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1.
Aust Vet J ; 95(3): 85-88, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28239856

RESUMO

BACKGROUND: This study was performed to investigate the efficacy of a morantel-abamectin combination for the treatment of macrocyclic lactone (ML)-resistant Parascaris spp. infections in foals. METHODS: Foals on five properties with a Parascaris faecal egg count (FEC) > 50 eggs per gram were used to estimate the FEC reduction (FECR) and efficacy of the anthelmintic combination. RESULTS & CONCLUSION: On all properties, resistance to ivermectin and abamectin was present and the Parascaris FECR in foals administered the morantel-abamectin combination was > 99%, indicating that this combination effectively controlled ML-resistant parasites.


Assuntos
Antinematódeos/uso terapêutico , Infecções por Ascaridida/veterinária , Ascaridoidea/efeitos dos fármacos , Doenças dos Cavalos/tratamento farmacológico , Ivermectina/análogos & derivados , Morantel/uso terapêutico , Animais , Antinematódeos/administração & dosagem , Infecções por Ascaridida/tratamento farmacológico , Infecções por Ascaridida/parasitologia , Combinação de Medicamentos , Resistência a Medicamentos , Doenças dos Cavalos/parasitologia , Cavalos/parasitologia , Ivermectina/administração & dosagem , Ivermectina/uso terapêutico , Morantel/administração & dosagem , Resultado do Tratamento
2.
Invert Neurosci ; 16(4): 10, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27995347

RESUMO

Nematode parasite infections pose a significant threat in human and veterinary medicine. At least a third of the world's population is at risk from nematode parasite infections. These infections not only cause health problems, but also cause loss of livestock production and hence, economic losses. Anthelmintic drugs are the mainstay by which control of nematode parasite infections is achieved. Many of the currently available anthelmintics act on nicotinic acetylcholine receptors (nAChRs). However, the detailed mode of action (MOA) of these anthelmintics is not clearly understood. Elucidation of the MOA of anthelmintics is highly desirable; an in-depth knowledge of the MOA will better inform on mechanisms of resistance development and on ways to slow down or overcome resistance. The cholinomimetic anthelmintic, morantel, has a complex MOA involving the activation and block of levamisole-sensitive single nAChR channels (L-type nAChR or L-nAChR). More recently, morantel has been demonstrated to activate Haemonchus contortus and Parascaris equorum ACR-26/ACR-27 nAChRs expressed in Xenopus laevis oocytes. Previous studies in our laboratory, however, have shown morantel does not activate the nicotine-sensitive nAChR (N-type nAChR or N-nAChR), Ascaris suum ACR-16 (Asu-ACR-16). In this study, we used two-electrode voltage-clamp (TEVC) electrophysiology to investigate the inhibitory effects of morantel, on expressed Asu-ACR-16 nAChRs in X. laevis oocytes. Our results show that morantel acts as a non-competitive antagonist on Asu-ACR-16. This non-competitive antagonism by morantel was further demonstrated to be voltage-sensitive. We conclude based on our findings that morantel is a non-competitive voltage-sensitive open channel blocker of Asu-ACR-16.


Assuntos
Anti-Helmínticos/farmacologia , Ascaris suum , Morantel/farmacologia , Antagonistas Nicotínicos/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Animais
3.
PLoS Pathog ; 11(12): e1005267, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26625142

RESUMO

Acetylcholine receptors are pentameric ligand-gated channels involved in excitatory neuro-transmission in both vertebrates and invertebrates. In nematodes, they represent major targets for cholinergic agonist or antagonist anthelmintic drugs. Despite the large diversity of acetylcholine-receptor subunit genes present in nematodes, only a few receptor subtypes have been characterized so far. Interestingly, parasitic nematodes affecting human or animal health possess two closely related members of this gene family, acr-26 and acr-27 that are essentially absent in free-living or plant parasitic species. Using the pathogenic parasitic nematode of ruminants, Haemonchus contortus, as a model, we found that Hco-ACR-26 and Hco-ACR-27 are co-expressed in body muscle cells. We demonstrated that co-expression of Hco-ACR-26 and Hco-ACR-27 in Xenopus laevis oocytes led to the functional expression of an acetylcholine-receptor highly sensitive to the anthelmintics morantel and pyrantel. Importantly we also reported that ACR-26 and ACR-27, from the distantly related parasitic nematode of horses, Parascaris equorum, also formed a functional acetylcholine-receptor highly sensitive to these two drugs. In Caenorhabditis elegans, a free-living model nematode, we demonstrated that heterologous expression of the H. contortus and P. equorum receptors drastically increased its sensitivity to morantel and pyrantel, mirroring the pharmacological properties observed in Xenopus oocytes. Our results are the first to describe significant molecular determinants of a novel class of nematode body wall muscle AChR.


Assuntos
Proteínas de Helminto/metabolismo , Nematoides/metabolismo , Receptores Colinérgicos/metabolismo , Animais , Anti-Helmínticos/farmacologia , Ascaridoidea/genética , Ascaridoidea/metabolismo , Sequência de Bases , Haemonchus/genética , Haemonchus/metabolismo , Proteínas de Helminto/genética , Hibridização In Situ , Dados de Sequência Molecular , Morantel/farmacologia , Nematoides/genética , Técnicas de Patch-Clamp , Filogenia , Reação em Cadeia da Polimerase , Receptores Colinérgicos/genética
4.
Neuropharmacology ; 79: 420-31, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24373904

RESUMO

Allosteric modulation is a general feature of nicotinic acetylcholine receptors, yet the structural components and movements important for conversions among functional states are not well understood. In this study, we examine the communication between the binding sites for agonist and the modulator morantel (Mor) of neuronal α3ß2 receptors, measuring evoked currents of receptors expressed in Xenopus oocytes with the two-electrode voltage-clamp method. We hypothesized that movement along an interface of ß sheets connecting the agonist and modulator sites is necessary for allosteric modulation. To address this, we created pairs of substituted cysteines that span the cleft formed where the outer ß sheet meets the ß sheet constituting the (-)-face of the α3 subunit; the three pairs were L158C-A179C, L158C-G181C and L158C-K183C. Employing a disulfide trapping approach in which bonds are formed between neighboring cysteines under oxidation conditions, we found that oxidation treatments decreased the amplitude of currents evoked by either the agonist (ACh) or co-applied agonist and modulator (ACh + Mor), by as much as 51%, consistent with the introduced bond decreasing channel efficacy. Reduction treatment increased evoked currents up to 89%. The magnitude of the oxidation effects depended on whether agonists were present during oxidation and on the cysteine pair. Additionally, the cysteine mutations themselves decreased Mor potentiation, implicating these residues in modulation. Our findings suggest that these ß sheets in the α3 subunit move with respect to each other during activation and modulation, and the residues studied highlight the contribution of this intramolecular allosteric pathway to receptor function.


Assuntos
Receptores Nicotínicos/metabolismo , Acetilcolina/metabolismo , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Sequência de Aminoácidos , Animais , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/fisiologia , Colinérgicos/farmacologia , Peróxido de Hidrogênio/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Modelos Moleculares , Morantel/farmacologia , Mutação , Oxidantes/farmacologia , Oxirredução/efeitos dos fármacos , Estrutura Secundária de Proteína , Ratos , Receptores Nicotínicos/genética , Xenopus laevis
5.
J Chromatogr A ; 1235: 103-14, 2012 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-22425209

RESUMO

Morantel, pyrantel and their drug-related metabolites in food of animal-origin are regulated as sum of residues which may be hydrolysed to N-methyl-1,3-propanediamine (NMPA). In this study, an isotope dilution liquid chromatography tandem mass spectrometry (LC-MS/MS) method with pentafluoropropionic acid anhydride (PFPA) derivatization was developed for the determination of NMPA in bovine muscle. A stable isotope labeled internal standard N-methyl-d(3)-3,3'-d(2)-propane-1,3-diamine (NMPA-d(5)) was synthesized as internal standard. NMPA was derivatized with PFPA to form an N,N'-bis (pentafluoroacyl) derivative (NMPA-PFPA) and analyzed by liquid chromatography triple quadrupole mass spectrometry (LC-QqQ-MS/MS) and liquid chromatography ion trap mass spectrometry (LC-IT-MS/MS) using negative ion electrospray ionization (ESI). Chromatographic behavior of several perfluorocarboxylic acid anhydride derivatives of NMPA and other structurally related diamines on C-18 and perfluorophenyl (PFP) columns was studied. Conversion of the parent drugs to NMPA under various hydrolysis conditions was evaluated. In addition, comparison of the matrix effect and linearity with isotopically labeled internal standard (I.S.) and analogous I.S. were performed and investigated. The method was validated using fortified bovine muscle samples. The apparent recovery (obtained after correction with an isotopically labeled I.S.) was between 89% and 97% and repeatability was less than 10%. The lowest LOD and LOQ (0.42 and 1.39µg/kg, respectively) were obtained with LC-QqQ-MS/MS.


Assuntos
Poluentes Ocupacionais do Ar/análise , Diaminas/análise , Músculos/química , Animais , Antinematódeos/análise , Bovinos , Cromatografia Líquida/métodos , Fluorcarbonetos/química , Limite de Detecção , Morantel/análise , Pirantel/análise , Espectrometria de Massas em Tandem/métodos
6.
Mol Pharmacol ; 81(2): 239-49, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22064677

RESUMO

We are interested in the allosteric modulation of neuronal nicotinic acetylcholine receptors (nAChRs). We have postulated that the anthelmintic morantel (Mor) positively modulates (potentiates) rat α3ß2 receptors through a site located at the ß(+)/α(-) interface that is homologous to the canonical agonist site (J Neurosci 29:8734-8742, 2009). On this basis, we aimed to determine the site specificity by studying differences in modulation between α3ß2 and α4ß2 receptors. We also compared modulation by Mor with that of the related compound oxantel (Oxa). Whereas Mor and Oxa each potentiated α3ß2 receptors 2-fold at saturating acetylcholine (ACh) concentrations, Mor had no effect on α4ß2 receptors, and Oxa inhibited ACh-evoked responses. The inhibition was noncompetitive, but not due to open channel block. Furthermore, the nature and extent of modulation did not depend on subunit stoichiometry. We studied six positions at the α(-) interface that differ between α3 and α4. Two positions (α3Ile57 and α3Thr115) help mediate the effects of the modulators but do not seem to contribute to specificity. Mutations in two others (α3Leu107 and α3Ile117) yielded receptors with appreciable α4-character; that is, Mor potentiation was reduced compared with wild-type α3ß2 control and Oxa inhibition was evident. A fifth position (α3Glu113) was unique in that it discriminated between the two compounds, showing no change in Mor potentiation from control but substantial Oxa inhibition. Our work has implications for rational drug design for nicotinic receptors and sheds light on mechanisms of allosteric modulation in nAChRs, especially the subtle differences between potentiation and inhibition.


Assuntos
Sítio Alostérico , Desenho de Fármacos , Receptores Nicotínicos/metabolismo , Regulação Alostérica , Animais , Anti-Helmínticos , Morantel , Mutação , Agonistas Nicotínicos/farmacologia , Antagonistas Nicotínicos/farmacologia , Subunidades Proteicas , Pirantel/análogos & derivados , Ratos , Receptores Nicotínicos/química
7.
J Neurosci ; 29(27): 8734-42, 2009 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-19587280

RESUMO

We are interested in the positive allosteric modulation of neuronal nicotinic acetylcholine (ACh) receptors and have recently shown that the anthelmintic compound morantel potentiates by enhancing channel gating of the alpha3beta2 subtype. Based on the demonstration that morantel-elicited currents were inhibited by the classic ACh competitor dihydro-beta-erythroidine in a noncompetitive manner and that morantel still potentiates at saturating concentrations of agonist (Wu et al., 2008), we hypothesized that morantel binds at the noncanonical beta2(+)/alpha3(-) subunit interface. In the present study, we created seven cysteine-substituted subunits by site-directed mutagenesis, choosing residues in the putative morantel binding site with the aid of structural homology models. We coexpressed the mutant subunits and their respective wild-type partners in Xenopus oocytes and characterized the morantel potentiation of ACh-evoked currents, as well as morantel-evoked currents, before and after treatment with a variety of methanethiosulfonate (MTS)-based compounds, using voltage-clamp recordings. The properties of four of the seven mutants, two residues on each side of the interface, were changed by MTS treatments. Coapplication with ACh enhanced the extent of MTS modification for alpha3A106Cbeta2 and alpha3beta2S192C receptors. The activities of two mutants, alpha3T115Cbeta2 and alpha3beta2T150C, were dramatically altered by MTS modification. For alpha3beta2T150C, while peak current amplitudes were reduced, potentiation was enhanced. For alpha3T115Cbeta2, both current amplitudes and potentiation were reduced. MTS modification and morantel were mutually inhibitory: MTS treatment decreased morantel-evoked currents and morantel decreased the rate of MTS modification. We conclude that the four residues showing MTS effects contribute to the morantel binding site.


Assuntos
Morantel/metabolismo , Neurônios/metabolismo , Subunidades Proteicas/metabolismo , Receptores Nicotínicos/metabolismo , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/genética , Animais , Potenciais Evocados/efeitos dos fármacos , Potenciais Evocados/genética , Feminino , Morantel/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Subunidades Proteicas/genética , Subunidades Proteicas/fisiologia , Ratos , Receptores Nicotínicos/genética , Receptores Nicotínicos/fisiologia , Xenopus laevis
8.
J Biol Chem ; 284(32): 21478-87, 2009 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-19506073

RESUMO

Nicotinic receptors (AChRs) play key roles in synaptic transmission. We explored activation of neuronal alpha7 and mammalian muscle AChRs by morantel and oxantel. Our results revealed a novel action of morantel as a high efficacy and more potent agonist than ACh of alpha7 receptors. The EC(50) for activation by morantel of both alpha7 and alpha7-5HT(3A) receptors is 7-fold lower than that determined for ACh. The minimum morantel concentration required to activate alpha7-5HT(3A) channels is 6-fold lower than that of ACh, and activation episodes are more prolonged than in the presence of ACh. By contrast, oxantel is a weak agonist of alpha7 and alpha7-5HT(3A), and both drugs are very low efficacy agonists of muscle AChRs. The replacement of Gln(57) in alpha7 by glycine, which is found in the equivalent position of the muscle AChR, decreases the efficacy for activation and turns morantel into a partial agonist. The reverse mutation in the muscle AChR (epsilonG57Q) increases 7-fold the efficacy of morantel. The mutations do not affect activation by ACh or oxantel, indicating that this position is selective for morantel. In silico studies show that the tetrahydropyrimidinyl group, common to both drugs, is close to Trp(149) of the principal face of the binding site, whereas the other cyclic group is proximal to Gln(57) of the complementary face in morantel but not in oxantel. Thus, position 57 at the complementary face is a key determinant of the high selectivity of morantel for alpha7. These results provide new information for further progress in drug design.


Assuntos
Glutamina/metabolismo , Morantel/metabolismo , Receptores Nicotínicos/metabolismo , Sítios de Ligação , Relação Dose-Resposta a Droga , Desenho de Fármacos , Eletrofisiologia/métodos , Humanos , Potenciais da Membrana , Modelos Biológicos , Modelos Químicos , Morantel/farmacologia , Músculos/metabolismo , Mutagênese Sítio-Dirigida , Mutação , Pirantel/análogos & derivados , Pirantel/metabolismo , Pirantel/farmacologia , Receptor Nicotínico de Acetilcolina alfa7
9.
Environ Toxicol Chem ; 28(2): 316-23, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18811226

RESUMO

Soil invertebrates in arable land are potentially exposed to veterinary medicines excreted by husbandry. The toxicity of three widely used pharmaceuticals was therefore investigated with the use of common soil invertebrates exposed in the laboratory in single- or two-species test system. The anthelmintic morantel did not cause significant mortality to either Folsomia fimetaria or Enchytraeus crypticus even at the highest tested concentration of 900 mg kg(-1) dry soil. The coccidiostatic monensin affected the reproduction of F. fimetaria and E. crypticus with soil concentrations estimated to cause a 10% effect at values of approximately 109 and 71.8 mg kg(-1) dry soil, respectively, but caused no mortality to adult. The anthelmintic ivermectin did not affect the survival of adult Hypoaspis aculeifer. Reproduction of H. aculeifer declined approximately 45% in response to ivermectin exposure of 5 mg kg(-1) dry soil. Ivermectin was highly toxic to F. fimetaria and affected the survival of adults with soil concentrations estimated to cause a 50% mortality at values of 5.3 mg kg(-1) dry soil in the single-species test system and 0.14 mg kg(-1) dry soil in the two-species test system. Reproduction of F. fimetaria was reduced by ivermectin with 10% effective concentration at 0.19 mg kg(-1) dry soil in the single-species test system and 0.02 mg kg(-1) dry soil in two-species test system. It was shown that species interactions may influence the response of test organisms to toxic substances. The data from this study and previously published data showed that, whereas ivermectin is likely to pose a risk to soil-dwelling invertebrates, adverse effects of morantel and monensin are unlikely to occur as a result of residue excretion from treated farm animals.


Assuntos
Anti-Helmínticos/toxicidade , Invertebrados/efeitos dos fármacos , Ivermectina/toxicidade , Morantel/toxicidade , Solo , Animais , Especificidade da Espécie
10.
Mol Pharmacol ; 74(2): 466-75, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18458055

RESUMO

We studied allosteric potentiation of rat alpha3beta2 neuronal nicotinic acetylcholine receptors (nAChRs) by the anthelmintic compound morantel. Macroscopic currents evoked by acetylcholine (ACh) from nAChRs expressed in Xenopus laevis oocytes increase up to 8-fold in the presence of low concentrations of morantel (< or =10 microM); the magnitude of the potentiation depends on both agonist and modulator concentrations. It is noteworthy that the potentiated currents exceed the maximum currents achieved by saturating (millimolar) concentrations of agonist. Studies of macroscopic currents elicited by prolonged drug applications (100-300 s) indicate that morantel does not increase alpha3beta2 receptor activity by reducing slow (> or =1 s) desensitization. Instead, using outside-out patch-clamp recordings, we demonstrate that morantel increases the frequency of single-channel openings and alters the bursting characteristics of the openings in a manner consistent with enhanced channel gating; these results quantitatively explain the macroscopic current potentiation. Morantel is a very weak agonist alone, but we show that the classic competitive antagonist dihydro-beta-erythroidine inhibits morantel-evoked currents noncompetitively, indicating that morantel does not bind to the canonical ACh binding sites.


Assuntos
Anti-Helmínticos/farmacologia , Ativação do Canal Iônico/efeitos dos fármacos , Morantel/farmacologia , Neurônios/efeitos dos fármacos , Receptores Nicotínicos/fisiologia , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Feminino , Ativação do Canal Iônico/fisiologia , Morantel/química , Neurônios/fisiologia , Ratos , Receptores Nicotínicos/química , Xenopus laevis
11.
Environ Toxicol Chem ; 27(4): 909-18, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18333693

RESUMO

A comparative hazard assessment of the antiparasitics ivermectin, albendazole, and morantel was performed, with a particular focus on bioavailability and uptake into biological membranes. The experimentally determined liposome-water distribution ratio at pH 7 (D(lipw) (pH 7)) of the positively charged morantel was 100 L/kg lipid. The D(lipw) (pH 7) of albendazole was 3,000 L/kg lipid. The membrane permeability determined with the parallel artificial membrane permeability assay was consistent with predictions from a quantitative structure-activity relationship (QSAR) for morantel but 14-fold lower than predicted for albendazole, which can be rationalized because neutral albendazole is, in fact, zwitterionic and the large dipole moment hinders permeation through hydrophobic membranes. An unusually large molecule, ivermectin was suspected to show decreased bioaccumulation because of its bulkiness, but experimental determination of solubility showed that it was 40-fold less soluble than expected from a QSAR between solubility and the octanol-water partition coefficient. In contrast, its membrane permeability appeared to be typical for a compound of the given hydrophobicity, but it was not possible to determine the membrane-water partition coefficient because of its low solubility and high affinity to the dialysis membrane of the experimental device. The D(lipw) (pH 7) for ivermectin of 2,700 L/kg lipid was calculated with a QSAR model. Morantel and albendazole were baseline toxicants in the bioluminescence inhibition test with Vibrio fischeri and a test for inhibition of photosynthesis in green algae. Only ivermectin exhibited a specific effect toward algae, but the excess toxicity was not very pronounced and might be biased by the uncertainty of the estimated hydrophobicity descriptor. Overall, we did not find any unexpected effect on nontarget endpoints.


Assuntos
Albendazol/toxicidade , Antiparasitários/toxicidade , Permeabilidade da Membrana Celular , Ivermectina/toxicidade , Morantel/toxicidade , Albendazol/química , Albendazol/farmacocinética , Animais , Antiparasitários/química , Antiparasitários/farmacocinética , Relação Dose-Resposta a Droga , Estabilidade de Medicamentos , Peixes/metabolismo , Ivermectina/química , Ivermectina/farmacocinética , Lipossomos/química , Morantel/química , Morantel/farmacocinética , Relação Quantitativa Estrutura-Atividade , Solubilidade
12.
Mol Pharmacol ; 71(5): 1407-15, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17314321

RESUMO

Nicotinic acetylcholine receptors (nAChRs) are pentameric neurotransmitter-gated ion channels that mediate synaptic transmission throughout the nervous system in vertebrates and invertebrates. Caenorhabditis elegans is a nonmammalian model for the study of the nervous system and a model of parasitic nematodes. Nematode muscle nAChRs are of considerable interest because they are targets for anthelmintic drugs. We show single-channel activity of C. elegans muscle nAChRs for the first time. Our results reveal that in the L1 larval stage acetylcholine (ACh) activates mainly a levamisole-sensitive nAChR (L-AChR). A single population of 39 pS channels, which are 5-fold more sensitive to levamisole than ACh, is detected. In contrast to mammalian nAChRs, open durations are longer for levamisole than for ACh. Studies in mutant strains reveal that UNC-38, UNC-63, and UNC-29 subunits are assembled into a single L-AChR in the L1 stage and that these subunits are irreplaceable, suggesting that they are vital for receptor function throughout development. Recordings from a strain mutated in the LEV-1 subunit show a main population of channels with lower conductance (26 pS), prolonged open durations, and reduced sensitivity to levamisole. Thus, although LEV-1 is preferentially incorporated into native L-AChRs, receptors lacking this subunit can still function. No single-channel activity from levamisole-insensitive nAChRs is detected. Thus, during neuromuscular transmission in C. elegans, the majority of ACh-activated current flows through L-AChRs. This study contributes to the understanding of the molecular mechanisms underlying functional diversity of the nAChR family and offers an excellent strategy to test novel antiparasitic drugs.


Assuntos
Caenorhabditis elegans/metabolismo , Ativação do Canal Iônico , Músculos/metabolismo , Receptores Nicotínicos/metabolismo , Acetilcolina/farmacologia , Animais , Caenorhabditis elegans/efeitos dos fármacos , Proteínas de Caenorhabditis elegans/genética , Ativação do Canal Iônico/efeitos dos fármacos , Levamisol/farmacologia , Morantel/farmacologia , Músculos/efeitos dos fármacos , Proteínas Mutantes/metabolismo , Pirantel/farmacologia
13.
J Helminthol ; 80(4): 393-6, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17125549

RESUMO

The gerbil Meriones unguiculatus, infected with three species of nematodes, each located in a separate part of the gastrointestinal tract, provided a reliable laboratory assay for the evaluation of broad-spectrum anthelmintic activity. Gerbils harbouring 6-day-old infections of Haemonchus contortus, Trichostrongylus colubriformis and T. sigmodontis were given selected broad-spectrum anthelmintics by gavage. Three benzimidazoles, thiabendazole, oxfendazole and albendazole, a tetrahydropyrimidine, morantel, an imidazothiazole, levamisole hydrochloride, a macrocyclic lactone, ivermectin and an experimental natural product, paraherquamide, were active against all three nematodes at various dosages. Trichostrongylus colubriformis was most sensitive to levamisole hydrochloride, morantel, thiabendazole and paraherquamide whereas ivermectin, oxfendazole and albendazole were more effective against H. contortus. All compounds were active against the caecal nematode T. sigmodontis although it was less sensitive than T. colubriformis. Haemonchus contortus was more sensitive than T. sigmodontis to all anthelmintics tested except thiabendazole.


Assuntos
Anti-Helmínticos/uso terapêutico , Gerbillinae/parasitologia , Trichostrongyloidea/efeitos dos fármacos , Tricostrongiloidíase/tratamento farmacológico , Albendazol/uso terapêutico , Animais , Benzimidazóis/uso terapêutico , Feminino , Hemoncose/tratamento farmacológico , Haemonchus/efeitos dos fármacos , Indolizinas/uso terapêutico , Ivermectina , Levamisol/uso terapêutico , Masculino , Morantel/uso terapêutico , Testes de Sensibilidade Parasitária , Compostos de Espiro/uso terapêutico , Tiabendazol/uso terapêutico , Tricostrongiloidíase/veterinária , Trichostrongylus/efeitos dos fármacos
14.
J Am Chem Soc ; 127(45): 15771-7, 2005 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-16277520

RESUMO

It is now known that the untreated discharge of pharmaceuticals into the environment can impact human health and development and lead to increased drug resistance in biota. Here, we present the first direct interface-specific studies that address the mobility of the widely used agricultural antibiotic morantel, which is commonly present in farm runoff. Surface-bound morantel was spectroscopically identified using second harmonic generation (SHG) via a two-photon resonance of its n-pi* transition and in the C-H stretching region by vibrational sum frequency generation (VSFG). Resonantly enhanced SHG adsorption isotherm measurements carried out at the silica/water interface between 6 x 10(-7) and 5 x 10(-5) M morantel concentration result in a free energy of adsorption of 42(2) kJ/mol at pH 7. Finally, real-time tracking of morantel interaction with the silica/water interface shows that the binding events are fully reversible, consistent with its high mobility in silica-rich soil environments. This work thus indicates that pharmaceuticals discharged into the environment can enter the groundwater supply of municipal water systems, at which point their removal is challenging. In addition, the high mobility of morantel in silica-rich soil environments could lead to developing increased interaction of this antibiotic with target organisms, which could respond by increased drug resistance.


Assuntos
Antinematódeos/química , Morantel/química , Dióxido de Silício/química , Água/química , Meio Ambiente , Lasers , Óptica e Fotônica , Espectrofotometria Ultravioleta , Análise Espectral
15.
Prev Vet Med ; 55(4): 217-40, 2002 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-12392874

RESUMO

A field experiment was carried out in Kolda (southern Senegal) from July 1986 to July 1988. Its goals were to: (1) describe the patterns of mortality of female Guinean goats by age, season and year; (2) assess preventive measures against respiratory diseases and gastrointestinal parasitism in reducing mortality; and (3) estimate the overall impact of these measures on survival to 1 year of age. Preventive measures for respiratory disease included vaccination against peste des petits ruminants (PPR) and pneumonic pasteurellosis (Pasteurella multocida types A and D). Control of gastrointestinal parasites was by deworming does with morantel (7.5mg kg(-1), three times during the rainy season). The effects of vaccines and deworming were tested in a randomised factorial field experiment with villages being the experimental units. A total of 19 villages, 113 goat herds and 1,458 goats were included in the study. Generalised linear models of survival for five cohorts of goats (defined by five different birth seasons) used a binomial assumption for the response distribution and a complementary log-log link. Explanatory variables included age, season, year, vaccination, deworming and their interactions. A complex a priori model was built on the basis of previous epidemiological knowledge; a purposely selected set of simpler models was compared to this full model by the Akaike information criterion (AIC) and derived statistics. Inference on 1-year survival and treatment effects accounted for model-selection uncertainty. It was carried out with a bootstrap procedure and used information from the whole set of selected models. Large variations in mortality by year and season were observed but no regular seasonal pattern was apparent. Mortality probabilities of kids in dewormed groups decreased quickly after birth, but remained elevated up to 9 months of age in the non-dewormed groups. Deworming lowered the risk of mortality. Vaccination alone was not protective (except during an observed outbreak of PPR).


Assuntos
Doenças das Cabras/epidemiologia , Doenças das Cabras/prevenção & controle , Enteropatias Parasitárias/veterinária , Peste dos Pequenos Ruminantes/veterinária , Animais , Anti-Helmínticos/uso terapêutico , Estudos de Coortes , Feminino , Doenças das Cabras/microbiologia , Doenças das Cabras/mortalidade , Doenças das Cabras/parasitologia , Cabras , Enteropatias Parasitárias/epidemiologia , Enteropatias Parasitárias/prevenção & controle , Modelos Lineares , Morantel/administração & dosagem , Pasteurella multocida/imunologia , Pasteurelose Pneumônica/epidemiologia , Pasteurelose Pneumônica/prevenção & controle , Peste dos Pequenos Ruminantes/epidemiologia , Peste dos Pequenos Ruminantes/prevenção & controle , Vírus da Peste dos Pequenos Ruminantes/imunologia , Estações do Ano , Senegal/epidemiologia , Análise de Sobrevida , Vacinação/veterinária
16.
Parasitol Res ; 88(10): 946-9, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12209338

RESUMO

Acid phosphatase (AP) activity was detected in 24 h culture media from adult Heligmosomoides polygyrus. Female and male excretion/secretion products showed similar specific activity. For both, the AP had a pH optimum of 4.0 and was inhibited by sodium fluoride, tartaric acid, and sodium orthovanadate. The release of AP by adult worms was significantly inhibited by adverse incubation conditions (temperatures of 20 degrees C and 4 degrees C), known physiological perturbers ( t-butylhydroperoxide and sodium azide), and broad spectrum anthelmintics (albendazole, levamisole, morantel, and ivermectin). These results indicate that the AP activity level in the culture medium may be an indicator of the physiological status of the worms.


Assuntos
Fosfatase Ácida/metabolismo , Nematospiroides dubius/enzimologia , Nematospiroides dubius/fisiologia , Albendazol/farmacologia , Animais , Antígenos de Helmintos/biossíntese , Meios de Cultura , Feminino , Concentração de Íons de Hidrogênio , Ivermectina/farmacologia , Levamisol/farmacologia , Masculino , Morantel/farmacologia , Sensibilidade e Especificidade , Fluoreto de Sódio/farmacologia , Tartaratos/farmacologia , Temperatura , Vanadatos/farmacologia
17.
Neuroscience ; 101(3): 785-91, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-11113327

RESUMO

Two homomer-forming nicotinic acetylcholine receptor subunits with 47% identity in their amino acid sequences were employed to compare the actions of cholinergic anthelmintics and ivermectin on expressed vertebrate and nematode nicotinic receptors of known molecular composition. Voltage-clamp electrophysiology was used to study recombinant nicotinic receptors expressed in Xenopus laevis oocytes following nuclear injection of cDNA encoding either chicken alpha7 or Caenorhabditis elegans ACR-16 (Ce21) subunits. Butamisole, morantel and metyridine were without agonist actions on either alpha7 or ACR-16 nicotinic receptors in the range 10nM-1mM. However, butamisole (pIC(50)=4.9 for both alpha7 and ACR-16) and morantel (pIC(50)=5.6 for alpha7 and 5.7 for ACR-16) antagonized responses of both alpha7 and ACR-16 receptors to acetylcholine. Metyridine (1mM) did not affect responses to acetylcholine of either receptor. Oxantel was without agonist actions on ACR-16, but was an acetylcholine antagonist (pIC(50)=5.4). In contrast, it was found to have low efficacy agonist action (pEC(50)=4.4) on alpha7 at concentrations in the range 10-300microM. In agreement with a previous study, ivermectin (30microM), an agonist of L-glutamate-gated chloride channels, enhanced the amplitude of responses to acetylcholine of alpha7 nicotinic receptors. However, this same concentration of ivermectin (30microM) did not potentiate the acetylcholine-induced responses of ACR-16, but rather resulted in a slight attenuation. We conclude that oxantel and ivermectin have identified new pharmacological differences between the chicken alpha7 nicotinic receptor and its C. elegans homologue ACR-16.


Assuntos
Anti-Helmínticos/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Galinhas/metabolismo , Pirantel/análogos & derivados , Receptores Nicotínicos/efeitos dos fármacos , Receptores Nicotínicos/metabolismo , Homologia de Sequência , Acetilcolina/farmacologia , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , DNA Complementar/efeitos dos fármacos , DNA Complementar/fisiologia , Feminino , Ivermectina/farmacologia , Morantel/farmacologia , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Pirantel/farmacologia , Piridinas/farmacologia , Receptores Nicotínicos/química , Receptores Nicotínicos/genética , Tiazóis/farmacologia , Xenopus laevis/metabolismo , Receptor Nicotínico de Acetilcolina alfa7
18.
Artigo em Inglês | MEDLINE | ID: mdl-10780168

RESUMO

The secretion of acetylcholinesterase (AChE) by female and male Heligmosomoides polygyrus was studied in different in vitro culture media. AChE secretion was increased in the presence of fetal calf serum or bovine serum albumin (BSA). In the absence of crowding effects, specific AChE activity in excretion/secretion products was higher for male (2.41 +/- 0.07 mumol min-1 l-1 mg-1) than for female (0.56 +/- 0.04 mumol min-1 mg-1) worms but on a per nematode basis both sexes showed comparable rates of secretion. Acetylthiocholine iodide was the favoured substrate of the enzyme. When the nematodes were incubated in vitro with albendazole (ABZ), ricobendazole (RBZ), mebendazole (MBZ), levamisole (LVM), morantel (MRT) or ivermectin (IVM), at concentrations from 1 mM to 10 nM, in RPMI medium for 2 or 6 h and then transferred to a drug-free medium (RPMI medium supplemented with 0.5% BSA) for 24 h or continuously exposed to the drugs in supplement-free medium (24 h), the concentration- and time-dependent inhibitory effects on AChE secretion were observed. The continued exposure to the drugs for all incubation periods (with a single exception for LVM 1 mM) produced the highest levels of inhibition. Under these conditions, the concentrations inhibiting the secretion of AChE by 50% (IC50) relative to drug-free controls were estimated. The IC50 values ranged from 0.012 microM (IVM) to 2.96 microM (MRT). The potential of this bioassay for the selective primary evaluation of new compounds with broad-spectrum anti-nematodal activity is discussed.


Assuntos
Acetilcolinesterase/metabolismo , Anti-Helmínticos/farmacologia , Avaliação Pré-Clínica de Medicamentos/veterinária , Nematospiroides dubius/efeitos dos fármacos , Acetilcolinesterase/análise , Albendazol/análogos & derivados , Albendazol/farmacologia , Animais , Colorimetria , Meios de Cultura , Feminino , Sangue Fetal/química , Ivermectina/farmacologia , Levamisol/farmacologia , Masculino , Mebendazol/farmacologia , Camundongos , Morantel/farmacologia , Nematospiroides dubius/enzimologia , Nematospiroides dubius/fisiologia , Soroalbumina Bovina/química , Infecções por Strongylida/tratamento farmacológico , Infecções por Strongylida/enzimologia , Infecções por Strongylida/parasitologia
19.
Int J Biochem Cell Biol ; 31(9): 961-75, 1999 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10533287

RESUMO

(1) The role of fumarate metabolism in the microaerophily of the Campylobacter genus and the effects of therapeutic agents against it were investigated. (2) NMR spectroscopy was employed to determine the properties of Campylobacter fumarase (Fum) and fumarate reductase (Frd). Radiotracer analysis was used to determine the production of carbon dioxide by Campylobacter cells. Standard microbiological techniques were used to measure the effects of environmental conditions and inhibitors on bacterial growth. (3) All Campylobacter species tested showed both Fum and Frd activities. Frd activity was observed with or without the addition of an exogenous electron donor in the particulate fractions obtained from lysates. Fumarate was oxidized to carbon dioxide via the acetyl-CoA cleavage pathway. The genes encoding proteins involved in fumarate metabolism were identified in the Campylobacter jejuni genome. Cells grew better in atmospheres with 5 and 10% oxygen levels. Fum activity was the same in cultures grown under different oxygen tensions and did not vary with the age of cultures. Frd activity was higher in cultures which grew at faster rates and decreased with the age of cultures. Four Frd inhibitors showed bactericidal effects against Campylobacter spp. with different potencies. The relative strengths of inhibition of the compounds followed the same order as the bactericidal effects. (4) The results suggested that Frd and Fum are constitutive and play a fundamental role in these microaerophiles which show characteristics of anaerobic metabolism, and that the Frd inhibitors tested would not be of therapeutic use.


Assuntos
Anti-Helmínticos/farmacologia , Campylobacter/metabolismo , Fumaratos/metabolismo , Animais , Campylobacter/efeitos dos fármacos , Campylobacter/crescimento & desenvolvimento , Concentração de Íons de Hidrogênio , Levamisol/farmacologia , Malatos/metabolismo , Morantel/farmacologia , Pirantel/análogos & derivados , Pirantel/farmacologia , Tiabendazol/farmacologia
20.
Vet Res Commun ; 22(5): 299-304, 1998 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-9778775

RESUMO

The in vitro activities of thiabendazole, levamisole, pyrantel, morantel and ivermectin against Oesophagostomum spp., the nodular worm of pigs, were determined and compared. The study was carried out using isolates of O. dentatum and O. quadrispinulatum, which had been defined in vivo. Infective larvae were exposed to the anthelmintics for 24 h and then placed in a micromotility meter. All the treatments significantly reduced the motility of the ensheathed L3 larvae, but the micromotility meter was not able to differentiate between anthelmintic resistant and anthelmintic susceptible isolates.


Assuntos
Anti-Helmínticos/farmacologia , Oesophagostomum/efeitos dos fármacos , Animais , Resistência a Medicamentos , Ivermectina/farmacologia , Larva/efeitos dos fármacos , Levamisol/farmacologia , Morantel/farmacologia , Pirantel/farmacologia , Suínos/parasitologia , Tiabendazol/farmacologia
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