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PubMed1988

Dexamethasone-induced changes in phosphorylation of the insulin and epidermal growth factor receptors and their substrates in intact rat hepatocytes.

Dexamethasone-induced changes in insulin and epidermal growth factor (EGF) receptor number, autophosphorylation, and kinase activity were studied in intact rat hepatocytes. Hepatocytes were freshly isolated from Sprague-Dawley rats treated with dexamethasone (1 mg/kg) for 4 days and from untreated littermates. Dexamethasone had no effect on insulin receptor number, while EGF receptor binding was slightly increased (21.3% vs. 17.2% binding/10(6) cells) after dexamethasone treatment. In hepatocytes from both control and dexamethasone-treated animals labeled with 32P, insulin induced tyrosine phosphorylation of the beta-subunit of the insulin receptor as well as of a 175K protein believed to be its endogenous substrate. The degree of phosphorylation of the insulin receptor was decreased 34% by dexamethasone treatment compared to the control value when studied in fasted animals. In contrast, phosphorylation was increased to a similar extent by dexamethasone treatment in fed animals. In addition, the beta-subunit of the insulin receptor extracted from dexamethasone-treated animals migrated on sodium dodecyl sulfate-polyacrylamide gel electrophoresis with a slightly increased mobility compared to normal (89 +/- 1.2K vs. 92.5 +/- 0.4K). EGF induced tyrosine phosphorylation of its own receptor and of a 120K protein in intact hepatocytes. Their degree of phosphorylation was decreased by 30% as a result of dexamethasone treatment in the fasted animal and was unchanged in the fed animals. Our data indicate that glucocorticoids modulate insulin and EGF receptor kinase activity, but the nature of their effect depends on other factors, including the dietary state of the animal. These studies also suggest that postreceptor changes account for a major component of glucocorticoid-induced insulin resistance.

Animals↗
PubMed1998

Inhibition of mitogen-activated protein kinase activity and proliferation of an early osteoblast cell line (MBA 15.4) by dexamethasone: role of protein phosphatases.

Chronic glucocorticoid therapy causes rapid bone loss and clinical osteoporosis. We found that although the glucocorticoid, dexamethasone, stimulated osteoblast maturation, it also inhibited proliferation of a preosteoblastic cell line, MBA-15.4. The dexamethasone-induced decline in preosteoblast proliferation correlated with a 30-40% reduction in protein kinase C/TPA-stimulated mitogen-activated protein kinase (MAPK) activity. These steroid effects only became evident after 6-24 h treatment, implying that dexamethasone acts on de novo synthesis of proteins. Because MAPK is inactivated by dephosphorylation of tyrosine and threonine residues, cells were treated concomitantly for 24 h with dexamethasone and inhibitors of tyrosine (sodium orthovanadate) and/or serine/threonine phosphatases (sodium fluoride). MAPK activity and cell proliferation were restored when MBA-15.4 cells were treated with vanadate, suggesting that dexamethasone up-regulates tyrosine phosphatase activity. Inactivation of serine/threonine phosphatases with sodium fluoride had no effect. Inhibition of the PKA pathway (which is growth inhibitory in mature osteoblasts) with H-89 did not reverse the effects of dexamethasone. Pretreatment with dexamethasone inhibited both peak- and extended activation plateau-phases of MAPK activity. Both phases were fully restored by pretreatment with vanadate, implicating more than one tyrosine phosphatase. Cycloheximide, alone or in combination with dexamethasone, prevented drop-off from plateau to basal levels, suggesting that an inducible dual-specificity phosphatase regulates the plateau-phase. We conclude that dexamethasone may inhibit preosteoblast growth via a novel tyrosine phosphatase pathway.

Animals↗
PubMed1997

Effectiveness versus efficacy: the limited value in clinical practice of high dose dexamethasone suppression testing in the differential diagnosis of adrenocorticotropin-dependent Cushing's syndrome.

High dose dexamethasone suppression testing has been widely employed in the differentiation between pituitary ACTH-dependent hypercortisolism [Cushing's disease (CD)] and the ectopic ACTH syndrome. We hypothesized that the high dose dexamethasone suppression test as it is performed in practice does not improve the ability to differentiate between these two types of ACTH-dependent Cushing's syndrome. Cases were drawn from 112 consecutive patients with ACTH-dependent Cushing's syndrome, who were then classified based upon results of inferior petrosal sinus sampling for ACTH levels. Analysis of test characteristics of high dose dexamethasone suppression testing was performed in the 73 patients for whom results are available. Statistical modeling was performed using the 68 cases with complete data on all assessed variables. Logistic regression models were used to predict the probability of pituitary-dependent Cushing's syndrome (CD) given the results of high dose dexamethasone suppression testing before and after adjustment for the contribution of a series of potential covariates. Of the 112 patients with ACTH-dependent Cushing's syndrome, 15.2% had the ectopic ACTH syndrome, and the remainder had pituitary-dependent Cushing's syndrome (CD). Patients with the ectopic ACTH syndrome were significantly older (mean, 51.9 vs. 40.2), were more likely to be male (58.8% vs. 27.4%), had shorter duration of clinical findings (mean, 11.6 vs. 39.9 months), were more likely to have hypokalemia (50% vs. 8.6%), had higher baseline 24-h urinary free cortisol [mean, 8317 vs. 1164 nmol/day (3015 vs. 422 microg)] and plasma ACTH levels [mean, 47 vs. 17 pmol/L (210 vs. 78 pg/mL)] and were less likely to suppress urinary free cortisol or plasma cortisol with high dose dexamethasone using the standard criterion of 50% or more suppression compared with patients with pituitary-dependent Cushing's syndrome. Based upon the standard criterion, the sensitivity and specificity of the high dose dexamethasone suppression test for the diagnosis of pituitary-dependent Cushing's syndrome were 81.0% and 66.7%, respectively. Although the mean percent suppression was significantly greater for patients with CD than for those with the ectopic ACTH syndrome (72.2% vs. 41.3%), the range of suppression was 0-99% for each diagnosis. The area under the receiver operating characteristic curve was 0.710 (95% confidence interval, 0.541-0.879). Logistic regression models were used to evaluate the probability of CD given the responsiveness to high dose dexamethasone suppression testing before and after adjustment for the potential contributions of other factors. A model including all of the variables (age, sex, duration, presence of hypokalemia, urinary free cortisol, and plasma ACTH) had a diagnostic accuracy of 92.7%. A model including all of these variables plus a binary variable indicating whether the patient met the criterion of suppression by 50% or more resulted in 95.6% accuracy, whereas substitution of this binary variable by percent suppression resulted in a model with 94.1% accuracy. There were no statistically significant differences among these models; their values for the c statistic, which is equivalent to the area under the curve in a receiver operating characteristic analysis, were all greater than 0.9. Logistic regression models indicate that the results of the dexamethasone suppression test add little to the differential diagnosis of ACTH-dependent Cushing's syndrome, especially after taking other clinical information into account. In our patient population, the sensitivity and specificity of the dexamethasone suppression test were less than those reported by others. However, because 20-33% of cases of ectopic ACTH syndrome are misdiagnosed with these logistic regression models, other techniques are necessary to achieve greater diagnostic accuracy.

ACTH Syndrome, Ectopic↗
PubMed1993

Dexamethasone inhibits corticotropin-induced accumulation of CYP11A and CYP17 messenger RNAs in bovine adrenocortical cells.

The effect of dexamethasone on ACTH-induced accumulation of CYP11A and CYP17 mRNAs was studied in bovine adrenocortical cells in primary culture. The cells were treated with either ACTH (1 microM) or the adenylate cyclase activator forskolin (25 microM) and/or dexamethasone (100 nM). The accumulation of CYP11A and CYP17 mRNAs was evaluated by Northern blot analysis with the use of [alpha-32P]deoxy-CTP-labeled bovine CYP11A and CYP17 cDNAs. Chloramphenicol acetyltransferase (CAT) activity was monitored in bovine adrenocortical cells transfected with recombinant plasmids containing either CYP11A or CYP17 regulatory regions coupled to the CAT reporter gene and treated with forskolin and/or dexamethasone. Dexamethasone treatment of the cells cultured in the presence of ACTH or forskolin resulted in about 50% suppression of both CYP11A and CYP17 mRNA accumulation, with a concomitant fall in cortisol secretion to about 60% of the stimulated value. The effects of dexamethasone on accumulation of CYP11A and CYP17 mRNAs and cortisol secretion were blocked by pretreatment of the cells with RU 486 (100 nM), while RU 486 had no effect on forskolin-induced accumulation of either mRNA or cortisol secretion. Dexamethasone also inhibited the forskolin-induced expression of the transfected CYP11A- or CYP17-CAT constructs in bovine adrenocortical cells. The inhibitory effect of dexamethasone was greatly reduced by cotreatment of the transfected cells with RU 486. It is concluded that dexamethasone inhibits the ACTH-induced accumulation of CYP11A and CYP17 mRNAs at a transcriptional level and that the effect of dexamethasone is mediated by the glucocorticoid receptor.

Adrenal Cortex↗
PubMed2001

Clonidine-induced antinociception and locomotor hypoactivity are reduced by dexamethasone in mice.

The effects of dexamethasone pretreatment on clonidine-induced antinociception and locomotor hypoactivity were investigated in mice. In the hot-plate and the tail-flick tests, dexamethasone administered intraperitoneally at a dose of 1 mg kg(-1), 30 or 60 min before clonidine, reduced clonidine antinociception in both tests and reduced clonidine-induced locomotor hypoactivity in the activity cage. When administered 15 min before clonidine, dexamethasone had no effect on clonidine antinociception. A higher dexamethasone dose (10 mg kg(-1)) induced the same effects observed at a dose of 1 mg kg(-1) in the hot-plate and the tail-flick tests, but the former dose had a stronger effect on locomotor hypoactivity. Dexamethasone (10 ng/mouse) administered intracerebroventricularly 30 min before clonidine was also able to reduce both clonidine-induced antinociception and locomotor hypoactivity. The protein synthesis inhibitor, cycloheximide, administered intraperitoneally at the dose of 10 mg kg(-1), 2 h before clonidine, was able to prevent dexamethasone effects on clonidine-induced antinociception. The glucocorticoid receptor antagonist RU-38486, administered intracerebroventricularly at the dose of 1 ng/mouse, was also able to block dexamethasone effects on clonidine-induced antinociception and locomotor hypoactivity, whereas both cycloheximide and RU-38486 per se did not influence pain sensitivity or locomotor activity. These results suggest that the dexamethasone effects on clonidine-induced antinociception and locomotor hypoactivity depend on the stimulating effects that dexamethasone exert, on the protein synthesis via the glucocorticoid receptor in the brain.

Adrenergic alpha-Agonists↗
PubMed2006

Effects of dexamethasone and aminophylline on survival of Jurkat and HL-60 cells.

The effects of dexamethasone and aminophylline on survival of Jurkat T-lymphocytic leukemia cells and HL-60 promyelocytic leukemia cells were investigated. Dexamethasone (10, 1000 nM) and aminophylline (1, 100 microM) induced apoptosis in Jurkat and HL-60 cells in a concentration-dependent manner. Treatment with a combination of dexamethasone (10 nM) and aminophylline (1 microM) significantly increased the number of apoptotic HL-60 cells, but not that of Jurkat cells, compared with dexamethasone (10 nM) or aminophylline (1 microM) treatment alone. Dexamethasone and aminophylline also increased the number of phospho-histone H2B (Ser(14))-positive Jurkat and HL-60 cells. Phospho-histone H2B (pH2B)-positive HL-60 cells were significantly increased by treatment with a combination of dexamethasone (10 nM) and aminophylline (1 microM), although no such effect was observed in Jurkat cells. On the other hand, simultaneous treatment with 10 nM dexamethasone and 1 muM aminophylline activated the 36-kDa MBP kinase, pro-apoptotic protein kinase in HL-60 cells. The activation of 36-kDa MBP kinase by dexamethasone and aminophylline was supported by studies showing an increase in the number of pH2B-positive and apoptotic Jurkat and HL-60 cells upon exposure to these drugs. Thus treatment with a combination of dexamethasone and aminophylline accelerates apoptosis of HL-60 cells via activation of 36-kDa MBP kinase and H2B phosphorylation.

Aminophylline↗
PubMed2001

Impaired cerebral cortical gray matter growth after treatment with dexamethasone for neonatal chronic lung disease.

OBJECTIVE: The specific aim of this study was to quantify at term the influence of postnatal systemic dexamethasone treatment for neonatal chronic lung disease on subsequent brain growth and development in premature infants without evidence of severe intraventricular hemorrhage or white matter injury. METHODS: Eighteen premature (23 to 31 weeks) infants, 7 treated with dexamethasone and 11 not treated, were studied at term, ie, 38 to 41 postconceptional weeks, by an advanced quantitative volumetric 3-dimensional magnetic resonance imaging (MRI) technique to quantify cerebral tissue volumes. Fourteen healthy term infants also were studied for comparison. A sequence of image processing algorithms was used to segment each of the MRI slices into the following separate tissue classes: cerebral cortical gray matter, basal ganglia/thalami, unmyelinated white matter, myelinated white matter, and cerebrospinal fluid, all classified based on magnetic resonance signal intensity and anatomic location. A final summing of voxels for each tissue class was performed to compute absolute volumes in milliliters. RESULTS: Cerebral cortical gray matter volume in premature infants treated with dexamethasone was reduced 35% when compared with gray matter volume in premature infants not treated with dexamethasone (mean +/- standard deviation, 130.3 +/- 54.0 vs 200.6 +/- 35.1 mL, respectively). Subcortical gray matter volumes (basal ganglia and thalami) and myelinated and unmyelinated white matter volumes were not significantly different among the treated and untreated groups. However, premature infants treated with dexamethasone exhibited a reduction (30%) in total cerebral tissue volume compared with total cerebral tissue volume in both the premature infants not treated with dexamethasone and the control term infants (312.7 +/- 43.7 vs 448.2 +/- 50.2 and 471.6 +/- 36.4 mL respectively). This latter finding relates primarily to the decrease in cerebral cortical gray matter volume. CONCLUSIONS: The data suggest an impairment in brain growth, principally affecting cerebral cortical gray matter, secondary to systemic dexamethasone therapy. Although the premature infants who received dexamethasone were smaller with more severe respiratory disease, these findings are consistent with growing evidence of a potential deleterious effect of dexamethasone on neonatal brain and subsequent neurodevelopmental outcome. This apparent deleterious effect should be taken into consideration by clinicians when weighing the potential risks and benefits of this therapy for low birth weight infants with neonatal chronic lung disease.

Case-Control Studies↗
PubMed2006

Adverse neonatal outcomes associated with antenatal dexamethasone versus antenatal betamethasone.

OBJECTIVE: Antenatal dexamethasone and betamethasone may not be equally efficacious in the prevention of adverse neonatal outcomes. We compared the risks of periventricular leukomalacia (PVL), intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP), and neonatal death among very low birth weight infants who were exposed to dexamethasone, betamethasone, or neither steroid. METHODS: Infants (401-1500 g) in the National Institute of Child Health and Human Development Neonatal Research Network were studied. Multivariate logistic regression analyses compared the 3 groups with regard to PVL, IVH, ROP, and neonatal death, adjusting for network center and selected covariates. RESULTS: A total of 3600 infants met entry criteria. Compared with no antenatal steroids, there were trends for a reduced risk for PVL associated with dexamethasone and betamethasone but no difference in risk between dexamethasone and betamethasone. Dexamethasone reduced the risk for IVH and severe IVH, compared with no antenatal steroid exposure. Betamethasone reduced the risk for IVH, severe IVH, and neonatal death, compared with no antenatal steroids. Compared with betamethasone, dexamethasone had a statistically significant increased risk for neonatal death. There were trends for greater risks associated with dexamethasone compared with betamethasone for IVH and severe ROP. CONCLUSIONS: Betamethasone was associated with a reduced risk for neonatal death, with trends of decreased risk for other adverse neonatal outcomes, compared with dexamethasone. It may be in the best interest of neonates to receive betamethasone rather than dexamethasone when available.

Betamethasone↗
PubMed2002

Regulation of equine lymphocyte beta-adrenoceptors under the influence of clenbuterol and dexamethasone.

In 12 healthy horses, the effects of the beta2-agonist clenbuterol and the glucocorticoid dexamethasone on the lymphocyte beta2-adrenoceptor density and affinity (determined by (-)-[125I]-iodocyanopindolol binding) as well as its responsiveness (assessed by lymphocyte cyclic AMP [cAMP] responses to 10 micromol/l (-)-isoprenaline) were studied. Clenbuterol treatment, 2 x 0.8 microg/kg/day i.v. for 12 days, decreased significantly ICYP binding sites by approximately 30-40%; concomitantly, lymphocyte cAMP response to (-)-isoprenaline was reduced. After withdrawal of clenbuterol, beta2-adrenoceptor density and responsiveness gradually increased, reaching predrug levels after 4 days. The effects of dexamethasone on clenbuterol-induced desensitisation were further investigated. Administration of dexamethasone (1 x 0.1 mg/kg/day, i.v. for 5 days) immediately after clenbuterol withdrawal accelerated beta2-adrenoceptor recovery: only 24 h after administration dexamethasone restored the number of binding sites and cAMP response to (-)-isoprenaline to levels statistically indistinguishable from values before clenbuterol treatment. Three days after dexamethasone administration, lymphocyte beta2-adrenoceptors were further increased about 2-fold the pretreatment values, and this increase declined gradually after dexamethasone withdrawal, reaching baseline values after 4 days. Furthermore, in groups exposed simultaneously to both drugs, dexamethasone completely prevented clenbuterol-induced decrease in lymphocyte beta2-adrenergic receptor density and responsiveness. No significant change was observed in the dissociation constant for ICYP in any of the situations. We conclude that dexamethasone (glucocorticoids) can reverse and prevent Clenbuterol-induced desensitisation (down-regulation) of the lymphocyte beta2-adrenoceptors and therefore, a combined therapy with clenbuterol and dexamethasone may be potentially beneficial in horses suffering from chronic obstructive pulmonary disease (COPD).

Adrenergic beta-Agonists↗
PubMed1990

Inhibition of vesicular stomatitis virus replication in dexamethasone-treated L929 cells.

We previously demonstrated that dexamethasone treatment of L929 cells inhibited plaque formation by vesicular stomatitis virus (VSV), encephalomyocarditis virus, or vaccinia virus. We now have characterized the antiviral effects of glucocorticoids in L929 cells. Dexamethasone did not directly inactivate VSV nor did steroid treatment of L929 cells affect virion adsorption or penetration. The VSV yield in L929 cells treated with dexamethasone for a period of only 4 or 8 hr was decreased by 50% when cells were infected the day following steroid treatment. Treating L929 cells with dexamethasone for a longer period resulted in greater inhibitions of virus synthesis. Interferon activity (less than 5 units/ml) was not detected in L929 cell culture fluids and cell sonicates from steroid-treated cells and the addition of antiserum to murine alpha/beta-interferon had no effect on the ability of dexamethasone to inhibit VSV replication. Dexamethasone treatment of L929 cells did not induce the production of double-stranded RNA-dependent protein kinase but did result in a slight elevation of 2-5A oligoadenylate synthetase activity, two enzymatic activities associated with the antiviral state induced by interferon. However, the elevated 2-5A synthetase activity was not associated with an inhibition of VSV RNA accumulation in dexamethasone-treated L929 cells. By contrast, the synthesis of all five VSV proteins was reduced by 50-75% in dexamethasone-treated L929 cells as early as 4 hr after infection. Thus, the dexamethasone-mediated inhibition of VSV replication in L929 cells is associated with decreased production of VSV structural proteins.

2',5'-Oligoadenylate Synthetase↗
PubMed2006

Dexamethasone mediates protection against acute pancreatitis via upregulation of pancreatitis-associated proteins.

AIM: To examine the influence of dexamethasone on pancreatitis-associated protein (PAP) gene expression using both in vitro and in vivo models of acute pancreatitis and to study how PAP gene expression correlates with severity of pancreatitis. METHODS: In vitro, IL-6 stimulated pancreas acinar AR42J cells were cultured with increasing concentrations of dexamethasone and assayed for PAP expression (RT-PCR). In vivo, pancreatitis was induced in rats by retrograde injection of 40 g/L taurocholate into the pancreatic duct. Animals were pretreated with dexamethasone (2 mg/kg) daily or saline for 4 d. Pancreata and serum were harvested after 24 h and gene expression levels of PAP I, II and III were measured by RT-PCR. Severity of pancreatitis was based on serum amylase, pancreatic wet weight, and histopathological score. RESULTS: In vitro, dexamethasone and IL-6 induced a marked transcription of PAP I, II and III genes in AR42J cells at 24 h (P < 0.05 for all comparisons). In vivo, pancreas mRNA levels of PAP I, II or III increased by 2.6-fold, 1.9-fold, and 1.3-fold respectively after dexamethasone treatment, compared with saline treated animals. Serum amylase levels and edema were significantly lower in the dexamethasone group compared with the saline group. Histopathologic evaluation revealed less inflammation and necrosis in pancreata obtained from dexamethasone treated animals (P < 0.05). CONCLUSION: Dexamethasone significantly decreases the severity of pancreatitis. The protective mechanism of dexamethasone may be via upregulating PAP gene expression during injury.

Acute Disease↗
PubMedDate not supplied

Comparison of ondansetron with ondansetron plus dexamethasone for antiemetic prophylaxis in children undergoing strabismus surgery.

BACKGROUND: Children undergoing strabismus surgery have a high incidence of postoperative nausea and vomiting. Ondansetron plus dexamethasone is effective in reducing its incidence in many surgical procedures. PURPOSE: To examine the efficacy of ondansetron plus dexamethasone in children undergoing strabismus surgery. PATIENTS AND METHODS: A randomized, placebo-controlled, double blind study of 100 children 2 to 12 years old, in American Society of Anesthesiologists classes I and II, and undergoing strabismus surgery with the use of general anesthesia was conducted. Children received normal saline (n = 31), an injection of 0.15 mg/kg of ondansetron (n = 39), or an injection of 0.15 mg/kg of ondansetron and 0.2 mg/kg of dexamethasone (n = 30). Postoperatively, children were monitored for the number of emetic episodes, Steward recovery score, and need for a rescue antiemetic. RESULTS: The incidence of vomiting was 64.5% in the group receiving saline, 33.3% in the group receiving ondansetron, and 10% in the group receiving ondansetron plus dexamethasone (P < .001). The incidence of early vomiting (0 to 4 hours) and the need for a rescue antiemetic were significantly lower in the groups receiving ondansetron (P < .01) and ondansetron plus dexamethasone (P < .001) compared with the group receiving saline; however, the former two groups were comparable in this regard. In the late postoperative period (4 to 24 hours), the incidence of vomiting and the need for a rescue antiemetic were not significantly different among the groups. Vomiting was significantly more severe in the group receiving saline compared with the groups receiving ondansetron and ondansetron plus dexamethasone at all times (P < .01 and P < .001, respectively). However, the latter two groups were comparable in this regard. CONCLUSION: Ondansetron and ondansetron plus dexamethasone were equally effective in preventing early nausea and vomiting in children following strabismus surgery. However, the efficacy of dexamethasone in late postoperative nausea and vomiting could not be demonstrated. Further studies with a large population and different doses of dexamethasone may be warranted.

Antiemetics↗
PubMedDate not supplied

Relation of plasma dexamethasone to clinical response.

OBJECTIVE: The clinical effects of high dosage pulse glucocorticosteroid (GS) infusion as a treatment for rheumatoid arthritis (RA) differ considerably between patients. The aim of the present study was to gain more insight into these differences in clinical response. METHODS: Twenty-three RA patients (6 M/17 F) with treatment-resistant active erosive disease were treated with GS pulse therapy, consisting of 3 infusions of 200 mg dexamethasone at 3-day intervals. Plasma dexamethasone and plasma cortisol levels, as well as the mononuclear cell glucocorticosteroid receptor density, were determined on days 0, 2, 6, 12 and 40 after the start of therapy. Clinical evaluation consisted of the Thompson articular index, the erythrocyte sedimentation rate (ESR), and the serum concentration of C reactive protein (CRP). RESULTS: Plasma dexamethasone levels in RA patients determined during pulse therapy revealed the existence of two groups. One group reached significantly (p < 0.05) higher plasma levels than another group comparable for age and sex. The CRP, ESR and Thompson joint score prior to the start of pulse therapy were all higher (p < 0.05) for the high plasma dexamethasone group. The decrease in ESR, CRP and the Thompson joint score was also significantly greater (all p < 0.05) for the high plasma dexamethasone group. Plasma cortisol, as well as the GS receptor density at the start of treatment, did not differ between the two groups; both decreased after the first pulse in both groups and returned to pre-treatment values shortly after the last infusion. CONCLUSION: The treatment of refractory RA with dexamethasone pulse therapy is, on average, beneficial. The high plasma dexamethasone levels reached might depend on the greater severity of the disease in these patients prior to the start of the treatment, and result in greater changes in the disease parameters. Glucocorticosteroid receptor density measurements made during and directly after high dose pulse dexamethasone treatment proved to be unreliable because of the high plasma dexamethasone levels.

Arthritis, Rheumatoid↗
PubMedDate not supplied

Effectiveness of high dose dexamethasone in the treatment of acute stroke.

A prospective double-blind placebo-controlled, randomised clinical trial was carried out to determine the effectiveness of short-course of high dose dexamethasone therapy on mortality and neurological recovery in stroke patients. During a sixteen month period of study, 230 patients with clinical diagnosis of stroke were seen. Of these, 40 were eligible for the study (27 were presumed to have had haemorrhagic stroke; and 13 were presumed to have had cerebral infarction). The commonest cause of exclusion was presentation after 24 hours of the ictus. Patients were sequentially paired and randomised into high dose dexamethasone and placebo groups in a double-blind fashion. There were twenty patients in either group. Of the 27 patients with haemorrhagic stroke, 15 were in the dexamethasone group and 12 in the placebo group. Of the 13 patients with cerebral infarction, 5 were in the dexamethasone group and 8 in the placebo group. Each patient received 100 mg of dexamethasone stat, and 16 mg every 6 hours for a period of 48 hours or equivalent volumes of placebo. Assessment of each patient was done using a neurological score. Sequential analysis by Armitage was employed, using survival at 1 month as the primary criterion of effectiveness. Survivors were followed-up for 6 months. At the end of one month, 16 patients (80%) had died in the dexamethasone group and 17 (85%) in the placebo group. The average day of death was six days in the dexamethasone group and 15 days in the placebo group, but this was not statistically significant. Of the seven survivors at one month, four were in the dexamethasone group and 3 in the placebo group. Five of them had cerebral infarction and two had haemorrhagic stroke. The two in the haemorrhagic subgroup who survived the first month died at the 2nd and 4th month respectively. At the end of six months, only the five patients with cerebral infarction were alive. Of these, 2 in the dexamethasone group were back at work while the third was chair-bound. The 2 survivors in the placebo group were chair and bed bound respectively. In conclusion, this study failed to demonstrate any benefit of a short-course of high dose steroid in improving the mortality of stroke patients and its use should be discouraged. However, possible benefit in the morbidity of survivors in the patients with cerebral infarction requires further studies.

Activities of Daily Living↗
PubMed2001

[Intravitreally injectable poly (D, L-Lactide) microspheres containing dexamethasone acetate for sustained release].

AIM: To prepare and evaluate dexamethasone acetate-loaded poly (d, l-lactide) microspheres for sustained release in vitro and their therapeutic effect on proliferative vitreoretinopathy in vivo. METHODS: The microspheres were prepared by a solvent evaporation/extraction technique. Properties such as geometric mean diameter, span, drug loading, rate of entrapment and release characteristics were evaluated. Differential scanning calorimetry and X-ray powder diffractometry were used to identify the physical phase of dexamethasone acetate in poly (d, l-lactide) matrix, and safety in vivo was examined. Effect of drug-loaded microspheres on suppression of experimental proliferative vitreoretinopathy was studied in albino rabbit eyes after an intravitreal injection of macrophages. RESULTS: The geometric mean diameter and span of the microspheres were 62.9 microns and 0.92, respectively. Drug loading and rate of entrapment of dexamethasone acetate in microspheres were 17.5% and 86.5%, respectively. Differential scanning calorimetry and X-ray powder diffractometry showed that dexamethasone acetate dispersed uniformly as molecules in poly (d, l-lactide) matrix. Ninety percent of the dexamethasone acetate was released in vitro from dexamethasone acetate after 48 days, while the same amount released from microspheres took 90 days. Storage under 4 degrees C in refrigerator or 25 degrees C in a dessicator at a relative humidity of 75% for 90 days had little effect on the properties of the microspheres. Intravitreal injection of microspheres showed a sustained release and continuous action of dexamethasone acetate for 84 days. After injection of activated macrophages, the groups of blank microspheres and dexamethasone acetate showed proliferation to different extent, while the base of the eye remained clear and no obvious proliferation was observed for the group of microspheres. A significant difference exists between these three groups. CONCLUSION: Poly (d, l-lactide) microspheres containing dexamethasone acetate is a potentially promising delivery system for the suppression of proliferative vitreoretinopathy.

Animals↗
PubMed2001

[Pharmacokinetics of site-specific delivery of dexamethasone-dextran prodrug in rat gastrointestinal tract].

AIM: To explore whether dexamethasone-dextran (260,000) has the characteristics of site-specific delivery in rat gastrointestinal tract. METHODS: Dexamethasone prodrug and dexamethasone were administered to rat ig at the dose of 5 mumol.kg-1. The distribution of dexamethasone in the contents and mucosa of different parts of the rat GI tract at different time intervals and its concentration in plasma were determined by HPLC. RESULTS: Dexamethasone was mainly released in the cecum and colon contents and mucosa after oral administration of dexamethasone prodrug. The absorption was reduced significantly. The peak time of the drug in plasma was 8.1 h, and the peak concentration was 32 micrograms.L-1. However, free dexamethasone was found mainly in the contents and mucosa of the stomach, proximal and distal small intestine. The peak time of the drug in plasma was 2.2 h, and the peak concentration was 2120 micrograms.L-1. CONCLUSION: Dexamethasone can be specifically delivered to the large intestine by using dexamethasone-dextran (260,000). It appears that the prodrug has a potential in the treatment of inflammatory bowel disease.

Animals↗
PubMed2003

Implementing potentially better practices to improve neonatal outcomes after reducing postnatal dexamethasone use in infants born between 501 and 1250 grams.

OBJECTIVE: The purpose of this article is to describe how a neonatal intensive care unit (NICU) was able to reduce substantially the use of postnatal dexamethasone in infants born between 501 and 1250 g while at the same time implementing a group of potentially better practices (PBPs) in an attempt to decrease the incidence and severity of chronic lung disease (CLD). METHODS: This study was both a retrospective chart review and an ongoing multicenter evidence-based investigation associated with the Vermont Oxford Network Neonatal Intensive Care Quality Improvement Collaborative (NIC/Q 2000). The NICU specifically made the reduction of CLD and dexamethasone use a priority and thus formulated a list of PBPs that could improve clinical outcomes across 3 time periods: era 1, standard NICU care that antedated the quality improvement project; era 2, gradual implementation of the PBPs; and era 3, full implementation of the PBPs. All infants who had a birth weight between 501 and 1250 g and were admitted to the NICU during the 3 study eras were included (era 1, n = 134; era 2, n = 73; era 3, n = 83). As part of the NIC/Q 2000 process, the NICU implemented 3 primary PBPs to improve clinical outcomes related to pulmonary disease: 1) gentle, low tidal volume resuscitation and ventilation, permissive hypercarbia, increased use of nasal continuous positive airway pressure; 2) decreased use of postnatal dexamethasone; and 3) vitamin A administration. The total dexamethasone use, the incidence of CLD, and the mortality rate were the primary outcomes of interest. Secondary outcomes included the severity of CLD, total ventilator and nasal continuous positive airway pressure days, grades 3 and 4 intracranial hemorrhage, periventricular leukomalacia, stages 3 and 4 retinopathy of prematurity, necrotizing enterocolitis, pneumothorax, length of stay, late-onset sepsis, and pneumonia. RESULTS: The percentage of infants who received dexamethasone during their NICU admission decreased from 49% in era 1 to 22% in era 3. Of those who received dexamethasone, the median number of days of exposure dropped from 23.0 in era 1 to 6.5 in era 3. The median total NICU exposure to dexamethasone in infants who received at least 1 dose declined from 3.5 mg/kg in era 1 to 0.9 mg/kg in era 3. The overall amount of dexamethasone administered per total patient population decreased 85% from era 1 to era 3. CLD was seen in 22% of infants in era 1 and 28% in era 3, a nonsignificant increase. The severity of CLD did not significantly change across the 3 eras, neither did the mortality rate. We observed a significant reduction in the use of mechanical ventilation as well as a decline in the incidence of late-onset sepsis and pneumonia, with no other significant change in morbidities or length of stay. CONCLUSIONS: Postnatal dexamethasone use in premature infants born between 501 and 1250 g can be sharply curtailed without a significant worsening in a broad range of clinical outcomes. Although a modest, nonsignificant trend was observed toward a greater number of infants needing supplemental oxygen at 36 weeks' postmenstrual age, the severity of CLD did not increase, the mortality rate did not rise, length of stay did not increase, and other benefits such as decreased use of mechanical ventilation and fewer episodes of nosocomial infection were documented.

Anti-Inflammatory Agents↗
PubMed1992

Ciglitazone prevents and reverses dexamethasone-induced hyperglycemia in female viable yellow mice.

Hypercorticism has been observed in numerous obese and diabetic animal models. Adrenalectomy reduces adiposity, hyperglycemia, hyperinsulinemia, and insulin resistance in these animals. The effects of adrenalectomy can be reversed by glucocorticoid replacement. Male and female viable yellow mice share all phenotypic expressions caused by the viable yellow mutation except that males are hyperglycemic and most females are either normoglycemic or only mildly hyperglycemic. The mechanisms that protect female viable yellow mice from hyperglycemia are not known. Implantation of dexamethasone pellets induced hyperglycemia in female viable yellow mice but had no effect on blood glucose of male viable yellow mice and male and female normal mice. The duration of dexamethasone-induced hyperglycemia correlated to the time endogenous plasma corticosterone levels were suppressed. Plasma insulin levels rose in normal mice but only transiently in viable yellow mice. Ciglitazone prevented and reversed dexamethasone-induced hyperglycemia in female viable yellow mice. Since female viable yellow mice, similar to male viable yellow mice, are obese, hyperinsulinemic and insulin resistant, and since dexamethasone is known to cause insulin resistance, these data suggest that dexamethasone increased insulin resistance to a degree that the protective mechanism was overwhelmed and hyperglycemia was induced. Ciglitazone, a compound known to improve insulin sensitivity, may prevent and reverse dexamethasone-induced hyperglycemia by ameliorating the additional insulin resistance caused by dexamethasone. On a molecular level, since dexamethasone suppresses glucose transport, an insulin-sensitive process in many tissues, whereas ciglitazone and other thiazolidinediones facilitate glucose transport, it is possible that ciglitazone prevents and reverses dexamethasone-induced hyperglycemia by regulating the glucose transport systems in insulin-sensitive tissues.

Administration, Oral↗