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With asphyxia, newborns may suffer cardiogenic shock with myocardial dysfunction and dysregulation of vasomotor tone resulting in multiorgan dysfunction. Vasoactive medications are often administered with limited evidence directing clinicians regarding the use of high-dose monotherapy with dopamine relative to combination treatment with dopamine and a second different agent. We hypothesized that the treatment of hypoxia-reoxygenated newborn piglets with combinations of vasoactive medications would improve systemic and regional hemodynamics. Instrumented newborn piglets were subjected to hypoxia-reoxygenation with subsequent infusion of high-dose dopamine or moderate-dose dopamine and one of epinephrine, milrinone or levosimendan. Treatment with high-dose dopamine improved systemic and mesenteric perfusion. The addition of low-dose epinephrine showed some benefits regarding pulmonary hypertension and should a non-catecholamine agent be added to dopamine, milrinone is preferred to levosimendan given benefits to mesenteric perfusion. We conclude that the selection of appropriate vasoactive medical therapy should be directed by the clinical effects desired. / Experimental Surgery

Few drugs are available to treat congestive heart failure and other cardiac diseases in horses. Pimobendan is an inodilator drug approved as Vetmedin® for treatment of canine cardiac disease. Previous research shows that pimobendan increases heart rate and contractility following intravenous administration in horses. The pharmacokinetics of oral pimobendan have not been investigated in horses. The hypothesis of this study was that pimobendan would be absorbed following oral administration to healthy adult horses and reach concentrations known to be therapeutic in other species. Additional objectives were to compare the absorption of compounded pimobendan capsules (C) and suspension (S) to Vetmedin® (V) and determine the effects of sample site on plasma drug concentrations in a pilot study using two horses. These two horses received C, S, or V (0.5 mg/kg via oral syringe, once) following a minimum 10 hour fast, using a crossover design with a minimum 1-week washout period. Samples were collected simultaneously from lateral thoracic and jugular catheters before and after drug administration at predetermined time points. Differences between formulation and sample site were analyzed by one-way ANOVA. After evaluation of the data from the initial 2 horses, an additional 4 horses received pimobendan, in the form of Vetmedin tablets® (V), in a similar manner. Only jugular samples were collected at the same predetermined time points. Plasma concentrations were determined by ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) and pharmacokinetic parameters determined by noncompartmental analysis. No significant differences were noted between formulations or sample site (P < 0.05). Concentrations in compounded formulations were 88%(S) and 90%(C) of label. For V, mean (±SD) maximum plasma concentration (Cmax) was 4.96 ± 2.13 ng/mL at 2.17 ± 0.98 hours, and area under the curve (AUC0-∞) was 22.1 ± 8.8*ng/mL. Concentration of the active metabolite of pimobendan, o-desmethyl-pimobendan, was below the limit of detection (0.07ng/mL) for all samples. At 0.5mg/kg orally, pimobendan plasma concentrations were considerably lower than reported in dogs and other species. There was no evidence of oral transmucosal absorption. Pimobendan was poorly absorbed in horses, regardless of formulation, and appears unlikely to have clinical effects. / Master of Science / The objective of this study was to determine the pharmacokinetics (i.e. evaluation of the drug concentration in the bloodstream over time by means of mathematical modeling) of pimobendan in healthy horses. Pimobendan is a drug used to treat two types of heart disease, myxomatous mitral value disease and dilated cardiomyopathy, in dogs. These diseases often lead to a syndrome, congestive heart failure (CHF), that has high mortality. CHF in horses also has high mortality, and treatments for horses in CHF are based on information from other species. In this study, the FDA approved formulation of pimobendan, Vetmedin®, was administered to six healthy mature horses at a dose of 0.5 mg/kg, which is twice the amount typically administered to dogs in a single dose. Additionally, we gave two of the horses compounded (uniquely formulated) pimobendan capsules and suspension to evaluate their equivalence to Vetmedin® tablets. We serially collected blood samples to measure plasma concentrations of pimobendan after administration of each drug. Our results showed that all three formulations of pimobendan lead to similar blood concentrations in each of the two horses individually. No formulation of pimobendan resulted in plasma levels of pimobendan known to be effective in other species. Overall, the average plasma concentrations of pimobendan in these horses was very low, it was approximately 1/10th the amount reported in canine pharmacokinetic studies of pimobendan. In conclusion, we determined that at a 0.5 mg/kg dose orally, pimobendan is poorly absorbed in horses and seems unlikely to have medical effects.

No description available.

L'apéline est l'agoniste du récepteur APJ-R (putative angiotensin II receptor like), récepteur couplé aux protéines G. Exprimée dans le coeur de plusieurs espèces dont l'homme, l'apéline joue un rôle important dans le système cardiovasculaire. L'apéline a un effet inotrope positif sur le coeur. Szokodi et al. ont démontré que cet effet était dû à l'activation de la cascade PLC-PKC et que les échangeurs sodium-hydrogène (NHE) et sodium-calcium (NCX) étaient impliqués. Ils ont également démontré que l'augmentation de la force contractile du myocarde n'était pas due à l'augmentation du courant calcique de type L (I[indice inférieur CaL]). Nous proposons que l'augmentation de la contractilité est due à un effet de l'apéline sur le courant sodique rapide (I[indice inférieur Na]). Matériel et Méthodes. La localisation du récepteur APJ-R fut faite par immunofluorescence sur des myocytes isolés du ventricule gauche de chien. Les mesures du courant sodique sur ces mêmes cellules furent faites par la méthode de patch-clamp en configuration cellule entière en voltage imposé. L'apéline 13 et l'apéline 17 furent perfusées à des concentrations de 100 nM pendant 20 minutes pour évaluer leurs effets sur le courant sodique. Résultats. Le récepteur APJ-R est localisé sur la membrane sarcoplasmique des myocytes au niveau des bandes Z, une structure clé pour la contraction, ce qui nous indique que la localisation du récepteur est propice à la modulation de la contraction cardiaque. L'apéline 13 et l'apéline 17 augmentent I[indice inférieur Max] du courant sodique de 39% et 61% respectivement comparativement au contrôle. En plus de l'augmentation du courant sodique, les deux formes d'apéline déplacent l'activation du canal sodique de -6,8 mV et -8,6 mV pour l'apéline 13 et 17 comparativement à la condition contrôle. Ce déplacement de l'activation vers des potentiels plus négatifs augmente l'excitabilité des myocytes cardiaques et pourrait ainsi moduler la contraction cardiaque. L'inactivation du canal sodique n'est pas modifiée par la présence des deux formes d'apéline. L'apéline ne modifie donc pas la disponibilité du canal en fonction du voltage. Le temps de réactivation est significativement augmenté par la présence d'apéline 13 et 17 ce qui a pour effet d'augmenter la période réfractaire au niveau du coeur. Conclusion. Le récepteur APJ est bien présent au niveau des bandes Z des myocytes suggérant son implication dans la contraction cardiaque. Nos résultats sur le courant sodique démontrent pour la première fois que l'apéline affecte significativement ce courant et que cette augmentation du courant sodique pourrait être responsable de l'augmentation de la contraction cardiaque par l'apéline.

No description available.