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PubMed2004

[Study on effect of dexamethasone on the expression of matrix metalloproteinase and its tissue inhibitors in hyperoxia-induced lung injury].

OBJECTIVE: To observe the effect of dexamethasone on the mRNA expression of matrix metalloproteinase (MMPs) and tissue inhibitor of metalloproteinase (TIMPs) in the lung tissue and to explore the protective mechanism of dexamethasone in hyperoxia-induced lung injury. METHODS: Thirty-two two-week old Wistar rats were randomly divided into atmospheric-air group (n=16) and hyperoxia group (n=16). After 7 days of continuous exposure to high concentration O (2)(>95%), the lung wet/dry(W/D) ratio, the protein content in bronchoalveolar lavage fluid(BALF) and histopathological changes of the lung were measured in 16 rats(8 in each group). The lung tissue specimens of the other 16 rats were cultured, 8 among which served as atmospheric-air control group, the remainder in the hyperoxia group were divided into hyperoxia control group,hyperoxia+dexamethasone (1 x 10(-8) mol/L) group, hyperoxia+dexamethasone (1 x 10(-6) mol/L) group, and hyperoxia+dexamethasone (1 x 10(-4) mol/L) group. Eight samples were examined in each group. After cultured for 24 hours, the lung tissue were collected and its mRNA expression of MMP-2, MMP-9, TIMP-1 and TIMP-2 were determined by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: 1. Pulmonary edema, hemorrhage and extensive inflammatory cells infiltration were observed in hyperoxia group, but no such changes were found in the atmospheric-air group. The lung W/D and the protein content in BALF in hyperoxia group were significantly higher than those in atmospheric air groups. 2. The mRNA expressions of MMP-2, MMP-9, TIMP-1, TIMP-2 and the ratio of MMP-2/TIMP-2, MMP-9/TIMP-1 were significantly higher in the hyperoxic group than those in the atmospheric-air group. 3. Dexamethasone could down-regulate the mRNA expressions of MMP-2 and MMP-9 in a concentration dependent manner. The mRNA expressions of TIMP-1, TIMP-2 also could be reduced by dexamethasone. Decreasing ratios of MMP-2/TIMP-2 and MMP-9/TIMP-1 were found in correlation with increasing concentration of dexamethasone. CONCLUSION: Dexamethasone can reduce the mRNA expressions of MMPs as well as regulate the balance of MMPs/TIMPs, which may be one of the mechanism of its protective effect on hyperoxia-induced lung injury.

Animals↗
PubMed2006

Screening for glutamate-induced and dexamethasone-downregulated epilepsy-related genes in rats by mRNA differential display.

BACKGROUND: It is known that excessive release of glutamate can induce excitotoxicity in neurons and lead to seizure. Dexamethasone has anti-seizure function. The aim of this study was to investigate glutamate-dexamethasone interaction in the pathogenesis of epilepsy, identify differentially expressed genes in the hippocampus of glutamate-induced epileptic rats by mRNA differential display, and observe the effects of dexamethasone on these genes expression. METHODS: Seizure models were established by injecting 5 microl (250 microg/microl) monosodium glutamate (MSG) into the lateral cerebral ventricle in rats. Dexamethasone (5 mg/kg) was injected intraperitoneally at 30 minutes after MSG inducing convulsion. The rats' behavior and electroencephalogram (EEG) were then recorded for 1 hour. The effects of dexamethasone on gene expression were observed in MSG-induced epileptic rats at 1 hour and 6 hours after the onset of seizure by mRNA differential display. The differentially expressed genes were confirmed by Dot blot. RESULTS: EEG and behaviors showed that MSG did induce seizure, and dexamethasone could clearly alleviate the symptom. mRNA differential display showed that MSG increased the expression of some genes in epileptic rats and dexamethasone could downregulate their expression. From more than 10 differentially expressed cDNA fragments, we identified a 226 bp cDNA fragment that was expressed higher in the hippocampus of epileptic rats than that in the control group. Its expression was reduced after the administration of dexamethasone. Sequence analysis and protein alignment showed that the predicted amino acid sequence of this cDNA fragment kept 43% identity to agmatinase, a member of the ureohydrolase superfamily. CONCLUSIONS: The results of the current study suggest that the product of the 226 bp cDNA has a function similar to agmatinase. Dexamethasone might relax alleviate seizure by inhibiting expression of the gene.

Animals↗
PubMed1991

Dexamethasone reduces endotoxin-induced tumor necrosis factor activity production in vitro by equine peritoneal macrophages.

This study evaluated the effect of dexamethasone on endotoxin-induced production of tumor necrosis factor (TNF) activity in vitro by equine peritoneal macrophages. Peritoneal macrophages from adult horses were cultured in the presence of dexamethasone (1-100 microM) for various time periods (2 hour, 0.5 hour, 0 hour) prior to the addition of endotoxin (5 ng/ml), then the secretion of TNF activity was evaluated. Macrophage supernatant concentrations of TNF activity were estimated by a modified in vitro cytotoxicity bioassay using the murine fibrosarcoma cell line, WEHI 164 clone 13. An experiment was performed to determine whether dexamethasone interfered with the cytolytic bioassay's ability to detect TNF activity. The endotoxin-induced TNF activity production by equine peritoneal macrophages was significantly reduced by co-incubation with 100 microM dexamethasone, but not by tested concentrations of dexamethasone less than 100 microM. This concentration of dexamethasone greatly exceeds those generally attained by therapeutic use of dexamethasone in horses. Preincubation time did not affect the ability of 100 microM dexamethasone to reduce TNF production by equine macrophages. The quantitation of equine TNF activity by its cytolytic bioassay was not altered by dexamethasone.

Analysis of Variance↗
PubMed1990

Transcriptional regulation of glutamine synthetase gene expression by dexamethasone in L6 muscle cells.

Dexamethasone increases glutamine synthetase activity and mRNA abundance in L6 muscle cells in culture, apparently by a glucocorticoid receptor-mediated process. The data in this report reveal that increased glutamine synthetase mRNA abundance is attributable at least in part to an enhanced rate of transcription of the glutamine synthetase gene. "Nuclear runoff" assays of glutamine synthetase gene expression were performed with purified myonuclei from dexamethasone-treated or untreated L6 skeletal muscle cells. These assays showed glutamine synthetase transcription to be increased approximately 2-fold as early as 1 h after incubation of cells with dexamethasone (10(-7) M); there was no increase in the rate of transcription of the beta-tubulin gene, which served as a control. The increase in glutamine synthetase gene transcription correlates with increased glutamine synthetase enzymatic activity after dexamethasone treatment. Studies with actinomycin D indicated that the half-life of glutamine synthetase mRNA (7-8 h) is not altered by dexamethasone. Therefore, the degradation of glutamine synthetase mRNA is not affected by dexamethasone, and the increased glutamine synthetase mRNA level is attributable to increased transcription. The dexamethasone-mediated increase in glutamine synthetase mRNA abundance is glucocorticoid receptor-mediated; RU38486 (a glucocorticoid receptor blocker) completely blocked the effect of dexamethasone. The dexamethasone-mediated increase in glutamine synthetase gene transcription and steady-state mRNA level was not blocked by cycloheximide, indicating a direct effect.

Blotting, Northern↗
PubMed1990

Dexamethasone effects on the hospital course of infants with bronchopulmonary dysplasia who are dependent on artificial ventilation.

A randomized double-blind placebo-controlled trial was conducted to evaluate the effects of enterally administered dexamethasone on the hospital course of infants with bronchopulmonary dysplasia. A total of 23 infants with a birth weight less than 1500 g who were dependent on artificial ventilation 3 to 4 weeks of age received dexamethasone (n = 12) or saline placebo (n = 11). Dexamethasone (0.5 mg/kg per day) was given in tapering doses for 7 days followed by hydrocortisone (8 mg/kg per day) which was progressively reduced for a total of 17 days of therapy. Infants who received dexamethasone required less oxygen on days 8 and 17 (P less than .05) and were more likely to extubate 8 days after therapy than infants in the control group (respectively 8/12 vs 3/11 infants, P less than .05; P = .12 after Yates correction). The use of dexamethasone significantly shortened median duration of mechanical ventilation (4 vs 22 days, P less than .05) but had no effect on length of oxygen therapy, hospitalization, home oxygen therapy, occurrence and severity of retinopathy of prematurity, rate of growth, and mortality. No significant complications resulted from dexamethasone therapy. Measurements of plasma dexamethasone levels confirmed the absorption of drug from the gastrointestinal tract (23.7 ng/mL in dexamethasone vs 4.6 ng/mL in the control group, P less than .05). Dexamethasone administration resulted in short-term improvements in pulmonary function but did not ameliorate the hospital course of infants with bronchopulmonary dysplasia.

Administration, Oral↗
PubMed1989

Dexamethasone stimulates arachidonic acid conversion to prostaglandin E2 in human amnion cells.

The purpose of this investigation was to study the mechanism of stimulation of PGE2 output from human amnion epithelial cells by the synthetic glucocorticoid dexamethasone. Cells incubated in serum-free pseudo-amniotic fluid produced very low levels of PGE2, even when arachidonic acid (1 microM) was present. Pretreatment of cells with dexamethasone (50 nM) for 21 h increased the PGE2 output 6- to 7-fold in 2-h incubations only in the presence of arachidonic acid. The RNA synthesis inhibitor, actinomycin D (1 microgram/ml), and the protein synthesis inhibitor, cycloheximide (40 micrograms/ml), each blocked dexamethasone-stimulated arachidonic acid conversion to PGE2. The time course of these events suggests that dexamethasone first initiates RNA synthesis. Acetylsalicylic acid, a specific and irreversible blocker of prostaglandin endoperoxide H synthase (cyclooxygenase), was used to determine whether dexamethasone could stimulate new enzyme synthesis. Cells treated first with acetylsalicylic acid (30 min) then dexamethasone (22 h) produced as much PGE2 in response to 1 microM arachidonate as did cells exposed to dexamethasone only. Exposing cells to acetylsalicylic acid after dexamethasone completely eliminated PGE2 output. These data suggest that dexamethasone stimulates the synthesis of prostaglandin endoperoxide H synthase.

Amnion↗
PubMed1986

Relationship between the increase in liver nuclear triiodothyronine-receptor sites and malic enzyme activation by dexamethasone.

Previous works have indicated that a glucocorticoid excess results in an increase in the maximal binding capacity of nuclear T3-receptors (MBC) and in the activity of cytosolic malic enzyme (ME) in the liver of the rat. In this paper, studies were undertaken to evaluate the degree of dependency between the changes in the nuclear T3-receptor number and the induction of a specific metabolic response of T3 evaluated by the activity of ME. The injection of graded daily doses of dexamethasone to adrenalectomized animals (Ax) induced a dose-related increase in MBC and ME activity, and their maximal values were reached with the same dose of dexamethasone. The time-related changes in MBC and ME after the administration of a daily dose of dexamethasone indicated that both parameters followed a progressive-time increase which was evident 24 h after the glucocorticoid until the highest level's were reached. MBC and ME were measured in thyroidectomized (Tx) rats and Tx plus Ax rats injected with dexamethasone (Tx + Ax + D). MBC increased significantly in Ax animals treated with dexamethasone (Ax + D) and in Tx + Ax + D compared with the Tx and control groups. ME activity was very low in Tx animals and dexamethasone injection to Tx + Ax animals did not increase the enzyme activity as occurred in the Ax group where the serum T3 level was in the normal range. These data indicate that the increase in ME activity by dexamethasone administration was associated to a simultaneous increase in the number of liver nuclear T3-receptors. Dexamethasone injected to hypothyroid animals failed to induce a ME activation as it was found in animals with normal T3 levels, suggesting a T3-mediated action of dexamethasone on ME activity by modification of the nuclear T3-receptor number.

Animals↗
PubMed1988

Chronic low-dose infusions of dexamethasone in rats: effects on blood pressure, body weight and plasma atrial natriuretic peptide.

Glucocorticoid-induced hypertension in rats has been studied using long-term, low-dose dexamethasone treatment. Dose-related increases in systolic blood pressure were achieved, without loss in body weight, with subcutaneous continuous infusions of 1, 2 and 5 micrograms dexamethasone per day, respectively, for 4 weeks. Rats treated with 10 micrograms dexamethasone per day lost weight at a rate of 10 g per week. Lower doses caused a significant reduction in weight gain compared with controls. Renin, aldosterone, plasma sodium and potassium concentrations were unaffected by dexamethasone treatment. Plasma atrial natriuretic peptide (ANP) concentrations were decreased by 40-50% by dexamethasone. These decreases were negatively correlated with increases in systolic blood pressure and haematocrit. Glucocorticoid-induced decreases in ANP contrast with ANP increases in response to mineralocorticoid treatment in rats with deoxycorticosterone-induced hypertension. Plasma concentrations of the endogenous glucocorticoid, corticosterone, were suppressed to the same very low levels by 5 and 10 micrograms dexamethasone per day; 1 and 2 micrograms doses were less effective. Unlike mineralocorticoid-induced hypertension, the pressor effects of dexamethasone were ameliorated but not abolished by dietary sodium restriction and were unaffected by sodium loading. Two micrograms of dexamethasone reduced plasma ANP in rats on either high- or low-sodium diets by 29 and 34%, respectively. We conclude that low-dose infusions (less than 5 micrograms/day) of dexamethasone are suitable for studying glucocorticoid-induced hypertension without the complications of weight loss that have been reported by others or of the mineralocorticoid-like side effects which endogenous glucocorticoids may exhibit.

Animals↗
PubMed1987

The effects of dexamethasone on in vitro collagen gene expression.

Glucocorticoids have been shown to be useful in the treatment of certain types of chronic liver disease both by inhibiting fibrosis and by improving liver function. We have previously demonstrated in an in vivo model of hepatic fibrogenesis that dexamethasone inhibits the synthesis of types I and IV collagen. In the present study we have evaluated the level of regulation responsible for the dexamethasone-induced changes in collagen gene expression in a defined in vitro system. Primary cultures of adult rat hepatocytes treated with and without dexamethasone under classical cell culture conditions or using defined media were evaluated for synthesis and abundance of procollagen and beta-actin mRNAs. Cells treated with dexamethasone had decreased types I and IV procollagen mRNA steady state levels due in part to diminished transcription rates of the genes. On the other hand, beta-actin mRNA levels were unaffected by dexamethasone. Transient expression experiments were performed to more precisely define the mechanism whereby dexamethasone affects type I procollagen gene transcription. The recombinant plasmid, pAZ1009, containing the mouse alpha 2(I) procollagen gene promoter linked to the chloramphenicol acetyltransferase gene, was transfected into mouse fibroblast cell lines. Cells transfected with the pAZ1009 plasmid in the presence of dexamethasone had a significant decrease in chloramphenicol acetyltransferase activity when compared to cells not exposed to dexamethasone. These data suggest that dexamethasone inhibits collagen synthesis through a direct effect on the collagen gene promoter and appears also to have a post-transcriptional effect on procollagen mRNA content.

Actins↗
PubMed1986

Pretranslational regulation of type I collagen, fibronectin, and a 50-kilodalton noncollagenous extracellular protein by dexamethasone in rat fibroblasts.

The effect of dexamethasone on the synthesis of total cellular and extracellular proteins and specifically on the synthesis of type I procollagen chains, fibronectin, and a 50-kDa extracellular noncollagenous polypeptide was examined in cultured rat dermal fibroblasts. A slight but consistent inhibition of total protein synthesis by dexamethasone was dose and time dependent. Treatment of cells with 1 microM dexamethasone for 24 h while abolishing procollagen synthesis nearly completely (less than 95%) had the opposite effect (5-7-fold increase) on the synthesis of an extracellular noncollagenous 50-kDa polypeptide. Dexamethasone did not significantly affect the rates of synthesis of fibronectin. Cell-free translation of mRNA from dexamethasone-treated cells revealed corresponding changes in the steady-state levels of functional mRNAs coding for procollagens, the 50-kDa polypeptide, and fibronectin. Northern blot hybridization using nick-translated cDNA plasmids coding for pro-alpha 1(I), fibronectin, and cytoplasmic beta-actin mRNA corroborated the data obtained from cell-free translation experiments. Run-off transcription assays using nuclei from cells treated with 1 microM dexamethasone for 24 h revealed that glucocorticoid treatment did not significantly affect the rate of transcription of type I collagen genes; similarly, the rate of transcription of fibronectin and cytoplasmic beta-actin genes also remained unchanged under these conditions. An analysis of the kinetics of decay of radiolabeled mRNA coding for pro-alpha 1(I), pro-alpha 2(I), and fibronectin in dexamethasone-treated cells revealed that procollagen mRNAs were turned over at an accelerated rate in glucocorticoid-treated cells. These data suggest that dexamethasone regulates type I collagen gene expression by preferentially decreasing the stability of pro-alpha 1(I) and pro-alpha2(I) mRNAs. Although dexamethasone increased the levels of translatable mRNAs coding for a 50-kDa polypeptide, the molecular mechanism(s) of how hormone exerts this effect remains unknown.

Animals↗
PubMed1977

Acceleration of canalicular development in lungs of fetal mice exposed transplacentally to dexamethasone.

Morphometric techniques were used to compare the volume density of air space (Vva) and the degree of maturation of pulmonary epithelium in normal fetal mouse lung and in lungs of fetuses exposed transplacentally to dexamethasone. Pregnant Bagg-Webster Swiss mice of 16 days' gestation were given injections of either saline or dexamethasone in doses ranging from 0.40 to 12.0 microng. per gm. of body weight, and killed at intervals thereafter. Fetuses were removed and weighed and their lungs prepared for morphometry using osmium-fixed, Epon-embedded tissue. In control lungs, Vva increased 10-fold between days 17 and 19, an increase from 1.5 to 15%. A 25-fold increase occurred during the same period in test fetal lungs exposed to 0.40 microng. per gm. or more of dexamethasone. When the degree of air space development was compared 24 hours after exposure, within a single weight group and, according to dose, a linear increase in air space was found; 0.1-microng. per gm. increment in dexamethasone produced a 0.66% increment in Vva. Body weight was an important determinant, in that fetuses in the lower weight range had much less response. The latter showed an increment of approximately 0.25% in Vva for each 0.1-microng. per gm. increment of dexamethasone. It can be emphasized from the present experiments that a maximal development of Vva could be achieved by amounts of dexamethasone too low to depress fetal or lung weight. The proportion of pulmonary epithelial cells containing osmiophilic granules increased in control lungs from 18% on day 17 to 42% on day 18. Test fetuses (17 days old) examined 24 hours after receiving either 0.40 or 0.80 microng. per mg. of dexamethasone showed no significant increase in this proportion; however, a significant increase in the proportion of cells containing osmiophilic granules was found in fetal lungs exposed to 2.0 microng. per mg. Whereas a significant increase in Vva was found within 14 hours of exposure, no increase in the proportion of cells containig osmiophilic granules was detectable at this time. It was concluded that air space development is a sensitive method for evaluating the effect of dexamethasone as it gives a clear dose-response curve in fetuses exposed to it 24 hours prior to sacrifice. Accelerated maturation of the presumptive type II cell could only be demonstrated within 24 hours by using higher doses than those required to initiate air space development. These observations suggest that the steps invovled in canal formation, which are assumed to reflect alterations in mesenchyme, may have a different sensitivity to dexamethasone than do those initiating the maturation of alveolar epithelial cells.

Animals↗
PubMed1984

Membrane permeability as a determinant of dexamethasone resistance in murine thymoma cells.

The variant MS23 of the murine thymoma cell line W7 , selected for growth at low concentrations of dexamethasone (7.5 nM), is cross-resistant to various unrelated drugs, including colchicine. By stepwise selection in combinations of dexamethasone and colchicine at increasing concentrations, we have isolated a series of variants with increased resistance to dexamethasone and cross-resistance to puromycin, colchicine, daunomycin, gramicidin, and vincristine. Surprisingly, resistance to triamcinolone acetonide, a glucocorticoid structurally related to dexamethasone, did not develop. Assays for specific dexamethasone and triamcinolone acetonide binding sites in variant cell extracts reveal that the glucocorticoid receptors of these variants are unchanged as compared to the W7 parental line. However, whole cell binding assays yielded reduced apparent affinity for dexamethasone in the MS23 variant and drastically reduced dexamethasone binding after selection for increased resistance. We demonstrate that this is due to reduced drug uptake. Procaine, a membrane-active anesthetic, potentiates uptake of puromycin and dexamethasone in the variants. The variants are stable, and karyotypic analysis did not reveal double minute chromosomal structures. These results demonstrate that permeability can be a rate-limiting step in steroid hormone action and is the basis for dexamethasone resistance in these variants.

Animals↗
PubMed1982

Characterization of a glucocorticoid receptor and the direct effect of dexamethasone on herpes simplex virus infection of rabbit corneal cells in culture.

Homogenates prepared from a previously established cell line derived from rabbit cornea contain a macromolecule with many properties of a glucocorticoid receptor, namely high affinity (KD = 6 x 10(-9)M) and saturable capacity (135 femtomoles/mg protein) for dexamethasone, extreme heat lability, and a pattern of competition similar to that found in other glucocorticoid target cells. Intact cells specifically bind dexamethasone with an affinity similar to that found in homogenates, and the amount of steroid bound at saturation is approximately 60,000 molecules of dexamethasone per cell. Specific dexamethasone binding was found to be localized to the cell nucleus. The corneal cells were susceptible to infection with herpes simplex virus (HSV). Dexamethasone increased cell susceptibility to the virus and facilitated the spread of the infection throughout the corneal cell culture. This effect was observed at concentrations of dexamethasone as low as 10(-9) M. Tetrahydrocortisol, an inactive glucocorticoid metabolite that does not compete with dexamethasone binding to the receptor, did not enhance HSV infection at a high concentration (10(-5) M). This study demonstrates a direct effect of dexamethasone on corneal cell-HSV interaction in the absence of exogenous immunologic factors. This effect of dexamethasone may be mediated by the glucocorticoid receptor.

Animals↗
PubMed1995

Dexamethasone-induced ocular hypertension in perfusion-cultured human eyes.

PURPOSE: Glucocorticoid administration can lead to the development of ocular hypertension and corticosteroid glaucoma in a subset of the population through a decrease in the aqueous humor outflow facility. The purpose of this study was to determine whether glucocorticoid treatment can directly affect the outflow facility of isolated, perfusion-cultured human eyes. METHODS: The anterior segments of human donor eyes from regional eye banks were placed in a constant flow, variable pressure perfusion culture system. Paired eyes were perfused in serum-free media with or without 10(-7) M dexamethasone for 12 days. Intraocular pressure was monitored daily. After incubation, the eyes were morphologically characterized by light microscopy, transmission and scanning electron microscopy, and scanning laser confocal microscopy. RESULTS: A significant increase in intraocular pressure developed in 13 of the 44 pairs of eyes perfused with dexamethasone with an average pressure rise of 17.5 +/- 3.8 mm Hg after 12 days of dexamethasone exposure. The contralateral control eyes, which did not receive dexamethasone, maintained a stable intraocular pressure during the same period. The outflow pathway of the untreated eyes appeared morphologically normal. In contrast, the dexamethasone-treated hypertensive eyes had thickened trabecular beams, decreased intertrabecular spaces, thickened juxtacanalicular tissue, activated trabecular meshwork cells, and increased amounts of amorphogranular extracellular material, especially in the juxtacanalicular tissue and beneath the endothelial lining of the canal of Schlemm. The dexamethasone-treated nonresponder eyes appeared to be morphologically similar to the untreated eyes, although several subtle dexamethasone-induced morphologic changes were evident. CONCLUSION: Dexamethasone treatment of isolated, perfusion-cultured human eyes led to the generation of ocular hypertension in approximately 30% of the dexamethasone-treated eyes. Steroid treatment resulted in morphologic changes in the trabecular meshwork similar to those reported for corticosteroid glaucoma and open angle glaucoma. This system may provide an acute model in which to study the pathogenic mechanisms involved in steroid glaucoma and primary open angle glaucoma.

Aged↗
PubMed1994

The effect of oral dexamethasone on the circadian rhythm of aqueous humor flow in humans.

PURPOSE: To determine if the circadian rhythm of plasma corticosteroid activity is necessary for the circadian rhythm of aqueous humor flow to occur in humans. METHODS: Twenty normal volunteers were recruited for this randomized, double-masked, placebo-controlled study. Oral dexamethasone was given at a dose of 0.5 mg every 6 hours; this is equivalent to more than two times the normal 24-hour endogenous adrenal corticosteroid production. This dosage schedule will maintain a relatively constant level of corticosteroid action throughout a 24-hour period. Topical fluorescein and a scanning fluorophotometer were used to measure the rate of aqueous humor flow. Subjects were studied on two separate days. On one study day, the subject took 0.5 mg of dexamethasone every 6 hours; on the other study day, the same subject took a placebo every 6 hours. RESULTS: During the morning, aqueous flow was 4.06 +/- 0.70 microliters/min (mean +/- SD) in subjects taking dexamethasone and 3.82 +/- 0.85 in subjects taking a placebo. This 6% higher dexamethasone flow was not significant (P = 0.10). During the afternoon, aqueous flow was 3.83 +/- 0.78 in subjects taking dexamethasone and 3.52 +/- 0.77 in subjects taking a placebo. This 9% higher dexamethasone flow was statistically significant (P = 0.02). The nighttime aqueous flow was 1.38 +/- 0.45 in subjects taking dexamethasone and 1.43 +/- 0.34 in subjects taking the placebo. There was not a significant difference between placebo and dexamethasone during the night (P = 0.40). On each day, intraocular pressure was measured at 8:00 AM, 4:00 PM, and 6:00 AM. When comparing dexamethasone to placebo, no significant difference was observed in any of the intraocular pressures. CONCLUSIONS: The study is interpreted as showing that the reduction of aqueous humor flow during sleep can occur in the absence of a comparable fall in plasma corticosteroid pathway.

Administration, Oral↗
PubMed1977

Combined growth-inhibitory responses and ultrastructural alterations produced by 1,3-bis(2-chloroethyl)-1-nitrosourea and dexamethasone in rat glioma cell cultures.

The effect of 0.0001 to 10 muM 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1 muM dexamethasone on cell proliferation was studied by measuring cell densities in control and drug-treated rat glioma (strain C6) monolayer cultures. When C6 cultures were exposed to 0.01 to 10 muM BCNU, the growth rates decreased for 2 days as control cell populations continued to proliferate at log phase rates. These growth-inhibitory responses were dose dependent and ranged from 20 to 80%, relative to control growth. Subsequently, the growth rates increased and the inhibitory responses ranged from 0 to 12% 4 days later. Cell densities in C6 cultures exposed to 1 muM dexamethasone for 1 day did not differ significantly from controls. Then cell proliferation ceased and the inhibitory response remained at 50% relative to controls in stationary phase. When 0.03 muM BCNU and 1 muM dexamethasone were supplied simultaneously to C6 cultures, a 35% inhibitory response occurred after 1 day. This response did not differ significantly from that observed with 0.03 muM BCNU alone. After 4 days, the inhibitory response did not decrease in cultures containing both drugs, but did decrease to 13% in the 0.03 muM BCNU-treated cultures. In 1 muM BCNU-treated cultures, the response was 66% after 1 day, which decreased to 21% 5 days later. When 1 muM BCNU was supplied to C6 cultures that were pretreated for 1 day with 1 muM dexamethasone, the response was 91% the following day, and this decreased to only 54% 5 days later. Dose-response curves showed that the inhibitory responses after 1 day in these pretreated cultures exposed to 0.001 to 10 muM BCNU increased up to 22% relative to the responses produced by either drug alone. After 5 days, the responses in the pretreated cultures exposed to 0.001 to 1 muM BCNU was 50%, which was similar to the response produced by 1 muM dexamethasone alone. Ultrastructural studies revealed that control and 1 muM BCNU-treated C6 cells contained 18 mitochondria, but the treated cells were 10% smaller after 1 day. Cells exposed to 1 muM dexamethasone for 1 day conount of granular endoplasmic reticulum increased greater than 80% in cells treated with BCNU for 1 day or dexamethasone for 2 days. C6 cells pretreated with dexamethasone and exposed to BCNU for an additional day (a) contained 23 mitochondria, (b) did not decrease in size, and (c) exhibited a greater than 250% increase in the amount of granular endoplasmic reticulum. These results demonstrate that combined growth-inhibitory responses and ultrastructural alterations occur when C6 cells are treated sequentially with 1 muM dexamethasone and BCNU.

Carmustine↗
PubMed1996

A controlled trial of dexamethasone to prevent bronchopulmonary dysplasia in surfactant-treated infants.

BACKGROUND: Surfactant therapy now has a well-established role in the treatment of neonates with respiratory distress syndrome but has failed to reduce the incidence of bronchopulmonary dysplasia (BPD). We conducted a double-blind, placebo-controlled trial to test the hypothesis that dexamethasone therapy given during the first 12 days of life to very low birth weight infants would be synergistic to surfactant in preventing BPD. METHODS: Seventy surfactant-pretreated infants (700-1500 g) who had severe respiratory distress syndrome (a/A ratio, 0.18 +/- 0.10; mean airway pressure, 11.1 +/- 1.9 cm H2O; fraction of inspired oxygen, 0.81 +/- 0.22) were enrolled to receive a 12-day course of dexamethasone (n = 36) or saline placebo (n = 34) starting within the first 12 hours after birth. The starting dose of dexamethasone was 0.5 mg/kg per day, and it was tapered progressively. RESULTS: Ventilator variables at 5 to 14 days were significantly improved in those infants who received dexamethasone compared with those who received the placebo. The effect seem to be more marked in infants weighting less than 1250 g at birth. Significantly more infants could be extubated by 14 days of age in the dexamethasone group (26 of 32 vs 14 of 32). Dexamethasone therapy reduced the incidence of BPD at 28 days (odds ratio, 0.1; 95% confidence interval, 0.03 to 0.3) and eliminated BPD at 36 weeks' postconceptional age. Dexamethasone-treated infants had greater weight loss at 14 days (12.9 +/- 6.4% vs 3.7 +/- 8.6%, respectively) and higher blood pressures from days 3 to 10. However, no differences were seen in time to regain birth weight, hypertension (1 infant in each group), or incidence of intraventricular hemorrhage. CONCLUSIONS: We found an additive effect between dexamethasone and surfactant in improving pulmonary status and reducing the incidence of BPD. Compared with the placebo, dexamethasone therapy was more effective in reducing the incidence of BPD in surfactant-pretreated very low birth weight infants.

Bronchopulmonary Dysplasia↗
PubMed1996

Use of low- and high-dose dexamethasone tests for distinguishing pituitary-dependent from adrenal tumor hyperadrenocorticism in dogs.

OBJECTIVE: To evaluate low- and high-dose dexamethasone suppression tests for differentiating pituitary dependent hyperadrenocorticism (PDH) from adrenal tumor hyperadrenocorticism (ATH) in dogs. DESIGN: Prospective study. ANIMALS: 181 dogs with PDH and 35 dogs with ATH. PROCEDURE: Plasma cortisol concentrations from dogs with naturally developing hyperadrenocorticism were evaluated before, and 4 and 8 hours after administration of standard low- and high-doses of dexamethasone (0.01 mg/kg of body weight, i.v., and 0.1 mg/kg, i.v.; respectively). RESULTS: In response to the low-dose test, all but 3 dogs had an 8-hours post-dexamethasone plasma cortisol concentration that was consistent with a diagnosis of hyperadrenocorticism, that is, > or = 1.4 micrograms/dl. Criteria used to distinguish PDH from ATH in response to low-dose dexamethasone included a 4-hour post-dexamethasone plasma cortisol concentration < 50% of the basal value or < 1.4 micrograms/dl, or an 8-hours post-dexamethasone plasma cortisol concentration < 50% of the basal concentration. Criteria used to distinguish PDH from ATH in response to high-dose dexamethasone included 4- or 8-hour post-dexamethasone plasma cortisol concentrations < 50% of the basal concentration or < 1.4 micrograms/dl. In response to the low-dose test, 111 dogs met criteria for suppression (each had PDH). In response to the high-dose test, 137 dogs met criteria for suppression (2 had ATH, 135 had PDH). Twenty-six dogs with PDH (12%) had indications of adrenal suppression in response to high-dose but not low-dose testing. CLINICAL IMPLICATIONS: Low-dose dexamethasone test has value as a discrimination test to distinguish dogs with PDH from those with ATH. The high-dose test need only be considered in dogs with hyperadrenocorticism that do not have adrenal suppression in response to the low-dose test.

Adrenal Cortex Neoplasms↗