Differential pharmacokinetics and pharmacokinetic/pharmacodynamic modelling of robenacoxib and ketoprofen in a feline model of inflammation.

Robenacoxib and ketoprofen are acidic nonsteroidal anti-inflammatory drugs (NSAIDs). Both are licensed for once daily administration in the cat, despite having short blood half-lives. This study reports the pharmacokinetic/pharmacodynamic (PK/PD) modelling of each drug in a feline model of inflammation. Eight cats were enrolled in a randomized, controlled, three-period cross-over study. In each period, sterile inflammation was induced by the injection of carrageenan into a subcutaneously implanted tissue cage, immediately before the subcutaneous injection of robenacoxib (2 mg/kg), ketoprofen (2 mg/kg) or placebo. Blood samples were taken for the determination of drug and serum thromboxane (Tx)B2 concentrations (measuring COX-1 activity). Tissue cage exudate samples were obtained for drug and prostaglandin (PG)E2 concentrations (measuring COX-2 activity). Individual animal pharmacokinetic and pharmacodynamic parameters for COX-1 and COX-2 inhibition were generated by PK/PD modelling. S(+) ketoprofen clearance scaled by bioavailability (CL/F) was 0.114 L/kg/h (elimination half-life = 1.62 h). For robenacoxib, blood CL/F was 0.684 L/kg/h (elimination half-life = 1.13 h). Exudate elimination half-lives were 25.9 and 41.5 h for S(+) ketoprofen and robenacoxib, respectively. Both drugs reduced exudate PGE2 concentration significantly between 6 and 36 h. Ketoprofen significantly suppressed (>97%) serum TxB2 between 4 min and 24 h, whereas suppression was mild and transient with robenacoxib. In vivo IC50 COX-1/IC50 COX-2 ratios were 66.9:1 for robenacoxib and 1:107 for S(+) ketoprofen. The carboxylic acid nature of both drugs may contribute to the prolonged COX-2 inhibition in exudate, despite short half-lives in blood.

Enantioselective pharmacokinetics of ketoprofen in piglets: the significance of neonatal age.

Following intravenous dose of 6mg/kg racemic ketoprofen, the chiral pharmacokinetics of ketoprofen was investigated in eight piglets aged 6 and 21days old. S-ketoprofen predominated over R-ketoprofen in plasma of the piglets in both age groups. The volumes of distribution of S-ketoprofen for the 6- and 21-day-old piglets were 241.7 (211.3-276.5) mL/kg and 155.0 (138.7-173.1) mL/kg, respectively, while the corresponding parameters for R-ketoprofen were 289.2 (250.3-334.2) mL/kg and 193.0 (168.7-220.8) mL/kg. The clearances of R-ketoprofen [948.4 (768.0-1171.2) mL/h/kg and 425 (319.1-566.0) mL/h/kg for the 6- and 21-day-old piglets, respectively] were significantly higher compared to the clearances of S-ketoprofen [57.3 (46.6-70.4) mL/h/kg and 33.8 (27.0-42.2) mL/h/kg for 6- and 21-day-old piglets, respectively]. The elimination half-life of S-ketoprofen was 3.4h for both age groups, while the elimination half-life of R-ketoprofen was 0.2h for the 6-day-old and 0.4h for the 21-day-old piglets. The clearances of both R- and S-ketoprofen were significantly higher in the 6-day-old piglets compared to when they were 21 days old. Furthermore, the volumes of distribution were larger in the youngest age group.

Antibacterial activity of sphagnum acid and other phenolic compounds found in Sphagnum papillosum against food-borne bacteria.

AIMS: To identify the phenolic compounds in the leaves of Sphagnum papillosum and examine their antibacterial activity at pH appropriate for the undissociated forms. METHODS AND RESULTS: Bacterial counts of overnight cultures showed that whilst growth of Staphylococcus aureus 50084 was impaired in the presence of milled leaves, the phenol-free fraction of holocellulose of S. papillosum had no bacteriostatic effect. Liquid chromatography-mass spectrometry analysis of an acetone-methanol extract of the leaves detected eight phenolic compounds. Antibacterial activity of the four dominating phenols specific to Sphagnum leaves, when assessed in vitro as minimal inhibitory concentrations (MICs), were generally >2.5 mg ml(-1). MIC values of the Sphagnum-specific compound 'sphagnum acid' [p-hydroxy-beta-(carboxymethyl)-cinnamic acid] were >5 mg ml(-1). No synergistic or antagonistic effects of the four dominating phenols were detected in plate assays. CONCLUSIONS: Sphagnum-derived phenolics exhibit antibacterial activity in vitro only at concentrations far in excess of those found in the leaves. SIGNIFICANCE AND IMPACT OF THE STUDY: We have both identified the phenolic compounds in S. papillosum and assessed their antibacterial activity. Our data indicate that phenolic compounds in isolation are not potent antibacterial agents and we question their potency against food-borne pathogens.

Pharmacokinetics and pharmacodynamics of meloxicam in piglets.

The pharmacokinetics and pharmacodynamics of meloxicam in piglets (16-23 days old) were studied using a stratified parallel group design. One group (n = 13) received 0.4 mg/kg meloxicam intravenously, while the other group (n = 12) received physiological saline solution. A carrageenan-sponge model of acute inflammation was used to evaluate the effects of meloxicam. The plasma clearance was low (0.061 L/kg/h), the volume of distribution was low (0.19 L/kg) and the elimination half-life was short (2.7 h). At most time points, the mean concentration of meloxicam in plasma exceeded the concentrations in exudate indicating a limited accumulation of the drug at the site of the inflammation. There were significant differences between the groups in the exudate prostaglandin E2 (PGE2) concentration, but the inhibition of PGE2 in the meloxicam group was limited. The inhibition of thromboxane B(2) (TXB2) production in serum in the meloxicam group was extensive, but of shorter duration than the PGE2 inhibition in exudate.

Cytotoxicity in Bacillus mojavensis is abolished following loss of surfactin synthesis: implications for assessment of toxicity and food poisoning potential.

Bacillus subtilis and the closely related species Bacillus pumilus and Bacillus licheniformis have periodically been suggested to play a role in the aetiology of food poisoning despite the fact that the organisms do not possess the genes associated with enteropathogenicity in Bacillus cereus. We show here that Bacillus mojavensis, an organism closely related to B. subtilis, is able to produce toxic components which identify as a complex of three different surfactin analogues. These cyclic lipopeptides were soluble in methanol, heat stable after treatment in a boiling water bath for 10 min, resistant to enzymatic degradation by pepsin, trypsin, endoprotease V8 and proteinase K and formed pores in planar lipid bilayers. They were cytotoxic when tested in a series of commonly used laboratory cytotoxicity assays, namely, lactate dehydrogenase release, haemolysis, inhibition of both protein synthesis in Vero cells and motility in boar sperm. We show that such in vitro markers of enterotoxicity are due entirely to production of cyclic lipopeptides since deletion of sfp, a gene essential for surfactin synthesis which abolished the cytotoxicity to Vero cells, boar sperm motility and haemolytic activity. Thus, the relevance of cyclic lipopeptides as food poisoning toxins needs to be evaluated in assays other than the cell cytotoxicity assays in common use.

Diarrhetic shellfish toxins: improvement of sample clean-up for HPLC determination.

Okadaic acid and dinophysistoxin-1, the principal toxic components in diarrhetic shellfish poisoning, may be detected by high-performance liquid chromatography and fluorometric measurement as 9-anthrylmethyl esters. However, "greasy" samples may occur and the fluorescent reagent 9-anthryldiazomethane may decompose during storage, resulting in impurities that may seriously interfere with quantitative determination. Ultrasonic treatment of the samples during derivatization with 9-anthryldiazomethane was found to improve reproducibility. This may result from increased access to reactive sites on toxins by 9-anthryldiazomethane due to disruption of micelles formed by toxins and other partly hydrophobic compounds. A procedure for cleaning the derivatized samples, using a 0.1 g silica cartridge column and different eluent compositions from that reported by LEE et al. (1987), was found to facilitate chromatogram interpretation. Deoxycholic acid, a commercial available bile acid, was found to be an acceptable internal standard. The 9-anthrylmethyl esters of okadaic acid, dinophysistoxin-1 and deoxycholic acid, were stable at 4 degrees C for at least seven days when stored dry or in methanol.

Effect of cooking on residues of the quinolones oxolinic acid and flumequine in fish.

The effect of cooking on residues of the quinolones oxolinic acid and flumequine in fish was investigated. Salmon containing residues of oxolinic acid and flumequine was boiled or baked in the oven. Samples of raw and cooked muscle, skin, and bone, as well as of the water in which the fish was boiled and juice from the baked fish, were analysed. Oxolinic acid and flumequine did not degrade at the temperatures reached when cooking the fish. However, fish muscle free from drug residues may be contaminated during boiling and baking due to leakage of the drug from reservoirs in the fish.

Benzathine penicillin G and procaine penicillin G in piglets: comparison of intramuscular and subcutaneous injection.

The disposition of penicillin G in piglets is described after intramuscular or subcutaneous injection of depot preparations. The piglets were injected with 33,000 IU/kg or 100,000 IU/kg benzathine + procaine penicillin G intramuscularly or subcutaneously, or 100,000 IU/kg procaine penicillin G intramuscularly or subcutaneously. Intramuscular injection of benzathine + procaine penicillin resulted in higher maximum concentrations in plasma (Cmax) than did subcutaneous injection. The mean residence time (MRT) of penicillin G was longer when the drugs were injected subcutaneously rather than intramuscularly. The plasma concentration versus time profiles of the subcutaneous injections of benzathine + procaine penicillin revealed secondary peaks, possibly reflecting a certain degree of inflammation at the injection site.

Quiste hidatídico pulmonar en un escolar: reporte de un caso / Pulmonary hydatid cyst in a schoolchild: a case report

Introducción: La parasitosis por Equinococus granulosus es un problema de salud pública en Chile. El hombre, huésped intermediario, se infecta por fecalismo, generando el Quiste Hidatídico (QH), con mayor frecuencia en hígado y pulmón. Su diagnóstico generalmente es incidental mediante radiografía de tórax (RTx). Habitualmente su tratamiento es quirúrgico. Presentación del caso: Escolar, sexo femenino, 6 años; consulta en Hospital de Yungay por exacerbación de dolor en hemitórax izquierdo (HI) de 4 días de evolución, no irradiado, tipo puntada, EVA10/10, comienzo súbito, con tope inspiratorio, limita la deambulación y se asocia ese día a fiebre de 38°C. Vivienda con servicios básicos, ocasionalmente faenan animales para consumo propio, actualmente sin mascotas. Examen físico: Murmullo Pulmonar (MP) disminuido en base izquierda. RTx muestra imagen redondeada. Se deriva a Hospital Clínico Herminda Martin de Chillán. Ingresa afebril, hospitalizándose en el Servicio de Cirugía Infantil. Exámenes de Laboratorio: PCR 57,5 mg/L, GB 15,88x103/uL, VHS 54 mm/hr. Imagenológico: Ecografía: Opacidad de 6,4 cm de diámetro en HI, que por alta endemia en la zona sugiere ser QH. Hígado normal. Al séptimo día de hospitalización se realiza Quistectomía Pulmonar, la extracción de membrana hidatídica confirma diagnóstico. Alta al séptimo día postoperatorio dada evolución asintomática y normalización de exámenes. Discusión: El diagnóstico de QH requiere de alta sospecha clínica, ayuda de exámenes e imagenología. Al tratamiento quirúrgico puede asociarse el uso de Albendazol si durante el procedimiento se genera ruptura del QH.

Introduction: The Equinococus granulosus’s parasitic infection is a public health problem in Chile. Human beings are intermediate host that get infected by contact with feces of an infected animal, creating the hydatid cyst (HQ), which is more often located in liver and lung. Its diagnosis is usually incidental throw a chest x-ray (RTx). Usually the treatment is surgical. Case report: Child, female, 6 years old. She consults in Yungay’s Hospital because of an episode of exacerbated left hemithorax (LH) pain of 4 days of evolution, none irradiated, with stabbing pleuritic character and EVA10/10 intensity, sudden onset that limitedambulation and that was associated with fever of 38°C. House with basic services where occasionally animal slaughters where done for their own consumption, currently without pets. Physicalexamination: pulmonary murmur (MP) decreased in LH. RTx showed a rounded image. She’s derived to Herminda MartinClinical Hospital of Chillán, where she’s hospitalized in the Pediatric Surgery Service presenting no fever. Laboratory Tests: CRP 57.5 mg/L, 15.88 GBx103/uL, VHS 54 mm/hr. Ultrasound-Scan: Opacity of 6.4 cm of diameter in LH, which, because the area was highly endemic, suggested a HQ. Normal liver. On the seventh day of hospitalization a Pulmonary Cystectomy is made. Hydatid membrane extraction confirmed diagnosis. Discharge on the seventh postoperative day because of asymptomatic evolution and normal tests results. Discussion: The diagnosis of HQ requires high clinical suspicion and imaging tests support. Surgical treatment may be associated with the use of albendazole if during the procedure the HQ is broken rupture.

Simultaneous determination of sulphadiazine and trimethoprim in plasma and tissues of cultured fish for residual and pharmacokinetic studies.

Clean-up and high-performance liquid chromatographic methods for the simultaneous determination of sulphadiazine and trimethoprim in fish plasma and tissues have been developed. The average recovery of sulphadiazine varied from 74% in liver to 92% in plasma, whereas that of trimethoprim varied from 60% in liver to 97% in plasma. The sample pretreatment procedures were simple, selective and robust, having a limit of quantification of 250 ng/ml for trimethoprim and 50 ng/ml for sulphadiazine in plasma, 15 ng/g for sulphadiazine and 80 ng/g for trimethoprim in muscle, and 30 ng/g for sulphadiazine and 160 ng/g for trimethoprim in liver. The assay was tested on plasma from Atlantic salmon treated with Tribrissen.

Simultaneous determination of residues of florfenicol and the metabolite florfenicol amine in fish tissues by high-performance liquid chromatography.

A simple and rapid high-performance liquid chromatographic method for the simultaneous extraction and determination of residues of florfenicol and its metabolite florfenicol amine in fish tissue, muscle and liver has been developed. The calibration curves were linear, the recovery of florfenicol was 99-107%, and the recovery of florfenicol amine was 94-100%. The detection limits for florfenicol and florfenicol amine were 20 ng/g in muscle and 50 ng/g in liver.

Reservoir of quinolone residues in fish.

Different tissues from salmon treated with the quinolones oxolinic acid, flumequine, enrofloxacin and sarafloxacin were analysed in search of possible reservoirs of the drugs. Residues of oxolinic acid and flumequine seem to be especially bound to bone, enrofloxacin to skin, and sarafloxacin to both skin and bone. The results showed that residues of these drugs were present in the fish for prolonged periods after the end of treatment.

Antibacterial properties of extracts from selected planktonic freshwater cyanobacteria--a comparative study of bacterial bioassays.

Aqueous and methanol extracts from five selected cyanobacteria were examined for antibacterial properties in six different bacterial bioassays. All five cyanobacteria revealed antibacterial properties. Methanol extracts made from Tychonema bourrellyi, Aphanizomenon flos-aquae and Cylindrospermopsis raciborskii showed the most pronounced inhibitory effects, Aqueous extracts made from Microcystis aeruginosa and T. bourrellyi possessed evident antibacterial properties. The bacterial bioassays were based on agar diffusion tests and included pour-plate methods commonly used to detect residues of antibacterial substances in food. In addition, a pourplate bioassay with Aeromonas hydrophila was developed and described. Antibacterial effects were observed in five of the six bacterial bioassays. No antibacterial effect was observed in the Micrococcus luteus bioassay. Bioassays based on Aer. hydrophila, Bacillus cereus and B. subtilis grown in Antibiotic Medium 8, pH5.85, seemed to be sensitive and suitable. The MIC value of diluted MeOH extracts made from C. raciborskii and T. bourrellyi against Aer. hydrophila corresponded to 38 mg freeze-dried cyanobacteria. Bacillus subtilis was more sensitive when grown in a culture medium with pH 5.85 than 7.9. The antibacterial properties of extracts from the cyanobacteria examined differed from defined cyanotoxins and antibacterial substances. The pattern of inhibition in the bacterial bioassays indicated that various antibacterial substances are involved.