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PubMed1999

Dexamethasone-mediated inhibition of calcium transients and ACTH release in a pituitary cell line (AtT-20).

In the corticotroph-like murine pituitary tumor cell line, AtT-20, adrenocorticotropic hormone release is triggered by corticotropin-releasing hormone and is attenuated by the synthetic adrenal steroid dexamethasone. The precise mechanisms by which dexamethasone inhibits secretion are under investigation. We examined whether dexamethasone can modulate release via regulation of calcium homeostasis. More specifically, we have evaluated the effects of dexamethasone on calcium current, intracellular calcium concentration, and adrenocorticotropic hormone release. Using perforated patch-clamp and calcium imaging with fura PE3/AM, we found that dexamethasone decreases calcium current and intracellular calcium levels. The inhibition of current by dexamethasone is not, however, altered by the calcium channel antagonists nifedipine (L-type) or omega-agatoxin IVA (P/Q-type), despite the presence of these calcium channel subtypes in AtT-20 cells and the exclusive coupling of adrenocorticotropic hormone release to the L-type channel in these cells. We also evaluated the temporal relationship between dexamethasone-mediated inhibition of secretion and calcium influx. Whereas a prolonged (2 h) incubation with dexamethasone inhibits corticotropin-induced release by approximately 40%, a rapid (10 min) incubation (a time interval sufficient for dexamethasone-mediated inhibition of calcium transients) does not inhibit release. These data suggest, therefore, that dexamethasone does, indeed, modulate calcium homeostasis in AtT-20 cells, but that this effect is not responsible for its inhibition of secretion.

Adrenocorticotropic Hormone↗
PubMed2002

Intraocular penetration and systemic absorption after topical application of dexamethasone disodium phosphate.

PURPOSE: To study the dexamethasone concentration in aqueous humor, vitreous, and serum of patients after repeated topical application of dexamethasone disodium phosphate. DESIGN: Prospective nonrandomized comparative trial. PARTICIPANTS: Twenty phakic patients scheduled for a first vitrectomy. METHODS: All participants received dexamethasone disodium phosphate drops according to an application schedule intended to result in steady-state drug concentrations. Starting on the preoperative day, they received 1 drop of dexamethasone disodium phosphate (0.1%) every 1 hours until the time of vitrectomy (total, 10 or 11 drops). At night, ointment containing dexamethasone (0.3 mg/g) and gentamicin (5 mg/g) was administered once. From 7 AM on, the drop application schedule was resumed. At the start of the vitrectomy, samples were taken from the aqueous humor, vitreous, and blood. MAIN OUTCOME MEASURES: The dexamethasone concentrations in the aqueous humor, vitreous, and serum measured by radioimmunoassay. RESULTS: The mean dexamethasone concentrations in the aqueous humor, vitreous, and serum were 30.5 ng/ml (range, 7.1-57.7; standard deviation [SD] 15.0), 1.1 ng/ml (range, 0.0-1.6; SD 0.4), and 0.7 ng/ml (range, 0.0-1.2; SD 0.4), respectively. CONCLUSIONS: Compared with previously tested administration routes (peribulbar or subconjunctival injection or oral administration), the penetration of dexamethasone into the vitreous after repeated drop application is negligible. Despite the frequent dosing schedule, the dexamethasone concentration in the aqueous humor is far lower than after a subconjunctival injection with dexamethasone disodium phosphate. Systemic uptake is low.

Absorption↗
PubMed1999

Randomized clinical trial of a new dexamethasone delivery system (Surodex) for treatment of post-cataract surgery inflammation.

OBJECTIVE: To evaluate the safety of Surodex Drug Delivery System (Oculex Pharmaceuticals, Inc., Sunnyvale, CA) containing dexamethasone 60 micrograms, for use in cataract surgery, and to compare its anti-inflammatory efficacy with conventional dexamethasone 0.1% eyedrops. DESIGN: Randomized, masked, and partially controlled trial. PARTICIPANTS: Sixty eyes of 60 Asian patients undergoing extracapsular cataract extraction with intraocular lens implantation were examined. Of these, 28 eyes of 28 patients served as control eyes. Patients were stratified for age and presence of diabetes mellitus. INTERVENTION: Surodex was inserted in the anterior chamber of 32 eyes at the conclusion of surgery. These eyes received placebo eyedrops four times a day after surgery for 4 weeks. Control eyes received neither Surodex nor a placebo implant but were prescribed conventional 0.1% dexamethasone eyedrops four times a day for 4 weeks. MAIN OUTCOME MEASURES: Anterior chamber cells and flare were clinically graded at the slit lamp. Anterior chamber flare was objectively assessed with the Kowa FM500 Laser Flare Meter (Kowa Co. Ltd, Tokyo, Japan) for up to 3 months after surgery. Intraocular pressure and corneal endothelial specular microscopy with morphometric cell analysis were performed for up to 1 year after surgery. RESULTS: Clinical slit-lamp assessment of anterior chamber flare and cells showed no difference between Surodex-treated eyes and dexamethasone eyedrop-treated eyes. Flare meter readings showed lower flare levels in the Surodex group at all postoperative visits compared with the dexamethasone eyedrop group. Flare reduction in the Surodex group reached statistical significance at days 4, 8, 15, and 30 after surgery. At 3 months, flare was reduced to preoperative levels in the Surodex group but was still raised in the dexamethasone eyedrop group. Five eyes in the dexamethasone eyedrop group required augmentation of steroids and were deemed therapeutic failures as opposed to one eye in the Surodex group. One patient in the dexamethasone eyedrop group developed postoperative open-angle glaucoma with profound visual field loss and optic disc cupping, resulting in hand movements vision. No significant difference in endothelial cell loss was noted between Surodex-inserted eyes and dexamethasone eyedrop-treated eyes for up to 1 year after surgery. CONCLUSIONS: Intraocular placement of a single Surodex is a safe and effective treatment method to reduce intraocular inflammation after cataract surgery. There was no statistical difference in efficacy between Surodex and 0.1% dexamethasone eyedrops in reducing intraocular inflammation, as measured by clinical methods, while Surodex was clearly superior to eyedrops in reducing aqueous flare as objectively assessed with the laser flare meter.

Aged↗
PubMed2000

Dexamethasone pre-treatment interferes with apoptotic death in glioma cells.

Glucocorticoids are known to influence the ability of cells to undergo apoptosis, directly inducing apoptosis in thymocytes while inhibiting it in hepatoma and carcinoma cells. Dexamethasone, a synthetic glucocorticoid, is reported to induce partial resistance to certain anticancer drugs in glioma cell lines. In the present study, the effect of dexamethasone on apoptosis of glioma and astrocytoma cell lines was investigated. Exposure of D384 human astrocytoma and C6 rat glioma cells to staurosporine induced apoptosis as judged by the formation of condensed nuclei and caspase activation. Pre-treatment of cells with dexamethasone caused a reduction in staurosporine-induced apoptosis. In addition, dexamethasone also conferred protection against the induction of apoptosis by anticancer agents including camptothecin and etoposide. The protective effect of dexamethasone was dose and time dependent, with maximal protection obtained with concentrations equal to or greater than 100 nM and a pre-incubation period of at least 24h. The earliest significant inhibition was seen with a pre-incubation period of 8h. Co-treatment with the glucocorticoid receptor antagonist RU38486 abolished the effect of dexamethasone, indicating that the protection due to dexamethasone is mediated via this receptor. Dexamethasone was found to induce a time-dependent up-regulation of Bcl-x(L) protein expression. However, the ability of cytochrome c/dATP to activate the caspase cascade in cytosolic extracts of D384 cells was unaffected by prior exposure of the cells to dexamethasone (1 microM) for 48 h. In conclusion, dexamethasone inhibits the induction of apoptosis in astrocytoma cells, probably via an up-regulation of Bcl-x(L), which could prevent cytochrome c release from mitochondria and subsequent caspase activation. Since glucocorticoids are often used in the treatment of gliomas to relieve cerebral oedema, the inhibition of apoptosis by these compounds could potentially interfere with the efficacy of chemotherapeutic drugs.

Animals↗
PubMed1999

Dexamethasone enhances the activity of rSP-C surfactant but not of exosurf in a rat model of the acute lung injury.

The possible enhancement of surfactant activity by pretreatment with a glucocorticosteroid (dexamethasone) was investigated in a rat lung lavage model of acute lung injury. Animals received a dose of dexamethasone (10 mg/kg i.p.) prior to the protein-free surfactant preparation Exosurf (pure phospholipids containing surfactant, Wellcome GmbH, Burgwedel, Germany) and a rSP-C based surfactant, respectively. Both surfactants were intratracheally instilled at doses of 25 and 100 mg phospholipids per kg body weight and were compared with pretreatment with dexamethasone at each dose level. These groups were also compared with untreated controls and to pretreatment with dexamethasone alone with respect to improvements in oxygenation, to inhibition of infiltration of polymorphonuclear neutrophil leukocytes (PMNL) and to influence formation of hyaline membranes. Dexamethasone alone had no influence on the reduced PaO(2) but reduced the infiltration of PMNL and the formation of hyaline membranes. Dexamethasone improved the oxygenation at both doses of rSP-C surfactant. At the low dose of rSP-C surfactant there were additional effects detectable with regard to histopathologic improvements. In contrast, dexamethasone had no additional effect on oxygenation and formation of hyaline membranes when combined with Exosurf. Only the infiltration of PMNL was decreased by combined treatment with dexamethasone and Exosurf. The effect was comparable to that of pretreatment with dexamethasone alone. In this animal model, pretreatment with dexamethasone showed additional effects on rSP-C surfactant that were superior to each treatment alone. From the comparison of rSP-C surfactant with the synthetic surfactant preparation Exosurf, we conclude that the activity of Exosurf cannot be improved substantially by additional pretreatment with drugs like glucocorticosteroids.

Animals↗
PubMed2003

Effect of dexamethasone on motor brachial plexus block with bupivacaine and with bupivacaine-loaded microspheres in a sheep model.

BACKGROUND AND OBJECTIVE: It has been suggested that dexamethasone potentiates the sensory block produced by bupivacaine when both drugs are loaded in microspheres. The aim of the study was to evaluate the effect of dexamethasone on the brachial plexus block obtained with plain bupivacaine and bupivacaine-loaded microspheres. METHODS: Dexamethasone alone (Group 5) or added to plain bupivacaine (75 mg) with (Groups 3 and 4) and without pH correction (Group 2) was compared with plain bupivacaine (75 mg; Group 1). The effect of a small dose of dexamethasone (0.42 mg) was then evaluated on the brachial plexus block obtained with bupivacaine (750 mg) as bupivacaine-loaded microspheres (Group 6). Dexamethasone was added either in the suspending medium (Group 7) or incorporated with bupivacaine into microspheres (Group 8). The motor block was evaluated in a plexus brachial sheep model. RESULTS: Dexamethasone alone did not produce any motor block. When added to plain bupivacaine without pH correction, complete motor block could not be obtained. When the pH was corrected, addition of dexamethasone to plain bupivacaine seemed to delay the onset of motor block and did not prolong its duration, and it had no effect on the pharmacokinetics of bupivacaine. With bupivacaine-loaded microspheres, the duration of complete motor block was reduced when a small dose of dexamethasone was added in the suspending medium. However, the duration of motor block was significantly prolonged when dexamethasone was incorporated with bupivacaine into microspheres. CONCLUSIONS: Despite the delayed onset of motor block, the incorporation of dexamethasone in bupivacaine-loaded microspheres dramatically increases the duration of action (700 +/- 485-5160 +/- 2136 min), which could be clinically relevant when such a drug-delivery system will be available.

Anesthetics, Local↗
PubMed1997

Role of lipocortin-1 in the anti-hyperalgesic actions of dexamethasone.

1. The effect of dexamethasone, lipocorton-1(2-26) and an antiserum to lipocortin-1(2-26) (LCPS1) upon the hyperalgesic activities in rats of carrageenin, bradykinin, tumour necrosis factor alpha (TNF alpha), interleukin-1(2), interleukin-6 (IL-6), interleukin-8 (IL-8), prostaglandin E beta (PGE2) and dopamine were investigated in a model of mechanical hyperalgesia. 2. Hyperalgesic responses to intraplantar (i.pl.) injections of carrageenin (100 micrograms), bradykinin (500 ng), TNF alpha (2.5 pg), IL-1 beta (0.5 pg), and IL-6 (1.0 ng), but not responses to IL-8 (0.1 ng), PGE2 (100 ng) and dopamine (10 micrograms), were inhibited by pretreatment with dexamethasone (0.5 mg kg-1, subcutaneously, s.c., or 0.04-5.0 micrograms/paw). 3. Inhibition of hyperalgesic responses to injections (i.pl.) of bradykinin (500 ng) and IL-1 beta (0.5 pg) by dexamethasone (0.5 mg kg-1, s.c.) was reversed by LCPS1 (0.5 ml kg-1, injected s.c., 24 h and 1 h before hyperalgesic substances) and hyperalgesic responses to injections (i.pl.) of bradykinin (500 ng), TNF alpha (2.5 pg) and IL-1 beta (0.5 pg), but not responses to PGE2 (100 ng), were inhibited by pretreatment with lipocortin-1(2-26) (100 micrograms/paw). Also, lipocortin-1(2-26) (30 and 100 micrograms ml-1 and dexamethasone (10 micrograms ml-1) inhibited TNF alpha release by cells of the J774 (murine macrophage-like) cell-line stimulated with LPS (3 micrograms ml-1), and LCPS1 partially reversed the inhibition by dexamethasone. These data are consistent with an important role for endogenous lipocortin-1(2-26) in mediating the anti-hyperalgesic effect of dexamethasone, with inhibiton of TNF alpha production by lipocortin-1(2-26) contributing, in part, to this role. 4. Although arachidonic acid by itself was not hyperalgesic, the hyperalgesic response to IL-1 beta (0.25 pg, i.pl.) was potentiated by arachidonic acid (50 micrograms) and the potentiated response was inhibited by dexamethasone (50 micrograms, i.pl.) and lipocortin-1(2-26) (100 micrograms, i.pl.). Also, lipocortin-1(2-26) (30 and 100 micrograms ml-1) inhibited/abolished PGE2 release by J774 cells stimulated with LPS (3 micrograms ml-1). These data suggest that, in inflammatory hyperalgesia, inhibition of the induction of cyclo-oxygenase 2 (COX-2), rather than phospholipase A2, by dexamethasone and lipocortin-1(2-26) accounts for the anti-hyperalgesic effects of these agents. 5. The above data support the notion that induction of lipocortin by dexamethasone plays a major role in the inhibition by dexamethasone of inflammatory hyperalgesia evoked by carrageenin, bradykinin and the cytokines TNF alpha, IL-1 beta and IL-6, and provides additional evidence that the biological activity of lipocortin resides within the peptide lipocortin-1(2-26). Further, the data suggest that inhibition of lipocortin-1(2-26) of eicosanoid production by COX-2 also contributes to the anti-hyperalgesic effect of lipocortin-1.

Animals↗
PubMed1998

The role of lipocortin-1 in the inhibitory action of dexamethasone on eosinophil trafficking in cutaneous inflammatory reactions in the mouse.

1. The ability of glucocorticosteroids to inhibit tissue eosinophilia may be an important feature of their anti-inflammatory action in allergic diseases. Our previous work showed that an effect of dexamethasone on the release of eosinophils from the bone marrow could explain its inhibitory action on eosinophil accumulation in a mouse air-pouch model. Thus, it was unclear from that study whether dexamethasone could interfere with the process of eosinophil trafficking. In the present study, therefore, we used a newly developed mouse model to evaluate the effects of systemic treatment with dexamethasone on the recruitment of (111)In-labelled blood eosinophils to sites of cutaneous inflammation in the mouse and whether lipocortin-1 (LC-1) was involved. 2. The i.d. injection of ovalbumin (OVA) in sensitized mice induced a dose-dependent recruitment of (111)In-labelled blood eosinophils which peaked at 4 to 8 h after antigen challenge. Systemic treatment with dexamethasone (50 microg per mouse, 3 h after antigen) effectively inhibited (111)In-eosinophil recruitment in this reaction by 70 to 85%. Similarly, a 1 h pretreatment with dexamethasone significantly suppressed (111)In-eosinophil induced by platelet-activating factor (PAF), leukotriene B4(LTB4) and the chemokine macrophage inflammatory protein-1alpha (MIP-1alpha) by 40 to 70%. 3. Two experimental approaches were used to evaluate the role of LC-1: treatment with LC-1 fragment Ac2-26 and use of an anti-LC-1 antiserum. LC-1 fragment Ac2-26 (100 microg per mouse) failed to affect (111)In-eosinophil recruitment. Moreover, pretreatment of animals with an anti-LC-1 antiserum failed to reverse the inhibitory effects of dexamethasone on (111)In-eosinophil recruitment induced by MIP-1alpha and by antigen in sensitized mice. 4. In contrast, the LC-1 fragment significantly inhibited glycogen-induced neutrophil recruitment into the peritoneal cavity of mice. Furthermore, the anti-LC-1 antiserum reversed the inhibitory effects of dexamethasone on the glycogen-induced neutrophil recruitment. 5. Thus, our results suggest that dexamethasone can inhibit the recruitment of eosinophils in mouse skin independent of an action on the bone marrow. However, by use of two different approaches, we showed that LC-1 does not play a role in mediating the inhibitory action of dexamethasone on eosinophil migration into cutaneous inflammatory reactions in the mouse. These data add further support to a LC-1-independent action of dexamethasone on eosinophils in vivo.

Animals↗
PubMed1987

Dexamethasone modulates the metabolism of type IV collagen and fibronectin in human basement-membrane-forming fibrosarcoma (HT-1080) cells.

The effect of dexamethasone on the synthesis and degradation of type IV collagen was studied in human fibrosarcoma cells, HT-1080. A dexamethasone concentration as low as 0.1 microM markedly increased collagen synthesis in HT-1080 cells labelled with [14C]proline. The increase in type IV collagen synthesis was not specific, since total protein synthesis was also increased. Further studies indicated that part of the increase was due to an increase in the specific radioactivity of the intracellular proline pool, after dexamethasone treatment. In fact, with dexamethasone concentrations of 0.1-10 microM the relative collagen synthesis was decreased, indicating that synthesis of other protein was increased more than that of type IV collagen. This was also confirmed by measuring the relative amount of type IV collagen RNA by using recombinant plasmid cDNA specific for the human procollagen pro alpha l (IV) RNA. The results indicated that relative collagen synthesis and the relative amount of type IV collagen messenger RNA was decreased similarly, indicating that dexamethasone affected type IV collagen synthesis at the pre-translational level. The dexamethasone-induced effect on total protein and collagen synthesis was maximal after 12-24 h. Dexamethasone induced a marked accumulation of collagen into the cell layer, leading to diminished deposition of soluble collagen into the medium. Since bacterial-collagenase treatment of the cell layer drastically decreased the collagen content of the dexamethasone-treated cells, this indicates that dexamethasone caused an accumulation of collagen into the extracellular matrix of the cell layer. In contrast, the amount of fibronectin was markedly increased in the medium. Dexamethasone decreased the type IV collagen-degrading activity in HT-1080 cells. The HT-1080 cells contained glucocorticoid receptors, as demonstrated by two different methods: by a whole-cell binding assay and by using a cytosol-gel-filtration method. The number of specific binding sites was similar to that in human skin fibroblasts. In conclusion, glucocorticoids affect the metabolism of type IV collagen and fibronectin in HT-1080 cells, and, since these cells contain specific glucocorticoid receptors, the effects are apparently receptor-mediated.

Basement Membrane↗
PubMed2000

Role of caspases in dexamethasone-induced apoptosis and activation of c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase in human eosinophils.

Eosinophils are the principal effector cells for the pathogenesis of allergic inflammation. Glucocorticoids such as dexamethasone have long been used therapeutically for eosinophilia in allergic inflammation by inducing eosinophil apoptosis, but little is known about the intracellular mechanisms mediating dexamethasone-induced apoptosis. In the present study, we investigated the effect of dexamethasone on three mitogen-activated protein kinases (MAPK) involved in the intracellular signalling pathway: c-Jun NH2-terminal kinase (JNK), p38 MAPK and extracellular signal-regulated kinase (ERK). We found that dexamethasone could activate JNK and p38 MAPK in a time-dependent manner but not ERK. Further, SB 203580, a specific p38 MAPK inhibitor, was additive with dexamethasone in inducing eosinophil apoptosis, while JNK1/2 antisense phosphorothioate oligodeoxynucleotides did not show any significant effect. These suggest that dexamethasone-induced JNK1/2 and p38 MAPK activation are not crucial to the induction of apoptosis. Pretreatment of eosinophils with benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD.FMK), a broad-spectrum caspase inhibitor, could inhibit dexamethasone-induced apoptosis in eosinophils dose-dependently. Moreover, Z-VAD.FMK partially inhibited dexamethasone-activated JNK and p38 MAPK activities. However, dexamethasone treatment did not activate specific caspase-3, -8 activity in eosinophils compared with spontaneous apoptosis. We therefore conclude that dexamethasone-induced apoptosis and activation of JNK and p38 MAPK activity in eosinophils are regulated by caspases but not through the common apoptosis-related caspase-3, -8 as in other cell types. Elucidation of the important role of caspases in eosinophil apoptosis may facilitate the development of more specific and effective treatment for allergic inflammation.

Amino Acid Chloromethyl Ketones↗
PubMed2002

Dexamethasone reduces acrosin activity of ram spermatozoa.

The aim of this study was to investigate the effect of dexamethasone on acrosin activity of spermatozoa in Chios rams during autumn (breeding season for sheep in Greece), in correlation with possible changes in blood testosterone. Dexamethasone was administered in four equal consecutive intramuscular injections, one every four hours (total dose: 3 mg kg(-1)). Total acrosin activity was determined in semen samples collected 48 h before and on the 4th and 7th day and thereafter once every week until the 77th day after dexamethasone administration. Blood samples for testosterone radioimmunoassays were collected 24 h before, during dexamethasone administration and on the 4th, 7th, 14th and 21st day after administration. Total acrosin activity in spermatozoa was reduced between days 7-28 after dexamethasone administration. Dexamethasone also induced a reduction in mean value and basal level of blood testosterone and inhibited its episodic secretion between 1 and 4 days after administration. As the reduction of acrosin activity appeared relatively soon after dexamethasone administration (7th day), it is likely that the increased amount of dexamethasone did not influence the synthesis of proacrosin in the late spermatids. As glucocorticoid receptors exist in the epididymis and accessory glands in various species, dexamethasone may have a direct influence on the synthesis and/or release of acrosin inhibitors in epididymal fluid or seminal plasma. These changes in acrosin activity in ovine spermatozoa mediated by dexamethasone may be of importance regarding the role of stress in the reduction of sperm fertilizing ability.

Acrosin↗
PubMed2001

Effect of prenatal dexamethasone on rat renal development.

BACKGROUND: Prenatal insults can program the developing fetus to develop diseases that manifest in later life. Dexamethasone is often administered to the developing fetus to accelerate pulmonary development. The purpose of the present study was to determine whether prenatal dexamethasone adversely affects renal development and predisposes rats to develop renal disease and hypertension in later life. METHODS: Pregnant rats were given either vehicle or two daily intraperitoneal injections of dexamethasone (0.2 mg/kg body weight) on gestational days: 11 and 12, 13 and 14, 15 and 16, 17 and 18, 19 and 20, or 20 and 21. Tail cuff blood pressure, glomerular number, and inulin clearance were measured in control and prenatal dexamethasone-treated rats when the rats were 60 to 90 days of age. RESULTS: Prenatal dexamethasone did not affect the length of gestation, the number of animals per litter, or the total body weight or kidney weight measured at one day of age. Offspring of rats administered dexamethasone on days 15 and 16 gestation had a 30% reduction in glomerular number compared with control at 60 to 70 days of age (24,236 +/- 441 vs. 30,453 +/- 579, P < 0.01). Rats receiving prenatal dexamethasone on days 17 and 18 had an approximate 20% reduction in glomeruli compared with control (P < 0.01). Offspring of rats receiving dexamethasone on days 15 and 16 gestation had systolic blood pressures at 60 to 90 days of age that were higher than any other group (P < 0.05). The glomerular filtration rate was comparable in all of the groups. CONCLUSIONS: This study shows that two daily doses of prenatal dexamethasone (0.2 mg/kg body weight) in rats do not produce intrauterine growth retardation. Adult offspring of rats that received prenatal dexamethasone during specific times of gestation have a reduced number of nephrons and hypertension.

Animals↗
PubMed1996

The expulsion of Echinostoma trivolvis: suppressive effects of dexamethasone on goblet cell hyperplasia and worm rejection in C3H/HeN mice.

C3H/HeN mice were infected with Echinostoma trivolvis metacercariae on day 0, given intramuscular injections of dexamethasone daily for 5 or 7 days, and necropsied on days 5, 8, 12, 15, 20 and 30 p. i. Controls consisted of mice that were infected with echinostomes, but were not treated with dexamethasone. Dexamethasone treatment caused a delay in worm expulsion from the small intestine of the hosts, and the increase in goblet cell numbers that occurred in untreated mice was markedly delayed in the treated mice. Mast cell number in the small intestine increased rapidly from just after day 5 p. i. and reached a peak on day 15 p. i. in both dexamethasone-treated and control mice, although the increase in cell numbers was delayed slightly in the dexamethasone-treated mice. The eosinophil number in the small intestine of dexamethasone-treated mice was suppressed until 8 days p. i. and then increased reaching a peak on day 12 p. i., although the number was about one half that of the control. As determined on day 12 p. i., the mean body area of worms from dexamethasone-treated animals was significantly greater than that of the controls. Histological examination of the small intestine showed that the goblet and Paneth cell hyperplasia seen in mice infected with E. trivolvis was suppressed by dexamethasone treatment. Transmission electron microscopy revealed no marked ultrastructural differences in the small intestine of the dexamethasone-treated and control mice except that the former had an increased number of intracristal granules in mitochondria, an increase in vesicles in the apical epithelial cells and an increase in amorphous bodies and autophagic vacuoles in the Paneth cells. These results indicate that dexamethasone treatment delayed the expulsion of E. trivolvis from the small intestine of the host mouse in association with the suppression of goblet cell hyperplasia and increase in the number of mast cells and eosinophils.

Animals↗
PubMed2000

In vivo and in vitro induction of human cytochrome P4503A4 by dexamethasone.

PURPOSE: The aims of these experiments were to determine the effect of a therapeutic regimen of dexamethasone on cytochrome P4503A4 (CYP3A4) activity in healthy volunteers; and the concentration-effect relationship between dexamethasone and CYP3A4 activity in primary human hepatocyte cultures. METHODS: The effect of dexamethasone (8 mg administered by mouth two times a day for 5 days) on CYP3A4 activity in 12 healthy volunteers was assessed with the erythromycin breath test and urinary ratio of dextromethorphan to 3-methoxymorphinan. Concentration-effect of dexamethasone on CYP3A4-dependent testosterone 6-beta-hydroxylation was determined in human hepatocytes treated with 2 to 250 micromol/L dexamethasone. RESULTS: The percent of erythromycin metabolized per hour increased from 2.20% +/- 0.60% (mean +/- SD) at baseline to 2.67% +/- 0.55% on day 5 of dexamethasone (mean increase in hepatic CYP3A4 activity 25.7% +/- 24.6%; P = .004). The mean urinary ratio of dextromethorphan to 3-methoxymorphinan was 28 (4.8 to 109) and 7 (1 to 23) at baseline and on day 5 of dexamethasone (mean decrease = 49%; P = .06). Substantial intersubject variability was observed in the extent of CYP3A4 induction. The extent of CYP3A4 induction was inversely correlated with baseline erythromycin breath test (r2 = 0.58). In hepatocytes, dexamethasone 2 to 250 micromol/L resulted in an average 1.7-fold to 6.9-fold increase in CYP3A4 activity, respectively. The extent of CYP3A4 induction with dexamethasone in hepatocyte preparations was inversely correlated with baseline activity (r2 = 0.59). CONCLUSIONS: These data demonstrate that dexamethasone at doses used clinically increased CYP3A4 activity with extensive intersubject variability and that the extent of CYP3A4 induction was, in part, predicted by the baseline activity of CYP3A4 in both healthy volunteers and human hepatocyte cultures.

Administration, Oral↗
PubMed2000

Dexamethasone for the prevention of postoperative nausea and vomiting: a quantitative systematic review.

UNLABELLED: The role of dexamethasone in the prevention of postoperative nausea and vomiting (PONV) is unclear. We reviewed efficacy and safety data of dexamethasone for prevention of PONV. A systematic search (MEDLINE, EMBASE, Cochrane Library, hand searching, bibliographies, all languages, up to April 1999) was done for full reports of randomized comparisons of dexamethasone with other antiemetics or placebo in surgical patients. Relevant end points were prevention of early PONV (0 to 6 h postoperatively), late PONV (0 to 24 h), and adverse effects. Data from 1,946 patients from 17 trials were analyzed: 598 received dexamethasone; 582 received ondansetron, granisetron, droperidol, metoclopramide, or perphenazine; 423 received a placebo; and 343 received a combination of dexamethasone with ondansetron or granisetron. With placebo, the incidence of early and late PONV was 35% and 50%, respectively. Sixteen different regimens of dexamethasone were tested, most frequently, 8 or 10 mg IV in adults, and 1 or 1.5 mg/kg IV in children. With these doses, the number needed to treat to prevent early and late vomiting compared with placebo in adults and children was 7.1 (95% CI 4.5 to 18), and 3.8 (2.9 to 5), respectively. In adults, the number needed to treat to prevent late nausea was 4.3 (2.3 to 26). The combination of dexamethasone with ondansetron or granisetron further decreased the risk of PONV; the number needed to treat to prevent late nausea and vomiting with the combined regimen compared with the 5-HT3 receptor antagonists alone was 7.7 (4.8 to 19) and 7.8 (4.1 to 66), respectively. There was a lack of data from comparisons with other antiemetics for sensible conclusions. There were no reports on dexamethasone-related adverse effects. IMPLICATIONS: When there is a high risk of postoperative nausea and vomiting, a single prophylactic dose of dexamethasone is antiemetic compared with placebo, without evidence of any clinically relevant toxicity in otherwise healthy patients. Late efficacy seems to be most pronounced. It is very likely that the best prophylaxis of postoperative nausea and vomiting currently available is achieved by combining dexamethasone with a 5-HT3 receptor antagonist. Optimal doses of this combination need to be identified.

Adult↗
PubMed1996

Randomized, placebo-controlled, double blinded trial of dexamethasone in African children with sepsis.

OBJECTIVE: To determine the effect of moderate dose dexamethasone administered before antibiotics on the outcome of African children with sepsis. METHODS: The design was a randomized, double blinded, placebo-controlled trial of dexamethasone (0.2 mg/kg) vs. placebo given intravenously before antibiotic therapy. Patients were recruited from the patient populations at two missionary hospitals. Primary outcome variables were determined before analysis of data. RESULTS: Seventy-two children with sepsis were enrolled in the study. Treatment with dexamethasone was not associated with improved outcome for any of six outcome variables: survival to discharge (83%, dexamethasone group; 89%, placebo group); hemodynamic stability at 48 h (33%, dexamethasone group; 49%, placebo group); median length of hospital stay (11 days, dexamethasone group; 11 days, placebo group); normal at discharge (90%, dexamethasone group; 75%, placebo group); normal at follow-up (90%, dexamethasone group; 72%, placebo group); and afebrile at 48 to 72 h (61%, dexamethasone group; 44%, placebo group). CONCLUSIONS: These data indicate that a moderate dose of dexamethasone given before antibiotic therapy did not improve outcome in the pediatric patients with sepsis whom we studied.

Adolescent↗
PubMed1976

Synthesis of type C virus particles from murine-cultured cells induced by iododeoxyuridine. V. Effect of interferon and its interaction with dexamethasone.

Previous studies have shown that in certain cell systems dexamethasone may enhance the production of type C viruses. Conversely, interferon has been shown to inhibit their production. Both appear to exert their influence late in the viral replication cycle rather than on the synthesis of viral-specific RNA. In this report dexamethasone and interferon have been used to study some aspects of the mechanisms involved in the synthesis of type C viruses in murine K-BALB cells following induction of virus production by iododeoxyuridine. Interferon inhibited production of xenotropic type C virus induced by iododeoxyuridine from K-BALB cells both in the absence and presence of dexamethasone, but it did not affect production of N-tropic type C virus. Exposure of the cells to interferon for longer than 12 h was required for maximum effect. Two types of inhibitory effects were observed: one diminished by dexamethasone when the steroid was added 24 h after interferon removal, and the second resistant to dexamethasone. The concentration of intracellular group-specific antigen was diminshed after interferon and increased after dexamethasone exposure. When induced cells were treated with both interferon and dexamethasone, the intracellular group-specific protein concentration was slightly increased, but virus production was reduced 10-fold compared with induced cells treated with dexamethasone alone. We conclude that interferon and dexamethasone may affect both the synthesis of viral proteins and the assembly or release of virus particles and that dexamethasone can partially nullify the inhibitory activity of interferon. The results also support previous conclusions that the regulatory mechanisms for synthesis of viral proteins and for the release of viral particles may differ and that controls for xenotropic and ecotropic virus formation may not be identical.

Animals↗
PubMed1998

Systematic review and meta-analysis of early postnatal dexamethasone for prevention of chronic lung disease.

AIM: To review systematically the evidence to determine whether dexamethasone treatment of very low birthweight infants begun within 14 days of age prevents chronic lung disease (CLD) without clinically significant side effects. METHODS: Randomised controlled trials of dexamethasone started within this time frame were identified through a search of electronic databases, proceedings of scientific meetings, and personal files. Meta-analyses using event rate ratio (ERR), event rate difference (ERD), and if significant, numbers needed to treat (NNT) for benefits and numbers needed to harm (NNH) for adverse effects were calculated. Weighted mean difference were used for continuous variables. Three prespecified subgroup analyses were performed for; (i) dexamethasone begun within 36 hours (hours) of birth; (ii) dexamethasone initiated between 7-14 days of age; or (iii) if surfactant treatment was used. RESULTS: Ten studies were included in the review; six where dexamethasone was initiated within 36 hours of age, four studies for dexamethasone started between 7 and 14 days and six studies using surfactant. Mortality ERR and NNT with 95% confidence intervals for dexamethasone initiated at 7-14 days of age were 0.35 (0.16, 0.74) and 8 (4, 30). ERRs and NNTs for CLD at 28 days and 36 weeks of postmenstrual age were 0.71 (0.61, 0.84), 8 (5, 17), and 0.57 (0.44, 0.76), 10 (6, 23) in the overall analyses. When dexamethasone was started at 7 to 14 days of age ERR and NNT for CLD at 36 weeks were 0.63 (0.47, 0.85) and 3 (2, 9). Clinically significant side effects included increased risk of hypertension, hyperglycaemia, and increased time to regain birthweight. CONCLUSIONS: These meta-analyses show a significant reduction in risk of CLD at 28 days and 36 weeks of postmenstrual age. In the subgroup where dexamethasone was started between 7 and 14 days of age mortality was significantly reduced. Caution is warranted in the routine use of dexamethasone because of lack of data on long term neurodevelopmental outcomes.

Chronic Disease↗