Robert P. Shrewsbury

Antipyrine kinetics following partial blood exchange with Fluosol-DA in the rat

The effects of partial blood exchange with Fluosol‐DA on hepatic microsomal oxidative metabolism have been studied in the rat. Antipyrine clearance (Cl) was used as an in‐vivo measure of the activity of the mixed function oxidase system. Rats were partially exchanged with Fluosol‐DA and dosed with antipyrine at selected time intervals following exchange. No change in antipyrine Cl was observed at 0.5 h, but there was a statistically significant decrease at 24 h and then an increase by more than 50% relative to control at 48 and 72 h. These data indicate that the effects of Fluosol‐DA on hepatic function are time‐dependent and that Fluosol‐DA has the potential both to inhibit and to enhance hepatic metabolism. The possibility of altered hepatic metabolism should be considered when patients transfused with Fluosol‐DA are given drugs primarily metabolized by the mixed function oxidase system.

Development of a computerized drug interaction database (medicomsm) for use in a patient specific environment

Drug Interactions are a clearly defined problem that we as health professionals must deal with on a day-by-day basis. It is by far the area of health care that demands more attention today and tomorrow than was possible in the past. The amount of reference sources and text material of drug interactions is growing at such a rate that it is almost impossible to recall essential information in a reasonable time frame. If the practitioner is to continue with an uninterrupted work flow and still maintain the best possible service for the patient, an immediate and accurate method is needed in the hands of the user … a computerized drug interaction database. The community health care standards would be ultimately raised to a level never before attainable and efficiency would continue with full utilization of professional practice. Combine then, drug interaction data with ancillary benefits such as cost containment, third party accounting, inventory control, and a multitude of other operational functions into a computerized database and the end product results in an enhanced, controlled, professional operation.

Effect of moderate haemodilution with Fluosol-DA or normal saline on low-dose phenytoin and (±)-5-(4-hydroxyphenyl)-5-phenylhydantoin kinetics

Phenytoin kinetics were determined in the rat following moderate (50%) blood exchange with either Fluosol‐DA or normal saline. Rats received an intravenous phenytoin dose (10 mg kg−1) 0ṁ5, 24, 48, or 72 h after exchange and were compared with non‐exchanged controls. Phenytoin t1/2 was not altered by exchange with either fluid. Its Cl and Vd were decreased and AUC increased 24, 48, and 72 h after saline exchange and 24 h after Fluosol‐DA exchange. (±)‐5‐(4‐Hydroxyphenyl)‐5‐phenylhydantoin (HPPH), a major metabolite of phenytoin, showed a decreased t1/2 and VHPPH 24, 48, and 72 h after exchange with either fluid; t1/2 was also reduced 0ṁ5 h after Fluosol‐DA exchange. The decreased Vd and VHPPH may result from changes in cardiac output secondary to haemodilution, or may represent a redistribution in the microcirculation. Fluosol‐DA appears to enhance phenytoin and HPPH metabolism 48 and 72 h after exchange.

Effect of moderate haemodilution with fluosol-DA or normal saline on indocyanine green and (+)-propranolol kinetics

Indocyanine green (ICG) and (+)‐propranolol kinetics were determined in the rat following moderate (50%) blood exchange with either Fluosol‐DA or 0ṁ9% NaCl (saline). Rats received an intravenous ICG dose (5 mg kg−1) before an intravenous dose of (+)‐propranolol (2ṁ5 mg kg−1) 0ṁ5, 24, 48 or 72 h after haemodilution and were compared with non‐exchanged controls. Haemodilution with Fluosol‐DA reduced the ICG elimination rate constant during the first 24 h while a significant reduction was seen 48 h after normal saline exchange. ICG clearances tended to be less than the control value, and were significantly reduced only at 24 h after Fluosol‐DA exchange due to a reduced Varea. (+)‐Propranolol half‐life was significantly increased 48 and 72 h after saline exchange; (+)‐propranolol clearance was only significantly reduced 72 h after Fluosol‐DA exchange. ICG clearance may be reflecting a hypovolaemic change which occurs after haemodilution, which would reduce the hepatic blood flow. However, (+)‐propranolol clearance was not altered, suggesting that the hepatic blood flow is not changed. It is possible that ICG clearance is changed due to alterations in its extraction ratio instead of hepatic blood flow changes.

Effect of moderate haemodilution with fluosol-DA or normal saline on ampicillin kinetics in the rat

The effects of haemodilution with either Fluosol‐DA or normal saline on renal excretion and glomerular filtration have been studied in the rat. Ampicillin clearance and renal creatinine clearance were used as in‐vivo measures of renal excretion and glomerular filtration, respectively. Rats were moderately exchanged with either fluid and evaluated after 0.5, 24, 48, or 72 h. After exchange, ampicillin clearance was higher, but not significantly different, and the apparent volume of distribution was increased significantly in some groups. These changes are consistent with the effects expected when plasma protein binding is reduced by haemodilution. The percent of ampicillin recovered in urine and the renal creatinine clearance were not statistically different in any group. Thus, moderate haemodilution with either fluid did not change renal function compared with unexchanged animals.

Dose‐dependent absorption of disodium etidronate

The gastrointestinal absorption of disodium etidronate (as [14C]disodium etidronate) was investigated in the rat proximal jejunum in‐situ. Studies using various initial concentrations of the drug suggested that etidronate absorption occurred by passive diffusion at initial concentrations below 0.08 M. At initial concentrations above 0.08 M, the rate of absorption was significantly greater than would be expected if passive diffusion was the only mechanism responsible for absorption. Etidronate absorption is not mediated by the carrier mechanism responsible for phosphate ion absorption.

Assessment and recommendations of compounding education in AACP member institutions.

In August 2009, the American Association of Colleges of Pharmacy (AACP) Council of Sections established a Task Force to assess the current status of compounding education at its member institutions and to provide recommendations for future direction. The Task Force conducted a survey in late June 2010 of faculty members enrolled in the AACP Pharmaceutics and Pharmacy Practice sections to gain qualitative information of the current state of compounding education. The survey results were then organized around eight curricular topics for which the Task Force members provided interpretations and recommendations. A final report was sent to the AACP Council of Sections on February 15, 2011. This publication provides the information contained in that final report to the professional community.

The Effect of Varying Percentages of Haemodilution with Fluosol-DA or Normal Saline on Antipyrine Metabolism in the Rat

Abstract— Antipyrine disposition and metabolism in conscious, unrestrained rats after 25 or 50% haemodilution with Fluosol or normal (0.9% NaCl) saline is reported. Rats received an intravenous antipyrine dose (20 mg kg−1) 0.5, 24, 48, or 72 h after haemodilution and its pharmacokinetic parameters have been compared with non‐exchanged control animals. Haemodilution 25% with Fluosol initially depressed antipyrine metabolism for 24 h by decreasing the antipyrine urinary excretion rate constant and the formation rate constants of 4‐hydroxyantipyrine (4‐OH) and 3‐hydroxymethylantipyrine (3‐OHME). Metabolism was then increased for 48 and 72 h with a slight increase in all rate constants. Haemodilution 50% with Fluosol produced a similar pattern but with significant increases in the 3‐OHME formation rate constant found at 48 and 72 h. Haemodilution 25% with saline reduced 4‐OH formation for 48 h. Haemodilution 50% with saline significantly reduced antipyrine urinary excretion at all times. After a significant increase in the 4‐OH and 3‐OHME formation rate constants at 24 h following 50% haemodilution with saline, the rate constants were significantly decreased at 48 and 72 h. Haemodilution 25% with Fluosol significantly reduced the antipyrine Vd at 0.5 and 72 h. After haemodilution 50% with Fluosol, the Vd alternated between values greater and less than control throughout the 72 h. Haemodilution 25 or 50% with saline had little influence on Vd.

Hypolipidaemic activity in rodents of boron analogs of phosphonoacetates and cyanoborane adducts of dialkyl aminomethylphosphonates

Boron analogues of phosphonoacetates proved to be potent hypolipidaemic agents in rodents, lowering both serum cholesterol and triglyceride levels. (C2H5O)3PBH2COOCH3 proved to be the most effective agent in mice, lowering serum cholesterol 46% and serum triglycerides 54% after 16 days. (C2H5O)3PBH2COOH and Na+H+(C2H5O)2(-O)PBH2COO- caused greater than a 40% reduction in lipids. The cyanoborane adducts of aminomethylphosphonates were generally less effective; (C6H5O)2P(O)CH2NH2BH2CN was the most effective, lowering serum cholesterol 32% and serum triglycerides 43% after 16 days. The phosphonoacetates appeared to lower lipid concentrations by several mechanisms. First, they lowered the de novo synthesis of cholesterol and triglycerides in the liver. Second, they accelerated the excretion of lipids into the bile and faeces. Thirdly, they modulated LDL and HDL-cholesterol contents in a manner which suggests they reduced the deposition of lipids in peripheral tissues, and accelerated the movement of cholesterol from tissues (e.g. plaques) to the liver for excretion into the bile.

The Effects of Amine-Carboxyborane Related Derivatives on UMR-106 Bone Metabolism.

The amine-carboxyboranes and related derivatives have been shown to be potent anti-inflammatory and anti-osteoporosis agents. Their action in part appears to be mediated by the modulation of cytokines, e.g. TNFα or IL-1. Previous studies have demonstrated that LPS induced macrophages release of TNFα maximally at 60 to 90 min. and IL-1 from 5 to 8 hr. The amine-carboxyboranes reduced significantly the release of these cytokines but also blocked TNFα high affinity binding to UMR-106 receptor at 90 min. at 10 μM, and IL-1 high affinity binding at 5 hr. at 12.5 μM. In addition, the agents suppressed IL-8 binding to CHO K1 high affinity receptor at 24 hr. at 50 μM and IL-2 binding to HuT-8 receptors at 25 μM at 90 min. and 5 hr. Correlation of metabolic events associated with osteoporosis showed that at 90 min., when TNFα receptor binding was reduced by the agents, calcium uptake into UMR-106 cells was reduced at 10 μM as well as the acid and alkaline phosphatases, and the prostaglandin cyclo-oxygenase activities and adhesion of leukocytes and macrophages to UMR-106 cell monolayers. At 5hr. when the agents reduced IL-1 binding to UMR-106 receptors, calcitonin and 1,25-dihydrovitamin D3 binding was reduced by the agents as was acid and alkaline phosphatase, and 5′-lipoxygenase activities and white blood cell adhesion. At this time calcium uptake and proline incorporation was increased significantly by the agents. At later times e.g. 18-48 hr. calcium uptake was still increased, and NAG activity was inhibited in the presence of the agents. These effects may be related more to the inhibition of other cytokine receptor binding, e.g. IL-8. Thus, many of the observed metabolic effects of amine-carboxyboranes as antiosteoporosis agents can be correlated with their inhibition of cytokine high affinity binding to target cell receptors.