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Biomedical subjects

V B Pizziconi

Publications and source records attributed to V B Pizziconi.

13 recordsLinked to original sources

Transplacental transport of N-acetylcysteine in an ovine model.

STUDY OBJECTIVE: Acetaminophen freely crosses the placenta, and acetaminophen ingestion is the most frequent intentional overdose in pregnancy. Although most patients do well after maternal treatment with the antidote N-acetylcysteine (NAC), fetal death with massive hepatic necrosis has occurred. It has never been shown whether NAC crosses the placenta to yield fetal plasma levels equal to those associated with hepatoprotective effects in human beings. Our study objective was to evaluate this in a widely accepted large animal model for maternal-fetal research. DESIGN AND TYPE OF PARTICIPANTS: A nonblinded experiment was performed using four domestic sheep at near-term gestation. INTERVENTIONS: NAC 150 mg/kg IV was administered to the ewe over 15 minutes. After induction of anesthesia, the fetal head was delivered surgically and a neck vein cannulated for blood sampling. Maternal and fetal blood samples were obtained at the end of NAC infusion, at 30- and then at 60-minute intervals for four hours. Plasma NAC levels were determined by gas chromatography/mass spectroscopy (detection limit, 2 micrograms/mL; quantification limit, 5 micrograms/mL). RESULTS: Maternal peak plasma NAC levels were 619, 631, 1,757, and 2,512, micrograms/mL, respectively, within 30 minutes of infusion. However, NAC was only minimally detectable in plasma of two fetal animals and transiently reached quantifiable levels in two others. None of the fetal animals attained serial plasma NAC levels that equalled those associated with therapeutic dosing or hepatoprotective effects in human beings. CONCLUSION: Transplacental transport of NAC is clinically insignificant in a mammalian model resembling the human being. These findings suggest that the human fetal liver is not protected from acetaminophen toxicity by maternal NAC therapy.

Acetylcysteine

Present status of the hemofiltration/molecular separation artificial kidney.

The hemofiltration/molecular separation (HFMS) artificial kidney concept, first proposed over a decade ago, involves continuous ultrafiltration from the blood stream followed by cleansing of the filtrate, with subsequent return to the body. Thus, the system is completely self-contained and portable. During recent preclinical trials on nephrectomized canines, HFMS was better than hemodialysis (HD) in several important ways. First, the removal or clearance of middle molecules was better with 0.34 m(2) HFMS than with 1 m(2) HD. Significant phosphate clearance was achieved, and the removal rate for creatinine was the same as that for urea. This uniform clearance extends to even higher molecular weight solutes and could potentially result in improved patient response. It mimics the real kidney, whereas membrane-limited dialysis undergoes a logarithmic decrease of clearance with molecular weight. This is due to the fact that solute transport through the membrane involves solution into its matrix followed by diffusion, and solute diffusivity decreases with molecular volume. In order to achieve this potential for hemofiltration-based systems, however, there are stringent requirements on both the membrane and the plasma proteins allowed to accumulate on the membrane surface.

Animals

Ultrafiltration of molecules through deposited protein layers.

A naturally deposited protein layer is shown to be highly compressible as witnessed by its resistance to the passage of both water and dissolved molecules. This protein layer can easily be much more important than the underlying membrane. Hydrodynamic methods can be employed to control this protein layer, even to the extreme of its extinction in a continuous flow system. The rejection properties are shown to be a function of both the tracer molecular weight and type. Some of the physical property variations are reviewed for plasma amd serum as a function of protein concentration.

Amino Acids

Correlation of pulsed flow vortex shedding.

Flow visualization experiments were performed leading to the development of a correlation for the vortex shedding from indentations perpendicular to the main stream flow and caused by the addition of a pulsed flow component. The peak pulse flow rate required for vortex shedding greatly exceeds the condition for flow reversal in the channel when the steady flow rate is low while the vortex shedding occurs close to the flow reversal condition when the steady flow rate is very high. The empirical correlation should be useful in assessing the practicality of utilizing this technique to augment mass transport in membrane separation processes. Vortex shedding provides substantial transport augmentation in the ultrafiltration of a flowing plasma stream, and recommendations for further study are outlined to improve our understanding of this phenomena.

Blood Flow Velocity

An efficient method for removing bilirubin.

Bilirubin is tightly bound to albumin, making hemoperfusion an ineffective treatment for hyperbilirubinemia. By adding a safe unbinding agent to the blood (solutizer), which itself is adsorbed, hemoperfusion can become efficient and practical. Canines were made hyperbilirubinemic with an intravenous infusion of a 5 mg/ml solution (with Na2CO3) for 1 hour. Peak concentrations of 14-22 mg/dl were reached in adult dogs (25-35 kg). Hemoperfusion was then initiated with or without (control) the solutizer (sodium benzoate). The bilirubin unbinding effect of sodium benzoate was rapid and effective. Because of the simultaneous adsorption of sodium benzoate, a small activated carbon section that was presaturated with the solutizer was located proximal to the main hemoperfusion column, in addition to continuous infusion to reach 20 mM in the blood. Comparison of the normalized bilirubin concentration for benzoate augmented hemoperfusion with the average for control dogs, shows that benzoate results in a threefold decrease in the normalized bilirubin concentration after 1.5 hr of hemoperfusion. Sodium benzoate may also have the advantage of protecting platelets during hemoperfusion.

Animals

Augmented hemoperfusion for hyperbilirubinemia.

Exchange transfusions and phototherapy are used to treat hyperbilirubinemia, each method having its own disadvantages. Hemoperfusion with coated activated charcoal (CAC) produces low removal rates due to the strong binding of bilirubin to albumin. Biocompatible chemical agents were investigated to selectively unbind the bilirubin into solution just prior to CAC exposure. In batch mock solution tests, the addition of sodium benzoate resulted in a 69% equilibrium bilirubin removal at 50 mM and 96% removal at 100 mM. During flow tests, adsorptive removal of sodium benzoate was so rapid that the CAC had to be pretreated with sodium benzoate solutions. In the absence of sodium benzoate, the outlet bilirubin was 50% of the inlet concentration at the passage of one void volume, with a rapid increase to 70% (30% removal). With sodium benzoate at 100 mM, the same 50% outlet/inlet percent was observed at one void volume throughput, but the outlet concentration fell to 6% of the inlet at 12 column void volumes (94% removal). Similar experiments with bovine plasma/blood and human plasma resulted in an average increase in bilirubin removal of 25% for the bovine and human plasma and 35% for the bovine blood at 100 mM benzoate. A significant decrease in platelet aggregation was measured with the addition of sodium benzoate, which makes this augmented hemoperfusion removal of bilirubin clinically attractive.

Benzoates