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1.
Sci Rep ; 10(1): 17073, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-33051517

RESUMO

Ivermectin is a widely used antiparasitic drug with known efficacy against several single-strain RNA viruses. Recent data shows significant reduction of SARS-CoV-2 replication in vitro by ivermectin concentrations not achievable with safe doses orally. Inhaled therapy has been used with success for other antiparasitics. An ethanol-based ivermectin formulation was administered once to 14 rats using a nebulizer capable of delivering particles with alveolar deposition. Rats were randomly assigned into three target dosing groups, lower dose (80-90 mg/kg), higher dose (110-140 mg/kg) or ethanol vehicle only. A toxicology profile including behavioral and weight monitoring, full blood count, biochemistry, necropsy and histological examination of the lungs was conducted. The pharmacokinetic profile of ivermectin in plasma and lungs was determined in all animals. There were no relevant changes in behavior or body weight. There was a delayed elevation in muscle enzymes compatible with rhabdomyolysis, that was also seen in the control group and has been attributed to the ethanol dose which was up to 11 g/kg in some animals. There were no histological anomalies in the lungs of any rat. Male animals received a higher ivermectin dose adjusted by adipose weight and reached higher plasma concentrations than females in the same dosing group (mean Cmax 86.2 ng/ml vs. 26.2 ng/ml in the lower dose group and 152 ng/ml vs. 51.8 ng/ml in the higher dose group). All subjects had detectable ivermectin concentrations in the lungs at seven days post intervention, up to 524.3 ng/g for high-dose male and 27.3 ng/g for low-dose females. nebulized ivermectin can reach pharmacodynamic concentrations in the lung tissue of rats, additional experiments are required to assess the safety of this formulation in larger animals.


Assuntos
Antiparasitários/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Ivermectina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Administração por Inalação , Animais , Antiparasitários/farmacocinética , Antiparasitários/farmacologia , Comportamento Animal/efeitos dos fármacos , Infecções por Coronavirus/patologia , Relação Dose-Resposta a Droga , Feminino , Meia-Vida , Ivermectina/farmacocinética , Ivermectina/farmacologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Necrose , Pandemias , Pneumonia Viral/patologia , Estudo de Prova de Conceito , Ratos , Ratos Sprague-Dawley , Transtornos Respiratórios/tratamento farmacológico , Transtornos Respiratórios/patologia
3.
Exp Parasitol ; 218: 107998, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32941889

RESUMO

The aims of this study were to evaluate the efficacy of two injectable formulations of doramectin (DRM) against Psoroptes ovis in sheep infested under controlled experimental conditions and to characterize the DRM plasma disposition kinetics in the infested animals. To this end, sheep were experimentally infested with a P. ovis strain from a farm with a history of treatment failure, and then treated either with DRM 1% (traditional preparation) on days 0 and 7 or with DRM 3.15% (long-acting formulation) on day 0. The efficacy of each treatment was calculated by counting live mites in skin scrapings. Plasma samples were obtained from each animal and DRM concentrations were measured by HPLC. After the two doses of DRM 1%, the maximum efficacy (98.8%) was reached on day 28, whereas after the single dose of DRM 3.15%, the maximum efficacy (100%) was reached on day 35 and ratified on day 42. The long-acting formulation allowed obtaining higher exposure and more sustained concentrations of DRM than the traditional preparation. Although both DRM formulations studied were effective according to international protocols, they did not reach 100% effectiveness in the time required for approved pharmaceutical products against sheep scab, according to Argentine regulations.


Assuntos
Inseticidas/uso terapêutico , Ivermectina/análogos & derivados , Infestações por Ácaros/veterinária , Psoroptidae/efeitos dos fármacos , Doenças dos Ovinos/tratamento farmacológico , Animais , Disponibilidade Biológica , Feminino , Meia-Vida , Injeções Subcutâneas/veterinária , Inseticidas/administração & dosagem , Inseticidas/sangue , Inseticidas/farmacologia , Ivermectina/administração & dosagem , Ivermectina/sangue , Ivermectina/farmacologia , Ivermectina/uso terapêutico , Masculino , Infestações por Ácaros/tratamento farmacológico , Psoroptidae/crescimento & desenvolvimento , Ovinos , Doenças dos Ovinos/parasitologia
4.
Cells ; 9(9)2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32942671

RESUMO

The small molecule macrocyclic lactone ivermectin, approved by the US Food and Drug Administration for parasitic infections, has received renewed attention in the last eight years due to its apparent exciting potential as an antiviral. It was identified in a high-throughput chemical screen as inhibiting recognition of the nuclear localizing Human Immunodeficiency Virus-1 (HIV-1) integrase protein by the host heterodimeric importin (IMP) α/ß1 complex, and has since been shown to bind directly to IMPα to induce conformational changes that prevent its normal function in mediating nuclear import of key viral and host proteins. Excitingly, cell culture experiments show robust antiviral action towards HIV-1, dengue virus (DENV), Zika virus, West Nile virus, Venezuelan equine encephalitis virus, Chikungunya virus, Pseudorabies virus, adenovirus, and SARS-CoV-2 (COVID-19). Phase III human clinical trials have been completed for DENV, with >50 trials currently in progress worldwide for SARS-CoV-2. This mini-review discusses the case for ivermectin as a host-directed broad-spectrum antiviral agent for a range of viruses, including SARS-CoV-2.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , HIV-1/efeitos dos fármacos , Ivermectina/farmacologia , Pneumonia Viral/tratamento farmacológico , Animais , Linhagem Celular , Chlorocebus aethiops , Dengue/tratamento farmacológico , Vírus da Dengue/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Integrase de HIV/efeitos dos fármacos , Inibidores de Integrase de HIV/farmacologia , Humanos , Pandemias , Células Vero , Zika virus/efeitos dos fármacos , Infecção por Zika virus/tratamento farmacológico
5.
Biomolecules ; 10(9)2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32967116

RESUMO

We report the results of our in silico study of approved drugs as potential treatments for COVID-19. The study is based on the analysis of normal modes of proteins. The drugs studied include chloroquine, ivermectin, remdesivir, sofosbuvir, boceprevir, and α-difluoromethylornithine (DMFO). We applied the tools we developed and standard tools used in the structural biology community. Our results indicate that small molecules selectively bind to stable, kinetically active residues and residues adjoining them on the surface of proteins and inside protein pockets, and that some prefer hydrophobic sites over other active sites. Our approach is not restricted to viruses and can facilitate rational drug design, as well as improve our understanding of molecular interactions, in general.


Assuntos
Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Pandemias , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/química , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/química , Alanina/farmacologia , Anticorpos Antivirais/imunologia , Reações Antígeno-Anticorpo , Antivirais/química , Antivirais/uso terapêutico , Betacoronavirus , Sítios de Ligação , Cloroquina/química , Cloroquina/farmacologia , Infecções por Coronavirus/prevenção & controle , Reposicionamento de Medicamentos , Eflornitina/química , Eflornitina/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ivermectina/química , Ivermectina/farmacologia , L-Lactato Desidrogenase/química , L-Lactato Desidrogenase/efeitos dos fármacos , Modelos Moleculares , Simulação de Acoplamento Molecular , Pandemias/prevenção & controle , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/efeitos dos fármacos , Pneumonia Viral/prevenção & controle , Prolina/análogos & derivados , Prolina/química , Prolina/farmacologia , Ligação Proteica , Conformação Proteica , Mapeamento de Interação de Proteínas , Receptores da Glicina/química , Receptores da Glicina/efeitos dos fármacos , Saposinas/química , Saposinas/efeitos dos fármacos , Sofosbuvir/química , Sofosbuvir/farmacologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/efeitos dos fármacos , Relação Estrutura-Atividade
6.
Int J Biol Macromol ; 163: 1787-1797, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32950529

RESUMO

The pandemic prevalence of COVID-19 has become a very serious global health issue. Scientists all over the world have been seriously attempting in the discovery of a drug to combat SARS-CoV-2. It has been found that RNA-dependent RNA polymerase (RdRp) plays a crucial role in SARS-CoV-2 replication, and thus could be a potential drug target. Here, comprehensive computational approaches including drug repurposing and molecular docking were employed to predict an effective drug candidate targeting RdRp of SARS-CoV-2. This study revealed that Rifabutin, Rifapentine, Fidaxomicin, 7-methyl-guanosine-5'-triphosphate-5'-guanosine and Ivermectin have a potential inhibitory interaction with RdRp of SARS-CoV-2 and could be effective drugs for COVID-19. In addition, virtual screening of the compounds from ZINC database also allowed the prediction of two compounds (ZINC09128258 and ZINC09883305) with pharmacophore features that interact effectively with RdRp of SARS-CoV-2, indicating their potentiality as effective inhibitors of the enzyme. Furthermore, ADME analysis along with analysis of toxicity was also undertaken to check the pharmacokinetics and drug-likeness properties of the two compounds. Comparative structural analysis of protein-inhibitor complexes revealed that the amino acids Y32, K47, Y122, Y129, H133, N138, D140, T141, S709 and N781 are crucial for drug surface hotspot in the RdRp of SARS-CoV-2.


Assuntos
Antivirais/química , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Pneumonia Viral/tratamento farmacológico , RNA Replicase/antagonistas & inibidores , Betacoronavirus/enzimologia , Infecções por Coronavirus/virologia , Fidaxomicina/química , Fidaxomicina/farmacologia , Humanos , Ivermectina/química , Ivermectina/farmacologia , Simulação de Acoplamento Molecular , Pandemias , Pneumonia Viral/virologia , Rifabutina/química , Rifabutina/farmacologia , Rifampina/análogos & derivados , Rifampina/química , Rifampina/farmacologia , Replicação Viral/efeitos dos fármacos
7.
PLoS One ; 15(8): e0237150, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760111

RESUMO

Prevention of canine heartworm disease caused by Dirofilaria immitis relies on chemoprophylaxis with macrocyclic lactone anthelmintics. Alarmingly, there are increased reports of D. immitis isolates with resistance to macrocyclic lactones and the ability to break through prophylaxis. Yet, there is not a well-established laboratory assay that can utilize biochemical phenotypes of microfilariae to predict drug resistance status. In this study we evaluated laboratory assays measuring cell permeability, metabolism, and P-glycoprotein-mediated efflux. Our assays revealed that trypan blue, propidium iodide staining, and resazurin metabolism could detect differences among D. immitis isolates but none of these approaches could accurately predict drug susceptibility status for all resistant isolates tested. P-glycoprotein assays suggested that the repertoire of P-gp expression is likely to vary among isolates, and investigation of pharmacological differences among different P-gp genes is warranted. Further research is needed to investigate and optimize laboratory assays for D. immitis microfilariae, and caution should be applied when adapting cell death assays to drug screening studies for nematode parasites.


Assuntos
Antinematódeos/farmacologia , Dirofilaria immitis/efeitos dos fármacos , Ivermectina/farmacologia , Macrolídeos/farmacologia , Fenótipo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Células Cultivadas , Dirofilaria immitis/metabolismo , Dirofilaria immitis/patogenicidade , Dirofilariose/parasitologia , Cães , Resistência a Medicamentos , Proteínas de Helminto/metabolismo
8.
Exp Parasitol ; 217: 107961, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32777223

RESUMO

Scabies is considered one of the commonest dermatological diseases that has a global health burden. Current treatment with ivermectin (IVM) is insufficient and potential drug resistance was noticed. Moxidectin (MOX), with a better pharmacological profile may be a promising alternative. The efficacy of moxidectin against Sarcoptes scabiei was assessed both in vitro and in vivo in comparison with ivermectin. For the in vitro assay, both drugs were used in two concentrations (50 µg/ml and 100 µg/ml). For the in vivo assay, twenty rabbits infected with Sarcoptes scabiei were divided into three groups: untreated, moxidectin-treated and ivermectin-treated with the same dose of 0.3 mg/kg once. Another four rabbits were used as a normal control non-infected group. Treatment efficacy was evaluated by clinical assessment, parasitological evaluation and histopathological examination of skin samples using Hematoxylin and eosin and toluidine blue for mast cell staining. Immune response was also assessed by immunohistochemical staining of CD3 T cells in skin samples. Our results showed that moxidectin had a high efficacy (100%) in killing mites when used in both concentrations (50 µg/ml, 100 µg/ml) in the in vitro assay. Concerning the in vivo assay, on day 14 post-treatment, all MOX-treated rabbits were mite-free with full clinical cure by the end of the study (D21) showing (100%) reduction of mites count. Also, marked improvement in the epidermis with absence of mites in skin samples were shown. Poor clinical and parasitological improvements were noted in the ivermectin-treated rabbits, when given as a single dose with a percentage reduction (60.67%) in the 2nd week and progressive increase in lesions and mites count in the 3rd week post-treatment. Regarding the immune response, MOX-treated group showed mild infiltration with both mast cells and CD3 T cells in comparison to severe infiltration with both types of cells in the untreated and IVM-treated group. On conclusion, our results demonstrated that a single dose of MOX was more effective than IVM, supporting MOX as a valuable therapeutic approach for scabies therapy.


Assuntos
Acaricidas/farmacologia , Macrolídeos/farmacologia , Sarcoptes scabiei/efeitos dos fármacos , Escabiose/tratamento farmacológico , Acaricidas/uso terapêutico , Animais , Biópsia por Agulha , Orelha Externa/efeitos dos fármacos , Orelha Externa/parasitologia , Orelha Externa/patologia , Imuno-Histoquímica , Ivermectina/farmacologia , Ivermectina/uso terapêutico , Macrolídeos/uso terapêutico , Masculino , Coelhos , Pele/parasitologia , Pele/patologia
9.
Artigo em Inglês | MEDLINE | ID: mdl-32660993

RESUMO

Previously, ivermectin (1 to 10 mg/kg of body weight) was shown to inhibit the liver-stage development of Plasmodium berghei in orally dosed mice. Here, ivermectin showed inhibition of the in vitro development of Plasmodium cynomolgi schizonts (50% inhibitory concentration [IC50], 10.42 µM) and hypnozoites (IC50, 29.24 µM) in primary macaque hepatocytes when administered as a high dose prophylactically but not when administered in radical cure mode. The safety, pharmacokinetics, and efficacy of oral ivermectin (0.3, 0.6, and 1.2 mg/kg) with and without chloroquine (10 mg/kg) administered for 7 consecutive days were evaluated for prophylaxis or radical cure of P. cynomolgi liver stages in rhesus macaques. No inhibition or delay to blood-stage P. cynomolgi parasitemia was observed at any ivermectin dose (0.3, 0.6, and 1.2 mg/kg). Ivermectin (0.6 and 1.2 mg/kg) and chloroquine (10 mg/kg) in combination were well-tolerated with no adverse events and no significant pharmacokinetic drug-drug interactions observed. Repeated daily ivermectin administration for 7 days did not inhibit ivermectin bioavailability. It was recently demonstrated that both ivermectin and chloroquine inhibit replication of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro Further ivermectin and chloroquine trials in humans are warranted to evaluate their role in Plasmodium vivax control and as adjunctive therapies against COVID-19 infections.


Assuntos
Antimaláricos/farmacologia , Cloroquina/farmacologia , Ivermectina/farmacologia , Fígado/efeitos dos fármacos , Malária/tratamento farmacológico , Plasmodium cynomolgi/efeitos dos fármacos , Animais , Antimaláricos/sangue , Antimaláricos/farmacocinética , Disponibilidade Biológica , Cloroquina/sangue , Cloroquina/farmacocinética , Esquema de Medicação , Combinação de Medicamentos , Sinergismo Farmacológico , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/parasitologia , Ivermectina/sangue , Ivermectina/farmacocinética , Fígado/parasitologia , Macaca mulatta , Malária/parasitologia , Masculino , Parasitemia/tratamento farmacológico , Plasmodium cynomolgi/crescimento & desenvolvimento , Plasmodium cynomolgi/patogenicidade , Cultura Primária de Células , Esquizontes/efeitos dos fármacos , Esquizontes/crescimento & desenvolvimento
10.
Aquat Toxicol ; 224: 105519, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32502848

RESUMO

Emamectin benzoate (EB) is a prophylactic pharmaceutical used to protect Atlantic salmon (Salmo salar) smolts migrating out of rivers and into the ocean against sea lice parasites. Randomized control trials comparing the marine survival of smolts treated with EB to a control group is used to calculate the fraction of marine mortality attributable to sea lice parasitism. However, it is assumed that there is no baseline difference in survival induced by the application of EB treatment. We used a combined laboratory and field study approach to investigate the potential impacts of EB treatment on behaviour and survival of hatchery-reared Atlantic salmon in western Norway. In aquaria experiments, EB-treated salmon smolts did not differ significantly in exploratory behaviour. Fish from treated groups responded similarly to simulated predator attack with spontaneous escape and elevated gill beat rate. Three rivers in the Osterfjord system of western Norway were selected for field experiments, Dale, Vosso, and Modalen. Dale River smolts were treated with intraperitoneal EB injections and had lower probability of detection in a wolf trap downstream of the release site than control smolts. Salmon smolts raised in the Vosso River hatchery were treated with EB delivered in their food and were detected on PIT antennas at the rivermouth of Vosso and Modalen at lower rates than control fish, but only when released at downstream sites. Calculation of risk ratios suggested that the bias in mortality caused by treatment with EB decreased the estimated survival of treated fish from an expected 18%to 46%, reducing the observable negative impact of sea lice on Atlantic salmon smolts in randomized control trials. The results suggest that estimates of the fraction of mortality attributable to sea lice may be underestimated due to lower baseline survival of treated fish caused by treatment and bring urgent attention towards a potential systematic underestimation of the impacts of sea lice on wild salmon.


Assuntos
Copépodes/efeitos dos fármacos , Ivermectina/análogos & derivados , Salmo salar/crescimento & desenvolvimento , Poluentes Químicos da Água/toxicidade , Migração Animal/efeitos dos fármacos , Animais , Brânquias/efeitos dos fármacos , Ivermectina/farmacologia , Ivermectina/toxicidade , Modelos Teóricos , Noruega , Distribuição Aleatória , Rios/química , Salmo salar/metabolismo , Análise de Sobrevida , Poluentes Químicos da Água/farmacologia
11.
Drug Res (Stuttg) ; 70(8): 337-340, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32559771

RESUMO

The world is faced with the dire challenge of finding an effective treatment against the rampaging COVID 19 pandemic. Amidst the crisis, reports of in vitro inhibitory activity of ivermectin, an approved anthelmintic, against the causative SARSCoV2 virus, have generated lot of optimism. In this article, we have fished and compiled the needed information on the drug, that will help readers and prospective investigators in having a quick overview. Though the primordial biological action of the drug is allosteric modulation of helminthic ion channel receptor, its in vitro activity against both RNA and DNA viruses is known for almost a decade. In the past two years, efficacy study in animal models of pseudorabies and zika virus was found to be favourable and unfavourable respectively. Only one clinical study evaluated the drug in dengue virus infection without any clinical efficacy. However, the proposed mechanism of drug action, by inhibiting the importin family of nucleus-cytoplasmic transporters along with favourable pharmacokinetics, warrants exploration of its role in COVID 19 through safely conducted clinical trials. Being an available and affordable drug, enlisted in WHO List of Essential Medicine, and a long track record of clinical safety, the drug is already in clinical trials the world over. As the pandemic continues to ravage human civilisation with unabated intensity, the world eagerly waits for a ray of hope emanating from the outcome of the ongoing trials with ivermectin as well as other drugs.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Ivermectina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Animais , Antivirais/química , Antivirais/economia , Antivirais/farmacologia , Betacoronavirus/genética , Modelos Animais de Doenças , Humanos , Ivermectina/química , Ivermectina/economia , Ivermectina/farmacologia , Pandemias
12.
J Antibiot (Tokyo) ; 73(9): 593-602, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32533071

RESUMO

Ivermectin proposes many potentials effects to treat a range of diseases, with its antimicrobial, antiviral, and anti-cancer properties as a wonder drug. It is highly effective against many microorganisms including some viruses. In this comprehensive systematic review, antiviral effects of ivermectin are summarized including in vitro and in vivo studies over the past 50 years. Several studies reported antiviral effects of ivermectin on RNA viruses such as Zika, dengue, yellow fever, West Nile, Hendra, Newcastle, Venezuelan equine encephalitis, chikungunya, Semliki Forest, Sindbis, Avian influenza A, Porcine Reproductive and Respiratory Syndrome, Human immunodeficiency virus type 1, and severe acute respiratory syndrome coronavirus 2. Furthermore, there are some studies showing antiviral effects of ivermectin against DNA viruses such as Equine herpes type 1, BK polyomavirus, pseudorabies, porcine circovirus 2, and bovine herpesvirus 1. Ivermectin plays a role in several biological mechanisms, therefore it could serve as a potential candidate in the treatment of a wide range of viruses including COVID-19 as well as other types of positive-sense single-stranded RNA viruses. In vivo studies of animal models revealed a broad range of antiviral effects of ivermectin, however, clinical trials are necessary to appraise the potential efficacy of ivermectin in clinical setting.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Vírus de DNA/efeitos dos fármacos , Ivermectina/uso terapêutico , Vírus de RNA/efeitos dos fármacos , Animais , Antivirais/química , Antivirais/farmacologia , Betacoronavirus/genética , Linhagem Celular/virologia , Modelos Animais de Doenças , Saúde Global , Humanos , Ivermectina/química , Ivermectina/farmacologia , Estrutura Molecular
13.
Parasitol Res ; 119(9): 3093-3097, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32591863

RESUMO

The efficacy of pyrantel pamoate, pyrvinium pamoate, ivermectin, and piperazine citrate against pinworm in cockroach was evaluated. Laboratory-reared German cockroaches naturally infected with Blatticola blattae were treated with the anthelmintics and necropsied at 3 to 35 days after treatment. Ivermectin at over 5 ppm and piperazine citrate at over 2000 ppm killed all the treated cockroaches. Pinworms were still detected in cockroaches given lower concentration of the aforementioned drugs. Administration of pyrantel pamoate (100-1000 ppm) and pyrvinium pamoate (2000 ppm) did not kill the cockroaches, and no pinworms were detected at 3 and 17 days after treatment. Thus, pyrantel pamoate and pyrvinium pamoate were found to be effective for deworming B. blattae in the German cockroaches, without causing mortality for the host. Our results showed that anthelmintics selection is essential for eradication of pinworms in cockroaches because of the toxicity for the host such as ivermectin or piperazine citrate. This is the first report of piperazine citrate toxicity in cockroaches.


Assuntos
Anti-Helmínticos/farmacologia , Baratas/parasitologia , Enterobíase/parasitologia , Enterobius/efeitos dos fármacos , Animais , Avaliação Pré-Clínica de Medicamentos , Enterobíase/tratamento farmacológico , Enterobius/fisiologia , Humanos , Ivermectina/farmacologia , Piperazinas/farmacologia , Pamoato de Pirantel/farmacologia
14.
Toxicol Appl Pharmacol ; 401: 115071, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32454055

RESUMO

Prostate Cancer (PCa) is the second most common cancer among men in United States after skin cancer. Conventional chemotherapeutic drugs available for PCa treatment are limited due to toxicity and resistance issues. Therefore, there is an urgent need to develop more effective treatment for advanced PCa. In this current study, we focused on evaluating the anti-cancer efficacy of Eprinomectin (EP), a novel avermectin analog against PC3 metastatic PCa cells. EP displayed robust inhibition of cell viability of PC3 cells in addition to suppressing the colony formation and wound healing capabilities. Our study showed that EP targets PC3 cells via inducing ROS and apoptosis activation. EP treatment enforces cell cycle arrest at G0/G1 phase via targeting cyclin-dependent kinase 4 (CDK4) and subsequent induction of apoptosis in PC3 cells. At the molecular level, EP effectively inhibited the expression of various cancer stem cell markers such as ALDH1, Sox-2, Nanog, Oct3/4 and CD44. Interestingly, EP also inhibited the activity of alkaline phosphatase, a maker of pluripotent stem cells. Of note, EP treatment resulted in the translocation of ß-catenin from the nucleus to the cytoplasm indicating that EP antagonizes Wnt/ß-catenin signaling pathway. Western blotting analysis revealed that EP downregulated the expression of key cell cycle markers such as cyclin D1, cyclin D3, CDK4, and c-Myc. In addition, EP inhibited the anti-apoptotic markers such as Mcl-1, XIAP, c-IAP1 and survivin in PC3 cells. On the other hand, EP treatment resulted in the activation of pH2A.X, Bad, caspase-9, caspase-3 and cleavage of PARP1. Taken together, our data suggests that EP is a potential agent to treat advanced PCa cells via modulating apoptosis signaling.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ivermectina/análogos & derivados , Lactonas/farmacologia , Compostos Macrocíclicos/farmacologia , Neoplasias da Próstata/metabolismo , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose/fisiologia , Citotoxinas/química , Citotoxinas/farmacologia , Citotoxinas/uso terapêutico , Relação Dose-Resposta a Droga , Humanos , Ivermectina/química , Ivermectina/farmacologia , Ivermectina/uso terapêutico , Lactonas/uso terapêutico , Compostos Macrocíclicos/química , Compostos Macrocíclicos/uso terapêutico , Masculino , Células PC-3 , Neoplasias da Próstata/tratamento farmacológico , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo
15.
Naunyn Schmiedebergs Arch Pharmacol ; 393(7): 1153-1156, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32462282

RESUMO

Ivermectin is an antiparasitic drug that has shown also an effective pharmacological activity towards various infective agents, including viruses. This paper proposes an alternative mechanism of action for this drug that makes it capable of having an antiviral action, also against the novel coronavirus, in addition to the processes already reported in literature.


Assuntos
Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Ivermectina/farmacologia , Pneumonia Viral/tratamento farmacológico , Antivirais/administração & dosagem , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/virologia , Humanos , Ivermectina/administração & dosagem , Pandemias , Pneumonia Viral/virologia
16.
Antiviral Res ; 178: 104787, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32251768

RESUMO

Although several clinical trials are now underway to test possible therapies, the worldwide response to the COVID-19 outbreak has been largely limited to monitoring/containment. We report here that Ivermectin, an FDA-approved anti-parasitic previously shown to have broad-spectrum anti-viral activity in vitro, is an inhibitor of the causative virus (SARS-CoV-2), with a single addition to Vero-hSLAM cells 2 h post infection with SARS-CoV-2 able to effect ~5000-fold reduction in viral RNA at 48 h. Ivermectin therefore warrants further investigation for possible benefits in humans.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/virologia , Aprovação de Drogas , Ivermectina/farmacologia , Ivermectina/uso terapêutico , Pneumonia Viral/virologia , Replicação Viral/efeitos dos fármacos , Animais , Austrália , Betacoronavirus/fisiologia , Chlorocebus aethiops , Infecções por Coronavirus/tratamento farmacológico , Humanos , Pandemias , Pneumonia Viral/tratamento farmacológico , Células Vero
17.
Am J Med Sci ; 359(2): 123-129, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32039764

RESUMO

BACKGROUND: The poor outcomes in epithelial ovarian cancer necessitate new treatments. In this work, we systematically analyzed the inhibitory effects of ivermectin and the molecular mechanism of its action in ovarian cancer. METHODS: The effects of ivermectin alone and its combination with cisplatin on growth and survival were examined using cultured ovarian cancer cells and a xenograft mouse model. The molecular mechanism of action of ivermectin, focusing on Akt/mTOR signaling, was elucidated. RESULTS: Ivermectin arrested growth in the G2/M phase and induced caspase-dependent apoptosis in ovarian cancer, regardless of specific cellular and molecular differences. Ivermectin significantly augmented the inhibitory effect of cisplatin on ovarian cancer cells in a dose-dependent manner. Mechanistically, ivermectin suppressed the phosphorylation of key molecules in the Akt/mTOR signaling pathway in ovarian cancer cells. In addition, overexpression of constitutively active Akt restored ivermectin-induced inhibition of Akt/mTOR, growth arrest and apoptosis. In an ovarian cancer xenograft mouse model, ivermectin alone significantly inhibited tumor growth. In combination with cisplatin, tumor growth was completely reversed over the entire duration of drug treatment without any toxicity. Furthermore, the concentrations of ivermectin used in our study are pharmacologically achievable. CONCLUSIONS: Our work suggests that ivermectin may be a useful addition to the treatment armamentarium for ovarian cancer and that targeting Akt/mTOR signaling is a therapeutic strategy to increase chemosensitivity in ovarian cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Divisão Celular/efeitos dos fármacos , Divisão Celular/genética , Linhagem Celular Tumoral , Cisplatino/farmacologia , Feminino , Fase G2/efeitos dos fármacos , Fase G2/genética , Humanos , Ivermectina/farmacologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/genética , Ensaios Antitumorais Modelo de Xenoenxerto
18.
J Helminthol ; 94: e130, 2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32103787

RESUMO

In a previous research work aimed at discovering natural helminthicides as alternatives to conventional synthetic drugs, Piper retrofractum fruit hexane extract (PHE) has been shown to possess promising nematocidal activity against the third-stage infective larvae of Strongyloides stercoralis. Thus, this study was designed to evaluate the chemical composition and the impact of PHE on symptom and structural alterations of S. stercoralis. Chemical analysis of PHE by gas chromatography-mass spectrometry demonstrated 26 different compounds, constituting 100% of the total composition. The main components were 4-acetylphenyl (4-benzoylphenoxy) acetate (14.86%) and octyl methoxycinnamate (12.72%). Nematocidal bioassays revealed promising potential of PHE against S. stercoralis larvae, with an LC50 value of 0.059 mg/ml, while the reference drug ivermectin exerted higher efficacy, with an LC50 value of 0.020 µg/ml. Behavioural observations under light microscopy revealed that PHE-treated S. stercoralis larvae moved slowly, became paralysed and eventually died during 24 h of incubation. The dead larvae appeared under light microscope as straight worms with unknown vacuoles of different sizes inside their internal bodies. Morphological alterations of the PHE-treated S. stercoralis larvae, such as straight bodies with swollen cuticle, faded transverse annulations and faded longitudinal striations, as well as shallow and smooth lateral longitudinal grooves, were seen clearly under scanning electron microscopy. Ultrastructural changes in the treated larvae, such as protruded lateral longitudinal grooves, loose muscle with vacuolation, dissociation between the hypodermis and cuticle and marked intracellular disorganization with vacuolation, were detected under transmission electron microscopy. The results of this study provide evidence that PHE is toxic against S. stercoralis and also a potential new alternative for anti-Strongyloides chemotherapy.


Assuntos
Antinematódeos/farmacologia , Larva/efeitos dos fármacos , Larva/ultraestrutura , Piper/química , Extratos Vegetais/farmacologia , Strongyloides stercoralis/efeitos dos fármacos , Animais , Cromatografia Gasosa , Frutas/química , Ivermectina/farmacologia , Larva/anatomia & histologia , Espectrometria de Massas , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Strongyloides stercoralis/ultraestrutura
19.
J Med Chem ; 63(4): 1750-1762, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32011136

RESUMO

Ivermectin is a powerful endectocide, which reduces the incidence of vector-borne diseases. Besides its strong insecticidal effect on mosquito vectors of the disease, ivermectin inhibits Plasmodium falciparum sporogonic and blood stage development and impairs Plasmodium berghei development inside hepatocytes, both in vitro and in vivo. Herein, we present the first report on structural modification of ivermectin to produce dual-action molecular hybrids with good structure-dependent in vitro activity against both the hepatic and erythrocytic stages of P. berghei and P. falciparum infection, suggesting inclusion of ivermectin antimalarial hybrids in malaria control strategies. The most active hybrid displayed over threefold and 10-fold higher in vitro activity than ivermectin against hepatic and blood stage infections, respectively. Although an overwhelming insecticidal effect against Anopheles stephensi mosquitoes in laboratory conditions was not noticed, in silico docking analysis supports allosteric binding to glutamate-gated chloride channels similar to ivermectin.


Assuntos
Antimaláricos/farmacologia , Ivermectina/análogos & derivados , Ivermectina/farmacologia , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Animais , Anopheles/efeitos dos fármacos , Antimaláricos/síntese química , Sítios de Ligação , Canais de Cloreto/química , Canais de Cloreto/metabolismo , Desenho de Fármacos , Inseticidas/síntese química , Inseticidas/farmacologia , Ivermectina/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium berghei/crescimento & desenvolvimento , Plasmodium falciparum/crescimento & desenvolvimento , Ligação Proteica , Relação Estrutura-Atividade
20.
Vet Parasitol ; 279: 109010, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32035291

RESUMO

In a context of nematodicidal resistance, anthelmintic combinations have emerged as a reliable pharmacological strategy to control gastrointestinal nematodes in grazing systems of livestock production. The current work evaluated the potential drug-drug interactions following the coadministration of two macrocyclic lactones (ML) ivermectin (IVM) and abamectin (ABM) to parasitized cattle using a pharmacokinetic/pharmacodynamic (PK/PD) approach. The kinetic behavior of both compounds administered either separately or coadministered was assessed and the therapeutic response of the combination was evaluated under different resistance scenarios. In the pharmacological trial, calves received a single subcutaneous (s.c.) injection of IVM (100 µg/Kg); a single s.c. injection of ABM (100 µg/Kg) or IVM + ABM (50 µg/Kg each) administered in different injection sites to reach a final ML dose of 100 µg/Kg (Farm 1). Plasma samples were taken from those animals up to 20 days post-treatment. IVM and ABM plasma concentrations were quantified by HPLC. A parasitological trial was carried out in three farms with different status of nematodes resistance to IVM. Experimental animals received IVM (200 µg/Kg), ABM (200 µg/Kg) or IVM + ABM (100 µg/Kg each) in Farm 2, and IVM + ABM (200 µg/Kg each) in Farms 3 and 4. The anthelmintic efficacy was determined by fecal egg count reduction test (FECRT). PK analysis showed similar trends for IVM kinetic behavior after coadministration with ABM. Conversely, the ABM elimination half-life was prolonged and the systemic exposure during the elimination phase was increased in the presence of IVM. Although IVM alone failed to control Cooperia spp., the combination IVM + ABM was the only treatment that achieved an efficacy higher than 95% against resistant Cooperia spp. in all farms. In fact, when Cooperia spp. was the main genus within the nematode population and Haemonchus spp. was susceptible or slightly resistant to ML (Farms 2 and 4), the total FECR for the combination IVM + ABM was higher than 90%. Instead, when the predominant nematode genus was a highly resistant Haemonchus spp. (Farm 3), the total FECR after the combined treatment was as low as the single treatments. Therefore, the rational use of these pharmacological tools should be mainly based on the knowledge of the epidemiology and the nematode susceptibility status in each cattle farm.


Assuntos
Antinematódeos/farmacologia , Doenças dos Bovinos/tratamento farmacológico , Haemonchus/efeitos dos fármacos , Ivermectina/análogos & derivados , Ivermectina/farmacologia , Rabditídios/efeitos dos fármacos , Animais , Antinematódeos/farmacocinética , Bovinos , Interações Medicamentosas , Hemoncose/tratamento farmacológico , Hemoncose/veterinária , Ivermectina/farmacocinética , Masculino , Distribuição Aleatória , Infecções por Rhabditida/tratamento farmacológico , Infecções por Rhabditida/veterinária
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