Pharmacokinetic and pharmacodynamic modelling of metoprolol in rabbits with liver failure

The pharmacokinetic and pharmacodynamic profiles of metoprolol were studied in adult male rabbits given 3.2 mg/kg i.v. before and during liver failure. The partition of metoprolol between blood cells and plasma averaged 1.14 in both conditions. Plasma protein binding, concentration-independent, was 32% and 17% in normal and pathological status, respectively. With normal liver function the terminal elimination half-life for the drug was 0.54-0.96 h, rising to 1.0-2.1 h in liver failure. Differences of the same order were observed for total plasma drug clearance (average 3.7 vs 1.5 1/h/kg), MRT (0.77 vs 1.92 h), AUC (0.9 vs 2.2 mg h/l) and k10 (3.17 vs 1.80 h-1). Liver impairment did not affect the volume of distribution of the central compartment, the steady-state volume of distribution and the other intercompartmental rate constants. Although metoprolol was eliminated in the urine, the amount excreted was low (1.5% of the administered dose) in both conditions. The pharmacokinetic model was extended by an 'effect compartment', which has no influence on the predetermined mass of drug in the body, to analyse the relationship between heart rate fall and changes in metoprolol plasma concentrations. After drug administration, heart rate fell rapidly about 90 beats in both states. The mean unbound plasma concentration producing 50% of this reduction was double during liver failure compared to normal condition (0.03 vs 0.07 mg/l), but the temporal aspects of drug equilibration with site of action were similar.     

Perfluorochemicals as US contrast agents for tumor imaging and hepatosplenography: preliminary clinical results

In animals, perfluorochemicals (PFCs) are effective ultrasound (US) contrast agents that produce hepatic, splenic, and tumor enhancement. The use of Fluosol-DA 20%, an emulsion of perfluorodecalin and perfluorotripropylamine, was studied in nine non-critically ill patients with cancer who had liver lesions. US studies without Fluosol were compared with studies obtained 24, 48, and 72 hours after Fluosol infusion. Vital signs and extensive laboratory analyses are performed before and after Fluosol infusion. Liver metastases from colonic, pancreatic, and gastric carcinoma exhibited rim or diffuse enhancement after a Fluosol dose of 1.6 g/kg or greater. Fluosol produced echogenic enhancement of the liver and spleen relative to kidney at a dose of 2.4 g/kg, allowing the detection of nonenhancing lesions. In addition, Fluosol at a dose of 1.6 g/kg or greater allowed detection of lesions not seen before contrast medium was administered in three of the seven patients studied. There was a mild increase in the level of serum glutamic oxaloacetic transaminase in two patients, one given 2.4 and the other 3.2 g/kg of Fluosol. Mild and transient allergic reactions without change in vital signs were experienced by two patients.     

Natural killer activity in patients with acute viral hepatitis.

Using the natural killer (NK) sensitive K562 cell line, enhanced NK cell cytotoxicity was demonstrable early in the course of acute hepatitis B while normal values were obtained in patients studied during convalescence. No evidence of enhanced NK activity was instead obtained in the course of acute non-A, non-B hepatitis. Serum levels of alpha-interferon, as determined by radioimmunoassay (RIA), were significantly increased in patients with acute hepatitis B showing enhanced NK cell activity but not in those with acute non-A, non-B hepatitis and normal NK cell activity. These results suggest that natural cytotoxicity may play a role early in the course of acute hepatitis type B, before antigen-specific T lymphocytes become fully operative.     

The nitric oxide pathway in pre-eclampsia: pathophysiological implications

Pre-eclampsia, one of the most significant health problems inhuman pregnancy, complicates 6-7% of all gestations and is theleading cause of fetal growth retardation, infant morbidityand mortality, premature birth and maternal death. Recent researchimplicates free radicals in the pathophysiology of pre-eclampsia.This review covers the biochemistry of nitric oxide (NO) andpossible interactions with other free radicals. Studies in therat show that pregnancy is associated with enhanced productionand responsiveness to NO in both reproductive tissues and bloodvessels. Rats infused with N^G-nitro-L-arginine methyl ester(L-NAME, a NO synthase inhibitor) have been used as an animalmodel of pre-eclampsia, and the effects of steroid hormoneson blood pressure in this model have been tested. Results suggestthat pre-eclampsia may be a state of NO deficiency. However,in humans there seem to be contradictions regarding the involvementof NO in maternal adaptation to pregnancy. It is suggested thatNO may be one of several systems that act in concert to maintaina symbiotic relationship between mother and fetus. However,the input of each system may be genetically determined.