Efficacy of a novel topical fipronil, (S)-methoprene, eprinomectin and praziquantel combination against naturally acquired intestinal nematode and cestode infections in cats.

The efficacy of a novel topical combination formulation of fipronil, (S)-methoprene, eprinomectin and praziquantel against naturally acquired intestinal nematode and cestode infections in cats was evaluated in seven negative control, blinded studies. Cats were selected based on a pre-treatment faecal examination indicating a patent infection with at least hookworms (two studies), Toxocara ascarids (one study), taeniid cestodes (two studies) or Dipylidium cestodes (two studies). In each study, cats were assigned randomly to blocks of two animals each, based on decreasing pre-treatment body weight and were randomly allocated to one of two groups of six to 12 cats: untreated (control) or treated with topical fipronil (8.3%, w/v), (S)-methoprene (10%, w/v), eprinomectin (0.4%, w/v) and praziquantel (8.3%, w/v) (BROADLINE(®), Merial) at 0.12 mL/kg body weight (providing a minimum of 10mg fipronil+12 mg S-methoprene+0.5mg eprinomectin+10mg praziquantel per kg body weight). The topical treatment was administered directly on the skin in the midline of the neck in a single spot once on Day 0. For parasite recovery and count, cats were euthanized humanely and necropsied seven or ten days after treatment. A single treatment with the novel topical combination product provided 91% efficacy against Ancylostoma braziliense, ≥ 99% efficacy against Ancylostoma tubaeforme, and >97% efficacy against Toxocara cati. Similarly, excellent efficacy was established against Taenia taeniaeformis, Dipylidium caninum and Diplopylidium spp. as demonstrated by >97% and up to 100% reductions of cestode counts in the treated cats when compared to the untreated controls (P<0.01). All cats accepted the treatment well based on health observations post-treatment and daily health observations. No adverse experiences or other health problems were observed throughout the studies. The results of this series of controlled studies demonstrated high efficacy and excellent acceptability of the novel topical combination formulation of fipronil, (S)-methoprene, eprinomectin and praziquantel against a broad range of feline intestinal nematode and cestode infections

Dry selection and wet evaluation for the rational discovery of new anthelmintics

Helminths infections remain a major problem in medical and public health. In this report, atom-based 2D bilinear indices, a TOMOCOMD-CARDD (QuBiLs-MAS module) molecular descriptor family and linear discriminant analysis (LDA) were used to find models that differentiate among anthelmintic and non-anthelmintic compounds. Two classification models obtained by using non-stochastic and stochastic 2D bilinear indices, classified correctly 86.64% and 84.66%, respectively, in the training set. Equation 1(2) correctly classified 141(135) out of 165 [85.45%(81.82%)] compounds in external validation set. Another LDA models were performed in order to get the most likely mechanism of action of anthelmintics. The model shows an accuracy of 86.84% in the training set and 94.44% in the external prediction set. Finally, we carry out an experiment to predict the biological profile of our ‘in-house’ collections of indole, indazole, quinoxaline and cinnoline derivatives (∼200 compounds). Subsequently, we selected a group of nine of the theoretically most active structures. Then, these chemicals were tested in an invitro assay and one good candidate (VA5-5c) as fasciolicide compound (100% of reduction at concentrations of 50 and 10 mg/L) was discovered.Yovani Marrero-Ponce acknowledges the support from USFQ with partial finance of project ID5455Peer Reviewe

Variación estacional de dactylogyrus sp. en dos unidades productoras de tilapia del estado de Morelos

En los centros acuícolas de Zacatepec y EI Rodeo Morelos, SEPESCA, se realizó un estudio con objeto de conocer la variación estacional de Dactylogyrus sp. así como la especie de pez, talla, sexo, temperatura y época del año en que se desarrolla el tremá

Novel Ligand-Base Approach ti Screening to Screening of Large Databases for Paramphistomicide Lead Generation

In this report, non-stochastic and stochastic 2D atom-based linear indices were used to the discrimination of paramphistomicide compounds from inactive ones. Two linear classification-based QSAR models were obtained. These equations, performed considering both non-stochastic and stochastic TOMOCOMD-CARDD descriptors, classify correctly 88.57% of chemicals in database, for a good Mathew’s correlation coefficient of 0.77. A few anthelmintics compounds and other drugs from the Merck Index, Negwer handbook, and Goodman & Gilman were selected/identified by the models as possible paramphistomicide, one of them was found in the recent literature as possessing this activity. The results demonstrate the usefulness of TOMOCOMD-CARDD method for drug discovery of new lead paramphistomicide compounds.En este informe se emplearon índices lineales estocásticos y no estocásticos en 2D, basados en átomos, para discriminar los compuestos de acción paramfistomicida de los inactivos. Se obtuvieron dos modelos lineales QSAR basados en la clasificación. Estas ecuaciones, llevadas a cabo teniendo en cuenta descriptores TOMOCOMD-CARDD tanto estocásticos como no estocásticos, clasifican correctamente el 88,57% de los elementos químicos de la base de datos, arrojando un buen coeficiente de correlación de Mathews del 0,77. Los modelos seleccionaron/identificaron algunos compuestos antihelmínticos y otros fármacos del índice Merck, del manual Negwer y de Goodman & Gilman como posibles paramfistomicidas, y la literatura reciente incluye a uno de ellos como poseedor de esta actividad. Los resultados demuestran la utilidad del método TOMOCOMD-CARDD para el descubrimiento de fármacos y de nuevos compuestos líderes de acción paramfistomicida

Development of the first georeferenced map of Rhipicephalus (Boophilus) spp. in Mexico from 1970 to date and prediction of its spatial distribution

The tick genus Ripicephalus (Boophilus), particularly R. microplus, is one of the most important ectoparasites that affects livestock health and considered an epidemiological risk because it causes significant economic losses due, mainly, to restrictions in the export of infested animals to several countries. Its spatial distribution has been tied to environmental factors, mainly warm temperatures and high relative humidity. In this work, we integrated a dataset consisting of 5843 records of Rhipicephalus spp., in Mexico covering close to 50 years to know which environmental variables mostly influence this ticks’ distribution. Occurrences were georeferenced using the software DIVA-GIS and the potential current distribution was modelled using the maximum entropy method (Maxent). The algorithm generated a map of high predictive capability (Area under the curve = 0.942), providing the various contribution and permutation importance of the tested variables. Precipitation seasonality, particularly in March, and isothermality were found to be the most significant climate variables in determining the probability of spatial distribution of Rhipicephalus spp. in Mexico (15.7%, 36.0% and 11.1%, respectively). Our findings demonstrate that Rhipicephalus has colonized Mexico widely, including areas characterized by different types of climate. We conclude that the Maxent distribution model using Rhipicephalus records and a set of environmental variables can predict the extent of the tick range in this country, information that should support the development of integrated control strategies

Efficacy of a novel topical combination of esafoxolaner, eprinomectin and praziquantel in cats against

NexGard® Combo, a novel topical antiparasitic product for cats, combines the insecticide/acaricide esafoxolaner with the nematocide eprinomectin and cestodicide praziquantel. The efficacy of this combination product was evaluated against two common endoparasites of global occurrence in cats, the nematode Toxocara cati and the cestode Dipylidium caninum, in five controlled studies using naturally or experimentally infected cats with parasites of North American, South African or European origin. Cats evaluated in these studies harbored patent infection of the target parasite confirmed through a pre-treatment fecal examination. In each study, cats were allocated randomly to two groups of equal size (8 or 10 cats per group per study), one group treated with a placebo (mineral oil) and the other with NexGard® Combo. Both treatments were administered once as a spot-on at 0.12 mL per kg body weight to deliver the minimum label dosage (1.44 mg/kg esafoxolaner, 0.48 mg/kg eprinomectin, and 10.0 mg/kg praziquantel) to the NexGard® Combo-treated cats. To determine efficacy, geometric mean parasite counts seven to 12 days after treatment of placebo-treated (control) cats and NexGard® Combo-treated cats were compared. The efficacy of NexGard® Combo was 98.8% and 100% against adult T. cati in two studies; and 98.0%, 98.3% and 93.2% against D. caninum in three studies. No adverse events related to treatment were observed throughout the studies. These studies demonstrate high efficacy against these major feline endoparasites and excellent acceptability of the novel topical antiparasitic combination of esafoxolaner, eprinomectin and praziquantel

Discovery of novel trichomonacidals using LDA-driven QSAR models and bond-based bilinear indices as molecular descriptors

Few years ago, the World Health Organization estimated the number of adults with trichomoniasis at 170 million worldwide, more than the combined numbers for gonorrhea, syphilis, and chlamydia. To combat this sexually transmitted disease, Metronidazole (MTZ) has emerged, since 1959, as a powerful drug for the systematic treatment of infected patients. However, increasing resistance to MTZ, adverse effects associated to high-dose MTZ therapies and very expensive conventional technologies related to the development of new trichomonacidals necessitate novel computational methods that shorten the drug discovery pipeline. Therefore, bond-based bilinear indices, new 2-D bond-based TOMOCOMD-CARDD Molecular Descriptors (MDs), and Linear Discriminant Analysis (LDA) are combined to discover novel antitrichomonal agents. Generated models, using non-stochastic and stochastic indices, are able to classify correctly the 90.11% (93.75%) and the 87.92% (87.50%) of chemicals in the training (test) sets, respectively. In addition, they show large Matthews' correlation coefficients (C) of 0.80 (0.86) and 0.76 (0.71) for the training (test) sets, respectively. The result of predictions on the 10% full-out cross-validation test also evidences the quality of both models. In order to test the models' predictive power, 12 compounds, already proved against Trichomonas vaginalis (Tv), are screened in a simulated virtual screening experiment. As a result, they correctly classified 9 out of 12 (75.00%) and 10 out of 12 (83.33%) of the chemicals, respectively, which were the most important criteria to validate the models. Finally, in order to prove the reach of TOMOCOMD-CARDD approach and to discover new trichomonacidals, these classification functions were applied to a set of eight chemicals which, in turn, were synthesized and tested toward in vitro activity against Tv. As a result, experimental observations confirm theoretical predictions to a great extent, since it is gained a correct classification of 87.50% (7/8) of chemicals. Biological tests also show several candidates as antitrichomonals, since almost all the compounds [VAM2-(3-8)] exhibit pronounced cytocidal activities of 100% at the concentration of 100 mg/mL and at 24 h (48 h) but VAM2-2: 99.37% (100%), and it is remarkable that these compounds do not show toxic activity in macrophage assays at this concentration. The Quantitative Structure-Activity Relationship (QSAR) models presented here could significantly reduce the number of synthesized and tested compounds as well as could act as virtual shortcuts to new chemical entities with trichomonacidal activity. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.Peer Reviewe

<i>Dry</i> selection and <i>wet</i> evaluation for the <i>rational</i> discovery of new anthelmintics

<p>Helminths infections remain a major problem in medical and public health. In this report, atom-based 2D bilinear indices, a <i>TOMOCOMD-</i><i>CARDD</i> (QuBiLs-MAS module) molecular descriptor family and linear discriminant analysis (LDA) were used to find models that differentiate among anthelmintic and non-anthelmintic compounds. Two classification models obtained by using non-stochastic and stochastic 2D bilinear indices, classified correctly 86.64% and 84.66%, respectively, in the training set. Equation 1(2) correctly classified 141(135) out of 165 [85.45%(81.82%)] compounds in external validation set. Another LDA models were performed in order to get the most likely mechanism of action of anthelmintics. The model shows an accuracy of 86.84% in the training set and 94.44% in the external prediction set. Finally, we carry out an experiment to predict the biological profile of our ‘in-house’ collections of indole, indazole, quinoxaline and cinnoline derivatives (∼200 compounds). Subsequently, we selected a group of nine of the theoretically most active structures. Then, these chemicals were tested in an <i>in</i> <i>vitro</i> assay and one good candidate (VA5-5c) as fasciolicide compound (100% of reduction at concentrations of 50 and 10 mg/L) was discovered.</p