Oral dexamethasone led to fewer treatment failures than did nebulized dexamethasone or placebo in children with mild croup.
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Uptake of dexamethasone incorporated into liposomes by macrophages and foam cells and its inhibitory effect on cellular cholesterol ester accumulation.
To confirm the efficacy of dexamethasone incorporated into liposomes in the treatment of atherosclerosis, the uptake of dexamethasone-liposomes by macrophages and foam cells and its inhibitory effect on cellular cholesterol ester accumulation in these cells were investigated in-vitro. Dexamethasone-liposomes were prepared with egg yolk phosphatidylcholine, cholesterol and dicetylphosphate in a lipid molar ratio of 7/2/1 by the hydration method. This was adjusted to three different particle sizes to clarify the influence of particle size on the uptake by the macrophages and foam cells, and the inhibitory effect on cellular cholesterol ester accumulation. The distribution of particle sizes of dexamethasone-liposomes were 518.7+/-49.5 nm (L500), 202.2+/-23.1 nm (L200), and 68.6+/-6.5 nm (L70), respectively. For each size, dexamethasone concentration and dexamethasone/lipid molar ratio in dexamethasone-liposome suspension were 1 mg dexamethasone mL-1 and 0.134 mol dexamethasone mol-1 total lipids, respectively. The zeta potential was approximately -70 mV for all sizes. Dexamethasone-liposomes or free dexamethasone were added to the macrophages in the presence of oxidized low density lipoprotein (oxLDL) and foam cells, and then incubated at 37 degrees C. The uptake amount of dexamethasone by the macrophages and foam cells after a 24-h incubation was L500>L200>free dexamethasone>L70. The macrophages in the presence of oxLDL and foam cells were incubated with dexamethasone-liposomes or free dexamethasone for 24 h at 37 degrees C to evaluate the inhibitory effect on the cellular cholesterol ester accumulation. The cellular cholesterol ester level in the macrophages treated with oxLDL was significantly increased compared with that in macrophages without additives. L500, L200 and free dexamethasone significantly inhibited this cholesterol ester accumulation. L500, L200 and free dexamethasone also significantly reduced cellular cholesterol ester accumulation in foam cells. In addition, the relationship between the area under the uptake amount of dexamethasone-time curve (AUC) and the inhibition rate of cholesterol ester accumulation in macrophages and foam cells was evaluated. The inhibition rate of cholesterol ester accumulation (%) was related to the AUC in both types of cell. These results suggested that dexamethasone-liposomes would be a useful approach to the development of a novel drug delivery system for atherosclerotic therapy. Furthermore, the prediction of the inhibitory effect of dexamethasone on cellular cholesterol ester accumulation may become possible by using the results of this study.
Animals↗
HPA hyperactivity with increased plasma cortisol affects dexamethasone metabolism and DST outcome.
Data suggests that dexamethasone bioavailability or pharmacokinetic factors contribute importantly to the outcome of the dexamethasone suppression test, and a relationship between plasma cortisol and plasma dexamethasone levels has been shown. To evaluate these data further, we studied plasma dexamethasone pharmacokinetics in 24 patients with major depression (15 suppressors and nine nonsuppressors) who received a 1 mg IV dexamethasone bolus at 09:00 h with blood samples collected at intervals over the next 14 h. We found that nonsuppressors had significantly shorter plasma dexamethasone half-life (P = 0.003) as well as significantly lower dexamethasone levels 10 h (P = 0.02) following IV dexamethasone administration. Moreover, upon clinical improvement of patients, the shortened dexamethasone half-life and lower dexamethasone levels disappeared in the five patients who switched from nonsuppression to suppression and were restudied by IV bolus. These 10-h post IV plasma dexamethasone level findings paralleled the results of the 1 mg overnight oral DST performed in these depressed patients (N = 22) where we found significantly lower 10 h plasma dexamethasone levels in nonsuppressors on admission compared to suppressors (P = 0.002) and again at discharge (P = 0.007). Interestingly, in the few patients who switched from suppression to nonsuppression over the course of hospitalization, 10-h post dose plasma dexamethasone levels simultaneously dropped. No difference in dexamethasone half-life was observed in the patients studied by oral and IV dexamethasone administration. These findings support the concept that metabolism of dexamethasone is significantly related to the activity of the HPA axis (particularly by plasma cortisol levels), and that dexamethasone pharmacokinetics can be modified by state-dependent phenomena.
Major Depressive Disorder↗
Failure to detect dexamethasone phosphate in the local venous blood postcathodic lontophoresis in humans.
STUDY DESIGN: A single-blind, 2-factor (4 treatments by 8 time points) repeated-measures study design. OBJECTIVE: To analytically determine dexamethasone and dexamethasone phosphate concentrations in plasma derived from proximal effluent venous blood, following cathodic iontophoresis. METHODS AND MEASURES: Six volunteers received the following dexamethasone phosphate (2.5 ml, 4 mg/ml) treatments to their wrists on separate occasions: cathodic iontophoresis (4 mA, 10 minutes or 4 mA, 20 minutes), passive application (10 or 20 minutes). Plasma samples from the ipsilateral antecubital vein were obtained 10 minutes prior to and half way through the treatment (5 or 10 minutes), at the end of the treatment (10 or 20 minutes), and posttreatment (15, 30, 60, 90, and 120 minutes). The present investigation examined: (1) the sensitivity and linearity of extraction and analysis of dexamethasone and dexamethasone phosphate; (2) the necessity for determining both; and (3) the plasma levels from proximal effluent venous blood following cathodic iontophoresis. RESULTS: The aggregate (n = 18) of the 6-point standard curves were linear for dexamethasone (r > 0.974) and dexamethasone phosphate (r > 0.829). In vitro dephosphorylation of dexamethasone phosphate to dexamethasone occurred in plasma at 37 degrees C and during freeze-thaw. Measurable dexamethasone or dexamethasone phosphate concentrations were absent at all time points and under all conditions in the human subjects. CONCLUSIONS: These results demonstrate the sensitivity of the current assay and the need for evaluating both forms of the drug, as in vitro dephosphorylation results in the presence of dexamethasone and dexamethasone phosphate in samples. Absence of measurable dexamethasone or dexamethasone phosphate in the proximal effluent venous blood may require re-evaluation of the extent of drug delivery during the clinical iontophoresis of dexamethasone phosphate.
Adult↗
Interstitial delivery of dexamethasone in the brain for the reduction of peritumoral edema.
Controlled-release polymers have facilitated the interstitial delivery of drugs within the central nervous system. In the present study, dexamethasone was incorporated into ethylene-vinyl acetate polymers, which were then implanted adjacent to a 9L gliosarcoma in the brain of Fischer 344 rats. The effect of interstitial delivery of dexamethasone on peritumoral edema was assessed and compared to the effect of dexamethasone delivered systemically. Eighty-five rats underwent intracranial implantation of the 9L gliosarcoma. Five days later, the animals were randomly assigned to one of four treatment groups: Group 1 received intracranial implantation of controlled-release polymers containing dexamethasone; Group 2 received intraperitoneal implantation of controlled-release polymers containing dexamethasone; Group 3 received serial intraperitoneal injections of dexamethasone; and Group 4 received sham treatment. The animals were sacrificed 3 days after initiation of therapy and their brains were removed for measurement of the water content (edema) in the tumor-bearing and contralateral hemispheres. Brain and plasma samples were analyzed by reverse-phase high-performance liquid chromatography to determine the tissue and plasma concentrations of dexamethasone. Measurement of the release kinetics of dexamethasone from the ethylene-vinyl acetate polymers in an in vitro system showed that the drug was released in a controlled, tapering fashion. During the first 3 days of controlled release in vitro, 330 micrograms of a total content of 7.5 mg of dexamethasone was released into the medium. Analysis of tissue for drug levels demonstrated, however, that the interstitial delivery of this fractional amount of dexamethasone within the brain resulted in levels 19 times higher than those achieved by administering the full dose of 7.5 mg systemically over a 3-day period. Conversely, the systemic administration of dexamethasone resulted in plasma levels 16 times higher than those measured in the interstitial delivery of dexamethasone in the brain. Brain-water content determinations showed that the interstitial controlled release of the fractional amount of dexamethasone within the brain was as effective in controlling peritumoral edema as systemic administration of the full dose by serial intraperitoneal injections. The study demonstrates the following: 1) controlled-release polymeric carriers deliver biologically active dexamethasone in a sustained fashion; 2) very high concentrations of dexamethasone in brain tissue can be achieved using interstitial polymer-mediated drug delivery while minimizing plasma concentrations of this drug which are sometimes associated with serious systemic side effects; and 3) peritumoral brain edema can be effectively treated by the interstitial delivery of dexamethasone directly within the tumor bed.
Animals↗
Radioimmunoassay for dexamethasone 17,21-dipropionate and its metabolites in plasma and urine after topical application.
A sensitive radioimmunoassay for dexamethasone 17,21-dipropionate and its four metabolites in human plasma and urine has been developed using single anti-dexamethasone antiserum. The antiserum was obtained by immunizing rabbits with dexamethasone-3-oxime-bovine serum albumin conjugate. All of the endogenous steroids tested cross-reacted less than 0.07%. Before radioimmunoassay, dexamethasone 17,21-dipropionate and dexamethasone 17-propionate were hydrolyzed to dexamethasone, and 6 beta-OH-dexamethasone 17-propionate was hydrolyzed to 6 beta-OH-dexamethasone in 3% ammonia/methanol at 5 C for 16 h. A standard curve was established with a useful range between 0.005 and 2 ng in the case of dexamethasone, between 0.05 and 5 ng in the case of 6 beta-OH-dexamethasone. Measurement of plasma concentrations and percent urinary excretion of the metabolites in healthy men was performed following occlusive dressing of dexamethasone 17,21-dipropionate cream and ointment. The main metabolites in plasma were dexamethasone 17-propionate and dexamethasone, which increased gradually and reached maximum levels (160-200 pg/mL) at 24-32 h after application. The major metabolites observed in urine were 6 beta-OH-dexamethasone 17-propionate and 6 beta-OH-dexamethasone. Total percentage of their urinary excretions within 72 h after application amounted to 0.28-0.50% of the dose administered.
Administration, Topical↗
Mechanism of the permissive action of dexamethasone on the glucagon-dependent activation of the phosphoenolpyruvate carboxykinase gene in cultured rat hepatocytes.
Rat hepatocytes were cultured for 24 h in the presence or absence of 100 nM dexamethasone (DX). After a medium change, phosphoenolpyruvate carboxykinase (PCK) was induced by addition of glucagon at different concentrations, from physiological 0.1 nM to hyperphysiological 10 nM, again in the presence or absence of 100 nM dexamethasone. 1. With dexamethasone addition during the culture and induction phase (DX+/+), 10 nM glucagon increased PCK mRNA abundance (Northern blot analysis) and activity (in vitro translation) synchronously to the same extent with maxima after 2 h and PCK enzyme activity after a time lag with a maximum after 6 h. The total detectable PCK mRNA amount was apparently also translationally active. 10 microM N6,2'-O-dibutyryladenosine 3',5'-(cyclic)phosphate (Bt2cAMP) as the second messenger had essentially the same effect as 10 nM glucagon. 2. In the absence of dexamethasone during the preculture and the induction phase (DX-/-), 10 nM glucagon and 10 microM Bt2cAMP could enhance PCK mRNA only about half-maximally. Glucagon or dexamethasone added alone in physiological concentrations of 0.1 nM and 100 nM, respectively, were unable to increase PCK mRNA. However, treatment of the cells with dexamethasone also enabled 0.1 nM glucagon to enhance PCK mRNA to a maximum after 2 h, independent of the presence of dexamethasone during the induction period (DX+/+ and DX+/- cells). Thus, dexamethasone was a permissive agent in that it shifted the sensitivity of the cells towards glucagon into the physiological concentration range. 3. In the presence of dexamethasone during the culture and induction phase (DX+/+) 0.1 nM glucagon maximally enhanced the transcription of the PCK gene (nuclear run on) fourfold after 30 min; in the absence of dexamethasone during both phases (DX-/-) glucagon was without any effect. The overall transcriptional rate was not significantly different in cells with and without dexamethasone during the culture and induction phase (DX+/+ vs. DX-/-). Thus, dexamethasone acted permissively mainly on the transcription of the PCK gene. 4. With culture in the presence of dexamethasone over decreasing periods of time, 1 nM glucagon could induce submaximal PCK mRNA amounts already after 1-3 h steroid culture. This restitution by dexamethasone of the PCK mRNA inducibility by glucagon was inhibited by cycloheximide. This suggested that ongoing protein synthesis was required for the permissive action of dexamethasone on the expression of the PCK gene. The results allow the following conclusions.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Follow-up at 15 years of preterm infants from a controlled trial of moderately early dexamethasone for the prevention of chronic lung disease.
OBJECTIVE: Postnatal dexamethasone treatment of ventilator-dependent preterm infants results in rapid improvement in lung function and reduction in chronic lung disease. However, limited data are available on long-term outcomes after such therapy. We studied growth, neurodevelopmental, and pulmonary outcomes at adolescence in children who had participated in a double-blind, placebo-controlled trial of dexamethasone beginning at 2 weeks of age for the prevention of chronic lung disease. METHODS: Thirty-six infants (birth weight < or =1250 g and gestational age < or =30 weeks) who were dependent on mechanical ventilation at 2 weeks of age received a 42-day course of dexamethasone, an 18-day course of dexamethasone, or saline placebo. Twenty-two children survived to 15 years (69% of the 42-day dexamethasone group, 67% of the 18-day dexamethasone group and 45% of the control group), and all were evaluated. Intact survival was defined as survival with normal neurologic examination, IQ >70, and receiving education in the regular classroom. RESULTS: There were no differences among groups for growth or incidence of neurologic abnormalities. The mean IQ for the 42-day dexamethasone group was 85 +/- 10 compared with 60 +/- 20 for the 18-day dexamethasone group and 73 +/- 23 for the control group. All children in the 42-day dexamethasone group were receiving education in the regular classroom compared with only 50% of the 18-day dexamethasone group and 40% of the control group. As a result, intact survival was significantly greater for the 42-day dexamethasone group (69%) than for either the 18-day dexamethasone group (25%) or the control group (18%). Pulmonary function was significantly better for the 42-day dexamethasone group compared with the 18-day dexamethasone group (eg, forced expiratory volume in 1 second: 90 +/- 16 vs 71 +/- 15% predicted, respectively). CONCLUSION: A 42-day course of dexamethasone therapy beginning at 2 weeks of age in preterm infants who are at high risk for severe chronic lung disease was associated with improved long-term neurodevelopmental outcome. Although additional research is needed to establish the optimal steroid preparation, dosage, and duration of therapy, these data support the view that moderately early (beginning at 1-2 weeks) corticosteroid treatment is advantageous for a select group of ventilator-dependent preterm infants.
Adolescent↗
The effects of dexamethasone treatment on immunoreactive and bioactive insulin-like growth factors (IGFs) and IGF-binding proteins in normal male volunteers.
Glucocorticoids inhibit somatic growth in man and laboratory animals, and have long been regarded as suppressors of both stimulated GH secretion and insulin-like growth factor (IGF) activity. Recent evidence suggests, however, that glucocorticoids can be potent GH secretagogues in their own right with concomitant increases in circulating IGF-I levels. IGFs circulate tightly bound to a group of high-affinity binding proteins (IGFBPs) which modulate their actions. In order to investigate the effects of glucocorticoids on serum levels of IGFs and IGFBPs, normal male volunteers were sampled over 24-h periods before and directly after treatment with dexamethasone (2 mg twice daily) for 96 h. Following dexamethasone administration, all volunteers showed a marked increase in mean +/- S.E.M. IGF-I levels over the 24-h sampling period (292.2 +/- 31.8 before dexamethasone, 425.9 +/- 37 micrograms/l after dexamethasone, P < 0.005); there was no change in mean IGF-II levels. Integrated mean insulin levels were raised by dexamethasone treatment (50 +/- 4.6 before dexamethasone, 117 +/- 13.4 mU/l after dexamethasone, P = 0.002) and IGFBP-1 was significantly suppressed (42.9 +/- 8.2 before dexamethasone, 28.0 +/- 7.9 micrograms/l after dexamethasone, P < 0.001). IGFBP-2 levels were similarly suppressed after dexamethasone (319.5 +/- 24.5 before dexamethasone, 214.8 +/- 8.5 micrograms/l after dexamethasone, P = 0.002), and there was a significant increase in IGFBP-3 levels from 3.24 +/- 0.25 to 3.67 +/- 0.32 mg/l (P = 0.0153). Mean IGF bioactivity over the sampling period after dexamethasone was reduced by approximately 60% (0.93 +/- 0.39 before dexamethasone, 0.39 +/- 0.05 U/ml after dexamethasone, P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Efficacy of oral and intravenous dexamethasone in horses with recurrent airway obstruction.
REASONS FOR PERFORMING STUDY: Although the efficacy of dexamethasone for the treatment of recurrent airway obstruction (RAO) has been documented, the speed of onset of effect and duration of action are unknown, as is the efficacy of orally administered dexamethasone with or without fasting. OBJECTIVES: To document the time of onset of effect and duration of action of a dexamethasone solution i.v. or orally with and without fasting. METHODS: Protocol 1 used 8 RAO-affected horses with airway obstruction in a crossover design experiment that compared the effect of i.v. saline and dexamethasone (0.1 mg/kg bwt) on pulmonary function over 4 h. Protocol 2 used 6 similar horses to compare, in a crossover design, the effects of dexamethasone i.v. (0.1 mg/kg bwt), dexamethasone per os (0.164 mg/kg bwt) with and without prior fasting, and dexamethasone per os (0.082 mg/kg) with fasting. RESULTS: Dexamethasone i.v. caused significant improvement in lung function within 2 h with a peak effect at 4-6 h. Dexamethasone per os was effective within 6 h with peak effect at 24 h at a dose of 0.164 mg/kg bwt prior to feeding. The duration of effect was, for all dexamethasone treatments, statistically significant for 30 h when compared to saline and tended to have a longer duration of effect when used orally. Dexamethasone per os at a dose of 0.164 mg/kg bwt to fed horses had mean effects comparable to dexamethasone at a dose of 0.082 mg/kg bwt per os given to fasted horses, indicating that feeding decreases bioavailability. CONCLUSIONS: Dexamethasone administered i.v. has a rapid onset of action in RAO-affected horses. Oral administration of a bioequivalent dose of the same solution to fasted horses is as effective as i.v. administration and tends to have longer duration of action. Fasting horses before oral administration of dexamethasone improves the efficacy of treatment. POTENTIAL RELEVANCE: Oral administration to fasted horses of a dexamethasone solution intended for i.v. use provides an effective treatment for RAO-affected animals.
Administration, Oral↗
An intravitreal device providing sustained release of cyclosporine and dexamethasone.
PURPOSE: A device that releases cyclosporine and dexamethasone into the eye for extended periods of time might be beneficial in diseases such as proliferative vitreoretinopathy and uveitis. In this study we examine the pharmacokinetics and toxicity of cyclosporine and dexamethasone combined in an intravitreal sustained-release device and the toxicity of a similar device containing only dexamethasone in rabbits. METHODS: Rabbits were divided into three groups for (1) evaluation of the drug tissue levels and device release kinetics following implantation of a device containing 100 micrograms of cyclosporine labeled with 2 microCi of 3H-cyclosporine and 2 mg of dexamethasone; (2) evaluation of the toxicity of this intravitreal device; and (3) evaluation of the toxicity of a similar device containing 2 mg of dexamethasone only. Cyclosporine was measured using a scintillation counter and dexamethasone was measured by high pressure liquid chromatography (HPLC). Toxicity was evaluated by electroretinography, clinical examination, and light microscopy. RESULTS: Vitreous concentrations of cyclosporine (+/- standard deviation) averaged 0.06 (+/- 0.02) microgram/ml over 10 weeks. The average dexamethasone concentration over the 10 week period was 2.9 (+/- 0.9) micrograms/ml. Devices containing cyclosporine and dexamethasone released each drug at rates similar to devices containing cyclosporine or dexamethasone alone. Devices containing both cyclosporine and dexamethasone caused reversible depressions in the b-wave amplitude of photopic and scotopic electroretinograms (ERG's). There was no evidence of toxicity associated with the devices containing dexamethasone only. There was no drug-related toxicity evident on clinical or histopathologic examination of eyes with devices containing the combination of cyclosporine and dexamethasone or dexamethasone alone. CONCLUSIONS: We conclude that the device maintains potentially therapeutic levels of both cyclosporine and dexamethasone in the vitreous. Reversible electroretinographic abnormalities are attributable to cyclosporine. A sustained-release device containing cyclosporine and dexamethasone may be useful for reducing inflammation in diseases such as proliferative vitreoretinopathy and uveitis.
Animals↗
Effectiveness of oral or nebulized dexamethasone for children with mild croup.
OBJECTIVE: To assess the efficacy of oral dexamethasone or nebulized dexamethasone sodium phosphate in children with mild croup. METHODS: Double-blind, placebo-controlled study of 264 children between 6 months and 6 years of age with symptoms of croup for fewer than 48 hours. Patients were excluded if they received racemic epinephrine or corticosteroid treatment. Other exclusion criteria included corticosteroid treatment during the 14 days prior to enrollment or complicating medical condition. Subjects randomly received oral dexamethasone (0.6 mg/kg), nebulized dexamethasone sodium phosphate (160 microg), or placebo. Telephone follow-up was obtained on days 1, 2, 3, 4, and 7. MAIN OUTCOME MEASURES: The primary outcome measure was treatment failure, defined as receiving corticosteroid or racemic epinephrine treatment during the 7 days after enrollment in the study. Secondary outcome measures included seeking additional care and the parental assessments of the patients' condition obtained during follow-up (worse, same, better, or gone). RESULTS: Eighty-five patients received oral dexamethasone, 91 received nebulized dexamethasone, and 88 received placebo. There were 3 treatment failures in the oral dexamethasone-treated group, 12 in the nebulized dexamethasone-treated group, and 10 in the placebo-treated group (P =.05). Ten children in the oral dexamethasone-treated group sought additional care compared with 27 and 29 in the nebulized dexamethasone-treated and placebo-treated groups, respectively (P =.002). Parents of children in the oral dexamethasone-treated group reported greater improvement on day 1 (P<.001) compared with the nebulized dexamethasone-treated and placebo-treated groups. CONCLUSIONS: Children with mild croup who receive oral dexamethasone treatment are less likely to seek subsequent medical care and demonstrate more rapid symptom resolution compared with children who receive nebulized dexamethasone or placebo treatment.
Administration, Inhalation↗
A comparison of the bioavailability and potency of dexamethasone phosphate and sulphate in man.
The metabolic fate and ACTH-suppressant activity of two injectable dexamethasone esters, 21-phosphate and 21-sulphate, were studied in healthy men. After i.v. injection of 20mg free steroid alcohol, dexamethasone phosphate was efficiently hydrolyzed to free dexamethasone, reaching its peak plasma concentration within 5 min. About 9% of the administered dose appeared in the urine as free dexamethasone. By contrast, virtually no free dexamethasone was found in plasma and urine after injection of dexamethasone sulphate. Pharmacokinetic analysis showed that dexamethasone sulphate had a shorter plasma half-life and a higher metabolic clearance rate than free dexamethasone. A larger fraction (60%) of dexamethasone sulphate was rapidly excreted unmetabolized in urine. The plasma cortisol level was significantly suppressed for more than 24h after dexamethasone phosphate, while the plasma cortisol profile after dexamethasone sulphate merely showed physiological circadian variations. When the steroid esters were injected after pretreatment with metyrapone, a definite suppression of plasma ACTH was noted after dexamethasone phosphate, but again, dexamethasone sulphate was ineffective. These results cast serious doubt on the clinical value of dexamethasone sulphate as an injectable glucocorticoid, and critical reevaluation of this preparation is needed.
Adrenocorticotropic Hormone↗
The low dose dexamethasone suppression test: effect of time of administration and dose.
The dexamethasone suppression test (DST) is used to determine the sensitivity of the hypothalamic-pituitary-adrenal axis (HPA-axis) to negative feedback. Dexamethasone is usually administered at 23:00 h or at midnight but this is often not convenient. The aim of this study was to determine whether the administration of dexamethasone at 21:00 h as compared to 23:00 h would alter the degree to which 08:00 h plasma cortisol was suppressed the following morning. Three healthy males (mean+/-SE: 32+/-7 yr) and 3 healthy females (mean+/-SE: 35+/-7 yr) took part in the study. Each subject was orally administered 1 of 3 doses of dexamethasone (0.25 mg, 0.5 mg, or 1.0 mg) on 3 separate occasions in random order at least a week apart. Each dose of dexamethasone was taken at either 21:00 h or 23:00 h so that each subject underwent 6 tests. The differences in cortisol suppression between times and doses of dexamethasone were assessed using Analysis of Variance. Plasma cortisol was suppressed less in response to 0.25 mg dexamethasone at both 21:00 h and 23:00 h as compared with doses of dexamethasone of 0.5 mg or 1.0 mg (p=0.004). Suppression of plasma cortisol in response to each dose of dexamethasone was similar regardless of the timing of dexamethasone administration (p=0.5). We conclude that in healthy subjects 0.25 mg dexamethasone suppresses plasma cortisol less than either 0.5 mg or 1.0 mg and that 0.5 mg dexamethasone suppresses plasma cortisol to a similar extent as 1.0 mg dexamethasone. Moreover, changing the administration time of dexamethasone from 23:00 h to 21:00 h does not effect the degree to which cortisol is suppressed in healthy subjects.
Adult↗
Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone.
BACKGROUND: Aprepitant is a neurokinin(1) receptor antagonist that, in combination with a corticosteroid and a 5-hydroxytryptamine(3) receptor antagonist, has been shown to be very effective in the prevention of chemotherapy-induced nausea and vomiting. At doses used for the management of chemotherapy-induced nausea and vomiting, aprepitant is a moderate inhibitor of cytochrome P4503A4 and may be used in conjunction with corticosteroids such as dexamethasone and methylprednisolone, which are substrates of cytochrome P4503A4. The effects of aprepitant on the these 2 corticosteroids were evaluated. METHODS: Study 1 was an open-label, randomized, incomplete-block, 3-period crossover study with 20 subjects. Treatment A consisted of a standard oral dexamethasone regimen for chemotherapy-induced nausea and vomiting (20 mg dexamethasone on day 1, 8 mg dexamethasone on days 2 to 5). Treatment B was used to examine the effects of oral aprepitant (125 mg aprepitant on day 1, 80 mg aprepitant on days 2 to 5) on the standard dexamethasone regimen. Treatment C was used to examine the effects of aprepitant on a modified dexamethasone regimen (12 mg dexamethasone on day 1, 4 mg dexamethasone on days 2 to 5). All subjects also received 32 mg ondansetron intravenously on day 1 only. Study 2 was a double-blind, randomized, placebo-controlled, 2-period crossover study with 10 subjects. Subjects in one group received a regimen consisting of 125 mg methylprednisolone intravenously on day 1 and 40 mg methylprednisolone orally on days 2 to 3. Subjects in the other group received oral aprepitant (125 mg aprepitant on day 1, 80 mg aprepitant on days 2 to 3) in addition to the methylprednisolone regimen. RESULTS: In study 1, the area under the concentration-time curve from 0 to 24 hours (AUC(0-24)) of oral dexamethasone on days 1 and 5 after the standard dexamethasone plus ondansetron regimen (treatment A) was increased 2.2-fold (P <.010) with coadministration of aprepitant (treatment B). Coadministration of aprepitant with the modified dexamethasone plus ondansetron regimen (treatment C) resulted in an AUC0-24 for dexamethasone similar to that observed after the standard dexamethasone plus ondansetron regimen (treatment A). In study 2, aprepitant increased the AUC0-24 of intravenous methylprednisolone 1.3-fold on day 1 (P <.010) and increased the AUC0-24 of oral methylprednisolone 2.5-fold on day 3 (P <.010). CONCLUSIONS: Coadministration of aprepitant with dexamethasone or methylprednisolone resulted in increased plasma concentrations of the corticosteroids. These findings suggest that the dose of these corticosteroids should be adjusted when given with aprepitant.
Adult↗
Vitamin A status and postnatal dexamethasone treatment in bronchopulmonary dysplasia.
OBJECTIVE: Vitamin A (retinol) plays an important role in epithelial regeneration during recovery from lung injury in bronchopulmonary dysplasia (BPD). Dexamethasone is used in the postnatal treatment of very low birth weight (VLBW) neonates with BPD. To test the hypothesis that the vitamin A status is critical for the beneficial pulmonary response to dexamethasone, we performed a prospective cohort study in which we characterized the changes in plasma concentrations of vitamin A and retinol-binding protein (RBP) in response to dexamethasone, and correlated these changes with the pulmonary outcome. METHODS: VLBW neonates (birth weight <1350 g, gestational age <31 weeks, postnatal age >10 days), who had presumptive diagnosis of severe BPD and need for high ventilatory support (fraction of inspired oxygen >/=.6, mean airway pressure >/=7 cm H(2)O), were treated with a seven-day course of dexamethasone (.5 mg/kg/d x 2 days,.25 mg/kg/d x 2 days,.1 mg/kg/d x 3 days). Plasma concentrations of vitamin A and RBP were determined sequentially at baseline, and during and after dexamethasone treatment. Pulmonary response to dexamethasone was graded daily using a composite ventilation score. The changes in plasma vitamin A and RBP concentrations were compared between infants with a positive (beneficial) pulmonary response to dexamethasone and those with a negative response. RESULTS: Among 23 infants studied, 13 showed a positive pulmonary response to dexamethasone, as indicated by successful weaning from supplemental oxygen and mechanical ventilation, whereas 10 showed a negative response. A significant, yet short-term, increase in plasma concentrations of both vitamin A and RBP was observed in most infants treated with dexamethasone. The plasma vitamin A and RBP responses to dexamethasone tended to be higher in infants with a positive pulmonary response than in those with a negative response. Accounting for gender, a vitamin A response with each 10.0 microg/dL increment in plasma vitamin A concentration was associated with a 60% increase in the odds favoring a positive pulmonary response to dexamethasone. CONCLUSION: Postnatal dexamethasone treatment in VLBW neonates with BPD induces a significant, yet short-term, increase in plasma concentrations of both vitamin A and RBP. This increase probably results from endogenous mobilization of vitamin A from the liver. Our data suggest that the beneficial pulmonary response to dexamethasone in infants with BPD is influenced, at least in part, by the vitamin A status, and that gender plays a role in this response.vitamin A, dexamethasone, bronchopulmonary dysplasia.
Bronchopulmonary Dysplasia↗
A multicenter, randomized open study of early corticosteroid treatment (OSECT) in preterm infants with respiratory illness: comparison of early and late treatment and of dexamethasone and inhaled budesonide.
AIM: To compare early (<3 days) with late (>15 days) steroid therapy and dexamethasone with inhaled budesonide in very preterm infants at risk of developing chronic lung disease. METHODS: Five hundred seventy infants from 47 neonatal intensive care units were enrolled. Criteria for enrollment included gestational age <30 weeks, postnatal age <72 hours, and need for mechanical ventilation and inspired oxygen concentration >30%. Infants were randomly allocated to 1 of 4 treatment groups in a factorial design: early (<72 hours) dexamethasone, early budesonide, delayed selective (>15 days) dexamethasone, and delayed selective budesonide. Dexamethasone was given in a tapering course beginning with 0.50 mg/kg/day in 2 divided doses for 3 days reducing by half until 12 days of therapy had elapsed. Budesonide was administered by metered dose inhaler and a spacing chamber in a dose of 400 microg/kg twice daily for 12 days. Delayed selective treatment was started if infants needed mechanical ventilation and >30% oxygen for >15 days. The factorial design allowed 2 major comparisons: early versus late treatment and systemic dexamethasone versus inhaled budesonide. The primary outcome was death or oxygen dependency at 36 weeks and analysis was on an intention-to-treat basis. Secondary outcome measures included death or major cerebral abnormality, duration of oxygen treatment, and complications of prematurity. Adverse effects were also monitored daily. RESULTS: There were no significant differences among the groups for the primary outcome. Early steroid treatment was associated with a lower primary outcome rate (odds ratio [OR]: 0.85; 95% confidence interval [CI]: 0.61,1.18) but even after adjustment for confounding variables the difference remained nonsignificant. Dexamethasone-treated infants also had a lower primary outcome rate (OR: 0.86; 95% CI: 0.62,1.20) but again this difference remained not significant after adjustment. For death before discharge, dexamethasone and early treatment had worse outcomes than budesonide and delayed selective treatment (OR: 1.42; 95% CI: 0.93,2.16; OR: 1.51; 95% CI: 0.99,2.30 after adjustment, respectively) with the results not quite reaching significance. Duration of supplementary oxygen was shorter in the early dexamethasone group (median: 31 days vs 40-44 days). Early dexamethasone was also associated with increased weight loss during the first 12 days of treatment (52 g vs 3 g) compared with early budesonide, but over 30 days there was no difference. In the early dexamethasone group, there was a reduced incidence of persistent ductus arteriosus (34% vs 52%-59%) and an increased risk of hyperglycemia (55% vs 29%-34%) compared with the other 3 groups. Dexamethasone was associated with an increased risk of hypertension and gastrointestinal problems compared with budesonide but only the former attained significance. CONCLUSIONS: Infants given early treatment and dexamethasone therapy had improved survival without chronic lung disease at 36 weeks compared with those given delayed selective treatment and inhaled budesonide, respectively, but results for survival to discharge were in the opposite direction; however, none of these findings attained statistical significance. Early dexamethasone treatment reduced the risk of persistent ductus arteriosus. Inhaled budesonide may be safer than dexamethasone, but there is no clear evidence that it is more or less effective.
Administration, Inhalation↗
A randomized trial of moderately early low-dose dexamethasone therapy in very low birth weight infants: dynamic pulmonary mechanics, oxygenation, and ventilation.
OBJECTIVE: Dexamethasone is used in very low birth weight (VLBW) ventilator-dependent infants to prevent or decrease the severity of chronic lung disease. We reported a significant increase in respiratory compliance during a 7-day weaning course of moderately early dexamethasone therapy (0.5 mg/kg/d) in VLBW infants, along with a shorter duration of mechanical ventilation and O2 supplementation. Although 0.5 mg/kg/d has been the most commonly used dose in preterm infants, the use of a lower dose of dexamethasone may reduce potential adverse effects of steroid therapy. Quantification of dynamic pulmonary mechanics in VLBW infants who receive low-dose dexamethasone has not been reported. The objective of this study was to compare the effect of 2 dose regimens of dexamethasone on dynamic pulmonary mechanics, mean airway pressure (MAP), and fractional inspired oxygen concentration (Fio2) in intubated VLBW infants who were at risk for chronic lung disease. METHODS: We studied 47 VLBW (birth weight: 550-1290 g; gestational age: 24-30 weeks) ventilator-dependent infants at 7 to 14 days of age. Twenty-three infants were randomized to receive dexamethasone at 0.5 mg/kg/d intravenously for 3 days (high dose), 0.25 mg/kg/d for 3 days, and 0.1 mg/kg/d during the 7th day; 24 infants received low-dose dexamethasone as 0.2 mg/kg/d for 3 days and 0.1 mg/kg/d for 4 days. Respiratory compliance (Crs) and resistance were measured before and on days 2, 5, and 7 of dexamethasone therapy. We recorded airway pressure, flow, and tidal volume, and mechanical breaths were analyzed. RESULTS: Crs significantly increased during dexamethasone therapy in both groups of infants when compared with baseline (74% increase in the high-dose group and 66% increase in the low-dose group). Dexamethasone increased tidal volume and significantly reduced Fio2 and MAP in both groups of infants. A transient increase in blood pressure was noted in both groups. CONCLUSIONS: Our findings indicate that 1) comparable significant increases in Crs are present in the low-dose dexamethasone as well as the high-dose dexamethasone groups on days 2, 5, and 7 of steroid therapy; and 2) MAP and Fio2 are significantly decreased during dexamethasone therapy in both groups of infants. We conclude that low-dose and high-dose dexamethasone, as used in this study, have comparable beneficial effects on dynamic pulmonary mechanics and subsequently on oxygen requirement and applied ventilatory support in VLBW infants.
Anti-Inflammatory Agents↗