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1.
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 Medicamentosas , Feminino , Meia-Vida , Ivermectina/administração & dosagem , Ivermectina/sangue , Masculino , Praziquantel/administração & dosagem , Praziquantel/sangue
2.
Chemosphere ; 234: 528-535, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31229714

RESUMO

Veterinary drugs enter the environment in many ways and may affect non-target organisms, including plants. The present project was focused on the biotransformation of ivermectin (IVM), one of the mostly used anthelmintics, in the model plant Arabidopsis thaliana. Our results certified the ability of plants to uptake IVM by roots and translocate it to the aboveground parts. Using UHPLC-MS/MS, six metabolites in roots and only the parent drug in rosettes were found after 24- and 72-h incubation of A. thaliana with IVM. The metabolites were formed only via hydroxylation and demethylation, with no IVM conjugates detected. Although IVM did not induce changes in the activity of antioxidant enzymes in A. thaliana rosettes, the expression of genes was significantly affected. Surprisingly, a higher number of transcripts, 300 and 438, respectively, was dysregulated in the rosettes than in roots. The significantly affected genes play role in response to salt, osmotic and water deprivation stress, in response to pathogens and in ion homeostasis. We hypothesize that the above described changes in gene transcription in A. thaliana resulted from disrupted ionic homeostasis caused by certain ionophore properties of IVM. Our results underlined the negative impact of IVM presence in the environment.


Assuntos
Arabidopsis/genética , Ivermectina/farmacocinética , Transcriptoma/efeitos dos fármacos , Anti-Helmínticos/metabolismo , Anti-Helmínticos/farmacocinética , Arabidopsis/efeitos dos fármacos , Arabidopsis/metabolismo , Biotransformação , Ivermectina/metabolismo , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/metabolismo , Espectrometria de Massas em Tandem
3.
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
4.
Vet Parasitol ; 268: 81-86, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30981310

RESUMO

This study aimed to determine the relationship between the variation in plasma concentration of ivermectin 3.15% over time and its efficacy against the cattle tick Rhipicephalus (Boophilus) microplus. In addition, a trial was conducted to infer if the application of successive treatments with ivermectin 3.15% could affect its accumulation in cattle. A noticeable variation of ivermectin plasma concentration was observed among the treated heifers. However, these differences did not have a significant effect onthe therapeutic efficacy of the treatment at the end of the trial. No significant differences were observed in the levels of tick infestations between heifers of the treated group; moreover, no significant correlation was detected between the plasma AUC0-21 of ivermectin 3.15% and the cumulative number of ticks of each heifer. Levels of therapeutic efficacy higher than 80% were observed only from day 7 post-treatment, when levels of ivermectin concentration were higher than 8 ng/ml. The lowest values of therapeutic efficacy were observed during the first and the second days post-treatment, when plasma concentrations of ivermectin 3.15% were lower than 8 ng/ml. Viable engorged females were collected from the heifers belonging to the treated group from days 1-5 post-treatment. There was a significant accumulation of the drug after the second dose of ivermectin 3.15%. Ivermectin concentrations in fat biopsies were 366 ng/g (51 days after the first treatment), 275 ng/g (51 days after the second treatment) and 15 ng/g (64 days after the second treatment). These results suggest that applications of successive treatments with ivermectin 3.15% might increase its accumulation in cattle tissues, extending the withdrawal period indicated for the commercial formulation.


Assuntos
Acaricidas/farmacocinética , Doenças dos Bovinos/tratamento farmacológico , Ivermectina/farmacocinética , Infestações por Carrapato/veterinária , Acaricidas/uso terapêutico , Animais , Bovinos/parasitologia , Feminino , Ivermectina/uso terapêutico , Rhipicephalus , Infestações por Carrapato/tratamento farmacológico
5.
Parasit Vectors ; 12(1): 124, 2019 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-30890165

RESUMO

BACKGROUND: Outdoor, early-biting, zoophagic behaviours by Anopheles farauti (s.s.) can compromise the effectiveness of bed nets for malaria control. In the Western Pacific region, pigs and dogs represent significant alternative blood sources for mosquitoes. Treating these animals with endectocides may impact mosquito survival and complement control measures. This hypothesis was explored using membrane feeding assays (MFAs), direct feeds on treated pigs, pharmacokinetic analyses and a transmission model. RESULTS: Ivermectin was 375-fold more mosquitocidal than moxidectin (24 h LC50 = 17.8 ng/ml vs 6.7 µg/ml) in MFAs, and reduced mosquito fecundity by > 50% at ≥ 5 ng/ml. Treatment of pigs with subcutaneous doses of 0.6 mg/kg ivermectin caused 100% mosquito mortality 8 days after administration. Lethal effects persisted for up to 15 days after administration (75% death within 10 days). CONCLUSION: The application of these empirical data to a unique malaria transmission model that used a three-host system (humans, pigs and dogs) predicts that the application of ivermectin will cause a significant reduction in the entomological inoculation rate (EIR = 100 to 0.35). However, this is contingent on local malaria vectors sourcing a significant proportion of their blood meals from pigs. This provides significant insights on the benefits of deploying endectocides alongside long-lasting insecticide-treated nets (LLINs) to address residual malaria transmission.


Assuntos
Anopheles/efeitos dos fármacos , Inseticidas/administração & dosagem , Ivermectina/administração & dosagem , Macrolídeos/administração & dosagem , Malária/prevenção & controle , Administração Cutânea , Animais , Comportamento Alimentar , Feminino , Fertilidade/efeitos dos fármacos , Inseticidas/sangue , Inseticidas/farmacocinética , Inseticidas/farmacologia , Ivermectina/sangue , Ivermectina/farmacocinética , Ivermectina/farmacologia , Macrolídeos/sangue , Macrolídeos/farmacocinética , Macrolídeos/farmacologia , Malária/transmissão , Modelos Biológicos , Controle de Mosquitos/métodos , Papua Nova Guiné , Distribuição Aleatória , Suínos
6.
Pest Manag Sci ; 75(10): 2756-2764, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30859694

RESUMO

BACKGROUND: Poorly water-soluble and photosensitive pesticide compounds are difficult to be formulated as environmentally friendly formulations with high efficacy. Conventional wettable powder, emulsifiable concentrate and emulsion in water have disadvantages of dust drift, overuse of organic solvent and low efficacy. Therefore, there is an urgent need to construct a novel formulation to improve the bioavailability of pesticides. RESULTS: An abamectin nanosuspension was developed using a wet-milling method combined with orthogonal experimental design. The average particle sizes of the abamectin nanosuspension measured by dynamic light scattering, scanning electron microscope and transmission electron microscope were 233, 90 and 140 nm, respectively. The zeta potential and sliding angle on cabbage leaves were -36.9 mV and 62°. Retention and anti-photolysis were around 1.5 and 1.6 times those of emulsions in water. Furthermore, the biological activity of the nanosuspension towards diamondback moths was approximately twice that of conventional formulations. CONCLUSION: This study provides an easy and scalable technique for constructing pesticide nanosuspensions. The preparation and composition of the nanosuspension avoid the use of organic solvents. Application of the highly effective nanoformulation will significantly enhance pesticide efficacy, and reduce the dosage and environmental pollution of the pesticide. © 2019 Society of Chemical Industry.


Assuntos
Acaricidas/farmacocinética , Antinematódeos/farmacocinética , Inseticidas/farmacocinética , Ivermectina/análogos & derivados , Nanopartículas/química , Disponibilidade Biológica , Ivermectina/farmacocinética , Tamanho da Partícula , Solubilidade , Molhabilidade
7.
Carbohydr Polym ; 214: 131-141, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30925981

RESUMO

Progress at elimination of malaria is limited by the challenges of reaching large rural population and ensuring patient adherence to adequate pharmacologic treatment. In the present study, a novel material (octadecylamine modified chondroitin sulfate) was synthesized, to fabricate a long acting release meshy gel system as an efficient weapon for protracted warfare to malaria. Ivermectin loaded meshy gels (IVM-MG) composed of different amount of phospholipids, triglyceride and modified chondroitin sulfate were formulated. They were in aqueous state with low viscosity before injection, but rapidly turned into gel state with significantly increased viscosity upon exposure to an aqueous environment after injection. In vitro study proved a sustained released effect in different releasing media. In vivo study showed no irritation at injection site and slowly drug release over a 30-day release period in rat model. Among the three IVM-MG formulations, IVM-MG-3 with the highest amount of octadecylamine modified chondroitin sulfate presented the highest viscosity increase after solution-gel transition, the least initial burst release, and the longest sustained release effect over 30 days in rat model. Furthermore, by using mathematical models, IVM-MG system could boost the efficacy of mass drug administration toward malaria elimination goals. Meshy gel systems for long-acting drug delivery have the potential to revolutionize treatment options for malaria and other diseases of which treatment adherence is essential for their efficacy.


Assuntos
Aminas/química , Antimaláricos/farmacocinética , Sulfatos de Condroitina/química , Portadores de Fármacos/química , Géis/química , Ivermectina/farmacocinética , Aminas/administração & dosagem , Aminas/síntese química , Animais , Antimaláricos/administração & dosagem , Sulfatos de Condroitina/administração & dosagem , Sulfatos de Condroitina/síntese química , Culicidae/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/química , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Liberação Controlada de Fármacos , Etanol/efeitos adversos , Etanol/química , Géis/administração & dosagem , Géis/síntese química , Injeções , Inseticidas/administração & dosagem , Inseticidas/farmacocinética , Ivermectina/administração & dosagem , Masculino , Camundongos , Modelos Teóricos , Ratos Wistar , Pele/patologia , Substâncias Viscoelásticas/administração & dosagem , Substâncias Viscoelásticas/síntese química , Substâncias Viscoelásticas/química , Viscosidade
8.
Vet Parasitol ; 266: 73-79, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30736951

RESUMO

We evaluated the comparative plasma disposition kinetics and efficacy of moxidectin (MXD), administered by the intraruminal (IR) or subcutaneous (SC) route at two different dosage levels (0.2 and 1 mg/kg) in feedlot calves. Additionally, the efficacy was compared to an ivermectin (IVM, SC administration) treated group. This study was divided into two separate studies, the "Pharmacokinetic (PK) study" and the "Efficacy study". The "PK study" involved 24 calves free of gastrointestinal nematodes (GIN), which were allocated into 4 groups (n = 6) and treated with MXD by either the SC or the IR route at the therapeutic (MXDSC0.2, MXDIR0.2, respectively) or at fivefold the therapeutic dose (MXDSC1.0, MXDIR1.0, respectively). Blood samples were collected from 3 h up to 14 days post-treatment. MXD concentrations in plasma samples were analyzed by HPLC. The "Efficacy study" included 125 calves naturally infected with GIN, which were allocated into five experimental groups (n = 25 each); the same four MXD-treated groups described for the "PK study", and an additional group treated by the SC route with IVM (IVMSC0.2). The efficacy of IVM given at its therapeutic dose and the different MXD groups at the therapeutic and fivefold the therapeutic dose was calculated by analysis of the individual efficacy using the package eggCounts-2.1-1' on the R software environment, version 3.5.0 (R Core Team, 2018). Daily weight gain (DWG) was also measured over the first 47 days of the fattening cycle. Independently of the administration route, MXD peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) were higher in groups treated with the higher dose (1.0 mg/kg), whereas a longer time to reach Cmax (Tmax) was observed after the IR treatments. The observed MXD efficacies were 85% (MXDSC0.2), 94% (MXDSC1.0), 84% (MXDIR0.2) and 99% (MXDIR1.0), at day +27. At day +27, all MXD-treated groups showed higher efficacies than the group having received IVM (45%). The post-treatment Cooperia spp. L3 counts were particularly low in the groups MXDSC1.0 and MXDIR1.0. All of the groups treated with MXD showed better DWG than the IVMSC0.2 group (P = 0.01). Dose and administration route modifications effectively improved the anthelmintic and productive performance of MXD. A high dose of MXD improved the control of IVM-resistant GIN in feedlot calves. However, this practice must be taken with caution, since MXD resistance could rapidly emerge, especially in grazing cattle.


Assuntos
Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/farmacocinética , Macrolídeos/administração & dosagem , Macrolídeos/farmacocinética , Animais , Anti-Helmínticos/uso terapêutico , Área Sob a Curva , Bovinos , Doenças dos Bovinos/tratamento farmacológico , Doenças dos Bovinos/parasitologia , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos/veterinária , Resistência a Medicamentos , Trato Gastrointestinal/parasitologia , Ivermectina/administração & dosagem , Ivermectina/farmacocinética , Ivermectina/uso terapêutico , Macrolídeos/uso terapêutico , Nematoides/efeitos dos fármacos , Contagem de Ovos de Parasitas , Resultado do Tratamento
9.
Ecotoxicol Environ Saf ; 169: 944-949, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30597795

RESUMO

Ivermectin (IVM), a macrocylic lactone from the avermectin family, is a potent broad-spectrum anthelmintic drug widely used in veterinary as well as human medicine. Although the health benefits of IVM treatment are particularly important, this drug also represents an environmental pollutant with potentially negative effects on many non-target species. To evaluate the ecotoxicological risk of IVM administration to livestock, information evaluating achievable environment-reaching concentration is needed. Therefore, the present study was designed to determine the excretion profile of subcutaneously administered IVM in sheep. The standard recommended dose of IVM (0.2 mg kg-1 b.w.) was used. UHPLC/MS/MS was used for the analysis of IVM faecal concentration. In addition, the effect of IVM on seed germination and early roots growth of white mustard (Sinapis alba L.) was evaluated in order to estimate the potential phytotoxic effect of IVM. Based on the obtained results, the parameters of IVM pharmacokinetics (maximum concentration (cmax), time to achieve maximum concentration (tmax), mean residence time (MRT), area under the curve (AUC)) were calculated. IVM elimination in sheep was slow, but faster than the elimination reported previously in cattle. Great interindividual differences were also observed. A two-peak profile of concentration curves indicate the importance of the active efflux of IVM via enterocytes. A "seed germination and early roots growth" test revealed significant IVM phytotoxicity (20% inhibition of root growth) even at 50 nM concentration, a level which may be found in the environment. This newly demonstrated phytotoxicity of IVM together with its well-known toxicity to invertebrates should be taken into account, and thus animals treated with IVM should not be kept in pastures, especially not in sites with high ecological value.


Assuntos
Anti-Helmínticos/farmacocinética , Anti-Helmínticos/toxicidade , Poluição Ambiental/efeitos adversos , Ivermectina/farmacocinética , Ivermectina/toxicidade , Sinapis/efeitos dos fármacos , Animais , Área Sob a Curva , Bovinos , Ecotoxicologia , Poluição Ambiental/análise , Fezes/química , Injeções Subcutâneas , Ovinos , Sinapis/crescimento & desenvolvimento
10.
Clin Pharmacol Ther ; 105(2): 388-401, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30125353

RESUMO

High-dose ivermectin, co-administered for 3 days with dihydroartemisinin-piperaquine (DP), killed mosquitoes feeding on individuals for at least 28 days posttreatment in a recent trial (IVERMAL), whereas 7 days was predicted pretrial. The current study assessed the relationship between ivermectin blood concentrations and the observed mosquitocidal effects against Anopheles gambiae s.s. Three days of ivermectin 0, 300, or 600 mcg/kg/day plus DP was randomly assigned to 141 adults with uncomplicated malaria in Kenya. During 28 days of follow-up, 1,393 venous and 335 paired capillary plasma samples, 850 mosquito-cluster mortality rates, and 524 QTcF-intervals were collected. Using pharmacokinetic/pharmacodynamic (PK/PD) modeling, we show a consistent correlation between predicted ivermectin concentrations and observed mosquitocidal-effects throughout the 28-day study duration, without invoking an unidentified mosquitocidal metabolite or drug-drug interaction. Ivermectin had no effect on piperaquine's PKs or QTcF-prolongation. The PK/PD model can be used to design new treatment regimens with predicted mosquitocidal effect. This methodology could be used to evaluate effectiveness of other endectocides.


Assuntos
Anopheles , Antimaláricos/farmacologia , Antimaláricos/farmacocinética , Artemisininas/farmacologia , Artemisininas/farmacocinética , Inseticidas/farmacologia , Inseticidas/farmacocinética , Ivermectina/farmacologia , Ivermectina/farmacocinética , Malária/tratamento farmacológico , Quinolinas/farmacologia , Quinolinas/farmacocinética , Adulto , Animais , Relação Dose-Resposta a Droga , Método Duplo-Cego , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Humanos , Quênia , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/epidemiologia , Masculino , Resultado do Tratamento
11.
Drug Res (Stuttg) ; 69(3): 173-180, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30103215

RESUMO

The bioavailability of ivermectin is modulated by lipid-based formulations and membrane efflux transporters such as Breast Cancer Resistance Protein and P-glycoprotein (BCRP and P-gp). We have investigated the effect of oleic acid on the uptake of ivermectin in vitro using Caco-2 cells and in vivo in the intestines of wild-type mice. Complex micelles (M) with oleic acid induced a significant increase (e. g. for M3 was 7-fold, p≤0.001) in the uptake of the drug in a time-dependent manner with no involvement of cholesterol in the mechanism. In vivo results showed a significant increase in the concentration of plasma and intestinal mucosa ivermectin (p≤0.01) in mice receiving oleic acid-based drug formulation. We also examined the expression of the drug efflux transporter, BCRP and P-gp in Caco-2 cells and found a significant decrease (p≤0.001) in their level in the presence of 5 mM oleic acid. Treatment of mice with oleic acid-based formulation showed a significant decrease in the activity of P-gp in the intestinal mucosa (p≤0.01). This study highlighted the effect of oleic acid in decreasing the expression and the activity of P-gp-mediated ivermectin efflux and in limiting the drug absorption by increasing its uptake and bioavailability in Caco-2 cells and intestine, respectively.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Ivermectina/farmacocinética , Ácido Oleico/farmacologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Interações Medicamentosas , Humanos , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Ivermectina/sangue , Camundongos
12.
J Vet Pharmacol Ther ; 42(2): 189-196, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30520071

RESUMO

The aim of the current study was to evaluate the in vivo pharmacokinetic of ivermectin (IVM) after the administration of a long-acting (LA) formulation to sheep and its impact on potential drug-drug interactions. The work included the evaluation of the comparative plasma profiles of IVM administered at a single therapeutic dose (200 µg/kg) and as LA formulation at 630 µg/kg. Additionally, IVM was measured in different gastrointestinal tissues at 15 days posttreatment with both IVM formulations. The impact of the long-lasting and enhanced IVM exposure on the disposition kinetics of abamectin (ABM) was also assessed. Plasma (IVM and ABM) and gastrointestinal (IVM) concentrations were analyzed by HPLC with fluorescent detection. In plasma, the calculated Cmax and AUC0-t values of the IVM-LA formulation were 1.47- and 3.35-fold higher compared with IVM 1% formulation, respectively. The T1/2ab and Tmax collected after administration of the LA formulation were 2- and 3.5-fold longer than those observed after administration of IVM 1% formulation, respectively. Significantly higher IVM concentrations were measured in the intestine mucosal tissues and luminal contents with the LA formulation, and in the liver, the increase was 7-fold higher than conventional formulation. There was no drug interaction between IVM and ABM after the single administration of ABM at 15 days post-administration of the IVM LA formulation. The characterization of the kinetic behavior of the LA formulation to sheep and its potential influence on drug-drug interactions is a further contribution to the field.


Assuntos
Anti-Helmínticos/farmacocinética , Ivermectina/farmacocinética , Ovinos/metabolismo , Animais , Anti-Helmínticos/análise , Anti-Helmínticos/sangue , Cromatografia Líquida de Alta Pressão/veterinária , Preparações de Ação Retardada , Interações Medicamentosas , Injeções Subcutâneas , Intestinos/química , Ivermectina/administração & dosagem , Ivermectina/análise , Ivermectina/sangue , Fígado/química , Masculino , Ovinos/parasitologia
13.
Artigo em Inglês | MEDLINE | ID: mdl-30323047

RESUMO

Soil-transmitted helminth (STH) infections still remain a major health problem in poor rural settings. The lack of efficacious drugs against all STH species raises interest in drug combinations. Drug-drug interactions (DDIs) are, however, of major concern, so careful in vitro and in vivo characterization is needed. The combination of tribendimidine with either ivermectin or oxantel pamoate targets a broad range of STHs and thus represents a promising treatment alternative. Drug-drug interactions, however, have not yet been investigated. Therefore, the effects of combinations of ivermectin, oxantel pamoate, and tribendimidine's active metabolite deacylated amidantel (dADT) on cytochrome P450 (CYP450) metabolism were evaluated, followed by a pharmacokinetic analysis of tribendimidine and ivermectin alone and in combination in healthy rats. Oxantel pamoate is only poorly absorbed and was therefore excluded from pharmacokinetic analysis. No evident effect was observed for tribendimidine-oxantel pamoate at the CYP450 metabolism level, whereas a combination of tribendimidine and ivermectin led to moderately increased CYP2D6 inhibition compared to ivermectin or tribendimidine alone. Coadministration of tribendimidine with ivermectin altered neither the time to maximum concentration of drug in plasma (T max) nor the elimination half-lives of dADT, the acetylated derivative of amidantel (adADT), and ivermectin. While the area under the concentration-versus-time curve (AUC) and maximum concentration of drug in plasma (C max) values of dADT, adADT, and ivermectin are reduced by coadministration, the change is insufficient to declare that a DDI has been detected. Further studies are necessary to understand the observed interaction of tribendimidine and ivermectin, which is not related to P450 metabolism, and its significance for the situation in humans.


Assuntos
Anti-Helmínticos/farmacocinética , Sistema Enzimático do Citocromo P-450/metabolismo , Ivermectina/farmacocinética , Fenilenodiaminas/farmacocinética , Pamoato de Pirantel/análogos & derivados , Animais , Anti-Helmínticos/farmacologia , Área Sob a Curva , Inibidores das Enzimas do Citocromo P-450/farmacocinética , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Interações Medicamentosas , Quimioterapia Combinada , Helmintíase Animal/tratamento farmacológico , Helmintos/efeitos dos fármacos , Ivermectina/farmacologia , Masculino , Fenilenodiaminas/farmacologia , Pamoato de Pirantel/farmacocinética , Pamoato de Pirantel/farmacologia , Ratos
14.
Br J Clin Pharmacol ; 85(3): 626-633, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30566757

RESUMO

AIMS: The anthelminthic ivermectin is receiving new attention as it is being repurposed for new indications such as mass drug administrations for the treatment of scabies or in malaria vector control. As its pharmacokinetics are still poorly understood, we aimed to characterize the population pharmacokinetics of ivermectin in plasma and dried blood spots (DBS), a sampling method better suited to field trials, with special focus on the influence of body composition and enterohepatic circulation. METHODS: We performed a clinical trial in 12 healthy volunteers who each received a single oral dose of 12 mg ivermectin, and collected peripheral venous and capillary DBS samples. We determined ivermectin concentrations in plasma and DBS by liquid chromatography tandem mass spectrometry using a fully automated and scalable extraction system for DBS sample processing. Pharmacokinetic data were analysed using non-linear mixed effects modelling. RESULTS: A two-compartment model with a transit absorption model, first-order elimination, and weight as an influential covariate on central volume of distribution and clearance best described the data. The model estimates (inter-individual variability) for a 70 kg subject were: apparent population clearance 7.7 (25%) l h-1 , and central and peripheral volumes of distribution 89 (10%) l and 234 (20%) l, respectively. Concentrations obtained from DBS samples were strongly linearly correlated (R2  = 0.97) with plasma concentrations, and on average 30% lower. CONCLUSION: The model accurately depicts population pharmacokinetics of plasma and DBS concentrations over time for oral ivermectin. The proposed analytical workflow is scalable and applicable to the requirements of mass drug administrations.


Assuntos
Antiparasitários/farmacocinética , Teste em Amostras de Sangue Seco , Ivermectina/farmacocinética , Administração Oral , Adulto , Antiparasitários/administração & dosagem , Reposicionamento de Medicamentos/normas , Estudos de Viabilidade , Feminino , Voluntários Saudáveis , Humanos , Ivermectina/administração & dosagem , Malária/prevenção & controle , Masculino , Administração Massiva de Medicamentos/normas , Modelos Biológicos , Mosquitos Vetores/efeitos dos fármacos , Escabiose/tratamento farmacológico , Fatores de Tempo , Adulto Jovem
15.
Colloids Surf B Biointerfaces ; 175: 291-299, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30553204

RESUMO

In an effort to improve the utilization of pesticides, an environmentally friendly carrier material was prepared to encapsulate pesticides and to prevent pesticides from decomposing under natural conditions with sustained-release effect. The carrier of feather keratin-hyaluronic acid (FK-HA) was prepared by Maillard reaction. Using avermectin (AVM) as a model drug, AVM/FK-HA was obtained by heating. Its structure and morphology were measured by SDS-PAGE, Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), thermal gravimetric analyzer (TGA) and dynamic light scattering (DLS). Furthermore, the encapsulation efficiency, anti-UV, sustained-release and toxicological properties were investigated. The results showed that AVM/FK-HA featured an average particle size of 473.82 nm, with nearly spherical shape. Furthermore, the material exhibited a high surface charge and was capable of homogeneous dispersion. The encapsulation efficiency was found to be as high as 81.25%. Compared to pure AVM, the pesticide encapsulated by FK-HA (i.e. AVM/FK-HA) could reduce drug decomposition by 20% after ultraviolet irradiation for 52 h. Moreover, mass ratio, temperature and varying pH values exhibited an effect on the sustained release of the drug and the release mechanism was consistent with Fick diffusion. Finally, the difference between the toxicological effects of AVM encapsulated by FK-HA and pure AVM were not significant.


Assuntos
Preparações de Ação Retardada/farmacocinética , Plumas/química , Ácido Hialurônico/química , Ivermectina/análogos & derivados , Queratinas/química , Animais , Galinhas , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos da radiação , Concentração de Íons de Hidrogênio , Ivermectina/química , Ivermectina/farmacocinética , Ivermectina/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura , Raios Ultravioleta
16.
Vet Parasitol ; 263: 18-22, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30389019

RESUMO

Psoroptic mange is an important parasitic disease that mainly affects beef cattle producing marked economic losses. Ivermectin (IVM) is considered one of the most effective treatments against psoroptic mange and is used worldwide to control both endo and ectoparasites in different species. The current work assessed the relationship between pharmacokinetic behavior of IVM and its efficacy against Psoroptes ovis after the subcutaneous administration of two commercial formulations in a cattle feedlot. Aberdeen Angus and Hereford steers were selected based on the presence of active mite infestations. Animals were allocated into 4 experimental groups and treated with a single (day 0) or repeated subcutaneous injection (days 0 and 7) of one of two commercial formulations of IVM (1%) at 0.2 mg/kg. Blood and skin samples were taken from 8 randomly selected animals of each experimental group to measure IVM concentrations by HPLC. Skin scrapings were also collected from six different sites in each animal, mites were counted and ranked based on a density score. Equivalent plasma concentrations of IVM were measured after the administration of IVM formulations under study. The repeated administration of both IVM formulations at day 0 and 7 accounted for a greater plasma drug availability compared with the single administration (P < 0.05). IVM was well distributed from the plasma to the skin without significant differences between both IVM formulations. There was a positive correlation between IVM concentrations in skin and plasma (r: 0.73 P < 0.0001). The mean ratios between IVM availabililty (measured as AUC) in the skin and in plasma were between 1.2 and 2.1. The repeated administration of IVM increased significantly the IVM concentrations in the skin of areas affected by mange. IVM failed to obtain a parasitological cure in the different groups affected by mange. The failure was observed with both formulations administeredat single or repeated doses. Based on the number of animals cured, the range of efficacy was between 0% on day 7 and 60% on day 28 post-treatment. No significant differences in the P. ovis density scores were observed after the IVM treatment at single or repeated doses. Additional studies are needed to confirm the presence of resistant strains of P.ovis and to establish the appropriate measures to control these parasitic infestations in feedlot cattle.


Assuntos
Composição de Medicamentos , Ivermectina/farmacocinética , Ivermectina/uso terapêutico , Infestações por Ácaros/veterinária , Ácaros/efeitos dos fármacos , Psoroptidae/efeitos dos fármacos , Falha de Tratamento , Animais , Bovinos , Doenças dos Bovinos/tratamento farmacológico , Doenças dos Bovinos/parasitologia , Injeções Subcutâneas , Ivermectina/administração & dosagem , Infestações por Ácaros/tratamento farmacológico , Doenças Parasitárias em Animais/tratamento farmacológico , Pele/parasitologia
17.
J Agric Food Chem ; 66(43): 11244-11253, 2018 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-30299946

RESUMO

Avermectin (AVM) as a nonsystemic pesticide possesses a low effective utilization rate. Studies of the multifunctional pesticide delivery system for improving biological activity are developing prosperously. In this study, multifunctional avermectin/polysuccinimide with glycine methyl ester nanoparticles (AVM-PGA) were prepared by the self-assembly process. The AVM loading capacity was up to 23.7%. After 24 h of UV irradiation, there was still about 70% of AVM remaining in PGA42 nanocarriers, as opposed to less than 5% of the free-form AVM. The rising ambient pH promoted the release of AVM using an in vitro releasing test, revealing a favorable pH-responsively controlled-release property. The mortality rate of Plutella xylostella with 2.5 µg/mL of AVM content of AVM-PGA42 was 96.3% after 48 h, while that of free AVM was only 51.5%. In addition, the AVM could be detected in stems and all leaves treated with AVM-PGA42 nanoparticles, whereas rare AVM was detected only in treated leaves for the free-form AVM, which achieved the transportation of nanocarriers carrying AVM in rice for the first time. Furthermore, the PGA nanoparticles performed a good growth promoting effect on rice. These results show that the AVM-PGA42 nanopesticides have a great potential application prospect to control the pest and improve the drug utilization efficiency on agriculture.


Assuntos
Ácido Aspártico/análogos & derivados , Ivermectina/análogos & derivados , Nanopartículas , Oryza/química , Peptídeos/química , Praguicidas/química , Animais , Ácido Aspártico/química , Ácido Aspártico/farmacocinética , Ivermectina/química , Ivermectina/farmacocinética , Lepidópteros , Peptídeos/farmacocinética , Praguicidas/farmacocinética , Folhas de Planta/química
18.
Am J Trop Med Hyg ; 99(6): 1580-1582, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30334520
19.
Vet Clin North Am Small Anim Pract ; 48(6): 991-1012, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30139545

RESUMO

Overdoses of macrocyclic lactones in dogs and cats can result in such signs as tremors, ataxia, seizures, coma, and blindness. Dogs with the ABCB1-1Δ gene defect are predisposed to macrocyclic lactone toxicosis at lower dosages than dogs without the defect. Intravenous lipid emulsion therapy has been suggested for treatment of macrocyclic lactone toxicosis but evidence of efficacy is limited. Initial decontamination and supportive care remain the mainstays of therapy for macrocyclic lactone toxicosis.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/farmacologia , Anti-Helmínticos/toxicidade , Doenças do Gato/induzido quimicamente , Doenças do Cão/induzido quimicamente , Ivermectina/análogos & derivados , Macrolídeos/toxicidade , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Doenças do Gato/genética , Doenças do Gato/terapia , Gatos , Doenças do Cão/genética , Doenças do Cão/terapia , Cães , Emulsões Gordurosas Intravenosas/uso terapêutico , Genótipo , Ivermectina/farmacocinética , Ivermectina/toxicidade , Lactonas , Macrolídeos/farmacocinética , Convulsões/induzido quimicamente , Convulsões/terapia , Convulsões/veterinária
20.
Vet Parasitol ; 256: 43-49, 2018 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-29887029

RESUMO

The study compared the pharmacokinetic (PK) behaviour and anthelmintic efficacy against susceptible and resistant nematodes following subcutaneous (SC) and oral administration of ivermectin (IVM) to cattle. Six commercial farms were involved: Farms 1 and 2 (IVM-susceptible nematode population) and Farms 3, 4, 5 and 6 (IVM-resistant nematode population). On each farm, forty-five calves naturally infected with gastrointestinal (GI) nematodes were randomly allocated into three groups (n = 15): untreated control, IVM SC administration, and IVM oral administration (both at 0.2 mg/kg). PK assessment (plasma and faeces) was performed on Farm 1. Efficacy was determined by Faecal Egg Count Reduction Test. IVM systemic availability upon SC administration (421 ±â€¯70.3 ng·d/mL) was higher (P < 0.05) compared to the oral treatment (132 ±â€¯31.3 ng·d/mL). However, higher (P < 0.05) faecal IVM concentrations were observed following oral treatment (9896 ±â€¯1931 ng·d/mL) compared to SC administration (4760 ±â€¯924 ng·d/mL). Similar (91-93%) IVM efficacy was observed on Farms 1 and 2 by both routes. Efficacy against resistant nematodes was slightly higher on Farms 3 and 4 after the oral (63 and 82%, respectively) compared to the SC (36 and 68%, respectively) treatment. However, there was complete therapeutic failure (0% efficacy) on Farm 5 and a very low response on Farm 6 (40 and 41% for SC and oral administration, respectively). Although larger faecal concentrations following IVM oral administration may increase drug exposure of GI adult worms, this does not always improve efficacy against resistant nematodes. The potential therapeutic advantages of oral treatments should be cautiously assessed, especially in presence of anthelmintic resistance.


Assuntos
Ivermectina/farmacologia , Ivermectina/farmacocinética , Nematoides/efeitos dos fármacos , Administração Intravenosa , Administração Oral , Animais , Antiparasitários/administração & dosagem , Antiparasitários/farmacocinética , Antiparasitários/farmacologia , Antiparasitários/uso terapêutico , Bovinos , Doenças dos Bovinos/tratamento farmacológico , Resistência a Medicamentos/efeitos dos fármacos , Ivermectina/administração & dosagem , Ivermectina/uso terapêutico , Infecções por Nematoides/tratamento farmacológico , Distribuição Aleatória
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