Fenofibrate: Metabolism and Species Differences for Peroxisome Proliferation in Cultured Hepatocytes

The hypolipidemic agent fenofibrate, which is a peroxisome proliferatorin some rodents in vivo, was studied in cultured hepatocytesfor its metabolism and effects on enzymatic induction relatedto peroxisome proliferation so as to lead to a better understandingof the mechanisms involved in peroxisome proliferation. [¹⁴C]Fenofibratewas completely metabolized within 24 hr by primary culturesof rat hepatocytes and the metabolic pattern corresponded tothat found in vivo. The main products were fenofibric acid andits glucuronidated form. Carbonyl reduction of fenofibric acidalso occurred. The metabolic pattern of [¹⁴C]Fenofibric acidwas nearly the same as that of fenofibrate. Fenofibrate, fenofibricacid, and its reduced metabolite all induced peroxisomal (cyanide-insensitive)palmitoyl-CoA oxidation activity (PCOA) in rat hepatocytes,whereas derivatives lacking the carboxyl group were nearly inactive.The known species differences with respect to sensitivity toperoxisome proliferators in vivo was mirrored in cultured cellsbecause fenofibric acid did not induce peroxisomal PCOA in primaryculture of guinea pig hepatocytes nor in the human hepatomacell line HepG2. The mechanistic association between the inductionof CYP4A1-catalyzed lauric acid -hydroxylase (LAH) activityand peroxisomal PCOA induction was investigated. Fenofibricacid concomitantly Induced LAH activity and peroxisomal PCOAin rat hepatocytes. Specific inhibition of LAH activity (–52%)by 10-undecynoic acid partially prevented induction of peroxisomalPCOA (–32%). The putative role of dicarboxylic acids,the oxidation product of -hydroxymonocarboxylic acids, in PCOAinduction was further substantiated by the observed inductionof peroxisomal PCOA by 1-12-dodecanedioic acid. We concludethat (1) fenofibric acid is the possible proximate peroxisomeproliferator of fenofibrate in rat hepatocytes, (2) culturedhepatocytes reflect in vivo sensitivity to fenofibrate withrespect to peroxisome proliferation, and (3) there is some evidencethat the catalytic activity of the CYP4A1 enzyme mediates, atleast in part, peroxisomal PCOA induction.     

Synthesis of thymosin α1 by fragment condensation using tert.-butyl side chain protection

A novel synthesis of thymosin α₁ by classical methods using seven tert. -butyl side chain protected fragments is described. Optimum conditions were found for the final DCC/HOBt coupling of the two key intermediates; decapeptide and octadecapeptide. Thymosin α₁ was purified by two stages of preparative HPLC (partial purification with C₈ and final purification with C₁₈ reverse phase silica gel) to give a 30% overall yield for the final four stages of synthesis (including catalytic hydrogenation of octadecapeptide, coupling, deprotection and purification). The product was shown to be homogeneous by thin-layer and paper high voltage electrophoresis, isoelectric focusing analysis, thin-layer chromatography and high performance liquid chromatography. Amino acid analysis, optical rotation, ¹ H-n.m.r. spectroscopy, FAB mass spectroscopy and peptide mapping after tryptic digestion confirmed the structure of thymosin α₁. Three minor stereoisomer contaminants were isolated by HPLC and characterized as [D-Lys¹⁴]-thymosin α₁, [D-Lys¹⁷]-thymosin α₁ and [D-Ala³]-thymosin α₁ resulting from racemization at Lys¹⁴, Lys¹⁷ and Ala³ during the coupling of the fragments. A final contaminant, isolated by HPLC, was characterized as N^α-isobutyloxycarbonyl-thymosin α₁ (15–28), which results from “wrong way opening” of an activated mixed anhydride.     

Stable Patterns Generated by Activator-Inhibitor Systems

The paper is concerned with a discrete morphogenetic model ofactivator-inhibitor type. The aim is to give a theoretical explanationfor what we understand as the first step in pattern formationfor a growing object: as long as the object remains small enough,its shape is spatially homogeneous, while passing a criticallength results in a spontaneous establishment of a non-homogeneousconfiguration. We show that, for parameters suitably chosen,there are many stable patterns that can be formed. This factimplies, in particular, a sensitive dependence of the establishedpattern from the perturbation that causes the object to leavethe homogeneous state.     

Inappropriate Discharges by the Implantable Cardioverter Defibrillator During Postoperative Testing: Implications for Intraoperative Assessment

Inappropriate shocks were delivered to a patient while in sinus rhythm by an implantable cardioverter defibrillator (ICD) during routine prehospital discharge testing. This was induced by the standard programmer when the "read" telemetry sequence was initiated. The ICD was removed and found to suffer from electrical artifact that was sensed as ventricular tachycardia during telemetry. To avoid inadvertent telemetry-induced shocks during routine testing, all ICDs should be interrogated, using a standard programmer, intraoperatively, with the unit in "defibrillation on" mode.     

U.S. Experience with the AddVent VDD(R) Pacing System

The AddVent pacemaker generator and model 1328C AV single-pass lead is a new pacemaker system capable of VDD or VDDR modes. The purpose of this study was to present the initial experience with AddVent in the United States and Canada. Between May 10, 1995 and May 3, 1996, 53 devices were implanted in 52 patients and followed for a mean of 217 (±39) days. At the predischarge, 1-, 3-, and 6-month follow-up evaluations, atrial sensing thresholds and ventricular sensing and capture thresholds were measured in the supine, sitting, and standing positions to evaluate stability of atrial sensing with respect to body posture at rest. At the 1-month follow-up, a treadmill exercise test was performed to evaluate atrial sensing during exercise and to evaluate two new features of the AddVent called "sensor-mediated rate smoothing" and "preferential P wave sensing." Atrial sensing thresholds were not significantly different (P > 0.05) among body postures for any follow-up period or among follow-up periods for each posture. At rest, the percentage of appropriately tracked P waves observed was > 99% at each follow-up period. During treadmill exercise, the percentage of appropriately tracked P waves was > 98.7%. Appropriate preferential P wave sensing and sensor-mediated rate smoothing (VDDR mode) was observed. The AddVent pacing system provides safe and effective pacing therapy. Several features of VDDR pacing offer advantages over standard VDD pacing.