Reversible Congestive Cardiomyopathy Due to Chronic Ventricular Tachycardia

A patient with congestive cardiomyopathy, induced by ventricular tachycardia, is presented. The patient had chronic ventricular tachycardia, which persisted 4 months and was eventually successfully treated by an antitachycardia pacemaker. A severe left ventricular dysfuncion persisted after treatment for some days and then gradually resolved. After 3 months the indices of left ventricular function returned to normal values. The tachycardia-induced ventricular dysfunction seems to be a reversible disorder.     

Leydig Cell Hyperplasia and Adenomas in Mice Treated with Finasteride, a 5{alpha}-Reductase Inhibitor: A Possible Mechanism

Finasteride is a selective inhibitor of the enzyme 5-reductasewhich is responsible for the conversion of testosterone (T)to dihydrotestosterone (DHT). Finasteride is indicated for thetreatment of benign prostatic hyperplasia in man ({small tilde}0.1mg/kg/day). The effect of long-term treatment was studied inmice given high doses (2.5, 25, and 250 mg/kg/day) of finasteridefor 83 weeks. In finasteride-treated mice, increased incidencesof testicular Leydig cell hyperplasia (52% compared to 24% incontrol group) at doses equal to or greater than 25 mg/kg/dayand Leydig cell adenomas (32% compared to 0.5% in control group)at 250 mg/kg/day were observed. There were no drug-related effectson the seminiferous tubules. Since luteinizing hor mone (LH)is a trophic hormone for Leydig cells, short-term studies (5to 14 weeks) were done to investigate the relationship betweenLeydig cell hyperplasia and serum LH levels in finasteride-treatedmice. In these studies, there was a positive correlation betweenthe drug-related increased incidence of Leydig cell hyperplasiaand a statistically significant (p 0.05) increase in serum LHlevels in finasteride-treated (250 mg/kg/day) mice. Furthermore,studies in castrated male mice showed that the suppression ofserum LH levels by T is reversible by inhibition of conversionof T to DHT with finasteride (250 mg/kg/day), supporting thehypothesis that DHT is involved in the regulation of LH releasein mice. The data presented support the conclusion that theeffects of finasteride on Leydig cells appear to be secondaryto increased serum LH levels and that they occur only at veryhigh doses when compared to the therapeutic dose (approximately0.1 mg/kg/day) in man.     

Subacute Toxicity of a Mixture of Nine Chemicals in Rats: Detecting Interactive Effects with a Fractionated Two-Level Factorial Design

The present study was intended (1) to find out whether simultaneousadministration of nine chemicals at a concentration equal tothe "no-observed-adverse-effect level" (NOAEL) for each of themwould result in a NOAEL for the combination and (2) to testthe usefulness of fractionated factorial models to detect possibleinteractions between chemicals in the mixture. A 4-week oral/inhalatory study in male Wistar rats was performed in whichthe toxicity (clinical chemistry, hematology, biochemistry,and pathology) of combinations of the nine compounds was examined.The study comprised 20 groups, 4 groups in the main part (n= 8) and 16 groups in the satellite part (n =5). In the mainstudy, the rats were simultaneously exposed to mixtures of allnine chemicals [dichloromethane, formaldehyde, aspirin, di(2-ethylhexyl)phtha-late,cadmium chloride, stannous chloride, butyl hydroxyanisol, loperamide,and spermine] at concentrations equal to the "minimum-observed-adverse-effectlevel" (MOAEL), NOAEL, or 1/3NOAEL. In the satellite study therats were simultaneously exposed to combinations of maximallyfive compounds at their MOAEL. These combinations jointly comprisea two-level factorial design with nine factors (=9 chemicals)in 16 experimental groups (1/32 fraction of a complete study).In the main part many effects on hematology and clinical chemistrywere encountered at the MOAEL. In addition, rats of the MOAELgroup showed hyperpla-sia of the transitional epithelium and/orsquamous metaplasia of the respiratory epithelium in the nose.Only very few adverse effects were encountered in the NOAELgroup. For most of the end points chosen, the factorial analysisrevealed main effects of the individual compounds and interactions(cases of nonadditivity) between the compounds. Despite allrestrictions and pitfalls that are associated with the use offractionated factorial designs, the present study shows theusefulness of this type of factorial design to study the jointadverse effects of defined chemical mixtures at effect levels.It was concluded that simultaneous exposure to these nine chemicalsdoes not constitute an evidently increased hazard compared toexposure to each of the chemicals separately, provided the exposurelevel of each chemical in the mixture is at most similar toor lower than its own NOAEL.     

Wide QRS Tachycardia Due to AV Nodal Reentry and a "Bystander" Bypass Tract with Slow Conduction Properties

An unusual mechanism for recurrent, wide QRS complex supraventricular tachycardia is described in this report. A 25-year-old man with normal PR and QRS intervals during sinus rhythm was shown to have preexcitation with a left bundle branch block pattern during tachycardia and during atrial pacing. Electrophysiologic studies demonstrated slow and decremental conduction properties in an accessory "bystander" AV pathway utilized for antegrade conduction during AV nodal reciprocating tachycardia. The differential diagnosis of this tachycardia is discussed in detail.     

Pharmacological Studies on the in vivo Cataractogenicity of Acetaminophen in Mice and Rabbits

Pharmacological Studies on the in Vivo Cataractogenicity ofAcetaminophen in Mice and Rabbits. LUBEK, B. M., AVARIA, M.,BASU, P. K., AND WELLS, P. G. (1988). Fundam Appl Toxicol 10,596–606. Acetaminophen can be enzymatically bioactivated,which may play a role in cataractogenesis. This study evaluatedthe relation of dose, sex, plasma drug concentration, cytochromesP-450 (P-450 and P448) induction, and hepatocellular toxicityto cataract-ogenic susceptibility in inbred mice and rabbits.C57BL/6 or DBA/2 mice, which respectively are genetically responsiveand nonresponsive to P448 induction, were treated with acetaminophen,300 to 1000 mg/kg intrapentoneally (ip), following pretreatmentwith the P448 inducer 3-methylcholanthrene (3-MC). Bilateralcataracts developed, independent of sex, in 83% of C57BL/6 micewithin 4 hr of acetaminophen administration, compared with 7%of DBA/2 mice. A dose-response relation for cataractogenesiswas evident in C57BL/6 mice using doses of 300 and 400 mg/kg,with the higher dose producing similar plasma acetaminophenconcentrations but twofold higher glucuronide concentrations.Both strains had increased plasma concentrations of glutamic-pyruvictransaminase (GPT). New Zealand white or Chinchilla pigmentedrabbits were treated with single or multiple doses of acetaminophen,500 to 1500 mg/kg/day ip, following pretreatment with a cytochromesP-450 inducer: pheno-barbital, 3-MC, or ß3-naphthoflavone.Acetaminophen given chronically caused lenticular opacitieswithin 1 week in 19 of 20 rabbits pretreated with P-450 inducers,regardless of pigmentation, but not in animals without priorP-450 induction. No opacities were observed after a single doseof acetaminophen, even with P-450 induction. There was no increasein plasma GPT in rabbits with any treatment. Over 85% of acetaminophenwas recovered in urine as a glucuronide conjugate, and the restas acetaminophen or conjugates with sulfate, cysteine, or N-acetylcysteine.Susceptibility to acetaminophen cataractogenesis can be geneticallypredetermined and may involve enzymatic bioactivation, possiblyindependent of hepatic biotrans-formation and toxicity.     

Development of a Testing Battery to Assess Chemical-Induced Immunotoxicity: National Toxicology Program's Guidelines for Immunotoxicity Evaluation in Mice

Development of a Testing Battery to Assess Chemical-InducedImmunotoxicity: National Toxicology Program's Guidelines forImmunotoxicity Evaluation in Mice. Luster, M. I., Munson, A.E., Thomas, P. T., Holsapple, M. P., Fenters, J. D., White,K. L., Jr., Lauer, L. D., Germolec, D. R., Rosenthal, G. J.,and Dean, J. H. (1988). Fundam. Appl. Toxicol..     

A Canine Model of Torsades de Pointes

Although quinidine has been reported to induce QT interval prolongation and torsades de pointes clinically, the only experimental model currently available for quinidine-induced torsades de pointes requires the concurrent use of ischemia, reperfusion and cardiac pacing of the isolated, perfused heart. Our purpose in this study was to determine the circumstances under which quinidine might elicit torsades de pointes consistently in the intact dog. We found that maintenance of therapeutic plasma quinidine concentrations, alone, did not induce the arrhythmia. Rather, arrhythmia induction required the additional application of aconitine, which induces early afterdepolarizations and triggered activity. When aconitine was applied to two epicardial sites in dogs having quinidine-induced QT interval prolongation greater than 10%, torsades de pointes occurred in 80% of instances. When QT prolongation was less than 10%, aconitine-induced torsades de pointes was seen in only 21% of animals. Our results suggest that in a previously healthy heart quinidine-induced QT prolongation is, itself, insufficient to induce torsades de pointes consistently, and two independent sites of ectopic activity are needed as well. The ectopic foci appear to modulate one another's impulse initiation or activation sequence, thereby giving rise to the classical "twisting of the points" associated with the arrhythmia.     

Electrical Safety During Electrophysiological Testing

This report describes the inadvertent induction of non-sustained atrial and ventricular arrhythmias due to the malfunction of a programmable cardiac stimulator. The malfunction occurred when line power resumed after a brief municipal power outage ("blackout") during an invasive electrophysiological study. The stimulator spontaneously delivered very high frequency pulses through the electrode catheter to the myocardium which resulted in atrial and ventricular arrhythmias. During bench testing, the stimulator delivered a continuous train of high frequency output pulses (greater than or equal to 1 mA) when line voltage resumed normal level after it had dropped below 65 VAC. Electrical safety during electrophysiological testing requires a stimulator design which is immune to altered operating conditions, and which shuts down if abnormal operating or output conditions are detected.     

PHOTOKERATOSCOPY: SOME THEORETICAL AND PRACTICAL CONSIDERATIONS OF THE TECHNIQUE

Some theoretical limitations of photokeratoscopy associated with the quantification of keratograms are discussed.
Representative keratograms of normal and abnormal corneas are presented to illustrate the practical limitations of any mire imaging technique.     

Perturbation of Generation Cycle of Human Leukemic Blast Cells by Cytostatic Therapy In Vivo: Effect of Corticosteroids

The in vivo cell cycle effects of intensiveshort-term corticosteroid treatment onbone marrow lymphoblasts have beenstudied in five patients with acute lymphoblastic leukemia. In repeated bonemarrow samples, the following parameters were determined: mitotic index,stathmokinetic index after vincristine,³H-thymidine labeling index and singlecell DNA content. It is concluded thatprednisone has a general destructive effect both on actively proliferating and onquiescent leukemic lymphoblasts. Besides, prednisone has an additional effecton proliferating lymphoblasts whichmanifests itself by a decreased influxfrom G₁ phase into DNA synthesis phase.From the present data it cannot be decided whether this is due to a depopulation of the G₁ pool or results from anarrest of cells in G₁. No evidence hasbeen found for selective cell death during DNA synthesis. Some implications ofthis cytokinetic perturbation for therapeutic combination of corticosteroidswith methotrexate and vincristine arediscussed.

Submitted on May 26, 1970 Revised on July 13, 1970 Accepted on July 19, 1970