-log10, respectively (at 6 µM). Ivermectin treatment showed the highest selectivity index. Combination drug therapy was also evaluated using remdesivir (6 µM) together with chloroquine (15 µM), ivermectin (2 µM) or doxycycline (15 µM) - above their IC50 values and at high macrophage cell viability of over 95%. The combination of remdesivir and ivermectin exhibited highly potent synergism by achieving significant reductions of about 7-log10 of live virus and 2.5-log10 of viral RNA in infected macrophages. This combination also resulted in the lowest cytokine levels of IL-6, TNF-α, and leukemia inhibitory factor. The next best synergistic combination was remdesivir with doxycycline, which decreased levels of live virus by ~3-log10 and viral RNA by ~1.5-log10. These results warrant further studies to explore the mechanisms of action of the combination therapy, as well as future in vivo experiments and clinical trials for the treatment of SARS-CoV-2 infection.


Assuntos
COVID-19 , Infecções por Coronavirus , Vírus da Hepatite Murina , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Humanos , Ivermectina/farmacologia , Camundongos , Pandemias , SARS-CoV-2
9.
ACS Appl Mater Interfaces ; 13(33): 39066-39075, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34387079

RESUMO

A controlled release formulation based on silica microcapsules is an ideal selection to improve both the effective utilization and duration of pesticides to decrease ecological damage. Herein, a simple and green method for preparing double-shelled microcapsules was developed using a newly prepared quaternary ammonium ionic liquid (IL) as the functional additive to entrap avermectin (Ave) in mesoporous silica nanospheres (MSNs) and tannic acid-Cu (TA-Cu) complex as the sealing agent to form the core-shell structure (Ave-IL@MSN@TA-Cu). The obtained microcapsules with an average size of 538 nm had pH-responsive release property and good stability in soil. The half-life of microcapsules (34.66 days) was 3 times that of Ave emulsifiable concentrate (EC) (11.55 days) in a test soil, which illustrated that microcapsules could protect Ave from rapid degradation by microorganisms by releasing TA, copper, and quaternary ammonium in the soil. Ave-IL@MSN@TA-Cu microcapsules had better nematicidal activity and antibacterial activity than Ave EC due to the synergistic effect of Ave, IL, and copper incorporated in the microcapsules. Pot experiments showed that the control efficacy of microcapsules was 87.10% against Meloidogyne incognita, which is better than that of Ave EC (41.94%) at the concentration of 1.0 mg/plant by the root-irrigation method after 60 days of treatment owing to the extended duration of Ave in microcapsules. The simple and green method for the preparation of double-shelled microcapsules based on natural quaternary ammonium IL would have tremendous potential for the extensive development of controlled release pesticide formulations.


Assuntos
Cápsulas/química , Preparações de Ação Retardada/química , Controle de Pragas/métodos , Praguicidas/química , Dióxido de Silício/química , Tylenchoidea/efeitos dos fármacos , Animais , Complexos de Coordenação/química , Cobre/química , Preparações de Ação Retardada/farmacologia , Composição de Medicamentos , Liberação Controlada de Fármacos , Química Verde , Concentração de Íons de Hidrogênio , Líquidos Iônicos/química , Ivermectina/análogos & derivados , Ivermectina/química , Ivermectina/farmacologia , Praguicidas/farmacologia , Porosidade , Compostos de Amônio Quaternário/química , Solubilidade , Taninos/química , Fatores de Tempo
10.
Am J Ther ; 28(3): e299-e318, 2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-34375047

RESUMO

BACKGROUND: After COVID-19 emerged on U.S shores, providers began reviewing the emerging basic science, translational, and clinical data to identify potentially effective treatment options. In addition, a multitude of both novel and repurposed therapeutic agents were used empirically and studied within clinical trials. AREAS OF UNCERTAINTY: The majority of trialed agents have failed to provide reproducible, definitive proof of efficacy in reducing the mortality of COVID-19 with the exception of corticosteroids in moderate to severe disease. Recently, evidence has emerged that the oral antiparasitic agent ivermectin exhibits numerous antiviral and anti-inflammatory mechanisms with trial results reporting significant outcome benefits. Given some have not passed peer review, several expert groups including Unitaid/World Health Organization have undertaken a systematic global effort to contact all active trial investigators to rapidly gather the data needed to grade and perform meta-analyses. DATA SOURCES: Data were sourced from published peer-reviewed studies, manuscripts posted to preprint servers, expert meta-analyses, and numerous epidemiological analyses of regions with ivermectin distribution campaigns. THERAPEUTIC ADVANCES: A large majority of randomized and observational controlled trials of ivermectin are reporting repeated, large magnitude improvements in clinical outcomes. Numerous prophylaxis trials demonstrate that regular ivermectin use leads to large reductions in transmission. Multiple, large "natural experiments" occurred in regions that initiated "ivermectin distribution" campaigns followed by tight, reproducible, temporally associated decreases in case counts and case fatality rates compared with nearby regions without such campaigns. CONCLUSIONS: Meta-analyses based on 18 randomized controlled treatment trials of ivermectin in COVID-19 have found large, statistically significant reductions in mortality, time to clinical recovery, and time to viral clearance. Furthermore, results from numerous controlled prophylaxis trials report significantly reduced risks of contracting COVID-19 with the regular use of ivermectin. Finally, the many examples of ivermectin distribution campaigns leading to rapid population-wide decreases in morbidity and mortality indicate that an oral agent effective in all phases of COVID-19 has been identified.


Assuntos
COVID-19 , Ivermectina/farmacologia , SARS-CoV-2/efeitos dos fármacos , Antiparasitários/farmacologia , COVID-19/tratamento farmacológico , COVID-19/prevenção & controle , COVID-19/transmissão , Transmissão de Doença Infecciosa/prevenção & controle , Humanos , Resultado do Tratamento
11.
PLoS Genet ; 17(7): e1009680, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34252082

RESUMO

The evolution of insecticide resistance represents a global constraint to agricultural production. Because of the extreme genetic diversity found in insects and the large numbers of genes involved in insecticide detoxification, better tools are needed to quickly identify and validate the involvement of putative resistance genes for improved monitoring, management, and countering of field-evolved insecticide resistance. The avermectins, emamectin benzoate (EB) and abamectin are relatively new pesticides with reduced environmental risk that target a wide number of insect pests, including the beet armyworm, Spodoptera exigua, an important global pest of many crops. Unfortunately, field resistance to avermectins recently evolved in the beet armyworm, threatening the sustainable use of this class of insecticides. Here, we report a high-quality chromosome-level assembly of the beet armyworm genome and use bulked segregant analysis (BSA) to identify the locus of avermectin resistance, which mapped on 15-16 Mbp of chromosome 17. Knockout of the CYP9A186 gene that maps within this region by CRISPR/Cas9 gene editing fully restored EB susceptibility, implicating this gene in avermectin resistance. Heterologous expression and in vitro functional assays further confirm that a natural substitution (F116V) found in the substrate recognition site 1 (SRS1) of the CYP9A186 protein results in enhanced metabolism of EB and abamectin. Hence, the combined approach of coupling gene editing with BSA allows for the rapid identification of metabolic resistance genes responsible for insecticide resistance, which is critical for effective monitoring and adaptive management of insecticide resistance.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Resistência a Inseticidas/genética , Spodoptera/genética , Animais , Mapeamento Cromossômico/métodos , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Edição de Genes/métodos , Genoma/genética , Inseticidas/farmacologia , Ivermectina/análogos & derivados , Ivermectina/farmacologia , Larva/genética , Spodoptera/metabolismo
12.
Ticks Tick Borne Dis ; 12(6): 101791, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34329928

RESUMO

The multi-host tick, Hyalomma anatolicum is a widely distributed vector of many pathogens of veterinary and public health importance. Ivermectin (IVM), as an alternative to control pyrethroid-resistant ticks, has been used extensively for the past 4-6 years in tropical and sub-tropical countries including India resulting in declining tick control efficacy. The present study used adult immersion test (AIT) to examine the resistance status of H. anatolicum collected from three districts in the Indian state of Gujarat against ivermectin. Probit analysis was used for calculation of concentration-mortality regressions; concentrations required for 50% mortality (LC50) and 95% mortality (LC95), along with confidence intervals; slope of mortality; % inhibition of oviposition; and discriminating concentration (DC). The calculated LC50 and LC95 estimates were utilized to determine resistance ratios (RR50, RR95) and the resistance levels (RL) of the field ticks compared to the susceptible population. The DC (2 x LC95) for IVM was calculated as 84.48 ppm, using susceptible H. anatolicum ticks (KHD). Lower estimates of the coefficient of non-determination (1-R2) for AIT ranged from 0.06 to 0.27, and the range of RR50 and RR95 values against IVM was estimated to be from 1.43 to 52.06 and 1.14 to 71.99, respectively, which indicated a varying degree of resistance among the field tick populations. Based on RR50 values, tick populations from Danta and Palanpur showed resistance level IV and II, respectively. Another four populations (Vadgam, Kankrej, Saraswati and Sidhpur) were classified as having level I resistance status against IVM. To our knowledge, this is the first report of ivermectin resistance in H. anatolicum from Gujarat, India.


Assuntos
Acaricidas/farmacologia , Resistência a Medicamentos , Ivermectina/farmacologia , Ixodidae/efeitos dos fármacos , Animais , Feminino , Índia , Mortalidade
13.
Proteins ; 89(11): 1425-1441, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34169568

RESUMO

The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) still has serious negative effects on health, social life, and economics. Recently, vaccines from various companies have been urgently approved to control SARS-CoV-2 infections. However, any specific antiviral drug has not been confirmed so far for regular treatment. An important target is the main protease (Mpro ), which plays a major role in replication of the virus. In this study, Gaussian and residue network models are employed to reveal two distinct potential allosteric sites on Mpro that can be evaluated as drug targets besides the active site. Then, Food and Drug Administration (FDA)-approved drugs are docked to three distinct sites with flexible docking using AutoDock Vina to identify potential drug candidates. Fourteen best molecule hits for the active site of Mpro are determined. Six of these also exhibit high docking scores for the potential allosteric regions. Full-atom molecular dynamics simulations with MM-GBSA method indicate that compounds docked to active and potential allosteric sites form stable interactions with high binding free energy (∆Gbind ) values. ∆Gbind values reach -52.06 kcal/mol for the active site, -51.08 kcal/mol for the potential allosteric site 1, and - 42.93 kcal/mol for the potential allosteric site 2. Energy decomposition calculations per residue elucidate key binding residues stabilizing the ligands that can further serve to design pharmacophores. This systematic and efficient computational analysis successfully determines ivermectine, diosmin, and selinexor currently subjected to clinical trials, and further proposes bromocriptine, elbasvir as Mpro inhibitor candidates to be evaluated against SARS-CoV-2 infections.


Assuntos
Antivirais/metabolismo , Benzofuranos/química , Proteases 3C de Coronavírus/metabolismo , Reposicionamento de Medicamentos/métodos , Imidazóis/química , Sítio Alostérico , Antivirais/química , Antivirais/farmacologia , Benzofuranos/metabolismo , Benzofuranos/farmacologia , Sítios de Ligação , Bromocriptina/química , Bromocriptina/metabolismo , Bromocriptina/farmacologia , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/química , Diosmina/química , Diosmina/metabolismo , Hidrazinas/química , Hidrazinas/metabolismo , Hidrazinas/farmacologia , Imidazóis/metabolismo , Imidazóis/farmacologia , Ivermectina/química , Ivermectina/metabolismo , Ivermectina/farmacologia , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Triazóis/química , Triazóis/metabolismo , Triazóis/farmacologia , Estados Unidos , United States Food and Drug Administration
14.
SAR QSAR Environ Res ; 32(7): 541-571, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34157880

RESUMO

Avermectins have been effectively used in medicine, veterinary medicine, and agriculture as antiparasitic agents for many years. However, there are still no reliable data on the main ecotoxicological characteristics of most individual avermectins. Although many QSAR models have been proposed to describe the acute toxicity of organic compounds towards Tetrahymena pyriformis (T. pyriformis), avermectins are outside the applicability domain of these models. The influence of the molecular structures of various organic compounds on the acute toxicity towards T. pyriformis was studied using the OCHEM web platform (https://ochem.eu). A data set of 1792 toxicants was used to create models. The QSAR (Quantitative Structure-Activity Relationship) models were developed using the molecular descriptors Dragon, ISIDA, CDK, PyDescriptor, alvaDesc, and SIRMS and machine learning methods, such as Least Squares Support Vector Machine and Transformer Convolutional Neural Network. The HYBOT descriptors and Random Forest were used for a comparative QSAR investigation. Since the best predictive ability was demonstrated by the Transformer Convolutional Neural Network model, it was used to predict the toxicity of individual avermectins towards T. pyriformis. During a structural interpretation of the developed QSAR model, we determined the significant molecular transformations that increase and decrease the acute toxicity of organic compounds.


Assuntos
Antiprotozoários/farmacologia , Ivermectina/análogos & derivados , Relação Quantitativa Estrutura-Atividade , Tetrahymena pyriformis/efeitos dos fármacos , Antiprotozoários/química , Bases de Dados de Compostos Químicos , Ivermectina/química , Ivermectina/farmacologia , Testes de Toxicidade Aguda
15.
Am J Ther ; 28(4): e434-e460, 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34145166

RESUMO

BACKGROUND: Repurposed medicines may have a role against the SARS-CoV-2 virus. The antiparasitic ivermectin, with antiviral and anti-inflammatory properties, has now been tested in numerous clinical trials. AREAS OF UNCERTAINTY: We assessed the efficacy of ivermectin treatment in reducing mortality, in secondary outcomes, and in chemoprophylaxis, among people with, or at high risk of, COVID-19 infection. DATA SOURCES: We searched bibliographic databases up to April 25, 2021. Two review authors sifted for studies, extracted data, and assessed risk of bias. Meta-analyses were conducted and certainty of the evidence was assessed using the GRADE approach and additionally in trial sequential analyses for mortality. Twenty-four randomized controlled trials involving 3406 participants met review inclusion. THERAPEUTIC ADVANCES: Meta-analysis of 15 trials found that ivermectin reduced risk of death compared with no ivermectin (average risk ratio 0.38, 95% confidence interval 0.19-0.73; n = 2438; I2 = 49%; moderate-certainty evidence). This result was confirmed in a trial sequential analysis using the same DerSimonian-Laird method that underpinned the unadjusted analysis. This was also robust against a trial sequential analysis using the Biggerstaff-Tweedie method. Low-certainty evidence found that ivermectin prophylaxis reduced COVID-19 infection by an average 86% (95% confidence interval 79%-91%). Secondary outcomes provided less certain evidence. Low-certainty evidence suggested that there may be no benefit with ivermectin for "need for mechanical ventilation," whereas effect estimates for "improvement" and "deterioration" clearly favored ivermectin use. Severe adverse events were rare among treatment trials and evidence of no difference was assessed as low certainty. Evidence on other secondary outcomes was very low certainty. CONCLUSIONS: Moderate-certainty evidence finds that large reductions in COVID-19 deaths are possible using ivermectin. Using ivermectin early in the clinical course may reduce numbers progressing to severe disease. The apparent safety and low cost suggest that ivermectin is likely to have a significant impact on the SARS-CoV-2 pandemic globally.


Assuntos
COVID-19 , Ivermectina/farmacologia , Antivirais/farmacologia , COVID-19/tratamento farmacológico , COVID-19/prevenção & controle , Humanos , SARS-CoV-2 , Resultado do Tratamento
17.
Mol Med Rep ; 24(1)2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33955514

RESUMO

A hypertrophic scar (HPS) is characterized by abnormal cell proliferation and the overproduction of extracellular matrix. Currently, the treatment options available for this remain unsatisfactory. Innovative treatments are required to attenuate or prevent hypertrophic scarring and the present study searched for a drug capable of becoming a new preventative and therapeutic strategy. Although the underlying mechanisms have not been fully clarified; it is widely accepted that the TGF­ß1/SMAD3 signaling pathway serves an essential role in HPS formation. In the present study, a compound library consisting of clinically used drugs was screened for their inhibitory activity against the SMAD3 protein. The results indicated that ivermectin was able to suppress the phosphorylation of SMAD3. Therefore, the present study further investigated whether ivermectin exhibited antifibrotic effects on HPS fibroblasts. The results demonstrated that ivermectin inhibited the proliferation of HPS fibroblasts and significantly decreased the production of type I collagen, α­smooth muscle actin and cellular communication network factor 2, as determined by analyzing the mRNA and protein expression levels. In conclusion, the results of the present study suggested that ivermectin may be a promising therapeutic agent for HPS.


Assuntos
Actinas/metabolismo , Cicatriz Hipertrófica/tratamento farmacológico , Cicatriz Hipertrófica/metabolismo , Colágeno Tipo I/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Fibroblastos/metabolismo , Ivermectina/farmacologia , Actinas/genética , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colágeno Tipo I/genética , Fator de Crescimento do Tecido Conjuntivo/genética , Regulação para Baixo/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Humanos , Masculino , Camundongos , Cultura Primária de Células , Proteína Smad3/antagonistas & inibidores , Proteína Smad3/metabolismo
18.
Arch Virol ; 166(7): 2005-2010, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33987753

RESUMO

We show that ivermectin, an FDA-approved anti-parasitic drug, effectively inhibits infection with hepatitis E virus (HEV) genotypes 1 and 3 in a range of cell culture models, including hepatic and extrahepatic cells. Long-term treatment showed no clear evidence of the development of drug resistance. Gene silencing of importin-α1, a cellular target of ivermectin and a key member of the host nuclear transport complex, inhibited viral replication and largely abolished the anti-HEV effect of ivermectin.


Assuntos
Vírus da Hepatite E/efeitos dos fármacos , Hepatite E/tratamento farmacológico , Ivermectina/farmacologia , Replicação Viral/efeitos dos fármacos , alfa Carioferinas/metabolismo , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Núcleo Celular/virologia , Hepatite E/metabolismo , Hepatite E/virologia , Humanos , Proteínas Nucleares/metabolismo
19.
Parasitol Res ; 120(7): 2641-2658, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33945012

RESUMO

Ivermectin (IVM) is one of the competitive treatments used for trichinellosis. However, several studies linked its efficacy with early diagnosis and administration to tackle the intestinal phase with limited activity being recorded against encysted larvae. The aim of this study was to employ niosomes for enhancing effectiveness of oral IVM against different stages of Trichinella spiralis (T. spiralis) infection with reference to nano-crystalline IVM. Mice were randomized into four groups: group Ι, 15 uninfected controls; group ΙΙ, 30 infected untreated controls; group ΙΙΙ, 30 infected nano-crystalline IVM treated, and group ΙV, 30 infected niosomal IVM treated. All groups were equally subdivided into 3 subgroups; (a) treated on the 1st day post infection (dpi), (b) treated on the 10th dpi, and (c) treated on the 30th dpi. Assessment was done by counting adult worms and larvae plus histopathological examination of jejunum and diaphragm. Biochemical assessment of oxidant/antioxidant status, angiogenic, and inflammatory biomarkers in intestinal and muscle tissues was also performed. Both niosomes and nano-crystals resulted in significant reduction in adult and larval counts compared to the infected untreated control with superior activity of niosomal IVM. The superiority of niosomes was expressed further by reduction of inflammation in both jejunal and muscle homogenates. Biochemical parameters showed highly significant differences in all treated mice compared to infected untreated control at different stages with highly significant effect of niosomal IVM. In conclusion, niosomal IVM efficacy exceeded the nano-crystalline IVM in treatment of different phases of trichinellosis.


Assuntos
Antiparasitários/administração & dosagem , Ivermectina/administração & dosagem , Trichinella spiralis/efeitos dos fármacos , Triquinelose/tratamento farmacológico , Animais , Antiparasitários/farmacocinética , Antiparasitários/uso terapêutico , Cromatografia Líquida de Alta Pressão , Diafragma , Inflamação/patologia , Ivermectina/farmacologia , Ivermectina/uso terapêutico , Jejuno/patologia , Larva/efeitos dos fármacos , Lipossomos , Masculino , Camundongos , Nanopartículas , Distribuição Aleatória , Trichinella spiralis/fisiologia , Triquinelose/diagnóstico , Zoonoses
20.
Vet Parasitol ; 293: 109430, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33901932

RESUMO

Ectoparasite infestations are not common in degus. Two cases are presented here where use of Stronghold® Plus/Revolution® Plus (selamectin and sarolaner topical solution) was successfully administered to a degu (Octodon degus) for treatment of naturally-occurring mite infesations. Selamectin (Stronghold®/Revolution®) has been demonstrated to be effective against naturally-occurring mite infections in dogs and selamectin is approved for use in dogs for the treatment of sarcoptic mange (caused by Sarcoptes scabiei) at a dose of 6 mg/kg. In the first case, a 2.6-years-old female degu housed in a group with four other degus was presented with pruritic skin reactions, restlessness and hairloss. Mites morphologically similar to Demodex sp. were detected in the deep skin scrapings. All four degus were treated with Stronghold® Plus/Revolution® Plus (30 mg/kg selamectin and 5 mg/kg sarolaner) once a week for a total of six treatments. The spot-on was administered topically on the dorsal cervical region. Following treatment the degu presenting with clinical signs showed a rapid improvement with the pruritus and overall dermatitis resolving within 2 weeks of treatment. Skin scrapes and microscopic examination of epidermal debris collected from the affected degu were negative for mites from day 14 onwards. In the second case, a group of four 4-6.5-years-old female and male degus that were housed together were infested with Ornithonyssus bacoti. All animals were treated with 30 mg/kg selamectin and 5 mg/kg sarolaner in four total weekly doses. One week later no living mites were found on the patients or in their environment. The four degus improved visibly, and within three weeks of treatment the skin lesions associated with the infestation subsided. The antiparasiticides showed a satisfactory efficacy and were well tolerated (n = 9 animals treated in a total).


Assuntos
Azetidinas , Ivermectina/análogos & derivados , Infestações por Ácaros , Octodon , Doenças dos Roedores , Compostos de Espiro , Administração Tópica , Animais , Antiparasitários/farmacologia , Antiparasitários/uso terapêutico , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Feminino , Ivermectina/farmacologia , Ivermectina/uso terapêutico , Masculino , Infestações por Ácaros/tratamento farmacológico , Infestações por Ácaros/veterinária , Ácaros/efeitos dos fármacos , Octodon/parasitologia , Doenças dos Roedores/tratamento farmacológico , Compostos de Espiro/farmacologia , Compostos de Espiro/uso terapêutico , Resultado do Tratamento
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