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1.
Vet Parasitol ; 277: 108992, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31835054

RESUMO

Eprinomectin (EPM) has been recently granted a marketing authorisation in the European Union for use in goats, with a zero-day milk withdrawal period. Considering the high prevalence of benzimidazole resistance worldwide and the economic implications of managing milk residues, EPM may today be considered the main (or even the only) affordable treatment option, at least in dairy goats in the EU. However, the chosen dose (1 mg/kg) seems to be suboptimal, especially for lactating goats, and the chosen route of administration (Pour-on) highly subject to inter-individual variability. Considering the scarcity of anthelmintic resources, such a dosage regimen might threat the sustainability of this crucial drug in goat milk production and needs to be urgently discussed and reassessed.


Assuntos
Indústria de Laticínios/normas , Doenças das Cabras/tratamento farmacológico , Ivermectina/análogos & derivados , Animais , Anti-Helmínticos/administração & dosagem , Indústria de Laticínios/legislação & jurisprudência , Indústria de Laticínios/tendências , União Europeia , Feminino , Cabras , Ivermectina/administração & dosagem
2.
Drug Deliv ; 26(1): 1104-1114, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31735104

RESUMO

Nanoemulgels are composed of O/W nanoemulsion and hydrogels and are considered as ideal carriers for the transdermal drug delivery because these have high affinity to load hydrophobic drugs. The stable formulation of eprinomectin (EPR) is very challenging because of it is high hydrophobic nature. In this work, we have prepared EPR loaded nanoemulgel for the treatment of endo- and ectoparasites. The surface morphology of optimized formulations was characterized by scanning electron microscopy. Additionally, skin permeability and irritation tests were conducted for in vitro safety and in vivo skin retention and pearmeation test of EPR nanoemulgel were conducted for efficacy study. Obtained results indicated that the optimized formulation had good shear-thinning behavior, bioadhesiveness properties, and are nanosized droplets with porous internal structure, which are required for topical application. Furthermore, this formulation has showed good skin permeability in comparison to suspension and has no skin irritating property. Overall, the obtained results proved that nanoemulgel is a promising carrier for transdermal drug delivery and EPR nanoemulgel is a promising formulation for the treatment of endo- and ectoparasites.


Assuntos
Emulsões/química , Géis/química , Ivermectina/análogos & derivados , Pele/metabolismo , Administração Cutânea , Animais , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Emulsões/administração & dosagem , Géis/administração & dosagem , Ivermectina/administração & dosagem , Ivermectina/química , Masculino , Camundongos , Camundongos Endogâmicos ICR , Nanopartículas/química , Permeabilidade , Ratos , Ratos Sprague-Dawley , Absorção Cutânea
3.
Parasit Vectors ; 12(1): 469, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601244

RESUMO

BACKGROUND: The larval stage of the tapeworm Echinococcus granulosus is the causative agent of hydatid disease in humans. This zoonotic parasitic infection remains a major health problem in certain areas of the world where is still endemic. In view of the ineffectiveness of some drug treatments, the surgical removal of cysts remains the preferred treatment option together with the administration of albendazole and mebendazole. However, severe side effects of these drugs have been reported which demands developing new scolicidal agents that confer suitable efficacy and fewer side effects during surgery. METHODS: To that purpose, in the present work we assessed the effectiveness of ivermectin (IVM), a macrocyclic lactone endectocide that has shown to be an effective nematocidal drug against other important parasitic infections. To overcome the limitations observed in some drug formulations and resistance, we used nano lipid carriers (NLCs) as a targeted and sustained drug delivery system for IVM. We evaluated the in vitro cestocidal and apoptotic effects of NLCs-loaded IVM versus IVM by quantifying the expression of caspase-3 mRNA. RESULTS: We found that after 60 and 120 min of administration, 800 µg/ml and 400 µg/ml NLCs-loaded IVM induced 100% mortality, respectively. On the other hand, the 800 µg/ml of IVM induced 100% mortality rate 150 min after administration. Additionally, we found that NLCs-loaded IVM induced higher mRNA caspase-3 expression suggesting a more potent apoptotic effect on the parasite. CONCLUSIONS: These data suggest that NLCs-loaded IVM may be a promising alternative to current treatments although in vivo studies are needed.


Assuntos
Antiparasitários/administração & dosagem , Equinococose/tratamento farmacológico , Echinococcus granulosus/efeitos dos fármacos , Ivermectina/administração & dosagem , Análise de Variância , Animais , Caspase 3/genética , Fragmentação do DNA , Portadores de Fármacos , Equinococose/parasitologia , Echinococcus granulosus/classificação , Echinococcus granulosus/genética , Echinococcus granulosus/ultraestrutura , Complexo IV da Cadeia de Transporte de Elétrons/genética , Técnicas de Genotipagem , Lipídeos , Microscopia Eletrônica de Varredura , Nanoestruturas , RNA Mensageiro/metabolismo , Ovinos
4.
Malar J ; 18(1): 332, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31564253

RESUMO

BACKGROUND: Misuse of long-lasting insecticidal nets together with resistance of vectors to most of the insecticides for indoor residual spraying and impregnated nets threaten malaria vector control interventions, requiring search for alternative control methods. Reports have shown that Anopheles mosquitoes die when they feed on endectocidal drugs used to treat humans and animals. A study was designed to investigate the efficacy of LongRange™ (eprinomectin 5%) on laboratory reared Anopheles arabiensis fed on treated calves. METHODS: Anopheles arabiensis from insectary colony was fed on three calves treated with therapeutic dose of LongRange™ eprinomectin (1 ml/50 kg) and on non-treated three other calves as control arm. For the feeding, mosquitoes were placed in paper cups covered with nylon cloth mesh and then allowed to feed on the necks of calves. Subsequently, mosquito survival, fecundity, egg hatchability, larval development and adult emergence were recorded. Data were entered and analysed by using SPSS version 20. The Kaplan-Meier survival analysis and independent sample t-test were used. RESULTS: All mosquitoes that fed on LongRange™ Eprinomectin treated calves died within 7 days following blood ingestion. The drug also slightly affected fecundity and hatchability of An. arabiensis. CONCLUSION: Treating livestock with LongRange™ (eprinomectin 5%) may serve as a supplementary control method for zoophagic An. arabiensis.


Assuntos
Anopheles , Inseticidas/administração & dosagem , Ivermectina/análogos & derivados , Controle de Mosquitos/métodos , Animais , Bioensaio , Bovinos , Comportamento Alimentar , Fertilidade , Injeções Subcutâneas , Ivermectina/administração & dosagem , Gado , Malária/transmissão , Mosquitos Vetores
5.
PLoS Negl Trop Dis ; 13(9): e0007685, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31483784

RESUMO

BACKGROUND: Despite decades of community-based mass drug administration (MDA) for neglected tropical diseases, it remains an open question as to what constitutes the best combination of community medicine distributors (CMDs) for achieving high (>65%/75%) treatment rates within a village. METHODS: Routine community-based MDA was evaluated in Mayuge District, Uganda. For one month, we tracked 6,148 individuals aged 1+ years in 1,118 households from 28 villages. Praziquantel, albendazole, and ivermectin were distributed to treat Schistosoma mansoni, lymphatic filariasis, and soil-transmitted helminths. The similarity/diversity between CMDs was observed and used to predict the division of labour and overall village treatment rates. The division of labour was calculated by dividing the lowest treatment rate by the highest treatment rate achieved by two CMDs within a village. CMD similarity was measured for 16 characteristics including friendship network overlap, demographic and socioeconomic factors, methods of CMD selection, and years as CMD. Relevant variables for MDA outcomes were selected through least absolute shrinkage and selection operators with leave-one-out cross validation. Final models were run with ordinary least squares regression and robust standard errors. RESULTS: The percentage of individuals treated with at least one drug varied across villages from 2.79-89.74%. The only significant predictor (p-value<0.05) of village treatment rates was the division of labour. The estimated difference between a perfectly equal (a 50-50 split of individuals treated) and unequal (one CMD treating no one) division of labour was 39.69%. A direct tie (close friendship) between CMDs was associated with a nearly twofold more equitable distribution of labour when compared to CMDs without a direct tie. CONCLUSIONS: An equitable distribution of labour between CMDs may be essential for achieving treatment targets of 65%/75% within community-based MDA. To improve the effectiveness of CMDs, national programmes should explore interventions that seek to facilitate communication, friendship, and equal partnership between CMDs.


Assuntos
Anti-Helmínticos/administração & dosagem , Agentes Comunitários de Saúde/estatística & dados numéricos , Filariose Linfática/tratamento farmacológico , Doenças Negligenciadas/tratamento farmacológico , Esquistossomose mansoni/tratamento farmacológico , Adolescente , Adulto , Idoso , Albendazol/administração & dosagem , Animais , Criança , Pré-Escolar , Medicina Comunitária/estatística & dados numéricos , Estudos Transversais , Feminino , Humanos , Lactente , Ivermectina/administração & dosagem , Masculino , Administração Massiva de Medicamentos , Pessoa de Meia-Idade , Praziquantel/administração & dosagem , População Rural , Uganda , Adulto Jovem
6.
PLoS Negl Trop Dis ; 13(9): e0007697, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31557154

RESUMO

BACKGROUND: Lymphatic filariasis (LF) is a neglected tropical disease, and the Global Program to Eliminate LF delivers mass drug administration (MDA) to 500 million people every year. Adverse events (AEs) are common after LF treatment. METHODOLOGY/PRINCIPAL FINDINGS: To better understand the pathogenesis of AEs, we studied LF-patients from a treatment trial. Plasma levels of many filarial antigens increased post-treatment in individuals with AEs, and this is consistent with parasite death. Circulating immune complexes were not elevated in these participants, and the classical complement cascade was not activated. Multiple cytokines increased after treatment in persons with AEs. A transcriptomic analysis was performed for nine individuals with moderate systemic AEs and nine matched controls. Differential gene expression analysis identified a significant transcriptional signature associated with post-treatment AEs; 744 genes were upregulated. The transcriptional signature was enriched for TLR and NF-κB signaling. Increased expression of seven out of the top eight genes upregulated in persons with AEs were validated by qRT-PCR, including TLR2. CONCLUSIONS/SIGNIFICANCE: This is the first global study of changes in gene expression associated with AEs after treatment of lymphatic filariasis. Changes in cytokines were consistent with prior studies and with the RNAseq data. These results suggest that Wolbachia lipoprotein is involved in AE development, because it activates TLR2-TLR6 and downstream NF-κB. Additionally, LPS Binding Protein (LBP, which shuttles lipoproteins to TLR2) increased post-treatment in individuals with AEs. Improved understanding of the pathogenesis of AEs may lead to improved management, increased MDA compliance, and accelerated LF elimination.


Assuntos
Filariose Linfática/tratamento farmacológico , Filaricidas/uso terapêutico , Adolescente , Adulto , Idoso , Albendazol/administração & dosagem , Albendazol/efeitos adversos , Antígenos de Helmintos/sangue , Citocinas/sangue , Citocinas/imunologia , Dietilcarbamazina/efeitos adversos , Dietilcarbamazina/uso terapêutico , Filariose Linfática/genética , Filariose Linfática/imunologia , Feminino , Filaricidas/efeitos adversos , Humanos , Ivermectina/administração & dosagem , Ivermectina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
7.
Malar J ; 18(1): 296, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31464619

RESUMO

BACKGROUND: Most malaria vector control programmes rely on indoor residual spraying of insecticides and insecticide-treated bed nets. This is effective against vector species that feed indoors at night and rest inside the house afterwards. In Central America, malaria vectors have different behaviours and are typically exophagic (i.e., bite outdoors), exophilic (i.e., remain outdoors after feeding), and zoophagic (i.e., as likely to feed on non-humans as humans). Thus, malaria elimination in Central America may require additional tactics. This pilot study investigated whether commercially-available products used to treat livestock for ticks could also be used to kill and/or sterilize zoophagic malaria vectors that feed on treated cattle in Belize. METHODS: Cattle were treated with either a pour-on formulation of 1% fipronil (3 heifers) or injection of 1% ivemectin (1 heifer). Control heifers (n = 2) were left untreated. Field-collected Anopheles albimanus contained in screen-top cages were strapped onto cattle at 2, 5, 7, and 14 days after treatment. Mosquito mortality was monitored once a day for 4 successive days. Surviving mosquitoes were dissected to assess blood meal digestion and ovarian development. RESULTS: A total of 1078 female An. albimanus mosquitoes were fed and monitored for mortality. Both fipronil and ivermectin significantly reduced survivorship of An. albimanus for up to 7 days after treatment. By 14 days, efficacy had declined. The ivermectin treatment completely lost its effectiveness and even though the fipronil-treated heifers were still killing significantly more mosquitoes than the untreated heifers, the amount of mosquito killing had diminished greatly. Both treatments significantly reduced ovary development in mosquitoes fed on treated cattle for the duration of the 2-week trial. CONCLUSIONS: Treatment of cattle in northern Belize with topical fipronil and injectable ivermectin had significant lethal and sublethal effects on wild An. albimanus females. These results suggest that efforts towards eliminating residual transmission of malaria by zoophagic vectors in Central America may benefit by the judicious, targeted treatment of livestock with mosquitocidal compounds, such as fipronil or ivermectin.


Assuntos
Inseticidas/administração & dosagem , Ivermectina/administração & dosagem , Controle de Mosquitos/métodos , Ovário/efeitos dos fármacos , Pirazóis/administração & dosagem , Administração Tópica , Animais , Belize , Bovinos , Comportamento Alimentar , Feminino , Injeções Intramusculares/efeitos adversos , Malária/prevenção & controle , Masculino , Mosquitos Vetores/parasitologia , Projetos Piloto
8.
PLoS Negl Trop Dis ; 13(7): e0007541, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31314753

RESUMO

BACKGROUND: The World Health Organization (WHO) currently recommends height or age-based dosing as alternatives to weight-based dosing for mass drug administration lymphatic filariasis (LF) elimination programs. The goals of our study were to compare these alternative dosing strategies to weight-based dosing and to develop and evaluate new height-based dosing pole scenarios. METHODOLOGY/PRINCIPAL FINDINGS: Age, height and weight data were collected from >26,000 individuals in five countries during a cluster randomized LF clinical trial. Weight-based dosing for diethylcarbamazine (DEC; 6 mg/kg) and ivermectin (IVM; 200 ug/kg) with tablet numbers derived from a table of weight intervals was treated as the "gold standard" for this study. Following WHO recommended age-based dosing of DEC and height-based dosing of IVM would have resulted in 32% and 27% of individuals receiving treatment doses below those recommended by weight-based dosing for DEC and IVM, respectively. Underdosing would have been especially common in adult males, who tend to have the highest LF prevalence in many endemic areas. We used a 3-step modeling approach to develop and evaluate new dosing pole cutoffs. First, we analyzed the clinical trial data using quantile regression to predict weight from height. We then used weight predictions to develop new dosing pole cutoff values. Finally, we compared different dosing pole cutoffs and age and height-based WHO dosing recommendations to weight-based dosing. We considered hundreds of scenarios including country- and sex-specific dosing poles. A simple dosing pole with a 6-tablet maximum for both DEC and IVM reduced the underdosing rate by 30% and 21%, respectively, and was nearly as effective as more complex pole combinations for reducing underdosing. CONCLUSIONS/SIGNIFICANCE: Using a novel modeling approach, we developed a simple dosing pole that would markedly reduce underdosing for DEC and IVM in MDA programs compared to current WHO recommended height or age-based dosing.


Assuntos
Cálculos da Dosagem de Medicamento , Filariose Linfática/prevenção & controle , Filaricidas/administração & dosagem , Administração Massiva de Medicamentos/métodos , Razão Cintura-Estatura , Adolescente , Adulto , Estatura , Peso Corporal , Criança , Estudos de Coortes , Dietilcarbamazina/administração & dosagem , Feminino , Saúde Global , Humanos , Ivermectina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Prevalência , Análise de Regressão , Adulto Jovem
10.
Emerg Infect Dis ; 25(8): 1574-1576, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31310225

RESUMO

We describe the outcomes of 16 cases of imported loiasis in Italy. Patients had microfilaremia <20,000/mL and were treated with high-dose albendazole for 28 days and a single dose of ivermectin. This combination might be an effective treatment option in nonendemic areas, when diethylcarbamazine, the drug of choice, is not available.


Assuntos
Albendazol/administração & dosagem , Antiprotozoários/administração & dosagem , Doenças Transmissíveis Importadas/tratamento farmacológico , Doenças Transmissíveis Importadas/parasitologia , Ivermectina/administração & dosagem , Loíase/tratamento farmacológico , Adolescente , Adulto , Idoso , Biomarcadores , Quimioterapia Combinada , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Itália , Loíase/parasitologia , Masculino , Pessoa de Meia-Idade , Avaliação de Sintomas , Resultado do Tratamento , Adulto Jovem
11.
Vet Parasitol ; 270 Suppl 1: S58-S63, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31182302

RESUMO

The efficacy of three consecutive monthly treatments with a novel topical product (Revolution® Plus/Stronghold® Plus, Zoetis) containing selamectin in combination with the isoxazoline, sarolaner, was compared with that of another topical isoxazoline, fluralaner [Bravecto® (fluralaner topical solution) for Cats, Merck] against Ixodes scapularis ticks on cats. Twenty-four cats were ranked by pre-treatment tick counts to form groups of three and were randomly allocated to be treated with placebo, the minimum label dosage of Revolution® Plus (6 mg/kg selamectin plus 1 mg/kg sarolaner) or the minimum label dosage of Bravecto® for Cats (40 mg/kg fluralaner) within the groups. On Days 0, 30, and 60, each cat in the placebo and Revolution® Plus-treated groups was treated topically, whereas cats in the Bravecto® for Cats-treated group were treated topically once on Day 0 with fluralaner and, subsequently, these animals were treated with the placebo on Days 30 and 60 to maintain masking. Doses were calculated based on weight to provide the minimum label dosage for each product; the calculated volume of product to be administered was rounded off to the nearest 0.1 mL. The selamectin plus sarolaner-treated cats received effective dosages of 5.29-7.12 mg/kg selamectin and 0.88-1.19 mg/kg sarolaner, while the fluralaner cats received dosages of 35.21-43.16 mg/kg fluralaner. Cats were infested with approximately 50 unfed viable adult I. scapularis ticks on Days 5, 12, 26, 40, 54, 68, 82, and 88. Efficacy was assessed at 48 h after each infestation. There were no adverse reactions to any treatment during the study. The placebo-treated cats maintained adequate tick infestations throughout the study. Three monthly treatments with selamectin plus sarolaner (Revolution® Plus) resulted in high and consistent efficacy against I. scapularis for up to 30 days after each treatment. Based on geometric means, efficacy was ≥99.1% at all time points assessed. Treatment with fluralaner (Bravecto® for Cats) provided high and consistent efficacy of ≥99.3% up to Day 70. On Day 84, efficacy was 90.1%; however, cats from which ticks were recovered on Day 84 had received approximately 4%-12% less than the minimum dosage of 40 mg/kg fluralaner. Three consecutive monthly treatments with Revolution® Plus or a single treatment with Bravecto® for Cats provided >90% control of I. scapularis ticks over a 12-week time period.


Assuntos
Antiparasitários/administração & dosagem , Azetidinas/administração & dosagem , Doenças do Gato/tratamento farmacológico , Isoxazóis/administração & dosagem , Ivermectina/análogos & derivados , Compostos de Espiro/administração & dosagem , Controle de Ácaros e Carrapatos , Infestações por Carrapato/veterinária , Administração Tópica , Animais , Gatos , Composição de Medicamentos/veterinária , Feminino , Ivermectina/administração & dosagem , Ixodes/efeitos dos fármacos , Masculino , Infestações por Carrapato/tratamento farmacológico , Resultado do Tratamento
12.
J Vet Pharmacol Ther ; 42(5): 497-504, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31183888

RESUMO

The purpose of this study was to determine the pharmacokinetic interaction between ivermectin (0.4 mg/kg) and praziquantel (10 mg/kg) administered either alone or co-administered to dogs after oral treatment. Twelve healthy cross-bred dogs (weighing 18-21 kg, aged 1-3 years) were allocated randomly into two groups of six dogs (four females, two males) each. In first group, the tablet forms of praziquantel and ivermectin were administered using a crossover design with a 15-day washout period, respectively. Second group received tablet form of ivermectin plus praziquantel. The plasma concentrations of ivermectin and praziquantel were determined by high-performance liquid chromatography using a fluorescence and ultraviolet detector, respectively. The pharmacokinetic parameters of ivermectin following oral alone-administration were as follows: elimination half-life (t1/2λz ) 110 ± 11.06 hr, area under the plasma concentration-time curve (AUC0-∞ ) 7,805 ± 1,768 hr. ng/ml, maximum concentration (Cmax ) 137 ± 48.09 ng/ml, and time to reach Cmax (Tmax ) 14.0 ± 4.90 hr. The pharmacokinetic parameters of praziquantel following oral alone-administration were as follows: t1/2λz 7.39 ± 3.86 hr, AUC0-∞ 4,301 ± 1,253 hr. ng/ml, Cmax 897 ± 245 ng/ml, and Tmax 5.33 ± 0.82 hr. The pharmacokinetics of ivermectin and praziquantel were not changed, except Tmax of praziquantel in the combined group. In conclusion, the combined formulation of ivermectin and praziquantel can be preferred in the treatment and prevention of diseases caused by susceptible parasites in dogs because no pharmacokinetic interaction was determined between them.


Assuntos
Antiparasitários/farmacocinética , Cães/sangue , Ivermectina/farmacocinética , Praziquantel/farmacocinética , Administração Oral , Animais , Antiparasitários/administração & dosagem , Área Sob a Curva , Interações de Medicamentos , Feminino , Meia-Vida , Ivermectina/administração & dosagem , Ivermectina/sangue , Masculino , Praziquantel/administração & dosagem , Praziquantel/sangue
13.
J Exp Clin Cancer Res ; 38(1): 265, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31215501

RESUMO

BACKGROUND: Discovery and development of novel drugs that are capable of overcoming drug resistance in tumor cells are urgently needed clinically. In this study, we sought to explore whether ivermectin (IVM), a macrolide antiparasitic agent, could overcome the resistance of cancer cells to the therapeutic drugs. METHODS: We used two solid tumor cell lines (HCT-8 colorectal cancer cells and MCF-7 breast cancer cells) and one hematologic tumor cell line (K562 chronic myeloid leukemia cells), which are resistant to the chemotherapeutic drugs vincristine and adriamycin respectively, and two xenograft mice models, including the solid tumor model in nude mice with the resistant HCT-8 cells and the leukemia model in NOD/SCID mice with the resistant K562 cells to investigate the reversal effect of IVM on the resistance in vitro and in vivo. MTT assay was used to investigate the effect of IVM on cancer cells growth in vitro. Flow cytometry, immunohistochemistry, and immunofluorescence were performed to investigate the reversal effect of IVM in vivo. Western blotting, qPCR, luciferase reporter assay and ChIP assay were used to detect the molecular mechanism of the reversal effect. Octet RED96 system and Co-IP were used to determine the interactions between IVM and EGFR. RESULTS: Our results indicated that ivermectin at its very low dose, which did not induce obvious cytotoxicity, drastically reversed the resistance of the tumor cells to the chemotherapeutic drugs both in vitro and in vivo. Mechanistically, ivermectin reversed the resistance mainly by reducing the expression of P-glycoprotein (P-gp) via inhibiting the epidermal growth factor receptor (EGFR), not by directly inhibiting P-gp activity. Ivermectin bound with the extracellular domain of EGFR, which inhibited the activation of EGFR and its downstream signaling cascade ERK/Akt/NF-κB. The inhibition of the transcriptional factor NF-κB led to the reduced P-gp transcription. CONCLUSIONS: These findings demonstrated that ivermectin significantly enhanced the anti-cancer efficacy of chemotherapeutic drugs to tumor cells, especially in the drug-resistant cells. Thus, ivermectin, a FDA-approved antiparasitic drug, could potentially be used in combination with chemotherapeutic agents to treat cancers and in particular, the drug-resistant cancers.


Assuntos
Doxorrubicina/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ivermectina/administração & dosagem , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Vincristina/administração & dosagem , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Reposicionamento de Medicamentos , Sinergismo Farmacológico , Receptores ErbB/metabolismo , Feminino , Células HCT116 , Humanos , Ivermectina/farmacologia , Células K562 , Células MCF-7 , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , NF-kappa B/metabolismo , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Vincristina/farmacologia
14.
Vet Parasitol ; 270: 1-6, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31213235

RESUMO

In 2016 suspected reduced ivermectin (IVM) efficacy in Oesophagostomum species in pigs was reported in England. Following this initial report, APHA raised awareness amongst private pig veterinary practitioners of the need to monitor the efficacy of the worm control on pig units. In 2017 another veterinary practitioner highlighted a potential in-field lack of IVM efficacy in treating Oesophagostomum species in sows on another breeder-finisher unit. In this trial, the efficacy of IVM against Oesophagostomum species worms has been investigated to determine whether suspected reduced efficacy (52% reduction in mean faecal egg count 14 days post ivermectin administration) on a mixed indoor and outdoor breeder-finisher pig farm in England reflected true IVM resistance under controlled experimental conditions. On days 0 and 40 of the trial, twenty helminth-naive pigs were artificially infected per os with 5000 Oesophagostomum L3 obtained from the farm under investigation. The pigs were allocated to treatment or control groups (n = 10 per group). Treatment group pigs received IVM (0.3 mg kg body weight) by sub-cutaneous injection as per manufacturer's instructions on day 44. Control group animals were left untreated. Faecal worm egg counts were monitored throughout the trial from day 15 post infection to determine time to patency. On day 50 all pigs were euthanased to assess the worm burdens. Resistance to IVM was confirmed in Oesophagostomum dentatum based on the results of a faecal egg count reduction test (FECRT) and a controlled efficacy test (CET). Efficacy based on mean reduction in faecal egg count of IVM-treated pigs compared to untreated control pigs was 86%. Mean reduction in IVM-treated pig worm burdens was 5% against an adult worm population and 94% against an L3/L4 population. The apparent discrepancy between FECRT and CET efficacy results appears to be due to egg development and/or oviposition suppression in IVM-treated female worms. The detection of IVM resistance in Oesophagostomum species worms for the first time in UK pigs is particularly important considering the global situation where resistance to pyrantel, levamisole and benzimidazole anthelmintics in Oesophagostomum species in pigs have already been reported. The results also provide an opportunity to discuss the wider issue of anthelmintic usage and efficacy on pig farms and highlight the need for wider surveillance for the occurrence of anthelmintic resistance in pigs.


Assuntos
Resistência a Medicamentos , Ivermectina/farmacologia , Esofagostomíase/veterinária , Oesophagostomum/efeitos dos fármacos , Doenças dos Suínos/parasitologia , Animais , Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/farmacologia , Inglaterra , Fezes/parasitologia , Ivermectina/administração & dosagem , Esofagostomíase/tratamento farmacológico , Esofagostomíase/parasitologia , Contagem de Ovos de Parasitas , Suínos , Doenças dos Suínos/tratamento farmacológico
16.
Acta Parasitol ; 64(3): 456-463, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31165992

RESUMO

PURPOSE: Concordance of multiple anthelmintic resistances for gastrointestinal nematodes in small ruminants by three average-based and two individually based fecal egg count reduction (FECR) tests was evaluated and corrected. METHODS: Sheep and goats (≥ 8 weeks) from five farms were randomly assigned to three treatment groups (I, II, III; n = 10 per group) and one untreated control group (Group IV; n = 10). Group I received fenbendazole at the dose rate of 5 and 10 mg/kg, Group II received ivermectin at the dose rate of 0.2 and 0.4 mg/kg, and Group III received levamisole at the dose rate of 8 and 12 mg/kg body weight orally for sheep and goat, respectively. Three average-based methods of FECR (FECR1, FECR2 and FECR3) and two individually based methods of FECR (iFECR1 and iFECR2) were evaluated. RESULTS: For fenbendazole resistance, Spearman correlation coefficient for FECR1 was non-significant with other formulae, but for FECR2 with FECR3, FECR3 with iFECR1 and iFECR1 with iFECR2 coincidence was significant at 1%, while for FECR2 with iFECR2 and FECR3 with iFECR2 it was significant at 5%. Spearman correlation coefficients for ivermectin resistance were significant at 1% level and for levamisole it showed significant coincidence at 1% for FECR1 with FECR2 and iFECR1, FECR2 with FECR3 and iFECR1, and iFECR1 with iFECR2, while for FECR1 with FECR3 and iFECR2 coincidence was significant at 5% level. Concordance of kappa values indicated that the coincidence of the prevalence of anthelmintic resistance (95% CI) among the five farms was non-significant. CONCLUSIONS: Concordance between the standard average-based FECR and individually based methods suggests that either method could be applied to small ruminant farms.


Assuntos
Anti-Helmínticos/administração & dosagem , Resistência a Medicamentos , Fezes/parasitologia , Doenças das Cabras/parasitologia , Nematoides/efeitos dos fármacos , Infecções por Nematoides/veterinária , Contagem de Ovos de Parasitas/métodos , Doenças dos Ovinos/parasitologia , Animais , Feminino , Fenbendazol/administração & dosagem , Trato Gastrointestinal/parasitologia , Doenças das Cabras/tratamento farmacológico , Cabras , Índia , Ivermectina/administração & dosagem , Levamisol/administração & dosagem , Masculino , Nematoides/isolamento & purificação , Nematoides/fisiologia , Infecções por Nematoides/parasitologia , Ovinos , Doenças dos Ovinos/tratamento farmacológico
17.
Vet Parasitol ; 270 Suppl 1: S38-S44, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31104940

RESUMO

The efficacy and safety of a new topical formulation containing selamectin plus sarolaner (Revolution® Plus / Stronghold® Plus, Zoetis) was evaluated for the prevention of heartworm (Dirofilaria immitis) disease and the treatment of roundworm infection in cats enrolled as veterinary patients in two field studies conducted in Japan. In the heartworm field study, 91 cats negative for D. immitis antigen and anti-D. immitis antibody were enrolled and received 9 monthly topical treatments with selamectin plus sarolaner during the period of April to December 2015. Efficacy was assessed by testing post-treatment blood samples collected 8, 12, and 15 months after initiation of treatment for the presence of D. immitis antigen and anti-D. immitis antibody. Eighty-seven cats completed the entire study and were included in the determination of efficacy. No D. immitis antigen or anti-D. immitis antibody were detected in any of the post-treatment samples. In the roundworm field study, completed in the period from April to November 2015, 64 cats with ≥100 roundworm eggs per gram (EPG) of feces were enrolled and allocated randomly in a 1:1 ratio, to receive either selamectin plus sarolaner or emodepside plus praziquantel (Profender®, Bayer). Treatments were administered topically on Days 0 and 30, and efficacy was assessed by fecal EPG counts conducted on Days 14, 30, and 60. All cats completed the entire study. At enrollment, all cats were infected with Toxocara cati. Compared to pre-treatment, geometric mean T. cati EPG counts on Days 14, 30, and 60 were reduced by >99.9% in both treatment groups. There were no treatment-related adverse events in either study. Monthly topical administration of Revolution® Plus / Stronghold® Plus providing a minimum of 6 mg/kg selamectin and 1 mg/kg sarolaner was safe and effective in the prevention of heartworm disease and the treatment of roundworm infection in cats enrolled as veterinary patients in Japan.


Assuntos
Antiparasitários/administração & dosagem , Azetidinas/administração & dosagem , Doenças do Gato/prevenção & controle , Dirofilariose/prevenção & controle , Enteropatias Parasitárias/veterinária , Ivermectina/análogos & derivados , Infecções por Nematoides/veterinária , Compostos de Espiro/administração & dosagem , Administração Tópica , Animais , Doenças do Gato/tratamento farmacológico , Doenças do Gato/parasitologia , Gatos , Dirofilaria immitis/efeitos dos fármacos , Dirofilaria immitis/imunologia , Dirofilariose/tratamento farmacológico , Dirofilariose/parasitologia , Composição de Medicamentos/veterinária , Feminino , Helmintíase/tratamento farmacológico , Helmintíase/parasitologia , Helmintíase/prevenção & controle , Enteropatias Parasitárias/tratamento farmacológico , Enteropatias Parasitárias/parasitologia , Enteropatias Parasitárias/prevenção & controle , Ivermectina/administração & dosagem , Masculino , Infecções por Nematoides/tratamento farmacológico , Infecções por Nematoides/parasitologia , Infecções por Nematoides/prevenção & controle , Contagem de Ovos de Parasitas/veterinária , Distribuição Aleatória , Toxocara/efeitos dos fármacos , Resultado do Tratamento
18.
PLoS Negl Trop Dis ; 13(5): e0007325, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31107869

RESUMO

BACKGROUND: A single co-administered dose of ivermectin (IVM) plus diethylcarbamazine (DEC) plus albendazole (ALB), or triple-drug therapy, was recently found to be more effective for clearing microfilariae (Mf) than standard DEC plus ALB currently used for mass drug administration programs for lymphatic filariasis (LF) outside of sub-Saharan Africa. Triple-drug therapy has not been previously tested in LF-uninfected individuals from Africa. This study evaluated the pharmacokinetics (PK), safety, and efficacy of triple-drug therapy in people with and without Wuchereria bancrofti infection in West Africa. METHODS: In this open-label cohort study, treatment-naïve microfilaremic (>50 mf/mL, n = 32) and uninfected (circulating filarial antigen negative, n = 24) adults residing in Agboville district, Côte d'Ivoire, were treated with a single dose of IVM plus DEC plus ALB, and evaluated for adverse events (AEs) until 7 days post treatment. Drug levels were assessed by liquid chromatography and mass spectrometry. Persons responsible for assessing AEs were blinded to participants' infection status. FINDINGS: There was no difference in AUC0-inf or Cmax between LF-infected and uninfected participants (P>0.05 for all comparisons). All subjects experienced mild AEs; 28% and 25% of infected and uninfected participants experienced grade 2 AEs, respectively. There were no severe or serious adverse events. Only fever (16 of 32 versus 4 of 24, P<0.001) and scrotal pain/swelling in males (6 of 20 versus 0 of 12, P = 0.025) were more frequent in infected than uninfected participants. All LF positive participants were amicrofilaremic at 7 days post-treatment and 27 of 31 (87%) remained amicrofilaremic 12 months after treatment. CONCLUSIONS: Moderate to heavy W. bancrofti infection did not affect PK parameters for IVM, DEC or ALB following a single co-administered dose of these drugs compared to uninfected individuals. The drugs were well tolerated. This study confirmed the efficacy of the triple-drug therapy for clearing W. bancrofti Mf and has added important information to support the use of this regimen in LF elimination programs in areas of Africa without co-endemic onchocerciasis or loiasis. TRIAL REGISTRATION: ClinicalTrials.gov NCT02845713.


Assuntos
Albendazol/administração & dosagem , Dietilcarbamazina/administração & dosagem , Filariose Linfática/tratamento farmacológico , Filaricidas/administração & dosagem , Ivermectina/administração & dosagem , Wuchereria bancrofti/efeitos dos fármacos , Adolescente , Adulto , Idoso , Albendazol/efeitos adversos , Albendazol/farmacocinética , Animais , Estudos de Coortes , Costa do Marfim , Dietilcarbamazina/efeitos adversos , Dietilcarbamazina/farmacocinética , Combinação de Medicamentos , Filariose Linfática/parasitologia , Feminino , Filaricidas/efeitos adversos , Filaricidas/farmacocinética , Humanos , Ivermectina/efeitos adversos , Ivermectina/farmacocinética , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Wuchereria bancrofti/fisiologia , Adulto Jovem
19.
PLoS Negl Trop Dis ; 13(5): e0007436, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31120872

RESUMO

Despite worldwide mass drug administration, it is estimated that 68 million individuals are still infected with lymphatic filariasis with 19 million hydrocele and 17 million lymphedema reported cases. Despite the staggering number of pathology cases, the majority of LF-infected individuals do not develop clinical symptoms and present a tightly regulated immune system characterized by higher frequencies of regulatory T cells (Treg), suppressed proliferation and Th2 cytokine responses accompanied with increased secretion of IL-10, TGF-ß and infection-specific IgG4. Nevertheless, the filarial-induced modulation of the host`s immune system and especially the role of regulatory immune cells like regulatory B (Breg) and Treg during an ongoing LF infection remains unknown. Thus, we analysed Breg and Treg frequencies in peripheral blood from Ghanaian uninfected endemic normals (EN), lymphedema (LE), asymptomatic patent (CFA+MF+) and latent (CFA+MF-) W. bancrofti-infected individuals as well as individuals who were previously infected with W. bancrofti (PI) but had cleared the infection due to the administration of ivermectin (IVM) and albendazole (ALB). In summary, we observed that IL-10-producing CD19+CD24highCD38dhigh Breg were specifically increased in patently infected (CFA+MF+) individuals. In addition, CD19+CD24highCD5+CD1dhigh and CD19+CD5+CD1dhighIL-10+ Breg as well as CD4+CD127-FOXP3+ Treg frequencies were significantly increased in both W. bancrofti-infected cohorts (CFA+MF+ and CFA+MF-). Interestingly, the PI cohort presented frequency levels of all studied regulatory immune cell populations comparable with the EN group. In conclusion, the results from this study show that an ongoing W. bancrofti infection induces distinct Breg and Treg populations in peripheral blood from Ghanaian volunteers. Those regulatory immune cell populations might contribute to the regulated state of the host immune system and are probably important for the survival and fertility (microfilaria release) of the helminth.


Assuntos
Anti-Helmínticos/administração & dosagem , Linfócitos B Reguladores/imunologia , Filariose Linfática/tratamento farmacológico , Filariose Linfática/imunologia , Interleucina-10/imunologia , Linfócitos T Reguladores/imunologia , Wuchereria bancrofti/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Albendazol/administração & dosagem , Animais , Filariose Linfática/genética , Filariose Linfática/parasitologia , Feminino , Gana , Humanos , Interleucina-10/genética , Ivermectina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Células Th2/imunologia , Adulto Jovem
20.
BMJ Case Rep ; 12(4)2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036733

RESUMO

Hypereosinophilic syndromes are rare in children. Sporadic, mild-severity FIP1L1-platelet-derived growth factor receptor α (PDGFRα) rearrangement cases have been reported, mainly in boys. We present the case of a 5-year-old girl referred from her African country of birth, due to severe constitutional symptoms, multifocal bone pain, headache, gastrointestinal complaints, cardiomyopathy and unexplained hypereosinophilia. She presented multiple end-organ diseases and striking bone involvement. Although she had a positive serology for Strongyloides stercoralis, extensive evaluation detected a FIP1L1-PDGFRA fusion gene. Systemic corticosteroids and low-dose imatinib were started and the child became asymptomatic. After 9 months of treatment, FIP1L1-PDGFRA was no longer detected.


Assuntos
Corticosteroides/uso terapêutico , Síndrome Hipereosinofílica/genética , Estrongiloidíase/parasitologia , Corticosteroides/administração & dosagem , África/epidemiologia , Albendazol/administração & dosagem , Albendazol/uso terapêutico , Animais , Anti-Helmínticos/uso terapêutico , Antiparasitários/uso terapêutico , Doenças Ósseas/diagnóstico por imagem , Doenças Ósseas/patologia , Pré-Escolar , Combinação de Medicamentos , Feminino , Humanos , Síndrome Hipereosinofílica/tratamento farmacológico , Síndrome Hipereosinofílica/patologia , Mesilato de Imatinib/administração & dosagem , Mesilato de Imatinib/uso terapêutico , Ivermectina/administração & dosagem , Ivermectina/uso terapêutico , Proteínas de Fusão Oncogênica , Inibidores de Proteínas Quinases/uso terapêutico , Doenças Raras , Receptor alfa de Fator de Crescimento Derivado de Plaquetas , Strongyloides stercoralis/imunologia , Estrongiloidíase/complicações , Estrongiloidíase/diagnóstico , Resultado do Tratamento , Fatores de Poliadenilação e Clivagem de mRNA
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