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

RESUMO

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


Assuntos
Antiparasitários/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Ivermectina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Administração por Inalação , Animais , Antiparasitários/farmacocinética , Antiparasitários/farmacologia , Comportamento Animal/efeitos dos fármacos , Infecções por Coronavirus/patologia , Relação Dose-Resposta a Droga , Feminino , Meia-Vida , Ivermectina/farmacocinética , Ivermectina/farmacologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Necrose , Pandemias , Pneumonia Viral/patologia , Estudo de Prova de Conceito , Ratos , Ratos Sprague-Dawley , Transtornos Respiratórios/tratamento farmacológico , Transtornos Respiratórios/patologia
2.
J Pharm Sci ; 109(12): 3574-3578, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32891630

RESUMO

SARS-CoV-2 utilizes the IMPα/ß1 heterodimer to enter host cell nuclei after gaining cellular access through the ACE2 receptor. Ivermectin has shown antiviral activity by inhibiting the formation of the importin-α (IMPα) and IMPß1 subunits as well as dissociating the IMPα/ß1 heterodimer and has in vitro efficacy against SARS-CoV-2. Plasma and lung ivermectin concentrations vs. time profiles in cattle were used to determine the apparent plasma to lung tissue partition coefficient of ivermectin. This coefficient, together with a simulated geometric mean plasma profile of ivermectin from a published population pharmacokinetic model, was utilized to develop a minimal physiologically-based pharmacokinetic (mPBPK) model. The mPBPK model accurately described the simulated ivermectin plasma concentration profile in humans. The mPBPK model was also used to simulate human lung exposure to ivermectin after 12, 30, and 120 mg oral doses. The simulated ivermectin lung exposures reached a maximum concentration of 772 ng/mL, far less than the estimated 1750 ng/mL IC50 reported for ivermectin against SARS-CoV-2 in vitro. Further studies of ivermectin either reformulated for inhaled delivery or in combination with other antivirals with differing mechanisms of action is needed to assess its therapeutic potential.


Assuntos
Antivirais/farmacocinética , Infecções por Coronavirus/tratamento farmacológico , Ivermectina/farmacocinética , Pulmão/metabolismo , Pneumonia Viral/tratamento farmacológico , Administração Oral , Animais , Antivirais/administração & dosagem , Antivirais/sangue , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/metabolismo , Bovinos , Simulação por Computador , Infecções por Coronavirus/metabolismo , Reposicionamento de Medicamentos , Humanos , Ivermectina/administração & dosagem , Ivermectina/sangue , Ivermectina/farmacologia , Modelos Biológicos , Pandemias , Pneumonia Viral/metabolismo
3.
PLoS One ; 15(8): e0236143, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790679

RESUMO

The focus of gastro-intestinal parasite control in the sheep industry is increasingly on finding a balance between maintaining productivity of the flock whilst minimising selection for anthelmintic resistance to preserve anthelmintic efficacy for the future. Periparturient ewes represent the major source of gastro-intestinal parasites for growing lambs and are therefore a priority for parasite control. This study examines the impact on ewe faecal egg counts (FECs), lamb FECs, lamb daily live weight gains (DLWGs) and pasture larval counts of treating groups of ewes two weeks prior to lambing with either, a long-acting moxidectin treatment, short-acting doramectin or control. Six groups of twenty ewes were allocated to individual paddocks, two groups allocated to each treatment, and weekly faecal sampling was performed throughout from the ewes and from six weeks after the start of lambing in the lambs. Treatment group was found to have a significant effect on both ewe FEC (p<0.001) and lamb FEC (p = 0.001) with the group receiving the long-acting anthelmintic having the lowest ewe and lamb FECs. There was no significant effect on the DLWGs of the lambs. Pasture larval counts at the end of the study period were lowest in the long-acting wormer treatment group. The use of long-acting moxidectin may be helpful as part of a parasite control programme by reducing the worm burdens of ewes and their lambs, decreasing the number of anthelmintic treatments required in that year and by reducing pasture contamination for those sheep which will graze the pasture in the next year. However, like all anthelmintics, its use should be judicious to avoid selection for resistance.


Assuntos
Criação de Animais Domésticos/métodos , Anti-Helmínticos/administração & dosagem , Infecções por Nematoides/veterinária , Doenças dos Ovinos/tratamento farmacológico , Ovinos/parasitologia , Animais , Anti-Helmínticos/farmacocinética , Fazendas , Fezes/parasitologia , Feminino , Meia-Vida , Ivermectina/administração & dosagem , Ivermectina/análogos & derivados , Ivermectina/farmacocinética , Larva , Macrolídeos/administração & dosagem , Macrolídeos/farmacocinética , Nematoides/isolamento & purificação , Infecções por Nematoides/diagnóstico , Infecções por Nematoides/tratamento farmacológico , Infecções por Nematoides/parasitologia , Contagem de Ovos de Parasitas/veterinária , Período Pós-Parto , Gravidez , Doenças dos Ovinos/diagnóstico , Doenças dos Ovinos/parasitologia
4.
Artigo em Inglês | MEDLINE | ID: mdl-32660993

RESUMO

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


Assuntos
Antimaláricos/farmacologia , Cloroquina/farmacologia , Ivermectina/farmacologia , Fígado/efeitos dos fármacos , Malária/tratamento farmacológico , Plasmodium cynomolgi/efeitos dos fármacos , Animais , Antimaláricos/sangue , Antimaláricos/farmacocinética , Disponibilidade Biológica , Cloroquina/sangue , Cloroquina/farmacocinética , Esquema de Medicação , Combinação de Medicamentos , Sinergismo Farmacológico , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/parasitologia , Ivermectina/sangue , Ivermectina/farmacocinética , Fígado/parasitologia , Macaca mulatta , Malária/parasitologia , Masculino , Parasitemia/tratamento farmacológico , Plasmodium cynomolgi/crescimento & desenvolvimento , Plasmodium cynomolgi/patogenicidade , Cultura Primária de Células , Esquizontes/efeitos dos fármacos , Esquizontes/crescimento & desenvolvimento
5.
J Environ Sci Health B ; 55(6): 517-524, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32065572

RESUMO

The current study estimated the dissipation rates of abamectin, chlorfenapyr and pyridaben acaricides in pods of green beans (Phaseolus vulgaris L.) under field conditions in Egypt. Pesticides were extracted and cleaned-up by QuEChERS method and were analyzed by HPLC. The dissipation of these acaricides followed the first order kinetics model with half-life (t1/2) values 1.00, 3.50 and 1.50 days for abamectin, chlorfenapyr and pyridaben, respectively. The lowest residues, at different time intervals of field application rate of each pesticide, were observed with abamectin followed by pyridaben and then chlorfenapyr. Pre-harvest intervals (PHIs) were 10.00, 13.50 and 6.00 days for abamectin, chlorfenapyr and pyridaben, respectively and were below the established European maximum residue limits (EU MRLs) 10-14, 14-21 and 7-10 days after application, respectively. If the fresh pods will be consumed after harvest, it is expected that the presence of these pesticides in the food will have a negative impact on human health. Therefore, the elimination of the residues of these harmful pesticides must be carried out.


Assuntos
Acaricidas/farmacocinética , Ivermectina/análogos & derivados , Phaseolus/efeitos dos fármacos , Piretrinas/farmacocinética , Piridazinas/farmacocinética , Acaricidas/análise , Fracionamento Químico , Cromatografia Líquida de Alta Pressão , Egito , Contaminação de Alimentos/análise , Humanos , Ivermectina/análise , Ivermectina/farmacocinética , Cinética , Resíduos de Praguicidas/análise , Phaseolus/metabolismo , Piretrinas/análise , Piridazinas/análise
6.
Vet Parasitol ; 279: 109010, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32035291

RESUMO

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


Assuntos
Antinematódeos/farmacologia , Doenças dos Bovinos/tratamento farmacológico , Haemonchus/efeitos dos fármacos , Ivermectina/análogos & derivados , Ivermectina/farmacologia , Rabditídios/efeitos dos fármacos , Animais , Antinematódeos/farmacocinética , Bovinos , Interações Medicamentosas , Hemoncose/tratamento farmacológico , Hemoncose/veterinária , Ivermectina/farmacocinética , Masculino , Distribuição Aleatória , Infecções por Rhabditida/tratamento farmacológico , Infecções por Rhabditida/veterinária
7.
Sci Rep ; 10(1): 932, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31969584

RESUMO

The avermectin derivative emamectin benzoate (EMB) has been widely used by salmon industries around the world to control sea lice infestations. Resistance to this anti-parasitic drug is also commonly reported in these industries. The objective of this study was to quantify the number of sea lice potentially exposed to sub-lethal concentrations of EMB while fish clear the drug after treatments. We assessed juvenile sea lice abundance after 38 EMB treatments on six Atlantic salmon farms, in a small archipelago in British Colombia, Canada, between 2007 and 2018. We fitted a standard EMB pharmacokinetic curve to determine the time when fish treated with this product would have EMB tissue concentrations below the recommended target therapeutic level. During the study, we estimated that for each sea lice treatment there was, on average, an abundance of 0.12 juvenile sea lice per fish during the time period when the concentrations of EMB would have been lower than 60ppb, the recommended therapeutic treatment level for sea lice. The findings from this study on metaphylactic anti-parasitic treatments identify a potential driver for drug resistance in sea lice that should be further explored.


Assuntos
Copépodes/efeitos dos fármacos , Ivermectina/análogos & derivados , Salmo salar/parasitologia , Animais , Antiparasitários/farmacocinética , Antiparasitários/farmacologia , Canadá , Colômbia , Relação Dose-Resposta a Droga , Resistência a Medicamentos , Ivermectina/farmacocinética , Ivermectina/farmacologia , Fatores de Risco , Salmo salar/metabolismo , Distribuição Tecidual
8.
Acta Trop ; 202: 105249, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31678122

RESUMO

Ivermectin is a widely used drug for the treatment of various neglected tropical diseases, such as lymphatic filariasis, onchocerciasis, and strongyloidiasis among others. Despite its excellent safety profile, there are few published studies of the use of ivermectin in children, pregnant and nursing women. In the present study, we report clinical data on ivermectin concentrations in breastmilk of a woman with Strongyloides stercoralis and HTLV-I coinfection. Ivermectin levels in breastmilk ranged from 1.4 to 20.8 ng/ml, with a mean of 9.26 ng/ml after a single dose of 200 µg/kg. We estimated the possible ivermectin exposure of the infant to be 1.1 µg/kg, 0.55% of the weight-adjusted percentage of the maternal dose. This value is largely under the threshold established by the World Health Organization for safe breastfeeding. Our results bolster previous findings on the secretion of ivermectin into breastmilk in healthy volunteers. The findings from this case study do not support exclusion of lactating women or interrupting lactation to accommodate it.


Assuntos
Ivermectina/farmacocinética , Strongyloides stercoralis , Estrongiloidíase/tratamento farmacológico , Adulto , Animais , Aleitamento Materno , Coinfecção/tratamento farmacológico , Coinfecção/metabolismo , Feminino , Infecções por HTLV-I/tratamento farmacológico , Infecções por HTLV-I/metabolismo , Humanos , Ivermectina/administração & dosagem , Ivermectina/uso terapêutico , Leite Humano/química , Leite Humano/efeitos dos fármacos , Doenças Negligenciadas , Strongyloides stercoralis/efeitos dos fármacos , Estrongiloidíase/metabolismo
9.
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
10.
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
11.
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
12.
Clin Pharmacol Ther ; 106(3): 661-667, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30993667

RESUMO

Ivermectin is a commonly used broad-spectrum antiparasitic drug, yet doses that produce consistent exposure coverage across age have not been characterized, and no data are available in children weighing < 15 kg. First, a population pharmacokinetic model is developed based on data from 200 children and 11 adults, treated with 100-600 µg/kg ivermectin. Second, model-based simulations are performed to identify a dosing strategy that achieves equivalent exposure coverage in children and adults. Median (90% confidence interval) clearance of 0.346 (0.12-0.73) L/hour/kg in pre-school-aged (2-5 years) children is similar to 0.352 (0.17-0.69) L/hour/kg in school-aged (6-12 years) children but higher than in adults (0.199 (0.10-0.31) L/hour/kg), resulting in significantly lower exposure in children following a 200 µg/kg dose. Simulations indicate that a dose increase to 300 and 250 µg/kg in children aged 2-5 and 6-12 years, respectively, will achieve equivalent ivermectin exposure coverage in children and adults.


Assuntos
Antiparasitários/administração & dosagem , Antiparasitários/farmacocinética , Ivermectina/administração & dosagem , Ivermectina/farmacocinética , Fatores Etários , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Humanos , Taxa de Depuração Metabólica , Modelos Biológicos
13.
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
14.
J Antimicrob Chemother ; 74(6): 1642-1647, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30859185

RESUMO

BACKGROUND: Yearly, millions of children are treated globally with ivermectin mainly for neglected tropical diseases. Anatomical, physiological and biochemical differences between children and adults may result in changes in pharmacokinetics. However, paediatric pharmacokinetic data of ivermectin are lacking. METHODS: In the framework of a randomized controlled dose-finding trial in rural Côte d'Ivoire, Trichuris trichiura-infected pre-school-aged children (PSAC, 2-5 years) and school-aged children (SAC, 6-12 years) were assigned to 100 or 200 µg/kg and 200, 400 or 600 µg/kg ivermectin, respectively (ISRCTN registry no. ISRCTN15871729). Capillary blood was collected on dried blood spot cards until 72 h post-treatment. Ivermectin was quantified by LC-MS/MS, and pharmacokinetic parameters were evaluated by non-compartmental analysis. RESULTS: C max and AUC increased in PSAC and SAC with ascending doses and were similar in both age groups when the current standard dose (200 µg/kg) was administered (∼23 ng/mL and ∼350 ng×h/mL, respectively). PSAC with lower BMI were associated with significantly higher AUCs. AUC and Cmax were ∼2-fold lower in children compared with parameters previously studied in adults, whereas body weight-adjusted CL/F (∼0.35 L/h/kg) was significantly higher in children. Tmax (∼6 h), t1/2 (∼18 h), mean residence time (MRTINF) (∼28 h) and V/F (∼8 L/kg) were similar in all paediatric treatment arms. CONCLUSIONS: A positive association of AUC or Cmax with dose was observed in both age groups. Undernutrition might influence the AUC of ivermectin in PSAC. Ivermectin shows a lower exposure profile in children compared with adults, highlighting the need to establish dosing recommendations for different age groups.


Assuntos
Antiparasitários/administração & dosagem , Antiparasitários/farmacocinética , Ivermectina/administração & dosagem , Ivermectina/farmacocinética , Tricuríase/tratamento farmacológico , Tricuríase/parasitologia , Trichuris/efeitos dos fármacos , Animais , Área Sob a Curva , Criança , Pré-Escolar , Cromatografia Líquida , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Espectrometria de Massas em Tandem , Resultado do Tratamento
15.
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
16.
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
17.
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
18.
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
20.
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
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