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PubMed2003

Dexamethasone-associated toxicity during induction chemotherapy for childhood acute lymphoblastic leukemia is augmented by concurrent use of daunomycin.

BACKGROUND: The goals of the current study were to examine the incidence and severity of toxicity resulting from dexamethasone and prednisone during induction therapy for children with precursor B-cell acute lymphoblastic leukemia (ALL) and to determine whether the addition of daunomycin affected toxicity. METHODS: Medical records of patients with precursor B-cell ALL from January 1996 through June 2000 were reviewed retrospectively for toxicity during the 4-week induction phase and the 2 weeks after the induction phase. RESULTS: One hundred seventy-six patients age < 14 years were diagnosed with precursor B-cell ALL from January 1996 through June 2000. Of the 156 evaluable patients, 106 were treated with prednisone and 50 with dexamethasone. Fifty-two patients received steroids, L-asparaginase, and vincristine, whereas 104 high-risk patients received daunomycin in addition to these 3 agents. The incidence of gastritis was significantly higher among patients receiving dexamethasone (P = 0.01); incidence rates of hyperglycemia, hypertension, and myopathy were similar for all treatment groups. Dexamethasone led to more weight gain than did prednisone (+11.9% vs. +5.4%; P = 0.002). Serious infections were observed in 27 (25.5%) and 18 (36%) patients receiving prednisone and dexamethasone, respectively (P < or = 0.2). Five patients, four of whom received prednisone and one of whom received dexamethasone, died of infection. The addition of daunomycin to treatment regimens increased overall toxicity (P < 0.01). When daunomycin was included in treatment regimens, toxicity was greater among patients receiving dexamethasone; in contrast, when daunomycin was not included, toxicity was equal for both treatment groups. Regardless of daunomycin use, there was no difference in the incidence of serious infection between the two groups. ALL treatment was not compromised by steroid-related toxicity in either group. CONCLUSIONS: The addition of daunomycin led to a much larger increase in dexamethasone-related toxicity compared with the increase in prednisone-related toxicity. Although the use of daunomycin enhanced dexamethasone-related toxicity, this enhancement did not result in a higher mortality rate or the alteration of planned ALL therapy.

Adolescent↗

PubMed1996

Stimulation of neonatal mouse calvarial bone resorption by the glucocorticoids hydrocortisone and dexamethasone.

In vitro stimulation of bone resorption was observed with the glucocorticoids hydrocortisone and dexamethasone. Dosage-dependent release of 45Ca from neonatal mouse calvarial bones was found for both steroids, with half-maximal responses for hydrocortisone and dexamethasone of 0.3 and 0.08 microM, respectively. Significant release of stable calcium (Ca2+), inorganic phosphate (Pi), and the lysosomal enzyme beta-N-acetylglucosaminidase was noted following treatment of mouse calvariae with either 1 microM hydrocortisone or 1 microM dexamethasone. Additionally, both 1 microM hydrocortisone and 1 microM dexamethasone elicited release of 3H from calvarial bones prelabeled with [3H]proline. The stimulation of bone resorption by the glucocorticoids, as assessed by 45Ca release, was sustained over 120 h of culture. Inhibition of 45Ca release from calvariae treated with either 1 microM hydrocortisone or 0.1 microM dexamethasone was observed with 0.01-30 nM salmon calcitonin (sCT), 0.1 mM acetazolamide, and 0.1 mM of the bisphosphonate AHPrBP. Inhibition of glucocorticoid-induced bone resorption by sCT occurred without "escape from calcitonin-induced inhibition." The 45Ca release stimulated by 1 microM hydrocortisone and 0.1 microM dexamethasone was also inhibited by 10 microM progesterone in a competitive manner and by 1 microM of the antiglucocorticoid RU38486, both of which are modulators of glucocorticoid binding. Prostaglandin E2 (PGE2) formation by 10 nM parathyroid hormone (PTH) in neonatal mouse calvarial bones was inhibited by both 1 microM hydrocortisone and 1 microM dexamethasone, but neither compound altered basal PGE2 formation. Exposure of calvarial bones to the mitotic inhibitors hydroxyurea and mitomycin C inhibited 45Ca release stimulated by 1 microM hydrocortisone and 1 microM dexamethasone. In contrast, addition of 1 ng/ml of recombinant murine granulocyte macrophage colony stimulating factor (rmGM-CSF) had no effect on 45Ca release elicited by the glucocorticoids. These results suggest that hydrocortisone and dexamethasone stimulate osteoclastic resorption in neonatal mouse calvariae by a receptor-mediated mechanism that is dependent on cellular replication.

Acetazolamide↗

PubMed2004

Dexamethasone induces human spinal ligament derived cells toward osteogenic differentiation.

Ossification of spinal ligament is characterized by heterotopic bone formation in the spinal ligaments that are normally composed of fibrous tissues. The pathogenesis of ossification of spinal ligament has been suggested to be associated with osteogenic differentiation of the spinal ligament cells. In order to address this hypothesis, cells derived from human spinal ligament were investigated for their osteogenic potential by the treatment of dexamethasone in vitro. Yellow ligaments were obtained from patients with spinal disorders except ossification of spinal ligament during surgery, and the adhering tissues were removed completely. Most of the ligament cells treated with vehicle exhibited a fibroblast-like spindle shape, while the dexamethasone-treated cells acquired a polygonal morphology. Growth of the ligament cells was suppressed by dexamethasone at a high concentration. Some of the vehicle treated-cells were alkaline phosphatase-positive, and dexamethasone increased the alkaline phosphatase-positive cells and alkaline phosphatase activity in the cells. Northern blot analysis demonstrated that mRNAs expression of pro-alpha1(I) collagen and alkaline phosphatase were promoted by dexamethasone. Analysis by reverse transcription-polymerase chain reaction showed that expression of osteocalcin mRNA was detected in the dexamethasone-treated cells but not in the vehicle-treated cells, and dexamethasone-induced osteocalcin mRNA expression was promoted by 1,25-dihydroxyvitamin D(3). Finally, mineralization of extracellular matrix in the cells was induced by the presence of dexamethasone and 1,25-dihydroxyvitamin D(3). These results suggest for the first time that dexamethasone has a possible involvement in the osteoblastic differentiation of human spinal ligament cells.

Alkaline Phosphatase↗

PubMed1987

Dexamethasone inhibits feedback regulation of the mitogenic activity of tumor necrosis factor, interleukin-1, and epidermal growth factor in human fibroblasts.

Tumor necrosis factor (TNF), interleukin-1 (IL-1), and epidermal growth factor (EGF) were mitogenic for human diploid FS-4 fibroblasts. Dexamethasone amplified the growth-stimulating action of all three agents. Amplification of the growth-stimulating action was maximal when dexamethasone was added along with TNF or EGF; no amplification was seen if the addition of dexamethasone was delayed for more than 3 hr. Prolonged simultaneous treatment with TNF and EGF resulted in less growth stimulation than treatment with EGF alone. Dexamethasone abolished this apparent antagonistic interaction between TNF and EGF. Dexamethasone also inhibited the antiviral action of TNF against encephalomyocarditis (EMC) virus in FS-4 cells. TNF and IL-1 increased the steady state level of interferon (IFN)-beta 2 mRNA but failed to induce detectable levels of IFN-beta 1 mRNA in FS-4 cells. Dexamethasone inhibited the increase of IFN-beta 2 mRNA levels by IL-1 or TNF. Inhibition of IFN-beta synthesis is likely to be responsible for the inhibition of the TNF-induced antiviral state by dexamethasone. Since IFNs suppress cell growth, inhibition of endogenous IFN-beta synthesis may also be responsible for the amplification by dexamethasone of the growth-stimulating action of TNF and IL-1. Amplification of the mitogenic action of EGF by dexamethasone appears to be mediated by different mechanism.

Cell Line↗

PubMed1994

31P NMR characterization of cellular metabolism during dexamethasone induced apoptosis in human leukemic cell lines.

31P NMR has been used to study the effects of dexamethasone on phosphorus metabolism in one dexamethasone (dex)-sensitive (CEM-C7) and three different dex-resistant (CEM-C1, CEM-4R4, and CEM-ICR27) human leukemic cell lines. The use of these cell lines, containing widely varying amounts of glucocorticoid receptors, made it possible to evaluate the receptor-mediated contributions to the modes of action of dexamethasone in these cells. To evaluate the effects of dexamethasone without any significant contribution from experimental conditions, all the experiments were done with parallel controls. Results obtained showed: 1) significantly different levels of phosphorylethanolamine (PE) and phosphorylcholine (PC) among cell lines, suggesting significant differences in phospholipid metabolism; 2) the dexamethasone induced reduction of phosphomonoester (PE+PC), ATP, and metabolic rates probably through glucocorticoid receptor mediated mechanisms; 3) the dexamethasone induced stimulation of cellular metabolism in a process which seems to be independent of glucocorticoid receptors; and 4) the dexamethasone induced alkaline shift of intracellular pH in all the cell lines except ICR27. The reduction in PME levels seems to be an earlier step in dexamethasone-induced apoptosis than the reduction in ATP. The degree of alkaline shift was found to correlate with the number of glucocorticoid receptors present. The possible involvement of phospholipid metabolites as second messengers in dexamethasone-induced apoptosis is discussed.

Adenosine Triphosphate↗

PubMed1997

Dexamethasone-induced suppression of apoptosis in human neutrophils requires continuous stimulation of new protein synthesis.

We examined the mechanisms of corticosteroid inhibition of cell death by apoptosis in human neutrophils. Suppression of apoptosis by dexamethasone was abolished by co-treatment with the protein synthesis inhibitor cycloheximide. At doses of 1 microg/mL cycloheximide did not reduce basal survival of neutrophils but effectively inhibited dexamethasone-induced increases in 24-h survival (24.4 +/- 8.7 vs. 49.6 +/- 10%, P < 0.01). Similar results were obtained with actinomycin D, an inhibitor of mRNA synthesis. The factor(s) responsible for mediating increased survival following dexamethasone treatment is not active extracellularly because dexamethasone-treated neutrophil-conditioned medium (CM) had no effect on the survival of naive neutrophils when the direct effects of dexamethasone were neutralized with the steroid antagonist RU-486. In contrast, LPS-treated neutrophil CM significantly increased neutrophil survival even after addition of polymyxin b. The survival effect of dexamethasone required the continuous presence of the agonist because addition of RU-486 caused prompt development of apoptosis in dexamethasone-treated cells. When naive and dexamethasone-treated cells were examined by mRNA differential display, a limited number of cDNA bands were consistently and reproducibly detected that were increased in intensity, indicating up-regulation by dexamethasone. Thus, corticosteroid regulation of neutrophil apoptosis is a specific effect that depends on continuous stimulation of synthesis of a (protein) survival factor.

Apoptosis↗

PubMed2001

Dexamethasone modulates TCR zeta chain expression and antigen receptor-mediated early signaling events in human T lymphocytes.

Dexamethasone is a potent anti-inflammatory and immunosupressive agent that has complex, yet incompletely defined, effects on the immune response. Here, we explored the effect of dexamethasone on the expression of TCR zeta chain and TCR/CD3-induced early signaling events in human T lymphocytes. Immunoblotting studies using TCR zeta chain specific mAb showed a dose-dependent biphasic effect of dexamethasone on TCR zeta chain expression, that is, it was increased when cells were incubated with 10 nM, whereas the expression was decreased when incubated with 100 nM dexamethasone. The dose-dependent biphasic effect of dexamethsone on the TCR zeta chain expression was also revealed by FACS analysis of permeabilized cells. Time course studies showed that upregulation of the TCR zeta chain at 10 nM dexamethasone reached maximum levels at 24 h and remained elevated up to 48 h. Other subunits of the TCR/CD3 complex were minimally affected under these conditions. The increased expression of the TCR zeta chain following treatment with 10 nM dexamethasone correlated with increased anti-CD3 antibody-induced tyrosine phosphorylation of the TCR zeta chain and downstream signaling intermediate ZAP-70 and PLC gamma with faster kinetics. Similarly, the induction of TCR zeta chain expression at 10 nM dexamethasone correlated with increased and more sustained TCR/CD3-mediated [Ca(2+)](i) response. Reporter gene assays using TCR zeta chain promoter-driven luciferase gene constructs in Jurkat cells showed that treatment with 10 nM dexamethasone increased TCR zeta chain promoter activity and that the region between -160 and +58 was responsible for the observed effect. These results suggest that dexamethasone primarily acts at the transcriptional level and differentially modulates TCR zeta chain expression and antigen receptor-mediated early signaling events in human peripheral T lymphocytes.

Adolescent↗

PubMed1994

Dexamethasone enhancement of betaglycan (TGF-beta type III receptor) gene expression in osteoblast-like cells.

Betaglycan (type III transforming growth factor-beta (TGF-beta) receptor) is a cell surface heparan/chondroitin sulfate proteoglycan that binds TGF-beta via its core protein and is abundantly expressed in osteoblastic cells. A previous report (Centrella et al., Mol. Cell. Biol. 11, 4490-4496, 1991) showed post-translational enhancement by glucocorticoid of TGF-beta binding to betaglycan. Upon the availability of the betaglycan cDNA, we investigated the effects of a glucocorticoid analogue, dexamethasone, on the regulation of betaglycan expression in osteoblast-like cells. Betaglycan mRNA was expressed as an approximately 6-kb band in MC3T3-E1 cells. The betaglycan mRNA level was enhanced severalfold by dexamethasone in these cells. The effect of dexamethasone on the betaglycan mRNA level was observed within 9 h and was sustained at least up to 48 h. The dexamethasone effect was dose-dependent, with a saturation concentration at 10(-7) M. Among the steroid hormones examined, dexamethasone exhibited the most potent effect on betaglycan mRNA expression, while retinoic acid also enhanced it moderately. Dexamethasone enhancement of betaglycan mRNA expression was blocked by actinomycin D, but it was not blocked by cycloheximide. Cross-linking experiments showed that dexamethasone treatment increased the binding of radiolabeled TGF-beta 1 to betaglycan, but did not affect binding to the type II receptor. A similar dexamethasone enhancement of betaglycan mRNA expression was also observed in a preosteoblast-like cell line, RCT1. These results suggest that dexamethasone enhances betaglycan expression at least in part via transcriptional events in osteoblasts and this would be one of the target points of glucocorticoid regulation of bone metabolism.

Animals↗

PubMed1995

The effects of dexamethasone on experimental brain tumors: I. Transcapillary transport and blood flow in RG-2 rat gliomas.

Dexamethasone dramatically improves cerebral edema associated with malignant gliomas. Although the pathophysiology of this effect is not clearly understood, many investigators have postulated that tumor capillary permeability is reduced by dexamethasone. We studied blood-to-tissue transport and blood flow in 178 RG-2 transplanted gliomas in a control group and four groups given dexamethasone at doses of 3, 6, 9, and 12 mg/kg for four days. 14C-alpha aminoisobutyric acid (AIB) was used to study blood-to-tissue transport in 31 animals; in an additional 27 animals 14C-AIB and 131I-iodoantipyrine (IAP) were used in double label experiments to study blood-to-tissue transport and blood flow. Regional measurements of the transfer constant (K) of AIB and blood flow (F) were made with quantitative autoradiography. There were significant differences between the control and dexamethasone-treated groups with regard to weight loss and plasma glucose. However, there was no significant effect of dexamethasone on values of K or F, regardless of the tumor or brain region examined, and regardless of the dose of dexamethasone administered. Analysis of the profiles of the transfer constant of AIB in the brain around tumor showed that the K of AIB decreased within 0.5 mm of the tumor edge in direct relationship to the dexamethasone dose. These results do not support the hypothesis that dexamethasone reduces brain tumor capillary permeability, and suggest that dexamethasone may decrease tumor-associated cerebral edema by effects on bulk flow away from the tumor margin.

Aminoisobutyric Acids↗

PubMed1995

Inhibition of some aspects of acute inflammation of guinea-pig lung by intraperitoneal dexamethasone and mifepristone: demonstration of agonist activity of mifepristone in the guinea-pig.

We have determined the inhibitory activity of dexamethasone as an inhibitor of histamine-induced plasma protein extravasation (PPE) in guinea-pig lung and skin, and of lipopolysaccharide (LPS)-induced neutrophilia and platelet activating factor (PAF)-induced eosinophilia in guinea-pig lungs. Dexamethasone inhibited PAF-induced eosinophilia in guinea-pig lung (ED50 1.4 mg/kg i.p.). Higher doses of dexamethasone were required to inhibit LPS-induced neutrophilia (ED50 10.8 mg/kg i.p.). However, at doses up to 150 mg/kg i.p. dexamethasone did not inhibit histamine-induced plasma protein extravasation (PPE) in guinea-pig lung, but did inhibit PPE in guinea-pig skin. These preparations have previously been shown to be equally sensitive to inhibition by the beta 2-adrenoceptor agonist salmeterol. Dexamethasone inhibited PAF-induced eosinophilia (5 mg/kg) or LPS-induced neutrophilia (50 mg/kg) when given 3 h or 1 h prior to challenge. Inhibitory activity was lost when dexamethasone was administered 23 h prior to LPS or 1 h after PAF. The glucocorticoid antagonist mifepristone (1-100 mg/kg i.p.) caused dose-related inhibition of PAF-induced eosinophilia but not of LPS-induced neutrophilia. The highest dose of mifepristone used (100 mg/kg) did not reverse the inhibitory actions of dexamethasone (50 mg/kg) on LPS-induced neutrophilia. We suggest that the different inhibitory activity of dexamethasone in the preparations studied indicates differences in the sensitivity of the target cells involved to inhibition by dexamethasone. We also suggest that inhibition of PAF-induced eosinophilia by mifepristone reflects the partial agonist activity of this agent, demonstrated by others in different experimental systems.

Acute Disease↗

PubMed2003

Dexamethasone reduces postoperative vomiting and pain after pediatric tonsillectomy.

PURPOSE: Previous studies on dexamethasone's antiemetic and analgesic potential in children undergoing tonsillectomy have produced conflicting results. The aim of this study was to evaluate the effects of a single dose of dexamethasone on the incidence and severity of postoperative vomiting and pain in children undergoing electrocautery tonsillectomy under standardized general anesthesia. METHODS: In a double-blinded study, 120 patients were randomly allocated to receive either dexamethasone 0.5 mg.kg(-1) (maximum dose 8 mg) iv or an equivalent volume of saline preoperatively. The incidence of early and late vomiting, need for rescue antiemetics, time to first oral intake, time to first demand of analgesia and analgesic consumption were compared in both groups. Pain scores used included Children's Hospital Eastern Ontario Pain Scale, "faces", and a 0-10 visual analogue pain scale. RESULTS: Compared with placebo, dexamethasone significantly decreased the incidence of early and late vomiting (P < 0.05, P < 0.001 respectively). Fewer patients in the dexamethasone group needed antiemetic rescue (P < 0.01). The time to first oral intake was shorter, and the time to first dose of analgesic was longer in the dexamethasone group (P < 0.01). Pain scores 30 min after extubation were lower (P < 0.05) in the dexamethasone group. At 12 and 24 hr postoperative swallowing was still significantly less painful in the dexamethasone group than in the control group (P < 0.01). CONCLUSION: Preoperative dexamethasone 0.5 mg.kg(-1) iv reduced both postoperative vomiting and pain in children after electrocautery tonsillectomy.

Anesthesia, General↗

PubMed2000

Dexamethasone enhances P-selectin mRNA expression in hyperoxic rat lungs.

OBJECTIVE AND DESIGN: To test the hypothesis that glucocorticoid administration would diminish the lung expression of P-selectin mRNA in hyperoxia-exposed rats. ANIMALS: Adult male Sprague-Dawley rats were divided into 6 separate groups containing 10 to 13 animals per group. TREATMENT: Rats were dosed with 1 mg/kg of dexamethasone or vehicle only, ip. Immediately after dosing, animals were placed in > 95 % oxygen. Some animals were maintained in room air and are presented as 0 h of exposure to hyperoxia. Another group of animals was dosed with 10 mg/kg lipopolysaccharide (LPS) ip immediately after dosing with either dexamethasone or vehicle as above. METHODS: At 24 or 48 h, lung samples were obtained, and lung weight to body weight ratios calculated. In the LPS studies, samples were obtained 4 h after LPS dosing. In a subset of animals, lung sections were hybridized for P-selectin mRNA. All data except for hybridizations were analyzed with three-way ANOVA, with subsequent post-hoc testing. P-selectin hybridizations were quantified by counting the number of positive vessels per high-powered field, and subsequently analyzed by unpaired Student's t-test. Immunohistochemical analyses for P-selectin expression were also performed to determine whether changes in P-selectin mRNA were associated with differences in protein expression. All data are expressed as means +/- SEM. RESULTS: Rats dosed with dexamethasone had higher lung/body weight ratios after 24 and 48 h of exposure to hyperoxia than did similarly exposed rats dosed only with vehicle (at 48 h, 0.87 +/- 0.04 versus 0.65 +/- 0.06, respectively, P < 0.05). The higher ratios in hyperoxic animals dosed with dexamethasone were associated with much higher levels of lung expression for P-selectin mRNA than was observed in similarly exposed rats dosed with vehicle alone (at 48 h, 3.93 +/- 1.02, versus 0.20 +/- 0.06, respectively, P < 0.01). In contrast dexamethasone dosing lead to lower lung P-selectin mRNA expression in animals exposed to LPS (1.23 +/- 1.08 in dexamethasone dosed animals versus 6.80 +/- 0.92 in vehicle only dosed animals). Consistent with the mRNA data, P-selectin immunoreactivity increased as a function of hyperoxia-exposure time in animals dosed with dexamethasone, while immunoreactivity decreased as a function of hyperoxia-exposure time in animals dosed with vehicle only. CONCLUSIONS: Increased P-selectin mRNA combined with increased P-selectin protein expression in animals exposed to hyperoxia and dosed with dexamethasone suggests that enhanced expression of P-selectin may contribute to the greater lung injury and inflammation caused by hyperoxia in rats treated with dexamethasone.

Animals↗

PubMed2005

Effect of intravitreal dexamethasone on vitreous vancomycin concentrations in patients with suspected postoperative bacterial endophthalmitis.

PURPOSE: To study intravitreal dexamethasone and vancomycin concentrations, when used together in patients with suspected postoperative bacterial endophthalmitis. Animal studies had suggested that dexamethasone might decrease the concentration of vancomycin. DESIGN: Prospective randomized clinical trial in a tertiary referral center. METHODS: Twenty-nine consecutive patients with suspected postoperative bacterial endophthalmitis underwent a vitreous biopsy followed by intravitreal injection of antibiotics (0.2 mg vancomycin, 0.05 mg gentamicin) and 400 mug dexamethasone or placebo. After 3-4 days, the intravitreal injection of antibiotics and dexamethasone or placebo was repeated. In 18 patients, a second biopsy was taken for repeat culture and measurement of vancomycin and dexamethasone concentrations. RESULTS: In 20/29 patients (69%) the first vitreous cultures were positive; the second culture was negative in all cases. Thirteen out of 29 patients received dexamethasone. Dexamethasone concentrations showed an average of 25 ng/ml 3 days after injection, with an estimated half-life of 5.5 h. Vancomycin concentrations in patients given dexamethasone tended to be higher compared with those in the placebo group (P=0.061). CONCLUSION: Intravitreal dexamethasone does not lead to decreased vancomycin concentrations, when given simultaneously in the treatment of patients with suspected bacterial endophthalmitis.

Aged↗

PubMed2006

Dexamethasone treatment in adults with pneumococcal meningitis: risk factors for death.

In experimental meningitis, adjunctive treatment with steroids reduces cerebrospinal fluid inflammation and thereby improves neurological outcome. On the basis of these findings, several clinical trials have assessed treatment with adjunctive steroids in bacterial meningitis, with conflicting results. Recently, the results of the European Dexamethasone Study showed a beneficial effect of adjunctive dexamethasone in adults with bacterial meningitis. In that study, the effect of dexamethasone on outcome was most striking in patients with pneumococcal meningitis. The aim of the present study was to further evaluate the effect of dexamethasone in adults with pneumococcal meningitis by performing a post hoc analysis of the European Dexamethasone Study. In a multivariate analysis, tachycardia (p=0.02), advanced age (p=0.03), low score on the Glasgow Coma Scale (p=0.03), positive blood culture (p=0.04), and absence of dexamethasone therapy (p=0.05) were independent predictors for death. Patients who were treated with adjunctive dexamethasone were less likely to develop both systemic and neurological complications during hospitalisation, compared with patients who received placebo. In conclusion, independent risk factors for death in pneumococcal meningitis are tachycardia, advanced age, low level of consciousness, bacteraemia, and absence of dexamethasone therapy. Treatment with adjunctive dexamethasone in adults with pneumococcal meningitis reduces both systemic and neurological complications.

Adult↗

PubMed1995

Colonic delivery of dexamethasone from a prodrug accelerates healing of colitis in rats without adrenal suppression.

BACKGROUND/AIMS: Dexamethasone-beta-D-glucuronide, a colon-specific prodrug of dexamethasone, may be useful in the treatment of ulcerative colitis and Crohn's colitis. The aim of this study was to evaluate colonic delivery and efficacy of this prodrug in the rat. METHODS: Distribution of dexamethasone in luminal contents and tissues of the gastrointestinal tract and in plasma was measured after oral administration of dexamethasone-beta-D-glucuronide or free dexamethasone. Efficacy of the prodrug and free drug was tested in an acetic acid-induced rat colitis model. Healing of induced colitis was assessed by measuring net intestinal fluid absorption, colonic surface area of ulceration, histology, and myeloperoxidase activity. Glucocorticosteroid toxicity was evaluated with serum corticosterone and plasma adrenocorticotropic hormone levels. RESULTS: The drug delivery index (a measure of relative targeting efficiency) was 6.7 and 8.6 in the cecal and colonic mucosa, respectively. The prodrug was significantly more potent than free drug in improving net colonic fluid absorption while significantly reducing surface area of ulceration and histological grade in colitic rats. Treatment with free dexamethasone significantly reduced serum corticosterone levels to subnormal levels, and treatment with the prodrug maintained serum corticosterone and plasma adrenocorticotropic hormone levels near control levels. CONCLUSIONS: The prodrug dexamethasone-beta-D-glucuronide delivers efficacious amounts of dexamethasone to the large intestine from lower doses than free dexamethasone.

Adrenal Cortex↗

PubMed1987

A comparison of changes in plasma thyrotropin beta- and alpha-subunits, and mouse thyrotropic tumor thyrotropin beta- and alpha-subunit mRNA concentrations after in vivo dexamethasone or T3 administration.

Dexamethasone, like T3, inhibits the production of TSH. T3 inhibits TSH synthesis by reducing transcription of the genes encoding TSH-beta and alpha-subunits. Little information is available concerning the effects of dexamethasone on the individual subunits, or the combined effects of dexamethasone with T3. In a preliminary study, hypothyroid mice bearing the thyrotropic tumor TtT 97 were treated with 25, 250, or 500 micrograms dexamethasone ip daily for ten days. Plasma levels of TSH and its subunits were unchanged after 25 micrograms of dexamethasone and maximally suppressed after 250 micrograms. Plasma TSH was reduced to 51% (P less than .02), free TSH-beta to 54% (P less than .01), and alpha-subunit to 62% (P less than .001) of control values. In two similar experiments hypothyroid mice bearing TtT 97 were treated with dexamethasone (250 micrograms), T3 (0.5 or 1 microgram), or both dexamethasone with T3 for 10 days. Total alpha-subunit and TSH-beta were calculated by adding 1/2 TSH + free subunit concentrations. In the experiment using 1 microgram of T3, total plasma alpha-subunit was reduced by dexamethasone to 72%, by T3 to 45% (P less than .02), and by combined treatment to 23% (P less than .01) of control values. In the experiment using 0.5 microgram of T3, total plasma alpha-subunit was reduced by dexamethasone to 66% (P less than .05), by T3 to 67% (P less than .05), and by combined treatment to 46% (P less than .02) of control values.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Effects of dexamethasone on glucose-induced insulin and proinsulin release in low and high insulin responders.

We compared the effects of dexamethasone-induced insulin resistance on B-cell secretory performance in 12 low insulin responders (LIR) and in eight high insulin responders (HIR). A hyperglycemic clamp (120 minutes) was performed before and after the subjects had ingested dexamethasone 3 mg x 2 for 2 1/2 days. Fasting levels of blood glucose increased from 4.60 +/- 0.13 to 5.74 +/- 0.23 mmol/L after dexamethasone in LIR and from 4.37 +/- 0.18 to 5.26 +/- 0.13 mmol/L in HIR. Dexamethasone treatment increased fasting levels of total immunoreactive insulin (IRI), C-peptide, and proinsulin, as well as the proinsulin to IRI ratio to a similar degree in LIR and HIR. The amount of glucose infused to uphold hyperglycemia during the clamp decreased by 54% after dexamethasone in LIR and by 46% in HIR. Mean level of stimulated IRI during the clamp increased after dexamethasone by 43% in LIR and by 53% in HIR. Mean level of stimulated C-peptide increased by 11% (not significant) in LIR and by 24% in HIR. Mean level of stimulated proinsulin increased by 86% in LIR and by 93% in HIR. The effects of dexamethasone on insulin secretion varied among individuals, since steroid treatment failed to affect IRI responses to glucose in two LIR and two HIR. The magnitude of dexamethasone effects on secretion was not correlated to pre-dexamethasone insulin sensitivity as assessed by a somatostatin-insulin-glucose infusion test (SIGIT) or by M/I (glucose infused/insulin level) ratios of the control clamp.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1992

Dexamethasone increases apolipoprotein A-I concentrations in medium and apolipoprotein A-I mRNA abundance from Hep G2 cells.

Glucocorticoid hormones increase high-density lipoprotein (HDL) levels in vivo. However, there is little known about the mechanism by which glucocorticoids alter HDL metabolism. Hep G2 cells were incubated with dexamethasone to determine the effect of glucocorticoids on apolipoprotein (apo) A-I secretion. Dexamethasone increased apo A-I concentration in a dose-dependent fashion. After 24 hours, 5.5 x 10(-5) mol/L dexamethasone increased apo A-I accumulation in culture medium by 54%. Detectable increases in apo A-I concentration were noted in medium by 5 hours of incubation and persisted up to 48 hours. Cellular apo A-I mRNA concentration increased by 28% after incubation with dexamethasone for 24 hours. The increase in apo A-I mRNA concentration was detectable within 3 hours after incubation with dexamethasone. In contrast, incubation with dexamethasone decreased apo B concentration by 43% in culture medium, but it had no effect on cellular apo B mRNA concentrations. Dexamethasone had little effect on cholesterol and triglyceride accumulation in the medium. Incubation with albumin alone did not affect apo A-I concentration, but it decreased apo B concentration by 30% in the medium. Incubation with albumin and dexamethasone had no effect on apo A-I concentration in medium and had no additive effect on apo B concentration. These data suggest dexamethasone increases secretion of apo A-I by Hep G2 cells by increasing mRNA levels.

Albumins↗