Prognostic significance of the evolution of left ventricular ejection fraction in patients with acute myocardial infarction not treated with thrombolytic therapy

Several controlled trials on the thrombolytic treatment of acutemyocardial infarction (AMI) have failed to demonstrate thatthrombolysis has a simultaneous positive effect on left ventricularfunction and survival. One explanation may be that spontaneouschanges in left ventricular function occurred during the progressionof AMI in control patients. The aim of this study was to evaluatethe spontaneous evolution of left ventricular ejection fraction(LVEF) and its prognostic influence on early (1 month) and late(1 year) mortality in patients with AMI. We studied 216 patientsadmitted to our CCU within 24 h of the onset of symptoms. LVEFwas determined by radionuclide ventriculography on admission(RNV1) and at the end of the necrotic phase (RNV2). Fourteenpatients died before RNV2. On the basis of LVEF values at RNV1,the remaining 202 patients were divided into two groups: thosewith a normal LVEF (55%), and those with an abnormal LVEF (<55%). Among patients with a normal LVEF at RNV1 (64 patients) a significantincrease (>12%) in LVEF at RNV2 was observed in 12.5%, asignificant decrease (>12%) in 12.5% and no change at allin 75%. All of these patients survived, regardless of the evolutionof LVEF. In patients with an abnormal LVEF at RNV1 (138) a significantincrease (>5%) in LVEF at RNV2 was observed in 72.5%, a significantdecrease (>5%) in 6.5% and no change at all in 21%. In patientswith a LVEF increase, both early and late mortality were significantlylower than in patients with a LVEF decrease: (early mortality4% vs 55.5%, P<0.001; late mortality 6% vs 66.6%, P<0.001)respectively. In patients without any LVEF change, mortalitywas significantly lower than in patients with a LVEF decrease:(early mortality 10% vs 55.5%, P = 0.01; late mortality 14%vs 66.6%, P=0.004) respectively. In conclusion, our data demonstrate that a significant increasein LVEF occurs in most patients with an early depression ofleft ventricular function. This behaviour is associated witha low early and late mortality in comparison with the patientswith a LVEF decrease and is independent of thrombolytic treatment.When the early measurement of LVEF is normal the prognosis isnot influenced by LVEF evolution. These findings must be keptin mind when LVEF is used as a prognostic index and as an end-pointfor the evaluation of the effects of thrombolytic therapy.     

Effect of Equilibration Zones on Stability, Uniformity, and Homogeneity Profiles of Vapors and Aerosols in the ADG Nose-Only Inhalation Exposure System

Effect of Equilibration Zones on Stability, Uniformity, andHomogeneity Profiles of Vapors and Aerosols in the ADG Nose-OnlyInhalation Exposure System. GREEN, J. D., HELKE, W. F., SCOTT,J. B., YAU, E. T., TRAINA, V. M., AND DIENER, R. M. (1984).Fundam. Appl. Toxicoi. 4, 768–777. A commercially available,inexpensive, nose-only exposure chamber was modified to includeremovable equilibration zones, and the effect of these zoneson chamber performance was determined. Since limited performancedata were available concerning this unit, a more extensive characterizationwas performed. EPA limit concentrations (5 mg/liter) of toluenevapor or corn oil aerosol, and relatively low concentrationsof uranine aerosol (50 pg/liter) were produced by standard techniques.The presence or absence of equilibration zones did not affectthe stability or uniformity of toluene vapor atmospheres, withthe coefficient of variation (CV) not exceeding 3.33% in allexperiments. In contrast, the presence of two equilibrationzones was found to progressively enhance the uniformity of theinhalable test aerosols in the animal exposure zone (CV 3.16%).Matrix sampling revealed that in both uranine and corn oil experiments,the center matrix point concentration was consistently lowerthan samples taken in the actual animal breathing zone. Equilibrationzones markedly reduced the difference between breathing zoneand center point concentrations. These performance data indicatedthat the modified ADG nose-only exposure system performed exceptionallywell with the materials that were studied. Results were comparableto those describing whole-body chamber performance. The readyavailability of this inexpensive prototype lends itself to standardizationof techniques between laboratories     

Tapetal Changes in Beagle Dogs following Oral Administration of CGS 14796C, A Potential Aromatase Inhibitor

Tapetal Changes in Beagle Dogs following Oral Administrationof CGS 14796C, A Potential Aromatase Inhibitor. SCHIAVO, D.M., GREEN, J. D., TRAINA, V. M., SPAET, R., AND ZAIDI, I. (1988)Fundam. Appl. Toxicol. 10, 329-334. CGS 14796C, m-l-[(4-[(l-imidazolyl)methyl]-cyclohexyl)methyl)imidazolesuccinate, has been evaluated as a potential aromatase inhibitor.As part of the safety evaluation program, a 3-month oral toxicitystudy was performed in which beagle dogs were administered CGS14796C by gavage at 5, 15, or 50 mg/kg/day. Ophthalmos-copically,changes in the tapetum lucidum affecting dogs from the 15 and50 mg/kg dose levels were diffuse areas of pigmentation varyingin appearance from a brownish peppered or mottled to a moreuniform brown similar to that of the nontapetal area of thefundus. Tapetal reflectivity was absent or markedly reduced.Within the pigmented area, multiple islets (yellow, green, ororange) of tapetal cells were visible, suggestive of destructionof the tapetum. In no instance was retinal destruction, edema,vascular changes, or detachment observed. Ophthalmoscopic examinationsperformed during recovery revealed changes of slight increasein tapetal islets, suggestive of a slight progression and organizationwithin the tapetum followed by an arrest of the toxic insultwithin the tapetal tissue. At light and electron microscopicexamination of the ocular tissues, the lesions were tapetalcell degeneration/atrophy. These results demonstrated that thetaptetum lucidum was a target tissue of toxicity for CGS 14796C,and indicated that the findings are without toxicological significancein atapetal species, including man, whose globes do not havethis Structure.     

Activation of CGS 12094 (Prinomide Metabolite) to 1,4-Benzoquinone by Myeloperoxidase: Implications for Human Idiosyncratic Agranulocytosis

Many marketed Pharmaceuticals are known to cause idiosyncraticagranulocytosis in humans. Similarly prinomide, an antiin-flammatorydrug, was associated with a low incidence of agranulocytosis(<0.3%) in clinical trials, even though chronic toxicitystudies in rodents and primates showed no evidence of agranulocytosiswith either prinomide or its parahydroxy metabolite, CGS 12094.To investigate mechanisms for this human specific toxicity,experiments were conducted to study the metabolism of prinomideand CGS 12094 by myeloperoxidase (MPO), a major enzyme of neutrophilsand leukocyte progenitor cells. Although prinomide was not metabolizedby human MPO, CGS 12094 was rapidly metabolized (>90%; 2min); this reaction was dependent on H₂O₂ and MPO and was inhibitedby azide. During the MPO-catalyzed metabolism of CGS 12094,reactive intermediates that irreversibly bound to protein andcysteine were generated. One of the reactive metabolites generatedwas identified by mass spectroscopy and trapping with cysteineas 1,4-benzoquinone, a compound implicated in the myelotoxicityassociated with benzene. Thus during conditions which lead toelevated levels of H₂O₂ (e.g., active inflammation), CGS 12094is rapidly metabolized by MPO to reactive intermediates thatmay be related to prinomide-induced agranulocytosis.