Age-Dependent Prevalence of Cardioembolic Sources Detected by TEE: Diagnostic and Therapeutic Implications

To define the prevalence of cardioembolic sources found by transesophageal echocardiography (TEE) in different age groups of patients with and without cryptogenic systemic embolism, TEE risk factors for cardiogenic embolism were identified from 341 consecutive patients referred for TEE. One hundred and thirty-five had cryptogenic cerebral or systemic peripheral embolic events (CEE) and 206 other indications for TEE (CTR). Cardioembolic sources were found in 40% of CEE and in 29% of CTR (P < 0.02). Specifically, left atrial (LA) thrombi (P < 0.0001), atrial septal aneurysm with right-to-left shunt (P < 0.002), and atherosclerotic aortic plaques (P < 0.02) were more frequent. The prevalence of potential cardioembolic sources was significantly higher in patients ≥ 70-years old than in younger patients (P < 0.03), specifically LA thrombi (P < 0.004) and atherosclerotic aortic plaques (P < 0.0001). In patients ≥ 70-years old, potential cardioembolic sources were found in 63% and in 40% in CEE and CTR (P = 0.073), respectively. However, LA thrombi were more frequent in CEE (P < 0.003). Thus, potential cardioembolic sources observed by TEE are found more frequently in patients ≥ 70-years old than in younger patients. LA thrombi were more frequent in CEE than in CTR patients ≥ 70-years old. In patients ≥ 70-years old with CEE who are eligible for an anticoagulant regimen, a search for potential cardioembolic sources by TEE should be considered.     

The Inhalation Toxicology, Genetic Toxicology, and Metabolism of Difluoromethane in the Rat

Difluoromethane (HFC32) is under development as a replacementfor chlorofluorocarbons (CFCs) in some refrigeration applications.It has been evaluated by standard studies of toxicity, developmentaltoxicity, and genotoxicity. In addition, the metabolism anddisposition of HFC32 was investigated and a physiologicallybased pharmacokinetic (PB-PK) model constructed. Inhalationof HFC32 (up to 50,000 ppm) caused no organ-specific effects,but resulted in slight maternal toxicity to the pregnant ratand rabbit and some fetotoxicity to the rat. HFC32 did not sensitizethe heart to adrenaline. The pharmacokinetics of [¹⁴C]difluoromethane(10,000 to 50,000 ppm/6 hr) revealed that about 2.1% of theinhaled HFC32 was absorbed and that steady state blood levelswere achieved within 2 hr and were proportional to dose. Carbondioxide was the major metabolite of HFC32 at all exposure levels.Carbon monoxide was not detected. The in vivo data were usedto validate a PB-PK model to describe the uptake and metabolismof HFC32. Absorption and distribution are adequately describedusing rat blood:air and tissue:air partition coefficients. Metabolism,which was linear across the dose range, was described by a firstorder rate constant (K_f=8.98 hr^–1). Of the absorbed HFC32,about 63% was metabolized at all doses; however, when metabolismwas expressed as a percentage of the inhaled dose it was muchlower, being about 1.4% of the HFC32 entering the airways. Overall,the results indicate that HFC32 is of very low toxicity andshould be an acceptable alternative to CFCs.     

CARBON DIOXIDE ELIMINATION FROM EACH LUNG DURING ENDOBRONCHIAL ANAESTHESIA: Effects of posture and pulmonary arterial pressure

The ventilation and carbon dioxide elimination of each lung,and pulmonary arterial pressure, were studied in 17 patientsduring the carry phases of anaesthesia for pulmonary surgery.The patients were ventilated mechanically to moderate hypocapnia.Expired tidal volume and carbon dioxide elimination rate ofthe lung to be operated on, and of the other lung, were similarin the supine position. There was a significant (P<0.01)increase in ventilation and a decrease in end-tidal PCO₂ ofthe upper lung after turning the patient on to the side. Simultaneously,the physiological deadspace fraction of tidal volume (VD/VT)increased from 42 to 45% (P<0.05). Mean pulmonary arterialpressure (MPAP) increased slightly as surgery on the chest wallcommenced. A concomitant increase of carbon dioxide eliminationfrom the upper lung occurred also, although the distributionof ventilation, between the lungs, was unchanged in comparisonwith the conditions during undisturbed anaesthesia. Individualchanges in MPAP (MPAP) and corresponding changes in VD/VT ((VD/VT))were negatively correlated (r=–0.68, P<0.01). The regressionequation was (VD/VT) (%) = 0.7–0.83 x MPAP (mm Hg). Itwas concluded that variations in pulmonary arterial pressureduring surgical stimulation may significantly affect the patternof carbon dioxide elimination in the lungs. However, there wasno evidence that these effects were important clinically     

Alveolar Retention and Clearance of Insoluble Particles in Rats Simulated by a New Physiology-Oriented Compartmental Kinetics Model

Alveolar Retention and Clearance of Insoluble Particles in RatsSimulated by a New Physiology-Oriented Compartmental KineticsModel. STOBER, W., MORROW, P. E., AND MORAWIETZ, G. (1990).Fundam Appl. Toxtcol. 15,329–349. A physiology-orientedcompartmental kinetics model of alveolar retention of inhaledinsoluble paniculate matter in rat lungs was proposed in a recentpaper, (W. Stober, P. E. Morrow, and M. D. Hoover, 1989, Fundam.Appl. Toxicol. 13, 823–843), and the retention patternsobtained with the model for a hypothetical set of input dataappeared to simulate phenomena which were observed in inhalationstudies with Fischer 344 rats. The present paper representsthe results of applying the new model for simulations of theactual experimental retention data of five different inhalationstudies with Fischer 344 rats exposed to three different materials.The experimental data showed that model adjustments had to bemade in order to account for clearance effects that appearedto be influenced by the age of the animals. After these adjustmentswere made and an appropriate set of values for the model parametersdescribing the respective exposure conditions was used, themodel was constrained to represent the empirical data of allof the studies by one unique set of parameter values. Changesin particular values of this set were considered to be acceptableonly if they reflected changes of relevant properties of theinhaled paniculate matter. The final simulations did not completelycomply with this self-imposed criterion. However, the degreeof compliance and the simulation quality achieved with a minimumof parameter variations seem to be unprecedented in retentionmodeling. The results of the study encourage attempts for furtherrefining the present model     

FLUMAZENIL IN ALCOHOL WITHDRAWAL: A DOUBLE-BLIND PLACEBO-CONTROLLED STUDY

The purpose of the present study was to study -aminobutyricacid (GABA)-A receptor function in alcohol-dependent subjectsduring withdrawal, using the benzodiazepine antagonist flumazenil.In particular, we wanted to examine the hypotheses that an endogenousinverse agonist ligand at the GABA-A benzodiazepine receptor(GBzR) is active during withdrawal (in which case flumazenilshould be anxiolytic), or whether chronic alcohol intake resultsin a shift in sensitivity of the receptor in the inverse agonistdirection (in which case flumazenil should be anxiogenic). Resultsfrom 15 alcohol-dependent subjects in a double-blind placebo-controlledcross-over study showed that flumazenil was neither anxiolyticnor anxiogenic, although withdrawal scores were reduced duringthe course of the study. The fact that flumazenil was not anxiogenic,as it is in panic disorder, suggests that the GBzR is functioningdifferently in these two clinically similar conditions.     

Subchronic and Chronic Inhalation Toxicity of Antimony Trioxide in the Rat

Fischer 344 rats were exposed by inhalation to Sb₂O₃ (antimonytrioxide) dust at exposure levels of 0, 0.25, 1.08, 4.92, and23.46 mg/m³ for 6 hr/day, 5 days/week for 13 weeks followedby a 27-week observation period. Subsequently, an inhalationon-cogenicity study was conducted at exposure levels of 0, 0.06,0.51, and 4.50 mg/m³ for 12 months followed by a 12-month observationperiod. The Sb₂O₃ in the subchronic study had a mass medianaerodynamic diameter (MMAD) of 3.05 ± 0.21 microns (mean± SD) with a geometric standard deviation (GSD) of 1.57± 0.06. In the chronic study, the MMAD was 3.76 ±0.84 and the GSD was 1.79 ± 0.32. Except for the eyes,no adverse clinical observations were attributed to Sb₂O₃ ineither study. In the subchronic study, corneal irregularitieswere seen after about 2 weeks of exposure and did not abateduring the observation period. In the chronic study, ophthalmoscopicevaluation at 24 months revealed a dose-related increase incataracts of 11, 24, 28, and 32% (both sexes combined) for eachgroup, respectively. Body weights were significantly lower (6%)than the control group's weights in the 23.46 mg/m³ males inthe subchronic study. These rats did not recover this weightduring the 27-week observation period. Body weights of the femalesin both studies and males in the chronic study were unaffected.There were no Sb₂O₃ effects on clinical chemistry or he-matologyin either study. Mean absolute and relative lung weights weresignificantly increased in the 4.92 and 23.46 mg/m³ groups inthe subchronic study. The 23.46 mg/m³ group's lung weights didnot recover to control levels during the 27-week observationperiod. Lung weights for rats in the chronic study were unaffected.Microscopic changes in the lungs in the subchronic and chronicstudy were limited to subacute-chronic interstitial inflammation,increased numbers of alveolar-in-traalveolar macrophages, foreignmaterial in the alveolar-in-traalveolar macrophages in the peribronchialand perivascular (chronic study only) lymphoid aggregates andin the peribronchial lymph nodes, granulomatous inflammation/granulomas,and fibrosis. In the chronic study, any observed neoplasms occurredwith comparable incidence among all groups and were within thehistorical range for controls. Clearance of Sb₂O₃ from the lungwas burden dependent and was reduced by 80/ in the 4.50 mg/m³group in the chronic study. The previously reported studies,which found Sb₂O₃ to be a carcinogen, were run at higher lungburdens. Under the exposure conditions of the current study,Sb₂O₃ was not a carcinogen.     

Deuterium Isotope Effect on the Metabolism of the Flame Retardant Tris(2,3-dibromopropyl) Phosphate in the Isolated Perfused Rat Liver

The metabolism of tris(2,3-dibromopropyl) phosphate (Tris-BP)was compared with that of completely deuterated Tris-BP (D15-Tris-BP)in an isolated, recirculating rat liver perfusion system inorder to determine the relative quantitative importance of twodifferent biotransformation pathways of Tris-BP: (i) cytochromeP450-mediated metabolism and (ii) GSH S-transferase-mediatedmetabolism. To accomplish this we quantitated the biliary excretionof S-(3-hydroxypropyl)glutathione (GSOH) as a marker metabolitefor cytochrome P450-mediated metabolism and that of S-(2,3-dihydroxypropyl)glutathione (GSOHOH) as a marker metabolite for GSH S-transferase-mediatedmetabolism. Completedeuterium substitution of Tris-BP significantlydecreased the formation of GSOH, whereas there was no effecton the formation of GSOHOH. Because our previous studies showeda large decrease in genotoxicity of D15-Tris-BP compared toTris-BP, the present results support our hypothesis that cytochromeP450-mediated metabolism is responsible for the genotoxic effectsof Tris BP in the rat liver.