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PubMed2000

[Dexamethasone for prophylaxis of postoperative nausea and vomiting. A meta-analysis of randomized controlled studies].

OBJECTIVE: Randomised controlled trials investigating the efficacy of dexamethasone alone or in combination with other antiemetics to prevent postoperative nausea and vomiting (PONV) were included in a meta-analysis to estimate the relative efficacy of these treatments. METHODS: Studies were systematically searched using Medline, EMBASE, the Cochrane-Library, and by manual screening the reference lists and current issues of locally available anaesthesia journals. Studies identified were divided into four different groups. For each subgroup an independent analysis was performed: 1. Dexamethasone vs. placebo, 2. Dexamethasone + other antiemetic vs. other antiemetic alone, 3. Dexamethasone + other antiemetic vs. dexamethasone alone, 4. Dexamethasone vs. other antiemetics. The main end point in each study was defined as complete absence of nausea, retching, and vomiting after prophylactic antiemetic treatment. The pooled odds-ratios, the relative risk (RR) and the numbers-needed-to-treat (NNT) with their corresponding 95%-confidence intervals (given in parentheses) were calculated using a random effects model. RESULTS: A total of 26 studies with 2561 patients were analysed. 1. As a sole antiemetic agent dexamethasone is superior to placebo to prevent PONV (RR: 0.49 (0.15-0.42); NNT: 3.4 (2.5-5.3)). 2. When dexamethasone and an other antiemetic (e.g. a 5-HT3-antagonist) are combined this drug combination is significantly more effective than the single antiemetic without dexamethasone (RR: 0.60 (0.46-0.78); NNT: 7.3 (5.7-10.2)). 3. A similar result was obtained when the dexamethasone combination was compared with dexamethasone alone. The combination is statistically superior (RR: 0.16 (0.08-0.32); NNT: 3.2 (2.2-6.3)). 4. Dexamethasone was usually compared with 5-HT3-antagonist and to a less extends also with dopamine antagonists. Summarising these studies, there was no significant difference concerning effectiveness (RR: 1.35 (0.99-1.85); NNT: 10.6 (5.6-92.6)). CONCLUSION: Dexamethasone has antiemetics effects that are superior to placebo treatment and are comparable with conventional antiemetic agents (e.g. 5-HT3-antagonist, dopamine antagonists). The drug is especially useful in combination with other antiemetics and increases the efficacy of the antiemetic partner drug.

Antiemetics↗
PubMed2004

Dexamethasone as a chemoprotectant in cancer chemotherapy: hematoprotective effects and altered pharmacokinetics and tissue distribution of carboplatin and gemcitabine.

PURPOSE: Hematoprotective strategies may offer new approaches to prevent chemotherapy-induced hematotoxicity. The present study was undertaken to investigate the chemoprotective effects of dexamethasone and its optimal dose and the underlying mechanisms. METHODS: Lethal toxicity and hematotoxicity of carboplatin were compared in CD-1 mice with or without dexamethasone pretreatment. Plasma and tissue pharmacokinetics of carboplatin were determined in CD-1 mice. Carboplatin was quantified by HPLC. Gemcitabine was analyzed by radioactivity counting. RESULTS: Pretreatment with dexamethasone prevented lethal toxicity of carboplatin in a dose- and schedule-dependent manner. The best protective effects of dexamethasone pretreatment as measured by survival were observed at the dose level of 0.1 mg/mouse per day for 5 days (80% vs 10% in controls). In contrast, posttreatment with dexamethasone had no protective effects. Pretreatment with dexamethasone significantly prevented the decrease in granulocyte counts. To elucidate the mechanisms by which dexamethasone pretreatment reduces hematotoxicity, we examined the effects of dexamethasone pretreatment on the pharmacokinetics of carboplatin and gemcitabine in CD-1 mice. No significant differences in plasma pharmacokinetics of carboplatin or gemcitabine were observed between control and mice pretreated with dexamethasone. However, dexamethasone pretreatment significantly decreased carboplatin and gemcitabine uptake in spleen and bone marrow with significant decreases in AUC, T(1/2), and C(max), and an increase in CL. CONCLUSIONS: To our knowledge, this is the first time that dexamethasone has been shown to significantly decrease host tissue uptake of chemotherapeutic agents, suggesting a mechanism responsible for the chemoprotective effects of dexamethasone. This study provides a basis for future study to evaluate dexamethasone as a chemoprotectant in cancer patients.

Animals↗
PubMed2005

Lack of therapeutic improvement of liver fibrosis in rats by dexamethasone in spite of ascites amelioration.

Pathophysiology of liver fibrosis (LF) includes hepatic parenchymal cell destruction and connective tissue formation. Although dexamethasone has been used in the liver diseases, there is controversy over the beneficial effects of dexamethasone on LF. Previous studies showed that CCAAT/enhancer binding protein-beta (C/EBPbeta) activation contributes to hepatocyte regeneration and dissolution of fibrosis and that dexamethasone activates C/EBPbeta whereas C/EBPbeta-mediated gene induction by dexamethasone is antagonized by a corepressor. The present study investigated the possible therapeutic effect of dexamethasone for the treatment of LF in rats. We injected rats with multiple doses of dimethylnitrosamine (DMN) for 4 weeks and then used the LF rats to determine whether dexamethasone treatment therapeutically improved liver functions and resolved fibers accumulated in the liver. Dexamethasone (100 microg/kg, po, three times per week for 4 weeks) failed to restore the body weight gain and liver weight decreased by LF. The body weight gain reduced during LF was further decreased by dexamethasone treatment. Animals were subjected to blood biochemical, liver histopathological and immunochemical analyses. Although dexamethasone treatment significantly reduced ascites in LF rats, the plasma albumin and total protein levels decreased in fibrotic rats were not restored. Impaired liver functions during LF including elevated plasma aminotransferases and bilirubin levels along with GSTA2 repression were not recovered by dexamethasone. Dexamethasone failed to decrease the fibrosis score and to eliminate the extracellular matrix and alpha-smooth muscle actin accumulated in the fibrotic liver. The results of the present study showed that dexamethasone ameliorated ascites in LF rats but failed to improve the liver functions and fiber accumulation, and that the possible beneficial effect of dexamethasone might result from anti-inflammatory effect but not from liver improvement.

Animals↗
PubMed1998

Dexamethasone concentration in vitreous and serum after oral administration.

PURPOSE: To determine the dexamethasone concentration in vitreous and serum of patients after oral administration of dexamethasone and to compare the results with the concentrations in vitreous and serum found in a previous study with peribulbar injection of 5 mg dexamethasone disodiumphosphate. METHODS: In a prospective study, 54 patients who were scheduled for vitrectomy received 7.5 mg dexamethasone orally at varied time intervals before surgery. A vitreous sample was taken from each patient and serum samples were collected at multiple time points from 32 out of 54 patients. Dexamethasone concentrations were measured by radioimmunoassay. RESULTS: Dexamethasone concentrations in serum ranged from 2.5 to 98.1 ng/ml (median, 61.6 ng/ml) between 1 and 3 hours after oral administration of 7.5 mg dexamethasone. Serum concentrations after peribulbar injection of 5 mg dexamethasone disodiumphosphate (containing 3.75 mg dexamethasone) were lower by a factor of 1.5. Concentrations in vitreous ranged from 1.7 to 23.4 ng/ml (median, 5.2 ng/ml) between 4 and 10 hours after oral administration. After peribulbar injection of 5 mg dexamethasone disodiumphosphate, the intravitreal concentrations were 3.9 times higher. CONCLUSIONS: An oral dose of 7.5 mg dexamethasone resulted in an intravitreal corticosteroid concentration with an anti-inflammatory potency that is clearly above physiological level. This concentration, however, is several times lower than is the intravitreal concentration after a peribulbar injection of 5 mg dexamethasone disodiumphosphate, although the two routes of administration resulted in nearly equal dexamethasone concentrations in serum. The higher intravitreal concentration after peribulbar injection is probably caused by diffusion from the serum and additional transscleral diffusion.

Administration, Oral↗
PubMed1998

Correlation of increased mortality with the suppression of radiation-inducible microsomal epoxide hydrolase and glutathione S-transferase gene expression by dexamethasone: effects on vitamin C and E-induced radioprotection.

Previous studies in this laboratory have shown that gamma-ray ionizing radiation in combination with oltipraz, a radioprotective agent, enhances hepatic microsomal epoxide hydrolase (mEH) and glutathione S-transferase (GST) expression. The present study was designed to investigate the effects of dexamethasone on the radiation-inducible expression of mEH and rGST genes and on the vitamin C and E-induced radioprotective effects in association with the expression of the genes. Treatment of rats with a single dose of dexamethasone (0.01-1 mg/kg, p.o.) caused a dose-dependent decrease in the constitutive mEH gene expression at 24 hr. The radiation-inducible mEH mRNA level (threefold increase after 3 Gy gamma-irradiation) was decreased by 21% and 88% by dexamethasone at the doses of 0.1 and 1 mg/kg, respectively. Although dexamethasone alone caused 2- to 5-fold increases in the hepatic rGSTA2 mRNA level, rats treated with dexamethasone prior to 3 Gy irradiation exhibited 80%-93% suppression in the radiation-inducible increases in the rGSTA2 mRNA level. The inducible rGSTA3 and rGSTA5 mRNA levels were also significantly decreased by dexamethasone, whereas the rGSTM1 mRNA level was reduced to a lesser extent. Vitamin C and/or E, however, failed to enhance the radiation-inducible increases in hepatic mEH and rGST mRNA levels. Whereas rats exposed to 3 Gy irradiation with or without vitamin C treatment (30 or 200 mg/kg/day, p.o., 2 days) exhibited approximately threefold increases in the mEH and rGSTA2/3/5 mRNA levels relative to untreated animals, dexamethasone treatment (1 mg/kg, p.o.) resulted in 64%-96% decreases in the mRNA levels at 24 hr. The inducible rGSTM1/2 mRNA levels in the vitamin C/E-treated rats were approximately 50% suppressed by dexamethasone. Although vitamin C and/or E treatment (200 mg/kg/day, p.o., 2 days) improved the 30-day survival rates of the 8 Gy gamma-irradiated mice from 39% up to 74%, the improved survival rate of gamma-irradiated animals was reduced to 30% by dexamethasone pretreatment (1 mg/kg/day, 2 days). The mean survival time of dexamethasone-treated animals was reduced to approximately 2 days from 14 days in the animals with total body irradiation alone. No significant hematologic changes were observed in mice at 10 days after dexamethasone plus gamma-irradiation, as compared with irradiation alone. These results demonstrate that: dexamethasone substantially suppresses radiation-inducible mEH, rGSTA and rGSTM expression in the liver; vitamins C/E exhibit radioprotective effects without enhancing radiation-inducible mEH and GST gene expression; and inhibition of radiation-inducible mEH and rGST gene expression in the vitamin C- and E-treated animals by dexamethasone was highly correlated with reduction in the survival rate and the mean survival time of gamma-irradiated animals.

Animals↗
PubMed1997

Dexamethasone abrogates the fibrogenic effect of transforming growth factor-beta in rat granuloma and granulation tissue fibroblasts.

Administration of TGF-beta, a fibrogenic inflammatory growth factor, promotes fibrosis and scarring. Dexamethasone, an anti-inflammatory steroid, inhibits wound healing and reduces fibrosis. The current studies were initiated to determine whether the co-administration of dexamethasone was able to abrogate the fibrogenic effect of TGF-beta. Polyvinyl alcohol sponges were implanted subcutaneously on the abdominal area of rats and directly injected with vehicle, dexamethasone, TGF-beta, or dexamethasone plus TGF-beta. Dexamethasone was able to block the fibrogenic effect of TGF-beta. Collagen and noncollagen protein synthesis was measured as a function of TGF-beta or dexamethasone concentrations in fibroblasts isolated from granulation tissue. Addition of dexamethasone to cultures treated simultaneously with TGF-beta blocked the fibrogenic response of TGF-beta. To study the molecular regulation of collagen gene expression by TGF-beta or dexamethasone, fibroblasts derived from granulation tissue were stably transfected with the ColCat 3.6 plasmid, which contains the rat pro alpha1(I) collagen promoter linked to the chloramphenicol acetyltransferase (CAT) gene. Dexamethasone decreased CAT activity whereas TGF-beta increased the activity of this reporter gene. The increase in CAT activity observed with TGF-beta treatment was significantly decreased when dexamethasone was added to the cultures, although CAT activity did not return to control level. Since collagen synthesis in fibroblasts treated simultaneously with dexamethasone and TGF-beta1 was found to be the same as that of untreated samples, the data indicate that there is a dexamethasone-mediated posttranscriptional regulation of pro alpha1(I) collagen mRNA. These studies demonstrate that at the in vivo level, the cellular level, and the molecular level, dexamethasone is able to block the fibrogenic effect of TGF-beta.

Animals↗
PubMed1993

Effect of dexamethasone on neutrophil accumulation and oedema formation in rabbit skin: an investigation of site of action.

1. The anti-inflammatory actions of dexamethasone on vascular and leukocyte responses in rabbit skin were investigated. 2. Neutrophil accumulation and oedema formation were simultaneously measured as the local accumulation of i.v. administered 111In-labelled neutrophils and 125I-labelled albumin. Systemically administered dexamethasone (3 mg kg-1) inhibited neutrophil accumulation induced by i.d. zymosan activated plasma (ZAP), N-formyl-methionyl-leucyl-phenylalanine (FMLP) and leukotriene B4 (LTB4) when co-injected with prostaglandin E2 (PGE2). Dexamethasone also inhibited oedema formation elicited by these stimuli and the responses induced by i.d. platelet activating factor (PAF)+PGE2 and bradykinin (BK)+PGE2. 3. Intradermal dexamethasone (2 x 10(-10) mol per site) but not indomethacin (10(-8) mol per site) inhibited oedema formation induced by i.d. ZAP+PGE2 and BK+PGE2. This inhibitory effect of dexamethasone was significant only with pretreatment periods of 4 h, shorter pretreatment periods resulting in greatly reduced effects. Intradermal dexamethasone had no effect on neutrophil accumulation induced by ZAP+PGE2. 4. Intradermal dexamethasone (2 x 10(-10) mol per site) had no effect on increase in blood flow induced by PGE2 as measured by 133Xenon clearance. 5. The accumulation of neutrophils isolated from donor rabbits pretreated with i.v. saline or dexamethasone (3 mg kg-1) was investigated in untreated recipient rabbits. The accumulation of neutrophils, induced by ZAP+PGE2, FMLP+PGE2 and LTB4+PGE2, from dexamethasone-pretreated donors was significantly smaller than the accumulation of neutrophils from saline-pretreated donors. 6. The results of this study suggest that dexamethasone can have a direct effect on vascular endothelial cells resulting in an inhibition of oedema formation. 7. Neutrophil accumulation can be inhibited by an effect of dexamethasone on the neutrophil itself or on the vascular endothelium. These results indicate that at least part of the inhibitory effect is on the circulating neutrophil induced by dexamethasone or a dexamethasone-induced product.

Animals↗
PubMed1991

Antimitogenic effects of dexamethasone in chemically transformed mouse fibroblasts.

Dexamethasone (a synthetic glucocorticoid) inhibited the entry into the S-phase of quiescent chemically transformed mouse fibroblasts (BP-A31) stimulated with 12-O-tetradecanoyl 13-acetate (TPA; a protein kinase-C activator) or with basic fibroblast growth factor. The basal rate of DNA synthesis was also strongly reduced by dexamethasone. In contrast, the mitogenic activity of insulin (acting via the insulin-like growth factor-I receptor) was little or not at all affected by dexamethasone. The antimitogenic activity of dexamethasone was enhanced when the steroid was included in the culture medium 24 h before the addition of mitogens. The effects of dexamethasone were glucocorticoid specific, partially reversed by the antiglucocorticoid RU 486, and prevented by cycloheximide (suggesting the involvement of glucocorticoid-induced protein synthesis in the antimitogenic activity of dexamethasone). Under the conditions of exponential growth in serum-free medium as well as in the presence of TPA, dexamethasone arrested the proliferation of sparsely seeded cells after a delay of 24-48 h. The BP-A31 cells are known to be constitutively competent and express at quiescence certain genes related to the G0/G1 transition in the original nontransformed A31 cell line. Of the transcripts corresponding to these genes, dexamethasone caused a rapid elimination of the JE mRNA, coding for a protein of the family of cytokines. The cell content of c-jun mRNA was also strongly reduced in the cells incubated at quiescence with dexamethasone (in the absence of mitogen). The presence of TPA along with dexamethasone prevented the elimination of c-jun, but not of JE mRNA. Short (30-min; together with the inducers) or long (24-h) treatment of the cells with dexamethasone did not prevent the induction of the c-fos gene expression by either TPA or basic fibroblast growth factor, indicating that dexamethasone does not interfere with mitogenic signal transduction. We conclude that in TPA-stimulated cells, the antiproliferative effect of dexamethasone is not due to interference with the expression of the c-jun gene, but may be related to the decreased level of the JE cytokine mRNA as well as to the synthesis of growth inhibitory protein(s).

Animals↗
PubMed1997

Early postnatal dexamethasone therapy for the prevention of chronic lung disease in preterm infants with respiratory distress syndrome: a multicenter clinical trial.

OBJECTIVES: To study whether early postnatal (<12 hours) dexamethasone therapy reduces the incidence of chronic lung disease in preterm infants with respiratory distress syndrome. MATERIALS AND METHODS: A multicenter randomized, double-blind clinical trial was undertaken on 262 (saline placebo, 130; dexamethasone, 132) preterm infants (<2000 g) who had respiratory distress syndrome and required mechanical ventilation shortly after birth. The sample size was calculated based on the 50% reduction in the incidence of chronic lung disease when early dexamethasone is used, allowing a 5% chance of a type I error and a 10% chance of a type II error. For infants who received dexamethasone, the dosing schedules were: 0.25 mg/kg/dose every 12 hours intravenously on days 1 through 7; 0.12 mg/kg/dose every 12 hours intravenously on days 8 through 14; 0.05 mg/kg/dose every 12 hours intravenously on days 15 through 21; and 0. 02 mg/kg/dose every 12 hours intravenously on days 22 through 28. A standard protocol for respiratory care was followed by the participating hospitals. The protocol emphasized the criteria of initiation and weaning from mechanical ventilation. The diagnosis of chronic lung disease based on oxygen dependence and abnormal chest roentgenogram was made at 28 days of age. To assess the effect of dexamethasone on pulmonary inflammatory response, serial tracheal aspirates were assayed for cell counts, protein, leukotriene B4, and 6-keto prostaglandin F1alpha. All infants were observed for possible side effects, including hypertension, hyperglycemia, sepsis, intraventricular hemorrhage, retinopathy of prematurity, cardiomyopathy, and alterations in calcium homeostasis, protein metabolism, and somatic growth. RESULTS: Infants in the dexamethasone group had a significantly lower incidence of chronic lung disease than infants in the placebo group either judged at 28 postnatal days (21/132 vs 40/130) or at 36 postconceptional weeks (20/132 vs 37/130). More infants in the dexamethasone group than in the placebo group were extubated during the study. There was no difference between the groups in mortality (39/130 vs 44/132); however, a higher proportion of infants in the dexamethasone group died in the late study period, probably attributable to infection or sepsis. There was no difference between the groups in duration of oxygen therapy and hospitalization. Early postnatal use of dexamethasone was associated with a significant decrease in tracheal aspirate cell counts, protein, leukotriene B4, and 6-keto prostaglandin F1alpha, suggesting a suppression of pulmonary inflammatory response. Significantly more infants in the dexamethasone group than in the placebo group had either bacteremia or clinical sepsis (43/132 vs 27/130). Other immediate, but transient, side effects observed in the dexamethasone group are: an increase in blood glucose and blood pressure, cardiac hypertrophy, hyperparathyroidism, and a transient delay in the rate of growth. CONCLUSIONS: In preterm infants with severe respiratory distress syndrome requiring assisted ventilation shortly after birth, early postnatal dexamethasone therapy reduces the incidence of chronic lung disease, probably on the basis of decreasing the pulmonary inflammatory process during the early neonatal period. Infection or sepsis is the major side effect that may affect the immediate outcome. Other observable side effects are transient. In view of the significant side effects and the lack of overall improvement in outcome and mortality, and the lack of long term follow-up data, the routine use of early dexamethasone therapy is not yet recommended.

Chronic Disease↗
PubMed1999

A three-day course of dexamethasone therapy to prevent chronic lung disease in ventilated neonates: a randomized trial.

BACKGROUND: Although several trials of early dexamethasone therapy have been completed to determine if such therapy would reduce mortality and chronic lung disease (CLD) in infants with respiratory distress, optimal duration and side effects of such therapy remain unknown. PURPOSE: The purpose of this study was: 1) to determine if a 3-day course of early dexamethasone therapy would reduce CLD and increase survival without CLD in neonates who received surfactant therapy for respiratory distress syndrome and 2) to determine adverse effects associated with such therapy. DESIGN: This was a prospective multicenter randomized trial comparing a 3-day course of dexamethasone therapy beginning at 24 to 48 hours of life to placebo therapy. Two hundred forty-one neonates (dexamethasone n = 118, placebo n = 123), who weighed between 500 g and 1500 g, received surfactant therapy, and were at significant risk for CLD or death using a model to predict CLD or death at 24 hours of life, were enrolled in the trial. Infants randomized to receive early dexamethasone were given 6 doses of dexamethasone at 12-hour intervals beginning at 24 to 48 hours of life. The primary outcomes compared were survival without CLD and CLD. CLD was defined by the need for supplemental oxygen at the gestational age of 36 weeks. Complication rates and adverse effects of study drug therapy were also compared. RESULTS: Neonates randomized to early dexamethasone treatment were more likely to survive without CLD (RR: 1.3; 95% CI: 1.03, 1.7) and were less likely to develop CLD (RR: 0.6; CI: 0.3, 0. 98). Mortality rates were not significantly different. Subsequent dexamethasone therapy use was less in early dexamethasone-treated neonates (RR: 0.8; CI: 0.7, 0.96). Very early (</=7 days of life) intestinal perforations were more common among dexamethasone-treated neonates (8% vs 1%). CONCLUSION: We conclude that an early 3-day course of dexamethasone therapy increases survival without CLD, reduces CLD, and reduces late dexamethasone therapy in high-risk, low birth weight infants who receive surfactant therapy for respiratory distress syndrome. Potential benefits of early dexamethasone therapy at the dosing schedule used in this trial need to be weighed against the risk for early intestinal perforation.

Analysis of Variance↗
PubMed2003

[Stimulation of fetal lung maturation with dexamethasone in unexpected premature labor].

INTRODUCTION: Preterm labour is most common complication of second half of pregnancy, incidence is 7 to 10% of all delivers. One of most important causes of increased mortality and morbidity of neonates is respiratory distress syndrome. Numerous studies prove that corticosteroids given antenatal to mother decrease the incidence of preterm delivered neonates. AIM OF THIS STUDY IS: To determined influence of dexamethasone given prepartal on maturation of neonatal lungs in correlation with gestational age. METHOD: This study include 150 pregnant women which delivered before 37 week of gestation. They are divide in three groups: two experimental and one control group. Group E1 consists of the pregnant women which received dexamethasone for five days in a single dose of 12 mg. Group E2 consists of the pregnant women which received dexamethasone less then five days, in a single dose of 12 mg. In the control group consists of the pregnant women which did not received dexamethasone. In this work we used gestational age in the moment of delivery. State of neonate is determined on the base of presence of clinical signs of respiratory distress syndrome after birth. Statistical method used in this work was test of proportion. RESULTS: In this work we find that there is a less number of neonates who has respiratory distress syndrome in group consists of the pregnant women which received dexamethasone for five days, 5 (10%). In group consists of the pregnant women which received dexamethasone less then five days, number of neonates with respiratory distress syndrome was 12 (24%). The number of neonates with respiratory distress syndrome in control group was 21 (42%). The value of test of proportion: K/E1 (the pregnant women received dexamethasone for five days)-z = 1.95, p < 0.05; K/E2 (pregnant women received dexamethasone less than five days)-z = 3.92, p < 0.05. In all three groups largest number of neonates with respiratory distress syndrome was between 31-34 week of gestation. Highest mortality of neonate with respiratory distress syndrome was in control group, 7 (14%), than in group consists of the pregnant women received dexamethasone lass then five days, 4 (8%). In group consist pregnant women received dexamethasone for five days, there were not cases of mortality caused by respiratory distress syndrome. The value of test of proportion was z = 2.85 (p < 0.05), between control group and group consists of the pregnant women received dexamethasone for five days. CONCLUSION: Dexamethasone accelerates maturation of fetal lungs, decrease number of neonates with respiratory distress syndrome and improves survival in preterm delivered neonates. Optimal gestational age for use of dexamethasone therapy is 31 to 34 weeks of gestation.

Dexamethasone↗
PubMed2003

[Cyclosporin A combined with dexamethasone in preventing and treating immune rejection after penetrating keratoplasty].

OBJECTIVE: To evaluate the efficacy of topical 1% cyclosporin A (CsA), 0.1% dexamethasone or 1% CsA combined with 0.1% dexamethasone in preventing and treating immune rejection after penetrating keratoplasty (PKP). METHODS: Eighty-six eyes from 86 PKP patients were randomly divided into 3 groups: (1) Thirty-one eyes were treated with 1% CsA and dexamethasone for 3 months. (2) Twenty-nine eyes were treated with 1% CsA for 3 months; (3) Twenty-six eyes were treated with 0.1% dexamethasone for 3 months. The rejected eyes of postoperation were given with the dexamethasone injection under conjunctiva and increased the frequency of CsA and dexamethasone eye drops. All patients were followed up for 1 to approximately 2 years. RESULTS: There was a statistical difference in the 3 groups in the postoperative immune rejection which occurred in 5 out of 29 (17.3% ) eyes treated with 1% CsA, 7 out of 26 (26.9%) treated with 0.1% dexamathasone, and 3 out of 31 (9.7%) with 1% CsA and dexamethasone. The immune rejection after PKP occurred in 15 eyes and 13 eyes were cured by sub-conjunctiva injection of dexamethasone combined with eye drops of 1% CsA and 0. 1% dexamethasone. CONCLUSION: The efficacy of CsA combined with dexamethasone topically is better than that of 1% CsA or 0.1% dexamethasone alone in preventing rejection episodes. It is effective to cure the graft rejection after PKP with sub-conjunctiva injection of dexamethasone combined with the eye drop of 1% CsA and 0.1% dexamethasone.

Adult↗
PubMed1991

The impact of dexamethasone pharmacokinetics on the DST: a review.

Even though the DST has not proved successful as a marker for depression, it has stimulated a considerable amount of research into the interaction between neuroendocrine function and mood states. With the objective of perfecting the DST methodology, investigators have explored the interaction between dexamethasone plasma concentrations and cortisol response, and have found that there is a significant inverse correlation between dexamethasone concentrations and cortisol concentrations. Although this relationship is one of the factors that affects cortisol response in depressed patients, it usually explains less than 20 percent of the variance of cortisol response. One can only conclude that the affective state explains a certain amount of the remaining variance. Dexamethasone plasma concentrations may be altered by a variety of drug and disease interactions. Many enzyme inducers, including phenytoin, carbamazepine, and phenobarbital, increase dexamethasone CL, but some drugs that might be expected to alter dexamethasone CL, such as cimetidine and tobacco smoke, do not affect it. Any disease that causes hepatic dysfunction could be expected to decrease dexamethasone CL, whereas renal failure may increase dexamethasone CL. Neither Cushing's syndrome nor congenital adrenal hyperplasia appear to alter dexamethasone CL. Alcoholism has a dual effect on the DST. Chronic alcohol abuse may cause a cushingoid state, which could interfere with the DST interpretation. Also, chronic alcohol use may result in hepatic dysfunction, or an induction of P-450 enzymes. As a result of these different actions, alcohol could result in either an increase or decrease in dexamethasone CL. Studies of dexamethasone pharmacokinetics conducted in depressed patients are few, but they generally agree that DST nonsuppressors exhibit an increased dexamethasone CL when compared with suppressors. The only two studies to investigate this population longitudinally report somewhat contradictory results; one study reports an increase in dexamethasone CL following recovery from depression, and the other a decrease. Since only one of the studies was conducted using intravenous dexamethasone, differences in bioavailability might explain some of the differences in results between the two studies. In spite of the unresolved questions, these studies have stimulated research into an entirely new area: the possibility that affective diseases may alter the pharmacokinetics of some drugs.

Depressive Disorder↗
PubMed1993

Corticotropin-releasing hormone stimulation following low-dose dexamethasone administration. A new test to distinguish Cushing's syndrome from pseudo-Cushing's states.

OBJECTIVE: The biochemical and phenotypic presentation of mild hypercortisolism in Cushing's syndrome is often indistinguishable from that seen in pseudo-Cushing's states such as depression. Both dexamethasone suppression and corticotropin-releasing hormone (CRH) stimulation tests have been used individually to distinguish these conditions, but neither approach has achieved a diagnostic accuracy greater than 85%. Therefore, we sought to develop a combined dexamethasone-CRH test that would take advantage of the altered sensitivity of patients with Cushing's syndrome to both dexamethasone and CRH and would achieve greater accuracy in the diagnosis of Cushing's syndrome. DESIGN: Prospective cohort study. SETTING: Tertiary care research hospital. PATIENTS: A total of 58 adults referred for evaluation of mild hypercortisolism (urine free cortisol level < 1000 nmol/d). The diagnosis of Cushing's syndrome was confirmed at surgery in 39 patients. The diagnosis of a pseudo-Cushing's state was made in 19 patients on the basis of extended follow-up (mean, 28 months) without progression of cushingoid features. INTERVENTION: The low-dose dexamethasone suppression test, the CRH stimulation test, and the CRH stimulation test started 2 hours after completion of low-dose dexamethasone suppression (the dexamethasone-CRH test) were performed in all patients. MAIN OUTCOME MEASURES: Sensitivity, specificity, and accuracy of the three procedures for diagnosis of Cushing's syndrome were calculated from plasma corticotropin, plasma cortisol, urine free cortisol, and urine 17-hydroxycorticosteroid values. RESULTS: The low-dose dexamethasone suppression test had 74% specificity, 69% sensitivity, and 71% diagnostic accuracy, using the standard criterion (17-hydroxycorticosteroid excretion level > 11.0 mumol/d on the second day of dexamethasone administration). With a urine free cortisol criterion for Cushing's syndrome of greater than 100 nmol/d, the low-dose dexamethasone suppression test had 100% specificity, 56% sensitivity, and 71% diagnostic accuracy. The CRH stimulation test without dexamethasone pretreatment had 100% specificity, 64% sensitivity, and 76% diagnostic accuracy. The diagnostic accuracy of the dexamethasone-CRH test for Cushing's syndrome was significantly greater than the accuracy of either the low-dose dexamethasone test or the CRH test alone (P < .01). A plasma cortisol concentration greater than 38 nmol/L measured 15 minutes after the administration of CRH correctly identified all cases of Cushing's syndrome and all cases of pseudo-Cushing's states (100% specificity, sensitivity, and diagnostic accuracy). CONCLUSION: The dexamethasone-CRH test is a more accurate test to distinguish Cushing's syndrome from pseudo-Cushing's states in patients with mild hypercortisolism.

17-Hydroxycorticosteroids↗
PubMed1990

Dexamethasone used as an antiemetic in chemotherapy protocols inhibits natural cytotoxic (NC) cell activity.

Because dexamethasone is often included as an antiemetic in chemotherapy protocols that involve cisplatin and because cisplatin has been shown to increase the in vitro lysis of tumor cells by natural cytotoxic (NC) effector cells, we determined the NC activity of 27 patients who received dexamethasone in conjunction with seven different cisplatin-based chemotherapy protocols. The results of this analysis showed that the NC activity of patients who received cisplatin-based chemotherapy protocols that included dexamethasone was reduced significantly 24 hours after treatment compared with before treatment (P less than 0.001). The addition of dexamethasone (at a concentration equivalent to the plasma level of patients treated with dexamethasone) to the in vitro assay of NC activity caused a significant decrease in NC activity compared with when dexamethasone was not added (P less than 0.001). There was no cumulative effect of dexamethasone in that the reduction of NC activity by dexamethasone was not significantly different in patients who had been treated previously at least four times and in patients who were treated for the first time. When dexamethasone was not included in the chemotherapy protocol the NC activity of 19 patients was not reduced 24 hours after treatment. These results indicate that dexamethasone causes a significant reduction in NC activity. Although the tumor surveillance role of human NC cells in vivo has not been established, the effect of dexamethasone on NC cells suggests that additional research of the effect of dexamethasone in cisplatin-based chemotherapy protocols is warranted.

Adult↗
PubMed1996

Effects of dexamethasone on bovine circulating T lymphocyte populations.

In cattle, gamma delta T cells represent a higher proportion of circulating T cells than in humans. Bovine gamma delta T cells can be recognized by expression of gamma delta cell receptor (gamma delta TCR) determinants or by a 215/230-kDa surface antigen (WC1). WC1 is expressed on 90% or more of circulating bovine gamma delta T cells. The effects of dexamethasone on this and other subsets (CD3, CD2, CD4, CD8) of peripheral blood T lymphocytes were determined by flow cytometric analysis. Twelve 15-month old bulls were injected with dexamethasone (0.04 mg/kg/day) for 3 consecutive days and four bulls were untreated controls. Blood samples were collected daily for 3 days before dexamethasone injections and for an additional 7 days starting on the third day. Data were recorded as percent positive cells and as mean fluorescent intensity (MFI) of positive cells. Initially, CD3+ cells represented 65-73% of all peripheral blood clear cells (PBMC). Dexamethasone reduced CD3+/- cells (PBMC). Dexamethasone reduced CD3+ cells to 30% and these recovered to 50% positive cells by 9 days after the last dexamethasone injection. Loss of CD3+ cells was not due to reductions in alpha beta T cells because dexamethasone did not influence the percent CD2+, CD4+, or CD8+ cells. However, percent WC1+ cells rapidly declined from a baseline of 26.4% of PBMC to < 6% by the final injection. During injections, the MFI of WC1 increased. The MFI of WC1 returned to control values 7 days after the last injection of dexamethasone, but the percent gamma delta T cells recovered to only 14% WC1+ PBMC by the final day of the study. During its maximum effects on WC1, dexamethasone also caused a profound decrease of L-selectin MFI on remaining PBMC (mostly alpha beta T cells and monocyte/macrophages). In a second trial, two-color analyses determined that dexamethasone did not increase apoptosis in WC1+ cells and did not reduce L-selectin MFI on either CD2+ of WC1+ cells. The cumulative results suggested that dexamethasone promoted gamma delta T cell migration out of peripheral blood via an L-selectin-independent mechanism and that dexamethasone did not alter alpha beta T cell migration kinetics.

Animals↗
PubMed1999

Dexamethasone suppresses vascular smooth muscle cell proliferation.

BACKGROUND: Experimental studies in vivo have demonstrated that dexamethasone inhibits neointimal hyperplasia following arterial injury. The mechanisms of this inhibition have not been clearly defined. Our objective was to test the hypothesis that dexamethasone directly suppresses smooth muscle cell (SMC) proliferation by inhibiting cell cycle progression and the expression of key cell cycle-dependent genes. METHODS: Cultured rat aortic SMC were treated with incremental concentrations of dexamethasone and cell number was determined after 72 h. To determine if dexamethasone inhibited cell cycle progression, cells were synchronized, then restimulated to enter the cell cycle, and treated with or without dexamethasone. DNA synthesis was determined 24 h after restimulation by measuring [3H]thymidine incorporation. To define the point of action of dexamethasone in the cell cycle, synchronized SMC were treated with dexamethasone (10(-7) M) at various time points after entry into the cell cycle. Flow cytometry and Northern blots were performed to examine cell cycle progression and the expression of smooth muscle cell cycle-dependent genes c-fos, c-myc, and thymidine kinase (TK). RESULTS: Dexamethasone treatment induced a concentration-dependent inhibition of SMC proliferation and DNA synthesis. The cell cycle progression of synchronized SMC from G1 into S phase was inhibited by dexamethasone, even when added as late as 16 h after restimulation. The expression of TK was suppressed by dexamethasone, while c-fos and c-myc were not affected. CONCLUSIONS: Dexamethasone inhibits the proliferation of SMC in a concentration-dependent fashion. This inhibition is associated with a block in cell cycle progression late in G1 phase of the cell cycle. Consistent with this finding, dexamethasone does not alter the expression of the early cell cycle-dependent genes c-fos and c-myc, but significantly inhibits the expression of TK, a marker of late G1 phase.

Animals↗
PubMed1988

Comparison of in vivo and in vitro glucocorticoid sensitivity in depression: relationship to the dexamethasone suppression test.

The effect of in vivo (1 mg) and in vitro (10(-7)-10(-10) M) dexamethasone administration on mitogen-induced lymphocyte proliferation was examined in drug-free depressed patients, nondepressed psychiatric patients, as well as normal controls, and was related to the results of a standard overnight Dexamethasone Suppression Test (DST). The effect of oral dexamethasone administration was also examined for its effect on lymphocyte cytosolic glucocorticoid receptor content. Oral dexamethasone administration significantly decreased both phytohemagglutinin (PHA) and concanavalin A (Con-A) induced lymphocyte proliferation, as well as glucocorticoid receptor number in suppressors, whereas dexamethasone failed to decrease these responses in nonsuppressors. Nonsuppressors had significantly lower serum dexamethasone levels compared to suppressors at both 8:00 AM and 4:00 PM. However, when differences in serum dexamethasone levels were covaried out, there were still significant differences between suppressors and nonsuppressors on the dexamethasone-induced mitogen changes, but the changes in glucocorticoid receptor content were no longer significant. In vitro incubation of lymphocytes with dexamethasone produced a dose-related decrease in mitogenesis, which was not different between the depressed and nondepressed groups. However, at physiologically relevant concentrations of dexamethasone (10(-9)-10(-10) M), nonsuppressors as compared to suppressors were more resistant to the immunosuppressive effects of in vitro dexamethasone on the Con-A response. The inhibitory effect of in vitro dexamethasone on Con-A-stimulated lymphocytes was positively correlated with basal 4:00 PM cortisol values. In conclusion, in vitro techniques are useful probes to assess glucocorticoid sensitivity in depression. The present results also further support the hypothesis that glucocorticoid insensitivity is associated with DST nonsuppression.

Adult↗