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A disadvantage of traditional equilibrium dialysis for highly protein bound drugs is the analytically low drug concentration found on the buffer side. We propose to replace a certain percentage of buffer with plasma containing drug in order to increase the total drug concentration on the buffer side. Computer simulations were performed to examine the effects of the percentage of plasma replacement of the buffer upon the increase of the total drug concentration on the buffer side after equilibrium dialysis. Further simulation results indicated that the development of a concise equation estimating the drug's equilibrium association binding constant (Ka) was feasible. Two high binding drugs, diazepam and nortriptyline, were examined to verify the advantages offered by the new proposed method and their Ka values were computed using the experimental results and the mathematical equation developed. The resulting data agreed well with theoretical predictions.

Methamphetamine is a sympathomimetic drug with CNS, cardiovascular and anorectic effects. We examined the Blood to Plasma (Blood/Plasma) partitioning and plasma protein binding (PB) of d-Methamphetamine (d-MAP), using whole rat blood. The mean Blood/Plasma ratio was around 1.2 and the fraction unbound (fᵤ) was 0.8. Further, we studied the influence of concentration, pH and the presence of 1-MAP on the Blood/Plasma ratio and PB of d-MAP. There was no significant change in the Blood/Plasma ratio and the PB values at different concentrations of d-MAP or in the presence of 1-MAP. There was a slight increase in the Blood/Plasma ratio and a slight but insignificant decrease in fᵤ with pH. The equilibrium binding constants (KA) of d-MAP with human serum albumin and α₁ -acid glycoprotein were also determined and they were found to be 213 and 2461 M⁻¹ respectively.

The purpose of this research was to evaluate the strategy of the military health service (MHS) to improve asthma outcomes through the use of clinical practice guidelines (CPGs). Outcomes were evaluated at the patient level and included inpatient/outpatient visits, prescriptions dispensed, number of exacerbations, number of beddays and direct cost of therapy. In addition, provider compliance to CPG recommendations was evaluated by measuring the proportion of subjects dispensed long-acting controller medications. A nonrandomized control-group before-after design with retrospective matched-pair DoD data was used for this research. The intervention used in this research was the formal asthma CPG-use process implemented by the Army in September of 2000. Compared to baseline measures, all outcomes improved significantly (p < 0.05) in the after period for both the subjects exposed, and not exposed, to the CPG-use process. Other than the improvement noted in the number of asthma exacerbations, which was greater in the exposed group than the non-exposed group (p < 0.001), there was no other difference between groups in the amount that outcomes improved. The proportion of subjects prescribed long-term controller medications increased significantly for subjects exposed to the CPG-use process (0.30 to 0.66, p < 0.001), and for those not exposed to the CPG-use process (0.30 to 0.66, p < 0.001). Although the findings of this research suggested that a formal CPG-use process to standardize asthma therapy was associated with decreased costs, this was not supported by results regarding the clinical outcomes. To further evaluate the effect of asthma CPGs on economic and clinical outcomes, additional research is needed.

Cocaine is a psychomotor stimulant which is widely abused. To understand the behavior of cocaine, the disposition kinetics of the compound were characterized using the rat as an animal model. A sensitive HPLC assay was developed to quantitate cocaine and metabolites (cocaethylene, norcocaine, benzoylecgonine, and benzoyl-norecgonine) in plasma and urine samples. Since ecgonine methyl ester has insufficient UV absorptivity, the quantitation of this compound in blood and urine was performed by a GC/NPD method. The effects of dose and route of administration on the disposition kinetics of cocaine were studied in male Sprague-Dawley rats. The total systemic clearance of cocaine following i.v. and s.c. administration are dose-independent. The clearance of cocaine (CL/F) following i.p. administration is dose-dependent. Cocaine absorption following subcutaneous injection was slow but complete (F = 1.0). The extraction ratio of cocaine in the lung (1-F) is about 0.18. The oral bioavailability of cocaine (F = 0.05) was low compared to i.p. administration (F = 0.35-0.63). Various properties of cocaine in the blood (blood clearance, blood to plasma ratio and plasma protein binding) were characterized using blood from the experimental animals and humans (male and female). Cocaine degradation in blood was dose-independent. In rat, cocaine degradation in blood was slow and due to the non-enzymatic degradation. In humans, cocaine is metabolized by a cholinesterase enzyme and this reaction can be inhibited by NaF. Ethanol had no influence on cocaine degradation either in human or rat blood. Cocaine blood to plasma ratio was dose-independent and was not influenced by NaF and ethanol. Plasma protein binding of cocaine in the rat was independent of concentration but depended upon plasma pH. Gender and time of the menstrual cycle had no influence on cocaine degradation, blood to plasma ratio or plasma protein binding in humans. A simple device has been modified for serial venous blood sampling which permits the simultaneous measurement of locomotor activity in the freely moving rat. The relationship between the locomotor activity following a single short i.v. infusion of cocaine and cocaine plasma concentrations can be adequately described by the Sigmoid-Emax model or by the same model coupled with an effect compartment.