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Modulation of the acute phase response and in vitro measurement of interleukin-1 activity following administration of dexamethasone to adjuvant-arthritic rats.

Adjuvant-arthritic (AA) rats were medicated with dexamethasone to determine if this glucocorticoid suppressed the activity of interleukin-1 (IL-1) or the acute phase response. Dexamethasone (0.1 mg/kg, p.o.) administered daily for two weeks to AA rats, significantly (p less than or equal to 0.01) decreased high splenic IL-1 production (60% inhibition). Dexamethasone at a 0.5 mg/kg dose reduced AA rat splenic IL-1 production below normal (100% inhibition). In addition, dexamethasone significantly inhibited the AA rat acute phase response as measured by reduction of plasma C-reactive protein levels and enhancement of plasma albumin and iron levels. Following medication with 0.02, 0.1 or 0.5 mg/kg dexamethasone, high plasma C-reactive protein levels decreased by 33, 77 and 95% respectively, compared to untreated AA controls. Under the same dosing regimen of 0.02, 0.1 or 0.5 mg/kg dexamethasone, plasma albumin levels increased by 44, 128 and 239% respectively, while plasma iron levels rose by 19, 64 and 98% respectively, compared to AA controls. At the 0.02, 0.1 and 0.5 mg/kg doses dexamethasone also significantly reduced injected and noninjected paw swelling in AA rats. In view of the ability of dexamethasone to decrease IL-1 production and the acute phase response often associated with it, it is possible that part of the anti-inflammatory activity of dexamethasone may stem from inhibition of IL-1 formation in vivo.

Animals↗
PubMed1986

Effects of dexamethasone injection on body retention and hepatic distribution of zinc, cadmium and metallothionein in newborn rats.

The liver of 7-day-old rats contains high levels of metallothionein (MT) and zinc, which can be reduced markedly following treatment of neonates with dexamethasone (1 mg/kg, s.c.) twice daily on days 3, 4, 5 and 6 postpartum. Prior treatment with trace amounts of 65Zn and 109Cd did neither alter the basal MT and zinc concentrations nor their response to dexamethasone. The turnover of 65Zn or 109Cd in newborn rats was studied by measuring the whole body retention of the radioisotopes. Between days 3 and 7 postpartum, the normal turnover of 65Zn was much faster than that of 109Cd, and dexamethasone treatment resulted in further decrease of 65Zn retention without significantly altering that of 109Cd. The data indicate that dexamethasone enhanced the excretion of 65Zn without any effect on 109Cd excretion. The dexamethasone treatment resulted in marked reduction in both hepatic Zn and MT levels in newborn rats. Gel filtration on Sephadex G-75 columns of hepatic cytosols isolated from 7-day-old rats showed significant amounts of total Zn and 65Zn bound to MT fraction. Moreover, dexamethasone treatment markedly reduced their binding to the MT fraction suggesting that most of the Zn lost from the liver of dexamethasone-treated animals was from MT. About 95% of 109Cd in the liver cytosol was present in the MT fraction of 109Cd-injected rats and dexamethasone had little effect on the binding of 109Cd to MT fraction despite a marked reduction in the binding of total Zn. These data suggest that unlike in adult rats, injection of dexamethasone results in marked decrease in hepatic levels of Zn and MT in neonatal rats.

Animals↗
PubMed2006

Dexamethasone mimics the inhibitory effect of chronic pain on the development of tolerance to morphine analgesia and compensates for morphine induced changes in G proteins gene expression.

It is previously reported that the HPA axis plays role in the inhibitory effect of pain on tolerance development to analgesic effect of opioids. The present study was designed to investigate whether the chronic co-administration of dexamethasone as a glucocorticoid is also able to prevent or reverse analgesic tolerance to morphine and to compare the expression of G(alphai/o) and G(beta) subunits of G proteins in the context of chronic dexamethasone, development of morphine tolerance and their combination. Analgesic tolerance to morphine was induced by chronic intraperitoneally (i.p.) administration of morphine 20 mg/kg to male Wistar rats weighing 200-240 g within 4 consecutive days and analgesia was assessed using tail-flick test. Chronic dexamethasone was applied using 4 daily i.p. injections. Lumbar spinal tissues were assayed for the expression of G(alphai/o) and G(beta) proteins using "semiquantitative PCR" normalized to beta-actin gene expression. Results showed that chronic administration of dexamethasone could reduce and reverse the development of tolerance in rats that received chronic i.p. injections of morphine. Chronic administration of dexamethasone significantly increased the expression of G(alphai/o), while chronic administration of morphine did not change its expression. The expression of G(beta), however, was increased after the chronic administration of morphine, but did not change after the administration of chronic dexamethasone. None of these increases were observed when morphine and dexamethasone were co-administered. We conclude that the development of tolerance to analgesic effect of morphine could be prevented and reversed by dexamethasone co-administration. The increase in G(alphai/o) genes expression produced by chronic dexamethasone may facilitate the opioid signaling pathway and compensate for morphine-induced tolerance.

Analgesics, Opioid↗
PubMed2005

Reduction of postoperative emetic episodes and analgesic requirements with dexamethasone in patients scheduled for dental surgery.

STUDY OBJECTIVE: To evaluate the antiemetic and analgesic effects of dexamethasone for the first 24 hours postoperatively in patients scheduled for dental surgery. DESIGN: Prospective, randomized, double-blind, placebo-controlled study. SETTING: University hospital. PATIENTS: One hundred twenty ASA physical status I and II patients (45 men, 75 women; aged 17-48 years) undergoing general anesthesia for dental surgery. INTERVENTIONS: Patients received intravenously placebo or dexamethasone at 3 different doses (4, 8, or 16 mg) at the end of the surgical procedure. A standard general anesthetic technique, including sevoflurane and nitrous oxide in oxygen, was used. MEASUREMENT AND MAIN RESULTS: Emetic episodes and analgesic requirements were evaluated. The rate of patients who were emesis free (no nausea, retching, or vomiting) during 0 to 24 hours after anesthesia was 63% with dexamethasone 4 mg (P = NS), 83% with dexamethasone 8 mg (P < .05), and 90% with dexamethasone 16 mg (P < .05), compared to placebo (60%). The need for diclofenac sodium for intolerable pain was less in patients who had received dexamethasone 8 mg or dexamethasone 16 mg than in those who had received placebo or dexamethasone 4 mg (P < .05). No clinically important adverse events were observed in any group. CONCLUSIONS: Prophylactic dexamethasone 8 mg is effective for the prevention of nausea and vomiting after dental surgery and in the management of postoperative pain. Increasing the dose to 16 mg provides no further benefit.

Adult↗
PubMed2004

Dexamethasone therapy in neonates treated with extracorporeal membrane oxygenation.

OBJECTIVE: To test the hypothesis that infants who received dexamethasone would have a shorter length of time on extracorporeal membrane oxygenation (ECMO). Study design Infants placed on ECMO for respiratory failure were randomly assigned to receive either dexamethasone for 3 days or placebo. Chest radiographs were scored through the use of a validated standard scoring system to assess lung injury. RESULTS: Thirty infants received dexamethasone and 29 received placebo. The median (25th%, 75th%) duration of time on ECMO was 143.5 (100, 313) hours in the dexamethasone group and 160 (111, 303) hours in the placebo group (not significant). Survival was 80% in the dexamethasone group and 83% in the placebo group. Radiographic lung injury scores (mean+/-SEM) were significantly improved in the dexamethasone group (10.5+/-0.6) versus placebo (12.3+/-0.5) on day 3 of ECMO (P=.013). Hypertension developed in 27 of the 30 infants receiving dexamethasone and 13 of the 29 infants in the placebo group during ECMO (P<.01). CONCLUSIONS: Dexamethasone given during the first 3 days of ECMO results in significant improvement in lung injury scores by day 3 of ECMO but does not significantly decrease the duration of ECMO or improve survival. The preponderance of evidence would not support the use of dexamethasone in this setting.

Anti-Inflammatory Agents↗
PubMed1997

Peribulbar corticosteroid injection: vitreal and serum concentrations after dexamethasone disodium phosphate injection.

PURPOSE: To study the dexamethasone level reached in human vitreous after a peribulbar injection of 5 mg of dexamethasone disodium phosphate and to assess its systemic uptake. METHODS: In a prospective study, 61 eyes of 61 patients scheduled for vitrectomy received a single peribulbar injection of 5 mg of dexamethasone disodium phosphate at varied intervals before surgery. At the start of vitrectomy, an undiluted vitreous sample was taken. In 22 patients, multiple serum samples were collected. Dexamethasone concentrations were measured by radioimmunoassay. The physiologic cortisol concentration was determined in the vitreous of 12 eyes of 12 patients who did not receive dexamethasone. RESULTS: An average dexamethasone peak concentration of approximately 13 ng/ml was reached in vitreous 6 to 7 hours after peribulbar injection. In serum the average peak concentration was approximately 60 ng/ml 20 to 30 minutes after peribulbar injection. The average physiologic cortisol concentration in vitreous was 5.1 ng/ml. CONCLUSIONS: After a peribulbar injection of 5 mg of dexamethasone disodium phosphate, an average intravitreal dexamethasone concentration is reached with a 75 times greater anti-inflammatory potency than physiologically present cortisol. Dexamethasone concentration in serum, however, is several times higher. Peribulbar injection is not just a local treatment but results in serum levels comparable to those achieved by a high oral dose.

Adult↗
PubMed2001

Differentiation of NG108-15 cells induced by the combined presence of dbcAMP and dexamethasone brings about the expression of N and P/Q types of calcium channels and the inhibitory influence of muscarinic receptors on calcium influx.

Differentiation of cholinergic cell line NG108-15 induced by a combination of dibutyryl cyclic AMP (dbcAMP) and dexamethasone enhances the cholinergic phenotype of the cells more than that induced by either agent alone. We investigated the effect of treatment with dbcAMP and dexamethasone on potassium depolarization-evoked influx of calcium and its regulation by the muscarinic agonist carbachol. Depolarization of control cells and of cells differentiated in the presence of dbcAMP or dexamethasone alone, or in the combined presence of dbcAMP and dexamethasone induced, respectively, 2.2-, 4.3-, 2.7- and 10.7-fold increases of the resting [Ca(2+)](i). Dexamethasone alone and the combination of dbcAMP and dexamethasone augmented the number of muscarinic receptors by 25 and 40%, respectively. Inhibitors of N (omega-conotoxin GVIA) or P/Q (omega-agatoxin TK) calcium channels had no effect on Ca(2+) influx in control cells, whereas in cells differentiated in the combined presence of dbcAMP and dexamethasone they significantly diminished the influx of Ca(2+) by 20 and 5%, respectively. Carbachol attenuated calcium influx in differentiated cells in an atropine-insensitive manner if it was present during stimulation. This effect of carbachol was probably due to an open-channel block of L type channels. In the presence of nifedipine, carbachol attenuated the influx of Ca(2+) into cells differentiated with dbcAMP and dexamethasone by 20% in an atropine-sensitive way. Data show that differentiation of NG108-15 cells by dbcAMP and dexamethasone promotes the expression of functional nifedipine-insensitive N and P/Q types of Ca(2+) channels and that the nifedipine-insensitive calcium influx becomes subject to inhibitory regulation by muscarinic receptors.

Animals↗
PubMed2002

Suppression of sodium pump activity and an increase in the intracellular Ca2+ concentration by dexamethasone in acidotic mouse brain.

The effects of dexamethasone on adenosine 5'-triphosphatase (ATPase) activity and the intracellular Ca(2+) concentration ([Ca(2+)](i)) were investigated in acidotic mouse brain. Dexamethasone (3 mg/kg, i.p.) or vehicle was administered 3 h before decapitation ischemia, and the brain concentration of adenosine 5'-triphosphate (ATP) was determined 0.5-2 min after ischemia. The effects of dexamethasone (0.3-3 mg/kg, i.p.) on Na(+),K(+)-activated ATPase (Na(+),K(+)-ATPase) and Ca(2+)-ATPase activities were evaluated at pH 7.4 and 6.8. Changes in [Ca(2+)](i) in an acidic medium were determined in hippocampal slices by microfluorometry using rhod-2 acetoxymethyl ester as a Ca(2+) marker, and the effects of dexamethasone (240 microg/l) was evaluated. Decapitation ischemia for 0.5 and 1 min reduced the brain ATP contents to 32% and 16% of the basal level, respectively. Dexamethasone slightly suppressed the extent of the decrease in the ATP level. Although dexamethasone did not affect Na(+),K(+)-ATPase activity at pH 7.4, the activity was suppressed by dexamethasone (3 mg/kg) to 68% at pH 6.8. The activity of Ca(2+)-ATPase was not affected by dexamethasone at either pH 7.4 or pH 6.8. When the pH of the medium of the brain slices was changed from 7.4 to 6.8, almost no increase in [Ca(2+)](i) was observed in the control group. The dexamethasone treatment increased [Ca(2+)](i) in the CA1 field and dentate gyrus immediately after induction of the acidic medium, the effect being significant after 150 s. Because anaerobic glucose metabolism in the early stage of ischemia enhances intracellular lactic acidosis, the findings may suggest a mechanism for the aggravation of ischemic neuronal damage by glucocorticoids.

Acidosis, Lactic↗
PubMed1999

Selective down-regulation of T cell- and non-T cell-derived tumour necrosis factor alpha by thalidomide: comparisons with dexamethasone.

Both thalidomide and dexamethasone have been shown to inhibit the production of tumour necrosis factor alpha (TNF-alpha), but little is known of their cellular selectivity. Inhibition of monocyte TNF-alpha expression has been implicated in the clinical efficacy of thalidomide, and it has been suggested that the drug modulates only monocyte-derived cytokines. Given the importance of T lymphocyte responses in immunological disorders in which treatment with thalidomide has been successful, it is pertinent to study the effects of this drug on T cell-derived TNF-alpha. In the present investigations we have examined the influence of both thalidomide and dexamethasone on mitogen-induced elaboration of TNF-alpha by CD3+ peripheral blood mononuclear cells (PBMC) and the T cell line MOLT-4. PBMC from healthy human volunteers were stimulated optimally with phytohaemagglutinin (PHA) in the presence of varying concentrations of thalidomide or dexamethasone, and supernatants assayed for TNF-alpha and interleukin 2 (IL-2). Concurrently, PHA-stimulated PBMC were treated with 1 x 10(-1) mM thalidomide or dexamethasone and the cells fixed, permeabilised, stained with anti-CD3 and anti-TNF-alpha fluorescently labelled antibodies and analysed by flow cytometry. MOLT-4 cells were cultured in the presence or absence of the drugs following activation with phorbol myristate acetate (PMA)/ionophore, and supernatants analysed by enzyme-linked immunosorbent assay (ELISA) for cytokine expression. Thalidomide was found to inhibit PBMC-derived TNF-alpha, but not IL-2. In contrast, dexamethasone down-regulated both TNF-alpha and IL-2 in a dose-dependent manner. Thalidomide and dexamethasone both suppressed intracellular levels of TNF-alpha in CD3+ PBMC, reducing percentages of double positive staining cells by 28 and 52%, respectively, compared with controls. In addition, TNF-alpha production by CD3- PBMC was inhibited by 31% by thalidomide and by 47% by dexamethasone. In order to determine whether thalidomide was acting directly on T cells, or indirectly through effects on accessory cells, TNF-alpha production in the T cell line MOLT-4 was investigated. TNF-alpha secretion by PMA/ionophore activated MOLT-4 cells was reduced by 80% following thalidomide treatment and close to background levels following dexamethasone treatment. To verify that thalidomide was acting selectively to down-regulate TNF-alpha, IL-2 production by MOLT-4 cells was also measured and found to be unaffected by the drug. In contrast, dexamethasone reduced MOLT-4-derived IL-2 levels by 20%. These observations suggest that thalidomide, in addition to its known inhibitory effect on monocyte-derived TNF-alpha, is capable also of down-regulating T cell-derived TNF-alpha in a direct and selective manner. In addition, the inhibition of intracellular levels of TNF-alpha strengthens the evidence that the inhibitory effect of thalidomide is at the level of transcription and/or translation and does not reduce cellular TNF-alpha secretion. Such effects could explain the efficacy of thalidomide treatment in various immunological disorders where T cell activation plays an important role in the pathogenesis of the disease.

CD3 Complex↗
PubMed2001

Modulation of serotonin2A receptor function in rats after repeated treatment with dexamethasone and L-type calcium channel antagonist nimodipine.

1. It has been conceivable that the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity plays an important role in the pathophysiology of depression. In the present study, we have investigated the effect of repeated treatment with dexamethasone on serotonin (5-HT) 1A, 5-HT2A and alpha1-adrenergic receptors in the rat frontal cortex. Moreover, several studies have suggested the effectiveness of L-type calcium channel antagonist nimodipine for the treatment of depression. We also investigated the effect of repeated treatment with nimodipine on 5-HT2A receptor in rats with repeated dexamethasone treatment. 2. Repeated treatment with dexamethasone (1 mg/kg/day for 14 days) increased the density of 5-HT2A receptor, but not 5-HT1A and alpha1-adrenergic receptors in the rat frontal cortex. 3. The density of 5-HT2A receptor in the rat frontal cortex was significantly increased 1 day after repeated treatment with dexamethasone, but was not increased 7 or 14 days after repeated treatment. Wet dog shakes (WDS) induced by (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (DOI), a 5-HT2A receptor agonist, in rats were significantly enhanced 1, 7 and 14 days after repeated treatment with dexamethasone, although the frequency of WDS gradually decreased after repeated treatment. 4. Repeated treatment with nimodipine (5 mg/kg/day for 14 days) attenuated DOI-induced WDS enhanced by repeated treatment with dexamethasone (1 mg/kg/day for 14 days), however, it did not change the density of 5-HT2A receptor. Repeated treatment with dexamethasone decreased locomotor activity and body weight, but repeated treatment with nimodipine did not recover these parameters. 5. The results of the present study suggest that repeated treatment with dexamethasone may selectively increase the 5-HT2A receptor in the rat frontal cortex and affect 5-HT2A receptor-mediated signal transduction. In addition, the intracellular calcium homeostasis by blocking calcium influx through L-type calcium channel may play an important role in the regulation of the 5-HT2A receptor function by dexamethasone.

Animals↗
PubMed2001

Dexamethasone induces limited apoptosis and extensive sublethal damage to specific subregions of the striatum and hippocampus: implications for mood disorders.

It has been shown previously that the synthetic corticosteroid dexamethasone induces apoptosis of granule cells in the dentate gyrus and striatopallidal neurons in the dorsomedial caudate-putamen. We investigated whether or not dexamethasone can induce damage to other neuronal populations. This issue was addressed using OX42 immunohistochemistry to visualise activated microglia and thereby gauge the extent of dexamethasone-induced neuronal death. A single dose of dexamethasone (20mg/kg, i.p.) administered to young male Sprague-Dawley rats induced a strong microglial reaction which was restricted to the striatum, the dentate gyrus and all of the CA subfields of the hippocampus. Some OX42-immunoreactive cells were also seen in the lateral septal nucleus. Subsequent quantitative analysis of silver/methenamine-stained sections confirmed that acute administration of dexamethasone induced apoptosis in the striatum and all regions of the hippocampus at doses as low as 0.7mg/kg. In contrast, dexamethasone failed to induce apoptosis in the lateral septal nucleus at doses up to 20mg/kg. The levels of dexamethasone-induced striatal and hippocampal apoptosis were attenuated by pretreatment with the corticosteroid receptor antagonist RU38486 (Mifepristone), which implies that the cell death was mediated by a corticosteroid receptor-dependent process. We further determined whether dexamethasone induced sublethal damage to neurons by quantifying reductions in the number of microtubule-associated protein-2-immunoreactive striatal and hippocampal cells following injection of the corticosteroid. Dexamethasone induced dramatic decreases in the striatum, with the dorsomedial caudate-putamen being particularly affected. Similar damage was seen in the hippocampus, with the dentate gyrus and CA1 and CA3 subfields being particularly vulnerable.Equivalent corticosteroid-induced neuronal damage may occur in mood disorders, where the levels of endogenous corticosteroids are often raised. Corticosteroid-induced damage of striatal and hippocampal neurons may also account for some of the cognitive deficits seen following administration of the drugs to healthy volunteers.

Animals↗
PubMed2000

Dexamethasone suppression of corticosteroid secretion: evaluation of the site of action by receptor measures and functional studies.

A dose of dexamethasone was determined in rats (50 micrograms/kg s.c.) that suppressed the corticosterone response to restraint stress by 80%. Corticosteroid receptor occupancy estimates found that the 50 micrograms/kg s.c. dose of dexamethasone had no significant effect on available glucocorticoid receptor (GR) or mineralocorticoid receptor (MR) binding in brain regions (hypothalamus, hippocampus and cortex); on the other hand dexamethasone produced a selective and significant decrease in available GR in peripheral tissues (pituitary and spleen). Functional studies showed that the 50 micrograms/kg s.c. dose of dexamethasone completely blocked the effects of corticotropin-releasing hormone (CRH; 0.3-3.0 micrograms/kg i.p.) on corticosterone secretion, but did not inhibit the corticosterone response to an adrenocorticotropin hormone (ACTH; 2.5 I.U./kg i.p.) challenge. These studies indicate that this dose of dexamethasone exerts its inhibitory effects on the HPA axis primarily by acting at GR in the pituitary. The plasma dexamethasone levels produced by this dose of dexamethasone are similar to those present in humans the afternoon after an oral dexamethasone suppression test (DST), a time at which many depressed patients escape from dexamethasone suppression. These results support and extend other studies which suggest that the DST provides a direct test of the effects of increased GR activation in the pituitary on ACTH and cortisol secretion.

Adrenal Cortex Hormones↗
PubMed1991

Transcriptional activation of the lipoprotein lipase gene in macrophages by dexamethasone.

The effect of dexamethasone on lipoprotein lipase (LPL) gene expression during macrophage differentiation was investigated by using the human monocytic leukemia cell line THP-1 and human monocyte-derived macrophages. Addition of dexamethasone to THP-1 cells increased steady-state levels of LPL mRNA and LPL mass accumulation in the medium during PMA-induced differentiation by 4-fold. Studies with human monocyte-derived macrophages showed a similar effect of dexamethasone on LPL expression. Peak LPL mRNA levels were achieved 24-h post-dexamethasone addition to THP-1 cells. Optimal stimulation of LPL mRNA occurred when dexamethasone was added 24 h after induction with PMA. Thereafter, there was rapid decline in responsiveness to dexamethasone. Induction of LPL mRNA in THP-1 cells was completely blocked by actinomycin D, suggesting that induction was transcription dependent. The stability of LPL mRNA was not influenced by dexamethasone. Treatment of THP-1 cells with PMA led to a 2-fold increase in specific binding of dexamethasone and a 4-fold increase in glucocorticoid receptor mRNA within 12 h. Thus, dexamethasone stimulates LPL gene expression during differentiation of human macrophages, a process that involves induction of glucocorticoid receptor synthesis and activation.

Blotting, Northern↗
PubMed1999

The effect of dexamethasone on some immunological parameters in cattle.

Immunosuppression as a consequence of acute and chronic stress can increase the susceptibility of cattle to a range of infectious diseases. In order to develop a panel of immune function assays for investigating the effects of potential stressors on immune competence in cattle, the effect of treatment with short- and long-acting preparations of the synthetic glucocorticoid dexamethasone was examined. Short-acting dexamethasone (dexamethasone sodium phosphate 0.08 mg/kg) followed 37 h later by long-acting dexamethasone (dexamethasone-21 isonicotinate 0.25 mg/kg) was injected intramuscularly and blood was collected to assess immune functions at intervals over the subsequent 11 days from 6 treated and 6 control Hereford steers. Dexamethasone induced leukocytosis (neutrophilia, eosinopenia, lymphopenia, monocytosis), an increased neutrophil:lymphocyte ratio, an elevated percentage of CD4+ lymphocytes, a decreased total CD8+ lymphocyte count, decreased total and percentage WC1+ lymphocytes, an elevated percentage of IL-2 receptor alpha (IL-2Ralpha)+ lymphocytes, and an elevated percentage of B lymphocytes. In vitro chemotaxis of peripheral blood neutrophils to human C5a and ovine IL-8 was increased by dexamethasone treatment. Lymphocyte proliferation in the presence of phytohaemagglutinin, and serum concentrations of IgM, but not IgA or IgG1, were suppressed by dexamethasone treatment, whereas mitogen-induced production of interferon-gamma (IFN-gamma), neutrophil expression of CD18, neutrophil myeloperoxidase activity and natural killer (NK) cell activity were not influenced by dexamethasone treatment. The results indicate the potential for haematology and immune function assays to reflect elevated activity of the hypothalamic-pituitary-adrenocortical axis in cattle. Immunological parameters may thus provide a useful adjunct to cortisol and behavioural observations for assessing the impact of stress on the welfare of cattle.

Animals↗
PubMed1999

The effects of dexamethasone on the response of bronchus-associated lymphoid tissue to intranasal administration of formalin-killed Pasteurella haemolytica A2 in goats.

A trial was conducted to observe the immediate and chronic effects in goats of dexamethasone administration on the bronchus-associated lymphoid tissue (BALT) response to intranasal administration of formalin-killed Pasteurella haemolytica A2. Twenty-four goats were divided into four groups. Those in group 1 were injected intramuscularly with 1 mg/kg dexamethasone on three consecutive days, followed by intranasal exposure to formalin-killed P. haemolytica A2 one day after the last dexamethasone treatment. The goats in group 2 were similarly injected with dexamethasone followed by intranasal exposure to formalin-killed P. haemolytica A2 21 days after the last dexamethasone treatment. The animals in group 3 were exposed intranasally to formalin-killed P. haemolytica A2 without prior dexamethasone treatment. The animals in group 4 were untreated controls. The intranasal exposures to formalin-killed P. haemolytica A2 were repeated 2 weeks later. Intranasal exposure to formalin-killed P. haemolytica 1 day after dexamethasone treatment further reduced the number and size of BALT compared to the untreated control. Significantly (p < 0.01) more reduction of BALT occurred in goats exposed to formalin-killed P. haemolytica A2 21 days after dexamethasone treatment. On the other hand, intranasal exposure of goats without prior dexamethasone treatment stimulated the BALT compared to the untreated controls.

Administration, Intranasal↗
PubMed1991

Colon-specific delivery of dexamethasone from a glucoside prodrug in the guinea pig.

Dexamethasone-beta-D-glucoside is a potential prodrug for colonic delivery of the antiinflammatory agent, dexamethasone. The ability of this prodrug to deliver dexamethasone selectively to the colon depends not only on its being slowly absorbed from the alimentary canal, but also on its having chemical and enzymatic stability in the stomach and small intestine. Once reaching the large bowel, it should be quantitatively hydrolyzed to release the active agent. The potential of dexamethasone-beta-D-glucoside for colon-specific delivery of dexamethasone is assessed by determining the rates of its hydrolysis down the alimentary canal of the guinea pig, an animal in which an inflammatory bowel disease model has been developed. The hydrolytic activity is examined in tissues and luminal contents of the stomach, proximal and distal segments of the small intestine, cecum, and colon. For the tissues, the greatest hydrolytic activity is in the proximal small intestine, while the stomach, cecum, and colon have only moderate activity. In contrast, the contents of the cecum and colon show greater activity than the contents of the small intestine and stomach. The luminal contents retained beta-glucosidase activity even after repeated centrifugation and resuspension in a buffer. The activity was unaffected by homogenization. These observations suggest that hydrolytic activity is associated with enzymes located on the surface of luminal cells. The movement and hydrolysis of dexamethasone-beta-D-glucoside down the gastrointestinal tract of the guinea pig are also examined. About 20 to 30% of an oral dose appears to reach the cecum. Here the prodrug is rapidly hydrolyzed to the active drug. From intravenous administration of the prodrug and drug, it is apparent that dexamethasone-beta-D-glucoside is poorly absorbed in the gastrointestinal tract (bioavailability, less than 1%). There is a ninefold selective advantage for delivery of dexamethasone in cecal tissues in the guinea pig under the conditions of this experiment. Thus, there is a potential for a decrease in the usual dose and a concomitant reduction in the systemic exposure to dexamethasone. Because humans have much less glucosidase activity in the small intestine, even greater site-selective delivery to the cecum and colon is expected.

Administration, Oral↗
PubMed1993

In vitro evaluation of dexamethasone-beta-D-glucuronide for colon-specific drug delivery.

Dexamethasone-beta-D-glucuronide is a potential prodrug for colonic delivery of the antiinflammatory corticosteroid dexamethasone. Previous studies [T. R. Tozer et al., Pharm. Res. 8:445-454 (1991)] indicated that a glucoside prodrug of dexamethasone was susceptible to hydrolysis in the upper gastrointestinal tract. Resistance of dexamethasone-beta-D-glucuronide to hydrolysis in the upper gastrointestinal tract was therefore assessed. Conventional, germfree, and colitic rats were used to examine enzyme levels along the gastrointestinal tract to compare the stability of two model substrates (p-nitrophenyl-beta-D-glucoside and -beta-D-glucuronide) and to evaluate the prodrug dexamethasone-beta-D-glucuronide. Hydrolytic activity was examined in the luminal contents, mucosa, and underlying muscle/connective tissues in all three types of rats. Enzymatic activity (beta-D-glucosidase and beta-D-glucuronidase) was greatest in the lumen of cecum and colon of conventional rats. In contrast, germ-free rats exhibited relatively high levels of beta-D-glucosidase activity (about 80% of total activity in the conventional rats) in the proximal small intestine (PSI) and the distal small intestine (DSI). Rats with induced colitis (acetic acid) showed reduced levels of luminal beta-D-glucuronidase activity in the large intestine; however, beta-D-glucosidase activity was relatively unchanged relative to that of the conventional rat. Mucosal beta-D-glucuronidase activity was significantly lower in the colitic rats compared with that in the conventional animals. Despite reduced luminal levels of beta-D-glucuronidase activity in the colitic rats, there was still a sharp gradient of activity between the small and the large intestines. Permeability of the glucoside and glucuronide prodrugs of dexamethasone through a monolayer of Caco-2 cells was relatively low compared to that of dexamethasone. The results indicate that dexamethasone-beta-D-glucuronide should be relatively stable and poorly absorbed in the upper gastrointestinal tract. Once the compound reaches the large intestine, it should be hydrolyzed to dexamethasone and glucuronic acid. Specificity of colonic delivery in humans should be even greater due to lower levels of beta-D-glucuronidase activity in the small intestine compared with that in the laboratory rat.

Animals↗
PubMed2002

Dexamethasone attenuates by colchicine induced Fos expression in the rat deep cerebellar and vestibular nuclei.

1. The intent of the present study was to find out whether dexamethasone pretreatment may affect the induction of Fos protein in cell nuclei of the cerebellar vestibular neuronal complex (CVNC) elicited by central administration of colchicine. Specifically, the rate of the dexamethasone-sensitive cell population was analyzed and compared at different levels of the CVNC using a light microscopic avidin-biotin peroxidase immunohistochemistry. 2. Male Wistar rats were pretreated with dexamethasone 3 days prior (2.5 mg/kg/day, s.c.) and 24 h after an intracerebroventricular delivery of colchicine (60 microg/10 microL). Animals were sacrificed 48 h after colchicine treatment by a transcardial perfusion with fixative. 3. Dexamethasone in itself had no effect on the activity of cells of the CVNC. However, in colchicine treated animals, which exhibited a large number of Fos-positive cells over the entire CVNC, the dexamethasone elicited a substantial reduction in the number of the Fos-immunoreactive cells over the CVNC. Distinct dexamethasone dependent reduction (50-90%) of Fos-immunoreactivity was observed in each of the deep cerebellar nuclei. On the other hand, less number of dexamethasone-sensitive cells were recognized in the vestibular structures. From these, maximal Fos-inhibition by dexamethasone was recognized in the medial vestibular nucleus, however, even in this case the number of suppressed cells did not exceed 50%. 4. The results provide for the first time evidence about the dexamethasone dependent reduction of Fos-immunoreactivity in the cells of the CVNC in response to stimulation elicited by colchicine. The data also indicate that the glucocorticoids might be involved in the regulation of some functions of the CVNC under stress conditions.

Animals↗