The relevance of therapeutic drug monitoring in plasma and erythrocytes in anti-cancer drug treatment.

Therapeutic drug monitoring generally focuses on the plasma compartment only. Differentiation between the total plasma concentration and the free fraction (plasma water) has been described for a number of limited drugs. Besides the plasma compartment, blood has also a cellular fraction which has by far the largest theoretical surface and volume for drug transport. It is with anti-cancer drugs that major progress has been made in the study of partition between the largest cellular blood compartment, i.e., erythrocytes, and the plasma compartment. The aim of the present review is to detail the progress made in predicting what a drug does in the body, i.e., pharmacodynamics including toxicity and plasma and/or red blood cell concentration monitoring. Furthermore, techniques generally used in anti-cancer drug monitoring are highlighted. Data for complex Bayesian statistical approaches and population kinetics studies are beyond the scope of this review, since this is generally limited to the plasma compartment only.     

Syntheses of Novel Pyridazinomorphinans by Inverse Electron Demand Cycloaddition and their Binding to μ and κ Receptors

A number of novel pyridazinomorphinans have been synthesized by the inverse electron demand Diels-Alder reaction of various 3,6-disubstituted 1,2,4,5-tetrazines with enamines derived from dihydrocodeinone and with codeinone. Reduction of some of the pyridazinomorphinans did not furnish the expected pyrroloepoxymorphinans; in all cases investigated reductive cleavage of the epoxybridge was observed to yield dihydropyridazino- or pyrrolomorphinans. The structures of all new compounds were assigned by the spectral data, that of the cycloadduct of codeinone was additionally verified by X-ray crystallography. Compounds 5a, 8, 11a , and 16 have been evaluated for their affinity at μ and κ opioid receptors in radioligand binding assays. Their ability to inhibit [³H]DAMGO binding at μ and [³H]U 69.593 binding at κ receptors, respectively as compared to codeine has been found to be lower.     

The HemoCue®, a point of care B-hemoglobin photometer, measures hemoglobin concentrations accurately when mixedin vitro with canine plasma and three hemoglobin-based oxygen carriers (HBOC)

PURPOSE: Accuracy of measurement of low hemoglobin concentrations using the HemoCue, a B-hemoglobin photometer (HemoCue AB, Angelholm, Sweden) may exhibit significant variability. Infusion of hemoglobin-based oxygen carriers (HBOC) results in low concentrations of plasma hemoglobin. Our study assessed B-hemoglobin photometer measurement accuracy of three HBOC: (hemoglobin glutamer-200 (bovine; Oxyglobin, Biopure Corp., Cambridge, MA, USA); hemoglobin glutamer-250 (bovine; Hemopure, Biopure Corp, Cambridge, MA, USA), and hemoglobin-raffimer, (human; Hemolink, Hemosol, Inc., Toronto, Ontario, Canada). METHODS: In the laboratory, 45 split canine plasma samples were mixed with hemoglobin glutamer-200 (8.13, 16.25, 32.5 g x L(-1) concentrations), 45 samples were mixed with hemoglobin glutamer-250 (8.13, 16.25, 32.5 g x L(-1) concentrations), 45 with hemoglobin-raffimer (12.5, 25.0, 50.0 g x L(-1) concentrations), and measured. Plasma samples without HBOC served as control. Hemoglobin concentration was determined by a laboratory analyzer (Coulter Corporation, Hiafeah, FL, USA) and B-hemoglobin photometer (HemoCue, Angelholm, Sweden). Two independent technicians performed blinded sample measurements and randomly tested each sample five times. Results were analyzed according to Bland and Altman analysis. RESULTS: B-hemoglobin photometer demonstrated high repeatability for all three HBOCs. Repeatability coefficients were 0.37 g x L(-1) and 0.48 g x L(-1) for hemoglobin glutamer-200, 0.39 g x L(-1) and 0.4 g x L(-1) for hemoglobin glutamer-250 and 1.07 g x L(-1) and 0.85 g x L(-1) for hemoglobin-raffimer. An acceptable agreement was found between the B-hemoglobin photometer and the laboratory analyzer for all three HBOCs tested. CONCLUSION: The B-hemoglobin photometer accurately determined the concentration of three HBOC solutions dissolved in canine plasma.     

The internal anatomy of the median nerve in the region of the elbow.

The internal anatomy of the median nerve in the region of the elbow has been studied by microdissection in 20 cadavers. Gross branching patterns were studied in an additional 14 cadavers. There are four major branches or branch groups: I to pronator teres, II to flexor carpi radialis, flexor digitorum superficialis, and palmaris longus; III to the anterior interosseous nerve; and IV to flexor digitorum superficialis. Three of these could be traced proximally within the main trunk of the median nerve, the average being I-10 cm; III-7.5 cm; IV-2 cm. This information should have clinical applications in repair and grafting of the median nerve near the elbow and in understanding clinical nerve compression sydromes.     

Non-immune therapy of IgA glomerulonephritis

Summary: The involvement of the IgA immune system and complement components in IgA glomerulonephritis (IgAGN) has prompted the use of immunosuppressive drugs in therapy, but none has so far been shown to alter the natural course of the disease. Because most patients with IgAGN present during the chronic phase of their illness, at the time when the initiating immune events may no longer be active, nonimmune therapy which targets the common pathway of progressive renal injury is likely to be more useful. There is increasing evidence that angiotensin-converting enzyme inhibitors (ACEI) reduce proteinuria and renal injury in patients with IgAGN, and this effect may be observed in both normotensive and hypertensive patients. Yet to be determined is whether this effect is specific for ACEI and whatever other effective antihypertensive drugs may achieve a similar result. Fish oil has recently been shown to retard the progression of renal failure in patients with aggressive IgAGN, but a narrow therapeutic window appears to exist for this form of treatment. Antiplatelet agents on their own appear to be ineffective but in combination with anticoagulation (low dose warfarin) have been shown to have an antiproteinuric effect and may preserve renal function in patients with progressive disease. Future directions of non-immune therapy of IgAGN include evaluation of the renoprotective effect of angiotensin II receptor antagonists, free-radical scavengers and antilipid drugs. More work should also be done to identify factors which put the patients at risk of developing progressive disease and which predict therapeutic response, as has been done recently with the identification of the deletion polymorphism of the angiotensin-converting enzyme gene as a marker of progressive disease and therapeutic response to ACEI in patients with IgAGN.