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C A Marra

Publications and source records attributed to C A Marra.

At least 37 records · Page 2Linked to original sources
PubMed1998

Cost-effectiveness analysis of abciximab: a Canadian hospital perspective.

OBJECTIVE: To assess the cost-effectiveness of abciximab therapy versus traditional practice in high-risk patients receiving percutaneous transluminal coronary angioplasty (PTCA) from a Canadian hospital perspective. DESIGN: A predictive decision analytic model using published clinical and economic evaluations, as well as costs of medical care in Canada. SUBJECTS: High-risk PTCA patients as defined by the Evaluation of c7E3 for Prevention of Ischemic Complications trial and the c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina trial. INTERVENTIONS: Two treatment strategies were compared: (1) abciximab 0.25 mg/kg intravenous bolus 10 minutes prior to PTCA followed by abciximab 10 micrograms/min intravenous infusion for 12 hours after the procedure, and (2) no abciximab adjunctive therapy at the time of PTCA. Both treatment strategies were combined with intravenous heparin up to 100 units/kg bolus pre-PTCA followed by bolus doses for 1 hour after PTCA per the protocol. Cumulative outcomes were considered up to 6 months after initial PTCA. RESULTS: At 6 months, 29% of the patients in the abciximab treatment arm compared with 33% in the no abciximab arm achieved one of the primary events. The most common adverse event experienced was major bleeding at 4% in the abciximab treatment arm versus 1.6% in the no abciximab arm. The average cost per patient for each strategy was $3261 Can ($1 Can = $0.686 US) (abciximab arm) versus $2073 Can (no abciximab arm), resulting in an incremental cost-effectiveness ratio of $29,700 Can per event-free patient. In univariate sensitivity analyses, the only controllable factor that changed the results of the cost-effectiveness outcome was the cost of abciximab. CONCLUSIONS: Although the use of abciximab as an adjunct to PTCA results in a reduction in event rates in high-risk patients compared with traditional treatment, there is an increased cost associated with this strategy.

Abciximab↗
PubMed1998

Chlamydia trachomatis in adolescents and adults. Clinical and economic implications.

The aim of this article is to provide an overview of the epidemiology, diagnosis, screening and pharmacotherapy of Chlamydia trachomatis infections in adolescents and adults, together with a critical review of economic studies published on this topic. C. trachomatis continues to produce enormous social and economic consequences despite advances in prevention, screening and treatment. Both infected men and women are at risk of developing sequelae, although women tend to have more serious complications. Several strategies are available for diagnosis and screening. In populations with a high prevalence of disease, DNA-amplification assays may be the most cost-effective approach for diagnosis and screening. Empirical treatment of all patients is also cost effective; however, it may not be feasible for all health systems. A single dose of azithromycin is the most cost-effective antimicrobial agent for treatment of C. trachomatis infection.

Adolescent↗
PubMed1998

Hormonal-induced changes on the lipid composition and DPH fluorescence anisotropy of erythrocyte ghost from pre- and postmenopausal women.

Fluorescence anisotropy determinations were performed on hypotonically lysed red blood cells from 12 healthy, free living, premenopausal and 10 postmenopausal women fed a self-selected diet. Fatty acid composition of phospholipids and cholesterol esters, lipid/lipid and lipid/protein ratios were also determined in erythrocyte ghosts along the menstrual cycle or during hormonal replacement therapy. The postmenopausal women were treated with transdermal 17-beta estradiol (approx, delivery rate of 50 micrograms/day) for a 5-week period and with a combination of percutaneous administration of estradiol and orally administered medroxyprogesterone acetate (5 mg/day) for 5 weeks more. Premenopausal women were studied in the mid-follicular and mid-luteal phases of their menstrual cycles. Membrane fluidity in cells from the luteal phase was greater than that observed in the follicular phase. After estradiol treatment, postmenopausal women exhibited a significant raise in the fluorescence anisotropy. The association with progesterone prevented the estrogen-induced increase of the anisotropy values. Estrogen administration also produced an increment in the relative content of cholesterol and membrane proteins that was reverted by progesterone addition. Changes induced by estradiol treatment in the fatty acid pattern of phospholipids and cholesterol esters were characterized by an increment in the monoenoic/saturated fatty acid ratio and linoleic relative content, with a concomitant decrease in the proportion of arachidonic and docosatetraenoic acids. These results suggest that the modification of the desaturase activities may be involved in a mechanism by which these hormonal-induced changes take place. The present study demonstrated that human erythrocyte fluidity is under hormonal control subjected through changes in the proportion and quality of the membrane lipids.

Adult↗
PubMed1995

Regulatory effect of various steroid hormones on the incorporation and metabolism of [14C]stearate in rat hepatoma cells in culture.

We have examined the incorporation and metabolism of [14C] stearic acid within the total lipids of HTC rat-hepatoma cells in suspension culture in presence and in absence of steroidal hormone stimulation. Both, glucocorticoids (dexamethasone, cortisol and corticosterone) and mineralocorticoids (deoxycorticosterone and aldosterone) as well as the estrogen beta-estradiol and the androgen testosterone enhanced the extent of delta 9 desaturation to oleic acid of the saturated precursors, whereas only the two mineralocorticoids affected the incorporation rate of the exogenous acid into total cellular lipids, thus promoting a little stimulation. Furthermore, all the hormones tested increased the radiolabelling of the total cellular phospholipids except deoxycorticosterone and testosterone, the former having no effect and the latter exerting a moderate inhibition. On the other hand, the incorporation of 14C into neutral lipids was stimulated by testosterone, in contrast to the inhibition of this parameter observed exclusively with either the mineralocorticoids or the estrogen. Within the phospholipid subclasses, the radiolabelling of phosphatidylcholine was augmented by means of all the steroids tested save deoxycorticosterone and testosterone, whereas phosphatidylethanolamine exhibited a decrease only in the presence of testosterone. In a similar fashion, within the neutral lipids, the predominating triglyceride fraction was preferentially labelled--at the expense of other subclasses of lesser abundance--upon treatment with the steroids except aldosterone, which exerted no effect. The results obtained were correlated with those changes observed in the mass distribution of the different lipid subclasses either with or without prior hormonal stimulation.

Animals↗
PubMed1994

Role of delta 9 desaturase activity in the maintenance of high levels of monoenoic fatty acids in hepatoma cultured cells.

The incorporation and delta 9 desaturation of exogenous [14C]stearic acid were studied in HTC 7288c cells in suspension. We examined the uptake of the acid over a wide range of concentrations (0-160 microM) after incubating the cells for 6 h in a chemically-defined medium. Under this experimental condition, the uptake of the labeled acid was more extensive than that obtained from static cultures or from monolayer of isolated hepatocytes of rats. At an external concentration of 160 microM ca. 52 nmoles of acid per mg of cellular protein was taken up. The production of oleic acid from [14C]stearate (delta 9 desaturation) correlated well with the uptake curve between 0-80 microM concentration. For higher stearate concentrations, the biosynthesis of oleic acid declined substantially and a plateau of 22 nmoles/mg cellular protein was reached. The incorporation and desaturation of an initial exogeneous concentration of [14C]stearic acid (80 microM) was also studied from 0-6 h. The results obtained demonstrated that the uptake of the substrate into cellular lipids was fast and non saturable. Quantitative gas-liquid chromatography of total cellular lipids under the different experimental conditions demonstrated a negative correlation between the decrease in the palmitic and palmitoleic acids and the increase in the intracellular levels of stearic and oleic acids. These analytical modifications took place with no changes in the saturated/monoenoic fatty acid ratio. This work also demonstrated a significant contribution of the stearoyl-CoA desaturase system to the high levels of oleic acid present in this kind of hepatoma cells.

Carcinoma, Hepatocellular↗
PubMed1992

Incorporation and metabolic conversion of saturated and unsaturated fatty acids in SK-Hep1 human hepatoma cells in culture.

We report here a study of the incorporation and metabolism of various long chain fatty acids in SK-Hep-1 cultured hepatoma cells. Medium supplementation with radiolabelled palmitic, stearic, linoleic, alpha-linolenic and eicosa-8,11,14-trienoic acids (1 microM, 24 H) resulted in an active uptake of each of these precursors by the cultures. Subsequent analysis of the cellular lipids indicated that they exhibit almost all the enzymic activities of polyunsaturated fatty acid metabolism that are characteristic of normal hepatic cells. With respect to the desaturation capacities of this cell line, although alpha-linolenic acid reacted more extensively than did linoleic acid and the conversion of 8,11,14-eicosatrienoic acid by the delta 5 specific enzyme was more avid than had been previously seen in normal rat or human liver: the saturated fatty acids constituted relatively poor substrates, being preferentially chain-elongated rather than (mono) desaturated at the delta 9 position. Analysis of the fatty acid profiles of total cellular lipids and of various lipid subclasses, however, revealed a relative paucity of essential fatty acids when compared with the abundance of endogenous monoenoic acids (particularly oleic). Of the total cellular fatty acids, 58% were present in the form of phospholipids; with 33% of the remaining 42% (i.e., the neutral lipids) being associated with triacylglycerol fraction. Within the total lipids, phosphatidyl-choline and phosphatidyl-ethanolamine were the major sites for the incorporation of all metabolic products derived from the incubated radiolabelled 16- and 18-carbon fatty acid precursors, whereas the phosphatidyl-inositol fraction was the predominant recipient of nascent arachidonic acid when the eicosatrienoate was the substrate. The express purpose of this investigation was to characterize the biochemical routes involved in the anabolism of various essential fatty acids in the human hepatocyte, through the use of cultured human hepatoma cells as an experimental model system. In view of the similarities between certain aspects of the polyunsaturated fatty acid metabolism of these cells and the corresponding properties of other mammalian hepatic or liver-derived tissues, the data presented here would thus constitute a significant beginning alone those lines. Moreover, considering the extreme difficulty in obtaining for such investigation relevant tissue samples from normal human sources, we regard these results- and the availability for use of this particular human hepatoma cell line-as important new developments in the effort to characterize a useful experimental model both for gaining immediate information and for designing future experiments.

Adenocarcinoma↗
PubMed1992

Glucocorticoid and mineralocorticoid hormones depress liver delta 5 desaturase activity through different mechanisms.

The effects of 11-deoxycorticosterone and aldosterone on liver delta 5 desaturase activity were examined. Both steroid hormones significantly depressed the conversion of [1-14C] eicosatrienoic acid to arachidonic acid. However, the mechanism of action of each of these hormones was different. The effect of 11-deoxycorticosterone was mediated by a soluble protein present in the liver cytosolic fraction. The biological activity of this protein, having a molecular weight lower than 25 kDa, was impaired by trypsin digestion. To determine whether the inhibitory protein was induced through glucocorticoid or mineralocorticoid receptor occupancy, cultured Morris minimal deviation hepatoma cells were pre-treated with the antiglucocorticoid cortexolone or the mineralocorticoid receptor antagonist spironolactone. The results obtained demonstrated that only glucocorticoid receptor structures were involved in the induction of this regulatory protein. The inhibitory response evoked by aldosterone was mediated by a different mechanism. In the case of aldosterone, the inhibitory action affected the microsomal membranes and was not mediated by a soluble protein messenger.

8,11,14-Eicosatrienoic Acid↗
PubMed1991

Inhibition of arachidonate biosynthesis in hepatoma tissue culture cells by 11-deoxycorticosterone-induced factor.

In this work it was demonstrated that the incubation of hepatoma cultured cells (HTC 7288 c) with 11-deoxycorticosterone (DOC) ranging from 0 to 10(-4) M concentration provoked a dose-dependent inhibition in the conversion of [1-14C] eicosatrienoic acid to arachidonic acid. This steroid also produced an increase in the uptake of exogenous 20:3 (n-6) acid. The depressive effect evoked by DOC on delta 5 desaturating activity was reflected on the fatty acid composition changes of the hepatoma cells. The delta 5 desaturase activity was inhibited by a soluble factor that would be induced by the hormone and that was present in the cytosol fraction from DOC-treated cells, corresponding to a low molecular mass below 25 kDa. Presently we report that an 11-beta-OH group on the steroid molecule is not an essential requirement for the production of a delta 5 desaturase inhibitory factor.

8,11,14-Eicosatrienoic Acid↗
PubMed1991

11-deoxycorticosterone, an inducer of a factor stimulating delta 9 desaturase activity in liver microsomes.

The effect of 11-deoxycorticosterone on the oxidative desaturation of [14C]palmitic to palmitoleic acid by liver microsomes was studied in the rat. Twenty-four hours after the hormone injection (1 mumol/kg rat) a significant increase in delta 9 desaturase activity was observed in crude microsomes. A similar stimulation was produced in washed microsomes by addition of a factor present in the 110,000 x g supernatant soluble fraction obtained after extracting crude microsomes from deoxycorticosterone-treated rats with a low ionic strength solution. The deoxycorticosterone-induced factor was also present in the cytosol fraction (110,000 x g supernatant) obtained from livers of hormone-treated animals. Since 11-deoxycorticosterone does not have an 11-beta-OH function, this study demonstrates that such a hydroxyl group is not an absolute requirement for the induction of the soluble factor that regulates delta 9 desaturase activity in response to steroid hormones.

Animals↗
PubMed1990

Mineralocorticoids modify rat liver delta 6 desaturase activity and other parameters of lipid metabolism.

The changes in linoleyl-CoA desaturase activity of rat liver microsomes were studied after a single intraperitoneal injection of 11-deoxycorticosterone or aldosterone at physiological doses. Fatty acid of plasma and different liver fractions, and physical properties of microsomal membranes were also investigated. It was found that the specific activity of delta 6 desaturase decreased 4-fold 24 hr after the injection of aldosterone or deoxycorticosterone. Pretreatment of the rats with aldosterone led to a significant decrease in the percent distribution of palmitic, arachidonic, docosapentaenoic and docosahexenoic acids, with a concomitant increase in palmitoleic, oleic and linoleic acids in plasma and liver homogenates, microsomes and cytosol fractions. A similar pattern was observed after deoxycorticosterone administration. The changes resulted in a decreased unsaturation index of all fractions studied and were well-correlated with the increase observed in fluorescence depolarization of the hydrophobic probe 1,6-diphenylhexatriene in liver microsomal membranes. The interlipid and lipid/protein ratios in microsomes remained constant after hormonal treatment. These results are consistent with the idea that the inhibition of delta 6 desaturase activity and the alterations in fatty acid composition induced by mineralocorticoids, are solely responsible for the measured decrease in liver microsomal membrane fluidity.

Aldosterone↗
PubMed1989

Influence of testosterone administration on the biosynthesis of unsaturated fatty acids in male and female rats.

The in vivo effect of testosterone administration to male or female rats on the biosynthesis of unsaturated fatty acids of liver was studied. Twenty-four hours after injection of testosterone (260 micrograms/kg), delta 9 desaturase activity increased significantly, whereas the activities of delta 5 and delta 6 desaturases were strongly depressed. These effects were more pronounced in female than in male animals. The fatty acid composition of plasma and liver (homogenates, crude microsomes and cytosol) showed differences between the sexes. In males, the percentage of palmitic acid and the 18:1/18:0 ratio were higher whereas the 20:4(n-6)/18:2(n-6) ratio was lower than in female rats. The administration of testosterone significantly modified the fatty acid pattern in all fractions studied. Analytical data correlated with alterations in the fatty acid desaturase activities caused by the hormone. It is suggested that the mechanism by which testosterone exerts its effect on unsaturated fatty acid biosynthesis is different that that previously demonstrated by glucocorticoid action. The effects produced by testosterone may be of biological significance in atherosclerosis pathogenesis.

Animals↗
PubMed1988

A dexamethasone-induced protein stimulates delta 9-desaturase activity in rat liver microsomes.

The effect of dexamethasone on the oxidative desaturation of [1-14C]palmitic to palmitoleic acid on rat liver microsomes, was studied. After 12 h of dexamethasone injection (1 mg/rat) a significant increase in delta 9-desaturase activity, was observed. This effect was also produced by a factor present in a 110,000 X g supernatant soluble fraction obtained after washing crude microsomes from dexamethasone-treated rats with a low ionic strength solution. The dexamethasone-induced factor was present not only in the liver cytosolic fraction of treated animals but also in the cytosol of isolated HTC cells previously incubated with the hormone. Dexamethasone would act via a newly synthesized modulatory factor. The effect depends on an unchanged protein structure, since its biological activity is impaired by trypsin digestion.

Animals↗
PubMed1988

Effect of various steroids on the biosynthesis of arachidonic acid in isolated hepatocytes and HTC cells.

The effect of various steroids on the incorporation and desaturation of eicosa-8,11,14-trienoic acid in normal hepatocytes and HTC cells was investigated. After 3 hr incubation with 11-deoxycorticosterone, both kinds of cells showed an increase in the incorporation of eicosatrienoic acid. In contrast, progesterone, cortexolone, 17-beta-estradiol, testosterone, estriol, aldosterone, corticosterone, dexamethasone, dehydroepiandrosterone, 11-beta-hydroxyandrosterone, 11-ketoaetiocholanolone, epiaetiocholanolone and 5-beta-pregnane-3 alpha,20 alpha-diol, provoked no significant changes in the uptake of the exogenous acid. Of all the steroids tested, only 11-deoxycorticosterone, dexamethasone and 17-beta-estradiol evoked a significant inhibition on the arachidonate biosynthesis in both kinds of cells. Testosterone, estriol, aldosterone and corticosterone provoked a significant inhibition of delta 5-desaturase in HTC cells. In dexamethasone, this effect was dose-dependent (0 to 10(-4) M). Simultaneous incubation with 17-beta-estradiol or 11-deoxycorticosterone with dexamethasone led to an extent of inhibition on arachidonate biosynthesis that did not surpass the effect of each drug. Pretreatment of isolated hepatocytes with the antiglucocorticoid, cortexolone, prevented the dexamethasone-induced inhibition of arachidonate biosynthesis. Normal rat liver microsomes preincubated in vitro with dexamethasone, 11-deoxycorticosterone, 17-beta-estradiol, corticosterone or estriol (10(-6) or 10(-4) M concentration), showed no significant changes in the delta 5-desaturase activity. The results obtained suggest that the effect of the steroids on arachidonic acid biosynthesis in normal hepatocytes and HTC cells requires receptor occupancy and probably is mediated through a common biochemical mechanism.

8,11,14-Eicosatrienoic Acid↗
PubMed1987

ACTH depresses delta 6 and delta 5 desaturation activity in rat adrenal gland and liver.

The in vivo and in vitro effect of ACTH on the biosynthesis of polyunsaturated fatty acid of rat adrenal gland and liver was studied. The administration of ACTH to intact rats produced a significant decrease in the conversion of [1-14C]linoleic acid to gamma-linolenic acid, [1-14C]alpha-linolenic acid to octadeca-6,9,12,15-tetraenoic acid, and [1-14C]eicosa-8,11,14-trienoic acid to arachidonic acid in liver and adrenal microsomes. Isolated adrenocortical cells and hepatocytes obtained from animals treated with ACTH showed a decrease in the incorporation and desaturation of exogenous [1-14C]eicosa-8,11,14-trienoic acid. The addition of ACTH to the incubation medium of adrenocortical cells and hepatocytes isolated from untreated rats also caused a decrease in delta 5 desaturation activity. The effect of ACTH on adrenal and liver desaturases could be produced as a consequence of the release of glucocorticoids, already measured in the experiments. However, the in vitro experiments carried out with hepatocytes isolated from untreated rats, where corticosterone was absent, indicated that ACTH can depress delta 5 desaturation per se.

8,11,14-Eicosatrienoic Acid↗
PubMed1986

Modulation of delta 6 and delta 5 rat liver microsomal desaturase activities by dexamethasone-induced factor.

This report supports evidence for the existence of a dexamethasone-induced factor that modulates fatty acid desaturase activities. Dexamethasone at a dose of 1 mg/rat produced a significant decrease in microsomal delta 6 and delta 5 desaturation activity 12 h after the injection. Both desaturase activities were depressed by a soluble factor present in the cytosolic fraction of cells, since the supernatant of microsomes separated at 110,000 X g from hormonal-treated rat liver homogenates, added to crude or washed control microsomes, was able to inhibit in vitro linoleic and homo-gamma-linolenic conversion to gamma-linolenic and arachidonic acids, respectively. The inhibitory factor was loosely bound to microsomes, since it was also present in a soluble fraction obtained after washing crude microsomes from dexamethasone-treated rats with a low-ionic-strength solution. Besides, trypsin digestion deactivates the dexamethasone-induced factor. Therefore, the depressing effect of glucocorticoids on delta 6 and delta 5 desaturation capacity depends on an unchanged protein structure present in the cytosolic fraction of the cell and whose biosynthesis is brought about by hormonal induction.

Animals↗