Effects of an anti-inflammatory VAP-1/SSAO inhibitor, PXS-4728A, on pulmonary neutrophil migration.

BACKGROUND AND PURPOSE: The persistent influx of neutrophils into the lung and subsequent tissue damage are characteristics of COPD, cystic fibrosis and acute lung inflammation. VAP-1/SSAO is an endothelial bound adhesion molecule with amine oxidase activity that is reported to be involved in neutrophil egress from the microvasculature during inflammation. This study explored the role of VAP-1/SSAO in neutrophilic lung mediated diseases and examined the therapeutic potential of the selective inhibitor PXS-4728A. METHODS: Mice treated with PXS-4728A underwent intra-vital microscopy visualization of the cremaster muscle upon CXCL1/KC stimulation. LPS inflammation, Klebsiella pneumoniae infection, cecal ligation and puncture as well as rhinovirus exacerbated asthma models were also assessed using PXS-4728A. RESULTS: Selective VAP-1/SSAO inhibition by PXS-4728A diminished leukocyte rolling and adherence induced by CXCL1/KC. Inhibition of VAP-1/SSAO also dampened the migration of neutrophils to the lungs in response to LPS, Klebsiella pneumoniae lung infection and CLP induced sepsis; whilst still allowing for normal neutrophil defense function, resulting in increased survival. The functional effects of this inhibition were demonstrated in the RV exacerbated asthma model, with a reduction in cellular infiltrate correlating with a reduction in airways hyperractivity. CONCLUSIONS AND IMPLICATIONS: This study demonstrates that the endothelial cell ligand VAP-1/SSAO contributes to the migration of neutrophils during acute lung inflammation, pulmonary infection and airway hyperractivity. These results highlight the potential of inhibiting of VAP-1/SSAO enzymatic function, by PXS-4728A, as a novel therapeutic approach in lung diseases that are characterized by neutrophilic pattern of inflammation.

Rápida eficacia de terbinafina oral en onicomicosis de los pies: experiencia clínica multicéntrica / Rapid efficacy of oral terbinafine in foot onychomycoses: multicentric clinical experience

Se presenta la experiencia clínica multicéntrica Chile-Uruguay en el tratamiento de la onicomicosis de los pies con Terbinafina oral administrada por 3 meses y en un período de observación postratamiento de 6 meses. Se incluyen 102 pacientes, 43 hombre y 59 mujeres, con una edad promedio de 50 años, que presentaban un cuadro clínico de onicomicosis de los pies, el que fue confirmado por la presencia de dermatofitos en el cultivo micológico inicial (73,5 por ciento trichophyton rubrum). Se seleccionó la uña más comprometida, en la que se evaluaron onicólisis, engrosamiento ungueal, cambio de coloración e inflamación paroniqueal como parámetros clínicos y la evaluación micológica se hizo por examen directo y cultivo. La uña seleccionada tuvo un crecimiento estadísticamente significativo tanto en la fase de tratamiento como la de postratamiento. Los signos clínicos mejoraron durante todo el seguimiento y el 73 por ciento a 86 por ciento de los pacientes alcanzó mejoría total de estos parámetros a los 9 meses de seguimiento. Los exámenes micológicos se fueron negativizando progresivamente, alcanzando en la evaluación final a los 9 meses un 85,9 por ciento y un 90,5 por ciento para exámenes directos y cultivos negativos, respectivamente. Recaídas con cultivos micológicos positivos fueron observadas en 3 pacientes (5 por ciento ). El medicamento fue bien tolerado y los efectos adversos mas frecuentes fueron los gastrointestinales en 11 pacientes. No hubo alteraciones de los parámetros bioquímicos hepáticos. En conclusión, la terbinafina aparece como un nuevo antimicótico de alta eficacia en un corto período de tratamiento

Analgesic effect and bioavailability of oral ketogan given as tablets or mixture to patients with chronic pain of malignant origin.

Thirteen cancer patients with moderate to severe chronic pain of malignant origin on treatment with Ketogan tablets were included in an open non-randomized cross-over study comparing the analgesic effect, side effects and serum concentrations of Ketogan tablets and mixture. The patients were six days in hospital and were dosed two days with tablets, two days with mixture and finally another two days with tablets. Recordings of pain and side effects and collection of blood samples prior to dosing and hourly thereafter until remedication were performed on the second day of each dosing period in a morning dose interval. The analgesic effect judged by visual analog score (VAS) and pain intensity differences (PID), the areas under the serum concentration time curves, and the average serum concentrations for the three groups were compared. It was not possible do detect any differences among the three groups concerning the analgesic effect, duration of analgesic effect, the serum concentrations and the side effects. The mean plasma half-life of ketobemidone was 2.74 h +/- 0.90 (SD) and the mean relative bioavailability of the mixture was slightly above 100%. Linear regression analysis revealed a significant correlation between ketobemidone serum concentrations and analgesic effect, VAS, for tablet one and for the mixture but not for tablet two, possibly due to the fixed dosing schedule and to the positive effect of hospitalization on the pain.

In vivo metabolism of the cardiovascular toxin, allylamine.

Previous evidence from this laboratory demonstrated that allylamine, a known cardiovascular toxin, is metabolized in vitro to acrolein, which has been hypothesized to act as a distal toxin. In this study, 3-hydroxypropylmercapturic acid was isolated and identified by MS, NMR, and 2D-NMR spectroscopy as the sole urinary metabolite of allylamine metabolism in vivo. Parallel experiments showed reduced glutathione (GSH) depletion in several organs (most marked in aorta, blood, and lung), which is consistent with GSH conjugation of the proposed acrolein intermediate. These findings indicate that allylamine was metabolized in vivo to a highly reactive aldehyde which was converted to a mercapturic acid through a GSH conjugation pathway; the exact mechanisms of cellular damage remain unclear.