Propuesta de una dosis de marbofloxacina para el tratamiento de infecciones asociadas a Escherichia coli en cabras de tres semanas de vida

Se estimó una dosis de marbofloxacina (MFX) para tratar infecciones gastrointestinales asociadas a Escherichia coli en cabras de tres semanas de vida. La farmacodinamia de MFX sobre E. coli se evaluó in vitro estimando las concentraciones inhibitoria mínima (CIM), bactericida mínima (CBM) y preventiva de mutantes (CPM). Marbofloxacina se administró en cabras de tres semanas de edad por vía subcutánea a una dosis de 2 mg/kg. Los parámetros farmacocinéticos se estimaron mediante análisis no compartimental. La dosis de MFX capaz de proteger al 95% de una población se calculó considerando la distribución poblacional de los parámetros farmacocinéticos. La eficacia de MFX se evaluó con la relación entre el área bajo la curva y la CPM (ABC/CPM) con un valor de corte de 22 h. Los resultados mostraron que la dosis estimada de MFX para alcanzar la remisión clínica de infecciones gastrointestinales causadas por E. coli y prevenir la emergencia de cepas resistentes en el 95% de una población de cabras de tres semanas de vida fue de 3,179 mg/kg, que a los fines prácticos se fijó en 3,5 mg/kg.

A dose of marbofloxacin (MFX) to treat gastrointestinal infections caused by Escherichia coli in 3-week-old goats was estimated. The pharmacodynamics of MFX against E. coli was evaluated in vitro by estimation of mínimum inhibitory concentration (MIC), mínimum bactericide concentration (MBC) and mutant prevention concentration (MPC). Marbofloxacin was administered to 3-week -old goats by subcutaneous route at the dose of 2 mg/kg. The pharmacokinetic parameters were estimated by non-compartmental analysis. The dose of MFX capable to protect the 95% of population was calculated considering the population distribution of pharmacokinetic parameters. The efficacy of MFX was evaluated by the relationship between the area under curve and MPC (AUC/MPC) with a cut-off value of 22 h. The results showed that the estimated dose of MFX to reach the clinical outcome of gastrointestinal infections caused by E. coli and to prevent the bacterial resistance at the 95% of the population of 3-week-old goats was 3.179 mg/kg, which for practical reasons was fixed at 3.5 mg/kg.

Fipronil sulfone induced higher cytotoxicity than fipronil in SH-SY5Y cells: Protection by antioxidants.

Fipronil is a broad spectrum insecticide from the phenyl pyrazole family, which targets GABA receptor. Limited information is available about the metabolite fipronil sulfone cytotoxic actions. This study examined in vitro neurotoxicity of fipronil and fipronil sulfone and evaluated Trolox (vitamin E analog) (0.3, 1µM), N-acetyl-cysteine (0.5, 1mM), melatonin (0.1, 1µM) and Tempol (superoxide dismutase analog) (0.3, 0.5mM) protective role in SH-SY5Y cells. MTT and LDH assays were carried out to assess the cytotoxicity of fipronil and fipronil sulfone at 3-100µM concentrations. Fipronil sulfone was more toxic than fipronil. Tempol showed the best neuroprotectant profile against fipronil (50 and 150µM) and fipronil sulfone (3 and 10µM) reaching control levels. Fipronil (100µM) and fipronil sulfone (3µM) treatments induced a 4.7- and 5-fold increases in lipid peroxides measured as malondialdehyde (MDA) and a 2.2- and 2.0-fold increases in the levels of nitric oxide (NO). These results suggest that oxidative stress observed may be one of the major mechanisms of fipronil-induced neurotoxicity and it may be attributed in part to fipronil disposition and metabolism. Our results led us postulate that metabolite fipronil sulfone might be responsible for the fipronil-induced toxicity rather than fipronil itself.

Pharmacokinetics, efficacy prediction indexes, and residue depletion of ribavirin in Atlantic salmon's (Salmo salar) muscle after oral administration in feed.

Ribavirin is an antiviral used in human medicine, but it has not been authorized for use in veterinary medicine although it is effective against infectious salmon anemia (ISA) virus, between others. In this study, we present a pharmacokinetic profile of ribavirin in Atlantic salmon (Salmo salar), efficacy prediction indexes, and the measure of its withdrawal time. To determine the pharmacokinetic profile, fishes were orally administered with a single ribavirin dose of 1.6 mg/kg bw, and then, plasma concentrations were measured at different times. From the time-vs.-concentration curve, Cmax = 413.57 ng/mL, Tmax  = 6.96 h, AUC = 21394.01 µg·h/mL, t1/2  = 81.61 h, and K10  = 0.0421/h were obtained. Ribavirin reached adequate concentrations during the pharmacokinetic study, with prediction indexes of Cmax /IC50  = 20.7, AUC/IC50  = 1069.7, and T>IC50  = 71 h, where IC is the inhibitory concentration 50%. For ribavirin depletion study, fishes were orally administered with a dairy dose of 1.6 mg/kg bw during 10 days. Concentrations were measured on edible tissue on different days post-treatment. A linear regression of the time vs. concentration was conducted, obtaining a withdrawal time of 1966 °C days. Results obtained reveal that the dose of 1.6 mg/kg bw orally administered is effective for ISA virus, originating a reasonable withdrawal period within the productive schedules of Atlantic salmon.

Effects of exposure to pyrethroid cyfluthrin on serotonin and dopamine levels in brain regions of male rats.

The effects of cyfluthrin oral exposure (1, 5, 10 and 20mg/kg bw, 6 days) on brain region monoamine levels of male rats were examined. Cyfluthrin-treated rats (1, 5 and 10mg/kg bw, orally 6 days), had no visible injury, i.e., no clinical signs of dysfunction were observed. However, rats treated with cyfluthrin at the highest dose (20mg/kg bw, orally 6 days) showed skeletal muscle contraction in the hind limbs, slight movement incoordination without any signs of dyskinesia and tremor after 1-2h of treatment. These signs were reversible at 6h after dose. After last dose of cyfluthrin, dopamine (DA) and serotonin (5-HT) and its metabolites levels were determined in brain regions hypothalamus, midbrain, hippocampus, striatum and prefrontal cortex by HPLC. Cyfluthrin (1mg/kg bw, orally 6 days) did not affect the DA, 5-HT and metabolites levels in the brain regions studied. Cyfluthrin (5, 10 and 20mg/kg bw, orally 6 days) caused a statistically significant decrease in DA and its metabolites DOPAC and HVA levels and in 5-HT and its metabolite 5-HIAA levels in a brain region- and dose-related manner. Moreover, cyfluthrin (20mg/kg bw, orally 6 days) evoked a statistically significant increase in 5-HT turnover in striatum and midbrain, and in DA turnover in striatum and prefrontal cortex. These findings indicate that serotoninergic and dopaminergic neurotransmission is affected by exposure to cyfluthrin and may contribute to the overall spectrum of neurotoxicity caused by this pyrethroid.

Fipronil induces CYP isoforms in rats.

The goal of the present study was to evaluate fipronil effects on the activities of drug metabolizing enzymes in rat liver microsomes. Rats were orally treated with fipronil at doses of 1, 5, 10 and 15 mg/kg bw/day for 6 days. Determinations of cytochrome P450 (CYP) enzyme activities were carried out in hepatic microsomes isolated from treated rats. The activities of some members of CYP2E, CYP1A, CYP2A, CYP2B and CYP3A subfamilies significantly increased after fipronil treatment in a dose-dependent manner as compared to control. The major effects were observed in the O-deethylation of ethoxyresorufin and O-demethylation of methoxyresorufin (reflecting CYP1A1/2 activities), in the O-depenthylation of pentoxyresorufin and 16ß-hydroxylation of testosterone (reflecting CYP2B1/2 activities), and in the N-demethylation of erythromycin and 6ß-hydroxylation of testosterone (reflecting CYP3A1/2 activities). Immunoblot studies revealed that fipronil increased the apoprotein levels of CYP1A1. Our results suggest that fipronil is an inducer of hepatic phase I CYP enzymes, causing an increased potential to interact with a wide range of xenobiotics or endogenous chemicals that are substrates of the CYP1A, CYP2B and CYP3A subfamilies. Further investigations are required to in vivo evaluate the potential of the metabolite fipronil sulfone as an inducer of phase I CYP enzymes.

Evidence for dose-additive effects of a type II pyrethroid mixture. In vitro assessment.

Despite the widespread use of pyrethroid insecticides that led to common exposure in the population, few studies have been conducted to quantitatively assess dose-additive effects of pyrethroids using a funcional measure involved in the common toxic mode of action. The aim of this study was to evaluate the potency and efficacy of 6 Type II pyretroids (α-cypermethrin, cyfluthrin, λ-cyhalothrin, deltamethrin, cyphenothrin and esfenvalerate) to evoke induction of both nitric oxide and lipid peroxides levels measured as malondialdehyde in three in vitro models (SH-SY5Y, HepG2 and Caco-2 human cells) as well as to test the hypothesis of dose additivity for mixtures of these same 6 pyrethroids. Concentration-responses for 6 pyrethroids were determined as well as the response to mixtures of all 6 pyrethroids. Additivity was tested assuming a dose-additive model. The human neuroblastoma SH-SY5Y cell line was the most sensitive in vitro model. The rank order of potency for cell SH-SY5Y viability MTT assay was deltamethrin>cyphenothrin>λ-cyhalothrin>cyfluthrin>esfenvalerate>α-cypermethrin. When 6 pyrethroids were present in the mixture at an equitoxic mixing ratio, the action on nitric oxide (NO) and lipid peroxides measured as malondialdehyde (MDA) production was consistent with a dose-additive model. The results of the present study are consistent with previous reports of additivity of pyrethroids in vivo e in vitro.

Depleción tisular de azaperona y su metabolito azaperol tras administración oral de azaperona en cerdo / Tissue depletion of azaperone and its metabolite azaperol after oral administration of azaperone in food-producing pigs

Azaperona es un tranquilizante de tipo butirofenona usado en ganado porcino. Los cerdos son particularmente sensibles al estrés durante el manejo y transporte al matadero. La azaperona es parcialmente metabolizada in vivo a azaperol, un metabolito con actividad farmacológica. Las concentraciones altas y persistentes de azaperona y azaperol en el lugar de inyección contraindican el uso de azaperona por vía intramuscular para el transporte de cerdos de producción de carne al matadero; el uso oral podría ser una alternativa para evitar residuos en el lugar de inyección. El presente estudio determinó la depleción en los tejidos de azaperona y su metabolito azaperol después de la administración oral de la formulación Stresnil®. Cerdos machos (30-45 kg de peso corporal) fueron tratados con Stresnil® (dosis oral única de 4 mg azaperona/kg de peso corporal) y se sacrificaron 6, 24 y 48 horas después de la administración. De cada animal se obtuvo músculo, piel + grasa, hígado y riñón. Azaperona y azaperol se analizaron por HPLC tras la extracción en fase sólida. Las concentraciones de azaperona más azaperol en todos los tejidos analizados no superaron el Límite Máximo de Residuos (LMR) establecidos por la Unión Europea (100 mg / kg en el músculo, el hígado, los riñones y la piel + grasa) en ningún momento del muestreo. Como consecuencia, según los resultados obtenidos en el presente estudio, los tejidos comestibles de los cerdos tratados por vía oral con 4 mg/kg de azaperona, 6 horas antes al sacrificio, podrían ser aceptables para garantizar la seguridad de los consumidores. Sin embargo, se estimó un tiempo de espera de cero horas por análisis de regresión lineal (AU)

Azaperone is a butyrophenone tranquilizer for swine. Food producing pigs are particularly sensitive to stress during handling and transport to the abattoir. In vivo, azaperone is partially metabolised to azaperol, a metabolite with pharmacological activity. The high and persistent concentrations of azaperone and azaperol in the injection site contra-indicates the use of azaperone using the intramuscular route for the transport of the food producing animals, pigs, to the slaughterhouse; the oral use could be an alternative to avoid residues at the injection site. The present study determined the tissue depletion of azaperone and its metabolite azaperol after oral administration of the formulation Stresnil®. Male pigs (30-45 kg of body weight) were treated with Stresnil® (single oral dose of 4 mg azaperone/kg body weight) and were sacrificed 6, 24 and 48 hours after the administration. Muscle, skin + fat, liver and kidney were collected from each animal. Azaperone and azaperol were assayed by HPLC after solid phase extraction. The concentrations of the azaperone plus azaperol in all analysed tissues did not exceed to the Maximum Residue Limit (MRL) established by the European Union (100 μg/kg in muscle, liver, kidney and skin plus fat) at any sampling time. As a consequence, from the results obtained in the present study, edible tissues of pigs treated orally with 4 mg/kg azaperone, 6 hours before to the sacrifice, might be acceptable to guarantee safety for the consumers. Nevertheless a withdrawal time of cero hours was estimated by linear regression analysis (AU)

Differential induction of cytochrome P450 isoforms and peroxisomal proliferation by cyfluthrin in male Wistar rats.

Cyfluthrin effects on in vivo drug metabolizing enzymes were evaluated using the oxidative substrate antipyrine. Antipyrine pharmacokinetics in plasma and urinary excretion of its major metabolites with and without cyfluthrin oral treatment (20mg/kg/day for 6 days) were investigated in rats. Cyfluthrin increased the apparent intrinsic clearance and decreased the antipyrine half-life at ß phase. Cyfluthrin also increased the clearance of the antipyrine metabolites, norantipyrine, 4-hydroxyantipyrine and 3-hydroxymethylantipyrine and the formation rate constants for each of the three metabolites measured in urine. These results suggest that cyfluthrin affects hepatic cytochrome P450 (CYP) system. In order to confirm, a second experiment was carried out. We evaluated the effects of repeated exposure to cyfluthrin on hepatic and renal CYP2E, CYP1A and CYP4A subfamilies and peroxisomal proliferation in rats following oral administration (10 and 20mg/kg/day for 6 days). At the highest dose, cyfluthrin increased renal and hepatic O-deethylation of ethoxyresorufin and O-demethylation of methoxyresorufin, metabolism mediated by the CYP1A subfamily. Liver and kidney were susceptible to cyfluthrin-dependent induction of 12- and 11-hydroxylation of lauric acid, suggesting CYP4A subfamily induction. Also cyfluthrin increased the ß-oxidation of palmitoyl-coenzyme A and carnitine acetyltransferase activity, supporting cyfluthrin as a peroxisome proliferator. In conclusion, the demonstration that cyfluthrin induced hepatic CYP1A, CYP4A subfamilies and peroxisomal proliferation raises the possibility of cyfluthrin could produce changes in oxidative stress.

Effects of exposure to amitraz on noradrenaline, serotonin and dopamine levels in brain regions of 30 and 60 days old male rats.

The effects of amitraz oral exposure (20, 50 and 80mg/kg bw, 5 days) on brain region monoamine levels of male rats at 30 and 60 days of age were examined. The amitraz-treated rats at the oral doses of 20 and 50mg/kg bw had no visible injury, i.e., any clinical signs of dysfunction observed in any of the animals. However, rats treated with amitraz at the highest dose (80mg/kg bw, 5 days) showed a slight motor incoordination after 1-2h of treatment. These signs were reversible approximately at 6h after dose. After the last dose of amitraz, NE, DA and 5-HT and its metabolites levels were determined in the brain regions hypothalamus, midbrain, prefrontal cortex, striatum and hippocampus by HPLC. Amitraz caused changes in the NE, DA and 5-HT and their metabolite levels in a brain regional-, dose- and age-related manner. In the brain regions studied, amitraz induced a statistically significant increase in 5-HT, NE and DA content with age interaction, but the NE increases in prefrontal cortex and hippocampus was without age interaction. Moreover, in the brain regions studied, amitraz induced a statistically significant decrease in the metabolite 5-HIAA, MHPG, DOPAC and HVA levels displaying an age interaction, excepting the 5-HIAA decrease in midbrain and the DOPAC decrease in hypothalamus and striatum which were without age interaction. Furthermore, amitraz evoked a statistically significant decrease in 5-HT, NE and DA turnover in the brain regions studied. The present findings indicate that amitraz significantly altered CNS monoaminergic neurotransmitters in a brain regional-, dose- and age-related manner.

Risk assessment of coccidostatics during feed cross-contamination: animal and human health aspects.

Coccidiosis, an intestinal plasmodium infection, is a major infectious disease in poultry and rabbits. Eleven different coccidiostats are licensed in the EU for the prevention of coccidiosis in these animal species. According to their chemical nature and main biological activity, these compounds can be grouped as ionophoric (monensin, lasalocid sodium, salinomycin, narasin, maduramicin and semduramicin) or non-ionophoric (robenidine, decoquinate, nicarbazin, diclazuril, and halofuginone) substances. Coccidiostats are used as feed additives, mixed upon request into the compounded feed. During the technical process of commercial feed production, cross-contamination of feed batches can result in the exposure of non-target animals and induce adverse health effects in these animals due to a specific sensitivity of mammalian species as compared to poultry. Residue formation in edible tissues of non-target species may result in unexpected human exposure through the consumption of animal products. This review presents recent risk assessments performed by the Scientific Panel on Contaminants in the Food Chain (CONTAM) of the European Food Safety Authority (EFSA). The health risk to non-target species that would result from the consumption of cross-contaminated feed with coccidostats at levels of 2, 5 or 10% was found to be negligible for most animal species with the exception of salinomycin and monensin in horses because of the particular sensitivity for which toxicity may occur when cross-contamination exceeds 2% and 5% respectively. Kinetic data and tissue analyses showed that residues of coccidiostats may occur in the liver and eggs in some cases. However, the level of residues of each coccidiostat in edible animal tissues remained sufficiently low that the aggregate exposure of consumers would not exceed the established acceptable daily intake (ADI) of each coccidiostat. It could be concluded that technical cross-contamination of animal feeds would not be expected to adversely affect the health of consumers.

Tinnitus and quality of life following vestibular schwannoma surgery.

OBJECTIVE: This study on patients undergoing surgery for vestibular schwannoma investigated tumour (i) the effect of pre-operative factors on tinnitus, (ii) the effect of translabyrinthine or hearing preservation surgical approaches on tinnitus, and (iii) the effect of postoperative tinnitus status on the patient's quality of life (QOL). METHODOLOGY: Seventy-nine patients who underwent vestibular schwannoma (VS) excision between 2001 and 2005 were selected. Postoperative tinnitus status was evaluated using a standard questionnaire for tinnitus, and QOL was measured using the Glasgow Benefit Inventory (GBI). RESULTS: Overall, 58% of patients noted tinnitus before tumour removal. Pre-operative tinnitus was not associated with age, gender, tumour size, or hearing thresholds. The total percentage of patients suffering postoperative tinnitus was 64%. Hearing preservation approaches showed no difference in terms of changes in tinnitus compared to the translabyrinthine approach. Twenty-one patients (30%) reported better QOL, 40 patients (56%) reported worse QOL, and 10 patients (14%) reported the same QOL. A significant association was found between tinnitus worsening as measured by GBI score and QOL. CONCLUSIONS: Most patients do not report significant changes in their tinnitus status after surgery. Tinnitus evolution is unpredictable and not related to the type of surgical approach. Thus, tinnitus should not be used as a criterion for selecting the surgical approach. Tinnitus worsening appears to influence QOL following surgery for VS.

Ani s 1 and Ani s 7 recombinant allergens are able to differentiate distinct Anisakis simplex-associated allergic clinical disorders.

Diagnosis in gastro-allergic anisakiasis (GAA) is straightforward, when clinical history is combined with further allergological evaluation of specific IgE by means of skin prick test and serum specific IgE. In Anisakis simplex sensitisation associated chronic urticaria (CU+), clinical evaluation of possible previous parasitism is difficult, and positive serum specific IgE could be due to cross-reactivity or other unknown factors. In this study, we evaluated the association between IgE seropositivity to the recombinant allergens Ani s 1 and Ani s 7 and several A. simplex-associated allergic disorders. Twenty-eight patients with GAA and 40 patients with CU+ were studied and their IgE responses were compared with a control group composed of patients with chronic urticaria not sensitized to A. simplex (CU-) according to the skin prick test, as well as a group of 15 healthy subjects not referring urticaria or currently A. simplex associated symptoms. 82.1% of GAA patients and 42.5% of CU+ patients were positive for Ani s 1 (P < 0.001), while the Ani s 7 allergen was recognized by 92.9 and 92.5% of sera from patients with GAA and CU+, respectively. The combined positivity obtained for both allergens reached 100% in GAA, and 95% in CU+. IgE determinations to Ani s 1 and Ani s 7 allergens are useful to diagnose the Anisakis infections and to differentiate among several A. simplex-associated allergic disorders. The IgE responses to Ani s 1 are mainly associated with GAA, while this molecule cannot be considered a major allergen in CU+ patients.

Effects of prenatal and postnatal exposure to amitraz on norepinephrine, serotonin and dopamine levels in brain regions of male and female rats.

The effects of maternal exposure to amitraz on brain region monoamine levels of male and female offspring rats at 60 days of age were observed. Maternal and offspring body weight, physical and general activity development were unaffected by the exposure of dams to amitraz (20mg/kgbw, orally on days 6-21 of pregnancy and 1-10 of lactation). Male and female offspring were sacrificed at 60 days of age and possible alterations in the content and metabolism of NE, DA and 5-HT were determined in brain regions by HPLC. The results showed that all these neurotransmitter systems were altered in a brain regional-related manner. In male and female offspring, amitraz induced a significant decrease in the prefrontal cortex 5-HT and its metabolite 5-HIAA and DA and its metabolites DOPAC and HVA levels with interaction of sex. Nevertheless, we verified that striatum DA and 5-HT and corresponding metabolite contents decreased in male and female offspring without statistical distinction of sex. In contrast, amitraz did not modify 5-HT content, but caused an increase in 5-HIAA content in the medulla oblongata and hippocampus in male and female offspring. Alterations in the hippocampus DA, DOPAC and HVA levels after amitraz exposure were also observed displaying a sex interaction. NE levels also showed a decrease after amitraz treatment in the prefrontal cortex and striatum without statistical sex interaction, but MHPG levels decreased in both regions with a sex interaction. Amitraz evoked increases in 5-HT turnover in the prefrontal cortex as well as in DA turnover in the striatum and hippocampus but decreases in NE turnover in the hypothalamus, prefrontal cortex and striatum. The present findings indicated that maternal exposure to amitraz altered noradrenergic, serotonergic and dopaminergic neurochemistry in their offspring in the prefrontal cortex, striatum and hippocampus, and those variations could be related to several alterations in the functions in which these brain regions are involved.

Development and validation of a liquid chromatography-fluorescence-mass spectrometry method to measure glyphosate and aminomethylphosphonic acid in rat plasma.

A simple and fast method has been developed and validated to measure glyphosate (GLYP) and aminomethylphosphonic acid (AMPA) in rat plasma based on reversed-phase high performance liquid chromatography (RP-HPLC) coupled to fluorescence (FLD) and electrospray ionization mass spectrometry (ESI-MS) detection. After protein precipitation with acetonitrile, GLYP and AMPA were derivatized with 9-fluorenylmethylchloroformate (FMOC-Cl) and then separated on a C(12) column (250mm×4.60mm i.d.) using a gradient of an ammonium formate (20mM, pH 8.5) and acetonitrile mobile phase. Selected ion monitoring (SIM) mode of the MS was used to obtain maximum sensitivity when quantifying GLYP and AMPA. The validation shows the method to be consistent and reliable, with an intra- and inter-day precision for GLYP and AMPA>9% for both detectors. For both compounds the accuracy ranged from 2.1% to 7.8% for the intra-day readings, and from 4.1% to 8.6% for the inter-day values. The efficacy of GLYP extraction ranged from 87% to 93% and it was between 76% and 88% for AMPA. Moreover, the limits of quantification (LOQ) for GLYP and AMPA were 5 and 10ng/mL, respectively with FLD, and 0.4 and 2ng/mL with ESI-MS. The method was successfully applied to simultaneously measure both compounds in rat plasma samples several days after oral administration of glyphosate.

Acute and repeated dose (4 weeks) oral toxicity studies of two antihypertensive peptides, RYLGY and AYFYPEL, that correspond to fragments (90-94) and (143-149) from alpha(s1)-casein.

The Lowpept is a powdered casein hydrolysate containing the antihypertensive peptides RYLGY and AYFYPEL, two sequences that correspond to alpha(s1)-casein f (90-94) (RYLGY) and alpha(s1)-casein f (143-149) (AYFYPEL). To support the safety, Lowpept has been examined in an acute and in a 4-week repeated dose oral toxicity studies in rats. Powdered casein hydrolysate administered in a single oral gavage dose of 2000 mg/kg resulted in no adverse events or mortality. Also, casein hydrolysate administered as a daily dose of 1000 mg/kg for 4 weeks by gavage resulted in no adverse events or mortality. No evidence or treatment-related toxicity was detected during both studies. Data analysis of body weight gain, food consumption, clinical observations, blood biochemical, haematology, organ weight ratios and histopathological findings did not show significant differences between control and treated groups. It is concluded that the casein hydrolysate containing the peptides RYLGY and AYFYPEL orally administered to rats was safe and that not treatment-related toxicity was detected even at the highest doses investigated in both acute (2000 mg/kg of body weight) and repeated dose (4 weeks) oral (1000 mg/kg of body weight) toxicity studies.

Diagnosing human anisakiasis: recombinant Ani s 1 and Ani s 7 allergens versus the UniCAP 100 fluorescence enzyme immunoassay.

Commercially available serological methods for serodiagnosis of human anisakiasis either are poorly specific or do not include some of the most relevant Anisakis allergens. The use of selected recombinant allergens may improve serodiagnosis. To compare the diagnostic and clinical values of enzyme-linked immunosorbent assay (ELISA) methods based on Ani s 1 and Ani s 7 recombinant allergens and of the UniCAP 100 fluorescence enzyme immunoassay (CAP FEIA) system, we tested sera from 495 allergic and 25 non-food-related allergic patients. The decay in specific IgE antibodies in serum was also investigated in 15 positive patients over a period of 6 to 38 months. Considering sera that tested positive by either Ani s 1 or Ani s 7 ELISA, the CAP FEIA classified 25% of sera as falsely positive, mainly in the group of patients with the lowest levels of anti-Anisakis IgE antibodies, and 1.28% of positive sera as falsely negative. Considering allergens individually, the overall sensitivities of Ani s 7 ELISA and Ani s 1 ELISA were 94% and 61%, respectively. The results also showed that anti-Anisakis IgE antibodies can be detected in serum for longer with Ani s 1 ELISA than with Ani s 7 ELISA and CAP FEIA (P < 0.01). Our findings suggest that ELISA methods with Ani s 7 and Ani s 1 allergens as targets of IgE antibodies are currently the best option for serodiagnosis of human anisakiasis, combining specificity and sensitivity. The different persistence of anti-Ani s 1 and anti-Ani s 7 antibodies in serum may help clinicians to distinguish between recent and old Anisakis infections.

Toxicokinetics of glyphosate and its metabolite aminomethyl phosphonic acid in rats.

The toxicokinetics of glyphosate after single 100 mgkg(-1) intravenous (i.v.) and 400 mgkg(-1) oral doses were studied in rats. Serial blood samples were obtained after i.v. and oral administration. Plasma concentrations of glyphosate and its metabolite amiomethyl phosphonic acid (AMPA) were determined by HPLC method. After i.v. and oral administration, plasma concentration-time curves were best described by a two-compartment open model. For glyphosate, the elimination half-lives (T(1/2beta)) from plasma were 9.99 h after i.v. and 14.38 h after oral administration. The total plasma clearance was not influenced by dose concentration or route and reached a value of 0.995 l h(-1)kg(-1). After i.v. administration, the apparent volume of distribution in the second compartment (V(2)) and volume of distribution at steady state (V(ss)) were 2.39 and 2.99 l kg(-1), respectively, suggesting a considerable diffusion of the herbicide into tissues. After oral administration, glyphosate was partially and slowly absorbed with a T(max) of 5.16 h. The oral bioavailability of glyphosate was found to be 23.21%. Glyphosate was converted to AMPA. The metabolite AMPA represented 6.49% of the parent drug plasma concentrations. The maximum plasma concentrations of glyphosate and AMPA were 4.62 and 0.416 microg ml(-1), respectively. The maximum plasma concentration of AMPA was achieved at 2.42 h. For AMPA, the elimination half-life (T(1/2beta)) was 15.08 h after oral administration of glyphosate parent compound.

The Anisakis simplex Ani s 7 major allergen as an indicator of true Anisakis infections.

Ani s 7 is currently the most important excretory/secretory (ES) Anisakis simplex allergen, as it is the only one recognized by 100% of infected patients. The allergenicity of this molecule is due mainly to the presence of a novel CX(17-25)CX(9-22)CX(8)CX(6) tandem repeat motif not seen in any previously reported protein. In this study we used this allergen as a model to investigate how ES allergens are recognized during Anisakis infections, and the usefulness of a recombinant fragment of Ani s 7 allergen (t-Ani s 7) as a marker of true Anisakis infections. The possible antigenic relationship between native Ani s 7 (nAni s 7) from Anisakis and Pseudoterranova decipens antigens was also investigated. Our results demonstrate that nAni s 7 is secreted and recognized by the immune system of rats only when the larvae are alive (i.e. during the acute phase of infection), and that this molecule is not present in, or is antigenically different from, Pseudoterranova allergens. The t-Ani s 7 polypeptide is a useful target for differentiating immunoglobulin E antibodies induced by true Anisakis infections from those induced by other antigens that may cross-react with Anisakis allergens, including P. decipiens. The results also support the hypothesis that the Ani s 7 major allergen does not participate in maintaining the antigenic stimulus during chronic infections.

Use and abuse of pyrethrins and synthetic pyrethroids in veterinary medicine.

Pyrethrin and pyrethroid insecticides are widely used in veterinary medicine for agricultural and domestic purposes. Although pyrethrins and pyrethroids are generally regarded as safe to animals, there have been reports of systemic poisoning in veterinary species. This review summarises the use of pyrethrins and pyrethroids in companion and food producing animals, including their mechanism of action and toxicity. The toxicokinetics of pyrethrins and pyrethroids are described, including absorption, distribution, metabolism (including interactions with other compounds affecting drug metabolising enzymes) and excretion, leading to the application of toxicokinetic/toxicodynamic concepts. Specific cases of pyrethroid poisoning in laboratory animals (including age-related toxicity), fish, companion and large animals are considered, including the high incidence of feline pyrethroids toxicosis following the extra-label use of topical formulations.

Documento de Consenso sobre el posible empleo de Ácido Conjugado Linoleico (CLA), como complemento alimenticio, en la infancia y la adolescencia / Consensus Document of possible use of Conjugated Linoleic Acid (CLA), as dietary supplement in childhood and adolescence

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