Enantiomeric Resolution of Drug Compounds by Liquid Chromatography

Novel techniques have recently emerged to separate chiral drug compounds into pure enantiomers. The mechanism, experimental difficulties, and applicability of these methods can vary greatly, and the choices involved are not straightforward. The most significant new advances in the field of chiral separations have come from work done with liquid chromatographic systems and chiral stationary-phase columns. This review describes several commonly used approaches to chiral separation, diastereomeric derivatization, chiral mobile-phase additives, and three major types of chiral stationary phases. Although no single method can be judged superior for every drug application, it appears that chiral stationary phases have received the most attention recently and they are emphasized here.     

The Rochester Diabetic Neuropathy Study: design, criteria for types of neuropathy, selection bias, and reproducibility of neuropathic tests

A cross-sectional survey and subsequent longitudinal study among diabetic residents of Rochester, MN--The Rochester Diabetic Neuropathy Study (RDNS)--is population-based and uses quantitative, validated, and unique end points to detect, classify, and stage neuropathy. Nondiabetic persons, drawn from the same population, serve as controls. For patients 10 to 70 years old, the RDNS cohort is representative of diabetics living in Rochester, MN. We assessed reproducibility of tests used to characterize and quantitate severity of neuropathy in 20 diabetic subjects without neuropathy and with varying severities of neuropathy. Using intraclass correlation coefficient (rI) as a measure of test reproducibility, we found high rI (usually 0.9 or better) with small confidence intervals for the Neurologic Disability Score (NDS); weakness subset of NDS (W-NDS); vibratory and cooling detection thresholds (using computer-assisted sensory examination [CASE] IV); compound muscle action potentials; sensory nerve action potentials; and motor nerve conduction velocities. There was good agreement among three trained observers for NDS and the W-NDS.     

De Barsy syndrome: Report of a case,literature review,and elastin gene expression studies of the skin

Several “progeroid” syndromes have now been identified. The De Barsy syndrome is an autosomal recessive syndrome of dwarfism, mental deficiency, an “aged” appearance at birth, abnormal elastic fibers on skin biopsy, and lax skin, large helices, eye abnormalities, lax joints, hypotonia, and athetoid posturing. We report one case and review 11 cases from the literature. To understand the abnormal appearance of the elastic fibers on biopsy, we performed elastin gene expression studies on fibroblasts cultured from our patient's skin. Molecular hybridization studies revealed reduced elastin mRNA steady-state levels as compared with age matched control individuals. Assuming normal rates of mRNA translation, reduced elastin synthesis would occur. Diminished dermal elastin content could explain the altered cutaneous elasticity, decreased elastic fibers in the skin, and many clinical manifestations of individuals with this condition.     

Loss of carbamazepine suspension through nasogastric feeding tubes

The apparent loss of carbamazepine suspension during administration through polyvinyl chloride nasogastric feeding tubes in vitro was studied. Twelve methods of administering carbamazepine suspension (100 mg/5 mL) were tested; the methods differed with respect to nasogastric tube size, presence and type of diluent, and type of flush solution. Undiluted or 50% diluted carbamazepine suspension 200 mg was drawn up in a syringe and forced through adult or pediatric nasogastric feeding tubes. The tubes were immediately flushed twice with 50 mL of sterile water, 0.9% sodium chloride solution, or 5% dextrose solution, by using the same syringe used to administer the suspension. Samples were collected and analyzed for carbamazepine concentration by high-performance liquid chromatography. Each administration method was tested six times, and the results were subjected to analysis of variance. Significant loss of carbamazepine was noted for four of the six methods in which undiluted suspension was administered. In these methods, adult and pediatric tubes were flushed with sterile water or 0.9% sodium chloride. No significant loss of drug occurred for any of the methods involving the use of diluent. Significant losses were associated with diluent and flush solution but not nasogastric tube size. Carbamazepine suspension should be mixed with an equal volume of diluent before being administered through nasogastric feeding tubes.     

Competitive control of the self-renewing T cell repertoire

We develop a mathematical model for the self-renewing part of the T cell repertoire. Assuming that self-renewing T cells have to be stimulated by immunogenic MHC-peptide complexes presented on the surfaces of antigen-presenting cells, we derive a model of T cell growth in which competition for MHC-peptide complexes limits T cell clone sizes and regulates the total number of self-renewing T cells in the animal. We show that for a sufficient diversity and/or degree of cross-reactivity, the total T cell number hardly depends upon the diversity of the T cell repertoire or the diversity of the set of presented peptides. Conversely, for repertoires of lower diversity and/or cross-reactivity, steady-state total T cell numbers may be limited by the diversity of the T cells. This provides a possible explanation for the limited repertoire expansion in some, but not all, mouse T cell re-constitution experiments. We suggest that the competitive interactions described by our model underlie the normal T cells numbers observed in transgenic mice, germ-free mice and various knockout mice.