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PubMed1997

In vitro delivery of dexamethasone using hydroxyapatite reservoirs.

Dexamethasone has been shown to stimulate bone nodule formation in vitro. A hydroxyapatite (HA) reservoir drug release device was designed to release dexamethasone in vitro. Two HA particle sizes (< 38 microns or 63-75 microns) were used to fabricate the reservoirs. Each HA reservoir was loaded with 2 mg of dexamethasone and suspended in 100 ml of 50% aqueous ethanol at 37 degrees C for a period of 28 days. The positive controls indicated a limited solubility of dexamethasone of 1.18 mg per 100 ml of 50% aqueous ethanol. Dexamethasone was not released from any of the HA reservoirs for the first 24 hours. The largest amount of dexamethasone (0.0137 microgram/microliter) was released from the 63-75 microns particle HA reservoirs. A significantly lesser amount (0.00855 microgram/microliter) of dexamethasone was released from the < 38 microns particle HA reservoirs. The results of this study suggest that a HA ceramic reservoir loaded with dexamethasone can be used to deliver dexamethasone over long periods of time.

Biocompatible Materials↗

PubMed1998

Beneficial effect of intravenous dexamethasone in children with mild to moderately severe acute chest syndrome complicating sickle cell disease.

Acute chest syndrome (ACS) in patients with sickle cell disease (SCD) has historically been managed with oxygen, antibiotics, and blood transfusions. Recently high-dose corticosteroid therapy was shown to reduce the duration of hospitalization in children with SCD and vaso-occlusive crisis. Therefore, we chose to assess the use of glucocorticoids in ACS. We conducted a randomized, double-blind placebo-controlled trial to evaluate the efficacy and toxicity of intravenous dexamethasone (0.3 mg/kg every 12 hours x 4 doses) in children with SCD hospitalized with mild to moderately severe ACS. Forty-three evaluable episodes of ACS occurred in 38 children (median age, 6.7 years). Twenty-two patients received dexamethasone and 21 patients received placebo. There were no statistically significant differences in demographic, clinical, or laboratory characteristics between the two groups. Mean hospital stay was shorter in the dexamethasone-treated group (47 hours v 80 hours; P = .005). Dexamethasone therapy prevented clinical deterioration and reduced the need for blood transfusions (P < .001 and = .013, respectively). Mean duration of oxygen and analgesic therapy, number of opioid doses, and the duration of fever was also significantly reduced in the dexamethasone-treated patients. Of seven patients readmitted within 72 hours after discharge (six after dexamethasone; P = .095), only one had respiratory complications (P = 1.00). No side effects clearly related to dexamethasone were observed. In a stepwise multiple linear regression analysis, gender and previous episodes of ACS were the only variables that appeared to predict response to dexamethasone, as measured by lengh of hospital stay. Intravenous dexamethasone has a beneficial effect in children with SCD hospitalized with mild to moderately severe acute chest syndrome. Further study of this therapeutic modality is indicated.

Acute Disease↗

PubMed1988

Treatment with dexamethasone of androgen excess in adolescent patients.

Fourteen hirsute girls, ages 12 to 22 years (mean +/- SD: 17.2 +/- 2.6 years), in whom 21-hydroxylase deficiency was excluded by a 1-hour intravenous alpha 1-24 corticotropin test, were evaluated by a 4-day dexamethasone test and then treated with a bedtime dose of dexamethasone (0.5 mg in 10 patients, 0.25 mg in four) for 0.6 to 3.4 years (1.3 +/- 0.8 years). Hirsutism decreased in four patients, did not change in nine, and increased in one. Of the 10 patients with irregular menses, only three developed regular cycles while taking dexamethasone. During long-term dexamethasone therapy, serum levels of testosterone decreased from 102 +/- 22 to 72 +/- 27 ng/dL, free testosterone from 35 +/- 11 to 19 +/- 8 pg/mL, and dehydroepiandrosterone sulfate from 396 +/- 138 to 171 +/- 101 micrograms/dL. Although free testosterone decreased to less than 15 pg/mL in eight of 14 patients with the suppression test, only four patients had free testosterone levels less than 15 pg/mL during therapy. Two of the 14 patients have had no recurrence of hirsutism or increase in serum androgens after 28 and 29 months, respectively, after dexamethasone therapy was discontinued. Oral contraceptives were given to nine patients inadequately responsive to bedtime dexamethasone therapy. The mean percent decrease of testosterone and free testosterone levels during oral contraceptive therapy was significantly greater than during long-term treatment with dexamethasone, and hirsutism lessened in all. We conclude that a single bedtime dose of dexamethasone is satisfactory only in patients who maintain serum free testosterone values less than 15 pg/mL without side effects. For other patients, either another glucocorticoid or, in most cases, ovulation suppression should be prescribed for adolescents with progressive hirsutism and elevated androgen levels.

17-Ketosteroids↗

PubMed2002

Dexamethasone in adults with bacterial meningitis.

BACKGROUND: Mortality and morbidity rates are high among adults with acute bacterial meningitis, especially those with pneumococcal meningitis. In studies of bacterial meningitis in animals, adjuvant treatment with corticosteroids has beneficial effects. METHODS: We conducted a prospective, randomized, double-blind, multicenter trial of adjuvant treatment with dexamethasone, as compared with placebo, in adults with acute bacterial meningitis. Dexamethasone (10 mg) or placebo was administered 15 to 20 minutes before or with the first dose of antibiotic and was given every 6 hours for four days. The primary outcome measure was the score on the Glasgow Outcome Scale at eight weeks (a score of 5, indicating a favorable outcome, vs. a score of 1 to 4, indicating an unfavorable outcome). A subgroup analysis according to the causative organism was performed. Analyses were performed on an intention-to-treat basis. RESULTS: A total of 301 patients were randomly assigned to a treatment group: 157 to the dexamethasone group and 144 to the placebo group. The base-line characteristics of the two groups were similar. Treatment with dexamethasone was associated with a reduction in the risk of an unfavorable outcome (relative risk, 0.59; 95 percent confidence interval, 0.37 to 0.94; P=0.03). Treatment with dexamethasone was also associated with a reduction in mortality (relative risk of death, 0.48; 95 percent confidence interval, 0.24 to 0.96; P=0.04). Among the patients with pneumococcal meningitis, there were unfavorable outcomes in 26 percent of the dexamethasone group, as compared with 52 percent of the placebo group (relative risk, 0.50; 95 percent confidence interval, 0.30 to 0.83; P=0.006). Gastrointestinal bleeding occurred in two patients in the dexamethasone group and in five patients in the placebo group. CONCLUSIONS: Early treatment with dexamethasone improves the outcome in adults with acute bacterial meningitis and does not increase the risk of gastrointestinal bleeding.

Acute Disease↗

PubMed2026

Low-Dose Perineural Dexamethasone Enhances Analgesia After Pediatric Hand Surgery Without Elevating Systemic Stress Markers: A Randomized Controlled Trial.

BACKGROUND: Supraclavicular brachial plexus block is a widely used technique for upper limb surgery in children. Although perineural dexamethasone has demonstrated efficacy in prolonging analgesia in adults, data on its optimal dosing and systemic safety in pediatric patients are limited. This study aimed to evaluate whether low-dose perineural dexamethasone can prolong postoperative analgesia without increasing systemic stress markers in young children undergoing hand or wrist surgery. METHODS: In this triple-blinded, randomized controlled trial (ClinicalTrials.gov Identifier: NCT06086392), 90 children aged 3 months to 6 years undergoing elective upper extremity surgery were assigned to receive supraclavicular brachial plexus block with 0.2% ropivacaine combined with either normal saline (control), dexamethasone 0.05 mg/kg, or dexamethasone 0.1 mg/kg. The primary outcome was time from arrival in the postanesthesia care unit to first administration of rescue opioid analgesia. Secondary outcomes included total opioid consumption, postoperative pain intensity using the FLACC scale, blood glucose levels, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and time to motor recovery. RESULTS: Both dexamethasone groups demonstrated significantly prolonged time to first opioid use compared with the control group (mean±SD: 19.4±2.2 h in the 0.1 mg/kg group, 16.0±1.9 h in the 0.05 mg/kg group, and 8.5±1.3 h in controls; P <0.0001). Total opioid consumption was significantly reduced in the dexamethasone groups. Postoperative pain scores were lower in both intervention groups, especially during the first 12 hours. No significant differences were found among groups in blood glucose, inflammatory markers, or incidence of nerve deficits. Motor recovery was delayed in the dexamethasone groups but did not interfere with early mobilization. CONCLUSIONS: Low-dose perineural dexamethasone (0.05 to 0.1 mg/kg) safely and effectively prolongs postoperative analgesia and reduces opioid needs in children undergoing upper limb surgery, without causing systemic metabolic or inflammatory disturbances. The 0.05 mg/kg dose may offer a more favorable balance between analgesic efficacy and motor recovery time. LEVEL OF EVIDENCE: Level I-randomized controlled trial.

Humans↗

PubMed1984

Dexamethasone and prednisolone in the horse: pharmacokinetics and action on the adrenal gland.

Pharmacokinetics of dexamethasone and prednisolone were studied in 6 horses given dexamethasone alcohol (IV or IM) or dexamethasone 21-isonicotinate as a solution IV or IM (50 micrograms/kg of body weight), prednisolone 21-sodium succinate IV or IM (0.6 mg/kg of body weight), or prednisolone acetate IM (0.6 mg/kg of body weight). Plasma concentrations were determined using a high-performance liquid chromatographic method. After dexamethasone alcohol (IV) or dexamethasone 21-isonicotinate (IV), the half-life of elimination was similar (53 minutes) for both formulations. After dexamethasone (alcohol and isonicotinate, IM), concentrations were low or nondetected. After prednisolone 21-sodium succinate (IV), the half-life of elimination (99.5 minutes) was significantly (P less than 0.01) longer than that for dexamethasone. After prednisolone 21-sodium succinate (IM), absorption was rapid and bioavailability was high. After prednisolone acetate (IM), absorption was slow and prednisolone was present in plasma for about 7 days. Due to the nonlinearity of prednisolone kinetics, a bioavailability higher than 100% was obtained. The basal plasma hydrocortisone concentration was approximately 70 ng/ml. After dexamethasone (IV or IM), plasma hydrocortisone values decreased after a 2-hour delay and returned to base line after a 3 to 4 day delay. After prednisolone 21-sodium succinate (IV or IM), plasma hydrocortisone decreased immediately (IV) or rapidly (IM) and returned to base line after a 24-hour delay. After prednisolone acetate (IM), plasma hydrocortisone decreased for up to 21 days.

Absorption↗

PubMed1993

Altered dexamethasone responsiveness and loss of growth control in tumorigenic mouse lung cell lines.

Glucocorticoid hormones induce differentiation, inhibit proliferation, and, in mice, reduce carcinogen-induced tumorigenesis of lung epithelial cells. Therefore we examined dexamethasone effects on tumorigenic and non-tumorigenic mouse lung epithelial-derived cell lines. Non-tumorigenic cells were growth inhibited and exhibited CAT activity in pMMTV-CAT transfectants in response to dexamethasone. Tumorigenic cell lines exhibited a range of responses to dexamethasone. While one tumorigenic line was growth-inhibited and responsive in CAT assays, 2 other tumorigenic cell lines were unresponsive both in CAT and in growth assays. A fourth tumorigenic cell line exhibited intermediate sensitivity in CAT assays and was actually growth-enhanced by dexamethasone. Although no difference between cell lines was observed in the abundance of glucocorticoid receptor protein on Western blots, the least dexamethasone-responsive tumorigenic lines exhibited very little binding of 3H-dexamethasone. Clones of tumorigenic lines stably transfected with the rat glucocorticoid receptor gene were more dexamethasone-sensitive in CAT assays and were growth-inhibited by dexamethasone. These data suggest that the neoplastic progression of cell lines derived from mouse lung frequently involves the acquisition of diminished glucocorticoid responsiveness.

Animals↗

PubMedDate not supplied

Alteration of pharmacokinetic parameters for pentobarbital by ischemic stroke and reversion to normal by dexamethasone treatment.

The values of the pharmacokinetic parameters for pentobarbital were determined in 18 cats, 12 of which were subjected to acute ischemic stroke by ligation of the left middle cerebral artery (LMCA). All 18 ats received 50 mg/kg sodium pentobarbital during operation. The following three experimental groups were formed: control (sham-operated); ischemic stroke plus administration of 4 mg/kg dexamethasone; and ischemic stroke without dexamethasone administration. Ischemic stroke significantly prolonged the plasma half-life of pentobarbital, but concurrent administration of dexamethasone prevented this effect. Ischemic stroke significantly reduced the plasma clearance of pentobarbital, but dexamethasone prevented this reduction. Ischemic stroke significantly increased the area under the plasma pentobarbital concentration-time curve, but dexamethasone prevented this increase. Ischemic stroke significantly reduced the volume of distribution, but dexamethasone did not prevent this reduction. The alterations of the value of these pharmacokinetic parameters for pentobarbital by ischemic stroke and reversion to normal by dexamethasone treatment are discussed in the light of certain known circulatory changes which occur secondary to ischemic stroke and dexamethasone treatment.

Animals↗

PubMed1995

Regulation of L-selectin and CD18 on bovine neutrophils by glucocorticoids: effects of cortisol and dexamethasone.

The responsiveness of bovine neutrophil L-selectin and CD18 to in vivo glucocorticoid administration was characterized by flow cytometric analysis. Blood was sampled intensively from dairy cows treated for 3 days with placebo, cortisol, or dexamethasone. Immunostaining was performed on whole blood (100 microliters) that was left unstimulated or was stimulated with platelet-activating factor (PAF; 1 microgram/ml blood) prior to incubation with fluorescein isothiocyanate-conjugated monoclonal antibodies against L-selectin and CD18. Results were expressed as the percentage of positive-staining cells and as mean fluorescence intensity (MFI) of those cells. Total leukocyte count and leukocyte differentials were also performed on all blood samples. Dexamethasone caused nearly complete down-regulation of L-selectin (P < .01) on the surface of gated cells and reduced to half the MFI of CD18 (P < .01). Compared with values for the placebo group, dexamethasone began to cause L-selectin down-regulation within 8 h after the first injection and these effects persisted until 48 h after the third injection. This was correlated in time with an acute reduction in the proportion of cells that stained positive for L-selectin (from 98% before dexamethasone injections to a low of 17% by 40 h after the first injection). Dexamethasone also caused leukocytosis and neutrophilia during this time interval. In contrast, CD18 down-regulation was delayed until 16 h after the second dexamethasone injection and persisted for roughly 8 days. However, at no time during the experiment did dexamethasone influence the proportion of gated cells staining positive for CD18 (always 100%). Effects of cortisol were generally similar in pattern to those of dexamethasone but were more subtle and more readily detected when PAF was added to blood prior to immunostaining. These results strongly suggest that one mechanism of the anti-inflammatory action of glucocorticoids is to induce dramatic down-regulation of L-selectin and CD18 adhesion molecules on blood neutrophils.

Animals↗

PubMed2006

HRQOL implications of treatment with dexamethasone for children with acute lymphoblastic leukemia (ALL).

BACKGROUND: Dexamethasone is increasingly used as the steroid of choice in trials for standard risk children with acute lymphoblastic leukemia (ALL). Improvements in event-free survival (EFS) have been attributed to lower CNS relapse rates, However, there are concerns that dexamethasone may be more toxic than previous conventional therapy with prednisone. Such toxicity raises questions about the implications for child neuropsychological function and HRQOL. Patients participating in the UK ALL 99/01 trial were randomized to receive dexamethasone or prednisone as their steroid in induction and maintenance chemotherapy. We compared the HRQOL and behavior in children randomized to receive both these agents. PROCEDURE: Standardized questionnaires to assess parent and child HRQOL at 3-6 months after diagnosis (T1) and 1 year later (T2) completed by mothers in family homes. Forty-five mothers of a child with ALL (32 male, 13 female; average age at T1, 7 years 3 months; at T2, 8 years 3 months) completed HRQOL questionnaires. RESULTS: For the total group, child HRQOL scores improved and behavior problems decreased significantly from T1 to T2. Comparison of HRQOL scores between the 17 children randomized to dexamethasone and 28 children randomized to prednisone showed no significant differences. The rate of improvement in HRQOL from T1 to T2 did not differ between children randomized to dexamethasone or prednisone. CONCLUSIONS: Dexamethasone is increasingly used in the treatment of ALL and has been linked with improved survival rates. Long-term use of dexamethasone raises questions about neuropsychologic toxicity. Although HRQOL increased significantly over the year for all children, the extent of this increase did not differ by chemotherapy. These results should contribute to lessened concerns about use of dexamethasone in the treatment of ALL.

Anti-Inflammatory Agents↗

PubMed2004

Randomized, double-blinded trial of low-dose dexamethasone: II. Functional residual capacity and pulmonary outcome in very low birth weight infants at risk for bronchopulmonary dysplasia.

We previously reported on a 7-day course of dexamethasone starting at 0.5 mg/kg/day in intubated very low birth weight (VLBW) infants, 7-14 days of age, with increased dynamic pulmonary compliance and decreased bronchopulmonary dysplasia (BPD). The effect of low-dose dexamethasone on functional residual capacity (FRC) in VLBW infants is unknown. The objective of this study was to compare the effect of two regimens of moderately early dexamethasone on FRC and passive respiratory compliance (Crs) in VLBW infants at risk for BPD. Sixty-two intubated VLBW infants were randomized (double-blinded) at 7-21 days of age; 29 patients (mean birth weight, 839 g) received "high" dose dexamethasone (0.5 mg/kg/day for 3 days, 0.25 mg/kg/day for 3 days, and 0.1 mg/kg/day on day 7, total dose of 2.35 mg/kg), and 33 infants (mean birth weight, 830 g) received "low-dose" dexamethasone (0.2 mg/kg/day for 3 days and 0.1 mg/kg/day for 4 days, total dose of 1 mg/kg). FRC and Crs were measured with the nitrogen washout technique and single breath occlusion technique, before and on days 2, 5, and 7 of therapy. Clinical outcome and early neurodevelopmental follow-up were evaluated. FRC significantly increased in the high-dose (19.3 ml/kg at baseline to 34 ml/kg on day 7; P < 0.001) and low-dose (18.1 ml/kg at baseline to 30.3 ml/kg on day 7; P < 0.001) dexamethasone groups when compared to baseline. There was a significant increase in Crs and a decrease in FiO2 within each group. The improvements in FRC and Crs were comparable between groups, and specific compliances (Crs/FRC) were not different. There were no significant differences in other clinical outcome parameters, including BPD and neurodevelopmental outcome. In conclusion, there are significant increases in FRC during a 7-day course of moderately early dexamethasone in VLBW infants. The lower total dose (1 mg/kg) appears as effective as the higher total dose of dexamethasone (2.35 mg/kg) in increasing FRC. Comparable significant increases in Crs were observed in both groups of infants. Additional long-term follow-up is underway.

Analysis of Variance↗

PubMed1995

Dexamethasone induces resistance to the lethal consequences of electron transport inhibition in cultured hepatocytes.

Pretreatment of cultured rat hepatocytes with 1 microM dexamethasone protected against cell killing by 5 microM rotenone and 1 mM cyanide. Simultaneous treatment (no pretreatment) was ineffective, as was pretreatment with 10 microM of sex hormones or the mineralocorticoid aldosterone. Protection by dexamethasone was blocked by 10 microM of glucocorticoid receptor antagonist, RU486, and by 1 microM of the inhibitor of protein synthesis, cycloheximide. Cells pretreated with dexamethasone for 6, 12, and 18 h showed increasing degrees of protection. Pretreatment with dexamethasone had no effect on either the decline of cellular ATP or the loss of the mitochondrial membrane potential. In addition, dexamethasone did not prevent the mitochondrial permeability transition. By contrast, dexamethasone prevented the increased release of [3H]arachidonic acid from phospholipids produced by cyanide. These data describe an inductive effect of dexamethasone in protecting cultured hepatocytes against inhibition of electron transport by rotenone and cyanide. It is concluded that pretreatment with dexamethasone prevents cell killing by inhibiting a mechanism that couples the mitochondrial permeability transition to the accelerated degradation of plasma membrane phospholipids.

Adenosine Triphosphate↗

PubMedDate not supplied

Dexamethasone in bacterial meningitis: to use or not to use?

Permanent neurologic disabilities are seen in up to a quarter of survivors of bacterial meningitis despite major improvements in therapy. Experimental studies have demonstrated that most of the pathology in meningitis is mediated by inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1), which are produced by host cells in response to bacterial invasion of the meninges. Dexamethasone has been used in a number of clinical trials to moderate the host response and to improve neurologic outcome of meningitis. Results of six randomized, placebo controlled trials are summarized in this review. Dexamethasone treatment did not lower mortality. Only a moderate, but not a significant reduction in the neurologic and audiologic sequelae was seen in dexamethasone recipients when Haemophilus influenzae type b (Hib) was the causative agent of meningitis. Following routine use of Hib vaccine, meningitis caused by this agent has virtually disappeared in the USA. Hence, findings from these trials may no longer be applicable in countries with high rates of immunization against Hib. Presently, there is little or no evidence showing a benefit of dexamethasone therapy in meningitis caused by S. pneumoniae or N. meningitidis. Global emergence of penicillin and cephalosporin resistant S. pneumoniae has raised new concerns about the use of dexamethasone in pneumococcal meningitis. Since dexamethasone significantly decreases the penetration and concentration of vancomycin and ceftriaxone in the CSF and delays CSF sterilization, adjunctive dexamethasone therapy may increase the risk of treatment failure in meningitis caused by antibiotic resistant pneumococci. An antibiotic combination should be used in the treatment of meningitis caused by antibiotic resistant pneumococci, particularly if dexamethasone is also being administered concurrently.

Animals↗

PubMed1976

Conditions affecting primary cell cultures of functional adult rat hepatocytes. II. Dexamethasone enhanced longevity and maintenance of morphology.

Primary monolayer cell cultures of adult rat hepatocytes underwent change in morphology and substantial cell loss between 1 and 3 days postinoculation. Dexamethasone-supplementation (1 micronM) of the culture medium maintained the polygonal epithelial morphology of the hepatocytes and increased longevity such that over 80% of the cells survived for 3 days and at least 30% for 8 or 9 days. This enhancement of survival was obtained up to 48 hr postinoculation, but the earlier the time of dexamethason supplementation the greater the effect. Removal of dexamethasone resulted in a decrease in longevity. The positive effect of dexamethasone on longevity was observed following dexamethasone replacement of insulin in supplemented cultures, but the combination of insulin and dexamethasone resulted in poorer survival than with dexamethasone alone. The results are interpreted to indicate that dexamethasone provided a requirement of the in vitro environment for survival and suggest that elaboration of a complex medium is required to maintain hepatocytes in culture.

Animals↗

PubMedDate not supplied

Effects of acetysal, dexamethasone and their combination on drug metabolizing enzyme systems in rat liver microsomes.

After 4 days of acetysal treatment (160 mg/kg body weight orally), the following were established: a higher acute toxicity of acetysal, an inducing effect on amidopyrin N-demethylase and analgin N-demethylase activity and increases in cytochrome P-450 and cytochrome b5 content. Aniline hydroxylase activity decreased, thiopental sleeping time was prolonged and UDP-glucuronyltransferase activity was not changed. Dexamethasone, at a dose of 5 mg/kg body weight p.o. for 4 days, did not change acetysal acute toxicity but at a dose of 100 mg/kg i.p. increased it. Thiopental sleeping time was shortened by dexamethasone (100 mg/kg i.p.) but was not changed by dexamethasone at 5 mg/kg p.o., alone or in combination. Dexamethasone at 5 mg/kg increased analgin N-demethylase and UDP-glucuronyltransferase activities, did not change cytochrome P-450 content and decreased aniline hydroxylase activity. The combination with 5 mg/kg dexamethasone increased the activity of amidopyrin N-demethylase, analgin N-demethylase and UDP-glucuronyltransferase and decreased those of amitriptyllin N-demethylase and aniline hydroxylase and cytochrome P-450 content. Ethylmorphine N-demethylase, benzphetamine N-demethylase, NADPH-cytochrome c reductase and glutathione S-transferase activities were not affected significantly by acetysal, dexamethasone or their combination. Hepatic carboxyl esterase was depressed by dexamethasone (5 mg/kg) and was increased by the combination. Lipid peroxidation was not changed by dexamethasone (5 mg/kg) but was decreased by acetysal and the combination.

Animals↗

PubMed2002

Comparison between buserelin and dexamethasone testing in the assessment of hirsutism.

Many hirsute women may present a form of functional ovarian hyperandrogenism (FOH), since they show an exaggerated 17-hydroxyprogesterone (17-OHP) response to GnRH agonists administration. As the failure of dexamethasone to reduce testosterone levels may be indicative of an ovarian source of androgen secretion, we evaluated the usefulness of dexamethasone suppression test, in comparison with buserelin challenge, in the assessment of hirsutism. Twenty-seven hirsute women (aged 15-42 yr) underwent ACTH and buserelin tests: 4 patients were heterozygotes for 21-OH deficiency and 8 patients were affected with FOH: 2 of the patients with hyperresponse to buserelin also had 21-hydroxylase deficiency. The results of the dexamethasone suppression test (2 mg/day for 7 days) were compared to those obtained after buserelin test. Basal T and delta4 levels (mean+/-SE) were higher than in controls (4.2+/-0.5 vs 2.2+/-0.2 nmol/l and 10.9+/-0.9 vs 5.9+/-0.6 nmol/l, p<0.02), while no differences were found in 17-OHP and DHEAS levels. A significant reduction (p<0.001) in T (1.8+/-0.4 nmol/l), delta4 (3.2+/-0.5 nmol/l) and DHEAS levels (2.4+/-0.3 micromol/l) was observed at the 3rd day of dexamethasone administration and no differences between sampling at 3rd, 5th and 7th day were found. Serum T was not suppressed in 6 cases, delta4 and DHEAS levels in 3 and 1 of them, respectively. Buserelin injection caused an excessive 17-OHP response in 8 patients, only 4 of them did not reduce T levels during dexamethasone. The sensitivity and specificity of the dexamethasone suppression test, with respect to the buserelin test, were 50% and 89%, respectively. In conclusion, 37% of hirsute patients had an abnormal responsiveness to buserelin and/or ACTH tests, indicating that hormonal investigations are mandatory. An ovarian origin of hirsutism was identified by buserelin test in 30% of patients and by dexamethasone in 22% of cases; only 4 of 8 patients showed concordant results to both tests. Therefore, buserelin challenge seems a more useful, cost-effective and less time consuming tool than dexamethasone administration in order to recognize the possible ovarian origin of hyperandrogenism.

Adolescent↗

PubMed1999

Dexamethasone enhances CTLA-4 expression during T cell activation.

T cell activation is enhanced by the costimulatory interaction of B7 on antigen-presenting cells and CD28 on T cells, resulting in long-term T cell proliferation, differentiation and production of large amounts of cytokines, such as interleukin (IL)-2. CTLA-4 is a co-stimulation receptor that shares 31% homology with CD28 and binds B7 family members with higher affinity. CTLA-4 is transiently expressed intracellularly and on the cell surface following activation of T cells. We have studied the kinetics of CTLA-4 expression and the effects of dexamethasone on CTLA-4 expression during T cell activation in cultures of mouse spleen cells stimulated by a mixture of immobilized anti-CD3 and anti-CD28 monoclonal antibodies (anti-CD3/CD28 mAb) or concanavalin A (ConA). CTLA-4 expression peaked on day 2 and returned to background levels after 7 days. Dexamethasone was found to potentiate CTLA-4 expression in a dose-dependent manner with an EC50 effective concentration 50%) of about 10(-8) M. In contrast, other immunosuppressive agents, such as rapamycin or cyclosporin A had no or an inhibitory effect on CTLA-4 expression, respectively. Dexamethasone also stimulated CD28 expression, but inhibited IL-2R expression during anti-CD3/CD28 mAb-induced mouse splenic T cell activation. Western blot analyses of lysates of activated mouse T cells showed that dexamethasone increased CTLA-4 protein levels twofold during anti-CD3/CD28 mAb-induced activation. Dexamethasone also enhanced CTLA-4 messenger RNA twofold as quantified by ribonuclease protection assay. The effects of dexamethasone on CTLA-4 expression were glucocorticoid-specific and completely inhibited by the glucocorticoid receptor antagonist mifepristone (RU486), indicating that the effect of dexamethasone on CTLA-4 expression is mediated through the glucocorticoid receptor. In conclusion, the immunosuppressive agent dexamethasone actually stimulates CTLA-4 expression, which is involved in downregulation of T cell activation.

Abatacept↗

PubMed1999

Dexamethasone-induced enhancement of resistance to ionizing radiation and chemotherapeutic agents in human tumor cells.

BACKGROUND: Dexamethasone-induced changes in radioresistance have previously been observed by several authors. Here, we examined effects of dexamethasone on resistance to ionizing radiation in 10 additional human cell lines and strains, and on resistance to carboplatin and paclitaxel in 13 fresh tumor samples. MATERIAL AND METHODS: Eight human carcinoma cell lines, a glioblastoma cell line and a strain of normal human diploid fibroblasts were arbitrarily chosen for these in-vitro studies. Effects on radiosensitivity were assessed using a conventional colony formation assay. Effects on resistance to the drugs were investigated prospectively (ATP cell viability assay) using 13 fresh tumor samples from consecutive patients operated for ovarian cancer within the context of a Swiss nation-wide randomized prospective clinical trial (SAKK 45/94). RESULTS: Dexamethasone promoted proliferation of 1 of the cell lines without affecting radiosensitivity, while it completely inhibited proliferation of another cell line (effects on radiosensitivity could thus not be examined). Furthermore, dexamethasone induced enhanced radioresistance in 1 of the 8 carcinoma cell lines examined. In the glioblastoma cell line, there was no effect on growth or radioresistance, nor in the fibroblasts. Treatment with dexamethasone enhanced resistance of the malignant cells to carboplatin in 4 of the 13 fresh tumor samples examined, while no enhancement in resistance to paclitaxel was observed. CONCLUSIONS: In agreement with previous reports, we found that dexamethasone may induce radioresistance in human carcinoma cells. Including the published data from the literature, dexamethasone induced enhancement in radioresistance in 4 of 12 carcinoma cell lines (33%), but not in 3 glioblastoma cell lines, nor in 3 fibroblast strains. Dexamethasone also induced enhanced resistance to carboplatin with a similar probability in fresh samples of ovarian cancer evaluated prospectively (in 4 of 13 samples; 31%). We worry that induction of resistance by corticosteroids given to patients undergoing either radiotherapy or chemotherapy with agents causing DNA damage might be associated with a reduced clinical responsiveness in a significant fraction of patients with a carcinoma.

Anti-Inflammatory Agents↗