Numerical simulations of pulsatile flow in an end-to-side anastomosis model.

A potential interaction between the local hemodynamics and the artery wall response has been suggested for vascular graft failure by intimal hyperplasia (IH). Among the various hemodynamic factors, wall shear stress has been implicated as the primary factor responsible for the development of IH. In order to explore the role of hemodynamics in the formation of IH in end-to-side anastomosis, computational fluid dynamics is employed. To validate the numerical simulations, comparisons with existing experimental data are performed for both steady and pulsatile flows. Generally, good agreement is observed with the velocity profiles whereas some discrepancies are found in wall shear stress (WSS) distributions. Using the same end-to-side anastomosis geometry, numerical simulations are extended using a femoral artery waveform to identify the possible role of unsteady hemodynamics. In the current simulations, Carreau-Yasuda model is used to account for the non-Newtonian nature of blood. Computations indicated a disturbed flow field at the artery-graft junction leading to locally elevated shear stresses on the vascular wall. Furthermore, the shear stress distribution followed the same behavior with oscillating magnitude over the entire flow cycle. Thus, distal IH observed in end-to-side artery-graft models may be caused by the fluctuations in WSS's along the wall.

The effect of age on the pharmacokinetics of pentazocine.

Pentazocine was administered intravenously to 18 subjects, surgical patients and volunteers, ranging in age from 22 to 90 years. When divided into a young group (10 subjects, age 22-48 years) and an elderly group (8 subjects, age 60-90 years), the total clearance decreased as function of age from 22.14 +/- 4.114 to 11.68 +/- 3.593 ml/min/kg, and the elimination half-life increased from 2.5 +/- 0.71 to 4.11 +/- 1.187 hours. No change in the apparent volume of distribution was observed. Implications of change in clearance and half-life on dosage regimen design are discussed.

Disposition and clinical side effects of pentazocine when administered during day and night.

The question of possible circadian rhythm upon administration of 6,11-dimethyl-2,6-methano-3-(3-methyl-2-butenyl)-1,2,3,4,5,6-hexahydro-3- benzazocin-8-ol (pentazocine, Talwin) (which was found to exist in beagle dogs) was studied in eight healthy, male volunteers. Six of the subjects resided in the USA, and two subjects joined the study group the night before the morning experiment from Europe. All blood concentration-time data after i.v. injection starting between 8-9 a.m. and 8-9p.m., respectively, were best fit by biexponential curves. The derived pharmacokinetic parameters were essentially identical to those reported in the literature. Overall, no statistically significant differences were found for any of the parameters between the day and night study. However, the two volunteers from Europe demonstrated significant differences in the volume of distribution. Although the sample number is too small to draw final conclusions, it indicates the need for further studies regarding possible influences by offsetting the biologic clock, or "jet-lag" on drug disposition. No differences were found in clinical effects between the day and night study. However, all clinical effects were significantly more pronounced after the first than after the second dose, regardless of time of administration.

Pilot study on bioavailability of coumarin and 7-hydroxycoumarin upon peroral administration of coumarin in a sustained-release dosage form.

Prolonged-release tablets containing coumarin were compared to intravenous and peroral administration of coumarin solution in man. Unchanged coumarin, the Phase 1 metabolite 7-hydroxycoumarin, and the Phase II metabolite 7-hydroxycoumarin glucuronide were determined in whole blood. Upon peroral administration, only approximately 1 per cent coumarin was found unchanged in the systemic circulation. However, the amount of the glucuronide found indicates complete absorption with extensive first-pass effect. When the prolonged-release dosage form was compared to the peroral solution, the extent of bioavailability of coumarin was 35 per cent, whereas the 7-hydroxycoumarin glucuronide was totally available. This supports the hypothesis that coumarin might be a prodrug and 7-hydroxycoumarin the active moiety. The drug liberation of coumarin from the sustained-release tablets follows first-order kinetics. A linear correlation was found between per-cent of drug released in vitro and the area under the concentration-time curve, AUC (O-t), of total 7-hydroxycoumarin (7HC + 7HCG).

Pharmacokinetics of coumarin and its 7-hydroxy-metabolites upon intravenous and peroral administration of coumarin in man.

The pharmacokinetics of coumarin (C) upon i.v. and p.o. administration and its metabolites 7-hydroxy-coumarin (7-HC) and 7-hydroxy-coumarin glucuronide (7-HCG) have been studied. Six healthy volunteers were involved in this investigation. Four of the volunteers participated in a crossover study. Coumarin was administered i.v. and p.o. in dose sizes of 0.25 mg/kg and 0.857 mg/kg, respectively. Coumarin is rapidly absorbed p.o., however the availability to systemic circulation is less than 4%. The rest of the dose appears quantitatively as 7-HC and 7-HCG in systemic circulation suggesting an extensive firstpass effect. Coumarin and 7-HCG are best fitted to an open two-compartment model, whereas 7-HC is best fitted to an open one-compartment model. The biological half-life of both C (0.80 vs. 1.02 h) and 7-HCG (1.47 vs. 1.15 h) was not significantly different for the two routes of administration. The large total clearance of C again suggests a first-pass effect; while that of 7-HCG, which is nearly exclusively eliminated into urine, indicates active tubular secretion of the glucuronide.

Pharmacokinetics of coumarin upon i.v. administration in man.

The disposition pharmacokinetics of coumarin has been studied after i.v. administration in man, and might be described best by an open two-compartment model. Three dose sizes have been studied, 0.125, 0.2 and 0.25 mg/kg. The mean biological half-life was found to be 1.81, 1.45 and 1.49 h, respectively, for the three dose sizes. Coumarin is extensively distributed. The volume of the central compartment apparently comprises the extracellular and intracellular fluid. The study indicates dose-dependent (non-linear) pharmacokinetics with respect to distribution.

Food-choking and drowning deaths prevented by external subdiaphragmatic compression. Physiological basis.

Applying subdiaphragmatic compression has been successful in saving victims of food-choking and drowning by expelling the asphyxiating bolus or aspirated water. Sudden elevation of the diaphragm compresses the lungs, which explosively forces air out through the trachea, ejecting the obstructing object. The flow rate, pressure, and volume of air expelled were determined in 10 subjects and found to be substantial, providing confirmation of the effectiveness of the procedure.