A prospective cross-over study comparing the pharmacokinetics of cyclosporine A and its metabolites after oral versus short-time intravenous cyclosporine A administration in pre-heart transplant patients.

Sometimes intravenous administration of cyclosporine (CsA) is essential before oral administration is possible. There are only a few reports available on the interindividual variability of CsA metabolism and different metabolite pattern depending on intravenous versus oral administration of CsA in heart transplant (HTx) patients. For effective inhibition of calcineurin we used a short infusion reaching peak concentrations after 2 hours. In a prospective cross-over study we compared the pharmacokinetics of CsA and its metabolites after oral (2.0 mg/kg body weight) versus intravenous (0.7 mg/kg body weight; 2-hour infusion) CsA administration (single test dose) in 7 pre-HTx patients. The pharmacokinetic parameters of CsA and its metabolites were analyzed using high-pressure liquid chromatography. The pharmacokinetic parameter area under the concentration time curve (AUC(0-infinity)) of CsA after intravenous administration was significantly lower (2903 ng*h*mL(-1)) than that after oral administration (4344 ng*h*mL(-1); P=.01). Peak concentrations, time to peak concentration, and terminal elimination half life were not significantly different. Short-time infusion of CsA resulted in a significant decrease in the AUC of the metabolites AM1 (3-fold), AM9 (10-fold), and AM1c (3-fold). A 2-hour infusion of CsA is just as effective as oral administration and the reduced amount of metabolites is advantageous for the patient.

Predominant inhibition of interleukin-6 synthesis in patient-specific endothelial cells by mTOR inhibitors below a concentration range where cell proliferation is affected and mitotic arrest takes place.

UNLABELLED: Organ rejection and inflammation are accompanied by endothelial cell activation. An in vitro model with patient-specific endothelial cells was used to study the impact of mTOR inhibitors on cell growth and release of proinflammatory cytokines. MATERIAL AND METHODS: Confluent monolayers of human saphenous vein endothelial cells were pretreated with everolimus or sirolimus followed by induction with tumour necrosis factor-alpha (TNF-alpha). RESULTS: Incubation with sirolimus or everolimus resulted in a dose-dependent deceleration of cell growth. Compared to control, cell count at high concentrations ceased to increase and remained at 60%. This mitotic arrest was accompanied by a dose-dependent inhibition of the TNF-alpha-induced in situ synthesis and release of interleukin-6 per cell by 60%. CONCLUSIONS: Under conditions mimicking cytokine-induced cell activation a predominant inhibitory effect of everolimus compared to sirolimus on endothelial cell proliferation was observed paralleled by an inhibition of proinflammatory cytokines. This might attenuate the acute proinflammatory status after transplantation.

Cytological evaluation of the tissue-implant reaction associated with subcutaneous implantation of polymers coated with titaniumcarboxonitride in vivo.

The aim of the present study was to evaluate the influence of titanium-coated polymers on the inflammatory response and remodeling of connective tissue during wound-healing processes. Discs of polyethyleneterephthalate (PET) and silicone as well as high-weight meshes of polypropylene (PP) were coated with a titaniumcarboxonitride (Ti(C,N,O)) layer by a plasma-assisted chemical vapor deposition process (PACVD) and implanted subcutaneously in the dorsal lumbar region of Wistar rats. Light microscopic and histological evaluation of capsule thickness, capsule quality, implant-tissue interface and collagen composition was performed 7, 14, 21 and 28 days post-operatively. All implants were surrounded by a fibrous capsule with decreasing thickness after 2-4 weeks post-implantation. Titaniumcarboxonitride-coated polymers showed no significant differences in capsule thickness and inflammatory cellular response. An increased collagen type III/I ratio, especially for titaniumcarboxonitride-coated materials, was found in week one after implantation remaining elevated up to week 4. This might be associated with disordered collagen metabolism and immature scar reaction. In contrast to previous in vitro experiments, Ti-coating of polymers did not improve biocompatibility after subcutaneous implantation in rats. Material reduction to low-weight meshes and enlargement of pore size may demonstrate a benefit of Ti-coated meshes with an increased biocompatibility.

Influence of ischaemic cardioplegic arrest on the haemodynamic efficacy of the PDE-III inhibitor, enoximone.

The haemodynamic support from an enoximone infusion (2 x bolus 0.5 mg.kg-1, infusion 0.5 micrograms.kg-1min-1) in the early postischaemic phase is modified by a transient diminution of the drug's positive inotropic and vasodilatory effect (1 to 4 h). Forty-five min after weaning off cardiopulmonary bypass (CPB) the initial increase in cardiac index (CI) induced by enoximone (+26 +/- 8%) faded and was no longer discernible in the control group. A significant increase in CI was observed again 4-6 h after cardioplegic arrest (ultimate steady state values greater than 10 h; CI +0.71.min-1 x m-2; +21%). This pharmacodynamic fading occurred in the presence of constant plasma concentrations of enoximone (442 +/- 31 ng.ml-1) and elevated high plasma norepinephrine (926 +/- 70 pg.ml-1). Two independent processes might be responsible for the ischaemia-induced complex time dependency of the pharmacodynamic effect: (1) sensitization of the adrenergic receptor pathway and/or activation of sarcolemmal Ca-influx, rapidly reversed during reperfusion, and (2) impaired sarcoplasmic reticulum responses, which are slowly repaired after weaning off CPB.

[Comparison of the hemodynamic effect of enoximone and dopamine in patients after coronary bypass operation]. / Vergleich der hämodynamischen Wirkung von Enoximon und Dopamin bei Patienten nach Koronarer Bypassoperation.

The efficacy of acute hemodynamic support with intravenous enoximone (n = 10), (2 x bolus 0.5 mg/kg, infusion 5.0 mcg/kg/min), dopamine (n = 10), (3-4.0 mcg/kg/min) over a 18-h period was investigated in patients to be weaned off cardio-pulmonary bypass (CPB) (placebo-controlled trial). Under steady-state conditions enoximone produced a substantial increase in cardiac index (20.6 +/- 1.7%), but no change in heart rate. The improvement in cardiac index with time until constant values were reached (6 h) was not directly paralleled by the plasma concentration of enoximone. Pharmacodynamically relevant concentrations were already present after 1 h of infusion (480 +/- 68 ng/ml) and were comparable with the value determined after 6 h (442 +/- 31 ng/ml). After 18 h of infusion, plasma concentration had reached 742 +/- 47 ng/ml without a further improvement in cardiac function. The augmentation of stroke volume index (23.3 +/- 2.5%) occurred concomitant with a decrease in systemic vascular resistance (-23.1 +/- 0.6%), obviously due to a decrease in diastolic arterial pressure (-12.0 +/- 3.8%). The pulmonary capillary wedge pressure remained unaffected, and there was only a slight decrease in pulmonary vascular resistance (-9.3 +/- 3.2%). During enoximone, as well as dopamine infusion, an increase (10 +/- 3.1 and 9 +/- 1.8%) in right atrial pressure was observed in contrast to the untreated control group. This is contradictory to the described drugs effect in patients suffering from congestive heart failure. In a concentration usually not causing cardioacceleration, dopamine was of minor hemodynamic support in the post-CPB period.(ABSTRACT TRUNCATED AT 250 WORDS)

Enoximone versus dopamine in patients being weaned from cardiopulmonary bypass.

The efficacy of acute haemodynamic support with intravenous enoximone (2 X bolus 0.5 mg/kg; infusion 5.0 micrograms/kg/min) versus dopamine (3.0-4.0 micrograms/kg/min), over an 18-hour period, was investigated in patients to be weaned from cardiopulmonary bypass (placebo-controlled trial). Under steady-state conditions, enoximone produced a substantial increase in cardiac index (20.6 +/- 1.7%), but no change in heart rate. The improvement in cardiac index with time until constant values were reached (6 h) was not directly paralleled by the plasma concentration of enoximone. Pharmacodynamically relevant concentrations were already present after 1 h of infusion (480 +/- 68 ng/ml) and comparable with the value determined after 6 h (442 +/- 37 ng/ml). After 18 h of infusion, plasma concentration had reached 742 +/- 47 ng/ml without a further improvement in cardiac function. The augmentation of stroke volume index (23.3 +/- 2.5%) occurred concomitantly with a decrease in systemic vascular resistance (-23.1 +/- 0.6%), obviously due to a decrease in diastolic arterial pressure (-12.0 +/- 3.8%). The pulmonary capillary wedge pressure remained unaffected. There was only a slight decrease in pulmonary vascular resistance (-9.3 +/- 3.2%). During both enoximone infusion and dopamine infusion, right atrial pressure increased (10.0 +/- 3.1 and 9.0 +/- 1.8%, respectively), in contrast to the untreated control group. This is contradictory to the drugs' described effect in patients suffering from congestive heart failure. At a concentration which would not normally cause cardiac acceleration, dopamine provided minor haemodynamic support in the period after cardiopulmonary bypass.(ABSTRACT TRUNCATED AT 250 WORDS)