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Perioperative infliximab application has marginal effects on ischemia–reperfusion injury in experimental small bowel transplantation in rats

Purpose  

Ischemia-reperfusion injury leads to impaired smooth muscle function and inflammatory reactions after intestinal transplantation. In previous studies, infliximab has been shown to effectively protect allogenic intestinal grafts in the early phase after transplantation with resulting improved contractility. This study was designed to reveal protective effects of infliximab on ischemia–reperfusion injury in isogenic transplantation.     

Statistical Comparison of Dissolution Profiles to Predict the Bioequivalence of Extended Release Formulations

Appropriate setting of dissolution specification of extended release (ER) formulations should include precise definition of a multidimensional space of complex definition and interpretation, including limits in dissolution parameters, lag time (t-lag), variability, and goodness of fit. This study aimed to set dissolution specifications of ER by developing drug-specific dissolution profile comparison tests (DPC tests) that are able to detect differences in release profiles between ER formulations that represent a lack of bioequivalence (BE). Dissolution profiles of test formulations were simulated using the Weibull and Hill models. Differential equations based in vivo–in vitro correlation (IVIVC) models were used to simulate plasma concentrations. BE trial simulations were employed to find the formulations likely to be declared bioequivalent and nonbioequivalent (BE space). Customization of DPC tests was made by adjusting the delta of a recently described tolerated difference test (TDT) or the limits of rejection of f2. Drug k _a (especially if k _a is small), formulation lag time (t-lag), the number of subjects included in the BE studies, and the number of sampled time points in the DPC test were the factors that affected the most these setups of dissolution specifications. Another recently described DPC test, permutation test (PT), showed excellent statistical power. All the formulations declared as similar with PT were also bioequivalent. Similar case-specific studies may support the biowaiving of ER drug formulations based on customized DPC tests.     

Local Treatment of Hepatic Metastases with Low-Level Direct Electric Current: Experimental Results

Background: Several authors have recently reported encouraging results from low-level direct current therapy in easily accessible malignant tumors. However, antitumoral effects in colorectal metastases have not been investigated experimentally. Methods: Using an animal model with induced hepatic metastases, we analyzed the effectiveness and the tumor growth dynamics after direct current application. Three weeks after induction tumor volumes were estimated with magnetic resonance imaging (MRI). Then direct current (80 C/cm³) was applied in the treatment group by means of one anode in the tumor center and four cathodes peripherally. In the control group electrodes were placed without applying current. Tumor growth dynamics was analyzed with MRI after 3 and 5 weeks. After this all animals were killed, and the livers histologically examined. Results: After 5 weeks MRI showed a 1.6-fold tumor enlargement in the treatment group versus a 2.9-fold enlargement in the control group (Student t test, P = 0.0051). The histopathologic analysis of the treated livers yielded a 21% complete response rate and a 78% partial response rate. No necroses were found in the control group. Conclusions: These results confirm the effectiveness of low-level direct current application as a potential modality for the treatment of hepatic metastases.     

In vivo nuclear magnetic resonance imaging of myocardial perfusion using the paramagnetic contrast agent manganese gluconate

Previous nuclear magnetic resonance (NMR) imaging studies have indicated that coronary occlusion does not produce sufficient changes in standard tissue relaxation times to allow the detection of acute ischemia. To identify acute myocardial perfusion abnormalities, the use of the paramagnetic agent manganese gluconate combined with calcium gluconate (MnGlu/CaGlu) was investigated in canine models of acute coronary artery occlusion. In vitro studies showed that MnGlu/CaGlu was a more efficient relaxing agent than gadolinium-DTPA (relaxivity of 7.8 versus 5.1 s-1 mM-1) and demonstrated affinity for normal myocardium. The distribution of MnGlu/CaGlu as measured by manganese-54 tracer studies was proportional to myocardial blood flow in both normal and ischemic tissue. Hearts excised from dogs after coronary artery occlusion and administration of 0.035 mM/kg MnGlu/CaGlu were imaged ex vivo using a relatively spin-lattice relaxation time (T1)-weighted gradient reversal technique (repetition time [TR] 50 ms and echo time [TE] 9 ms). These images showed increased signal intensity in the normally perfused myocardium with a mean signal intensity ratio of hypoperfused to normal myocardium of 0.55 +/- 0.12 (mean +/- SD). In vivo images obtained in nine dogs after coronary artery occlusion and administration of the same dose of MnGlu/CaGlu demonstrated the region of hypoperfused myocardium in six dogs with a signal intensity ratio of hypoperfused to normal myocardium of 0.64 +/- 0.23 (p less than 0.05 versus control). When a higher dose of 0.1 mM/kg MnGlu/CaGlu was utilized and in vivo imaging was performed using a relatively spin-spin relaxation time (T2)-weighted (TR gated, TE 60 ms) spin-echo sequence in six dogs, the signal intensity of normal myocardium was decreased.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dose-Related Hemodynamic and Electrocardiographic Effects of the Calcium Promoter BAY y 5959 in the Presence or Absence of Congestive Heart Failure

Objectives. The aim of this study was to assess the cardiovascular effects of BAY y 5959, a calcium promoter modulating myocardial calcium channels, in the presence or absence of congestive heart failure.

Background. There is still a clinical need for short-term administration of intravenous positive inotropes. BAY y 5959 was developed as a new approach to increase myocardial performance by selectively enhancing calcium influx in the myocytes.

Methods. Forty-one patients (21 without and 20 with congestive heart failure) were studied in an open label, dose-ranging study. Hemodynamic variables (including left ventricular [LV] angiography) and plasma samples were obtained at baseline and after 20 min of intravenous infusion of BAY y 5959 at doses ranging from 0.25 to 4.5 μg/kg body weight per min.

Results. In both study groups, BAY y 5959 produced dose-dependent increases in the indexes of inotropic state, without affecting isovolumetric relaxation rate. The magnitude of the response was comparable in patients with or without heart failure (average 38% increase in maximal first derivative of LV pressure [dP/dt max] at plasma levels of 100 μg/liter). BAY y 5959 also induced mild but statistically significant bradycardia and significantly decreased end-systolic volume while producing a leftward shift of the pressure-volume loop. Mean aortic pressure was unaffected at doses up to 3.0 μg/kg per min, and cardiac index improved in patients with heart failure at doses of 2.0 μg/kg per min (+23%, p < 0.05). However, at a dose of 4.5 μg/kg per min, mean aortic pressure and LV systolic wall stress increased, suggesting systemic vasoconstriction. The QT interval was also prolonged significantly at most doses.

Conclusions. BAY y 5959 exhibits positive inotropic effects in patients with and without heart failure. The optimal response— combining bradycardia, reduced preload and improved cardiac output—appeared to be achieved at a dose of 2.0 μg/kg per min. The impact of QT prolongation with regard to potential antiarrhythmic or proarrhythmic effects is unclear at this time.