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PubMed2000

Differential anti-inflammatory and anti-oxidative effects of dexamethasone and N-acetylcysteine in endotoxin-induced lung inflammation.

Inhalation of bacterial endotoxin induces an acute inflammation in the lower respiratory tract. In this study, the anti-inflammatory effects of the anti-oxidant N-acetylcysteine (NAC) and the glucocorticoid dexamethasone were investigated in mice exposed to aerosolized endotoxin (lipopolysaccharide (LPS)). Powerful reduction of neutrophils in bronchoalveolar lavage fluid (BALF) was obtained by a single i.p. injection of dexamethasone (10 mg/kg), whereas treatment with NAC only resulted in reduction of neutrophils when administered at a high dose (500 mg/kg). Measurement of cytokine and chemokine expression in lung tissue revealed a significant decrease of tumour necrosis factor-alpha, IL-1alpha, IL-1beta IL-6, IL- 12p40, and MIP-1alpha mRNA when mice where treated with dexamethasone but not when treated with NAC. Analysis of oxidative burst demonstrated a remarkable reduction of oxygen radicals in BALF neutrophils after treatment with dexamethasone, whereas the effect of NAC was not significantly different from that in untreated animals. In conclusion, dexamethasone exerted both anti-inflammatory and anti-oxidative effects in acute airway inflammation, probably by blocking early events in the inflammatory cascade. In contrast, treatment with NAC resulted in a weak reduction of the inflammatory response but no inhibition of proinflammatory cytokines or reduction of oxidative burst in neutrophils. These results demonstrate dramatic differences in efficiency and also indicate that the two drugs have different actions. Combined treatment with NAC and dexamethasone revealed an additive action but no synergy was observed.

Acetylcysteine↗
PubMed1998

The low-dose dexamethasone suppression test in patients with adrenal incidentalomas: comparisons with clinically euadrenal subjects and patients with Cushing's syndrome.

OBJECTIVE: Increasing evidence favours subtle glucocorticoid excess in many patients with adrenal incidentalomas. However, existing evidence is based mainly on the overnight dexamethasone suppression test, a test that is commonly abnormal even among clinically euadrenal subjects. The aim of the present study was to evaluate patients with adrenal incidentalomas for subtle glucocorticoid excess by the more specific low-dose dexamethasone test (LDDST). Moreover, since the criteria of what constitutes an abnormal cortisol response following this test have been largely anecdotal, we report our results in comparison with those obtained in clinically euadrenal subjects, and patients with Cushing's syndrome. DESIGN: A prospective study of 57 patients with adrenal incidentalomas with CT characteristics highly suggestive of benign adrenocortical adenomas and 85 clinically euadrenal subjects consisting of 54 obese women with BMI > 30 kg/m2 (range 30-54.7), 13 women with BMI < 30 kg/m2 (range 20.3-29.6) and 18 healthy volunteers (10 women and eight men) over 40 years of age (mean age 51.7 +/- 9.9, range 40-74; mean BMI 30 +/- 6.6, range 20.3-47.5 kg/m2). A retrospective analysis was performed on 60 patients with a confirmed diagnosis of Cushing's syndrome. MEASUREMENTS: All subjects were admitted to the endocrine ward and underwent a standard LDDST, as follows: after a 48-h stabilization period, a 24-h urine collection for basal urinary free cortisol was performed. Basal serum cortisol and plasma ACTH were measured at 0800 h the following day, and subjects were started on dexamethasone 0.5 mg 6-hourly for 2 days. Post-dexamethasone cortisol and ACTH levels were measured at 0800 h, 6 h after the last dose of dexamethasone. RESULTS: Following dexamethasone suppression serum cortisol concentrations became undetectable (< 28 nmol/l) in all clinically euadrenal subjects. In patients with incidentally discovered adrenal masses, post-LDDST cortisol concentrations were undetectable in 12 (21%), between 28-140 nmol/l in 38 (67%), and 140-216 nmol/l in seven (12%) patients; post-LDDST cortisol values correlated positively with the size of the adenoma (r = +0.482, P < 0.001). Post-LDDST cortisol concentrations in patients with Cushing's syndrome ranged from 85 to 1786 nmol/l; in 3/42 (7%) patients with ACTH-dependent Cushing's syndrome cortisol concentrations were < 140 nmol/l. CONCLUSIONS: On the basis of our data in a large group of clinically euadrenal subjects, we suggest that following LDDST cortisol concentrations should become undetectable with the currently used radioimmunoassays. In patients with adrenal incidentalomas, application of the LDDST confirmed the presence of incomplete suppression of cortisol in the majority of patients. We suggest that the LDDST is a sensitive index of autonomous cortisol production in patients with adrenal incidentalomas; following this test a grading of subtle glucocorticoid excess may be obtained but future studies correlating biochemical, clinical and epidemiological data are required, in order to develop widely agreed cut-off levels of clinically significant glucocorticoid excess in these patients.

Adrenal Cortex Function Tests↗
PubMed1999

The continuous 7-hour intravenous dexamethasone suppression test in the differential diagnosis of ACTH-dependent Cushing's syndrome.

OBJECTIVE: A recent report showing disappointingly low sensitivity and specificity for the oral high dose dexamethasone test in the differential diagnosis of Cushing's syndrome prompted us to re-evaluate the results obtained in our centre using the continuous 7-hour intravenous dexamethasone suppression test for this purpose. PATIENTS: 105 patients with ACTH-dependent Cushing's syndrome were included in this study; 78 with Cushing's disease, 8 with ectopic ACTH-secreting tumours and 19 were classified as 'of unknown aetiology'. RESULTS: In 74/78 (94.9%) of patients with Cushing's disease and in 3/8 (37.5%) patients with the ectopic ACTH syndrome, a plasma cortisol decrease > 190 nmol/l at 7 h as compared to baseline values was achieved in the continuous 7-hour intravenous dexamethasone suppression test. Using a plasma cortisol decrease > 190 nmol/l at 7 h as compared to baseline values as the cut-off value, the sensitivity and specificity of the continuous 7-hour intravenous dexamethasone suppression test for the diagnosis of Cushing's disease in patients with ACTH-dependent Cushing's syndrome were 94.9% and 62.5%, respectively. CONCLUSIONS: In patients with ACTH-dependent Cushing's syndrome with a plasma cortisol decrease > 190 nmol/l at 7 h in the continuous 7-hour intravenous dexamethasone suppression test, additional localizing investigations such as bilateral simultaneous inferior petrosal sinus sampling and/or pentetreotide scintigraphy should be performed when no clearly discernible pituitary adenoma is observed on MRI studies. Patients with ACTH-dependent Cushing's syndrome with a plasma cortisol decrease < 190 nmol/l at 7 h in the continuous 7-hour intravenous dexamethasone suppression test should also undergo bilateral simultaneous inferior petrosal sinus sampling and/or pentetreotide scintigraphy to demonstrate the presence of a nonpituitary source of ACTH overproduction.

ACTH Syndrome, Ectopic↗
PubMed2001

Growth restriction in dexamethasone-treated preterm infants may be mediated by reduced IGF-I and IGFBP-3 plasma concentrations.

OBJECTIVE: Preterm infants receiving dexamethasone for respiratory morbidity frequently suffer restricted growth. The aim of this study was to investigate the interactions between dexamethasone treatment regimen and circulating IGFBP-3 and IGF-I levels, and the associations between these variables and linear growth rate in preterm babies receiving dexamethasone for chronic lung disease of prematurity. DESIGN: A randomised, unblinded, clinical trial of two different courses of dexamethasone: a 42-day tapering course (the long course) and a repeatable 3 day pulse course. PATIENTS: Forty preterm infants (19 in the pulse group, 21 in the long group) with a birthweight < or = 1250 g who were ventilated at 7 days of age. MEASUREMENTS: Lower leg length was measured thrice weekly by knemometry, and IGFBP-3 and IGF-I levels were measured prior to commencing treatment, at 14 and 42 days of treatment and at 36 weeks postmenstrual age (PMA). Interactions between variables were analysed by stepwise regression analysis and analysis of covariance (ANCOVA). Associations between variables were assessed by correlation coefficients. RESULTS: In an ANCOVA, mean daily dose of dexamethasone/kg (MDDD) and treatment group both significantly influenced IGFBP-3 levels (P = 0.0009 and P = 0.017, respectively), and tended to influence IGF-I levels similarly (P = 0.098 and P = 0.07). MDDD also significantly influenced mean daily increase in lower leg length (MDILL; P < 0.01). IGFBP-3 and IGF-I levels were significantly related to MDILL (ANCOVA: P < 0.01). The correlation coefficients for IGFBP-3 and IGF-I levels and MDILL were 0.2 and 0.3 (both P < 0.0001), respectively. IGFBP-3 and IGF-I levels were highly correlated (r(2) = 0.52, P < 0.0001) and both increased significantly with increasing PMA (P < 0.0001). IGF-I levels were higher in females (P = 0.036). CONCLUSION: This study provides evidence that the growth-restricting effects of dexamethasone may be mediated, at least in part, via suppression of the IGF axis. Both dexamethasone dose and treatment regimen influence circulating IGF-I and IGFBP-3 levels, and both are important in inducing growth restriction.

Analysis of Variance↗
PubMed1999

Prophylactic therapy with combined granisetron and dexamethasone for the prevention of post-operative vomiting in children.

This study was undertaken to compare the efficacy and safety of granisetron, a 5-hydroxytryptamine type 3 receptor antagonist, and dexamethasone and each drug alone for the prevention of post-operative vomiting by children, with no history of motion sickness and/or previous post-operative vomiting, undergoing general inhalational anaesthesia for surgery (inguinal hernia and phimosis). In a randomized, double-blind manner, 150 children, ASA physical status 1, aged 4-10 years, were assigned to receive granisetron 40 mg kg-1, dexamethasone 150 mg kg-1, or granisetron 40 mg kg-1 plus dexamethasone 150 mg kg-1 intravenously immediately after inhalation induction of anaesthesia (n = 50 of each). A complete response, defined as no emesis and no need for another rescue anti-emetic during the first 24 h after anaesthesia, was 86% with granisetron, 68% with dexamethasone and 98% with granisetron plus dexamethasone, respectively (P < 0.05; overall Fisher's exact probability test). No clinically serious adverse events were observed in any of the groups. In conclusion, prophylactic therapy with combined granisetron and dexamethasone was more effective than was each anti-emetic alone for the prevention of vomiting after paediatric surgery.

Anesthesia, Inhalation↗
PubMed1999

Effect of maternal dexamethasone treatment and ambient temperature on prolactin receptor abundance in Brown adipose and hepatic tissue in the foetus and new-born lamb.

We investigated the influence of maternal dexamethasone treatment and ambient temperature on prolactin receptor (PRLR) abundance in brown adipose tissue (BAT) and hepatic tissue from foetuses and 6-h-old lambs delivered by caesarean section. Lambs were either delivered into a warm (30 degrees C; WD) or cool (15 degrees C; CD) ambient temperature at 140 days gestation, 2 days after dexamethasone treatment, or at 146 days gestation for controls. Uncoupling protein-1 (UCP1) content of BAT was higher in dexamethasone-treated groups compared to controls. A range of tissue-specific PRLR isoforms was detected. For the long form of PRLR in BAT these isoforms had molecular weights of 66, 54, 34 and 19 kD compared with 88, 76, 66, 58, 54 and 48 kD in liver. In BAT, isoforms of the short form of PRLR had molecular weights of 66, 62, 54, 48, 33 and 31 kD compared with 82, 66, 56, 54, 48, 40 and 33 kD in liver. Dexamethasone treatment in CD lambs resulted in higher abundance of the 54 kD isoform of the short form of PRLR in liver, whilst in BAT dexamethasone resulted in a greater abundance of the 48 kD isoform of the short form, and lower abundance of the 66 kD isoform of the long form of PRLR, compared to controls. A negative correlation (r2 = 0.52) was observed between abundance of 66 kD isoform for the long form of PRLR and UCP1, compared with positive correlations (r2 = 0.58-0.60) for the abundance of the 54 and 48 kD isoforms for the short form of PRLR and UCP1. In conclusion, maternal dexamethasone treatment 1 week before term alters the abundance of PRLR isoforms in a tissue-specific manner. This response is dependent on ambient temperature after birth and may provide a critical endocrine signal for maximising non-shivering thermogenesis.

Adipose Tissue, Brown↗
PubMed2000

Blunted pituitary-adrenocortical stress response in adult rats following neonatal dexamethasone treatment.

Glucocorticoids have a prominent impact on the maturation of the stress-related neuroendocrine system and on the postnatal establishment of adaptive behaviour. The present study aimed at investigating the stress responsiveness of the hypothalamo-pituitary-adrenocortical (HPA) axis in young and adult rats after neonatal treatment with the synthetic glucocorticoid agonist, dexamethasone. Newborn male Wistar rats were injected s.c. with 1 microg/g dexamethasone on postnatal days 1, 3 and 5. Circulating adrenocorticotropic hormone (ACTH) and corticosterone concentrations were measured in the resting state and following a 30-min cold stress at the age of 10 days, as well as after a 30-min restraint stress at the age of 14 weeks. Also in adults, pituitary and adrenocortical hormone responsiveness was evaluated after i.v. administration of 2 microg/kg corticotropin releasing hormone (CRH). In addition, glucocorticoid (GR) and mineralocorticoid receptor (MR) binding capacities were assessed in the pituitaries of adult rats. The results showed that at day 10 basal ACTH concentration was elevated while the cold stress-evoked ACTH response was attenuated in the dexamethasone-treated rats. As adults, treated rats showed a suppressed elevation of both ACTH and corticosterone plasma concentrations in response to restraint, while basal hormonal concentrations were not altered. There was no difference in the magnitude of the CRH-induced elevation of ACTH and corticosterone concentrations initially; however, the dexamethasone-treated animals showed a prolonged secretion of both hormones. These animals also showed a selective decrease in pituitary GR binding capacity. Neonatal dexamethasone treatment strongly suppressed body weight gain, and adrenal and thymus weights in the early phase of postnatal development. By adulthood, the body and adrenal weights were normalized while thymus weight was greater than in controls. These findings indicate that neonatal dexamethasone treatment permanently alters HPA axis activity by reducing stress responses to cold and restraint probably through supra-pituitary actions, and by decreasing the effectiveness of feedback through a diminished GR binding in the pituitary.

Adrenal Glands↗
PubMed1998

Effect of dexamethasone on interleukin-1beta-(IL-1beta)-induced nuclear factor-kappaB (NF-kappaB) and kappaB-dependent transcription in epithelial cells.

The production of inflammatory mediators by epithelial cells in inflammatory lung diseases may represent an important target for the anti-inflammatory effects of glucocorticoids. Nuclear factor-kappaB (NF-kappaB) is a major activator of inflammatory genes and has been proposed as a target for inhibition by glucocorticoids. We have used human pulmonary type-II A549 and airway epithelial BEAS-2B cells to investigate the effect of glucocorticoids on NF-kappaB regulation and kappaB-dependent transcription. In A549 cells following interleukin-1beta (IL-1beta) treatment, there was no effect of dexamethasone on the disappearance of I kappaB alpha protein, its subsequent reappearance 90-min later or the rapid induction of I kappaB alpha mRNA and transcription rate. Expression of p65 and p50/p105 proteins were also unaffected by dexamethasone. In addition, the rapid IL-1beta-induction of NF-kappaB DNA binding and p65 nuclear localisation was unaffected by short (1-6 hours) dexamethasone pre-treatments. Similarly, BEAS-2B cells showed no effect of dexamethasone on IL-1beta-induced NF-kappaB (p50/p65). Stable transfection of a kappaB-dependent reporter in A549 cells resulted in an 8-9-fold activation by IL-1beta or phorbol ester, that was repressed 30-40% by dexamethasone. However, in these cells, IL-1beta induction of inducible nitric oxide synthase, granulocyte-macrophage colony stimulating factor and cyclooxygenase-2 mRNA showed 70-90% repression by dexamethsone. We, therefore, conclude that in these epithelial cells, the repressive effects of glucocorticoids are not mediated by up-regulation of I kappaB alpha, decreased p50/p65 gene expression or inhibition of NF-kappaB DNA binding. Furthermore, since the maximal repression of IL-1beta or phorbol-ester-induced kappaB-dependent transcription by dexamethasone was less than 40%, simple inhibition of kappaB-dependent transcription cannot by itself account for the full repressive effects of glucocorticoids observed in these cells.

Cell Line↗
PubMedDate not supplied

Renal function in adult rats subjected to prenatal dexamethasone.

1. Prenatal dexamethasone leads to low birth weight and compromises organogenesis, but its effects on nephrogenesis in male and female rats have not yet been investigated extensively. Reduced renal mass may be responsible for hypertension and renal haemodynamic and morphological adjustments to maintain the glomerular filtration rate (GFR). Subsequently, these compensatory mechanisms determine glomerular sclerosis and irreversible reduction in GFR. When a high-protein diet is associated with reduced renal mass, it accelerates glomerular sclerosis and the decline in renal function. The aim of the present study was to evaluate whether rats subjected to prenatal dexamethasone and a high-protein diet during growth present a premature decline in renal function. 2. The number of nephrons and renal haemodynamics were estimated in Wistar rats fed a high-protein diet (40% protein) after weaning in offspring of dams treated with either dexamethasone (0.1 mg/kg per day) or its vehicle (control; physiological solution, 0.1 mL/kg per day) during gestation. 3. At 70 days of age, rat offspring were anaesthetized and prepared surgically for renal haemodynamic measurements. 4. Mean arterial pressure (MAP), renal blood flow (RBF) and GFR were measured using a blood pressure transducer, a flow probe and inulin clearance, respectively. 5. The number of nephrons was counted using the acid-maceration technique. 6. Dexamethasone during pregnancy induced a lower weight gain in the dams (65%; P < 0.0001) and a lower birth weight in both male and female offspring (14 and 13%, respectively; P < 0.01). 7. Compared with control, the number of nephrons in male rats was reduced by 13% (30 703 +/- 1262 vs 26 308 +/- 1305, respectively; P < 0.05), but was unaltered in female rats (23 197 +/- 553 vs 24 231 +/- 1009, respectively). 8. Male and female rats did not show any alteration in MAP. In addition, they did not show any alteration in renal vascular resistance, RBF, filtration fraction or GFR. 9. In conclusion, prenatally administered dexamethasone (0.1 mg/kg during the entire pregnancy) induced a low birth weight. The magnitude of the reduction in nephrogenesis in male offspring from mothers treated with dexamethasone was not sufficient to alter renal function (measured at 70 days), even when rats had been fed a high-protein diet.

Animals↗
PubMed1997

Down-regulation of 5-hydroxytryptamine7 receptors by dexamethasone in rat frontocortical astrocytes.

Astrocytes derived from rat frontal cortex contain 5-hydroxytryptamine7 (5-HT)7 receptors positively coupled to adenylyl cyclase. In the present study, we investigated the effects of glucocorticoids on adenylyl cyclase activity and 5-HT7 receptor gene expression in astrocytes. Addition of dexamethasone (0.01-100 nM, 12-72 h) to the culture medium decreased cyclic AMP formation induced by 5-HT in a time- and concentration-dependent manner. Dexamethasone treatment (10 nM, 48 h) reduced maximum responses of cyclic AMP formation induced by 5-HT and 5-carboxamidotryptamine without alterations in the EC50 value. In contrast, treatment with the mineralocorticoid aldosterone (48 h) had no significant effects on 5-HT-induced cyclic AMP formation with concentrations up to 10 nM. It was observed that dexamethasone treatment (1-100 nM, 3-72 h) also decreased the expression of 5-HT7 receptor mRNA, using reverse transcription and polymerase chain reaction analysis. A significant reduction in expression of 5-HT7 mRNA appeared at 3 h of dexamethasone treatment and reached a maximum at 6 h of treatment. On the other hand, dexamethasone treatment (10 nM, 48 h) did not affect basal levels of cyclic AMP and cyclic AMP synthesis stimulated by isoproterenol, N-ethylcarboxamidoadenosine, cholera toxin, and forskolin. These results suggest that dexamethasone decreases the expression of the 5-HT7 receptor gene and, consequently, 5-HT7 receptor-mediated signal transduction in frontocortical astrocytes.

Adenosine↗
PubMed2000

Dexamethasone induces lipocalin-type prostaglandin D synthase gene expression in mouse neuronal cells.

Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is responsible for the production of PGD(2), the main PG in the CNS. PGD(2) is an endogenous sleep inducer, and it is involved in the control of odor and pain responses and body temperature. In addition, PGD synthase transports lipophilic molecules in the subarachnoid space and CSF. By northern and western assays we show that the synthetic glucocorticoid dexamethasone, an inhibitor of PG production in most tissues, induces L-PGDS mRNA and protein in a dose- and time-dependent fashion in mouse neuronal GT1-7 cells. Accordingly, dexamethasone increases cellular L-PGDS enzymatic activity. Dexamethasone induced L-PGDS gene transcription in run-on assays and activated the mouse L-PGDS gene promoter in transiently transfected cells. It is interesting that the tumor promoter 12-O-tetradecanoyl-phorbol 13-acetate (TPA), which induces the synthesis of PGs in many tissues, inhibited the increase in L-PGDS expression induced by dexamethasone. In contrast, neither dexamethasone nor TPA affected the expression of cyclooxygenases-1 and -2. Our data demonstrate that dexamethasone induces L-PGDS gene transcription in neuronal cells.

Animals↗
PubMed2000

Dexamethasone blocks sepsis-induced protection of the heart from ischemia reperfusion injury.

Previous investigations have shown that sepsis, while causing cardiac dysfunction, can protect the heart from ischemia-reperfusion injury. Sepsis-induced protection may be due to nitric oxide produced by an inducible form of nitric oxide synthase generated in response to cytokines released during sepsis. The glucocorticoid dexamethasone has been shown to inhibit the synthesis of the inducible form of nitric oxide synthase (iNOS). The goals of this study were to determine if dexamethasone would prevent sepsis-induced cardiac dysfunction and sepsis-induced protection of the heart from ischemia-reperfusion injury. In this experiment, rats were made septic by injecting Escherichia coli into the dorsal subcutaneous space. Control rats were injected with sterile saline. At the time of surgery, some of the control and septic animals were injected intraperitoneally with dexamethasone (3 mg/kg). The next day, 24-26 hr after injection of the first dose of E. coli, animals were anesthetized, and hearts were removed and studied in the isovolumic beating-heart preparation. Left ventricular end diastolic pressure was set to 5 mmHg, and left ventricular pressure was measured continuously throughout the protocol. Left ventricular developed pressure (LVDP) was used as an index of LV function. After stabilization, hearts were made globally ischemic for 35 min and then reperfused for 25 min. As has been shown previously, sepsis depressed LVDP but also protected the heart from further depression of LVDP by ischemia and reperfusion. Dexamethasone prevented both sepsis-induced cardiac dysfunction and sepsis-induced protection of the heart from ischemia-reperfusion injury. In addition plasma nitrite/nitrate levels were not different from control levels in the dexamethasone-treated septic rats whereas levels were elevated in the septic animals. The dexamethasone mediated abrogation of sepsis-induced cardiac dysfunction and protection during ischemia-reperfusion injury may be due to suppression of nitric oxide production.

Analysis of Variance↗
PubMed1982

Effect of dexamethasone on steroidogenesis and on adrenocortical cyclic AMP and cyclic GMP responses to ACTH.

The inhibitory action of dexamethasone on the adrenal steroidogenic response to ACTH was confirmed by im administration of graded doses (5, 10 and 30 ng) of synthetic beta 1-24 ACTH to young adult male rats which had received dexamethasone (0.1 mg/100 g bw) 4 hr prior to sacrifice. Following this, kinetic studies were performed by measuring plasma corticosterone, adrenocortical cyclic AMP and cyclic GMP before and 4, 12 and 30 min after administration of either 10 or 30 ng of ACTH. These doses were selected because their effects could be either completely or partially inhibited by dexamethasone. In rats without dexamethasone all the doses of ACTH which were checked induced an increase in both corticosterone and cyclic AMP and a decrease in cyclic GMP. With the smallest dose of ACTH the earlier administration of dexamethasone resulted in complete suppression of both the steroidogenic response and the cyclic AMP response. With the largest dose of ACTH both responses were diminished. In dexamethasone-treated rats the decrease in cyclic GMP was significantly less pronounced 4 min after ACTH than it was in non-treated rats. These results support the view that cyclic AMP and cyclic GMP might both be concerned with the mechanism of acute adrenal steroidogenesis.

Adrenal Cortex↗
PubMed2000

Excess of glucocorticoids impairs whole-body antioxidant status in young rats. relation to the effect of dexamethasone in soleus muscle and spleen.

The action of glucocorticoids in high doses is catabolic, but not much is known about the accompanying effects on antioxidative capacity of the entire body. Animals were treated (or not) with dexamethasone (Dex) 2 mg/kg b.w. d-1 during 5 consecutive days followed by recovery, during which an additional group received 3-hydroxy-3-methylbutyrate (40 mg/kg b.w.). Animals were killed after treatment with Dex, and after 5 days of the recovery period. Dexamethasone treatment decreased appetite almost twofold (from 20 g/day to 10 g/day, P < 0.001). Feed restriction, however, seemed to have only minor impact on the effects observed since body weight loss of pair-fed rats after the 5th day of treatment was only 2% and Dex-treated rats decrease in body weight was 22% (P < 0.05). In turn, wet weight of the soleus muscle (expressed per body weight) did not significantly decrease after Dex treatment, suggesting relative resistance of oxidative type muscles to the catabolic action of dexamethasone. Spleen wet weight expressed per body weight dropped by 65% (P<0.001). Additionally, there was a 46% reduction (P<0.001) of blood glutathione (GSH/Hb), and 36% (P < 0.001) of muscle glutathione (GSH/tissue wet weight). This suggests that dexamethasone directly and/or indirectly impaired antioxidant reactions. This was further confirmed by a significant (49%) decline of SOD-1 activity in erythrocytes isolated from the group treated with dexamethasone. Another index of lipid peroxidation (TBARS) was also significantly increased. Activity of blood plasma CK increased by 73% (P<0.001) in Dex-treated rats, indicating moderate injury of muscle tissue. In conclusion, young growing rats were sensitive to the dosage of dexamethasone, but in contrast to lymphoid tissue, could easily compensate the outcomes of impaired antioxidative defence within 5 days of recovery.

Age Factors↗
PubMed1996

High leptin concentrations in serum of very obese children are further stimulated by dexamethasone.

Serum leptin concentrations and the levels of ob mRNA in adipocytes in obese humans are elevated. Hyperphagia and obesity are characteristics of hypercortisolism. We have therefore asked whether or not leptin levels were elevated in very obese children, and whether or not dexamethasone would increase leptin levels in obese children. A single dose dexamethasone suppression test was performed in ten obese children (5 girls, 5 boys; age 6 to 16 yrs, mean 12 +/- 1, median 12 yrs) to rule out hypercortisolism. Body mass index (BMI) in the ten children was calculated to be 27-45 kg/m2. Venous blood was sampled before dexamethasone was given in the evening and at 9.00 a.m. the following morning. Endogenous cortisol production was suppressed in all patients. Leptin levels, as measured by a newly developed specific radioimmunoassay, were 31.6 +/- 12.9 microg/l, range 19.2-59.9 microg/l before dexamethasone and 39.9 +/- 16.5 microg/l, range 26.3-80.3 microg/l after dexamethasone in the obese children (ANOVA, p = 0.01). Simple regression analysis revealed that serum levels correlated significantly with body mass index (r = 0.82, p < 0.001). Non-obese children (BMI < 27 kg/m2) had leptin levels between 0.1 and 33.3 microg/l, median 2.2 microg/l (N = 713). Girls (5.5 +/- 4.6 microg/l) (N = 401) had significantly higher leptin levels than boys (1.7 +/- 2.1 microg/l (N = 312) (p < 0.0001). We conclude that 1) high serum leptin concentrations are present in obese children. 2) A single dose of dexamethasone significantly increases the high leptin serum levels in these children. We hypothesize that glucocorticosteroids up-regulate leptin levels in the human.

Adolescent↗
PubMedDate not supplied

Dexamethasone inhibits glioma-induced formation of capillary like structures in vitro and angiogenesis in vivo.

Dexamethasone is used frequently in brain tumor therapy of patients. In animal models it is known to inhibit the angiogenesis of solid tumors. We addressed the question, if this is also true in brain tumors. C6 malignant glioma and 9L gliosarcoma cells were implanted into rat-brains. Dexamethasone 3 mg/kg/d intraperitoneal increased the survival compared to saline treated controls. The tumors size and the vascular density were smaller in the dexamethasone groups in both models. In vitro dexamethasone inhibited the growth of the C6 cells but not of 9L cells. Thus the growth inhibition of brain tumors in vivo appeared to be mediated partly by direct growth inhibition of tumor cells in C6 cells but additionally by antiangiogenesis in both tumor models. Several in vitro models were used to address the mechanisms of antiangiogenesis. There was no effect of dexamethasone on the proliferation of central nervous endothelial cells and no effect on the formation of capillary like structures on matrigel. Dexamethasone inhibited, however, the formation of capillary like structures in a coculture model with glioma cells in vitro. Surprisingly, progesterone had the same effect in this model. The in vitro effect was mediated via glucocorticoid receptors since receptor antagonists could inhibit it. The primary target appeared to be the tumor cell because only this cell had the complete set of receptors. These data show, that antiangiogenic therapeutic effects are possible by influencing primarily the tumor cell. This way of targeting might be of value for future developments of new strategies.

Animals↗
PubMed1982

Dexamethasone proves deleterious in cerebral malaria. A double-blind trial in 100 comatose patients.

High-dose dexamethasone was compared with placebo in a double-blind trial involving 100 comatose patients with strictly defined cerebral malaria. The two treatment groups, whose members were six to 70 years old, proved comparable on admission. There were eight deaths in the dexamethasone group and nine in the placebo group (no significant difference; P = 0.8); at post-mortem examination the brain showed features diagnostic of cerebral malaria in all but one patient who died. Dexamethasone prolonged coma among the survivors: the interval between the start of treatment and the full recovery of consciousness was 63.2 +/- 5.9 hours (mean +/- S.E.M.) in the dexamethasone group, as compared with 47.4 +/- 3.2 hours in the placebo group (P = 0.02). Complications, including pneumonia and gastrointestinal bleeding, occurred in 26 patients given dexamethasone and 11 given placebo (P = 0.004). Only five patients had neurologic sequelae. Results were similar in a subgroup of 28 children six to 14 years old. Dexamethasone is deleterious in cerebral malaria and should no longer be used.

Adolescent↗
PubMed1988

Dexamethasone therapy for bacterial meningitis. Results of two double-blind, placebo-controlled trials.

We enrolled 200 infants and older children with bacterial meningitis in two prospective double-blind, placebo-controlled trials to evaluate the efficacy of dexamethasone therapy in addition to either cefuroxime (Study 1) or ceftriaxone (Study 2). Altogether, 98 patients received placebo and 102 received dexamethasone (0.15 mg per kilogram of body weight every six hours for four days). At the beginning of therapy, the clinical and demographic characteristics of the patients in the treatment groups were comparable. The mean increase in the cerebrospinal fluid concentration of glucose and the decreases in lactate and protein levels after 24 hours of therapy were significantly greater in those who received dexamethasone than in those who received placebo (glucose, 2.0 vs. 0.4 mmol per liter [36.0 vs. 6.9 mg per deciliter], P less than 0.001; lactate, 4.0 vs. 2.1 mmol per liter [38.3 vs. 19.8 mg per deciliter], P less than 0.001; and protein, 0.64 vs. 0.25 g per liter [64.0 vs. 25.3 mg per deciliter], P less than 0.05). One patient in the placebo group in Study 1 died. As compared with those who received placebo, the patients who received dexamethasone became afebrile earlier (1.6 vs. 5.0 days; P less than 0.001) and were less likely to acquire moderate or more severe bilateral sensorineural hearing loss (15.5 vs. 3.3 percent; P less than 0.01). Twelve patients in the two placebo groups (14 percent) had severe or profound bilateral hearing loss requiring the use of a hearing aid, as compared with 1 (1 percent) in the two dexamethasone groups (P less than 0.001). We conclude that dexamethasone is beneficial in the treatment of infants and children with bacterial meningitis, particularly in preventing deafness.

Bacterial Infections↗