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Hypercortisolemia decreases dexamethasone half-life in rabbit.

The pharmacokinetics of dexamethasone have been found to be related to endogenous hypothalamic-pituitary-adrenal (HPA) axis activity. Lower plasma dexamethasone levels in psychiatric patients (especially depressed) who are dexamethasone suppression test (DST) nonsuppressors have previously been reported. Since DST nonsuppression is one measure of HPA axis hyperactivity and is usually associated with relatively increased plasma cortisol levels and lower post dose plasma dexamethasone levels, we hypothesized that hypercortisolemia can induce a more rapid disappearance of dexamethasone from plasma. We therefore studied the kinetics of dexamethasone in rabbits before and after a period of sustained hypercortisolemia produced by administration of IM hydrocortisone acetate, a slowly absorbed salt of cortisol. Mean dexamethasone half-life decreased significantly from baseline of 1.92 h on day zero in seven rabbits to 1.17 h on experimental day 17 of induced hypercortisolemia (P < 0.001), while there was no significant change in saline treated controls (n = 3). Dexamethasone half-life had returned to the baseline levels when retested 88 days later on experimental day 105. The results indicate that pronounced hypercortisolemia decreases dexamethasone half-life in rabbits, and support the concept that increased circulating cortisol levels induce hepatic enzymes that metabolize dexamethasone. Thus, the lower postdexamethasone plasma dexamethasone levels and decreased dexamethasone half-life in DST nonsuppressors may in part reflect the effect of prior or coincident hypercortisolemia.

Animals↗
PubMed2000

Dexamethasone concentration in the subretinal fluid after a subconjunctival injection, a peribulbar injection, or an oral dose.

PURPOSE: To determine dexamethasone concentrations in the subretinal fluid of patients after a peribulbar injection, a subconjunctival injection, or an oral dose of dexamethasone and to compare the results with those of previous similar studies of dexamethasone concentrations in the vitreous. DESIGN: Prospective, nonrandomized, comparative trial. PARTICIPANTS: One hundred forty-eight patients with a rhegmatogenous retinal detachment. METHODS: Fifty patients received a peribulbar injection of 5 mg dexamethasone disodium phosphate, 49 received a subconjunctival injection of 2.5 mg dexamethasone disodium phosphate, and 49 received an oral dose of 7. 5 mg dexamethasone at various time intervals before surgery. At the time of surgery, a subretinal fluid sample was taken from each patient. MAIN OUTCOME MEASURES: The dexamethasone concentration in the subretinal fluid measured by radioimmunoassay. RESULTS: The estimated maximum dexamethasone concentrations in the subretinal fluid after the peribulbar injection, the subconjunctival injection, and the oral dose were, respectively, 82.2 ng/ml (standard error, 17. 6), 359 ng/ml (standard error, 80.2), and 12.3 ng/ml (standard error, 1.61). Corrected for dose, the maximum dexamethasone concentrations after subconjunctival injection and peribulbar injection were, respectively, 120 (95% confidence interval, 54/180) and 13 (95% confidence interval, 6.8/20) times greater than after oral administration. CONCLUSIONS: A subconjunctival injection of dexamethasone disodium phosphate is more effective in delivering dexamethasone into the subretinal fluid of patients with a rhegmatogenous retinal detachment compared with peribulbar injection or oral administration. The subretinal dexamethasone concentrations were higher than concentrations measured in the vitreous in previous studies with a similar setup after all three delivery methods.

Administration, Oral↗
PubMed2000

Effect of one morning meal and a bolus of dexamethasone on 24-hour variation of serum leptin levels in humans.

OBJECTIVE: We have previously shown that morning administration of dexamethasone in combination with food induces a doubling of serum leptin levels starting at 7 hours after dexamethasone administration, with a maximum effect at 10 hours, the latest time point that we have studied. However, dexamethasone given in the absence of food had no effect on serum leptin at 10 hours. The present experiment was undertaken to determine the duration of the effect of dexamethasone on 24-hour serum leptin under fasted and fed conditions in humans. RESEARCH METHODS AND PROCEDURES: Six healthy non-obese male volunteers were studied under the following four conditions: 1) dexamethasone (2 mg intravenously, given at 0900 hours) with fasting; 2) dexamethasone with food (1,700 kcal, 55% carbohydrate, 15% protein, and 30% fat, given in one meal 2 hours after dexamethasone administration at 1100 hours); 3) saline with food (same meal); 4) saline with fasting. Serum leptin, glucose, insulin, and cortisol were monitored every 30 minutes for 24 hours. RESULTS: 1) Under the fasting condition, dexamethasone increased leptin nocturnal secretion between 2100 and 2400 hours. 2) A single meal (1,700 kcal) at 1100 hours increased nocturnal leptin secretion when compared with the fasting condition. The peak increase of leptin was 123% over baseline between 2100 and 2400 hours, 10 to 14 hours after the meal. 3) In the fed + dexamethasone condition, leptin levels increased from baseline starting 8 hours after dexamethasone injection, reached a maximum increase of 260% between 2100 and 2400 hours, then decreased thereafter, remaining elevated compared to baseline for 16 hours. There was a correlation between 24-hour leptin secretion and insulin secretion after a single morning meal. DISCUSSION: A single bolus of dexamethasone, given before a single large meal, produces a delayed (6-hour) but long-lasting increase in serum leptin (over 16 hours). Under fasted conditions, dexamethasone does not increase daytime leptin but does increase leptin during the night.

Adult↗
PubMed1991

Dexamethasone inhibits the hexose monophosphate shunt in activated rat peritoneal macrophages by reducing hexokinase-dependent sugar uptake.

Dexamethasone decreases 2-D-deoxyglucose (2-dGlc) uptake and accumulation into rat peritoneal macrophages in vitro in a concentration- and time-dependent manner (Ki for 1 microM-dexamethasone after a 2 h exposure = 0.71 +/- 0.21 microM; Ki for 0.1 microM-dexamethasone after exposure for 4 h = 0.10 +/- 0.06 microM). The inhibition of 2-dGlc uptake is consistent with a decrease in the coupling between endofacial hexokinase activity and the sugar transporter. The evidence for this is: (1) the Km for zero-trans 2-dGlc uptake in quiescent macrophages was increased by dexamethasone, but there was no significant effect on the Vmax.; (2) dexamethasone increased the rate of exit of sugar from cells preloaded with 2-dGlc; (3). the free sugar accumulation within the cytosol of the cells above the external solution concentration was significantly decreased by dexamethasone. These effects of dexamethasone on 2-dGlc transport were antagonized by simultaneous exposure to the steroid RU 38486 (Ki = 0.04 +/- 0.01 microM; 4 h incubation). Although dexamethasone inhibited zero-trans uptake, the maximum rate of infinite-trans exchange uptake of 2-dGlc into cells preloaded with 3-O-methyl-D-glucose (40 mM) was unaltered by dexamethasone or RU 38486, indicating that the dexamethasone-dependent decrease in zero-trans uptake was not due to a change in the number of transporters in the plasma membrane. Dexamethasone also inhibited the phorbol myristate acetate-induced stimulation of hexose monophosphate shunt (HMPS) activity, and this was reversed by RU 38486. Cytochalasin B, the potent sugar-transport inhibitor, inhibited HMPS activity and 2-d[2,6-3H]Glc uptake equally, indicating a single site of action. By contrast, dexamethasone showed differential inhibition of HMPS activity and 2-d[2,6-3H]Glc uptake, suggesting that it not only acts by decreasing the coupling between hexokinase and sugar transport, but also at one or more additional points.

Animals↗
PubMed2000

The cytochrome P450 3A4 inhibitor itraconazole markedly increases the plasma concentrations of dexamethasone and enhances its adrenal-suppressant effect.

OBJECTIVE: To examine the possible interaction of itraconazole with orally and intravenously administered dexamethasone. METHODS: In a randomized, double-blind, placebo-controlled crossover study with four phases, eight healthy subjects took either 200 mg itraconazole (in two phases) or placebo (in two phases) orally once daily for 4 days. On day 4 each subject received an oral dose of 4.5 mg dexamethasone or an intravenous dose of 5.0 mg dexamethasone sodium phosphate during both itraconazole and placebo phases. Plasma dexamethasone and cortisol concentrations were determined by HPLC up to 71 hours, itraconazole and hydroxyitraconazole up to 23 hours. RESULTS: Itraconazole decreased the systemic clearance of intravenously administered dexamethasone by 68% (P < .001), increased the total area under the plasma dexamethasone concentration-time curve [AUC(0-infinity)] 3.3-fold (P < .001), and prolonged the elimination half-life of dexamethasone 3.2-fold (P < .001). The AUC(0-infinity) of oral dexamethasone was increased 3.7-fold (P < .001), the peak plasma concentration 1.7-fold (P < .001), and the elimination half-life 2.8-fold (P < .001) by itraconazole. The morning plasma cortisol concentrations measured 47 and 71 hours after administration of dexamethasone were substantially lower after exposure to itraconazole than to placebo (P < .001). Accordingly, the adrenal-suppressant effect of dexamethasone was greatly enhanced during the itraconazole phases. CONCLUSIONS: Itraconazole markedly increases the systemic exposure to and effects of dexamethasone. A careful follow-up is recommended when itraconazole or other potent inhibitors of the cytochrome P450 3A4 are added to the drug regimen of patients receiving dexamethasone.

Administration, Oral↗
PubMed1978

Dexamethasone modulates binding and action of epidermal growth factor in serum-free cell culture.

Experiments probing the mechanism by which glucocorticoids modulate cell proliferation were carried out on serum-free cell cultures of quiescent human diploid foreskin (HF) cells. Added alone, the synthetic glucocorticoid dexamethasone had no effect on cell number. However, dexamethasone enhanced the mitogenic response of HF cells to epidermal growth factor (EGF) by 50% at all EGF concentrations. The mitogenic action of EGF was maximally promoted by a dexamethasone concentration of 100 ng/ml (0.25 muM). Binding studies with (125)I-labeled EGF ((125)I-EGF) suggested that dexamethasone caused this "permissive" effect by modulating cell surface receptors for EGF. Paralleling their increased responsiveness to EGF growth stimulation, dexamethasone-treated cells exhibited a 50-100% increased ability to bind physiological concentrations of (125)I-EGF. A binding increase was apparent after a 4-hr dexamethasone treatment. The dexamethasone-treated cells maintained an increased ability to bind (125)I-EGF during the prolonged exposure to EGF that was required to stimulate cell division. Moreover, the increase in (125)I-EGF binding exhibited a dexamethasone dose-dependence similar to that for the enhancement of EGF mitogenesis, suggesting a relationship between the dexamethasone effects on binding and growth. An investigation of the binding increase showed that it was specific for glucocorticoids, and required protein synthesis. The enhancement of (125)I-EGF binding diminished with increasing concentrations of (125)I-EGF, indicating that dexamethasone caused a qualitative change in the EGF receptors (possibly a change in receptor affinity or cooperativity). The alteration in (125)I-EGF binding may occur as part of a far-reaching dexamethasone-mediated change in the cell surface, because dexamethasone treatment slightly increased the ability of HF cells to bind (125)I-insulin, and decreased by half their ability to bind (125)I-thrombin.

Cell Division↗
PubMed2002

Small-dose dexamethasone reduces nausea and vomiting after laparoscopic cholecystectomy: a comparison of tropisetron with saline.

UNLABELLED: Dexamethasone is an effective antiemetic drug, but the efficacy of small-dose dexamethasone 5 mg on the prophylaxis of postoperative nausea and vomiting (PONV) in patients undergoing laparoscopic cholecystectomy has not been evaluated. We, therefore, evaluated the prophylactic effect of small-dose dexamethasone (5 mg) on PONV in patients undergoing laparoscopic cholecystectomy. Tropisetron and saline served as controls. One-hundred-twenty patients scheduled for laparoscopic cholecystectomy were enrolled in a randomized, double-blinded, placebo-controlled study. At the induction of anesthesia, the Dexamethasone group received IV dexamethasone 5 mg, the Tropisetron group received IV tropisetron 2 mg, and the Placebo group received IV saline. We found that both dexamethasone and tropisetron significantly decreased the following variables: the total incidence of PONV (P < 0.01), more than four vomiting episodes (P < 0.05), and the proportions of patients requiring rescue antiemetics (P < 0.05). The differences between the Dexamethasone and Tropisetron groups were not significant. We conclude that prophylactic IV dexamethasone 5 mg significantly reduces the incidence of PONV in patients undergoing laparoscopic cholecystectomy. At this dose, dexamethasone is as effective as tropisetron 2 mg and is more effective than placebo. IMPLICATIONS: We evaluated the prophylactic effect of small-dose dexamethasone (5 mg) on postoperative nausea and vomiting (PONV) in patients undergoing laparoscopic cholecystectomy. Tropisetron (2 mg) and saline served as controls. We found that dexamethasone 5 mg (IV) significantly reduced the incidence of PONV in these patients, and, at this dose, dexamethasone was as effective as tropisetron and was more effective than placebo.

Adult↗
PubMed1999

Growth hormone and insulin-like growth factor-I therapy promote protein deposition and growth in dexamethasone-treated piglets.

BACKGROUND: Dexamethasone treatment facilitates the weaning of premature infants from mechanical ventilation but impairs protein homeostasis, lean tissue deposition, and growth. The current study was conducted to investigate whether dexamethasone mediates these effects by reducing protein synthesis or elevating protein breakdown, and whether adjuvant growth hormone+/-insulin-like growth factor-I therapy can attenuate such effects. METHODS: Piglets (n = 24) were randomized to placebo, a tapered course of dexamethasone (0.5, 0.3, 0.2 mg/kg per day for 5, 5 and 4 days each, respectively), dexamethasone + growth hormone 0.1 mg/kg per day, or dexamethasone + growth hormone + insulin-like growth factor-I 0.1 mg/kg per day for 14 days. On day 13, 15N-glycine was administered as a single oral dose, and urine was collected at timed intervals during the subsequent 48 hours. RESULTS: Total urinary N and cumulative 15N excretion were higher in all dexamethasone groups than in control subjects. Protein synthesis was suppressed, whereas protein breakdown was unaltered by dexamethasone. Adjunctive growth hormone+/-insulin-like growth factor-I therapy enhanced protein synthesis, but only combined therapy improved net protein gain compared with dexamethasone alone. Higher circulating insulin-like growth factor-I may have mediated the greater net protein gain. Blood urea nitrogen was elevated in all dexamethasone-treated groups at days 6 and 11 but was normalized by day 15 with adjunctive growth hormone+/-insulin-like growth factor-I. From a functional perspective, both adjunctive growth hormone and growth hormone+/-insulin-like growth factor-I partially attenuated the dexamethasone-induced reduction in weight and length gain but not in whole body lean and fat mass. CONCLUSION: Adjunctive growth hormone+/-insulin-like growth factor-I therapy partially reverses the dexamethasone-induced reduction in protein synthesis, resulting in improved growth when given concurrently with a low tapering dose of dexamethasone.

Animals↗
PubMed2003

Randomized study of IVIg and high-dose dexamethasone therapy for children with chronic idiopathic thrombocytopenic purpura.

PURPOSE: To investigate whether pulsed high-dose dexamethasone is more efficacious than intravenous immunoglobulin (IVIg) as treatment of symptomatic chronic idiopathic thrombocytopenic purpura (ITP) in childhood. METHODS: In a 2:1-randomized study, 23 children with chronic ITP received dexamethasone (0.6 mg/kg per day for 4 consecutive days once monthly for 6 months, n = 15) or IVIg (800 mg/kg intravenously once monthly for 6 months, n = 8). After four courses of treatment a crossover was offered to nonresponders. A total of 20 children received dexamethasone and 11 received IVIg. RESULTS: One of the 8 IVIg patients and 2 of the 15 dexamethasone patients achieved complete response, defined as a platelet count of at least 150 x 10(9)/L for more than 3 months without treatment. Two of the 15 dexamethasone patients achieved partial response, defined as a platelet count of at least 30 x 10(9)/L for more than 3 months without treatment. One of the 8 IVIg patients and 5 of the 15 dexamethasone patients discontinued treatment. Five patients crossed over from IVIg to dexamethasone (one complete response) and three from dexamethasone to IVIg (none responded). In summary, 5 of the 20 dexamethasone patients achieved a complete or partial response and 1 of the 11 IVIg patients achieved a complete response. Platelet counts of at least 30 x 10(9)/L by day 3 were reached in 9 of the 12 (75%) dexamethasone patients and all 8 (100%) IVIg children using available data. Five years after study completion, two of the three children who achieved a complete response and one of the two with a partial response to dexamethasone were in remission, as was the child with a complete response to IVIg. CONCLUSIONS: Treatment with pulsed high-dose dexamethasone is not always effective in children with chronic ITP, but it is worth trying in severe symptomatic chronic childhood ITP.

Adolescent↗
PubMed2006

Intratympanic injection of dexamethasone: time course of inner ear distribution and conversion to its active form.

HYPOTHESIS: Intratympanically injected dexamethasone 21-phosphate is converted to its active form dexamethasone in the inner ear and follows the distribution of the glucocorticoid receptor. BACKGROUND: Although dexamethasone is routinely delivered intratympanically for hearing loss, we know little of its inner ear pharmacokinetics. Dexamethasone 21-phosphate is the pharmaceutical compound available for injection, but it must be converted to its biologically active form (dexamethasone) to bind to the glucocorticoid receptor. Therefore, the current study was conducted to determine the time course of dexamethasone 21-phosphate movement from the middle ear into the inner ear, its conversion to dexamethasone, and the distribution of both forms relative to the glucocorticoid receptor. METHODS: BALB/c mice were injected intratympanically with the prodrug dexamethasone 21-phosphate and inner ears collected at postinjection times ranging from 5 minutes to 7 days. Ears were immunohistochemically stained for dexamethasone 21-phosphate, dexamethasone, and the glucocorticoid receptor. RESULTS: Both forms of dexamethasone were seen in the inner ear within 15 minutes, reaching their highest staining intensity at 1 hour. Neither drug was seen after 24 hours. The strongest staining occurred in the spiral ligament, organ of Corti, spiral ganglion, and vestibular sensory epithelia. Distribution of the drug paralleled locations of the glucocorticoid receptor except in the stria vascularis marginal cells, which stained heavily for the receptor but not the drug. CONCLUSION: Dexamethasone rapidly travels from the middle ear into the inner ear and converts to its active form. The drug distribution follows that of the glucocorticoid receptor. However, it probably has little impact on ear tissues after 24 hours.

Animals↗
PubMed2004

The effect of dexamethasone on human mucin 1 expression and antibody-dependent complement sensitivity in a prostate cancer cell line in vitro and in vivo.

Dexamethasone has been shown to up-regulate human mucin 1 (MUC1) expression in certain types of cancer cell lines in vitro, suggesting that this gluocorticoid may enhance MUC1-based immunotherapies. Here we investigated the effect of dexamethasone on MUC1 expression in the DU145 human prostate cancer cell line in terms of antibody-mediated complement-dependent cell lysis. Cells treated with 1 x 10-8 m dexamethasone in vitro expressed maximal levels of MUC1 after 6 days, with an approximately 3-fold increase over MUC1 levels on untreated cells. DU145 cells were highly resistant to lysis by anti-MUC1 antibody and complement, and their susceptibility to antibody and complement was unaffected by dexamethasone treatment. However, dexamethasone also induced expression of the complement inhibitor decay accelerating factor (DAF) on DU145 cells. Blocking or overcoming the function of DAF resulted in enhanced complement-dependent lysis of dexamethasone-treated cells with anti-MUC1 antibodies, indicating that the failure of dexamethasone to enhance the complement susceptibility of DU145 cells was caused by the up-regulated expression of DAF. We also investigated MUC1 expression in vivo and found that MUC1 expression was significantly up-regulated on tumour cells isolated from immune-deficient mice that had been injected with dexamethasone. However, in contrast to in vitro data, there was no difference between the levels of DAF expressed on tumour-derived DU145 cells isolated from either phosphate buffered saline (PBS)-treated or dexamethasone-treated mice, and tumour cells isolated from dexamethasone-treated mice were more sensitive to complement-mediated lysis. In the broad context of immunotherapy, the in vivo data support the use of dexamethasone as an adjunct treatment. Up-regulated DAF expression would not be a favourable outcome of dexamethasone treatment in terms of complement-dependent antibody therapy, but the in vivo data caution against extrapolation of in vitro data with regard to the modulation of complement inhibitors reported here and elsewhere.

Animals↗
PubMed1989

Acute dexamethasone suppression of ACTH secretion stimulated by human corticotrophin releasing hormone, AVP and hypoglycaemia.

In order to obtain more insight into the mechanisms regulating endogenous ACTH secretion in humans we studied the inhibitory effect of acute i.v. dexamethasone administration on ACTH release under various conditions. Six male volunteers were subjected to six different protocols. After combined i.v. injection of 100 micrograms corticotrophin releasing hormone (CRH) and 100 micrograms growth hormone releasing hormone (GRH) there was the expected rise in ACTH (area under the curve, 1053 +/- 204 (SE) (pmol/l) min) and cortisol (59788 +/- 10098 (nmol/l) min) rise which was suppressed by prior i.v. injection of 2 mg dexamethasone (ACTH: 444 +/- 63 (pmol/l) min; cortisol: 28528 +/- 2152 (nmol/l) min). Insulin hypoglycaemia (IH) led to a more pronounced ACTH and cortisol rise compared with CRH (6307 +/- 817 (pmol/l) min and 82080 +/- 21934 (nmol/l) min, respectively) which was not completely suppressed by prior pretreatment with dexamethasone (ACTH, 580 +/- 103 (pmol/l) min; cortisol: 55649 +/- 5821 (nmol/l) min). Combined AVP/CRH injection (10 IU/100 micrograms) after pretreatment with dexamethasone (344 +/- 41 (pmol/l) min for ACTH; 32832 +/- 3173 (nmol/l) min for cortisol) could not reproduce the ACTH secretion following IH after pretreatment with dexamethasone (579 +/- 103 (pmol/l) min for ACTH and 55649 +/- 5821 (nmol/l) min for cortisol). In all subjects a saline control with 2 mg dexamethasone was performed. These findings confirm the acute inhibitory effect of glucocorticoids on CRH-stimulated ACTH secretion. Since CRH-induced ACTH secretion is almost completely abolished by administration of dexamethasone the ACTH rise following IH after dexamethasone can not be mediated by endogenous CRH alone. Moreover, since the addition of AVP to CRH (after dexamethasone suppression) could not reproduce the ACTH rise during IH after dexamethasone pretreatment, an additional, yet unknown factor stimulating ACTH secretion may be involved. In the same protocols, no significant difference could be observed comparing IH and GRH induced GH secretion (4948 +/- 1172 (mU/l) min vs 3596 +/- 820 (mU/l) min, NS); furthermore, in contrast to results obtained by chronic steroid administration, acute i.v. dexamethasone pretreatment did not affect IH or GRH-induced GH secretion (4110 +/- 666 (mU/l) min vs 2916 +/- 462 (mU/l) min, NS). The GRH-stimulated GH secretion (3596 +/- 820 (mU/l) min) was not suppressed by prior intravenous treatment with dexamethasone (2916 +/- 504 (mU/l) min, NS).

Adrenocorticotropic Hormone↗
PubMed2002

Antenatal dexamethasone: effect on ovine placental 11beta-hydroxysteroid dehydrogenase type 2 expression and fetal growth.

Antenatal glucocorticoids are routinely given to women at risk for preterm delivery. The fetus is protected from excessive glucocorticoids by the placental enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD-2), which catalyzes the conversion of cortisol to its biologically inactive metabolite, cortisone. We examined the effects of antenatal dexamethasone on the expression of placental 11beta-HSD-2 in fetal sheep. Ewes were randomized to receive repeated or single courses of dexamethasone or placebo beginning at 76-78 or 104-106 d of gestation, respectively. In the single course group, the ewes received dexamethasone (6 mg, n = 7) or placebo (n = 6) as four intramuscular injections over 48 h up to 18 h before placental harvest. In the repeated course group, the ewes received the same treatment (dexamethasone, n = 10, or placebo, n = 9) once a week for 5 consecutive weeks starting at 76-78 d of gestation. Placental harvest occurred at 106-108 d of gestation in the four groups. By semi-quantitative RT-PCR, we found that placental 11beta-HSD-2 expression was lower in the fetuses of ewes exposed to a single course of dexamethasone than placebo (p < 0.05). Placental 11beta-HSD-2 expression did not differ significantly between fetuses of ewes treated with repeated courses of dexamethasone compared with placebo, or a single course of dexamethasone. Fetuses of dexamethasone treated ewes weighed less than those of placebo treated ewes (ANOVA, main effects for dexamethasone versus placebo treatment: F = 14.5, p = 0.007). Fetuses of ewes exposed to repeated courses of dexamethasone weighed less than those of ewes exposed to placebo or a single course of dexamethasone (p < 0.05). We conclude that maternal antenatal dexamethasone treatment reduces placental 11beta-HSD-2 expression and fetal weight at mid-gestation in the ovine pregnancy.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗
PubMed1989

Dexamethasone regulates the glucose transport system in primary cultured adipocytes: different mechanisms of insulin resistance after acute and chronic exposure.

We have studied the ability of dexamethasone to regulate the glucose transport system in primary cultured adipocytes and delineated the mechanisms of insulin resistance after both acute and chronic treatment. Acutely, 20 nM dexamethasone led to a 65% decrease in basal and a 31% decrement in maximally insulin-stimulated glucose transport (ED50 = 3-4 nM; t1/2 = 50 min). These effects were maximal by 90-120 min, and a plateau was maintained over an additional 1-1.5 h. Chronic dexamethasone exposure (24 h) led to a more profound decrease in basal (77%; ED50 = 0.4 nM) and maximally stimulated (55%; ED50 = 1.0 nM) rates of glucose transport and shifted the transport: insulin dose-response curve to the right by increasing the half-maximally effective insulin concentration from 0.2 to 0.4 ng/ml. Dexamethasone did not affect cell surface insulin binding over 24 h. Both the short and long term effects of dexamethasone were partially blocked by the combined presence of insulin during preincubation and were not modulated by glucose. We also assessed effects on the number and cellular distribution of glucose transporter proteins using the cytochalasin-B binding assay. After 2 h, dexamethasone (30 nM) decreased the number of glucose transporters in plasma membranes by 30% in basal cells and by 41% in maximally insulin-stimulated cells, while increasing the number of low density microsomal transporters by 22-23% (P = NS). Transporter number in a total cellular membrane fraction was unaltered by short term dexamethasone. Chronic dexamethasone exposure (24 h) decreased plasma membrane and low density microsomal transporters by 30-50% in both basal and insulin-stimulated cells and depleted transporters by 43% in a total cellular membrane fraction. In conclusion, 1) dexamethasone induces progressive insulin resistance by sequentially regulating multiple aspects of the insulin-responsive glucose transport system. At early times (2 h) dexamethasone impairs insulin's ability to translocate intracellular glucose transporters to the cell surface and with more chronic exposure (24 h), depletes the total number of cellular transporters. 2) Glucose modulates desensitization of the glucose transport system by insulin, but not by dexamethasone, and thus, there are both glucose-dependent and -independent mechanisms of insulin resistance. 3) Insulin can heterologously inhibit dexamethasone's effects on glucose transport at both early and late phases of desensitization. These studies highlight the complex hormonal regulation at the glucose transport system.

Adipose Tissue↗
PubMed1992

The regulation of lipoprotein lipase gene expression by dexamethasone in isolated rat adipocytes.

Lipoprotein lipase (LPL) is an enzyme found in adipose tissue that is important in the hydrolysis of triglyceride rich lipoproteins, and in the uptake of FFA lipid into the adipocyte. To examine the effects of glucocorticoids on adipose tissue LPL, male Sprague-Dawley rats were injected with dexamethasone (1 mg/kg) every other day for 10 days, followed by measurement of LPL in epididymal adipose tissue. Compared to sham-injected controls, heparin-releasable LPL activity and LPL mass in the dexamethasone-treated rats were 44% and 62% of those in control rats, respectively. Adipocytes were prepared from the fat pads and pulse labeled with [35S]methionine, demonstrating a decrease in the LPL synthetic rate in the treated rats to 57% of the rate in control rats. In addition, LPL mRNA was quantitated by Northern blotting, demonstrating a decrease in LPL mRNA in the dexamethasone-treated rats. A simultaneous decrease in the message for gamma-actin was also noted. To examine the effects of dexamethasone on LPL in vitro, adipocytes were prepared from normal rats and treated with dexamethasone for 24 h in vitro. Dexamethasone decreased heparin-releasable LPL activity in cultured adipocytes to 40 +/- 6% of the control value (P less than 0.01). This decrease in LPL activity was accompanied by a decrease in the LPL synthetic rate using [35S]methionine labeling, to 33% of the control value, and no specific change in LPL turnover or secretion. In addition, dexamethasone added to adipocytes decreased LPL mRNA levels. Because the combination of insulin plus dexamethasone has been shown to yield synergistic increases in LPL in adipose tissue pieces, insulin was added to isolated adipocytes in combination with dexamethasone. Whereas insulin and dexamethasone individually had opposite effects on LPL, the combination of insulin plus dexamethasone resulted in no change in any aspect of LPL gene expression. Thus, dexamethasone resulted in a decrease in adipocyte LPL mRNA levels both when added to cultured adipocytes in vitro as well as when injected into rats. This decreased LPL mRNA level yielded corresponding changes in the LPL synthetic rate and LPL activity.

Actins↗
PubMed1995

The oxazolidinedione CP-92,768-2 partially protects insulin receptor substrate-1 from dexamethasone down-regulation in 3T3-L1 adipocytes.

Oxazolidinediones are a class of oral antidiabetic agents that are closely related structurally and pharmacologically to thiazolidinediones. The thiazolidinediones have been shown to partially reverse the loss in insulin-responsive glucose uptake caused by chronic treatment with dexamethasone. This study was conducted to determine certain aspects of the mechanism of thiazolidinedione and oxazolidinedione action. We selected the oxazolidinedione CP-92,768-2 (5-[2-[(5-methyl2-phenyl-4-oxazolyl)methyl]5-benzofuranyl methyl]2,4- oxazolidinedione) to determine whether these agents could reverse the dexamethasone-induced down-regulation of IRS-1, the insulin receptor substrate-1. In 3T3-L1 adipocytes, dexamethasone treatment resulted in down-regulation of IRS-1 to 60% of control values. Simultaneous treatment with CP-92,768-2 significantly increased IRS-1 to 78% of the control value (EC50, < 10 nM), although it did not completely reverse the dexamethasone effect at any concentration tested. CP-92,768-2 alone did not have any effect on IRS-1. CP-92,768-2 did not affect the stability of IRS-1 protein in the presence or absence of dexamethasone, as measured by [35S]methionine pulse-chase labeling. Dexamethasone decreased messenger RNA (mRNA) for IRS-1 after 24 h of treatment to 40% of the control value. CP-92,768-2 partially reversed this decrease in IRS-1 mRNA to 65% of the control value after 24 h of treatment, but had no effect on IRS-1 mRNA in the absence of dexamethasone. Dexamethasone down-regulated the insulin stimulation of [3H]thymidine incorporation to 68% of the control value. Dexamethasone in the presence of CP-92,768-2 down-regulated insulin stimulation of thymidine incorporation by only 9%. Dexamethasone also down-regulated the expression of phosphoenolpyruvate carboxykinase (PEPCK) protein by 50%. CP-92,768-2 partially protected PEPCK from the dexamethasone down-regulation. Conversely, the up-regulation of expression of PEPCK and IRS-1 produced by dexamethasone in KRC-7 hepatoma cells was not affected by CP-92,768-2. One contribution of oxazolidinediones to an increase in insulin responsiveness in the presence of glucocorticoids may be the up-regulation of IRS-1 in adipose cells.

3T3 Cells↗
PubMed1983

Determination of plasma dexamethasone in the mother and the newborn after administration of the hormone in a clinical trial.

A RIA method is described for the measurement of dexamethasone in maternal, cord, and neonate plasma in a collaborative multicenter clinical trial to evaluate the efficacy of antenatal steroid therapy in the prevention of respiratory distress syndrome. The antiserum raised against dexamethasone-3-carboxymethyloxime-BSA conjugate was highly specific in that the endogenous steroids and 11-dehydrodexamethasone, a metabolite of dexamethasone, had a cross-reaction of less than 2.0%. Both pregnancy and cord plasma had to be purified by either gel filtration and/or paper chromatography. The overall recoveries of dexamethasone were 75.3 +/- 6.7% and 48.9 +/-6.7% for maternal and cord plasma samples, respectively. The intra- and interassay coefficients of variance for maternal plasma were 8.4% ad 9.1%, respectively, and for cord plasma were 11.9% and 10.9%, respectively. There was a good correlation between the dexamethasone values obtained by RIA when compared with those obtained by performance liquid chromatography in some cord plasma specimens. The recoveries of added dexamethasone and its metabolite by high performance liquid chromatography were also found to be good. The average maternal plasma dexamethasone level was 37 ng/ml 2 h after im injections of 5 mg dexamethasone phosphate every 12 h. The half-life of dexamethasone measured after the discontinuation of the drug was 216 min. Dexamethasone appeared too be cleared very rapidly from the circulation of the fetus and neonate. Because 11-dehydrodexamethasone was not present in significant amounts in the neonate, it was concluded that other factors in addition to the conversion of dexamethasone to its 11 dehydro metabolite were responsible for the rapid clearance of dexamethasone from fetal and neonatal circulation.

Antibody Specificity↗
PubMed2003

The effects of single-dose dexamethasone on wound healing in rats.

UNLABELLED: Dexamethasone effectively decreases the incidence of nausea and vomiting among pediatric and adult patients. In this study, we evaluated the effects of single-dose dexamethasone on wound healing in a prospective, randomized, experimental animal model. Anesthesia was induced with thiopental 100 mg/kg intraperitoneally. Dexamethasone 1 mg/kg was administered intraperitoneally in a dexamethasone group, and physiological saline was administered in a control group. Collagenization, epithelization, and fibroblast content were significantly less in the dexamethasone group compared with the control group (P values of 0.002, 0.041, and 0.023, respectively). The vascularity and the degree of inflammatory cells were more intense in the dexamethasone group compared with the control group (P values of 0.023 and 0.002, respectively). The white blood cell count was similar in the control (7.84 +/- 2.09) and dexamethasone (6.98 +/- 2.12) groups. The mean hydroxyproline level was 0.72 +/- 0.13 mg/g in the dexamethasone and 1.03 +/- 0.19 mg/g in the control group. Hydroxyproline levels were significantly less in the dexamethasone group (P = 0.001). We conclude that dexamethasone at 1 mg/kg may have negative effects on wound healing. IMPLICATIONS: We evaluated the effects of dexamethasone on wound healing in a prospective, randomized, experimental animal model. Our results show that dexamethasone at 1 mg/kg may have negative effects on wound healing.

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