Effect of hypotension preceding death on the function of lungs from donors with nonbeating hearts

BACKGROUND: A shortage of suitable brain-dead donors continues to severely limit lung transplantation. Use of donors with nonbeating hearts has been suggested as a solution. Lungs are unique, in that aerobic metabolism can continue in the absence of blood circulation because oxygen is present in airways and alveoli. Animal studies have shown reasonable cadaveric graft function up to several hours after sudden death by drug administration. However, hemodynamic instability before death may worsen lung function through activation and pulmonary sequestration of neutrophils and release of inflammatory mediators. Because many potential cadaveric donors experience hypotension before death, this study was undertaken to assess the effect of hypotensive shock on cadaveric lung viability. METHODS: A rat isolated lung reperfusion model was used to assess pulmonary function over 3 hours of reperfusion or until gross pulmonary edema developed. Twenty-five rats were randomly allocated to the following study groups, which were based on status before lung harvest: (1) control: no interventions; (2) hypotensive: 1 hour of hypotension by exsanguination to a mean blood pressure of 30 to 40 mm Hg; (3) cadaver: death by cervical dislocation followed by 3 hours of in situ lung ischemia; (4) hypotensive + 3 hours cadaver: 1 hour of hemorrhagic shock, followed by death and 3 hours of in situ ischemia; (5) hypotensive + 2 hours cadaver: similar to group 4, except the in situ ischemia was abbreviated to 2 hours. RESULTS: No significant differences were found among group 1, 2, or 3 lungs with regard to wet to dry weight ratios, gas exchange, and pulmonary arterial or airway pressures. However, all group 4 lungs became grossly hemorrhagic and developed severe pulmonary edema within 10 minutes of reperfusion. Group 5 lungs fared only marginally better, with two of five lungs tolerating 3 hours of reperfusion. CONCLUSIONS: A period of hypotension before death severely impairs cadaveric lung viability.     

Decreased anterior cingulate gyrus metabolic rate in schizophrenia

Although the majority of physicians entering residency training in Canada will enjoy fulfilling careers in their chosen specialty, today's postgraduate training system has its critics. Among them are the new graduates who are not satisfied with the residency positions offered to them and practising physicians who would like to re-enter the system to train in a new specialty but find themselves locked out.     

Orally active inhibitors of human leukocyte elastase. II. Disposition of L-694,458 in rats and rhesus monkeys

The disposition of L-694,458, a potent monocyclic beta-lactam inhibitor of human leukocyte elastase, was studied in male Sprague-Dawley rats and rhesus monkeys. After iv dosing, L-694,458 exhibited similar pharmacokinetic parameters in rats and rhesus monkeys. The mean values for its plasma clearance, terminal half-life, and volume of distribution at steady state were 27 ml/min/kg, 1.8 hr, and 4.0 liters/kg in rats and 34 ml/min/kg, 2.3 hr, and 5 liters/kg in rhesus monkeys. The bioavailability of a 10 mg/kg oral dose was higher in rats (65%) than in rhesus monkeys (39%). In both species, concentrations of L-694,458 in plasma increased more than proportionally when the oral dose was increased from 10 mg/kg to 40 mg/kg. In monkeys a protracted plasma concentration-time profile was observed at 40 mg/kg, characterized by a delayed T(max) (8-24 hr) and a long terminal half-life (6 hr). [3H]L-694,458 was well absorbed after oral dosing to rats at 10 mg/kg, as indicated by the high recovery of radioactivity in bile (83%) and urine (6%) of bile duct-cannulated rats. Only approximately 5% or less of the radioactivity in bile, urine, and feces was a result of intact L-694,458, indicating that the compound was being eliminated by metabolism, followed by excretion of the metabolites in feces, via bile. Demethylenation of the methylenedioxyphenyl group resulting in the catechol was the primary metabolic pathway in human and rhesus monkey liver microsomes. In rat liver microsomes, the major metabolite was the N-oxide of the methyl-substituted piperazine nitrogen. In rats dosed iv and orally with [3H]L-694,458, concentrations of radioactivity were highest in the lung (the primary target tissue), adrenals, and liver. L-694,458 was unstable in rat blood and plasma, degrading via a pathway believed to be catalyzed by B-esterases and to involve cleavage of the beta-lactam ring and loss of the methylpiperazine phenoxy group. In vitro studies indicated that in human liver, L-694,458 was metabolized by CYP3A and 2C isozymes, and in both monkey and human liver microsomes the compound acted as an inhibitor of testosterone 6beta-hydroxylation.