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1.
Vet Parasitol ; 318: 109929, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37080069

RESUMO

Citrus fruits are consumed all over the world and their by-products are used for animal feed and essential oils production. This study aimed to evaluate the in vitro and in vivo activity of Citrus aurantium var. Dulcis essential oil (CaEO) combined with ABZ against benzimidazole resistant Haemonchus contortus. In vitro egg hatching assays (EHA) were performed using CaEO and ABZ to estimate the effective concentration to achieve 50% egg death (EC50) values and calculate the test essential oil and drug combinations using a simplex-centroid mixture design. These concentrations were used for a second round of EHAs. Sixteen sheep were randomly allocated into two groups and treated with ABZ and the combination of CaEO and ABZ, and faecal egg count reduction tests were performed. In the first round of EHA, CaEO and ABZ showed EC50 values of 0.57 and 0.0048 mg mL-1, respectively. The H. contortus strain used in the study was shown to be highly benzimidazole resistant, with only 1.5% of parasites having susceptible ß-tubulin SNP genotypes. The ABZ reduced the shedding of nematode eggs by 78%, however, its combination with CaEO reduced faecal egg counts by only 9%. The present study is important to highlight the interferences of natural products in anthelmintic metabolism and consequently in drug efficacy.


Assuntos
Anti-Helmínticos , Citrus , Hemoncose , Haemonchus , Nematoides , Óleos Voláteis , Doenças dos Ovinos , Animais , Ovinos , Albendazol/farmacologia , Albendazol/uso terapêutico , Óleos Voláteis/farmacologia , Óleos Voláteis/uso terapêutico , Anti-Helmínticos/farmacologia , Anti-Helmínticos/uso terapêutico , Benzimidazóis/farmacologia , Fezes/parasitologia , Doenças dos Ovinos/tratamento farmacológico , Doenças dos Ovinos/parasitologia , Contagem de Ovos de Parasitas/veterinária , Resistência a Medicamentos , Hemoncose/tratamento farmacológico , Hemoncose/veterinária , Hemoncose/parasitologia
2.
Vet Parasitol ; 290: 109345, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33482425

RESUMO

The resistance of Haemonchus contortus to synthetic anthelmintics is of increasing concern; and different strategies are being evaluated to improve parasite control. The present study investigated the in vitro effects of combinations of synthetic compounds and monoterpenes. Additionally, the chemical association of the best combinations and their impact on the ultrastructural and biophysical properties of H. contortus eggs was evaluated. We assessed the efficacy of the monoterpenes, carvacrol, thymol, r-carvone, s-carvone, citral, and p-cymene and the anthelmintics, albendazole and levamisole using the egg hatch test (EHT) and the larval migration inhibition test (LMIT), respectively. The minimum effective concentrations of the monoterpenes, according to the EHT (efficacy ranging from 4.4%-11.8%) and LMIT (efficacy ranging from 5.6%-7.4%), were used in combination with different concentrations of synthetic compounds, and the IC50 and synergism rate (SR) were calculated. Fourier-transform infrared spectroscopy (FTIR) was used to analyze the chemical association between the best combinations as revealed by the in vitro tests (albendazole and levamisole with r-carvone or s-carvone). Atomic force microscopy (AFM) was used to assess the ultrastructural and biophysical properties of H. contortus eggs treated with the albendazole and r-carvone combination. Among the monoterpenes, the highest efficacies were exhibited by carvacrol (IC50 = 185.9 µg/mL) and thymol (IC50 = 187.0 µg/mL), according to the EHT, and s-carvone and carvacrol (IC50 = 1526.0 and 1785.3 µg/mL, respectively), according to the LMIT. According to the EHT, albendazole showed a slight statistically significant synergism in combination with r-carvone (SR = 3.8) and s-carvone (SR = 3.0). According to the LMIT, among the monoterpenes, r-carvone (SR = 1.7) and s-carvone (SR = 1.7) showed an increase in efficacy with levamisole; however, this was not statistically significant. The FTIR spectra of albendazole and levamisole, in association with r-carvone and s-carvone, indicated the presence of chemical interactions between the synthetic and natural molecules, contributing to the possible synergistic effects of these associations. Eggs treated with albendazole and r-carvone showed an increase in roughness and a decrease in height, suggesting that the treatment induced damage to the egg surface and an overflow of its internal contents. Overall, the combination of albendazole with r-carvone and s-carvone was efficacious against H. contortus, demonstrating a chemical association between the compounds; the significant changes in the egg ultrastructure justify this efficacy.


Assuntos
Anti-Helmínticos/síntese química , Anti-Helmínticos/farmacologia , Haemonchus/efeitos dos fármacos , Monoterpenos/química , Monoterpenos/farmacologia , Animais , Haemonchus/ultraestrutura , Larva/efeitos dos fármacos , Larva/fisiologia , Microscopia de Força Atômica , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Óvulo/efeitos dos fármacos , Espectroscopia de Infravermelho com Transformada de Fourier , Relação Estrutura-Atividade
3.
J Vet Pharmacol Ther ; 32(1): 49-55, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19161455

RESUMO

The purpose of this study was to investigate the stereospecific pharmacokinetics of ketorolac (KT) in goats following a single 2 mg/kg intravenous (i.v.) dose and a single 6 mg/kg oral dose. A stereoselective high pressure liquid chromatography assay was used to quantify ketorolac plasma concentrations. Pharmacokinetic parameters for both stereoisomers were estimated by model independent methods. Following an i.v. dose, the plasma concentration profiles for the stereoisomers were similar with half-lives of 1.05 +/- 0.62 h for R-KT and 1.05 +/- 0.61 h for S-KT. Clearance values for R- and S-KT after an i.v. dose were 0.53 +/- 0.23 and 0.54 +/- 0.23 L.h/kg, respectively. Following an oral dose, the terminal half-lives were longer with values of 34.08 +/- 11.81 and 33.97 +/- 12.19 h for R-KT and S-KT, respectively. The average bioavailability was 133 +/- 23% for R-KT and S-KT, respectively. The longer half-lives and high apparent bioavailability after oral dosing are suggestive of a slow absorption process in the gastrointestinal tract and recycling. The results indicate that interconversion of the stereoisomers of ketorolac is absent in goats. However, studies with individual isomers are needed before any conclusion can be drawn about the lack of bioinversion.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Inibidores de Ciclo-Oxigenase/farmacocinética , Cabras/metabolismo , Cetorolaco/farmacocinética , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Área Sob a Curva , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Inibidores de Ciclo-Oxigenase/administração & dosagem , Inibidores de Ciclo-Oxigenase/química , Relação Dose-Resposta a Droga , Cabras/sangue , Meia-Vida , Infusões Intravenosas/veterinária , Absorção Intestinal , Cetorolaco/administração & dosagem , Cetorolaco/sangue , Cetorolaco/química , Masculino , Taxa de Depuração Metabólica , Distribuição Aleatória , Estereoisomerismo
4.
Cell Death Discov ; 1: 15009, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-27551444

RESUMO

Necroptosis and signaling regulated by RIP1 kinase activity is emerging as a key driver of inflammation in a variety of disease settings. A significant amount has been learned about how RIP1 regulates necrotic cell death through the use of the RIP1 kinase inhibitor Necrostatin-1 (Nec-1). Nec-1 has been a transformational tool for exploring the function of RIP1 kinase activity; however, its utility is somewhat limited by moderate potency, off-target activity against indoleamine-2,3-dioxygenase (IDO), and poor pharmacokinetic properties. These limitations of Nec-1 have driven an effort to identify next-generation tools to study RIP1 function, and have led to the identification of 7-Cl-O-Nec-1 (Nec-1s), which has improved pharmacokinetic properties and lacks IDO inhibitory activity. Here we describe the characterization of GSK'963, a chiral small-molecule inhibitor of RIP1 kinase that is chemically distinct from both Nec-1 and Nec-1s. GSK'963 is significantly more potent than Nec-1 in both biochemical and cellular assays, inhibiting RIP1-dependent cell death with an IC50 of between 1 and 4 nM in human and murine cells. GSK'963 is >10 000-fold selective for RIP1 over 339 other kinases, lacks measurable activity against IDO and has an inactive enantiomer, GSK'962, which can be used to confirm on-target effects. The increased in vitro potency of GSK'963 also translates in vivo, where GSK'963 provides much greater protection from hypothermia at matched doses to Nec-1, in a model of TNF-induced sterile shock. Together, we believe GSK'963 represents a next-generation tool for examining the function of RIP1 in vitro and in vivo, and should help to clarify our current understanding of the role of RIP1 in contributing to disease pathogenesis.

5.
Eur J Pharmacol ; 358(1): 1-8, 1998 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-9809862

RESUMO

The present study examined the effects of 3,4-methylenedioxymethamphetamine (MDMA), before and after once a week dosing, on the behavior of rats responding under a fixed ratio 20 schedule of reinforcement. Acutely, cumulative doses of MDMA dose-dependently decreased responding when compared to a series of water injections. Rats were then separated into two groups, one of which received only weekly MDMA ('paired') while the other received an additional injection of water each week ('unpaired'). Weekly dosing with MDMA resulted in significantly increased responding at low doses in the paired group but not in the unpaired group. When water injections were readministered there was a significant increase in responding in both groups. During the weekly regimen, locomotor activity also increased significantly over time after both water and MDMA injections. In conclusion, it appears that even weekly dosing with a small amount of MDMA can have long-lasting effects that are manifested in both operant and spontaneous behavior and that may be mediated by a conditioning mechanism.


Assuntos
Condicionamento Operante/efeitos dos fármacos , Alucinógenos/farmacologia , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Animais , Relação Dose-Resposta a Droga , Esquema de Medicação , Alucinógenos/administração & dosagem , Masculino , Atividade Motora/efeitos dos fármacos , N-Metil-3,4-Metilenodioxianfetamina/administração & dosagem , Ratos , Ratos Sprague-Dawley , Esquema de Reforço , Água/administração & dosagem
6.
J Drug Target ; 5(6): 415-41, 1998.
Artigo em Inglês | MEDLINE | ID: mdl-9783675

RESUMO

During this century, several investigators reported that certain viruses, metals, drugs, and other solutes could bypass systemic circulation and enter the brain and/or cerebrospinal fluid directly following nasal administration. Although evidence clearly suggests that the olfactory epithelium and its olfactory cells play a major role, little is known about the mechanisms of direct transport of solutes into the brain. An overview of what is known about these mechanisms may aid in further research in this field, including studies of direct drug delivery to the central nervous system. This review, in addition to summarizing the literature to date, clearly describes the intricate association of the anatomical features involved in direct entry of solutes into the brain following nasal administration. To aid in the understanding of the possible routes a solute can take after nasal administration, the anatomy of the olfactory epithelium and surrounding tissues is described, and a detailed scheme delineating the emerging pathways is presented. Techniques used in delineating these pathways and studies supporting a particular pathway are discussed in greater detail. Finally, some factors influencing the direct transport of solutes to the cerebrospinal fluid and brain are summarized.


Assuntos
Sistema Nervoso Central/metabolismo , Sistemas de Liberação de Medicamentos , Administração Intranasal , Animais , Líquido Cefalorraquidiano , Condutos Olfatórios/metabolismo , Farmacocinética
7.
J Vet Pharmacol Ther ; 30(5): 437-42, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17803736

RESUMO

The purpose of this study was to establish the stereospecific pharmacokinetics of ketorolac (KT) in calves following a single 2 mg/kg intravenous (i.v.) and a single 8 mg/kg oral dose. Plasma concentrations were determined using a stereoselective HPLC assay. Pharmacokinetic parameters for both the stereoisomers were estimated by model-independent methods. Following an i.v. dose, the plasma concentration profiles of the stereoisomers were similar with half-lives of 5.9 +/- 5.1 h for R-KT and 6.0 +/- 4.9 h for S-KT. Clearance values for R- and S-KT after an i.v. dose were 0.0470 +/- 0.0370 and 0.0480 +/- 0.0370 L/h/kg respectively. After an oral dose, the terminal half-lives were longer than following i.v. administration with values of 14.77 +/- 3.08 and 14.55 +/- 2.95 h for R-KT and S-KT respectively. The average oral bioavailability was 86.5 +/- 20.6% for R-KT and 86.7 +/- 20.3% for S-KT. The results indicate that the stereoisomers of KT have similar pharmacokinetic profiles in calves. Although, unlike humans, bioinversion between KT stereoisomers appears minimal in calves, studies with individual isomers are needed before any firm conclusions can be drawn about this lack of KT bioinversion.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Bovinos/metabolismo , Cetorolaco/farmacocinética , Administração Oral , Animais , Animais Recém-Nascidos/metabolismo , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/sangue , Anti-Inflamatórios não Esteroides/química , Área Sob a Curva , Estudos Cross-Over , Injeções Intravenosas/veterinária , Isomerismo , Cetorolaco/administração & dosagem , Cetorolaco/sangue , Cetorolaco/química , Masculino
8.
Xenobiotica ; 35(2): 191-210, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16019946

RESUMO

The prediction of human pharmacokinetics is often based on in vivo preclinical pharmacokinetic data. However, to date, no clear guidance has been available about the relative ability of the major preclinical species to estimate human oral exposure. The study was conducted to survey the literature on oral pharmacokinetic parameters in rat, dog, monkey and human, and to compare various methods for prediction of oral exposure in humans. Fifty-six non-peptide xenobiotics were identified with oral pharmacokinetic data in rat, dog, monkey and human, and comparison of the data from each species to humans was conducted along with an evaluation of the molecular features of these compounds. Monkey liver blood flow-based oral exposure was qualitatively and quantitatively more predictive of human oral exposure than rat or dog. Furthermore, generation of data in three versus two preclinical species did not always improve human predictivity. The use of molecular properties did not substantially improve the prediction of human oral exposure compared with the prediction from monkey alone. These observations confirm the continued importance of non-human primates in preclinical pharmacokinetics, and also have implications for pharmacokinetic lead optimization and for prediction of human pharmacokinetic parameters from in vivo preclinical data.


Assuntos
Xenobióticos/farmacologia , Administração Oral , Animais , Área Sob a Curva , Cães , Haplorrinos , Humanos , Modelos Estatísticos , Ratos , Software , Especificidade da Espécie , Xenobióticos/administração & dosagem , Xenobióticos/farmacocinética
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