Biologically active secondary metabolites from the ascomycete A111-95. 1. Production, isolation and biological activities.
(41/284)
Eight secondary metabolites were isolated from submerged cultures of the ascomycete A111-95 during a search for new nematicidal metabolites. (-)-Galiellalactone (7) and compound 2 are metabolites previously obtained from cultures of Galiella rufa while the compounds 1, 3, 4, 5, 6 and 8 (3 and 4 were obtained as an unseparable mixture), were isolated as natural products for the first time. Compound 2, pregaliellalactone (5) and the mixture of 3 and 4 showed nematicidal activities towards Caenorhabditis elegans and Meloidogyne incognita. All compounds showed moderate or weak cytotoxic activities. (+info)
Lungworm (Crenosoma vulpis) infection in dogs on Prince Edward Island.
(42/284)
Crenosoma vulpis is a nematode lungworm that is highly prevalent in the red fox population of Atlantic Canada. Dogs are susceptible to infection with clinical signs consisting primarily of a chronic cough. A recent report of C. vulpis infection in 3 dogs on Prince Edward Island prompted an investigation into the importance of this parasite as a cause of chronic respiratory disease in Island dogs. A general prevalence was determined through the necropsy of dogs euthanized at the local humane society. Lungs were removed and examined for parasites using a lung flush technique. Rectal feces was collected and examined for first-stage larvae using the Baermann technique and zinc sulfate centrifugal flotation. Ten of 310 dogs (3.2%) were positive with 0-35 worms (mean = 11.0 +/- 13.4) recovered. First-stage larvae of C. vulpis were recovered in the rectal feces of the one animal in which no worms were recovered on lung flush. A second survey was conducted examining fecal samples with the Baermann technique from afebrile dogs with presenting signs of chronic cough that had no history of recent anthelmintic treatment and showed no signs of cardiac disease, based on physical examination. Fifteen of 55 dogs examined (27.3%) were definitively diagnosed as C. vulpis-positive. All of the infected dogs were treated with fenbendazole (50 mg/kg body weight, p.o. q24 h for 3-7 days). Clinical signs resolved in all of the dogs and fecal samples were negative 2-4 weeks posttreatment. It was concluded that C. vulpis infection was a significant cause of upper respiratory disease in dogs on Prince Edward Island and should be considered in all dogs with presenting signs of chronic cough. (+info)
Mutation spectrum of 1,2-dibromo-3-chloropropane, an endocrine disruptor, in the lacI transgenic Big Blue Rat2 fibroblast cell line.
(43/284)
1,2-Dibromo-3-chloropropane (DBCP), a soil fumigant against nematodes, has been extensively studied for genotoxicity, carcinogenicity and damage to male reproduction-related organs, as a possible endocrine disruptor. However, the precise mechanisms involved in DBCP-induced mutagenesis and carcinogenesis are as yet unknown. Thus, in this study the mutagenicity and mutation spectrum of DBCP was determined using the lacI transgenic Big Blue Rat2 fibroblast cell line. In determining the optimal concentration of DBCP in Big Blue Rat2 fibroblast cells, the 50% inhibition concentration was calculated to be 0.75 mM. When cells were exposed to DBCP concentrations of 0.21, 0.39 and 0.75 mM, the respective relative survival rates were approximately 80, 70 and 50%. The mean mutant frequencies (MFs) (x 10(-5), +/- SEM) of the medium and 1% DMSO solvent controls were determined as 6.43 +/- 0.616 and 5.28 +/- 1.086, respectively. The MFs (x 10(-5), +/- SEM) of cells exposed to 0.21, 0.39 and 0.75 mM DBCP were 8.09 +/- 1.02, 10.86 +/- 2.17 and 12.26 +/- 0.79, respectively, with a dose-dependent effect (ANOVA, P = 0.007). Moreover, MF values for the 0.75 and 0.39 mM DBCP-treated groups were statistically significant (ANOVA, P < 0.05). The majority of recovered mutations (31/40, 77.5%) were single base pair substitutions in the DBCP-induced groups. Among 31 single base pair substitutions, 25 (62.5%) occurred at G:C base pairs, while six (15%) were at A:T base pairs. The predominant mutation was G:C-->A:T transitions (16/40, 40%), followed by G:C-->T:A transversions (9/40, 22.5%). We conclude that DBCP is a possible base substitution mutagen, especially at guanine bases. (+info)
Paraherquamide and 2-deoxy-paraherquamide distinguish cholinergic receptor subtypes in Ascaris muscle.
(44/284)
Paraherquamide is a novel natural anthelmintic product with a mode of action that is incompletely characterized. Nicotine and cholinergic-anthelmintic agonists of different chemical classes were used to produce contraction in Ascaris muscle strips. Paraherquamide and a semisynthetic derivative, 2-deoxy-paraherquamide, antagonized these responses. Analysis of the actions of the antagonists was made using the simple competitive model and nonlinear regression to estimate the pK(B) values of the antagonists. The analysis was tested using Clark plots. The pK(B) values for paraherquamide were: nicotine, 5.86 +/- 0.14; levamisole, 6.61 +/- 0.19; pyrantel, 6.50 +/- 0.11; and bephenium, 6.75 +/- 0.15. The pK(B) of nicotine was significantly different from the pK(B) values for levamisole, pyrantel, and bephenium, showing that paraherquamide can distinguish a subtype of cholinergic receptors sensitive to nicotine and a subtype of cholinergic receptors sensitive to levamisole, pyrantel, and bephenium. The pK(B) values for 2-deoxy-paraherquamide were: levamisole, 5.31 +/- 0.13; pyrantel, 5.63 +/- 0.10; and bephenium, 6.07 +/- 0.13. The Clark plots of the antagonism illustrated the degree of fit to the competitive model for 2-deoxy-paraherquamide. 2-Deoxy-paraherquamide selectively antagonized the effects of bephenium; the pK(B) values of levamisole and pyrantel were significantly different from the pK(B) of bephenium. Paraherquamide and 2-deoxy-paraherquamide are selective competitive cholinergic antagonists that distinguish subtypes of cholinergic receptor in Ascaris muscle corresponding to nicotine-, levamisole-, and bephenium-sensitive receptors. (+info)
Epidermal growth factor receptor dependence in human tumors: more than just expression?
(45/284)
The epidermal growth factor receptor (EGFR) is a rational target for antitumor strategies. EGFR signaling causes increased proliferation, decreased apoptosis, and enhanced tumor cell motility and neo-angiogenesis. The EGFR is expressed or highly expressed in a variety of human tumors of epithelial origin. ZD1839 (Iressa) is an orally active, selective EGFR tyrosine kinase inhibitor, which blocks signal transduction pathways implicated in proliferation and survival of cancer cells. The lack of a consistent method of evaluating levels of EGFR has caused a disparity in reports of the EGFR as a prognostic factor; however, for some tumors, EGFR is a strong prognostic indicator associated with more aggressive disease and reduced survival. So far, no clear association between EGFR levels and response to EGFR-targeted agents has been found. Preclinical studies with ZD1839 have noted a relationship between the two in some cases, but not others. EGFR signaling may be increased by a number of mechanisms in addition to high expression levels of EGFR, including receptor mutations, heterodimerization with other members of this receptor family such as HER2 (erbB2), increased expression of (autocrine/ paracrine) ligands, and alterations in molecules that control receptor signaling output. Each of these components could be assessed to give an indication of the magnitude of EGFR signal amplification. Evaluation of signaling components downstream from EGFR should provide information on the activation of the EGFR pathway. Until EGFR-based assays predictive of a response to receptor-targeted therapies are available, there is no clear justification for stratifying patients by EGFR status or excluding patients with low EGFR levels from trials with ZD1839 or other EGFR inhibitors. (+info)
We present an unusual case of cerebellar ataxia in a 2 year old girl several days after treatment with piperazine citrate for suspected worm infestation. This is the first reported case of delayed onset neurotoxicity following the therapeutic administration of piperazine in a previously well child. (+info)
Fenbendazole pharmacokinetics, metabolism, and potentiation in horses.
(47/284)
The present study was designed to describe the pharmacokinetics and fecal excretion of fenbendazole (FBZ) and fenbendazole sulphoxide (FBZSO) and their metabolites in horses, to investigate the effects which concurrent feeding has on the absorption and pharmacokinetics of FBZ, and to determine the effect of coadministration of the metabolic inhibitor piperonyl-butoxide on the in vivo pharmacokinetics and in vitro liver microsomal metabolism of sulfide and sulfoxide benzimidazoles. The effect of piperonyl-butoxide on the enantiomeric genesis of the sulfoxide moiety was also investigated. Following administration of FBZSO and FBZ, the fenbendazole sulphone metabolite predominated in plasma, and the C(max) and area under the plasma curve (AUC) values for each moiety were larger (P < 0.001) following FBZSO than FBZ. In feces the administered parent molecule predominated. The combined AUC for active benzimidazole moieties following oral administration of FBZ (10 mg/kg) in horses was almost 4 times as high in unfed horses (2.19 microg x h/ml) than in fed horses (0.59 microg x h/ml), and coadministration of piperonyl-butoxide significantly increased the AUC and C(max) of active moieties following intravenous administration of FBZSO and oral administration of FBZ. When FBZSO was administered i.v. as a racemate, the first enantiomer of oxfendazole (FBZSO-1) predominated in plasma, however, following coadministration with piperonyl-butoxide, the second enantiomer of oxfendazole (FBZSO-2) predominated for 10 h. Piperonyl-butoxide significantly reduced the oxidative metabolism of FBZSO and FBZ in equine liver microsomes and altered the ratio of enantiomers FBZSO-1/FBZSO-2 from >4:1 to 1:1. It is concluded that in horses efficacy of FBZSO and FBZ could be improved by administration to unfed animals and coadministration with piperonyl-butoxide. (+info)
Two genes encoding fruit body lectins of Pleurotus cornucopiae: sequence similarity with the lectin of a nematode-trapping fungus.
(48/284)
Our previous studies on the fruit body lectin of Pleurotus cornucopiae revealed the existence of three isolectins, composed of two homodimers and one heterodimer of 16- and 15-kDa subunits. In this study, two genes encoding the lectins were cloned and characterized. Both genes encoded 144 amino acids and only 5 amino acids were different within the coding region, but the nucleotide sequences of the 5'-upstream and 3'-downstream regions differed extensively. Southern hybridization with gene-specific probes showed that one gene encoded the 16-kDa and the other encoded the 15-kDa subunit. Functional lectins were synthesized in Escherichia coli under the direction of these genes. On SDS-PAGE, the recombinant lectins showed the same banding patterns as the native lectins. In amino acid sequence, these lectins showed extensive similarity with the lectin from a nematode-trapping ascomycete fungus, Arthrobotrys oligospora, suggesting that the lectins might also function in capturing nematodes. (+info)