Class III Antiarrhythmic Effects of Dofetilide in Rabbit Atrial Myocardium

BACKGROUND: Dofetilide is a new class III antiarrhythmic agent with demonstrated efficacy in ventricular and atrial tachyarrhythmias. We investigated its class III actions and their modulation by stimulation rate in rabbit atrial myocardium. METHODS AND RESULTS: Standard microelectrode techniques were used to record action potentials from rabbit atrial tissue at varying stimulation rates. Dofetilide produced a dose-dependent prolongation of action potential duration at concentrations from 1 nM to 1 μM at an interstimulus interval of 1000 ms. Action potential duration at 90% repolarization (action potential duration) was prolonged from 116 +/- 11.7 ms in control solutions to 13.9 ms at 1 nM dofetilide and 186 +/- 49.3 ms at 1 μM dofetilide (P <.05 for 1 nM vs control; P <.01 for 1 μM vs control). Reduction of interstimulus interval to 500 ms has no significant effect on action potential duration prolongation by dofetilide (P <.05 for 1 nM vs control; P <.01 for 1 μM vs control). Reduction of interstimulus interval to 500 ms had no significant effect on action potential duration prolongation by dofetilide. At faster rates than this, and particularly at an interstimulus interval less than 330 ms, a marked "reverse rate dependence" of the class III effect was observed. Specifically, the high therapeutic concentration of 10 nM showed no effect on action potential duration at interstimulus interval of 250 ms or 200 ms, and even at a concentration of 30 nM, the small class III effect was no longer statistically significant at these rates. CONCLUSIONS: Dofetilide prolongs action potential duration in rabbit atrial myocardium, but this effect is significantly attenuated at stimulation rates above 2 Hz.     

Thyroid structure and function in bovine β-mannosidosis

Summary In bovine -mannosidosis, the thyroid in the affected newborn shows marked cytoplasmic vacuolation. There is an associated reduction in the serum concentrations of thyroxine and tri-iodothyronine.     

A phase I trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L-778,123 and radiotherapy for locally advanced pancreatic cancer.

PURPOSE: Preclinical and clinical studies have demonstrated that inhibition of prenylation can radiosensitize cell lines with activation of Ras and produce clinical response in patients with cancer. The aim of this study was to determine the maximally tolerated dose of the dual farnesyltransferase and geranylgeranyltransferase I inhibitor L-778,123 in combination with radiotherapy for patients with locally advanced pancreatic cancer. EXPERIMENTAL DESIGN: L-778,123 was given by continuous intravenous infusion with concomitant radiotherapy to 59.4 Gy in standard fractions. Two L-778,123 dose levels were tested: 280 mg/m2/day over weeks 1, 2, 4, and 5 for dose level 1; and 560 mg/m2/day over weeks 1, 2, 4, 5, and 7 for dose level 2. RESULTS: There were no dose-limiting toxicities observed in the eight patients treated on dose level 1. Two of the four patients on dose level 2 experienced dose-limiting toxicities consisting of grade 3 diarrhea in one case and grade 3 gastrointestinal hemorrhage associated with grade 3 thrombocytopenia and neutropenia in the other case. Other common toxicities were mild neutropenia, dehydration, hyperglycemia, and nausea/vomiting. One patient on dose level 1 showed a partial response of 6 months in duration. Both reversible inhibition of HDJ2 farnesylation and radiosensitization of a study patient-derived cell line were demonstrated in the presence of L-778,123. K-RAS mutations were found in three of the four patients evaluated. CONCLUSIONS: The combination of L-778,123 and radiotherapy at dose level 1 showed acceptable toxicity in patients with locally advanced pancreatic cancer. Radiosensitization of a patient-derived pancreatic cancer cell line was observed.     

Sensorless flow and head estimation in the VentrAssist rotary blood pump

Flow rate and pressure difference (or head) are key variables needed in the control of implantable rotary blood pumps. However, use of flow and/or pressure probes can decrease reliability and increase system power consumption and expense. For a given fluid viscosity, the flow state is determined by any 2 of the 4 pump variables: Flow, pressure difference, speed, and motor input power can be used. Thus, if viscosity is known or if its influence is sufficiently small, flow rate and pressure difference can be estimated from the motor speed and motor input power. For the VentrAssist centrifugal blood pump, which uses a hydrodynamic bearing, sensorless flow and pressure head estimation accuracy of 2 of our impeller designs were compared for a viscosity range of 1.2 to 4.5 mPas. This showed impeller design optimization can improve estimation accuracy. We also compared estimation accuracy using 2 blood analogues used in vitro, aqueous glycerol and red blood cells suspended in Haemaccel. The nature of the blood analogue and not only the viscosity of the fluid seems to influence estimation accuracy in our pump.     

Idiopathic arterial calcification of infancy: sonographic and magnetic resonance findings with pathologic correlation

Idiopathic arterial calcification of infancy is a rare condition characterized by extensive arterial calcification and stenoses of large and medium sized arteries. We report the sonographic and magnetic resonance angiographic findings of this entity and correlate them with the findings at autopsy. Received: 20 October 1997 Accepted: 21 November 1997     

Taurine inhibition of metal-stimulated catecholamine oxidation

Taurine is an abundant amino acid found in mammalian tissues and it has been suggested to have cyto-protective functions. The aim of the present study was to determine if taurine had the potential to reduce oxidative stress associated with metal-stimulated catecholamine oxidation. Taurine and structural analogs of taurine were tested for their ability to inhibit metal-stimulated quinone formation from dopamine or L-dopa. Oxidative damage to proteins and lipids were also assessedin vitro and the effects of taurine were determined. Taurine (20 mM) was found to decrease significantly ferric iron (50–500 μM)- and manganese (10 μM)-stimulated L-dopa or dopamine oxidation. Taurine had no effect on zinc-induced dopamine oxidation and slightly potentiated copper- and NaIO₄-stimulated quinone formation. Ferric iron-stimulated lipid peroxidation was not affected by taurine (1–20 mM). Protein carbonyl formation induced by ferric iron (500 μM) and L-dopa (500 μM) was significantly reduced by 10 mM taurine. The cytotoxicity of L-dopa (250 μM) and ferric chloride (75 μM) to LLC-PK₁ cells was attenuated by 10 mM taurine or hypotaurine. Homotaurine alone stimulated L-dopa oxidation and potentiated the cytotoxic effects of ferric iron. Homotaurine was found to be cytotoxic when combined with L-dopa or L-dopa/iron. In contrast, hypotaurine inhibited quinone formation and protected LLC-PK₁ cells. These studies suggest that taurine may exhibit cytoprotective effects against the oxidation products of catecholamines by acting as a scavenger for free radicals and cytotoxic quinones.