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Biomedical subjects

R Coleman

Publications and source records attributed to R Coleman.

At least 19 recordsLinked to original sources
PubMed1996

Off-label drug use in human immunodeficiency virus disease.

We wished to determine the extent to which drugs used to treat HIV disease and its clinical manifestations are prescribed for conditions other than those listed on the U.S. Food and Drug Administration's approved drug label, how such "off-label" use varies by patient characteristics and type of HIV-related medical condition, and the extent to which physicians alter the way they treat HIV-related conditions because of reimbursement problems associated with off-label drug use. We surveyed 1,530 primary care providers for people with HIV disease between February and May 1993. A three-part survey instrument was used to obtain data on the drugs prescribed for the last three patients with HIV disease treated by the provider, the preferred choice of therapy for 32 specific HIV-related conditions, and the extent to which providers faced reimbursement problems regarding the use of drugs for off-label indications. Three drug compendia were used as cited sources of off-label drug uses. In all, 387 (32%) evaluable surveys were returned, yielding data on 1,148 patients. The majority (81%) of patients received at least one drug off-label, and almost half (40%) of all reported drug therapy was off-label. Most off-label drug use was for treatment and prevention of HIV-related opportunistic infections, which frequently represented the community standard of practice (e.g., trimethoprim/sulfamethoxazole for prevention of Pneumocystis carinii pneumonia), or the de facto standard of practice when no licensed therapies were available (e.g., drugs for treatment of Mycobacterium avium complex, MAC). More than 75% of off-label usage was cited in at least one of the three authoritative medical compendia. The use of drugs for off-label indications in HIV care is common and frequently represents community standards of care. Reliance on drug compendia for support of off-label drug use accounts for the majority of such uses, although many legitimate off-label uses may not be included because of compendia publication lag. The prevalence of off-label drug use in routine clinical practice and the development of newer and more costly drugs for treatment of HIV and its medical complications argues for the articulation of an explicit national reimbursement policy for off-label uses of prescription drugs so that medically appropriate therapies will be available to those with insurance in a rational, consistent way.

AIDS-Related Opportunistic Infections↗
PubMed1996

S-adenosyl-L-methionine prevents disruption of canalicular function and pericanalicular cytoskeleton integrity caused by cyclosporin A in isolated rat hepatocyte couplets.

Isolated rat hepatocyte couplets were used to study the effect of S-adenosyl-L methionine (SAMe) treatment on disruption of canalicular function caused by cyclosporin A (CyA). Canalicular function was assessed by counting the percentage of couplets that were able to accumulate the fluorescent cholephile choly-lysyl-fluorescein (CLF) into the canalicular vacuole between the two cells, i.e., canalicular vacuole accumulation (CVA). Cotreatment with 1 mmol/L SAMe prevented the inhibition of canalicular vacuole accumulation caused by CyA (75 nmol/L and 100 nmol/L), whereas treatment with it after CyA was unsuccessful. SAMe prevented the dose dependent reduction caused by CyA (5 nmol/L-1 mumol/L) both on CVA and on retention of CLF preaccumulated within the canaliculus, the effect on retention being complete. No difference in intracellular content of reduced glutathione (GSH) between the control and any dose level of the immunosuppressor, with or without SAMe treatment was observed, suggesting that changes in intracellular reduced GSH levels are not involved in the effects of SAMe. F-actin was stained with fluorescein-isothiocyanate phalloidin and fluorescence measurements were performed by confocal microscopy. The ratio of the percanalicular area fluorescence/total couplet fluorescence, indicative of F-actin distribution, significantly decreased with CyA. However, cotreatment of CyA with SAMe protected the integrity of the pericanalicular cytoskeleton, suggesting that this beneficial effect on canalicular function may maintain canalicular contractions and/or preserve tight junction function. Results are discussed in relation to possible involvement of the transmethylation pathway, modifications in membrane fluidity, effects on bile acid transport, and of inhibition of uptake of CyA. They suggest that SAMe could be a good candidate for protecting against CyA-induced membrane dysfunction.

Actins↗
PubMed1996

Comparison of the effects of redox cycling and arylating quinones on hepatobiliary function and glutathione homeostasis in rat hepatocyte couplets.

Menadione (2-methyl-1,4-naphthoquinone, a redox cycling and arylating quinone; 5-100 microM) inhibited the canalicular vacuolar accumulation (CVA) of a fluorescent bile acid, cholyl-lysyl-fluorescein (CLF), in rat hepatocyte couplets. This was associated with depletion of reduced glutathione and accumulation of oxidized glutathione, the latter indicating that the concentrations of menadione used were able to induce oxidative stress. There was no associated cytotoxicity as indicated by ATP content. Treatment of couplets with the redox cycling quinone 2,3-dimethoxy-1,4-naphthoquinone (up to 100 microM) had relatively little effect on CVA, suggesting that the magnitude of reactive oxygen formation induced by this compound was insufficient to disrupt canalicular integrity. In comparison, the arylation of protein thiol groups by p-benzoquinone (up to 100 microM) proved to be more potent in inhibiting canalicular vacuolar accumulation. The predominant mechanism of menadione-induced inhibition of couplet hepatobiliary function is therefore more likely to involve the arylation of critical thiol groups (such as those in the F-actin cytoskeleton) rather than their oxidation. The oxidative effects of menadione could, however, potentiate the deleterious effects induced by arylation, such as by reduced glutathione depletion.

Adenosine Triphosphate↗
PubMed1996

PK 11195 aggravates 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced hepatic porphyria in rats.

There is evidence to suggest that peripheral-type benzodiazepine receptors (PBR) are involved in porphyrin transport during erythroid differentiation, and it is possible that these receptors have an important role in heme biosynthesis. We examined the biochemical and ultrastructural alterations in rat liver following experimentally induced acute hepatic porphyria, as well as the effects of the administration of a selective PBR ligand, PK 11195. The most severe pathological conditions were found in rats that received a combined treatment of the porphyrinogenic agent 3,5-diethoxycarbonyl-1,4- dihydrocollidine (DDC) and PK 11195. Transmission electron microscopy showed a correlation between the ultrastructural pathology of the liver, the total porphyrin levels in urine and liver, and the porphobilinogen levels in urine. Hepatocytes in this acute porphyria showed the development of large secondary lysosomes containing crystalline aggregates of protoporphyrin. Bile canaliculi were grossly enlarged, contained aggregates of protoporphyrin crystals, and showed the presence of bile thrombi. In addition, prominent bundles of collagen fibers (fibrosis) were commonly found in livers of rats that had been treated with DDC or DDC and PK 11195. We conclude that the administration of PK 11195 to porphyric rats aggravates porphyrin accumulation and cellular damage in the liver. Perhaps this evidence suggests that PK 11195 blocks the binding of protoporphyrin IX to PBR, thus elevating the content of protoporphyrin IX in liver.

Animals↗
PubMed1996

Directional-tip endotracheal tubes for blind nasotracheal intubation.

OBJECTIVES: To compare initial success rates of blind nasotracheal intubation using directional-tip endotracheal tubes vs standard endotracheal tubes. METHODS: A prospective trial comparing directional-tip and standard endotracheal tubes during initial attempts at blind nasotracheal intubation (BNTI) at a university hospital ED. Using an alternating schedule, the directional-tip or standard tube was used for the first attempt at BNT1. An attempt was defined as beginning when the tube was placed through the nose into the posterior pharynx and ending when the patient was intubated or the tube was removed from the nares. After the intubation, the physician graded the difficulty of the technique (i.e., easy/routine, intermediate, difficult, or unable to intubate nasally). RESULTS: There were 49 patients entered over 5 months. Patient presentations for the intubations were trauma (45.8%), overdose (33.3%), respiratory/cardiac event (12.5%), seizure (2.1%), and other (6.3%). Intubation was successful on the first attempt in 18 of 21 patients (86%; 95% CI, 64% to 97%) for the directional-tip tube vs 16 of 28 patients (57%; 95% CI, 37% to 76%) for the standard tube (p = 0.03). The groups did not differ in age, sex, clinical presentation, or perceived difficulty of intubation. Only 1 patient could not be intubated nasally and was subsequently intubated orally. CONCLUSION: The use of directional-tip tubes may improve the success rate of the first attempt at BNTI.

Adolescent↗
PubMed1995

Cloning of a new "finger" protein gene (ZNF173) within the class I region of the human MHC.

The human major histocompatability complex contains genes of both immune and nonimmune importance. Recently, several genes encoding novel, non-HLA products have been described in this area. We have performed positional cloning of short fragment cDNA sequences from the class I region of the human MHC using a hybridization selection approach. This report describes isolation of full-length cDNA clones and partial genomic clones that encode a protein that contains two domains rich in cysteine and histidine similar to those characteristic of metal-dependent DNA binding proteins (C3HC4). The predicted protein also contains a domain thought to form a coiled-coil that may promote dimerization. A third feature is a polyglutamic acid region near the carboxyl terminus of the conceptual protein. Because of these properties, we have named this gene product acid finger protein (AFP). Although the biological role of AFP is unknown at present, one potential function is binding of nucleic acids. The gene (ZNF173) is expressed in multiple tissues and is conserved among mammals. In particular, the mouse and human coding regions are highly conserved. In addition to AFP, other related sequences have been localized to the MHC, suggesting that multiple AFP-like genes exist in this area.

Amino Acid Sequence↗
PubMed1995

Fractionation of livers following diosgenin treatment to elevate biliary cholesterol.

The plant saponin, diosgenin, is known to induce a marked increase in biliary cholesterol/phospholipid ratio. We reasoned that putative biliary lipid supply vesicles might be similarly enriched with cholesterol. Seven-day diosgenin feeding to rats resulted in significantly increased biliary cholesterol and cholesterol/phospholipid ratio, but had no effect on total cholesterol or phospholipid content of the liver. Subcellular fractionation of livers showed no selective increase in any fraction (nuclear, mitochondrial, lysosomal, microsomal) of the homogenate. Further subfractionation of microsomal or nuclear (plasma membrane) fractions also showed no difference between control and diosgenin groups. Thus, no intracellular vesicle fraction has been identified with the provision of the enhanced biliary cholesterol and the results are discussed in terms of the possible involvement of cytosolic lipid-binding proteins as putative lipid carriers to the canalicular membrane as an alternative to the presence of the lipid in lipid supply vesicles.

Animals↗
PubMed1995

Reducing the levels of formaldehyde exposure in gross anatomy laboratories.

BACKGROUND: A method is described in which formaldehyde levels are greatly reduced in our gross anatomy laboratory in order to comply with increasingly severe safety and health regulations. METHODS: A novel type of dissection "bed" has been introduced which incorporates an internal motor that causes a downflow of formaldehyde-rich vapors, which are absorbed by a replaceable active carbon filtration system. RESULTS: Use of the new dissection "beds" has resulted in the recirculated air being virtually formaldehyde-free. Formaldehyde vapor levels in our gross anatomy laboratory have been greatly reduced and are typically in the range of 0.03-0.09 ppm. CONCLUSIONS: The new system allows us to comply with safety and health regulations and provide a dissection room with an excellent working environment.

Air Pollution, Indoor↗
PubMed1995

Hepatobiliary function and toxicity in vitro using isolated hepatocyte couplets.

1. Hepatocyte couplets can be routinely prepared from rat liver to produce a suitable in vitro model for polarized primary cells. 2. Centrifugal elutriation provides a means of producing enriched subpopulations of periportal and perivenous couplets from the same liver, thus providing a means of studying the influence of zonal heterogeneity on hepatobiliary function. 3. The maintenance of structural and secretory polarity demonstrated by hepatocyte couplets provides a convenient in vitro system for mechanistic studies of factors both regulatory and adversely affecting hepatobiliary functions. 4. Couplets are also uniquely appropriate for specific studies of regulation at the biliary pole, on the performance of junctions and on the maintenance and rate of transcytotic movement. 5. The possibility also exists that effects of an in vivo pre-exposure to agents causing hepatobiliary dysfunction can be assessed in couplets ex vivo.

Animals↗
PubMed1995

Depletion of total salivary gland protein in blood-fed Anopheles mosquitoes.

Reduction in total salivary gland protein from four anopheline vectors of human malaria, Anopheles stephensi Liston, An. albimanus Wiedmann, An. gambiae Giles, and An. freeborni Aitken, was quantified after mosquitoes blood-fed to repletion on human volunteers, hamsters or through a Baudruche artificial membrane. Total salivary gland protein from pools of six unfed mosquitoes ranged from 4.33 to 7.91 micrograms/ml. The difference between the total protein of glands from unfed and blood-fed mosquitoes for all species ranged from 1.77 to 3.12 (micrograms/ml for six pooled salivary glands. Total salivary gland protein for mosquitoes blood-fed to repletion was significantly less than that of unfed controls from the same cohort. Reduction in total salivary gland protein for An. freeborni and An stephensi blood fed to repletion on human volunteers, hamsters, and a Baudruche membrane ranged from 24 to 46%, from 43 to 56%, and from 24 to 51%, respectively. An. stephensi mosquitoes were allowed to blood feed on humans for 0 (unfed), 0.5-, 1.0-, 2.0-min time periods or to repletion (> 2-5 min). As feeding time increased, there was a significant decrease in total amount of protein in the salivary glands. This decrease was proportional over time, indicating that salivation occurred continuously from the beginning (probing) of blood feeding to withdrawal of the mosquito mouthparts at repletion. These data indicate that during blood feeding there difference between species in the salivary gland output measured as amount of protein depleted from the salivary glands and that depletion of salivary protein from the glands occurred continuously as mosquitoes fed to repletion.

Animals↗
PubMed1995

Ultrastructural changes in mitochondria of the adrenal cortex of iron-deficient rats.

Male Sprague-Dawley rats aged 3 weeks that were maintained on an iron-deficient diet for 4-5 weeks developed severe anemia with markedly reduced hemoglobin levels (4.11 +/- 0.20 Hb g% versus controls 12.74 +/- 0.15 Hb g%). On sacrifice, the adrenal glands were removed and processed for light and transmission electron microscopy and enzyme cytochemistry. The major histological and ultrastructural changes in the adrenal cortex in response to the iron deficiency were seen in cells of the zona fasciculata, especially in its outer region, and to a lesser degree in cells of the zona reticularis. Structural changes were seen in the mitochondria of these cells, which often became grossly enlarged and developed unusual electron-dense inclusions. In addition, the lipid droplets in the iron-deficient cells of these regions were much less developed and less prominent compared with controls. Quantitative cytochemical localization of succinic dehydrogenase (SDH) activity in the adrenal glands showed that in iron-deficient rats there was an increase in SDH activity in the zona fasciculata (46%) and in the zona reticularis (74%), whereas there was a reduction of approximately 41% in SDH activity in the zona glomerulosa. Serum corticosterone levels were significantly raised in the iron-deficient rats compared with the control rats. Our results indicate that severe nutritional iron deficiency in rats causes ultrastructural and cytochemical changes in the mitochondria of the adrenal cortex accompanied by increased secretion of corticosterone.

Adrenal Cortex↗
PubMed1994

Disruption of canalicular function in isolated rat hepatocyte couplets caused by cyclosporin A.

Isolated rat hepatocyte couplets were used to study the effects of different concentrations of cyclosporin A in relation to canalicular function. Canalicular function was assessed by counting the percentage of couplets which were able to accumulate the fluorescent cholephile cholyl lysyl fluorescein (CLF) into the canalicular vacuole between the two cells, i.e. canalicular vacuole accumulation (CVA). At lower doses, the immunosuppressor increased the CVA, reaching 121 +/- 3.86% of control at 25 nM cyclosporin A. However, higher doses of cyclosporin A induced a concentration-dependent inhibition of CVA to 64.0 +/- 3.51% of control at 100 nM. Modifications in canalicular area (as % couplet area) were also observed. Image analysis of the fluorescent image showed that cyclosporin A (25 nM) increased canalicular area by 25% (of control); however, this parameter decreased to 36% of control at 100 nM cyclosporin A. In addition, at 100 nM, cyclosporin A reduced the proportion of couplets retaining CLF within the canaliculus to 75.0 +/- 6.59% of control. Treatment of couplets with cyclosporin A (0-2 microM) for 15 min revealed that reduced glutathione (GSH) intracellular content does not change significantly at these doses. However, alteration in pericanalicular F-actin at 100 nM cyclosporin A may be an important factor in the disruption of the canalicular function induced by higher doses of the immunosuppressor.

Actins↗