Plasma Levels Of Dexamethasone Research Articles

PMON98 High-dose dexamethasone suppression test in ACTH-dependent Cushing's syndrome: Lessons learned on the lack of cortisol suppression

Abstract Background The overnight 8-mg high-dose dexamethasone suppression test (HDDST) has been used to discern Cushing's disease from ectopic ACTH production. However, because of its reported low diagnostic accuracy, its use is limited to the assessment of ACTH-dependent Cushing's disease when combined with a corticotropin releasing hormone (CRH) or a desmopressin stimulation test. We evaluated a patient with Cushing's disease in whom the HDDST failed to identify the pituitary source. We point to limitations in test interpretation and highlight the need of future studies to enhance understanding of the clinical utility of this non-invasive test. Clinical Case A 42-year-old male presented with lower extremity cellulitis and hypertensive emergency. He reported increased abdominal girth, easy bruising, severe back pain and proximal muscle weakness and noted headache and blurred vision. Exam was pertinent for obesity (body mass index 31.5 kg/m2), moon facies, dorso-cervical hump and prominent abdominal striae. Lumbar and thoracic compression fractures were noted on imaging. The elevated 24-hour urinary free cortisol level (198 ug/dL; reference: 10-100 ug/24hr) and lack of suppression on the overnight 1-mg dexamethasone suppression test (morning cortisol 23.7 ug/dL) confirmed Cushing's syndrome; a high ACTH level of 92 pg/dL defined it as ACTH-dependent. The 8-mg HDDST resulted in only a 9.7% reduction of his baseline morning cortisol. The patient was not on any medications that enhanced dexamethasone clearance. Serum dexamethasone levels were measured to aid in test interpretation and, although a level was provided, reference values for the single overnight 8-mg dose of dexamethasone were lacking. A CRH stimulation test was performed and resulted in a 60% increase in ACTH levels from baseline, supporting the diagnosis of Cushing's disease. Additionally, a pituitary MRI revealed a suprasellar 2.5×1.5×1.3 cm mass. Due to ambiguity posed by the HDDST result, despite tumor size, neurosurgery requested inferior petrosal sinus sampling (IPSS). Prior to this procedure, the patient underwent an overnight 16-mg HDDST. While limited information remains on the diagnostic performance of this test, we observed that the baseline morning cortisol decreased by 53.9%. IPSS confirmed the diagnosis of Cushing's disease and pathology identified a corticotroph adenoma. Conclusion The diagnosis of Cushing's disease is complex and recommendations continue to evolve. Th role of the HDDST in combination with another dynamic test remains clinically relevant. It is important that when considering a HDDST, clinicians review medication history to exclude agents that may interfere with dexamethasone metabolism. Our case highlights the need of studies that determine an appropriate reference range for dexamethasone plasma levels after a single 8-mg overnight dose and that evaluate the diagnostic performance of the HDDST in this context. It also brings attention to the need of further elucidating the diagnostic utility of a higher dexamethasone dose in the evaluation of ACTH-dependent Cushing's syndrome. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

The pharmacokinetics and pharmacodynamics of dexamethasone following epidural SP-102 or intravenous dexamethasone sodium phosphate injection in subjects with lumbosacral radicular pain.

To evaluate the pharmacokinetics, pharmacodynamics (PD), safety, and tolerability of epidural SP-102 (10 mg dexamethasone sodium phosphate injectable gel) compared to an intravenous injection of 10 mg dexamethasone sodium phosphate, USP (IV USP). Subjects with lumbosacral radiculopathy received a single dose of epidural SP-102, followed by a single dose of IV USP 4 weeks later. Dexamethasone plasma levels, cortisol levels, white blood cells (WBC), and blood glucose levels were assessed. Twelve subjects entered and completed the study. The mean total dexamethasone exposure (AUClast and AUCinf) following SP-102 by epidural injection was equivalent to the total exposure following IV USP. A lower mean plasma Cmax (~50% lower) was observed following epidural administration compared to IV injection. PD parameters were similar between treatments. Adverse events (AEs) were mild, with no serious AEs or study discontinuations due to AEs. In this small study, epidural SP-102 injection was well tolerated, was not associated with greater systemic dexamethasone exposure than IV USP, and both treatments had similar PD effects on cortisol suppression, blood glucose, and WBC levels.

The In Vivo Recovery/Survivaland Pharmacokinetic Properties of Dexamethasone Sodium Phosphate Encapsulated in Autologous Erythrocytes

IntroductionCrohn's disease and Ataxia Telangiectasia have been managed by extended release of dexamethasone from autologous red blood cells (RBC) with encapsulated dexamethasone sodium phosphate DSP. The EryDexSystem (EDS) is an automated system that loads RBC ex vivo using hypotonic opening of RBC followed by hypertonic resealing of the RBC and washing to prepare the DSP-RBC for infusion. In vivo, DSP is dephosphorylated within the RBC to dexamethasone which passively diffuses into the plasma. The objective of this two-phase study was to elucidate pharmacokinetics (PK) and in vivo 24-hour recovery of RBCs as well as RBC survival (T50) properties of RBC encapsulated DSP.Materials and MethodsThe study was conduct in two separate Phases, A and B. Phase A, the 24-hour RBC recovery and T50 survival phase, was designed as a randomized, concurrently controlled, single-blind, single-center study to determine the in vivo kinetics of EDS-processed autologous RBC. Healthy volunteer consenting subjects were randomized to receive autologous RBCs prepared using EDS and loaded with either 15-20mg DSP (Group 1A) or sham hypotonic saline (Group 2A). EDS prepared RBC were radiolabeled with 51-Cr following standard methods, and the in vivo labeled RBC followed over 49 days post infusion.The Phase B PK study was designed as an open-label, single-center Phase I study that evaluated two dose levels of DSP encapsulated in RBCs using the EDS. Healthy volunteer consenting subjects were randomized to receive autologous RBCs loaded with either 2.5-5 mg DSP (Group 1B) or 15-20 mg (Group 2B). Post-infusion plasma levels of dexamethasone were followed (over 42 days).Both studies conformed to the Declaration of Helsinki.ResultsPhase A: Ten subjects (3male; 7 female) were randomized to Groups 1A or 2A. The mean 24-hour RBC recovery ± SD [95% CL] was 77.9 ± 3.3% [73.8-81.9%] and 72.7 ± 10.5% [57.8-85.7%] for Groups 1A and 2A, respectively. The mean ± SD RBC life span in Group 1A was 84.3 ± 8.3 days with a mean T50 of 42.1 ± 4.1 [95% CL: 37.0, 47.3] days, whereas these values were 88.9 ± 6.2 days and 44.4 ± 3.1 [95% CL: 40.6, 48.3] days, respectively, in Group 2A. Sixteen (16) treatment-emergent adverse events (TEAEs) were recorded in Group 1A and 23 in Group 2A. All TEAEs were judged to be unlikely related to the treatment.Phase B: Eighteen subjects (12 male; 6 female) were randomized to Groups 2A and 2B. The actual DSP loading doses (mean ± SEM) were 4.2±0.27 mg and 16.9±0.90 mg. Release of dexamethasone from RBCs in vivo peaked at 1 hour after the end of IV infusion independent of the dose. A detailed summary of the PK parameters for dexamethasone for each treatment group is shown in Table 1. A sustained release of dexamethasone could be detected until 14 and 35 days after the single IV infusion ofEryDex in Group 1B and 2B, respectively. Six (6) TEAEs were reported in each group and were judged to be unlikely related to the study drug or procedure.ConclusionThe results for the mean RBC in vivo recovery for DSP-loaded EDS-processed cells meet the FDA criteria for 24-hour RBC recovery of ≥ 75%, without adverse impact on the survival of EDS-processed RBCs. Most of the dexamethasone was rapidly released from the RBCs in vivo with a maximum peak occurring 1 hour after the end of the intravenous infusion, independent of the dose administered, but sustained release of dexamethasone could be detected until 14 and 35 days post infusion for the low and high doses, respectively. DSP-loaded autologous RBCs prepared using the EDS delivered a sustained dose of dexamethasone in vivo. Additional efficacy studies in targeted patient populations are indicated. [Display omitted] DisclosuresSzczepiorkowski:EryDel S.P.A.: Research Funding. Ferrari:EryDel S.P.A.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Benatti:EryDel S.P.A.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Mambrini:EryDel S.P.A.: Employment, Equity Ownership. Hartman:EryDel S.P.A.: Consultancy. Dumont:EryDel S.P.A.: Research Funding.

Evaluation of dexamethasone as a chemoprotectant for CCNU‐induced bone marrow suppression in dogs*

In mice and people, administering corticosteroids before chemotherapy can reduce the severity of myelosuppression without reducing antitumour effects. This study investigated whether pretreatment with dexamethasone would reduce the incidence of grade 4 neutropenia in dogs receiving CCNU. Twenty-five dogs received dexamethasone [0.1 mg kg(-1) per os (PO) every 12 h] for 5 days and on the sixth day received CCNU (90 mg m(-2) PO). Historical dogs (n = 67) received CCNU alone (90 mg m(-2) PO). Forty-five percent of historical dogs had grade 4 neutropenia, while 64% of dogs pretreated with dexamethasone had grade 4 neutropenia (P = 0.16). Dexamethasone plasma levels were quantified by enzyme-linked immunosorbent assay in three healthy dogs. Peak plasma concentrations after a single oral 0.1-mg kg(-1) dose were <80 ng mL(-1), the minimum level associated with chemoprotective effects of dexamethasone in people. Pretreatment with dexamethasone did not reduce the incidence of grade 4 neutropenia in dogs receiving CCNU.

Pharmacokinetics of CIPRODEX ® otic in pediatric and adolescent patients

Describe the pharmacokinetics of ciprofloxacin and dexamethasone after administration of CIPRODEX Otic Suspension (CIP/DEX) into the middle ears of children. Open-label, single-dose, pharmacokinetic studies, administering four drops of CIP/DEX instilled into each middle ear through the tympanostomy tubes immediately following tube placement. Blood was collected for 6h and analyzed for ciprofloxacin and dexamethasone concentrations using a validated liquid chromatography and tandem mass spectrometry (LC/MS/MS) method. The study was conducted through a referral pediatric otolaryngology practice with actual surgical procedures performed in an ambulatory care center. Twenty-five randomly selected patients, 1-14 years of age (mean age, 5 years), receiving tympanostomy tubes. Peak ciprofloxacin plasma levels were observed at about 1h, with a mean C(max) of 1.33+/-0.96 ng/mL (range <0.5-3.45 ng/mL) and an estimated half-life of 3.0+/-1.2h. Peak dexamethasone plasma levels were observed within 2h with a mean C(max) of 0.90+/-1.04 ng/mL (range <0.05-5.10 ng/mL) and an estimated half-life of 3.9+/-2.9h. These results demonstrated low systemic exposure of ciprofloxacin and dexamethasone following topical otic administration in pediatric patients.

Glucocorticoid-mediated inhibition of chemotherapy in ovarian carcinomas

The glucocorticoid dexamethasone is frequently used as a co-treatment in cytotoxic cancer therapy, e.g. to prevent nausea, to protect normal tissue or for other reasons. While the potent pro-apoptotic properties and supportive effects of glucocorticoids to tumour therapy in lymphoid cells are well studied, the impact on the cytotoxic treatment of ovarian carcinoma is unknown. We tested apoptosis-induction, viability, tumour growth and protein expression using established cell lines, primary cell lines freshly isolated from patient material and a xenograft on nude mice. We found a general induction of resistance toward cytotoxic therapy by DEX-co-treatment in most of the examined ovarian cancer cells treated in vitro, ex vivo or in vivo. Resistance occurred independently of cell density and was found at peak plasma levels of dexamethasone and below. Mechanistically, the dexamethasone-induced expression of survival genes may be involved in the resistance. These data show that glucocorticoid-induced resistance is common in ovarian carcinomas implicating that the use of glucocorticoids may be harmful for cancer patients.

Dexamethasone metabolism in dexamethasone suppression test suppressors and nonsuppressors

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 β-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 β-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.

Effects of dexamethasone on airway hyper-responsiveness to the adenosine A1 receptor agonist cyclo-pentyl adenosine in an allergic rabbit model.

1. New Zealand White (NZW) rabbits were immunized within 24 h of birth with Alternaria tenuis in aluminium hydroxide (Al (OH)3) (i.p.) or sham immunized (saline plus Al (OH)3 i.p.) and subsequently injected with the allergen (i.p.) or sham-immunized for the next 3 months. At 3 months of age, baseline airway responsiveness was assessed using cyclo-pentyl adenosine (CPA). Bronchoalveolar lavage (BAL) was performed in all animals and samples of peripheral blood were collected from some animals for estimation of dexamethasone levels. In some animals, blood was collected at the end of the experiment and cellular function was assessed by measurement of ex vivo proliferation of mononuclear cells in response to phytohaemagglutinin (PHA). 2. Allergen immunization significantly increased baseline airway responsiveness to inhaled CPA (P<0.05) in comparison with sham-immunized animals, at 3 months after immunization. Dexamethasone (0.5 mg kg(-1) day(-1)) treatment for 1 month did not modify this established airway hyper-responsiveness to CPA. Dexamethasone treatment did not affect either total or differential cell numbers in BAL fluid during the 4 week period, although significant plasma levels of dexamethasone were achieved in dexamethasone treated animals. 3. Treatment of rabbits with dexamethasone (0.1 mg kg(-1) i.p.), 6 h prior to each allergen injection from the neonatal stage, significantly reduced baseline airway hyper-responsiveness to CPA measured at 3 months (P<0.05). There was no significant difference in either total or differential cell numbers in BAL fluid, or any difference in mitogen-induced proliferation of mononuclear cells between dexamethasone and vehicle treated rabbits. 4. These results suggest that introduction of glucocorticosteroids in early life can prevent baseline airway hyper-responsiveness to inhaled CPA in allergic rabbits. However, once established, such underlying airway hyper-responsiveness is difficult to resolve, even with prolonged treatment with glucocorticosteroids.

Disturbed glucocorticoid receptor autoregulation and corticotropin response to dexamethasone in depressives pretreated with metyrapone

We studied glucocorticoid receptor autoregulation and corticotropin response to dexamethasone in depressed patients and controls, attempting to control for the confounding effect of endogenous glucocorticoids. After depletion of endogenous cortisol, depressed patients showed an attenuated suppressibility of corticortropin by dexamethasone in the face of unchanged dexamethasone plasma levels. β-endorphin levels were strongly correlated with adrenocorticotropic hormone (ACTH) concentrations. Although metyrapone administration resulted in a marked rise of glucocorticoid receptor sites per cell in controls, this effect was not present in depressives. These data support the hypothesis of a decreased glucocorticoid receptor plasticity and a partial steroid resistance in depression.

Effect of Vasopressin and Naloxone Alone and in Combination on Cortisol Secretion after Dexamethasone Pretreatment

In order to further examine the possible role of endogenous opioid peptides and vasopressin in the phenomenon of dexamethasone nonsuppression, we studied the effect of naloxone, vasopressin, and vasopressin-naloxone combination on cortisol secretion following dexamethasone pretreatment. Nine healthy males were given 1 mg dexamethasone at 23.00 h. The following day starting at 12.30 h and at 90-min intervals they received intravenously naloxone (0.2 mg/kg), arginine vasopressin 3 units, or the two drugs combined. The order of drug administration was counterbalanced using a Latin square design. Blood samples were drawn at 15-min intervals, and plasma aliquots were assayed for cortisol and dexamethasone. Naloxone failed to induce an escape from dexamethasone suppression. Four of the 9 subjects responded with an escape from dexamethasone suppression in response to vasopressin alone. The observed variability in response to vasopressin was unrelated to dexamethasone plasma levels but was associated with a decrease in systolic blood pressure. Peak cortisol levels were lowest in response to naloxone and highest in response to vasopressin. There was no evidence of an increased cortisol response to the coadministration of naloxone with vasopressin compared to vasopressin alone. These results fail to implicate an opioidergic mechanism in the pathophysiology of dexamethasone nonsuppression.

Dexamethasone Suppression Test and Plasma Dexamethasone Levels in Bulimia

A 1-mg dexamethasone suppression test (DST) was carried out in 66 women with bulimia and in 26 age- and sex-matched controls. Blood samples were obtained at 4 PM on the day following dexamethasone ingestion, and levels of cortisol and of dexamethasone in the plasma were measured. Thirty-two percent of the patients vs only 7% of the controls had plasma cortisol levels of 140 nmol/L (5 micrograms/dL) or greater following the DST (a positive DST). The plasma levels of dexamethasone varied substantially, and there was a significant inverse relationship between the plasma level of cortisol and that of dexamethasone. Patients with positive DST results had lower levels of plasma dexamethasone than did those with negative DST results, and the mean plasma level of dexamethasone was lower in the bulimic group than in the control group. These results suggest that factors other than a disturbance of hypothalamic-pituitary-adrenal activity may contribute to positive DST results in bulimia.

Multisteroid analysis after DST in depressed patients — A controlled study

111 consecutively admitted in-patients with a depressive syndrome received a dexamethasone suppresion test (DST) after all known factors which might confound the test results had been carefully excluded. Plasma concentrations of cortisol, corticosterone and dexamethasone were compared with several diagnostic evaluations (RDC, DSM-III, ICD-9) in a controlled study. The positive predictive value of nonsuppressed corticosteroid levels was only moderate for each diagnostic category. Diagnostic specificities were 84.6% for major depression, endogenous subtype (RDC), 71.2% for melancholia (DSM-III) and 86.8% for endogenous depression (IDC-9) when using a post-DST cortisol value above 50 ng/ml (5 μg/dl) as the referent value to define DST nonsuppression. Combined determination of cortisol and corticosterone as an index of dexamethasone-induced suppression raised the sensitivity rate considerably at the cost of the predictive value for major diagnostic categories. Dexamethasone plasma levels were reciprocally correlated with cortisol levels and neglect of samples with low plasma dexamethasone contents improved the diagnostic performance for endogenous depression according to RDC and ICD-9, but not for DSM-III melancholia. Although it would be speculative to suppose that the observed low dexamethasone levels are involved in DST nonsuppression, the present findings emphasize that multisteroid analysis which includes dexamethasone is important in future studies designed to explore the clinical utility of the DST.

Association between low plasma levels of dexamethasone and elevated levels of cortisol in psychiatric patients given dexamethasone.

In psychiatric inpatients, positive results on 40 dexamethasone suppression tests (elevated cortisol levels) were strongly associated with low plasma levels of dexamethasone. Bioavailability or pharmacokinetic factors may contribute importantly to the outcome of the dexamethasone suppression test.

Dexamethasone suppression tests: usefulness of simultaneous measurement of plasma cortisol and dexamethasone.

The effect of oral dexamethasone on the plasma content of cortisol and dexamethasone was investigated in 175 patients suspected of having Cushing's syndrome. Plasma concentrations of cortisol and dexamethasone were measured by specific radioimmunoassays at 08.00 h following administration of either a low-low (0.5 mg), low (1.0 mg), high (4.0 mg) or high-high (8.0 or more mg) dose of dexamethasone at midnight. All seventeen patients with documented Cushing's syndrome exhibited resistance to the action of low-low and/or low dose dexamethasone on suppression of 08.00 h plasma cortisol content. Nine of twelve patients with pituitary dependent Cushing's syndrome had plasma cortisol values of less than 166 nmol/l following high-high dose testing. In 157 patients with suspected Cushing's syndrome, standard dexamethasone testing was considered unsatisfactory in at least 20%. After low-low or low dose tests 11% had supranormal cortisol values, but plasma cortisol content overlapped with values observed in patients with Cushing's syndrome only when plasma dexamethasone content was less than 5.6 nmol/l. Twelve per cent of patients suspected of having Cushing's syndrome had sufficient elevation of plasma dexamethasone values after low dose testing so that marked reduction of plasma cortisol might be expected even in patients with pituitary dependent Cushing's syndrome. Four patients receiving anticonvulsants had subnormal plasma levels of dexamethasone for the dose administered, but all exhibited normal suppression when plasma levels of dexamethasone and cortisol were correlated simultaneously. In summary, there is considerable variation in the plasma content of dexamethasone following oral doses. Simultaneous measurement of both plasma levels of dexamethasone and cortisol has proved most useful in identifying patients with unsatisfactory dexamethasone suppression tests.