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Background: Monocarboxylate transporter 8 (MCT8) is the first thyroid hormone transporter that has been linked to a human disease. Besides genetic alterations other factors might impair MCT8 activity., Aim: This study aimed at investigating whether some common drugs having a structural similarity with TH and/or whose treatment is associated with thyroid function test abnormalities, or which behave as antagonists of TH action can inhibit MCT8-mediated T 3 transport., Methods: [ 125 I]T 3 uptake and efflux were measured in COS-7 cells transiently transfected with hMCT8 before and after exposure to increasing concentrations of hydrocortisone, dexamethasone, prednisone, prednisolone, amiodarone, desethylamiodarone, dronedarone, buspirone, carbamazepine, valproic acid, and L-carnitine. The mode of inhibition was also determined., Results: Dexamethasone significantly inhibited T 3 uptake at 10 μM; hydrocortisone reduced T 3 uptake only at high concentrations, i.e. at 500 and 1000 μM; prednisone and prednisolone were devoid of inhibitory potential. Amiodarone caused a reduction of T 3 uptake by MCT8 only at the highest concentrations used (44% at 50 μM and 68% at 100 μM), and this effect was weaker than that produced by desethylamiodarone and dronedarone; buspirone resulted a potent inhibitor, reducing T 3 uptake at 0.1-10 μM. L-Carnitine inhibited T 3 uptake only at 500 mM and 1 M. Kinetic experiments revealed a noncompetitive mode of inhibition for all compounds. All drugs inhibiting T 3 uptake did not affect T 3 release., Conclusion: This study shows a novel effect of some common drugs, which is inhibition of T 3 transport mediated by MCT8. Specifically, dexamethasone, buspirone, desethylamiodarone, and dronedarone behave as potent inhibitors of MCT8., (© 2021. Italian Society of Endocrinology (SIE).)

The pharmacokinetic (PK) parameters of dexamethasone (DEX) in 11 species were collected from the literature and clearances (CL) assessed by basic allometric methods, and concentration-time course profiles were fitted using two PK models incorporating physiological or allometric scaling. Plots of log CL vs. log body weights (BW) correlated reasonably with R 2  = 0.91, with a maximum ratio of actual to fitted CL of 6 (for pig). A minimal physiologically-based pharmacokinetic (mPBPK) model containing blood and two lumped tissue compartments and integrated utilization of physiological parameters was compared to an allometric two-compartment model (a2CM). The plasma PK profiles of DEX from 11 species were analyzed jointly, with the mPBPK model having conserved partition coefficients (K p ), physiologic blood and tissue volumes, and species-specific CL values. The DEX PK profiles were reasonably captured by the mPBPK model for 9 of 11 species in the joint analysis with three fitted parameters (besides CL) including an overall tissue-to-plasma partition coefficient of 1.07. The a2CM with distribution CL and central and peripheral volumes scaled allometrically fitted the plasma concentration profiles similarly but required a total of six parameters (besides CL). Overall, the literature reported that DEX CL values exhibit moderate variability (mean = 0.64 L/h/kg; coefficient of variation = 105%), but distribution parameters were largely conserved across most species., (© 2021 John Wiley & Sons Ltd.)

Background and Aim: Dexamethasone Suppression Test (DST), recommended for Cushing's Syndrome (CS) diagnosis, explores the pituitary feedback to glucocorticoids. Its diagnostic accuracy could be affected by dexamethasone bioavailability, and therefore, we have developed and validated a dexamethasone threshold after 1-mg DST., Materials and Methods: We studied 200 subjects: 125 patients were considered retrospectively and 75 were enrolled prospectively as the validation cohort. Serum dexamethasone, Late Night Salivary Cortisol (LNSC), and Urinary Free Cortisol (UFC) were measured with LC-MS/MS. Normal LNSC and UFC levels were used to exclude CS. The lower 2.5th percentile of dexamethasone distribution in non-CS patients with cortisol ≤ 50 nmol/L after 1-mg DST was used as threshold., Results: 16 patients were CS and 184 non-CS (108 adrenal incidentaloma and 76 excluded CS); 4.5 nmol/L resulted the calculated threshold. Cortisol after 1-mg DST confirmed high sensitivity (100% at 50 nmol/L cut-off) and moderate-low specificity (63%, increased to 91% at 138 nmol/L) to diagnose CS in the whole cohort of patients. We could reduce the number of false-positive results (from 10 to 6 and from 7 to 4 in AI and excluded CS) considering adequate dexamethasone levels. Dexamethasone levels were not affected by hypercortisolism, age, gender, smoke, weight, and creatinine. 6% of non-CS patients did not achieve adequate dexamethasone levels (40% of tests with serum cortisol > 138 nmol/L after 1-mg DST)., Conclusions: We developed and validated the routine dexamethasone measurement during 1-mg DST: it is independent from patient's clinical presentation, and it should be used to increase the specificity of serum cortisol levels.

Thymus-derived T regulatory (tTregs) cells play a crucial role in the maintenance of tolerance and immune homeostasis. Mechanisms and factors regulating tTreg development and function are widely investigated, but to a large degree still remain unclear. Our previous findings demonstrated that, in physiological conditions, the development and suppressive function of tTregs demonstrated day/night rhythmicity, which correlated with the concentration of plasma corticosterone and the expression of glucocorticoid receptors. In this study we ask whether synthetic glucocorticoids commonly used to inhibit excessive activity of the immune system, can modulate the development and suppressive function of tTregs in vivo depending on the time of administration. Young C57BL/6 male and female mice were injected intraperitoneally with a single dose of dexamethasone at two time points of the day: 7.00-8.00 a.m. and 7.00-8.00 p.m. The experimental can be used to indicate on the potentially expected positive or adverse side effects and can constitute also a good model for the assessment of the effects of long-term therapy. The results of our studies demonstrated the increase of the percentage of tTregs at both time points in male mice, but only in the evening in females. The suppressive activity of tTregs increased independently on the day time of in female mice, but in the morning only in males. We concluded that in the condition of dexamethasone supplementation, the elevated suppressive potential of tTregs is balanced by the induction apoptosis in order to prevent excessive suppression., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

The cortisol response to glucocorticoid intervention has, in spite of several studies in horses, not been fully characterized with regard to the determinants of onset, intensity and duration of response. Therefore, dexamethasone and cortisol response data were collected in a study applying a constant rate infusion regimen of dexamethasone (0.17, 1.7 and 17 μg/kg) to six Standardbreds. Plasma was analysed for dexamethasone and cortisol concentrations using UHPLC-MS/MS. Dexamethasone displayed linear kinetics within the concentration range studied. A turnover model of oscillatory behaviour accurately mimicked cortisol data. The mean baseline concentration range was 34-57 μg/L, the fractional turnover rate 0.47-1.5 1/h, the amplitude parameter 6.8-24 μg/L, the maximum inhibitory capacity 0.77-0.97, the drug potency 6-65 ng/L and the sigmoidicity factor 0.7-30. This analysis provided a better understanding of the time course of the cortisol response in horses. This includes baseline variability within and between horses and determinants of the equilibrium concentration-response relationship. The analysis also challenged a protocol for a dexamethasone suppression test design and indicated future improvement to increase the predictability of the test., (© 2015 John Wiley & Sons Ltd.)

This study was conducted to explore the effects of specific psychosocial paradigm on predator animal posttraumatic stress model and to test the hypothesis that psychosocially stressed rats would exibit abnormal levels of cortisol and a larger suppression of cortisol levels after the application of dexamethasone. Animals were divided in two groups: experimental and control groups. The experimental group was exposed to two types of stressors: acute immobilization stress, and combined predator stress and daily social stress with application of dexamethasone. Blood sampling was performed at three different times. We found statistically significant results after analyzing the differences between cortisol levels in different times of blood sampling in the group of animals exposed to stress with dexamethasone application. Statistical significance was found when we compared the experimental group with the control group in terms of elevated cortisol levels during blood sampling after stress paradigm exposition. Many significant disruptions in the functioning of the hypothalamic-pituitary-adrenal axis were observed, such as decrease in basal cortisol levels and enhanced dexamethasone-induced inhibition of cortisol levels. These findings are important because their impact can translate to human individuals with posttraumatic stress disorder, which is the most important role of every animal model in research., (Copyright © 2016. Published by Elsevier Taiwan.)

Background: In suspected hypercortisolism, the 1 mg dexamethasone suppression test is the usual initial test. In fertile women, false-positive test results are often due to the use of oral contraceptives. By elevating cortisol-binding globulin these contraceptives increase the total serum cortisol concentration. The aim of this study was to assess the duration and degree of influence of oral contraceptives on the low-dose dexamethasone suppression test., Methods: Thirteen healthy female volunteers without symptoms or signs of overt hypercortisolism, aged 18-55 years, who were using oral contraceptives, underwent a 1 mg dexamethasone suppression test. Tests were repeated one and six weeks after withdrawal of the contraceptive. In addition, 24-hour urinary cortisol excretion and late-night salivary cortisol were measured., Results: Of the 13 volunteers (62%) eight had inadequate suppression of cortisol by 1 mg dexamethasone while using oral contraceptives. One week after the contraceptive was withdrawn, the number of false-positive results significantly decreased to 1 (8%, p < 0.02). Six weeks after discontinuation, all tests were normal. None of the 24-hour urinary cortisol samples and just one late-night salivary cortisol level was elevated., Conclusion: The results of the 1 mg dexamethasone suppression test performed one week after cessation of oral contraceptives are accurate in almost all subjects. In case of inadequate suppression, a second test may be performed after six weeks. In this manner the 1 mg dexamethasone suppression test can reliably be done at the end of a seven-day break from contraceptive use in nearly all cases.

Immunologic graft rejection is one of the main causes of short and long-term graft failure in corneal transplantation. Steroids are the most commonly used immunosuppressive agents for postoperative management and prevention of corneal graft rejection. However, steroids delivered in eye drops are rapidly cleared from the surface of the eye, so the required frequency of dosing for corneal graft rejection management can be as high as once every 2h. Additionally, these eye drops are often prescribed for daily use for 1 year or longer, which can result in poor patient compliance and steroid-related side effects. Here, we report a biodegradable nanoparticle system composed of Generally Regarded as Safe (GRAS) materials that can provide sustained release of corticosteroids to prevent corneal graft rejection following subconjunctival injection provided initially during transplant surgery. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles containing dexamethasone sodium phosphate (DSP) exhibited a size of 200 nm, 8 wt.% drug loading, and sustained drug release over 15 days in vitro under sink conditions. DSP-loaded nanoparticles provided sustained ocular drug levels for at least 7 days after subconjunctival administration in rats, and prevented corneal allograft rejection over the entire 9-week study when administered weekly. In contrast, control treatment groups that received weekly injections of either placebo nanoparticles, saline, or DSP in solution demonstrated corneal graft rejection accompanied by severe corneal edema, neovascularization and opacity that occurred in ≤ 4 weeks. Local controlled release of corticosteroids may reduce the rate of corneal graft rejection, perhaps especially in the days immediately following surgery when risk of rejection is highest and when typical steroid eye drop administration requirements are particularly onerous., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: The amygdala (AMG) plays a facilitatory role in the hypothalamic-pituitary-adrenal (HPA) axis. The effect of the AMG on the negative feedback exerted by glucocorticoids (GC) is not clear. We investigated the effect of repeated electrical stimulation of the AMG on the feedback action of GC upon the adrenocortical (AC) response to stressful stimuli., Methods: Rats received electrical stimulation into the central amygdalar nucleus once daily for 4 days. At days 5 and 12 after the onset of stimulation, rats were treated with dexamethasone (Dex) or vehicle and were exposed to either photic or acoustic stress stimuli, and serum corticosterone (CS) was measured. In another group of rats, we measured the binding of Dex to the hippocampal cytosol at 5 and 12 days after the AMG stimulation., Results: At 5 and 12 days after the onset of stimulation or a sham control, stress increased the serum CS level. In the sham group, Dex completely inhibited the CS response, but at 5 days after stimulation, it was significantly less effective in doing this. At day 12, Dex was as effective as in the control group. AMG stimulation delayed the return of CS response to basal levels and caused a significant decrease in the binding capacity of Dex to hippocampal cytosol., Conclusion: Electrical stimulation of the AMG caused a transient impairment of the feedback action of GC upon the stress response. This effect may be due to the decrease in hippocampal corticosteroid receptors. This suggests that the impaired GC feedback caused by AMG stimulation may be involved in the facilitatory effect of the AMG on the function of the AC axis., (© 2015 S. Karger AG, Basel.)

Reasons for Performing the Study: Dexamethasone is an anti-inflammatory drug commonly used in equine medicine. Insulin sensitivity decreases with prolonged dexamethasone administration, but little information is available about the duration of this side effect after long-term treatment ends., Objectives: To determine how long it takes for blood glucose, insulin and markers of insulin sensitivity to return to normal ranges after extended dexamethasone treatment has ceased., Study Design: Experimental study., Methods: Eight healthy, mature, mixed-breed horses received 0.04 mg/kg bwt/day oral dexamethasone for 21 days. Blood samples were taken weekly during dexamethasone treatment (Days -21, -14 and -7). Following the final dose of dexamethasone on Day 0, blood samples were taken on Days 1-6, 8, 10, 12, 15 and 22. Day -21 represents baseline or normal blood predexamethasone., Results: On Day 1, plasma glucose and insulin concentrations and the modified insulin-to-glucose ratio (a proxy for pancreatic β cell responsiveness) were higher and the reciprocal of the square root of insulin (a proxy for the estimate of insulin sensitivity) was lower, in comparison with Day -21 values. Blood glucose concentrations dropped and returned to Day -21 values by Day 2. Insulin concentrations remained elevated until Day 3. Values for the modified insulin-to-glucose ratio decreased and returned to Day -21 concentrations by Day 4. Values for the reciprocal of the square root of insulin did not return to Day -21 values until Day 15., Conclusions: These results indicate that, in contrast to blood glucose concentrations, which return to normal quickly (within 2 days after treatment ends), the pancreatic insulin-secreting response has a delayed recovery., (© 2014 EVJ Ltd.)

Many inflammatory and autoimmune diseases are treated using synthetic glucocorticoids. However, excessive glucocorticoid can often cause unpredictable effects including muscle atrophy. Endogenous glucocorticoid levels robustly fluctuate in a circadian manner and peak just before the onset of the active phase in both humans and nocturnal rodents. The present study determines whether muscle atrophy induced by exogenous glucocorticoid can be avoided by optimizing dosing times. We administered single daily doses of the glucocorticoid analog dexamethasone (Dex) to mice for 10 days at the times of day corresponding to peak (early night) or trough (early morning) endogenous glucocorticoid levels. Administration at the acrophase of endogenous glucocorticoids significantly attenuated Dex-induced wasting of the gastrocnemius (Ga) and tibialis anterior (TA) muscles that comprise mostly fast-twitch muscle fibers. Real-time RT-PCR revealed that the Dex-induced mRNA expression of genes encoding the atrophy-related ubiquitin ligases Muscle Atrophy F-box (Fbxo32, also known as MAFbx/Atrogin-1) and Muscle RING finger 1 (Trim63, also known as MuRF1) in the Ga and TA muscles was significantly attenuated by Dex when administered during the early night. Dex negligibly affected the weight of the soleus (So) muscle that mostly comprises slow-twitch muscle fibers, but significantly and similarly decreased the weight of the spleen at both dosing times. These results suggest that glucocorticoid-induced muscle atrophy can be attenuated by optimizing the dosing schedule.

Objectives: We sought to evaluate whether there is variability in blood dexamethasone levels after a standard 1 mg/kg dose of dexamethasone administered before infant cardiopulmonary bypass. We hypothesized that postoperative dexamethasone drug levels are highly variable, and that the infant stress response is related inversely to the amount of dexamethasone measured in the blood., Methods: Thirty-two infants (age, ≤365 days) received 1 mg/kg of dexamethasone before cardiopulmonary bypass (CPB) initiation. Blood was analyzed for cortisol, adrenocorticotropin, and interleukin (IL)-6, IL-8, and IL-10 levels after anesthesia induction, after CPB, after intensive care unit (ICU) arrival, and 4, 8, 12, and 24 hours after surgery. Patients were grouped as high dexamethasone (≥15 μg/dL) or low dexamethasone (<15 μg/dL) based on their level at ICU arrival., Results: Dexamethasone levels varied significantly between the high (n = 22) and low (n = 10) dexamethasone groups throughout the entire postoperative course and were correlated highly with cortisol response. Patients with high dexamethasone levels had postoperative cortisol levels that were lower than their pre-CPB baseline cortisol levels. Cortisol levels remained low throughout the first 24 postoperative hours even after dexamethasone levels neared zero. There were no significant differences between groups in the duration of mechanical ventilation or ICU length of stay., Conclusions: Dexamethasone levels are highly variable at ICU arrival, despite standardized 1 mg/kg dosing before CPB initiation., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background/aim: It is significant for patients with traumatic brain injury (TBI) to receive prehospital emergency treatment as early as possible to reduce mortality. Therefore, a new prefilled multi-drug injector was developed to improve the treatment of TBI. Here, we studied the pharmacokinetics of dexamethasone (DXM) and nefopam using the injector to investigate the significance of drug interactions and the necessity of dose adjustment., Methods: Rats were administered DXM and nefopam intramuscularly alone or in combination using the injector. The concentrations of DXM and nefopam were measured by means of HPLC. The noncompartmental approach was used to calculate pharmacokinetic parameters., Results: All animals appeared to tolerate the injection very well. The maximum concentration 90% confidence interval (CI) of nefopam was in the bioequivalence range when nefopam was co-administered with DXM. However, the AUC 90% CI of nefopam was out of the range. A statistically significant alteration was also observed in the clearance of nefopam. The co-administration exhibited no significant influence on the pharmacokinetic parameters of DXM., Conclusions: These results indicate that the co-administration of DXM and nefopam using the prefilled multi-drug injector significantly alters some pharmacokinetic parameters of nefopam and has a minor effect on DXM pharmacokinetics., (© 2014 S. Karger AG, Basel.)

Synthetic glucocorticoids, like dexamethasone (dex), restrict growth of the fetus and program its adult physiology, in part by altering placental phenotype. The route and timing of dex administration determine the fetal and adult outcomes, but whether these factors affect placental phenotype remains unknown. This study compared placental morphology, amino acid transport, and gene expression in mice given dex orally or by subcutaneous injection over the periods of most rapid placental (Days [D] 11-16) or fetal (D14-19) growth (term is D21). Compared with untreated and saline-injected controls, both dex treatments reduced placental weight at D16 and 19 and fetal weight and total labyrinthine volume at D19 to a similar extent. Only oral dex treatment from D11 to D16 reduced labyrinthine fetal capillary volume on D16 and increased placental ¹⁴C-methylaminoisobutyric acid (MeAIB) clearance at D19, 3 days after treatment ended. Neither route of dex treatment altered placental expression of Slc38a, Hsd11b, or the glucocorticoid receptor, Nr3c1, at D16. In contrast, both routes of dex treatment from D14 to D19 increased placental Hsd11b2 expression and labyrinthine maternal vessel volume. Furthermore, injection per se altered placental expression of Nr3c1, Hsd11b1, and specific Slc38a isoforms in an age-related manner. Overall, MeAIB clearance was not related to Slc38a transporter expression but was correlated inversely with maternal corticosterone concentrations when dex was undetectable in maternal plasma at D19. The effects of dex on placental phenotype, therefore, depend on both the route and timing of administration and may relate to local glucocorticoid availability during and after the treatment period.

The pharmacokinetics of dexamethasone (DEX) were investigated after an intravenous (IV) or intramuscular (IM) bolus injection of 0.3mg/kg bodyweight DEX sodium phosphate in pigs. The plasma concentrations of DEX were determined using a validated high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method and the pharmacokinetics were determined by one-compartmental analysis. The mean area under the plasma concentration-time curve and the mean elimination half-life were 133.07 ± 39.59 ng.h/mL and 0.77 h, and 173.24 ± 53.59 ngh/mL and 1.06 h following IV and IM administration, respectively. The volume of distribution and clearance recorded after IV administration were 2.78 ± 0.88 L/kg and 2.39 ± 0.57 L/hkg, respectively. An IM bolus injection of DEX sodium phosphate in pigs resulted in a fast and complete absorption, with a mean maximal plasma concentration of 80.94 ± 21.29 ng/mL at 0.35 ± 0.21 h and a high absolute bioavailability of 131.06 ± 26.05%., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate the toxicokinetics and tolerability (local ocular and general toxicity) of the anti-inflammatory agent, dexamethasone phosphate (a prodrug of dexamethasone) delivered to the eye in rabbits by transscleral iontophoresis., Methods: Female rabbits (n=6/group) received dexamethasone phosphate (40 mg/mL ophthalmic solution, EGP-437) transsclerally to the right eye (OD) using the Eyegate(®) II ocular iontophoresis delivery system once biweekly for 24 consecutive weeks at current doses of 10, 14, and 20 mA-min and current levels up to, and including -4 mA for 3.5-5 min. The study included 2 control groups (n=6/group): (1) a noniontophoresis control [an ocular applicator-loaded citrate buffer (placebo) without current] and (2) an iontophoresis control (a citrate buffer plus cathode iontophoresis at 20 mA-min, -4 mA for 5 min). Recoverability was evaluated 4 weeks following the last dose in 2 animals per group. The left eye (OS) was untreated and served as an internal control for each animal. Ocular and general safety of dexamethasone phosphate and dexamethasone were assessed. Other evaluations included toxicokinetics, ophthalmic examinations, intraocular pressure (IOP) measurements, electroretinographs, clinical observations, body weight, hematology and serum chemistry, gross necropsy, organ weight, and microscopic histopathology., Results: The biweekly transscleral iontophoresis with either the citrate buffer or dexamethasone phosphate at cathodic doses up to, and including 20 mA-min and currents up to, and including -4 mA for 24 weeks was well-tolerated. Transient signs of conjunctival hyperemia and chemosis, mild corneal opacity, and fluorescein staining of the cornea were noted and attributed to expected ocular reactions to the temporary placement of the ocular applicator and application of iontophoresis. There were no dexamethasone phosphate-, dexamethasone-, or iontophoresis-related effects on IOP, electroretinography, or histopathology. Reductions in body weight gain, anemia, decreased leukocyte and lymphocyte counts, compromised liver function, enlarged liver, and reduced spleen weight were consistent with systemic corticosteroid-mediated pharmacology, repeated use of anesthesia, stress, and sedentariness, and unlikely to be related to iontophoresis application., Conclusions: The results of this investigation suggest that repeated transscleral iontophoresis with dexamethasone phosphate may be safe for use as a treatment for inflammatory ocular disorders that require prolonged and/or repeated corticosteroid therapy.

We examined the effects of development, exogenous, and endogenous glucocorticoids on Na(+),K(+)-ATPase activity and subunit protein expression in ovine cerebral cortices and renal cortices. Ewes at 60%, 80%, and 90% gestation, newborns, and adults received 4 dexamethasone or placebo injections. Cerebral cortex Na(+),K(+)-ATPase activity was higher (P < .05) in placebo-treated newborns than fetuses of placebo-treated ewes and adults, α(1)-expression was higher at 90% gestation than the other ages; α(2)-expression was higher in newborns than fetuses; α(3)-expression was higher in newborns than 60% gestation; β(1)-expression was higher in newborns than the other ages, and β(2)-expression higher at 60% than 80% and 90% gestation, and in adults. Renal cortex Na(+),K(+)-ATPase activity was higher in placebo-treated adults and newborns than fetuses. Cerebral cortex Na(+),K(+)-ATPase activity was higher in dexamethasone- than placebo-treated adults, and α(1)-expression higher in fetuses of dexamethasone- than placebo-treated ewes at 60% and 80% gestation. Renal cortex Na(+),K(+)-ATPase activity and α(1)-expression were higher in fetuses of dexamethasone- than placebo-treated ewes at each gestational age, and β(1)-expression was higher in fetuses of dexamethasone- than placebo-treated ewes at 90% gestation and in dexamethasone- than placebo-treated adults. Cerebral cortex Na(+),K(+)-ATPase activity, α(1)-expression, β(1)-expression, and renal cortex α(1)-expression correlated directly with increases in fetal cortisol. In conclusion, Na(+),K(+)-ATPase activity and subunit expression exhibit specific developmental patterns in brain and kidney; exogenous glucocorticoids regulate activity and subunit expression in brain and kidney at some ages; endogenous increases in fetal cortisol regulate cerebral Na(+),K(+)-ATPase, but exogenous glucocorticoids have a greater effect on renal than cerebral Na(+),K(+)-ATPase.

Objective: To determine the effects of 2 maternal injections with dexamethasone on the calculated oxygen and glucose deliveries to fetal cerebral and peripheral circulations during acute hypoxemia in sheep., Study Design: Beginning at 124 days, ewes received 2 intramuscular injections of either dexamethasone (2 x 12 mg, n = 10) or saline solution (2 x 2 mL, n = 12) 24 hours apart. Hypoxemia (1 hour) was induced 32 hours after the first injection (H1) and 3 days after the second (H2)., Results: In saline solution-treated fetuses, glucose delivery was unchanged or increased in femoral and carotid circulations, respectively, during H1 and H2. In dexamethasone-treated fetuses, the increase in glucose delivery to the head tended to be greater during H1 and was significantly enhanced in dexamethasone- vs saline solution-treated fetuses during H2., Conclusion: Two maternal injections with dexamethasone significantly enhanced glucose delivery to the head during acute hypoxemia in the ovine fetus.

Clinical similarities between Cushing's syndrome and obesity/metabolic syndrome have led to speculation of a role for glucocorticoids (GCs) in the etiopathogenesis of obesity. People with idiopathic obesity have normal circulating cortisol concentrations. However, there may be considerable interindividual variation in GC sensitivity. The objective of this study was to determine whether enhanced GC sensitivity in the absence of GC excess was a characteristic of obese people with cushingoid features. We studied 12 obese subjects with cushingoid features in the absence of Cushing's syndrome and six slim control participants. Data recorded included BMI, waist-to-hip ratio, blood pressure, glucose and insulin response to 75 g oral glucose challenge, and low-dose (0.25 mg) overnight dexamethasone (DEX) suppression test (ODST-0.25 mg). To study GC-sensitivity in vitro, we performed dose-response studies of DEX-induced suppression of interleukin-6 (IL-6) secretion in skin fibroblast cultures. Seven obese subjects were normosensitive and five subjects hypersensitive to GCs in vitro. ODST-0.25 mg resulted in a median suppression of cortisol from baseline of 32% in normosensitive and 60% in hypersensitive obese subjects (P < 0.004). No other clinical or biochemical measures were discriminatory between these two groups. These data from two independent measures of GC sensitivity suggest that enhanced GC sensitivity may characterize a substantial proportion of obese people with cushingoid appearance.

Objective: Glucocorticoids are widely used before preterm delivery and in preterm infants may bear serious adverse effects. Better knowledge about the circulating glucocorticoid milieu after glucocorticoid treatment could improve treatment modalities. Therefore, we investigated the influence of exogenous glucocorticoids and clinical factors on serum cortisol (F) levels and circulating glucocorticoid bioactivity (GBA) in preterm infants., Design: Eighty-nine infants (gestational age (GA) 23.6-33.1 weeks at birth) were enrolled in a prospective cohort study in two tertiary neonatal centres., Methods: Cord, day of birth (D0), fourth day (D4) and 36 weeks postmenstrual age serum F and GBA levels were measured., Results: The cord GBA was 5.8-fold and D0 GBA 2.3-fold higher in the infants exposed to antenatal steroids within 12 h before birth when compared with those unexposed or exposed >7 days before birth (95% CI 3.8-8.6; P<0.0001, and 1.8-3.0; P<0.0001 respectively). In the infants treated with early postnatal dexamethasone, D4 GBA was 1.7-fold (1.3-2.2; P<0.0005) higher when compared with levels in the infants without this treatment. Clinical factors indicating perinatal distress, such as Apgar scores <7 and low GA, were associated with higher cord, D0 and D4 serum F levels., Conclusions: Both ante- and postnatally administered glucocorticoids increase circulating GBA not attributable to endogenous F. Perinatal distress and preceding glucocorticoid treatment need to be taken into account when circulating glucocorticoid milieu is evaluated in preterm infants. The GBA assay may prove to be a useful instrument in the development of new glucocorticoid treatment strategies.

Administration of bacterial endotoxin (lipopolysachharide; LPS) elevates proinflammatory cytokines, such as interleukin-1beta (IL-1beta) and IL-6, and activates the hypothalamic-pituitary-adrenal (HPA) axis. Corticosterone (CORT), the glucocorticoid (GC) effector hormone of the HPA axis in rats, inhibits both proinflammatory cytokine production/release and activity of the HPA axis itself. Exposure to chronic or repeated stressors often induces resistance to the effects of GCs. The following experiments were conducted to test the hypothesis that an acute stressor, inescapable tailshock (IS), alters responsivity of the HPA axis and proinflammatory cytokine system to dexamethasone (DEX), a synthetic GC. First, we examined the ability of various doses of DEX to suppress proinflammatory cytokine and HPA activity in response to LPS challenge 24 h after either home cage (HCC) or IS treatment. Upon finding resistance to DEX in IS animals, we examined the duration of the altered response to DEX by testing animals 1, 4 and 21 days after IS. To test whether IS animals were selectively resistant to the suppressive effects of DEX on the response to LPS, the ability of DEX to suppress HPA activity in response to a non-inflammatory stressor, exposure to an elevated "pedestal", was assessed. Again, DEX resistance was observed in IS animals. Finally, we examined whether changes in the responsivity to DEX were dependent upon the controllability of the stressor. The induction of DEX resistance was independent of the degree of behavioral control that the animal had over the stressor. Thus, a single session of IS induces DEX resistance of both HPA axis and cytokine responses measured in vivo.

The results from a quantitative structure-property relationship (QSPR) model was integrated into a fifth-generation pharmacokinetic/pharmacodynamic (PK/PD) model of corticosteroid receptor/gene-mediated effects. The proposed model was developed using previously reported tyrosine aminotransferase (TAT) activity data following a 50 mg/kg intravenous dose of methylprednisolone in male adrenalectomized (ADX) rats. Induced TAT activity is a classical measure of corticosteroid genomic effects and the typical time course shows an initial lag-time, a slow rise to peak response, and a gradual return toward baseline values. The TAT activity profiles were subsequently predicted for two additional steroids (dexamethasone and hydrocortisone), which were confirmed experimentally. Two groups of male ADX Wistar rats (n = 18 each) were given either 0.1 mg/kg dexamethasone or 50 mg/kg hydrocortisone by penile vein injections. Plasma drug concentrations and liver TAT activity were measured at various time points. Baseline TAT activity was significantly lower in this study as compared to previous reports. Model simulations well captured the pharmacodynamic data once initial conditions were corrected for observed baseline values. Additional TAT profiles reported in the literature for prednisolone were also reasonably predicted using the final model. This study serves as a demonstration of how in vitro pharmacologic data and QSPR modeling results may be incorporated into existing mechanistic PK/PD models to anticipate the effects of other chemically related compounds., (Copyright 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92:881-889, 2003)

In this experimental study the influence of glycocorticosteroids on the course of infection and prognosis in 75 rats with diffuse peritonitis was examined. We focused on the relation between doses, moment of pharmacotherapy introduction and the course of disease. To achieve this we estimated the dexamethasone doses and moment of its introduction on C-reactive protein (CRP), TNF-alpha and its soluble type I--p55 and type II--p75 receptors' concentrations in examined animals' serum. A diffuse peritonitis was elicited in study animals by means of cecum ligation and perforation (CLP). Cytokine concentrations were estimated with ELISA test. In group 1 (test) no steroids were given. In group 2 20 mg/kg b.m., and in group 3 100 mg/kg b.m. dexamethasone was given 2 hrs before CLP. In group 4 dexamethasone was used in the dose of 20 mg/kg b.m., and in group 3--of 100 mg/kg b.m. 8 hrs after CLP. The results of this study show that glycocorticosteroids administered during the initial phase of experimental diffuse peritonitis display favorable action decreasing animal mortality rate regardless of the dose. However, glycocorticosteroids given in the developed septic syndrome decrease the pro-inflammatory cytokine serum concentration regardless of the dose, still not affecting the animal mortality rate.

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

Purpose: The aims of these experiments were to determine the effect of a therapeutic regimen of dexamethasone on cytochrome P4503A4 (CYP3A4) activity in healthy volunteers; and the concentration-effect relationship between dexamethasone and CYP3A4 activity in primary human hepatocyte cultures., Methods: The effect of dexamethasone (8 mg administered by mouth two times a day for 5 days) on CYP3A4 activity in 12 healthy volunteers was assessed with the erythromycin breath test and urinary ratio of dextromethorphan to 3-methoxymorphinan. Concentration-effect of dexamethasone on CYP3A4-dependent testosterone 6-beta-hydroxylation was determined in human hepatocytes treated with 2 to 250 micromol/L dexamethasone., Results: The percent of erythromycin metabolized per hour increased from 2.20% +/- 0.60% (mean +/- SD) at baseline to 2.67% +/- 0.55% on day 5 of dexamethasone (mean increase in hepatic CYP3A4 activity 25.7% +/- 24.6%; P = .004). The mean urinary ratio of dextromethorphan to 3-methoxymorphinan was 28 (4.8 to 109) and 7 (1 to 23) at baseline and on day 5 of dexamethasone (mean decrease = 49%; P = .06). Substantial intersubject variability was observed in the extent of CYP3A4 induction. The extent of CYP3A4 induction was inversely correlated with baseline erythromycin breath test (r2 = 0.58). In hepatocytes, dexamethasone 2 to 250 micromol/L resulted in an average 1.7-fold to 6.9-fold increase in CYP3A4 activity, respectively. The extent of CYP3A4 induction with dexamethasone in hepatocyte preparations was inversely correlated with baseline activity (r2 = 0.59)., Conclusions: These data demonstrate that dexamethasone at doses used clinically increased CYP3A4 activity with extensive intersubject variability and that the extent of CYP3A4 induction was, in part, predicted by the baseline activity of CYP3A4 in both healthy volunteers and human hepatocyte cultures.

Background: Variable dexamethasone kinetics is a possible confound in the dexamethasone suppression test. Modifications to include dexamethasone plasma levels and specific dexamethasone "windows" have been proposed. Our study aims to validate our proposed dexamethasone windows in an independent sample of 121 subjects., Methods: We performed dexamethasone suppression tests in 162 subjects with mixed psychiatric diagnoses. Dexamethasone levels and beta-phase half-life of dexamethasone were computed for suppressors and nonsuppressors., Results: Dexamethasone levels were lower in nonsuppressors than in suppressors. Dexamethasone levels correlated inversely with cortisol levels in the total sample, but were nonsignificant or weakly associated in those samples restricted to the windows. The beta-phase half-life of dexamethasone was shorter in nonsuppressors. The dexamethasone windows were validated at 3:00 PM and 10:00 PM. We propose 4.0 ng/mL as a revised upper limit of the 8:00 AM dexamethasone window., Conclusions: The plasma dexamethasone level is confirmed as a confound in the dexamethasone suppression test through more rapid dexamethasone clearance in nonsuppressors. Application of dexamethasone windows will reduce this source of test variance.

Objective: The clinical effects of high dosage pulse glucocorticosteroid (GS) infusion as a treatment for rheumatoid arthritis (RA) differ considerably between patients. The aim of the present study was to gain more insight into these differences in clinical response., Methods: Twenty-three RA patients (6 M/17 F) with treatment-resistant active erosive disease were treated with GS pulse therapy, consisting of 3 infusions of 200 mg dexamethasone at 3-day intervals. Plasma dexamethasone and plasma cortisol levels, as well as the mononuclear cell glucocorticosteroid receptor density, were determined on days 0, 2, 6, 12 and 40 after the start of therapy. Clinical evaluation consisted of the Thompson articular index, the erythrocyte sedimentation rate (ESR), and the serum concentration of C reactive protein (CRP)., Results: Plasma dexamethasone levels in RA patients determined during pulse therapy revealed the existence of two groups. One group reached significantly (p < 0.05) higher plasma levels than another group comparable for age and sex. The CRP, ESR and Thompson joint score prior to the start of pulse therapy were all higher (p < 0.05) for the high plasma dexamethasone group. The decrease in ESR, CRP and the Thompson joint score was also significantly greater (all p < 0.05) for the high plasma dexamethasone group. Plasma cortisol, as well as the GS receptor density at the start of treatment, did not differ between the two groups; both decreased after the first pulse in both groups and returned to pre-treatment values shortly after the last infusion., Conclusion: The treatment of refractory RA with dexamethasone pulse therapy is, on average, beneficial. The high plasma dexamethasone levels reached might depend on the greater severity of the disease in these patients prior to the start of the treatment, and result in greater changes in the disease parameters. Glucocorticosteroid receptor density measurements made during and directly after high dose pulse dexamethasone treatment proved to be unreliable because of the high plasma dexamethasone levels.

Objective: Leptin, the obese gene product, is thought to regulate body fat through its action on hypothalamic receptors that influence satiety. The hormonal regulation of leptin is important, since it might affect adiposity. Leptin regulation in man is poorly understood. We studied the relation between endogenous cortisol and leptin levels as well as the acute and chronic effects of a low dose of dexamethasone (DEX) on plasma leptin levels in healthy male volunteers. SUBJECTS AND EXPERIMENTAL PROTOCOL: The correlation between basal plasma levels of leptin and cortisol and the chronic effect of DEX treatment were studied in 12 subjects. Plasma leptin and cortisol levels were determined every other hour for 24 h, before and after 2 weeks of oral administration of 0.1 mg DEX twice daily. The acute effect was studied in 20 subjects, who received 1 mg DEX at 2300 h. Fasting blood samples were taken at 0800 h on the same day (i.e. before DEX) and on the day after., Results: Under basal conditions, we found a correlation between mean plasma levels of leptin and cortisol (r = 0.7, P<0.02). Mean plasma leptin levels had increased by 50% after 2 weeks of DEX treatment (P<0.05). The circadian rhythm of leptin was preserved, but the night peak occurred 2.5 h earlier (P<0.05). Fasting plasma leptin levels were 20% higher 9 h after 1 mg DEX orally than at the same time on the day before (P<0.002)., Conclusion: Physiological variations in cortisol are involved in the regulation of leptin.

Background: Previous studies have shown wide variation in plasma dexamethasone (DEX) concentrations following a standard 1-mg dexamethasone suppression test (DST), and significantly lower DEX concentrations in DST nonsuppressors compared with suppressors, suggesting that DEX pharmacokinetics/bioavailability is an important variable associated with DST nonsuppression., Methods: To determine the effect of plasma DEX levels on the DST in Chinese depressives, we measured plasma DEX and post-DEX cortisol levels at 4:00 PM in a group of 50 depressed outpatients, 28 anxiety outpatients, and 33 normal subjects during the course of 1-mg oral overnight DST., Results: We found a significant difference in the plasma DEX levels between DST nonsuppressors and suppressors in the depression group and overall subject population, and a significant negative correlation between the plasma DEX and cortisol levels in the depression, anxiety, and total groups. Within a DEX "window", the DST performance was enhanced, whereas the relationships between plasma DEX and post-DEX cortisol levels remained equally strong., Conclusions: Our findings support a relationship between plasma DEX and post-DEX cortisol levels, a relationship that might be superimposed on the hypothalamic-pituitary-adrenal axis. Comparing our "window" range with those of previous studies, we suggest that Chinese depressives may have lower limits of plasma DEX window, and that ethnicity may be an intervening variable in both DST response and pharmacokinetics of DEX.

Although leptin reverses obesity in rodents, its function and regulation in humans are unknown. Glucocorticoids have been reported to stimulate leptin production in both rodents and humans, but data assessing the effect of obesity on dynamic leptin secretory responses are unavailable. We, therefore, studied 52 lean and obese subjects [20 men and 32 women; aged 19-84 yr; body mass index (BMI) range, 16-47 kg/m2] randomized to treatment with dexamethasone (total dose, 10 mg/4 days) or placebo. Compared with placebo, dexamethasone increased (P = 0.0001) plasma leptin levels by 64-111% above baseline values within 2-4 days. The increases occurred in all ages, showed no sexual dimorphism, and were particularly robust in obese subjects. After dexamethasone treatment, significant interactions were observed between the change in plasma leptin and BMI (P = 0.0001), baseline plasma leptin (P = 0.0006) and plasma dexamethasone levels (P = 0.04), but not age (P = 0.28); an apparent interaction with plasma insulin no longer was significant after controlling for BMI. These results confirm dexamethasone-induced hyperleptinemia in humans and further demonstrate that the response is not defective in obesity.

Background: To compare the pharmacokinetics of orally administered dexamethasone with intramuscular administration in antenatal patients at risk of preterm delivery., Method: Ten antenatal patients at risk for preterm delivery were given two intramuscular and then one oral dose of dexamethasone. Plasma which was collected at set intervals following the first intramuscular dose and the oral dose was assayed for dexamenthasone. The results were analyzed using pharmacokinetic data-fitting software and pharMacokinetic parameters calculated., Results: After oral adminIstration of dexamethasone the mean maximum plasma concentration obtained was 65% that of the intramuscular dose and the bioavailability of the oral route was calculated as 72% of the intramuscular route. The terminal half-lives of dexamethasone were similar for both routes., Conclusions: These limited data would suggest that if dexamethasone is to be administered orally, which would be both preferable to patients and more economic, then a proportionately increased dose of oral dexamethasone would be required to provide similar maternal plasma pharmacokinetics to the intramuscular dose in current use. Further, larger studies are now required to confirm this.

Administration of exogenous glucocorticoids has been shown to enhance deposition of intramuscular fat in cattle. In this study, six pairs of genetically identical (cloned) steers were used to determine the effects of an implant containing 100 mg of dexamethasone on intramuscular fat deposition and on other carcass and meat quality traits. One steer in each pair served as a negative control (CON), whereas the other steer received a dexamethasone implant 30 to 60 d from slaughter (DEX). Treatment with dexamethasone did not (P > .05) enhance intramuscular fat deposition. However, DEX steers had greater (.33 cm; P < .05) thickness of external fat, larger (5.94 cm2; P < .05) longissimus muscle areas, and higher (1.9 percentage points; P < .05) dressing percentages than did CON steers. In addition, treatment with dexamethasone increased (P < .01) serum insulin concentrations. Dexamethasone had no effect (P > .05) on cooked beef palatability traits or on 24-h calpastatin activity. Although the DEX implant tested in this study was not effective for improving carcass quality grade, use of the implant increased external fat thickness and was effective for increasing carcass muscularity and dressing percentage.

Glucocorticoid (GCC) therapy usually inhibits inflammatory diseases, but certain regimens can trigger relapses. Clinical use of steroids is not uniform and in some instances may be dangerous. In the present study, GCCs modified the course of experimental allergic encephalomyelitis (EAE) in Lewis rats, a model of inflammatory CNS disease. Continuous treatment with dexamethasone (DEX) completely blocked EAE. RU 486, a GCC antagonist, counteracted the effects of endogenous GCCs and worsened EAE. Sudden withdrawal of DEX also caused severe clinical and histologic exacerbations at a time when paired saline-treated animals had completely recovered. In rats that had complete clinical recovery from EAE, and would not have relapsed without this acute steroid deficit, a short pulse of DEX was followed by severe exacerbations. In contrast, a slow steroid taper prevented exacerbations. Abrupt discontinuation of GCCs provokes inflammatory brain disease.

An enzyme immunoassay (EIA) was developed for detection of dexamethasone in equine blood. Dexamethasone 21-hemisuccinate-bovine serum albumin was used for immunization of rabbits, and prednisolone 21-hemisuccinate-horseradish peroxidase was used as enzyme conjugate. The assay had sensitivity in the low-picogram range (detection limit, 0.3 pg/well, 50% inhibition of binding at 4.5 +/- 0.7 pg/well). Apart from cortisol, which was recognized by the antiserum at concentration > 8.5 ng/ml, the dexamethasone antiserum failed to interfere with endogenous steroids, but cross-reacted with triamcinolone, flumethasone, and betamethasone. Thus, the antiserum was used to perform simultaneous screening for these synthetic glucocorticoids and to confirm their identity by combining reverse-phase high-performance liquid chromatography (RP-HPLC) and EIA. The immunoreactivity obtained by direct serum measurements was characterized by means of 2 independent RP-HPLC systems. Serum extracts were submitted to RP-HPLC systems I and II, and the fractions were tested by EIA. Immunoreactive peaks were identified by comparing their retention time with that of the standard glucocorticoids used for calibration. Coinjection of an internal standard (methylprednisolone) in RP-HPLC system II yielded reproducible relative retention times. The effectiveness of the test system was evaluated, using blood from a horse treated with commonly used veterinary preparations of dexamethasone. Administration of the free alcohol of dexamethasone and of dexamethasone 21-trioxaundecanoate, both given IV, was detected, and the identity of each was confirmed for up to 48 hours. Intramuscular administration of dexamethasone 21-isonicotinate was continued for at least 14 days after injection of a therapeutic dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma samples were collected from jugular, uterine and utero-ovarian veins during glucocorticoid induced parturition. Plasma oestrogens, corticosteroids and progesterone were determined by competitive protein binding methods. Corticosteroids and progesterone began to decline within 8 to 10 h following DXMS treatment. Corticoids were only temporarily suppressed, while progesterone fell to minimum levels and remained low through calving. At this stage of gestation (270 days) peripheral plasma progesterone was primarily of ovarian origin. Pre-treatment with HCG appeared to support progesterone production by the CL despite DXMS treatment in 2 of 6 cows. These 2 cows failed to calve within the expected 96 h after DXMS. Plasma oestrogens did not show significant increased until 24 h after DXMS treatment. Cows which responded to DXMS treatment (calved) had significantly higher oestrogen levels than those which did not respond. It was concluded that oestrogens probably play a permissive rather than an initiating role in parturition.

The effects of 3 mg orally administered dexamethasone on the intraocular pressure (IOP) were examined in four patients with primary open-angle glaucoma hospitalized for this study. Plasma-free glucocorticoid activity was measured by a radioreceptor assay. Diurnal rhythms of IOP and plasma-free glucocorticoid activity were detected prior to administration of dexamethasone. The plasma-free glucocorticoid activity rose two- to threefold in the 30-min period following steroid administration and then declined throughout the rest of the day. IOP was approximately 2 mmHg higher in the 0-4-hr period and approximately 5.5 mmHg higher in the 4-8-hr period following the pharmacologic doses of dexamethasone compared with similar periods on control days. The increase in the IOP was highly significant (P less than 0.006) in the latter time period. These findings suggest that the glucocorticoids may have a greater role in regulating IOP than generally has been appreciated.

Quality control serum samples and postdexamethasone plasma pools were used to compare 16 commercial cortisol radioimmunoassay kits with the competitive protein-binding assay for plasma glucocorticoids that we used to standardize the dexamethasone suppression test (DST). Thirteen radioimmunoassays gave higher criterion values for the DST than those established using the competitive protein-binding assay. The range of radioimmunoassay criterion values was 4.34 to 8.70 mu mg/dL. Possible explanations are given for these findings, and their importance to the clinical utility of the DST are emphasized. Each laboratory should validate its own criterion cortisol value for depression based on local data, including appropriate control groups.

Fifty patients with severe depression were separated into two groups by the responses of their plasma 11-hydroxycorticosteriod levels to a midnight dose of 2 mg. of dexamethasone. Clinical and questionary comparisons were made between the two groups of patients, who were similar as regards age, sex, and length of symptoms before admission to hospital. No differences were found between the groups of severely ill patients as regards the severity of their depression and anxiety assessed by questionary. Nevertheless, agitation was significantly greater in the patients whose corticosteroid levels were not suppressed by dexamethasone and adverse childhood experiences in those whose levels were suppressed.

Rats were conditioned to avoid shock on a free-operant avoidance schedule in which no exteroceptive stimulus signaled impending shock. Injections of adrenocorticotropic hormone (ACTH) or dexamethasone raised blood levels of glucocorticoids. These increases were accompanied by changes in avoidance performance: there was a higher frequency of long-duration interresponse times, a greater stability among them, and fewer short interresponse times, total responses, and shocks.

Use of the midnight dexamethasone suppression test showed that the plasma 11-hydroxycorticosteroid (11-O.H.C.S.) level did not undergo its normal reduction in 14 out of 27 patients with severe depression. Resistance to dexamethasone suppression correlated with the clinical rating of the severity of depression, while recovery from depression was associated with return of normal responsiveness to dexamethasone. The explanation of these findings is unknown.