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3.
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
5.
Lancet Infect Dis ; 21(8): e234-e245, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34237261

RESUMO

Tungiasis (sand flea disease) is an epidermal parasitic skin disease occurring in resource-limited communities. There is no standard treatment for tungiasis, and available treatment options are scarce. To our knowledge, this is the first systematic review aimed to assess randomised controlled trials (RCTs) investigating interventions for tungiasis. We systematically searched databases including MEDLINE (EBSCOhost), CENTRAL, CINAHL, PubMed, Web of Science, SciELO, LILACS and Embase (Scopus) for RCTs in any language, from inception of the databases until June 12, 2021. RCTs exploring preventive and therapeutic interventions for tungiasis were eligible. We used the revised Cochrane Collaboration's risk of bias tool to assess the risk of bias and Jadad scale to quantify the methodological quality of the RCTs. Of the 1839 identified records, only eight RCTs involving 808 participants were included, and several methodological deficiencies were identified in most of the trials. Trial interventions included: oral drugs niridazole and ivermectin and topical interventions of ivermectin lotion, metrifonate lotion, thiabendazole lotion, thiabendazole ointment, dimeticones (NYDA), and a neem seed and coconut oils-based mixture for treatment and coconut oil-based lotion (Zanzarin) for prevention. The coconut oil-based lotion for prevention and dimeticones for treatment of tungiasis have displayed the most promise. Most of the RCTs included in this study had low methodological quality. There is a clear unmet need for high-quality RCTs examining safe and effective prevention and treatment alternatives of tungiasis in endemic settings.


Assuntos
Antiparasitários/administração & dosagem , Tunga , Tungíase/tratamento farmacológico , Administração Oral , Administração Tópica , Animais , Humanos , Ivermectina/administração & dosagem , Niridazol/administração & dosagem , Pomadas , Ensaios Clínicos Controlados Aleatórios como Assunto , Tiabendazol/administração & dosagem , Resultado do Tratamento , Tungíase/epidemiologia
6.
Diabetes Metab Syndr ; 15(4): 102186, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34237554

RESUMO

AIMS: This systematic review and meta-analysis aims to investigate the effect of ivermectin on mortality in patients with COVID-19. METHODS: A comprehensive systematic literature search was performed using PubMed, Scopus, Embase, and Clinicaltrials.gov from the inception of databases up until April 9, 2021. The intervention group was ivermectin and the control group was standard of care or placebo. The primary outcome was mortality reported as risk ratio (RR). RESULTS: There were 9 RCTs comprising of 1788 patients included in this meta-analysis. Ivermectin was associated with decreased mortality (RR 0.39 [95% 0.20-0.74], p = 0.004; I2: 58.2%, p = 0.051). Subgroup analysis in patients with severe COVID-19 showed borderline statistical significance towards mortality reduction (RR 0.42 [95% 0.18-1.00], p = 0.052; I2: 68.3, p = 0.013). The benefit of ivermectin and mortality was reduced by hypertension (RR 1.08 [95% CI 1.03-1.13], p = 0.001); but was not influenced by age (p = 0.657), sex (p = 0.466), diabetes (p = 0.429). Sensitivity analysis using fixed-effect model showed that ivermectin decreased mortality in general (RR 0.43 [95% CI 0.29-0.62], p < 0.001) and severe COVID-19 subgroup (RR 0.48 [95% CI 0.32-0.72], p < 0.001). CONCLUSIONS: Ivermectin was associated with decreased mortality in COVID-19 with a low certainty of evidence. Further adequately powered double-blinded placebo-controlled RCTs are required for definite conclusion.


Assuntos
Antiparasitários/uso terapêutico , COVID-19/mortalidade , Ivermectina/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , COVID-19/tratamento farmacológico , COVID-19/virologia , Humanos , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Taxa de Sobrevida
7.
Molecules ; 26(14)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34299479

RESUMO

A library of seventeen novel ether phospholipid analogues, containing 5-membered heterocyclic rings (1,2,3-triazolyl, isoxazolyl, 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl) in the lipid portion were designed and synthesized aiming to identify optimised miltefosine analogues. The compounds were evaluated for their in vitro antiparasitic activity against Leishmania infantum and Leishmania donovani intracellular amastigotes, against Trypanosoma brucei brucei and against different developmental stages of Trypanosoma cruzi. The nature of the substituents of the heterocyclic ring (tail) and the oligomethylene spacer between the head group and the heterocyclic ring was found to affect the activity and toxicity of these compounds leading to a significantly improved understanding of their structure-activity relationships. The early ADMET profile of the new derivatives did not reveal major liabilities for the potent compounds. The 1,2,3-triazole derivative 27 substituted by a decyl tail, an undecyl spacer and a choline head group exhibited broad spectrum antiparasitic activity. It possessed low micromolar activity against the intracellular amastigotes of two L. infantum strains and T. cruzi Y strain epimastigotes, intracellular amastigotes and trypomastigotes, while its cytotoxicity concentration (CC50) against THP-1 macrophages ranged between 50 and 100 µM. Altogether, our work paves the way for the development of improved ether phospholipid derivatives to control neglected tropical diseases.


Assuntos
Antiparasitários/síntese química , Antiparasitários/farmacologia , Doença de Chagas/tratamento farmacológico , Desenho de Fármacos , Leishmaniose/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Fosfolipídeos/farmacologia , Doença de Chagas/parasitologia , Química Click , Humanos , Leishmania/efeitos dos fármacos , Leishmaniose/parasitologia , Relação Estrutura-Atividade , Trypanosoma cruzi/efeitos dos fármacos
8.
Vet Parasitol ; 296: 109510, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34217073

RESUMO

Bovine ostertagiasis causes significant production losses to the cattle industry. Protective immunity induced by natural infection is slow to develop and anthelmintic resistance is rapidly developing. There is a need to advance alternatives for control of gastrointestinal nematode parasites. The present study investigated the effects of repeated, drug-truncated infections (rDTI) on development of protective immunity and attenuation of a challenge infection by O. ostertagi. Helminth-free calves were randomly assigned to either a rDTI or a control group (n = 5). The rDTI group received daily oral infections of 5000 Ostertagia L3 for 5 consecutive days, then were drug-treated on 14 and 15 days post infection (dpi), to attenuate O. ostertagi at the late fourth larval (L4) through young adult stages. DTI was repeated 3 weeks after the drug treatment. A total of 5 DTIs were administered to the DTI-treated animals. Non-DTI-treated, control animals received tap water as infection control. All animals were drug-treated at the same time. Animals were challenge-infected 4 weeks following the final round of rDTI. The results show that eggs per gram of feces (EPG) in the rDTI group were significantly reduced (P < 0.05) from 21 to 39 dpi, with an overall reduction in cumulative EPG. The control group exhibited reduced (P = 0.0564) average weight gains when compared to those of the rDTI group during weeks 4-5 post infection, a period coinciding with peak EPG output of control animals. Antigen-specific IgG, IgE and IgA responses were detected after the 2nd DTI, and stronger antibody recall responses were elicited by challenge infection. High levels of antigen-specific peripheral blood mononuclear cell (PBMC)/T cell proliferation to whole worm and excretory-secretory (ES) antigens were detected in rDTI-treated animals. These data indicate that partial protective immunity against ostertagiasis, involving cell-mediated and humoral responses, can be attained by rDTI which allowed for maximal antigen exposure from staggered parasitic developmental stages. The data suggest that rDTI can be used as a model to study host-parasite interactions and identify parasite antigens responsible for eliciting host protective immune responses.


Assuntos
Doenças dos Bovinos , Imunidade , Ostertagíase , Animais , Anticorpos Anti-Helmínticos , Antiparasitários/imunologia , Antiparasitários/uso terapêutico , Bovinos , Doenças dos Bovinos/tratamento farmacológico , Doenças dos Bovinos/imunologia , Doenças dos Bovinos/prevenção & controle , Fezes , Leucócitos Mononucleares , Ostertagia/imunologia , Ostertagíase/tratamento farmacológico , Ostertagíase/imunologia , Ostertagíase/prevenção & controle , Ostertagíase/veterinária , Óvulo , Contagem de Ovos de Parasitas/veterinária
9.
Cochrane Database Syst Rev ; 7: CD015017, 2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-34318930

RESUMO

BACKGROUND: Ivermectin, an antiparasitic agent used to treat parasitic infestations, inhibits the replication of viruses in vitro. The molecular hypothesis of ivermectin's antiviral mode of action suggests an inhibitory effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in the early stages of infection. Currently, evidence on efficacy and safety of ivermectin for prevention of SARS-CoV-2 infection and COVID-19 treatment is conflicting. OBJECTIVES: To assess the efficacy and safety of ivermectin compared to no treatment, standard of care, placebo, or any other proven intervention for people with COVID-19 receiving treatment as inpatients or outpatients, and for prevention of an infection with SARS-CoV-2 (postexposure prophylaxis). SEARCH METHODS: We searched the Cochrane COVID-19 Study Register, Web of Science (Emerging Citation Index and Science Citation Index), medRxiv, and Research Square, identifying completed and ongoing studies without language restrictions to 26 May 2021. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing ivermectin to no treatment, standard of care, placebo, or another proven intervention for treatment of people with confirmed COVID-19 diagnosis, irrespective of disease severity, treated in inpatient or outpatient settings, and for prevention of SARS-CoV-2 infection. Co-interventions had to be the same in both study arms.  We excluded studies comparing ivermectin to other pharmacological interventions with unproven efficacy. DATA COLLECTION AND ANALYSIS: We assessed RCTs for bias, using the Cochrane risk of bias 2 tool. The primary analysis excluded studies with high risk of bias. We used GRADE to rate the certainty of evidence for the following outcomes 1. to treat inpatients with moderate-to-severe COVID-19: mortality, clinical worsening or improvement, adverse events, quality of life, duration of hospitalization, and viral clearance; 2. to treat outpatients with mild COVID-19: mortality, clinical worsening or improvement, admission to hospital, adverse events, quality of life, and viral clearance; (3) to prevent SARS-CoV-2 infection: SARS-CoV-2 infection, development of COVID-19 symptoms, adverse events, mortality, admission to hospital, and quality of life. MAIN RESULTS: We found 14 studies with 1678 participants investigating ivermectin compared to no treatment, placebo, or standard of care. No study compared ivermectin to an intervention with proven efficacy. There were nine studies treating participants with moderate COVID-19 in inpatient settings and four treating mild COVID-19 cases in outpatient settings. One study investigated ivermectin for prevention of SARS-CoV-2 infection. Eight studies had an open-label design, six were double-blind and placebo-controlled. Of the 41 study results contributed by included studies, about one third were at overall high risk of bias.  Ivermectin doses and treatment duration varied among included studies.  We identified 31 ongoing and 18 studies awaiting classification until publication of results or clarification of inconsistencies. Ivermectin compared to placebo or standard of care for inpatient COVID-19 treatment We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.14 to 2.51; 2 studies, 185 participants; very low-certainty evidence) and clinical worsening up to day 28 assessed as need for invasive mechanical ventilation (IMV) (RR 0.55, 95% CI 0.11 to 2.59; 2 studies, 185 participants; very low-certainty evidence) or need for supplemental oxygen (0 participants required supplemental oxygen; 1 study, 45 participants; very low-certainty evidence), adverse events within 28 days (RR 1.21, 95% CI 0.50 to 2.97; 1 study, 152 participants; very low-certainty evidence), and viral clearance at day seven (RR 1.82, 95% CI 0.51 to 6.48; 2 studies, 159 participants; very low-certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on clinical improvement up to 28 days (RR 1.03, 95% CI 0.78 to 1.35; 1 study; 73 participants; low-certainty evidence) and duration of hospitalization (mean difference (MD) -0.10 days, 95% CI -2.43 to 2.23; 1 study; 45 participants; low-certainty evidence). No study reported quality of life up to 28 days. Ivermectin compared to placebo or standard of care for outpatient COVID-19 treatment We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality up to 28 days (RR 0.33, 95% CI 0.01 to 8.05; 2 studies, 422 participants; very low-certainty evidence) and clinical worsening up to 14 days assessed as need for IMV (RR 2.97, 95% CI 0.12 to 72.47; 1 study, 398 participants; very low-certainty evidence) or non-IMV or high flow oxygen requirement (0 participants required non-IMV or high flow; 1 study, 398 participants; very low-certainty evidence). We are uncertain whether ivermectin compared to placebo reduces or increases viral clearance at seven days (RR 3.00, 95% CI 0.13 to 67.06; 1 study, 24 participants; low-certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on the number of participants with symptoms resolved up to 14 days (RR 1.04, 95% CI 0.89 to 1.21; 1 study, 398 participants; low-certainty evidence) and adverse events within 28 days (RR 0.95, 95% CI 0.86 to 1.05; 2 studies, 422 participants; low-certainty evidence). None of the studies reporting duration of symptoms were eligible for primary analysis. No study reported hospital admission or quality of life up to 14 days. Ivermectin compared to no treatment for prevention of SARS-CoV-2 infection We found one study. Mortality up to 28 days was the only outcome eligible for primary analysis. We are uncertain whether ivermectin reduces or increases mortality compared to no treatment (0 participants died; 1 study, 304 participants; very low-certainty evidence). The study reported results for development of COVID-19 symptoms and adverse events up to 14 days that were included in a secondary analysis due to high risk of bias. No study reported SARS-CoV-2 infection, hospital admission, and quality of life up to 14 days. AUTHORS' CONCLUSIONS: Based on the current very low- to low-certainty evidence, we are uncertain about the efficacy and safety of ivermectin used to treat or prevent COVID-19. The completed studies are small and few are considered high quality. Several studies are underway that may produce clearer answers in review updates. Overall, the reliable evidence available does not support the use ivermectin for treatment or prevention of COVID-19 outside of well-designed randomized trials.


Assuntos
Antiparasitários/uso terapêutico , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Ivermectina/uso terapêutico , Antiparasitários/efeitos adversos , Antivirais/efeitos adversos , COVID-19/mortalidade , COVID-19/prevenção & controle , COVID-19/virologia , Causas de Morte , Humanos , Ivermectina/efeitos adversos , Placebos/uso terapêutico , Profilaxia Pós-Exposição , Ensaios Clínicos Controlados Aleatórios como Assunto , Respiração Artificial/estatística & dados numéricos , SARS-CoV-2/efeitos dos fármacos , Fatores de Tempo , Resultado do Tratamento
10.
Exp Parasitol ; 226-227: 108121, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34097889

RESUMO

Cystic echinococcosis (CE), a parasitic larval cystic stage of a small taeniid-type tapeworm (Echinococcus granulosus), causes illness in intermediate hosts and has become a threat to global public health. Currently, chemical compounds recommended by the WHO targeting CE are albendazole and mebendazole, however, none of them shows enhanced efficacy. Novel molecular compounds are urgently required to treat this disease. Our group uncover a drug, termed harmine (HM), that may be capable of treating CE. In this study, we aim to evaluate the anti-parasitic efficacy and the mechanism of DNA damage of HM against E. granulosus. In vitro, the results indicated that, within two and three days of treatment, ABZ killed 30.4% and 35.3% of protoscoleces, whereas HM killed 52.7% and 100% of protoscoleces, respectively. Furthermore, the presence of abnormalities in the internal structure of protoscoleces was examined by ultrastructural images of TEM, and the result showed that there were scattered nucleoli and heterochromatin margination phenomenon by HM treatment. DNA damage of protoscoleces was examined by using the comet assay, and results showed the DNA of protoscoleces was damaged. Moreover, EgATM, EgP53, EgTopo2a and EgRad54 genes were used to support the DNA damage by HM treatment, and results showed that all four genes were upregulated expression. In further, the result of HM treatment was tested by using designed siRNA to inhibit the expression of EgTopo2a and EgRad54. The results demonstrated that the viability was 88.75 ± 2.11% after suppressing the expression of EgTopo2a, which was significantly higher than that for HM alone group (P < 0.01). The viability was 10.11 ± 2.60% after transfected with EgRad54 siRNA, which was significantly lower compared with the HM alone group (P < 0.01). Based on our preliminary data, HM demonstrated significant parasiticidal activity against E. granulosus in vitro without obvious toxicity towards its host cells, suggesting that HM can be a potential anti-echinococcosis drug. HM was found to induce DNA damages of CE by activating the EgATM-EgP53-EgTopo2a signaling pathway. We therefore surmise that DNA damage response may be one of the mechanisms of HM against the parasite.


Assuntos
Antiparasitários/farmacologia , Dano ao DNA/efeitos dos fármacos , Equinococose/tratamento farmacológico , Echinococcus granulosus/efeitos dos fármacos , Harmina/farmacologia , Animais , Antiparasitários/uso terapêutico , Ensaio Cometa , Echinococcus granulosus/genética , Echinococcus granulosus/ultraestrutura , Harmina/uso terapêutico , Microscopia Eletrônica de Transmissão , Inibidores da Monoaminoxidase/farmacologia , RNA Interferente Pequeno/química , RNA Interferente Pequeno/fisiologia , Reação em Cadeia da Polimerase em Tempo Real , Ovinos
11.
Eur J Med Chem ; 222: 113610, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34144354

RESUMO

A structure activity relationship (SAR) study of a library of 56 compounds (54 ruthenium and 2 osmium derivatives) based on the trithiolato-bridged dinuclear ruthenium(II)-arene scaffold (general formula [(η6-arene)2Ru2(µ2-SR)3]+, symmetric and [(η6-arene)2Ru2(µ2-SR1)2(µ2-SR2)]+, mixed, respectively) is reported. The 56 compounds (of which 34 are newly designed drug candidates) were synthesized by introducing chemical modifications at the level of bridge thiols, and they were grouped into eight families according to their structural features. The selected fittings were guided by previous results and focused on a fine-tuning of the physico-chemical and steric properties. Newly synthesized complexes were characterized by NMR spectroscopy, mass spectrometry and elemental analysis, and four single-crystal X-ray structures were obtained. The in vitro biological assessment of the compounds was realized by applying a three-step screening cascade: (i) evaluation of the activity against Toxoplasma gondii RH strain tachyzoites expressing ß-galactosidase (T. gondii-ß-gal) grown in human foreskin fibroblast monolayers (HFF) and assessment of toxicity in non-infected HFF host cells; (ii) dose-response assays using selected compound, and (iii) studies on the effects in murine splenocytes. A primary screening was performed at 1 and 0.1 µM, and resulted in the selection of 39 compounds that inhibited parasite proliferation at 1 µM by more than 95% and reduced the viability of HFF by less than 49%. In the secondary screening, dose-response assays showed that the selected compounds exhibited half maximal inhibitory concentration (IC50) values for T. gondii-ß-gal between 0.01 µM and 0.45 µM, with 30 compounds displaying an IC50 lower than 0.1 µM. When applied to non-infected HFF monolayers at 2.5 µM, 8 compounds caused more than 90% and 31 compounds more than 30% viability impairment. The tertiary screening included 14 compounds that did not cause HFF viability loss higher than 50% at 2.5 µM. These derivatives were assessed for potential immunosuppressive activities. First, splenocyte viability was assessed after treatment of cells with concanavalin A (ConA) and lipopolysaccharide (LPS) with compounds applied at 0.1 and 0.5 µM. Subsequently, the 5 compounds exhibiting the lowest splenocyte toxicity were further evaluated for their potential to inhibit B and T cell proliferation. Overall, compound 55 [(η6-p-MeC6H4Pri)2Ru2(µ2-SC6H4-o-CF3)2(µ2-SC6H4-p-OH)]Cl exhibited the most favorable features, and will be investigated as a scaffold for further optimization in terms of anti-parasitic efficacy and drug-like properties.


Assuntos
Antiparasitários/farmacologia , Complexos de Coordenação/farmacologia , Rutênio/farmacologia , Compostos de Sulfidrila/farmacologia , Toxoplasma/efeitos dos fármacos , Antiparasitários/síntese química , Antiparasitários/química , Linhagem Celular , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Rutênio/química , Relação Estrutura-Atividade , Compostos de Sulfidrila/química
12.
Eur J Med Chem ; 222: 113625, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34146914

RESUMO

Dicationic diamidines have been well established as potent antiparasitic agents with proven activity against tropical diseases like trypanosomiasis and malaria. This work presents the synthesis of new mono and diflexible triaryl amidines (6a-c, 13a,b and 17), their aza analogues (23 and 27) and respective methoxyamidine prodrugs (5, 7, 12a,b, 22 and 26). All diamidines were assessed in vitro against Trypanosoma brucei rhodesiense (T. b. r.) and Plasmodium falciparum (P. f.) where they displayed potent to moderate activities at the nanomolar level with IC50s = 11-378 nM for T. b. r. and 4-323 nM against P. f.. In vivo efficacy testing against T. b. r. STIB900 has shown the monoflexible diamidine 6c as the most potent derivative in this study eliciting 4/4 cures of infected mice for a treatment period of >60 days upon a 4 × 5 mg/kg dose i. p. treatment. Moreover, thermal melting analysis measurement ΔTm for this series of diamidines/poly (dA-dT) complexes fell between 0.5 and 19 °C with 6c showing the highest binding to the DNA minor groove. Finally, a 50 ns molecular dynamics study of an AT-rich DNA dodecamer with compound 6c revealed a strong binding complex supported by vdW and electrostatic interactions.


Assuntos
Amidinas/farmacologia , Antiparasitários/farmacologia , Compostos Aza/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Pró-Fármacos/farmacologia , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Amidinas/síntese química , Amidinas/química , Antiparasitários/síntese química , Antiparasitários/química , Compostos Aza/síntese química , Compostos Aza/química , Relação Dose-Resposta a Droga , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-Atividade , Trypanosoma brucei rhodesiense/enzimologia
13.
Cochrane Database Syst Rev ; 6: CD013117, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34184757

RESUMO

BACKGROUND: Malaria is transmitted through the bite of Plasmodium-infected adult female Anopheles mosquitoes. Ivermectin, an anti-parasitic drug, acts by killing mosquitoes that are exposed to the drug while feeding on the blood of people (known as blood feeds) who have ingested the drug. This effect on mosquitoes has been demonstrated by individual randomized trials. This effect has generated interest in using ivermectin as a tool for malaria control. OBJECTIVES: To assess the effect of community administration of ivermectin on malaria transmission. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group (CIDG) Specialized Register, CENTRAL, MEDLINE, Embase, LILACS, Science Citation index - expanded, the World Health Organization (WHO) International Clinical Trials Registry Platform, ClinicalTrials.gov, and the National Institutes of Health (NIH) RePORTER database to 14 January 2021. We checked the reference lists of included studies for other potentially relevant studies, and contacted researchers working in the field for unpublished and ongoing trials. SELECTION CRITERIA: We included cluster-randomized controlled trials (cRCTs) that compared ivermectin, as single or multiple doses, with a control treatment or placebo given to populations living in malaria-endemic areas, in the context of mass drug administration. Primary outcomes were prevalence of malaria parasite infection and incidence of clinical malaria in the community. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data on the number of events and the number of participants in each trial arm at the time of assessment. For rate data, we noted the total time at risk in each trial arm. To assess risk of bias, we used Cochrane's RoB 2 tool for cRCTs. We documented the method of data analysis, any adjustments for clustering or other covariates, and recorded the estimate of the intra-cluster correlation (ICC) coefficient. We re-analysed the trial data provided by the trial authors to adjust for cluster effects. We used a Poisson mixed-effect model with small sample size correction, and a cluster-level analysis using the linear weighted model to adequately adjust for clustering.  MAIN RESULTS: We included one cRCT and identified six ongoing trials.  The included cRCT examined the incidence of malaria in eight villages in Burkina Faso, randomized to two arms. Both trial arms received a single dose of ivermectin 150 µg/kg to 200 µg/kg, together with a dose of albendazole. The villages in the intervention arm received an additional five doses of ivermectin, once every three weeks. Children were enrolled into an active cohort, in which they were repeatedly screened for malaria infection.  The primary outcome was the cumulative incidence of uncomplicated malaria in a cohort of children aged five years and younger, over the 18-week study. We judged the study to be at high risk of bias, as the analysis did not account for clustering or correlation between participants in the same village. The study did not demonstrate an effect of Ivermectin on the cumulative incidence of uncomplicated malaria in the cohort of children over the 18-week study (risk ratio 0.86, 95% confidence interval (CI) 0.62 to 1.17; P = 0.2607; very low-certainty evidence). AUTHORS' CONCLUSIONS: We are uncertain whether community administration of ivermectin has an effect on malaria transmission, based on one trial published to date.


Assuntos
Antiparasitários/administração & dosagem , Ivermectina/administração & dosagem , Malária/transmissão , Controle de Mosquitos , Animais , Antiparasitários/efeitos adversos , Antiparasitários/sangue , Viés , Burkina Faso/epidemiologia , Pré-Escolar , Análise de Dados , Humanos , Incidência , Lactente , Ivermectina/efeitos adversos , Ivermectina/sangue , Malária/epidemiologia , Malária/prevenção & controle , Projetos Piloto , Prevalência , Ensaios Clínicos Controlados Aleatórios como Assunto
14.
Molecules ; 26(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072937

RESUMO

The unique electron deficiency and coordination property of boron led to a wide range of applications in chemistry, energy research, materials science and the life sciences. The use of boron-containing compounds as pharmaceutical agents has a long history, and recent developments have produced encouraging strides. Boron agents have been used for both radiotherapy and chemotherapy. In radiotherapy, boron neutron capture therapy (BNCT) has been investigated to treat various types of tumors, such as glioblastoma multiforme (GBM) of brain, head and neck tumors, etc. Boron agents playing essential roles in such treatments and other well-established areas have been discussed elsewhere. Organoboron compounds used to treat various diseases besides tumor treatments through BNCT technology have also marked an important milestone. Following the clinical introduction of bortezomib as an anti-cancer agent, benzoxaborole drugs, tavaborole and crisaborole, have been approved for clinical use in the treatments of onychomycosis and atopic dermatitis. Some heterocyclic organoboron compounds represent potentially promising candidates for anti-infective drugs. This review highlights the clinical applications and perspectives of organoboron compounds with the natural boron atoms in disease treatments without neutron irradiation. The main topic focuses on the therapeutic applications of organoboron compounds in the diseases of tuberculosis and antifungal activity, malaria, neglected tropical diseases and cryptosporidiosis and toxoplasmosis.


Assuntos
Boro/química , Boro/metabolismo , Boro/farmacologia , Antibacterianos/farmacologia , Antiparasitários/farmacologia , Terapia por Captura de Nêutron de Boro/métodos , Terapia por Captura de Nêutron de Boro/tendências , Bortezomib/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Criptosporidiose/tratamento farmacológico , Dermatite Atópica/tratamento farmacológico , Eczema/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Humanos , Malária/tratamento farmacológico , Onicomicose/tratamento farmacológico , Toxoplasmose/tratamento farmacológico , Tuberculose/tratamento farmacológico
15.
Life Sci ; 280: 119752, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34171382

RESUMO

AIMS: Angiotensin-converting enzyme 2 (ACE2) is a key negative regulator of the renin-angiotensin system and also a major receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we reveal a role for NF-κB in human lung cell expression of ACE2, and we further explore the potential utility of repurposing NF-κB inhibitors to downregulate ACE2. MAIN METHODS: Expression of ACE2 was assessed by Western blotting and RT-qPCR in multiple human lung cell lines with or without NF-κB inhibitor treatment. Surface ACE2 expression and intracellular reactive oxygen species (ROS) levels were measured with flow cytometry. p50 was knocked down with siRNA. Cytotoxicity was monitored by PARP cleavage and MTS assay. KEY FINDINGS: Pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor, suppressed endogenous ACE2 mRNA and protein expression in H322M and Calu-3 cells. The ROS level in H322M cells was increased after PDTC treatment, and pretreatment with N-acetyl-cysteine (NAC) reversed PDTC-induced ACE2 suppression. Meanwhile, treatment with hydrogen peroxide augmented ACE2 suppression in H322M cells with p50 knockdown. Two repurposed NF-κB inhibitors, the anthelmintic drug triclabendazole and the antiprotozoal drug emetine, also reduced ACE2 mRNA and protein levels. Moreover, zinc supplementation augmented the suppressive effects of triclabendazole and emetine on ACE2 expression in H322M and Calu-3 cells. SIGNIFICANCE: These results suggest that ACE2 expression is modulated by ROS and NF-κB signaling in human lung cells, and the combination of zinc with triclabendazole or emetine shows promise for clinical treatment of ACE2-related disease.


Assuntos
Enzima de Conversão de Angiotensina 2/genética , Antiparasitários/farmacologia , Regulação para Baixo/efeitos dos fármacos , Emetina/farmacologia , NF-kappa B/antagonistas & inibidores , Triclabendazol/farmacologia , Zinco/farmacologia , COVID-19/tratamento farmacológico , COVID-19/genética , Linhagem Celular , Reposicionamento de Medicamentos , Humanos , Pulmão/citologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pirrolidinas/farmacologia , Tiocarbamatos/farmacologia
16.
Int J Mol Sci ; 22(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34069111

RESUMO

In colon cancer, wingless (Wnt)/ß-catenin signaling is frequently upregulated; however, the creation of a molecular therapeutic agent targeting this pathway is still under investigation. This research aimed to study how nitazoxanide can affect Wnt/ß-catenin signaling in colon cancer cells (HCT-116) and a mouse colon cancer model. Our study included 2 experiments; the first was to test the cytotoxic activity of nitazoxanide in an in vitro study on a colon cancer cell line (HCT-116) versus normal colon cells (FHC) and to highlight the proapoptotic effect by MTT assay, flow cytometry and real-time polymerase chain reaction (RT-PCR). The second experiment tested the in vivo cytotoxic effect of nitazoxanide against 1,2-dimethylhydrazine (DMH) prompted cancer in mice. Mice were grouped as saline, DMH control and DMH + nitazoxanide [100 or 200 mg per kg]. Colon levels of Wnt and ß-catenin proteins were assessed by Western blotting while proliferation was measured via immunostaining for proliferating cell nuclear antigen (PCNA). Treating HCT-116 cells with nitazoxanide (inhibitory concentration 50 (IC50) = 11.07 µM) revealed that it has a more cytotoxic effect when compared to 5-flurouracil (IC50 = 11.36 µM). Moreover, it showed relatively high IC50 value (non-cytotoxic) against the normal colon cells. Nitazoxanide induced apoptosis by 15.86-fold compared to control and arrested the cell cycle. Furthermore, nitazoxanide upregulated proapoptotic proteins (P53 and BAX) and caspases but downregulated BCL-2. Nitazoxanide downregulated Wnt/ß-catenin/glycogen synthase kinase-3ß (GSK-3ß) signaling and PCNA staining in the current mouse model. Hence, our findings highlighted the cytotoxic effect of nitazoxanide and pointed out the effect on Wnt/ß-catenin/GSK-3ß signaling.


Assuntos
Antiparasitários/farmacologia , Neoplasias do Colo/tratamento farmacológico , Nitrocompostos/farmacologia , Tiazóis/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Antiparasitários/química , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Células HCT116 , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Nitrocompostos/química , Antígeno Nuclear de Célula em Proliferação/imunologia , Antígeno Nuclear de Célula em Proliferação/metabolismo , Tiazóis/química , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/metabolismo
17.
Fish Shellfish Immunol ; 115: 179-188, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34153430

RESUMO

Propolis is a viscous, waxy, resinous substance that is produced from the exudates of flowers and buds by the action of salivary enzymes of honey bees. Propolis may differ in color (brown, red or green), with color being influenced by the chemical composition and age of the product. Propolis has a special distinctive odor owing to the high concentration of volatile essential oils. It is composed of 5% pollen grains, 10% essential and aromatic oils, 30% wax, 50% resin and balsams, and other minor trace substances. Natural propolis products may be useful for a range of applications in aquaculture systems instead of relying on the application of synthetic compounds to manage many ailments that affect business profitability. It has been reported in several studies that propolis enhances performance, economics, immunity response and disease resistance in different fish species. This present review discusses the functional actions of propolis and the prospects of its use as an antimicrobial, antioxidant, immune-modulatory, antiseptic, antiparasitic, anti-inflammatory and food additive in aquaculture production. In summary, propolis could be a natural supplement that has the potential to improve fish health status and immunity thereby enhancing growth and productivity of the fish industry as well as economic efficiency.


Assuntos
Aquicultura , Peixes/fisiologia , Própole/administração & dosagem , Própole/química , Fenômenos Fisiológicos da Nutrição Animal , Animais , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/química , Anti-Infecciosos Locais/administração & dosagem , Anti-Infecciosos Locais/química , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Antioxidantes/administração & dosagem , Antioxidantes/química , Antiparasitários/administração & dosagem , Antiparasitários/química , Aditivos Alimentares/administração & dosagem , Aditivos Alimentares/química , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/química
19.
Adv Protein Chem Struct Biol ; 125: 193-213, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33931139

RESUMO

Parasitic organisms of various genera have threatened humankind. Although they are not always fatal but can damage the well-being of an individual in terms of both economic and societal crisis. Marked progress has been made toward eliminating those pathogenic organisms, however, complete removal is still not possible. Several antiparasitic drug moieties have been largely commercialized and are routinely used at the same time novel drug candidates are still required. Programmed cell death (PCD) is a vital biological phenomenon inside every organism. Particularly, induction of the death signaling inside the parasitic species through selective targeting of effective drug candidates is one of the major strategies to combat these infectious organisms. In this chapter significance of apoptosis induction to eliminate the parasitic disease has been illustrated with suitable references. Moreover, we have shared our own experiences of apoptosis induction in eliminating a World Health Organization enlisted Neglected Tropical Disease, lymphatic filariasis. On the other hand, we have also tried to put some light on the mechanism of apoptosis in different parasites.


Assuntos
Antiparasitários/uso terapêutico , Apoptose , Desenvolvimento de Medicamentos , Doenças Parasitárias , Transdução de Sinais , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Humanos , Doenças Parasitárias/tratamento farmacológico , Doenças Parasitárias/imunologia , Doenças Parasitárias/parasitologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
20.
PLoS Negl Trop Dis ; 15(5): e0009011, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33979331

RESUMO

BACKGROUND: The existence of locations with low but stable onchocerciasis prevalence is not well understood. An often suggested yet poorly investigated explanation is that the infection spills over from neighbouring locations with higher infection densities. METHODOLOGY: We adapted the stochastic individual based model ONCHOSIM to enable the simulation of multiple villages, with separate blackfly (intermediate host) and human populations, which are connected through the regular movement of the villagers and/or the flies. With this model we explore the impact of the type, direction and degree of connectedness, and of the impact of localized or full-area mass drug administration (MDA) over a range of connected village settings. PRINCIPAL FINDINGS: In settings with annual fly biting rates (ABR) below the threshold needed for stable local transmission, persistence of onchocerciasis prevalence can well be explained by regular human traffic and/or fly movement from locations with higher ABR. Elimination of onchocerciasis will then theoretically be reached by only implementing MDA in the higher prevalence area, although lingering infection in the low prevalence location can trigger resurgence of transmission in the total region when MDA is stopped too soon. Expanding MDA implementation to the lower ABR location can therefore shorten the duration of MDA needed. For example, when prevalence spill-over is due to human traffic, and both locations have about equal populations, then the MDA duration can be shortened by up to three years. If the lower ABR location has twice as many inhabitants, the reduction can even be up to six years, but if spill-over is due to fly movement, the expected reduction is less than a year. CONCLUSIONS/SIGNIFICANCE: Although MDA implementation might not always be necessary in locations with stable low onchocerciasis prevalence, in many circumstances it is recommended to accelerate achieving elimination in the wider area.


Assuntos
Antiparasitários/uso terapêutico , Controle de Doenças Transmissíveis/métodos , Ivermectina/uso terapêutico , Administração Massiva de Medicamentos/métodos , Oncocercose , Animais , Erradicação de Doenças , Humanos , Mordeduras e Picadas de Insetos/parasitologia , Ivermectina/administração & dosagem , Onchocerca/efeitos dos fármacos , Oncocercose/epidemiologia , Oncocercose/prevenção & controle , Oncocercose/transmissão , Simuliidae/parasitologia
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