Application of capillary electrophoresis and related techniques to drug metabolism studies

The use of capillary electrophoresis (CE) for the separation of small organic molecules such as pharmaceutical agents and drug/xenobiotic metabolites has become increasingly popular. This has arisen, at least in part, from the complimentary mode of separation afforded by CE when compared to the more mature technique of HPLC. Other qualities of CE include relative ease of method of development, rapid analysis, and low solvent consumption. The recent introduction of a variety of detector systems (including UV diode array, laser-induced fluorescence, conductivity) and the demonstrated coupling of CE to MS have also aided acceptance of this technology. In the present report, we review the role of CE coupled to various detector systems including a mass spectrometer for the characterization of both in vitro and in vivo derived drug metabolite mixtures. Attributes of CE for this application are demonstrated by discussion of metabolism studies of the neuroleptic agent haloperidol. Various aspects of the development and use of CE and CE-MS for the characterization of haloperidol metabolites, including criteria for selection of parameters such as pH, ionic strength, extent of organic modification, and the use of nonaqueous capillary zone electrophoresis are discussed. We also consider potential limitations of CE and CE-MS for drug metabolism research and describe the introduction of membrane preconcentration-CE (mPC-CE) and mPC-CE-MS as a solution that overcomes the rather poor concentration limits of detection of CE methods without compromising the resolution of analytes or separation efficiency of this technique.     

Prophylactic use of factor VIII: an economic evaluation

BACKGROUND: Since the introduction of exogenous factor VIII therapy, several studies have explored the clinical benefits of prophylactic use of factor VIII. Little research, though, has focused on the economic aspects of this regimen. We conducted a cost analysis using data from the Orthopedic Outcomes Study, a prospective, cross-national study of the clinical outcomes associated with different patterns of factor VIII utilization to examine the health care costs incurred and expenditures averted in patients receiving on-demand versus prophylactic use of factor VIII in hemophilia. METHODS AND ANALYSIS: 831 patients with severe hemophilia aged 1 to 31 years, from 19 centers around the world were included in the cost analysis. Patients were categorized into three groups according to the number of weeks during the study years in which they received prophylactic regimens of factor VIII. For each subject, we estimated the costs of hospitalization, surgery, days lost from school or work, and factor VIII utilization. Costs were then stratified by age and by joint score to assess confounding, and a multivariate model developed to determine the relationship between use of factor VIII prophylaxis and total costs, while controlling for potential confounders. RESULTS: Patients who received factor VIII episodically incurred substantially greater disability-related costs (days lost from school or work, days hospitalized due to hemophilia, surgery) than patients who received factor VIII prophylactically for some or all of the study period. For all treatment regimens, most disability-related costs were accounted for by hospitalization for hemophilia-related conditions. The cost of factor VIII itself was substantial in all treatment categories but was highest among patients who received year-round prophylaxis, exceeding the savings resulting from reduced disability and other health care expenditures. CONCLUSIONS: Reductions in non-factor health care costs and disability associated with prophylactic use of factor VIII in hemophilia were substantial and helped somewhat to offset the much higher costs of this regimen. For certain subgroups, frequent episodic treatment may be more expensive than full-time prophylaxis. However, because of the very high cost of year-round prophylactic use of factor VIII, total health care expenditures were highest among patients receiving this therapeutic regimen. However, because prophylaxis clearly offers important clinical benefits, this approach may be warranted on medical rather than economic grounds.     

Determination of antioxidative potential of biological fluids by using semiconductor chemical sensors

A procedure has been developed for determining the concentrations of superoxide anion radical (SOAR) in aprotonic fluids by using semiconductor chemical sensors. SOAR life in pure solutions is 6.3 hours. Supplements of biological fluids (blood, urine, plasma) increase the rate of SOAR death. There is a great difference in the reaction rate of SOAR with biological fluids in apparently healthy and ill individuals. It is suggested that the above procedure opens vistas both for studies of vital activity and for diagnosis of abnormalities.     

Relative stability of alloys

A mathematical function, the relative stability, is defined which combines advantages of Darken's stability and excess stability function. The relative stability is finite over the entire composition range and approaches the value of one in terminal regions. A simple classification is given whether a solution phase is more stable than an ideal solution, less stable or even unstable in terms of values of the relative stability > 1, <1 or <0, respectively. The zero's of this function represent spinodal points. This concept is explained for binary regular solutions and applied to non-simple phases with strong deviations from regular solution behavior, specifically the liquid Cu-O and Cu-S alloys. An extension to ternary systems is given and the direction-dependency of the stabilities is discussed. A quantitative analysis in terms of the relative stability is given for the example of Fe-Cu-Ni alloys.     

Segmental renin sampling and partial nephrectomy in renal hypertension

Selective renin sampling from renal vein tributaries identified a high-renin source in the lower pole of the left kidney in a 16-year-old boy who had gradually developed hypertension after blunt left renal trauma. Localized renin secretion from the ischemic pole was associated with suppression of renin secretion from both the contralateral kidney and the normal part of the affected kidney. Removal of ischemic tissue by partial nephrectomy produced sustained correction of hypertension. The findings indicate that segmental renin sampling can define indications for partial nephrectomy in renal hypertension.     

Immediate microscopic detection of an actinomycete in the soil producing a luminescent antibiotic

The effects of 10-day pretreatment with i.p. injections of zinc chloride, 16 mg/kg, on gastric secretion and on gastric ulceration induced by stress or by acid accumulation were examined in pylorus-occluded rats. Zinc chloride pretreatment significantly reduced the volume of gastric secretion and the total acid output as well as the incidence of gastric ulcers induced either by stress or by acid accumulation. The findings support the idea zinc compounds may be useful in the treatment of gastric ulcers.