Plasma Dexamethasone Levels Research Articles

Assessment of plasma dexamethasone levels after 1-mg dexamethasone suppression test in adults with obesity.

The 1-mg overnight dexamethasone suppression test is the most frequently used screening test for Cushing's syndrome. It has been proposed that people with obesity may have insufficient plasma dexamethasone levels for the test which may result in false positives. We sought to compare the plasma dexamethasone levels after 1-mg dexamethasone suppression test in healthy obese participants and in optimal-weight participants. A total of 30 optimal-weight participants (BMI ≤ 25 kg/m2 ) and 62 obese participants (BMI > 25 kg/m2 ) were enroled in the study. Obese participants were further divided into class 1 (25-29.9 kg/m2 ) and class 2 (>30 kg/m2 ). After a standard overnight 1-mg dexamethasone suppression test, blood samples were obtained for serum cortisol and plasma dexamethasone levels. Plasma dexamethasone levels were quantified using liquid chromatography - mass spectrometry (LC-MS/MS). No significant difference in plasma dexamethasone levels were found between obese and optimal-weight participants (3.31 ± 1.35 vs. 2.82 ± 1.11 nmol/L, mean ± SD; p = .09 respectively). There were also no correlations found between sex, BMI, body surface area and plasma dexamethasone levels. There was also no significant difference in the proportion of participants who achieved a plasma dexamethasone level >3.3 nmol/L in comparison between obesity class 1, obesity class 2, and optimal-weight groups. Our results suggest that obesity does not affect plasma dexamethasone levels. However, dexamethasone measurement may still be helpful in patients who are being investigated for Cushing's syndrome and suspected to have a false-positive DST.

FRI172 Assessment Of Plasma Dexamethasone Levels After 1-mg Dexamethasone Suppression Test In Adults With Obesity

Abstract Disclosure: P. Paopongpaiboon: None. P. Santisitthanon: None. N. Houngngam: None. T. Snabboon: None. P. Boonchaya-anant: None. Background: The 1-mg overnight dexamethasone suppression test is the most frequently used screening test for Cushing’s syndrome. It has been proposed that obese patients may have insufficient plasma dexamethasone levels for the test which may result in false positives. We sought to compare the plasma dexamethasone levels after 1-mg DST in healthy obese participants and in normal-weight participants. Methods: A total of 30 normal-weight participants (BMI ≤ 25 kg/m2) and 62 obese participants (BMI >25 kg/m2) were enrolled in the study. Obese patients were further divided into class 1 (25 - 29.9 kg/m2) and class 2 (>30 kg/m2). After a standard overnight 1-mg dexamethasone suppression test, blood samples were obtained for serum cortisol and plasma dexamethasone levels. Plasma dexamethasone levels were quantified using liquid chromatography - mass spectrometry (LC-MS/MS). Results: No significant difference in plasma dexamethasone levels were found between obese and normal-weight participants (3.31 ± 1.35 vs 2.82 ± 1.11 nmol/L, mean ± SD; P=0.09 respectively). There were also no correlations found between sex, BMI, body surface area (BSA) and plasma dexamethasone levels. There was also no significant difference in the proportion of participants who achieved a plasma dexamethasone level > 3.3 nmol/L in comparison between obesity class 1, obesity class 2, and normal-weight groups. Conclusion: We did not find a difference in plasma dexamethasone levels after 1-mg DST between obese and normal-weight participants. Our results suggest that BMI does not affect plasma dexamethasone levels and routine dexamethasone measurement may not help to identify false-positives using the 1-mg DST. Presentation: Friday, June 16, 2023

Vitamin D levels do not cause vitamin-drug interactions with dexamethasone or dasatinib in mice.

Vitamin D3 (VD3) induces intestinal CYP3A that metabolizes orally administered anti-leukemic chemotherapeutic substrates dexamethasone (DEX) and dasatinib potentially causing a vitamin-drug interaction. To determine the impact of VD3 status on systemic exposure and efficacy of these chemotherapeutic agents, we used VD3 sufficient and deficient mice and performed pharmacokinetic and anti-leukemic efficacy studies. Female C57BL/6J and hCYP3A4 transgenic VD3 deficient mice had significantly lower duodenal (but not hepatic) mouse Cyp3a11 and hCYP3A4 expression compared to VD3 sufficient mice, while duodenal expression of Mdr1a, Bcrp and Mrp4 were significantly higher in deficient mice. When the effect of VD3 status on DEX systemic exposure was compared following a discontinuous oral DEX regimen, similar to that used to treat pediatric acute lymphoblastic leukemia patients, male VD3 deficient mice had significantly higher mean plasma DEX levels (31.7 nM) compared to sufficient mice (12.43 nM) at days 3.5 but not at any later timepoints. Following a single oral gavage of DEX, there was a statistically, but not practically, significant decrease in DEX systemic exposure in VD3 deficient vs. sufficient mice. While VD3 status had no effect on oral dasatinib’s area under the plasma drug concentration-time curve, VD3 deficient male mice had significantly higher dasatinib plasma levels at t = 0.25 hr. Dexamethasone was unable to reverse the poorer survival of VD3 sufficient vs. deficient mice to BCR-ABL leukemia. In conclusion, although VD3 levels significantly altered intestinal mouse Cyp3a in female mice, DEX plasma exposure was only transiently different for orally administered DEX and dasatinib in male mice. Likewise, the small effect size of VD3 deficiency on single oral dose DEX clearance suggests that the clinical significance of VD3 levels on DEX systemic exposure are likely to be limited.

Impact of dose and duration of therapy on dexamethasone pharmacokinetics in childhood acute lymphoblastic leukaemia—a report from the UKALL 2011 trial

IntroductionThe use of dexamethasone in acute lymphoblastic leukaemia therapy contributes to short- and long-term toxicities. The UKALL 2011 randomised trial investigated whether a more intense dexamethasone dose (10 mg/m2/d x 14d, short vs 6 mg/m2/d x 28d, standard) would lead to a more rapid cytoreduction and reduced adverse effects associated with longer durations of steroids in induction. The impact of dose and duration on dexamethasone pharmacokinetics was investigated. MethodsBlood samples were obtained on one of the first three and last three days of induction dexamethasone dosing at time points up to 8 h after oral administration. Plasma dexamethasone levels were quantified in 1084 plasma samples obtained from 174 children and a population pharmacokinetic model developed. ResultsDrug exposure varied significantly between patients, with a >12-fold variation in AUC0–12h values and a marked overlap in dexamethasone exposures between dose levels. Intuitively, AUC0–12h was significantly higher with short dosing (10 mg/m2/d), but cumulative exposure was significantly higher with standard dosing over 28 days, after a higher cumulative dose. Concomitant rasburicase administration was associated with a 60% higher dexamethasone clearance. Day 8 bone marrow response was comparable between dosing arms, but those with <5% blast count exhibited a greater mean dexamethasone exposure than those with >5%. No statistical differences were observed between arms in terms of steroid-related toxicity or minimal residual disease at the end of induction. ConclusionThe potential significance of dexamethasone AUC0–12h on early response and higher cumulative exposure on the standard arm suggest that duration of therapy and exposure may be more important factors than absolute dose from a clinical pharmacology perspective.

Asparaginase combined with discontinuous dexamethasone improves antileukemic efficacy without increasing osteonecrosis in preclinical models.

IntroductionCombination therapy for acute lymphoblastic leukemia (ALL) is highly effective but results in significant toxicity including osteonecrosis. Asparaginase is known to potentiate both the antileukemic and osteonecrosis-inducing effects of dexamethasone. The schedule of dexamethasone alters osteonecrosis risk. However, the effects of the interaction with asparaginase are unknown when dexamethasone is given on a discontinuous schedule.MethodsUsing the murine model of osteonecrosis, we compared the frequency of osteonecrosis in mice receiving discontinuous dexamethasone (3.5 days/ week) with mice receiving asparaginase and discontinuous dexamethasone. We then tested the effect on antileukemic efficacy using six pediatric ALL xenografts.ResultsThe addition of asparaginase to discontinuous dexamethasone did not alter the rate of osteonecrosis compared to dexamethasone alone (7/35 in dexamethasone with asparaginase combination vs. 10/36 in dexamethasone alone, p = 0.62) despite increasing steady-state plasma dexamethasone levels (103.9 nM vs. 33.4 nM, p = 9.2x10-7). Combination therapy with asparaginase and dexamethasone demonstrated synergistic antileukemic effects across all six xenografts studied.ConclusionsWhen discontinuous dexamethasone was given, its anti-leukemic activity synergized with asparaginase but the osteonecrosis-worsening effects of asparaginase (above dexamethasone alone) were not observed. Thus, there is a favorable drug interaction (unchanged toxicity, synergistic efficacy) between discontinuous dexamethasone and asparaginase.

Zoledronic Acid Reduces Osteonecrosis and Anti-Leukemic Efficacy in Murine Models of Acute Lymphoblastic Leukemia Therapy

Background: Osteonecrosis and osteopenia frequently complicate acute lymphoblastic leukemia (ALL) therapy. Interventions which reduce these bony toxicities without impairing the anti-leukemic efficacy of therapy are lacking. Case reports suggest that bisphosphonates may reduce the pain associated with osteonecrosis; however, it is unclear if they are effective in preventing or reducing the progression of osteonecrosis or modifying bone density loss during therapy. Their impact on the anti-leukemic efficacy of therapy is also unknown.Methods: We tested the efficacy of the bisphosphonate zoledronic acid (ZA) in the murine model of osteonecrosis. Four-week-old Balb/c mice were treated with dexamethasone (2mg/L in drinking water) and PEGylated-asparaginase [1200IU/kg intraperitoneal (IP) weekly] for 6 weeks. To test whether ZA could prevent osteonecrosis, mice received ZA 100ug/kg IP weekly starting with therapy initiation (early zoledronic acid group, receiving 6 total doses). To test whether ZA could prevent the progression of osteonecrosis, ZA administration was delayed until the fourth week of therapy (late zoledronic acid group, receiving 2 total doses) after osteonecrosis processes have already begun. All mice were humanly euthanized at 10 weeks post-natal. At the end of the 6 week therapy, osteonecrosis was assessed histologically at the distal femur, while bone density and quality measurements were obtained from the proximal tibia using the Siemeons Inveon uCT system.To test the impact of zoledronic acid on the anti-leukemic efficacy of therapy, nine-week-old B6 mice were injected with 2000 Arf-/- Bcr/Abl+ syngeneic acute lymphoblastic leukemia cells. Mice received three weeks of therapy identical to the osteonecrosis studies (including zoledronic acid randomization), except dexamethasone was increased to 4mg/L in the drinking water. Mice were sacrificed when moribund and leukemia as cause of death was confirmed by peripheral white blood cell count and spleen weight.Results: Osteonecrosis was reduced in the early zoledronic acid group compared to the control group (12/69 limbs vs. 25/72 limbs, p=0.03). The incidence of osteonecrosis in the late zoledronic acid group (19/56 limbs) was identical to that in the control group (p=1). Both zoledronic acid interventions increased the cortical thickness of the tibia [median 0.12mm in therapy treated controls; 0.18mm in early zoledronic acid group (p=<0.001 vs. control); 0.15mm in late zoledronic acid group (p=<0.001 vs. control)]. Thinner cortical wall thickness was associated with an increased risk of osteonecrosis in univariate analysis (p=0.03) but not in multivariate analysis including treatment arm (p=0.32). Epiphyseal arteriopathy, the preceding vascular lesion in osteonecrosis, was less common in early zoledronic acid mice vs. controls (15/60 vs. 28/51, p=0.002). Late zoledronic acid administration resulted in a similar rate of arteriopathy (22/47) compared to controls (p=0.55). There was no difference in the incidence of asparaginase plasma concentrations <1u/mL (p=0.25) or in plasma dexamethasone levels (p=0.67) in mice receiving ZA vs. control treated mice.Because early zoledronic acid administration reduced the rate of osteonecrosis and improved bone density, we tested its effect on the anti-leukemic efficacy of therapy. Mice that received zoledronic acid and chemotherapy had a shorter survival than mice receiving chemotherapy alone (mean 36 vs. 41.6 days, log-rank p=0.046, Figure 1).Conclusion: Zoledronic acid administration early in acute lymphoblastic leukemia therapy reduces osteonecrosis and osteopenia. Zoledronic acid is ineffective in reducing osteonecrosis when given later in therapy. However, the use of zoledronic acid impairs the combined anti-leukemic efficacy of dexamethasone and asparaginase. Further studies are underway to understand this relationship. [Display omitted] DisclosuresRelling:Shire Pharmaceuticals: Research Funding.

Safety of Microdose Dexamethasone Acetate in the Eversense Long-Term Implantable Continuous Glucose Monitoring System

Background: Dexamethasone (DEX) is used in a variety of implantable medical devices to decrease inflammation and improve outcomes. The implantable Eversense® CGM System (Senseonics, Inc.) includes a silicone collar which slowly releases DEX acetate throughout the lifetime of the sensor. Studies were performed to characterize the potential user risk to dexamethasone acetate exposure. Methods: Clinical trial subjects underwent frequent blood sampling for analysis of plasma DEX levels. Chemical testing of 90-day sensor explants was used to measure residual DEX content. Finally, a post market clinical follow-up study (PMCF) is currently ongoing which monitors the rate of serious device-related, procedure-related, or drug (DEX) related adverse events through approximately 24 months. Results: In two trials (N=161, 86 with 2 sensors, 75 with 1 sensor), blood tests were performed to the 2 ng/mL level with no detectable plasma DEX. In a third trial (N=35), the limit of detection was reduced to 0.050 ng/mL. Blood samples from 8 patients inserted with one sensor had no measurable DEX plasma levels. Among 27 patients inserted with two sensors, the highest level of DEX detected was 0.114 ng/mL on day 2 post-insertion. All samples were below the detectable limit by day 8. Literature review states at plasma levels &amp;lt; 1 ng/mL no systemic effect occurs. Testing of sensor explants determined that 0.3 mg of DEX is eluted over 90 days. No adverse events related to exposure to DEX have been reported to date in the PMCF Conclusions: Dexamethasone acetate, which was selected to reduce the inflammatory response of the implantable sensor, was found to be safe. Plasma DEX levels after extended use are well below the concentration necessary for a pharmacological response, demonstrating safety of the Eversense Sensor with regard to clinical adverse effects attributable to chronic DEX exposure and that this risk should not grow over time. Disclosure E.L. Kelley: Employee; Self; Senseonics. H. Haridas: Employee; Self; Senseonics. C. Lorenz: Employee; Self; Senseonics.

In the overnight dexamethasone suppression test, 1.0 mg loading is superior to 0.5 mg loading for diagnosing subclinical adrenal Cushing's syndrome based on plasma dexamethasone levels determined using liquid chromatography-tandem mass spectrometry.

The low-dose dexamethasone suppression test (DST) is one of the commonly used initial tests for endogenous Cushing's syndrome (CS). However, there are two loading dose regimens (0.5-mg and 1-mg), which may cause some confusion in daily practice in Japan; furthermore, there are no reports regarding whether 0.5-mg DST is a better loading dose for detecting adrenal subclinical CS (SCS) based on the plasma dexamethasone (DEX) levels. Therefore, the aims of this study were (a) to develop a novel assay to measure DEX by using liquid chromatography tandem-mass spectrometry (LC-MS/MS) and (b) to compare between the 0.5-mg and 1-mg DST for SCS diagnosis based on the DEX levels. The study retrospectively analyzed 52 consecutive subjects hospitalized for diagnosis of adrenal incidentaloma but who did not exhibit an overt CS phenotype; eight (15.4%) patients were affected with adrenal SCS. Inter-individual variability of DEX levels after the DST was high, but intra-individual variability was low. DEX levels after 1-mg loading in each patient was around two times higher than those after 0.5-mg loading (ρ = 0.853 and p < 0.001). There were 45 (86.5%) and 17 (32.7%) subjects with DEX levels ≤2.2 ng/mL after the 0.5-mg and 1-mg DST, respectively (p < 0.001). Twenty-eight (93.3%) of 30 subjects and four (21.1%) of 19 subjects with detectable ACTH levels after the 0.5-mg and 1.0-mg DST, respectively, did not exhibit DEX levels >2.2 ng/mL. These results clearly indicate that the 1-mg DST is superior to 0.5-mg loading for the diagnosis of adrenal SCS.

Toxicity and Pharmacokinetics of Sustained-Release Dexamethasone in Beagle Dogs

The purpose of the present study was to examine the potential ocular and systemic toxicity and toxicokinetics/pharmacokinetics of sustained-release dexamethasone in canines. In this non-randomized study, intracanalicular depots (dexamethasone-loaded or placebo vehicle) were inserted into both eyes of 33 beagles. Tear fluid and plasma were collected for toxicokinetic/pharmacokinetic analysis of dexamethasone, ophthalmic examinations were performed for signs of toxicity, and urine and blood samples were collected for urinalysis, hematology, clinical chemistry, and coagulation analysis. Animals were observed daily for signs of toxicity. Macroscopic and microscopic evaluations were performed. Mean dexamethasone tear fluid concentration from the dexamethasone group decreased from 4245 ng/mL 6-h post-insertion to 1044 ng/mL on Day 35. All plasma dexamethasone levels were below the limit of quantitation. No systemic or ocular toxicities were attributed to the dexamethasone depot. Sustained-release dexamethasone produced no identifiable ocular or systemic toxicity in this animal model, and pharmacokinetics demonstrated a tapered, sustained drug release. Ocular Therapeutix.

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.

Dose-Related Inhibition of Proinflammatory Cytokine Release from Neutrophils of the Newborn by Dexamethasone, Betamethasone, and Hydrocortisone

The objective of this study was to determine the doses of dexamethasone (DEX), betamethasone (BET), and hydrocortisone (HC) that effectively inhibit the release of two potent proinflammatory chemokines, interleukin 8 (IL-8) and macrophage inflammatory protein alpha (MIP), from polymorphonuclear neutrophils (PMNs) of the newborn. Human PMNs were isolated from cord blood (n = 18). Chemokines were measured from PMN cell culture supernatants after 18 h of stimulation using tumor necrosis factor (1 ng/ml), with and without pretreatment by DEX (10^–10 to 10^–6 M) versus HC or BET (10^–10 to 10^–5 M). Maximal inhibitions of IL-8 release by BET, DEX, and HC were 97, 91, and 91%, respectively. For MIP, the maximal inhibitions by BET, DEX, and HC were 88, 69, and 70%, respectively. The 50% inhibitory concentrations by DEX, BET, and HC for IL-8 release were 3.4 ± (SE) 1.6 × 10^–9, 1.8 ± 7.4 × 10^–8, and 1.8 ± 0.5 × 10^–7 M, respectively. The 50% inhibitory concentrations by DEX, BET, and HC for MIP release were 1.0 ± (SE) 0.5 × 10^–8, 3.8 ± 3.1 × 10^–8, and 4.8 ± 1.6 × 10^–7 M, respectively. In vitro, these corticosteroids effectively inhibited the release of two structurally different chemokines that are found in the airway lavage fluids of infants developing bronchopulmonary dysplasia. When compared to plasma DEX levels previously reported during the treatment of bronchopulmonary dysplasia, our results suggest that the doses of DEX, and potentially BET, needed to treat chronic lung disease may be more than five to ten times lower than those of current DEX regimens.

Hypercortisolemia decreases dexamethasone half-life in rabbit

The pharmacokinetics of dexamethasone have been found to be related to endogenous hypothalamic-pituitary-adrenal (HPA) axis activity. Lower plasma dexamethasone levels in psychiatric patients (especially depressed) who are dexamethasone suppression test (DST) nonsuppressors have previously been reported. Since DST nonsuppression is one measure of HPA axis hyperactivity and is usually associated with relatively increased plasma cortisol levels and lower post dose plasma dexamethasone levels, we hypothesized that hypercortisolemia can induce a more rapid disappearance of dexamethasone from plasma. We therefore studied the kinetics of dexamethasone in rabbits before and after a period of sustained hypercortisolemia produced by administration of IM hydrocortisone acetate, a slowly absorbed salt of cortisol. Mean dexamethasone half-life decreased significantly from baseline of 1.92 h on day zero in seven rabbits to 1.17 h on experimental day 17 of induced hypercortisolemia ( P<0.001), while there was no significant change in saline treated controls ( n=3). Dexamethasone half-life had returned to the baseline levels when retested 88 days later on experimental day 105. The results indicate that pronounced hypercortisolemia decreases dexamethasone half-life in rabbits, and support the concept that increased circulating cortisol levels induce hepatic enzymes that metabolize dexamethasone. Thus, the lower postdexamethasone plasma dexamethasone levels and decreased dexamethasone half-life in DST nonsuppressors may in part reflect the effect of prior or coincident hypercortisolemia.

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.

Dexamethasone suppression of corticosteroid secretion: evaluation of the site of action by receptor measures and functional studies.

A dose of dexamethasone was determined in rats (50 micrograms/kg s.c.) that suppressed the corticosterone response to restraint stress by 80%. Corticosteroid receptor occupancy estimates found that the 50 micrograms/kg s.c. dose of dexamethasone had no significant effect on available glucocorticoid receptor (GR) or mineralocorticoid receptor (MR) binding in brain regions (hypothalamus, hippocampus and cortex); on the other hand dexamethasone produced a selective and significant decrease in available GR in peripheral tissues (pituitary and spleen). Functional studies showed that the 50 micrograms/kg s.c. dose of dexamethasone completely blocked the effects of corticotropin-releasing hormone (CRH; 0.3-3.0 micrograms/kg i.p.) on corticosterone secretion, but did not inhibit the corticosterone response to an adrenocorticotropin hormone (ACTH; 2.5 I.U./kg i.p.) challenge. These studies indicate that this dose of dexamethasone exerts its inhibitory effects on the HPA axis primarily by acting at GR in the pituitary. The plasma dexamethasone levels produced by this dose of dexamethasone are similar to those present in humans the afternoon after an oral dexamethasone suppression test (DST), a time at which many depressed patients escape from dexamethasone suppression. These results support and extend other studies which suggest that the DST provides a direct test of the effects of increased GR activation in the pituitary on ACTH and cortisol secretion.

The lower limits of dexamethasone window in Chinese depressives

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.

The effect of repeated human corticotropin-releasing hormone administration on dexamethasone-suppressed pituitary—adrenocortical activity in healthy subjects

A dexamethasone suppression test (DST) using a dosage of 1.5 mg dexamethasone was administered two times in randomized order to 10 healthy male subjects. From 2300 hours to 0700 hours subjects were injected repeatedly with either increasing dosages of human corticotropin-releasing hormone (hCRH) or 0.9% saline. In comparison to saline administration, in which cortisol levels remained suppressed, the time course of cortisol concentrations with hCRH stimulation showed a biphasic secretory pattern. According to a criterion level of a minimum of 40 ng/mL plasma for nonsuppression, the majority of the subjects changed their DST status to nonsuppression with hCRH. Adrenocorticotropic hormone secretion also differed significantly between saline and hCRH administration. During stimulation with hCRH, plasma dexamethasone levels were slightly and nonsignificantly reduced in the morning hours. Our results indicate that repeated dosages of hCRH impair the dexamethasone-induced suppression in man and support an involvement of CRH also in mediation of the DST nonsuppression during depressive illness.

Pharmacokinetics of dexamethasone and its relationship to dexamethasone suppression test outcome in depressed patients and healthy control subjects

The pharmacokinetics of dexamethasone (DEX) were studied in 9 drug-free melancholically depressed patients and 10 healthy control subjects matched by sex and age. Each subject received 1 mg of DEX administered orally and by the (i.v.) route at 11:00 PM and serial blood samples were collected over the next 17 hours until 4:00 PM. There were no significant differences between the diagnostic groups and DEX bioavailability, peak plasma level, time to maximum concentration, or in elimination half-life after oral administration. Bioavailability estimates indicated that DEX absorption was incomplete and variable mean = 61%, SD = 14) in controls as well as depressed patients. In both groups there was a wide interindividual variability in plasma DEX levels following both oral and i.v. routes of administration. This variability could not be reliably predicted by differences in age, sex, or weight between subjects. The factors that accounted for most the variability in 4:00 PM plasma DEX levels after oral administration were clearance, bioavailability, and time to reach maximum concentration. Plasma DEX levels were lower in 3 depressed nonsuppressors compared to 3 matched controls who suppressed. No single pharmacokinetic factor was shown to be responsible for the lower DEX levels in the depressed nonsuppressors. These results indicate that plasma DEX levels need to be measured in each individual during the DST procedure so that this information may be taken into consideration when interpreting DST results.

Do glucocorticoids contribute to the abnormalities in serotonin transporter expression and function seen in depression? An animal model

Adrenocorticosteroids and serotonergic neurons exert reciprocal regulatory actions, and both are abnormal in depression. We evaluated whether glucocorticoids influence the serotonin transporter in rat platelets and brain by infusing dexamethasone for 26 days, sufficient for replacement of the entire platelet population. Effectiveness was verified by measurement of plasma dexamethasone levels, adrenal atrophy, and growth inhibition. At the end of the infusion, we examined [3H]paroxetine binding to platelet, hippocampal, and cerebrocortical membranes, and [3H]serotonin uptake into platelets and synaptosomes. Dexamethasone slightly reduced platelet [3H]paroxetine binding (12%) and had no effect on binding in brain. Platelet [3H]serotonin uptake was unaffected, but synaptosomal uptake was significantly reduced. In neither platelets nor synaptosomes did dexamethasone alter imipramine's ability to inhibit uptake. Thus, elevated glucocorticoids are not responsible for reduced platelet serotonin transporter expression in depression, nor for resistance to imipramine's effect in platelets in elderly depression; however, reduced synaptosomal [3H]serotonin uptake indicates that glucocorticoids can affect transport efficiency, even when the number of transporter molecules is unaltered.

Site-specific dexamethasone delivery for the prevention of neointimal thickening after vascular stent implantation

Site-directed pharmacologic therapy using drug-impregnated polymers may achieve high local tissue levels at sites of arterial injury without systemic side effects. The aim of this study was to determine whether sustained, local administration of the synthetic glucocorticoid dexamethasone reduces the severity of intimal hyperplasia induced by arterial stenting in a porcine model of restenosis. Dexamethasone-impregnated silicone polymers (20% loading by weight) were formulated and tested in vitro to determine the time course of drug release. Oversized metallic stents were implanted in both carotid arteries of 14 juvenile Yorkshire farm pigs. A dexamethasone-impregnated polymer matrix was then placed around the external surface of the stented artery on one side, and a control polymer was placed contralaterally in an identical manner. Two animals were killed 5 days after stent implantation and the remainder after 35 +/- 1 days. Ex-vivo dexamethasone release from the silicone polymers was estimated to be 5 mg/day for the first 3 days and 0.3 mg/day thereafter. The arterial tissue dexamethasone levels after 5 days were 1307 +/- 498 ng/g of tissue on the treated side and 7.5 +/- 1.0 ng/g of tissue on the control side. The plasma dexamethasone level was 1.6 +/- 0.3 ng/ml, with no step-up in concentration across the segment surrounded by the drug-impregnated polymer. After 35 days, macroscopic examination and computerized morphometric analysis showed a substantial difference in the extent of polymer-induced adventitial and perivascular scarring but no difference in the extent of neointimal thickening. The adventitia:media ratio was 2.99 +/- 0.33 on the dexamethasone-treated side but 4.29 +/- 0.36 on the control side (P < 0.02). The intima:media ratios were 0.48 +/- 0.09 and 0.52 +/- 0.07, respectively. Sustained, local dexamethasone therapy has potent anti-inflammatory and anti-fibrotic effects but, with the dose and route of administration used in this study, does not reduce the intimal hyperplastic response to injury in this model.

The limbic-hypothalamic-pituitary-adrenal axis in Huntington's disease

The functional integrity of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis was studied in 10 patients with Huntington's disease (HD) and 10 age- and weight-matched control subjects by measuring basal ACTH and cortisol secretion, analyzing the subjects' ACTH and cortisol responses to corticotropin-releasing hormone (CRH) challenge, and by means of the dexamethasone-suppression test (DST). Basal cortisol and ACTH levels were significantly higher in patients with HD compared with controls. Following CRH administration, ACTH responses tended to be blunted in concert with normal cortisol levels. Two patients with HD and one control subject were DST nonsuppressors. Post-DST plasma dexamethasone levels were 57% lower among patients compared with the control group. Only in the HD group age was there an important variable in influencing spontaneous cortisol secretion as well as plasma dexamethasone levels during DST. These results suggest that patients with HD have an endogenous CRH overdrive, possibly due to a loss of (GABA) γ-aminobutyric acid-containing neurons, and that age might have an effect on the outcome of LHPA axis function tests in patients only.