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PubMed1984

Human growth hormone-secreting pituitary adenoma cells in long-term culture: effects of dexamethasone and growth hormone releasing factor.

Growth hormone-secreting human pituitary adenoma cells in long-term culture show a decline in GH secretion. We investigated the effects of dexamethasone on GH production and on the responsiveness of the adenoma cells to various drugs. Twenty-four-hour GH secretion by cultures from seven acromegalics was consistently stimulated by 100 nM-dexamethasone. In four out of seven cultures the effect of dexamethasone occurred within 24 h. After 3 weeks in culture the decline in GH secretion by control cultures was over 90%, while in dexamethasone-treated cultures this was limited to less than 50%. The effect of dexamethasone was dose-dependent over a range of 1 nmol/l to 10 mumol/l. Dexamethasone stimulated not only GH secretion (fivefold), but also GH content (twofold). Cycloheximide and actinomycin D blocked the stimulatory effect of dexamethasone on GH secretion, the latter irreversibly. After 4 days of treatment with 100 nM-dexamethasone, the relative effects of somatostatin, prostaglandin E1, bromocriptine and thyrotrophin releasing hormone were the same in treated and untreated cultures. However, the response to synthetic GH releasing factor (GRF) was greatly enhanced by pretreatment of adenoma cells with dexamethasone (100 and 5 nmol/l). Cells unresponsive to small concentrations of GRF could be stimulated effectively by GRF after pretreatment with dexamethasone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma↗
PubMed1997

Dexamethasone and 11-dehydrodexamethasone as tools to investigate the isozymes of 11 beta-hydroxysteroid dehydrogenase in vitro and in vivo.

Dexamethasone is used in the clinic to test the sensitivity of the hypothalamic-pituitary-adrenal axis to negative feedback. It has also been proposed that metabolism of dexamethasone might differentiate between the activities of the two isozymes of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD1 and 11 beta HSD2). We have developed a gas chromatographic mass spectrometric assay for dexamethasone and 11-dehydrodexamethasone and have confirmed in vitro that dexamethasone is a substrate for 11 beta-HSD2 but not 11 beta-HSD1 (conversion to 11-dehydrodexamethasone 0.6 +/- 0.3% in homogenates of rat liver with NADP+ for 11 beta-HSD1, and 29.4 +/- 10.3% and 40.0 +/- 2.0% in homogenates of rat and human kidney respectively with NAD+ for 11 beta-HSD2). However, we have also made the novel observation that 11-dehydrodexamethasone is a substrate for both isozymes (conversion to dexamethasone 65.0 +/- 20.4% for 11 beta HSD1 and 53.5 +/- 20.8% and 69.0 +/- 4.5% for 11 beta HSD2, rat and human respectively). In healthy humans, the concentrations of 11-dehydrodexamethasone in plasma after an intravenous bolus of dexamethasone were less than 10% of those of dexamethasone, and 11-dehydrodexamethasone was detected (at 0.8-65.0 nM) in plasma from only 11 of 20 subjects at 0900 h on the morning after oral dexamethasone (0.1-1 mg taken at 2400 h). Concentrations of 11-dehydrodexamethasone did not correlate with the degree of suppression of plasma cortisol. Thus dexamethasone is not useful in differentiating the activities of the isozymes of 11 beta-HSD in vivo and variations in 11 beta-HSD activity do not explain the interindividual variability in suppression of plasma cortisol by low doses of dexamethasone.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2005

Dexamethasone administration attenuates the inhibitory effect of lipopolysaccharide on IGF-I and IGF-binding protein-3 in adult rats.

The aim of this study was to investigate whether glucocorticoid administration had a beneficial effect on serum concentrations of insulin-like growth factor I (IGF-I) and on IGF-binding protein 3 (IGFBP-3) in rats injected with lipopolysaccharide (LPS). Adult male rats were injected with LPS or saline and pretreated with dexamethasone or saline. Dexamethasone administration decreased growth hormone (GH) receptor and IGF-I mRNA levels in the liver of control rats. LPS decreased GH receptor and IGF-I gene expression in the liver of saline-treated rats but not in the liver of dexamethasone-pretreated rats. In the kidney, GH receptor mRNA levels were not modified by dexamethasone or LPS treatment. However, LPS decreased renal IGF-I gene expression and dexamethasone pretreatment prevented this decrease. Serum concentrations of IGF-I were decreased by LPS, and dexamethasone pretreatment attenuated this effect. The gene expression of IGFBP-3 in the liver and kidney and its circulating levels were decreased by LPS. In control rats dexamethasone increased circulating IGFBP-3 and its gene expression in the liver, and decreased the proteolysis of this protein. Dexamethasone pretreatment attenuated the LPS-induced decrease in IGFBP-3 gene expression in the liver and prevented the LPS-induced decrease in IGFBP-3 gene expression in the kidney. Moreover, dexamethasone pretreatment attenuated the LPS-induced decrease in serum concentrations of IGFBP-3 and decreased the LPS-induced IGFBP-3 proteolysis in serum. In conclusion, dexamethasone pretreatment partially attenuates the inhibitory effect of LPS on serum IGF-I by blocking the decrease of its gene expression in the kidney as well as by attenuating the decrease in serum concentrations of IGFBP-3.

Animals↗
PubMed2006

Dexamethasone in adults with community-acquired bacterial meningitis.

Bacterial meningitis in adults is a severe disease with high fatality and morbidity rates. Experimental studies have shown that the inflammatory response in the subarachnoid space is associated with an unfavourable outcome. In these experiments, corticosteroids, and in particular dexamethasone, were able to reduce the inflammatory cascades in the subarachnoid space. The use of corticosteroids as adjunctive therapy in adults with bacterial meningitis has been evaluated in six studies, performed over a time period of 40 years. Most studies on adjunctive dexamethasone therapy in adults with bacterial meningitis were limited by methodological flaws. In 2002, a study with sufficient statistical power to show significant differences was published. This European Dexamethasone Study showed that adjunctive dexamethasone therapy reduced the rate of unfavourable outcomes in adults with bacterial meningitis from 25% to 15%. In this study, adjunctive treatment with dexamethasone was given before or with the first dose of antibacterials, without serious adverse effects. A quantitative review showed a consistent beneficial effect of dexamethasone on mortality and a borderline statistical beneficial effect on neurological sequelae. On the basis of the available evidence, adjunctive dexamethasone therapy should be initiated before or with the first dose of antibacterials and continued for 4 days in all adults with suspected or proven bacterial meningitis, regardless of bacterial aetiology. In patients with both meningitis and septic shock, dexamethasone therapy cannot be unequivocally recommended, but the use of lower doses seems reasonable at present. Since prompt use of dexamethasone and appropriate antibacterials improves the prognosis of adults with bacterial meningitis, hospitals will require protocols to include dexamethasone with the initial antibacterial therapy.

Adult↗
PubMed2000

Dexamethasone-induced insulin resistance in 3T3-L1 adipocytes is due to inhibition of glucose transport rather than insulin signal transduction.

Glucocorticoids reportedly induce insulin resistance. In this study, we investigated the mechanism of glucocorticoid-induced insulin resistance using 3T3-L1 adipocytes in which treatment with dexamethasone has been shown to impair the insulin-induced increase in glucose uptake. In 3T3-L1 adipocytes treated with dexamethasone, the GLUT1 protein expression level was decreased by 30%, which possibly caused decreased basal glucose uptake. On the other hand, dexamethasone treatment did not alter the amount of GLUT4 protein in total cell lysates but decreased the insulin-stimulated GLUT4 translocation to the plasma membrane, which possibly caused decreased insulin-stimulated glucose uptake. Dexamethasone did not alter tyrosine phosphorylation of insulin receptors, and it significantly decreased protein expression and tyrosine phosphorylation of insulin receptor substrate (IRS)-1. Interestingly, however, protein expression and tyrosine phosphorylation of IRS-2 were increased. To investigate whether the reduced IRS-1 content is involved in insulin resistance, IRS-1 was overexpressed in dexamethasone-treated 3T3-L1 adipocytes using an adenovirus transfection system. Despite protein expression and phosphorylation levels of IRS-1 being normalized, insulin-induced 2-deoxy-D-[3H]glucose uptake impaired by dexamethasone showed no significant improvement. Subsequently, we examined the effect of dexamethasone on the glucose uptake increase induced by overexpression of GLUT2-tagged p110alpha, constitutively active Akt (myristoylated Akt), oxidative stress (30 mU glucose oxidase for 2 h), 2 mmol/l 5-aminoimidazole-4-carboxamide ribonucleoside for 30 min, and osmotic shock (600 mmol/l sorbitol for 30 min). Dexamethasone treatment clearly inhibited the increases in glucose uptake produced by these agents. Thus, in conclusion, the GLUT1 decrease may be involved in the dexamethasone-induced decrease in basal glucose transport activity, and the mechanism of dexamethasone-induced insulin resistance in glucose transport activity (rather than the inhibition of phosphatidylinositol 3-kinase activation resulting from a decreased IRS-1 content) is likely to underlie impaired glucose transporter regulation.

3T3 Cells↗
PubMed2002

Lontophoretic administration of dexamethasone into the tarsocrural joint in horses.

OBJECTIVE: To determine whether iontophoretic administration of dexamethasone to horses results in detectable concentrations in synovial fluid, plasma, and urine. ANIMALS: 6 adult mares. PROCEDURE: Iontophoresis was used to administer dexamethasone. Treatments (4 mA for 20 minutes) were administered to a tarsocrural joint of each mare. The drug electrode contained 3 ml of dexamethasone sodium phosphate at a concentration of 4 or 10 mg/ml. Samples of synovial fluid, blood, and urine were obtained before and 0.5, 4, 8, and 24 hours after each treatment. All samples were tested for dexamethasone using an ELISA. Synovial fluid also was evaluated for dexamethasone, using high-performance liquid chromatography. RESULTS: The lower and upper limits of detection for dexamethasone in synovial fluid with the ELISA were 0.21 and 1.5 ng/ml, respectively. Dexamethasone administered at a concentration of 10 mg/ml was detected by the ELISA in synovial fluid of 5 mares from 0.5 to 24 hours and in urine of 4 mares from 0.5 to 8 hours after each treatment, but it was not detected in plasma. Mean synovial fluid concentration of dexamethasone was 1.01 ng/ml. Dexamethasone administered at a concentration of 4 mg/ml was detected by the ELISA in urine of 2 mares at 0.5 and 4 hours after treatment, but it was not detected in synovial fluid or plasma. CONCLUSIONS AND CLINICAL RELEVANCE: Iontophoresis cannot be considered an effective method for delivery of dexamethasone to synovial fluid of horses, because drug concentrations achieved in this study were less than therapeutic concentrations.

Animals↗
PubMed2006

Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: a randomized trial.

BACKGROUND: High-altitude pulmonary edema (HAPE) is caused by exaggerated hypoxic pulmonary vasoconstriction associated with decreased bioavailability of nitric oxide in the lungs and by impaired reabsorption of alveolar fluid. OBJECTIVE: To investigate whether dexamethasone or tadalafil reduces the incidence of HAPE and acute mountain sickness (AMS) in adults with a history of HAPE. DESIGN: Randomized, double-blind, placebo-controlled study performed in summer 2003. SETTING: Ascent from 490 m within 24 hours and stay for 2 nights at 4559 m. PATIENTS: 29 adults with previous HAPE. INTERVENTION: Prophylactic tadalafil (10 mg), dexamethasone (8 mg), or placebo twice daily during ascent and stay at 4559 m. MEASUREMENTS: Chest radiography was used to diagnose HAPE. A Lake Louise score greater than 4 defined AMS. Systolic pulmonary artery pressure was measured by using Doppler echocardiography, and nasal potentials were measured as a surrogate marker of alveolar sodium transport. RESULTS: Two participants who received tadalafil developed severe AMS on arrival at 4559 m and withdrew from the study; they did not have HAPE at that time. High-altitude pulmonary edema developed in 7 of 9 participants receiving placebo and 1 of the remaining 8 participants receiving tadalafil but in none of the 10 participants receiving dexamethasone (P = 0.007 for tadalafil vs. placebo; P < 0.001 for dexamethasone vs. placebo). Eight of 9 participants receiving placebo, 7 of 10 receiving tadalafil, and 3 of 10 receiving dexamethasone had AMS (P = 1.0 for tadalafil vs. placebo; P = 0.020 for dexamethasone vs. placebo). At high altitude, systolic pulmonary artery pressure increased less in participants receiving dexamethasone (16 mm Hg [95% CI, 9 to 23 mm Hg]) and tadalafil (13 mm Hg [CI, 6 to 20 mm Hg]) than in those receiving placebo (28 mm Hg [CI, 20 to 36 mm Hg]) (P = 0.005 for tadalafil vs. placebo; P = 0.012 for dexamethasone vs. placebo). No statistically significant difference between groups was found in change in nasal potentials and expression of leukocyte sodium transport protein messenger RNA. LIMITATIONS: The study involved a small sample of adults with a history of HAPE. CONCLUSIONS: Both dexamethasone and tadalafil decrease systolic pulmonary artery pressure and may reduce the incidence of HAPE in adults with a history of HAPE. Dexamethasone prophylaxis may also reduce the incidence of AMS in these adults. ClinicalTrials.gov identifier: NCT00274430.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1992

Dexamethasone prevents epileptiform activity induced by morphine in in vivo and in vitro experiments.

The inhibitory effects exerted by dexamethasone on the epileptiform activity induced by morphine were investigated in two different experimental models with two different animal species. In the first series of experiments, dexamethasone administered i.v. in rabbits 30 min before i.c.v. administration of morphine completely prevented both epileptiform and background EEG as well as behavioral alterations induced by morphine. Cycloheximide (a protein synthesis inhibitor) pretreatment reversed the antagonistic effect induced by dexamethasone on the behavioral and EEG alterations induced by morphine. In the second series of experiments, the effects exerted by dexamethasone were investigated on morphine-induced CA1 epileptiform bursting on rat hippocampal slices in vitro. Dexamethasone pretreatment 10 to 60 min before morphine strongly prevented the morphine effects in a concentration- and time-dependent manner. Sixty min of dexamethasone pretreatment also prevented the epileptiform bursting induced by the selective mu opiate receptor agonist DAMGO, whereas it did not significantly affect the increase of the CA1 population spike amplitude due to the selective delta opiate receptor agonist DPDPE. The addition of cycloheximide to the slice-perfusing medium containing dexamethasone prevented the inhibitory effects of the drug toward the morphine and DAMGO-induced CA1 epileptiform bursting. Our results indicate that dexamethasone induces an inhibition on the epileptiform activity induced by morphine and DAMGO. The time lag (30-60 min) which is necessary for revealing the inhibitory influence of dexamethasone on opiate epileptiform activity induced both in vivo and in vitro, and the inhibitory effect exerted by cycloheximide on dexamethasone activity strongly support the hypothesis of a genomic corticosteroid effect within the central nervous system.

Animals↗
PubMed2004

Short term efficacy of intravenous dexamethasone and methylprednisolone therapy in steroid resistant nephrotic syndrome.

OBJECTIVE: To compare the short term efficacy of intravenous pulses of methylprednisolone and dexamethasone in treatment of steroid resistant nephrotic syndrome in children. METHOD: We prospectively treated 81 children with idiopathic steroid resistant nephrotic syndrome with six alternate-day pulses of intravenous dexamethasone (5 mg/kg) or methylprednisolone (30 mg/kg). Fifty-nine patients received dexamethasone and 22 were treated with methylprednisolone. Two patients in dexamethasone and one in methylprednisolone group developed serious infection during administration of alternate-day pulses and could not complete the therapy. RESULTS: The median age at treatment was 38 (36-74.7) months. Of patients who completed therapy, 20 (35.1 percent) (95 PERCNT CI 22.9-48.9) and 7 (33.1 percent) (95 percent CI 14.6-56.9) patients in dexamethasone and methylprednisolone group, respectively achieved complete remission. Following alternate day pu1ses the median urinary albumin to creatinine ratio decreased from 9.2 to 1.5 (P less tha 0.005) in dexamethasone group and from 12.1 to 0.7 (P less than 0.005) in methylprednisolone group. The median reduction in urinary albumin to creatinine ratio was 54.1 PERCNT (95 percent CI 32.7- 83.9) and 63.2 percent (95 percent CI 23.5- 100) in dexamethasone and methylprednisolone group respectively. The chief side effects of therapy were transient hypertension or worsening of preexisting hypertension, which occurred in 31 (54.4 percent) patients in dexamethasone group and 10 (47.6 percent) in the methylprednisolone group. The hypertension was satisfactorily controlled on antihypertensive drugs. One or more side effects were observed in 66.7 percent (95 percent CI 52.9-78.6) children receiving dexamethasone therapy and 61.9percent (95 percent CI 38.4-81.9) receiving methylprednisolone, which was comparable. CONCLUSIONS: We conclude that intravenous dexamethasone is as effective as methylprednisolone in inducing remission in patients with steroid resistant nephrotic syndrome.

Adolescent↗
PubMed1991

Regulation of cytochrome P450IIC12 expression by interleukin-1 alpha, interleukin-6, and dexamethasone.

During the acute phase response to bacterial endotoxin in rats, hepatic levels of cytochrome P450IIC12 [AH, reduced flavoprotein:oxygen oxidoreductase (RH hydroxylating), EC 1.14.14.1] (P450IIC12) apoenzyme and mRNA are suppressed. We set out to determine the effects of potential humoral mediators of inflammation on the expression of P450IIC12 in female rats. A single injection of 12,000 or 60,000 units of interleukin-1 alpha had no effect on total cytochrome P450 content or P450IIC12 mRNA measured 12 hr later, although P450IIC12 apoenzyme was slightly but significantly increased by the higher dose. In the second experiment, animals were given dexamethasone (100 micrograms/kg at -30 min), interleukin-1 alpha (30,000 units/kg at 0, 2, and 4 hr), or both and were sacrificed at 12 hr. Treatment with interleukin-1 alpha alone significantly suppressed total cytochrome P450, P450IIC12 apoenzyme, and P450IIC12 mRNA to 77, 53, and 65% of control levels, respectively; beta-actin mRNA was significantly increased (206% of control levels). Treatment with dexamethasone alone suppressed total cytochrome P450 and P450IIC12 mRNA (73% of controls) but did not significantly affect P450IIC12 apoenzyme measured 12.5 hr later. Again, beta-actin mRNA was increased. When both interleukin-1 alpha and dexamethasone were given, total cytochrome P450 and P450IIC12 mRNA (43% of controls) were suppressed, and beta-actin mRNA was significantly increased. In the third experiment, animals were injected at 0 and 12 hr with dexamethasone (83 micrograms/kg), interleukin-6 (33 micrograms/kg), or both. Interleukin-6 alone did not significantly affect total cytochrome P450 or P450IIC12 apoenzyme or mRNA. Dexamethasone alone suppressed P450IIC12 apoenzyme and mRNA (to 52 and 41%, respectively, of controls). Treatment with both interleukin-6 and dexamethasone significantly suppressed total cytochrome P450 and P450IIC12 apoenzyme and mRNA; suppression of P450IIC12 mRNA (to 16% of controls) was greater than with dexamethasone alone. No change in the transcription rate of CYP2C12 was observed 24 hr after initiation of treatment with dexamethasone (83 micrograms/kg at 0 and 12 hr) or 12 hr after initiation of treatment with interleukin-1 alpha (30,000 units/kg at 0, 2, and 4 hr). We conclude that, in this model, interleukin-1 alpha and glucocorticoids are important mediators of the suppression of hepatic P450IIC12 expression during inflammation. Interleukin-6 was not as potent, but it did potentiate the effects of dexamethasone. Suppression of P450IIC12 expression by dexamethasone and interleukin-1 alpha appeared to be mediated at a pretranslational level, but the possibility of a transcriptional effect needs to be further investigated.

Actins↗
PubMed1980

Influence of dexamethasone on peripheral metabolic parameters of cortisol in the adult male conscious guinea-pig.

The influence of dexamethasone on distribution, metabolism and protein binding of cortisol was studied in conscious adult male guinea-pigs, under chronic cannulation, by a single injection technique for cortisol metabolic parameters and Sephadex equilibrium dialysis procedure for protein binding. The results showed that biological half-life of cortisol (51-55 min) was identical in control and in dexamethasone-treated guinea-pigs (low plasma cortisol level). The apparent volume of distribution of cortisol, which was higher in control (550 +/- 20 ml) than in dexamethasone-treated animals (380 +/- 30 ml), was related to the higher plasma cortisol level in controls (0.96 +/- 0.07 mumole/l) as compared to dexamethasone-treated animals (0.12 +/- 0.02 mole/l). When a high cortisol concentration was infused in dexamethasone-treated guinea-pigs in order to produce hig plasma cortisol level, plasma cortisol MCR increased by 80% (P less than 0.001) reflecting increases of 50% (P less than 0.001) in the apparent volume of distribution and decreases of 19% (0.01 less than P less 0.02) in the half-life cortisol compared to dexamethasone-treated animals (low plasma cortisol level). Although the plasma cortisol level was higher (P less than 0.001) in dexamethasone-treated animals infused with non-labelled cortisol (2.9 +/- 0.02 mumol/l) than in controls (0.96 +/- 0.07 mumol/l), the identical values of the apparent volume of distribution in dexamethasone-treated animals infused with non-labelled cortisol and in controls suggested that dexamethasone could alter the distribution of cortisol, and therefore its metabolism. Dexamethasone did not modify the transcortin-binding capacity and did not complete with cortisol on transcortin sites in guinea-pig plasma.

Animals↗
PubMed1995

Effects of early dexamethasone therapy on pulmonary mechanics and chronic lung disease in very low birth weight infants: a randomized, controlled trial.

OBJECTIVE: To determine the changes in pulmonary mechanics before and during early dexamethasone therapy, and to evaluate the effect of dexamethasone on the duration of mechanical ventilation in very low birth weight (VLBW) ventilator-dependent infants at risk for chronic lung disease (CLD). METHODS: A prospective randomized trial was conducted. Forty-three patients (birth weight 600 to 1500 g, gestational age 24 to 32 weeks) who failed to be weaned from the respirator at 7 to 14 days of age were enrolled; 23 infants received a 7-day course of dexamethasone (0.5 mg/kg/day intravenously for 3 days, 0.25 mg/kg/day for 3 days, and 0.1 mg/kg/day for 1 day), and 20 patients were in the control group. At similar mean airway pressure (MAP) and fractional inspired oxygen concentration (FiO2), respiratory system mechanics were measured before and on days 2, 5, and 7 of the study. Airway pressure, flow and tidal volume (VT) were recorded and only mechanical breaths were analyzed. Respiratory compliance (Crs) and respiratory resistance (Rrs) were calculated by two factor least mean square analysis. RESULTS: Eighty-three percent of infants in the dexamethasone group and 90% in the control group received surfactant in the first 24 hours of life. There was a significant increase in Crs and VT in the dexamethasone group as compared with the control group (P < .001). No major changes in Rrs were observed. Dexamethasone therapy significantly decreased FiO2 and MAP P < .001) and facilitated successful weaning from mechanical ventilation. In addition to a shorter duration of mechanical ventilation (P < .01), the occurrence of CLD (FiO2 > 0.21 at 36 weeks of corrected gestational age, chest radiograph changes) was significantly decreased in the dexamethasone group (P < .01). Except for a transient increase in blood pressure and serum glucose, there were no significant differences in infection rates, intraventricular hemorrhage, or retinopathy of prematurity. Thirteen patients in the control group received dexamethasone at a later age. CONCLUSIONS: Our findings indicate that: 1) early dexamethasone therapy in VLBW infants markedly improves respiratory compliance and tidal volume, reduces FiO2 and MAP requirements, and facilitates extubation in these infants; 2) early dexamethasone therapy reduces the duration of mechanical ventilation and decreases CLD (at 28 days and 36 weeks) in a population of VLBW infants largely treated with surfactant.

Chronic Disease↗
PubMed1995

Dexamethasone up-regulates A3 adenosine receptors in rat basophilic leukemia (RBL-2H3) cells.

The cross-linking of surface IgE receptors by multi-functional Ags promotes the degranulation of mast cells. Previous studies have indicated that the nucleoside adenosine potentiates this response by activating putative A3 adenosine receptors (AR) coupled to phospholipase C in mast cells or their cultured analogues, rat basophilic leukemia (RBL-2H3) cells. Moreover, it has been shown that exposure of RBL-2H3 cells to dexamethasone attenuated antigen-mediated mast cell degranulation, but potentiated the response elicited by adenosine. To determine whether the A3AR is a potential site of action of dexamethasone, we have assessed the status of these receptors in RBL-2H3 cells treated with and without dexamethasone. Treatment with dexamethasone (100 nM) for 24 h resulted in an increase in the number of A3AR to 217 +/- 50% of control. The increased receptor expression was both time- and concentration-dependent, with optimal increases observed following 16 h of treatment and using 100 nM of dexamethasone. No increase in the level of the A2aAR was detectable following dexamethasone treatment. Northern blotting studies indicated a 2.7 +/- 0.3-fold increase in A3AR mRNA in RBL-2H3 cells treated with dexamethasone for 24 h. Dexamethasone also increased the expression of G protein alpha i2, alpha i3, alpha s, and beta subunits by two- to threefold. Activation of the A3AR by aminophenylethyladenosine (APNEA) following dexamethasone treatment enhanced the production of inositol phosphates and the mobilization of intracellular Ca2+. From these data, it is concluded that dexamethasone increases the expression of both A3AR and G proteins in RBL-2H3 cells which contributes to the enhanced response to adenosine.

Animals↗
PubMed1996

Identification of a novel dexamethasone responsive enhancer in the human CYP3A5 gene and its activation in human and rat liver cells.

The human liver cytochromes P450 3A (CYP3As), orthologous to the rat glucocorticoid inducible forms, are composed of at least four differentially expressed members. To begin the study of the molecular events in the glucocorticoid regulation of CYP3A5, we fused 5' sequences of CYP3A5 to the chloramphenicol acetyltransferase gene in a vector that contains the herpes simplex virus thymidine kinase promoter. In HepG2 cells, the largest 5' CYP3A5 gene fragment (1.4 kb) suppressed the TK promoter. However, suppression was overcome by addition of 10 microM dexamethasone. A series of unidirectional deletions revealed a unique 219-bp fragment (-891 to -1109 bp upstream from the transcriptional start site) that conferred dexamethasone responsiveness on the TK promoter regardless of either the distance or orientation from the promoter and thus appears to be an enhancer. Nucleotide sequence analysis of this CYP3A5 enhancer revealed no consensus 15-bp glucocorticoid responsive element (GRE) (GGTACANNNTGTTCT); however, two GRE "half-sites" (TGTTCT) were found separated by 160 bp. Although dexamethasone stimulated the CYP3A5 enhancer only 3-4-fold in HepG2 cells, the CYP3A5 enhancer was stimulated 7- and 12-fold in immortalized primary human hepatocytes and primary rat hepatocyte cultures, respectively. The glucocorticoid receptor (GCR) seems to be indispensable to this process because 1) dexamethasone induction can be blocked by the antiglucocorticoid RU-486, 2) dexamethasone-dependent transcriptional activation of the CYP3A5 enhancer in HepG2 cells required cotransfection of an expression vector containing the intact GCR, yet 3) cotransfection with a plasmid that contains a mutation in the ligand binding domain of the GCR does not activate the CYP3A5 enhancer in the presence of dexamethasone. To further localize the dexamethasone responsive region of the 219-bp CYP3A5 enhancer, it was subdivided and fused to the TKCAT expression vector. Transfection analysis in HepG2 cells demonstrated that neither GRE half-site can independently confer dexamethasone responsiveness on the TK promoter. Block mutations of either of the two GRE half-sites or point mutations at specific GCR binding sites eliminates dexamethasone inducibility, demonstrating the half-sites need to interact. Electromobility shift assays indicate that the CYP3A5 5'-GRE half-site 1) specifically binds purified GCR, 2) can displace binding of the GCR to a consensus GRE, and 3) shifts a protein in HepG2 nuclear extracts that is supershifted by GCR antibody, demonstrating that this enhancer is an authentic GRE. This is the first study to demonstrate that a member of the human CYP3A gene family contains an enhancer that binds the GCR and that this binding is critical to transcriptional activation by dexamethasone.

Animals↗
PubMed1996

Dexamethasone-cyclodextrin-polymer co-complexes in aqueous eye drops. Aqueous humor pharmacokinetics in humans.

PURPOSE: To test an aqueous eye drop solution containing a high concentration of dexamethasone in a cyclodextrin-based drug delivery system. This system increases both drug solubility in aqueous eye drops and drug permeability into the eye, through drug cyclodextrin-polymer co-complexes. METHODS: 2-hydroxypropyl-beta-cyclodextrin is a water-soluble oligosaccharide that can be used to dissolve lipophilic drugs, such as dexamethasone, in aqueous solutions. Co-complexation with a polymer further increases the solubility and increases drug permeability through biologic membranes. Eye drops containing dexamethasone (0.32% and 0.67%), 2-hydroxypropyl-beta-cyclodextrin, and polymer were given to patients before cataract surgery, and the resultant dexamethasone concentration was measured from aqueous humor samples. RESULTS: The dexamethasone-cyclodextrin drops give a significantly higher concentration of dexamethasone in aqueous humor than dexamethasone alcohol 0.1% (Maxidex). Heating of the dexamethasone-cyclodextrin-polymer co-complexes appears to enhance the permeability of the drug into the eye. CONCLUSIONS: The cyclodextrin-based drug delivery system enhances both the solubility of dexamethasone in aqueous eye drops and the permeability of the drug into the human eye. Dexamethasone concentration levels in the human aqueous humor exceed those reported with currently available steroid eye drops.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1997

Effects of dexamethasone on sodium-potassium-chloride cotransport in trabecular meshwork cells.

PURPOSE: Previous studies in the authors' laboratory have shown that bovine and human trabecular meshwork (TM) cells possess a robust sodium-potassium-chloride (Na-K-Cl) cotransport system that functions in regulating intracellular volume and may play a central role in modulating outflow facility across the TM. Dexamethasone, which can induce ocular hypertension, has been found to increase resistance to aqueous outflow across the TM. The current study was conducted to investigate the hypothesis that alteration of TM cell Na-K-Cl cotransport function, regulation, or both may be an underlying factor in steroid-induced glaucoma. To this end, the authors evaluated the effects of dexamethasone treatment of TM cells on Na-K-Cl cotransport activity and cotransporter protein expression. METHODS: Cultured bovine and human TM cell monolayers were exposed to dexamethasone (10(-9) to 10(-6) M) for varying times, then evaluated for Na-K-Cl cotransport activity or harvested for cellular membrane proteins. Cotransport activity was assessed as bumetanide-sensitive K influx. Cotransport protein expression was evaluated by Western blot analysis of cellular proteins using a monoclonal antibody to the human colonic T84 epithelial cell Na-K-Cl cotransporter. RESULTS: The authors found that 24- and 48-hour exposures of human and bovine TM cells to dexamethasone stimulates Na-K-Cl cotransport activity (10(-8) to 10(-6) M dexamethasone in human cells; 10(-8) and 10(-7) M in bovine cells). The authors also found that dexamethasone (10(-8) M) stimulates Na-K-Cl cotransport activity of TM cells with exposure times as early as 12 hours and up to 5 days. In addition, the authors found that the level of Na-K-Cl cotransport protein expressed in TM cells is modulated by dexamethasone. When bovine or human TM cells are exposed to 10(-8) or 10(-6) M dexamethasone for 2 to 5 days, cotransporter protein expression is increased. With longer exposures, however, cotransporter protein levels decrease below control levels. Finally, the authors found that TM cells exposed to dexamethasone become unresponsive to regulation by hypertonicity and vasopressin. CONCLUSIONS: The authors' findings suggest that dexamethasone may be exerting its effect, at least in part, through altering Na-K-Cl cotransport function and regulation in TM cells.

Animals↗
PubMed2000

Randomized trial of alpha-interferon or dexamethasone as maintenance treatment for multiple myeloma.

In order to assess the role of alpha-interferon or dexamethasone as maintenance therapy for multiple myeloma, 172 consecutive, previously untreated patients with disease of low or intermediate tumor mass received primary therapy with oral melphalan and intermittent, high-dose dexamethasone (MD), repeated monthly. Within 5 months, 84 responding patients were assigned at random to maintenance treatment with alpha-interferon (3 mU s.c. 3 x weekly) or dexamethasone (20 mg/m2 p.o. each morning for 4 days) repeated monthly until relapse. Upon relapse, MD was resumed for 2 cycles and second responses were maintained with 4-day courses of melphalan-dexamethasone until second relapse. Initial response was achieved in 88 patients (51%) after a median 0.7 month and no more than 3 courses of MD, a frequency of response similar to that observed previously with dexamethasone alone. There were identical median remissions of 10 months with interferon or dexamethasone, both maintenance regimens being associated with infrequent, mild, and reversible side effects. Significantly more patients responded again to resumption of MD after disease relapse to interferon (82%) than to dexamethasone (44%) (P = 0.001). The median remission from randomization to melphalan-resistant second relapse was 32 months for patients maintained initially on interferon compared to 19 months for those on dexamethasone (P = 0.01). These findings supported an advantage for interferon in remission maintenance by increasing the frequency of tumor recontrol with later treatment that included dexamethasone.

Adult↗
PubMed2001

Effects of dexamethasone on tooth eruption in rats: differences in incisor and molar eruption.

A requirement for tooth eruption is the resorption of alveolar bone. Because bone resorption is stimulated by dexamethasone both in vivo and in vitro, dexamethasone 21-phosphate, a soluble form of dexamethasone, was injected into rats to determine its effect on tooth eruption. Such dexamethasone injections accelerate the time of intra-osseous eruption in rat incisors but do not accelerate the eruption time of rat molars when injected into rats. The injections of dexamethasone 21-phosphate also accelerate the time of eyelid opening in the postnatal rats, as well as retarding growth, as measured by body weight. These effects of dexamethasone 21-phosphate parallel the effects of epidermal growth factor injections, including the absence of an effect on molar eruption. This suggests that the molecular signals for the initiation of tooth eruption (i.e., onset of bone resorption) differ between rat incisors and molars. Given that rat incisors are teeth of continuous eruption whereas rat molars are teeth of limited eruption, as are human teeth, care must be taken in extrapolating results derived from rat incisors to human dentition. In vitro, dexamethasone has no effect on the gene expression of either osteoprotegerin or epidermal growth factor in dental follicle cells derived from molars. Because osteoprotegerin expression during normal tooth eruption is transitorily inhibited early postnatally in the molar dental follicle to allow osteoclast formation, the absence of inhibition of its expression by dexamethasone could explain why dexamethasone does not accelerate eruption in molars.

Animals↗