scholarly journals Improving glucocorticoid replacement therapy using a novel modified-release hydrocortisone tablet: a pharmacokinetic study

2009 ◽  
Vol 161 (1) ◽  
pp. 119-130 ◽  
Author(s):  
Gudmundur Johannsson ◽  
Ragnhildur Bergthorsdottir ◽  
Anna G Nilsson ◽  
Hans Lennernas ◽  
Thomas Hedner ◽  
...  
Keyword(s):  
Single Dose ◽  
Replacement Therapy ◽  
Plasma Cortisol ◽  
Plasma Concentrations ◽  
Pharmacokinetic Studies ◽  
Double Blind ◽  
Once Daily ◽  
Physiological Serum ◽  
Cortisol Levels ◽  
Dual Release

BackgroundEndogenous plasma cortisol levels have a well-defined circadian rhythm. The aim of this project is to develop a once daily oral dual-release formulation for cortisol replacement therapy that mimics the diurnal variation in the plasma cortisol profile.ObjectiveTo determine single-dose plasma pharmacokinetics and dose-proportionality of oral 5 and 20 mg dual-release hydrocortisone tablets in healthy volunteers. In addition, the effect of food intake was investigated for the 20 mg dose.DesignA randomised, controlled, two-way cross-over, double-blind, phase I study of oral hydrocortisone (modified (dual) release; 5 and 20 mg) with an open food-interaction arm.MethodsThe single dose pharmacokinetic studies were performed with betamethasone suppression. The two first study days were blinded and randomised between morning administration of 5 and 20 mg tablet in a fasting state. The third day was open with a 20 mg tablet taken 30 min after a high-calorie, high-fat meal. The plasma samples were assayed using both a validated LC–MS/MS and an immunoassay. The plasma pharmacokinetic variables were calculated using non-compartmental data analysis.ResultsThe time to reach a clinically significant plasma concentration of cortisol (>200 nmol/l) was within 20 min and a mean peak of 431 (s.d. 126) nmol/l was obtained within 50 min after administration of the 20 mg tablet. Plasma cortisol levels remained above 200 nmol/l for around 6 h thereafter and all plasma concentrations 18–24 h after intake were below 50 nmol/l. In the fed state the time to reach 200 nmol/l was delayed by 28 and 9 min based on LC–MS/MS and immunoassay, respectively. The 5 and 20 mg tablets produced an increase in plasma exposure of cortisol that was not fully dose proportional.ConclusionThe dual release hydrocortisone tablet with once-daily administration produced a diurnal plasma cortisol profile mimicking the physiological serum cortisol profile.

scholarly journals Achieving a physiological cortisol profile with once-daily dual-release hydrocortisone: a pharmacokinetic study

2016 ◽  
Vol 175 (1) ◽  
pp. 85-93 ◽  
Author(s):  
Gudmundur Johannsson ◽  
Hans Lennernäs ◽  
Claudio Marelli ◽  
Kevin Rockich ◽  
Stanko Skrtic
Keyword(s):  
Replacement Therapy ◽  
Plasma Concentrations ◽  
Open Label ◽  
Post Dose ◽  
Time Curve ◽  
Once Daily ◽  
Concentration Time ◽  
Endogenous Cortisol ◽  
Dual Release ◽  
Dose Proportional

Objective Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy was developed to provide a cortisol exposure−time profile that closely resembles the physiological cortisol profile. This study aimed to characterize single-dose pharmacokinetics (PK) of DR-HC 5–20mg and assess intrasubject variability. Methods Thirty-one healthy Japanese or non-Hispanic Caucasian volunteers aged 20−55 years participated in this randomized, open-label, PK study. Single doses of DR-HC 5, 15 (3×5), and 20mg were administered orally after an overnight fast and suppression of endogenous cortisol secretion. After estimating the endogenous cortisol profile, PK of DR-HC over 24h were evaluated to assess dose proportionality and impact of ethnicity. Plasma cortisol concentrations were analyzed using liquid chromatography−tandem mass spectrometry. PK parameters were calculated from individual cortisol concentration−time profiles. Results DR-HC 20mg provided higher than endogenous cortisol plasma concentrations 0−4h post-dose but similar concentrations later in the profile. Cortisol concentrations and PK exposure parameters increased with increasing doses. Mean maximal serum concentration (Cmax) was 82.0 and 178.1ng/mL, while mean area under the concentration−time curve (AUC)0−∞ was 562.8 and 1180.8h×ng/mL with DR-HC 5 and 20mg respectively. Within-subject PK variability was low (<15%) for DR-HC 20mg. All exposure PK parameters were less than dose proportional (slope <1). PK differences between ethnicities were explained by body weight differences. Conclusions DR-HC replacement resembles the daily normal cortisol profile. Within-subject day-to-day PK variability was low, underpinning the safety of DR-HC for replacement therapy. DR-HC PK were less than dose proportional – an important consideration when managing intercurrent illness in patients with adrenal insufficiency.

scholarly journals Elevation of plasma somatolactin concentrations during acidosis in rainbow trout (Oncorhynchus mykiss)

1996 ◽  
Vol 199 (5) ◽  
pp. 1043-1051 ◽  
Author(s):  
S Kakizawa ◽  
T Kaneko ◽  
T Hirano
Keyword(s):  
Rainbow Trout ◽  
Plasma Cortisol ◽  
Initial Level ◽  
Plasma Concentrations ◽  
Water Acidification ◽  
Acid Base ◽  
Exposed Fish ◽  
Rainbow Trout Oncorhynchus Mykiss ◽  
Blood Ph ◽  
Cortisol Levels

Somatolactin (SL) is a putative pituitary hormone of the growth hormone (GH)/prolactin (PRL) family in fish; its physiological function has yet to be determined. Acidosis was induced in rainbow trout (Oncorhynchus mykiss) by exposure to acidic water (pH 4.5) or by exhaustive exercise, and plasma concentrations of SL, PRL and GH as well as other plasma parameters were examined. A decrease in blood pH was observed in fish from 1 day after water acidification until the end of the experiment at day 7. Plasma SL levels in the acid-exposed fish increased, reached a peak on day 1 and then returned to the initial level by day 4. No change was seen in plasma concentrations of PRL throughout the experiment. Plasma levels of GH, in contrast, decreased in the acid-exposed fish on days 2 and 4. Plasma cortisol levels in the acid-exposed fish were higher than the control level on days 4 and 7, although plasma cortisol levels did not increase above the initial level in response to water acidification. There was no significant change in the expression of SL-, PRL- and GH-mRNA in the pituitary gland. Levels of plasma Na+ and lactate were reduced 12 h after water acidification and remained low throughout the experiment. Exhaustive exercise in shallow water at neutral pH (7.5) resulted in a transient but pronounced acidosis, associated with increases in plasma SL, cortisol, Ca2+, phosphate and lactate levels. Plasma SL levels returned to the initial level along with the recovery of blood acid-base status. In contrast, plasma cortisol levels stayed elevated even 24 h after exercise. There was no correlation between plasma PRL and GH levels and blood pH. Elevation of plasma SL levels during acidosis suggests the possible involvement of SL in acid-base regulation in rainbow trout.

scholarly journals 179 Dasotraline in Children With Attention Deficit Hyperactivity Disorder: Results of a Randomized, Double-Blind, Placebo-Controlled Study

CNS Spectrums ◽  
2018 ◽  
Vol 23 (1) ◽  
pp. 102-103
Author(s):  
Robert Goldman ◽  
Lenard Adler ◽  
Thomas Spencer ◽  
Robert Findling ◽  
Seth C. Hopkins ◽  
...  
Keyword(s):  
Weight Loss ◽  
Repeated Measures ◽  
Mixed Model ◽  
Rating Scale ◽  
Plasma Concentrations ◽  
Fixed Dose ◽  
Controlled Study ◽  
Double Blind ◽  
Once Daily ◽  
Stable Plasma

AbstractObjectivesOnce-daily dosing with dasotraline, a novel dopamine and norepinephrine reuptake inhibitor, achieves stable plasma concentrations over 24 hours with once-daily dosing. This study evaluated dasotraline in children aged 6–12 years (NCT02428088).MethodsPatients were randomized 1:1:1 to 6 weeks of once-daily, fixed-dose dasotraline 2 or 4 mg/day, or placebo. The primary efficacy endpoint was change from baseline (CFB) at Week 6 in ADHD Rating Scale Version IV – Home Version (ADHD RS-IV HV) total score, using a mixed model for repeated measures (MMRM) in the intent-to-treat (ITT) population. Secondary endpoints included Clinical Global Impression-Severity (CGI-S) score and safety endpoints.ResultsThe mean age of 342 randomized patients was 9.1 [SD: 1.9] years; 66.7% were male. Overall, 79% of patients completed the study. In the ITT population (N=336), ADHD RS-IV HV total score improved significantly with dasotraline 4 mg/day vs placebo(least squares [LS] mean [SE] CFB at Week 6: –17.53 [±1.31] vs –11.36 [±1.29], respectively, p<0.001; effect size [ES]: 0.48). Inattentiveness and hyperactivity/impulsivity subscale scores significantly improved with 4 mg/day vs placebo at Week 6 (p=0.001, p=0.003, respectively). Improvement in CGI-S score was statistically significant with dasotraline 4 mg/day vs placebo(LS mean [SE] CFB at Week 6: –1.39 [±0.12] vs –1.04 [±0.12], respectively, p=0.040; ES: 0.29). No significant improvement was observed on the ADHD RS-IV HV total score and the CGI-S score for dasotraline 2 mg/day vs placebo. The most frequent treatment-emergent AEs (≥5% and higher than placebo) were (2 mg/day; 4 mg/day; placebo): insomnia (15.3%; 21.7%; 4.3%, all terms combined), decreased appetite (12.6%; 21.7%; 5.2%), weight loss (5.4%; 8.7%; 0%), irritability (3.6%; 7.0%; 6.0%), nasopharyngitis (0.9%; 5.2%; 0.9%), and nausea (0%; 5.2%; 2.6%).ConclusionsCompared with placebo, dasotraline 4 mg/day significantly improved ADHD symptoms in children, as assessed by ADHD RS-IV HV total score and inattentiveness and hyperactivity/impulsivity subscale scores. Dasotraline was generally well tolerated; most common AEs were insomnia, decreased appetite, weight loss and irritability.Funding AcknowledgementsStudy sponsored by Sunovion Pharmaceuticals Inc.

scholarly journals The effect of social stress on adrenal axis activity in horses: the importance of monitoring corticosteroid-binding globulin capacity

1998 ◽  
Vol 157 (3) ◽  
pp. 425-432 ◽  
Author(s):  
SL Alexander ◽  
CH Irvine
Keyword(s):  
Social Stress ◽  
Plasma Cortisol ◽  
Binding Capacity ◽  
Plasma Concentrations ◽  
Social Instability ◽  
Total Cortisol ◽  
Adrenal Axis ◽  
Free Cortisol ◽  
Corticosteroid Binding Globulin ◽  
Cortisol Levels

Plasma cortisol is largely bound to corticosteroid-binding globulin (CBG), which regulates its bioavailability by restricting exit from capillaries. Levels of CBG may be altered by several factors including stress and this can influence the amount of cortisol reaching cells. This study investigated the effect of social instability on plasma concentrations of CBG, total and free (not protein bound) cortisol in horses. Horses new to our research herd ('newcomers') were confined in a small yard with four dominant resident horses for 3-4 h daily for 3-4 (n = 5) or 9-14 (n = 3) days. Jugular blood was collected in the mornings from newcomers before the period of stress began ('pre-stress'), and then before each day's stress. Residents were bled before stress on the first and thirteenth day. Residents always behaved aggressively towards newcomers. By the end of the stress period, all newcomers were subordinate to residents. In newcomers (n = 8) after 3-4 days of social stress, CBG binding capacity had fallen (P = 0.0025), while free cortisol concentrations had risen (P = 0.0016) from pre-stress values. In contrast, total cortisol did not change. In residents, CBG had decreased slightly but significantly (P = 0.0162) after 12 days of stress. Residents and newcomers did not differ in pre-stress CBG binding capacity, total or free cortisol concentrations. However, by the second week of stress, CBG binding capacity was lower (P = 0.015) and free cortisol higher (P = 0.030) in newcomers (n = 3) than in residents. Total cortisol did not differ between the groups. In conclusion social stress clearly affected the adrenal axis of subordinate newcomer horses, lowering the binding capacity of CBG and raising free cortisol concentrations. However, no effect of stress could be detected when only total cortisol was measured. Therefore, to assess adrenal axis status accurately in horses, it is essential to monitor the binding capacity of CBG and free cortisol concentrations in addition to total cortisol levels.

A New Perioperative Glucocorticosteroid Replacement Therapy for Cushing's Syndrome

2020 ◽  
Author(s):  
Liang Wang ◽  
Lin Yang ◽  
Yuanxing Yang ◽  
Zhe Cui ◽  
Liming Li
Keyword(s):  
Replacement Therapy ◽  
Intravenous Injection ◽  
Cushing’S Syndrome ◽  
Plasma Cortisol ◽  
Clinical Symptoms ◽  
Adrenal Adenoma ◽  
Cushing's Syndrome ◽  
Simple Method ◽  
Urine Cortisol ◽  
Cortisol Levels

Abstract Background: To evaluate the safety and effects of a new perioperative glucocorticosteroid replacement therapy for Cushing,s syndrome.Methods: A simple method of glucocorticosteroid replacement therapy as follow was adopted for 83 cases of Cushing's syndrome patient which were diagnosed before the operation: No glucocorticosteroid was used before operation, but during adrenal adenoma resection 100 mg hydrocortisone was given by intravenous injection，and another 200 mg hydrocortisone was given on the day of surgery. On day 1 and day 2 postoperative, 100 mg/12h and 100 mg/24h hydrocortisone were given by intravenous injection respectively. Prednisone(10mg/8h) was given from the day 2 postoperative by oral administration, then 5mg was reduced once a week until a maintenance dosage (5mg) was reached. Clinical symptoms were observed, plasma cortisol and 24h urine cortisol levels were intermittently measured post-operation to evaluate the safety and the curative effect of this new glucocorticosteroid replacement therapy.Results: Adrenal insufficiency and steroid withdrawal syndrome did not occur with all patients. Compared with the concentration of urine cortisol preoperation, it was significantly decreased on the day 7 postoperative. Plasma cortisol concentration was significantly decreased on day 6 postoperative compared with preoperative. All the patients were followed up to 6 months, plasma cortisol and 24h urine cortisol levels were all normal.Conclusions: This new glucocorticosteroid replacement therapy was safe, simple, and effective.

scholarly journals Pilot Study of the Relationship between Deck Level and Journey Duration on Plasma Cortisol, Epinephrine and Norepinephrine Levels in Italian Heavy Pigs

Animals ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1578
Author(s):  
Giancarlo Bozzo ◽  
Barbara Padalino ◽  
Elisabetta Bonerba ◽  
Roberta Barrasso ◽  
Vincenzo Tufarelli ◽  
...  
Keyword(s):  
Pilot Study ◽  
Plasma Cortisol ◽  
Structural Characteristics ◽  
Stress Hormones ◽  
Plasma Concentrations ◽  
Activation Patterns ◽  
Blood Samples ◽  
Cortisol Levels ◽  
Council Regulation ◽  
The Relationship

The aim of this pilot study was to evaluate the relationship between journey duration, deck level and activation patterns of the hypothalamic-pituitary-adrenocortical axis (HPA) and sympathetic adrenal medullary system (SAM) in pigs. A total of 90 pigs were examined. The animals came from three different Italian farms associated with the same slaughterhouse located in Bari (Apulia region-Italy). A group of thirty animals was transported from Pordenone (11 h journey); a second group was transported from Terni (6.5 h journey); a third group was transported from Benevento (3 h journey). The animals were transported in the same vehicle, which complied with the structural characteristics indicated in the Council Regulation (EC) No. 1/2005. The truck was composed of a lorry and a trailer, each one divided into three decks. Only the animals transported in the trailer were tested for the study. Before transportation, blood samples were collected on each farm, at 6:00 a.m., from 30 pigs randomly selected out of 135 pigs ready to be transported. Blood samples were also collected during slaughter to evaluate plasma cortisol, epinephrine and norepinephrine, around 6:00 a.m. A journey duration of 11 h was associated with significantly higher plasma concentrations of stress hormones compared with shorter journeys. This increase was proportional to the journey duration, with the pigs travelling for 6.5 h displaying intermediate concentrations between those noticed after 3 h and 11 h journeys. The interaction between deck and journey distance was not significant on epinephrine, norepinephrine or cortisol levels collected at arrival. There was a significant effect of deck level on norepinephrine levels (p < 0.0001), a tendency to influence epinephrine levels (p = 0.073) but no effect on cortisol levels (p = 0.945). Overall, we observed that an 11 h-long journey seemed to impact negatively on pigs’ HPA-SAM activity, likely requiring the animals to spend more time in the lairage facilities to recover.

scholarly journals First use of cenerimod, a selective S1P1 receptor modulator, for the treatment of SLE: a double-blind, randomised, placebo-controlled, proof-of-concept study

2019 ◽  
Vol 6 (1) ◽  
pp. e000354 ◽  
Author(s):  
Viktoria Hermann ◽  
Anastas Batalov ◽  
Svetlana Smakotina ◽  
Pierre-Eric Juif ◽  
Peter Cornelisse
Keyword(s):  
Lymphocyte Count ◽  
Activity Index ◽  
Plasma Concentrations ◽  
Total Lymphocyte Count ◽  
Controlled Study ◽  
Double Blind ◽  
Once Daily ◽  
Receptor Modulator ◽  
Total Lymphocyte ◽  
Dsdna Antibodies

ObjectiveTo investigate the pharmacodynamics, pharmacokinetics and safety of cenerimod—a potent, oral, selective sphingosine 1-phosphate 1 receptor modulator—in patients with SLE.MethodsThis multicentre, double-blind, placebo-controlled study was conducted in two parts. In part A, patients with SLE were randomised 1:1:1:1 to receive oral cenerimod 0.5, 1 or 2 mg, or placebo once daily for 12 weeks. Following an interim safety review of part A, additional patients were randomised 3:1 for part B and received cenerimod 4 mg or placebo once daily for 12 weeks. Endpoints included changes in total lymphocyte count, SLE Disease Activity Index-2000 (SLEDAI-2K) score (modified (mSLEDAI-2K) to exclude leucopenia), biomarker anti-double-stranded DNA (anti-dsDNA) antibodies, pharmacokinetic assessments and treatment-emergent adverse events (TEAEs).ResultsPart A included 49 patients (1:1:1:1 receiving cenerimod 0.5, 1 or 2 mg, or placebo) and part B included 18 patients (13 cenerimod; 5 placebo). Cenerimod caused a statistically significant dose-dependent reduction in total lymphocyte count from baseline to end of treatment (EOT). Compared with placebo at EOT, cenerimod 4 mg had an estimated treatment effect on change from baseline in mSLEDAI-2K score of −2.420 (p=0.0306), and on anti-dsDNA antibodies of −64.55 U/mL (p=0.0082), suggesting clinical and biological improvement in these exploratory efficacy analyses. Trough plasma concentrations were dose proportional and reached steady-state conditions after 4 weeks of once daily dosing. All groups reported similar, non-dose-related frequencies of TEAEs (cenerimod 0.5 mg: 41.7%; 1 mg: 41.7%; 2 mg: 46.2%; 4 mg: 38.5% and placebo: 58.8%). A small, dose-related, non-clinically relevant decrease in heart rate was only observed in the first 6 hours after initiation.ConclusionsWith an acceptable safety profile, the efficacy findings suggest that cenerimod has the potential to treat patients with SLE. Further investigation in larger patient populations with longer treatment duration is warranted.

scholarly journals VT-1161 Dosed Once Daily or Once Weekly Exhibits Potent Efficacy in Treatment of Dermatophytosis in a Guinea Pig Model

2015 ◽  
Vol 59 (4) ◽  
pp. 1992-1997 ◽  
Author(s):  
E. P. Garvey ◽  
W. J. Hoekstra ◽  
W. R. Moore ◽  
R. J. Schotzinger ◽  
L. Long ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Oral Treatment ◽  
Plasma Concentrations ◽  
Pig Model ◽  
Pharmacokinetic Studies ◽  
Once Daily ◽  
Guinea Pig Model ◽  
Oral Doses

ABSTRACTCurrent therapies used to treat dermatophytoses such as onychomycosis are effective but display room for improvement in efficacy, safety, and convenience of dosing. We report here that the investigational agent VT-1161 displays potentin vitroantifungal activity against dermatophytes, with MIC values in the range of ≤0.016 to 0.5 μg/ml. In pharmacokinetic studies supporting testing in a guinea pig model of dermatophytosis, VT-1161 plasma concentrations following single oral doses were dose proportional and persisted at or above the MIC values for at least 48 h, indicating potentialin vivoefficacy with once-daily and possibly once-weekly dosing. Subsequently, in a guinea pig dermatophytosis model utilizingTrichophyton mentagrophytesand at oral doses of 5, 10, or 25 mg/kg of body weight once daily or 70 mg/kg once weekly, VT-1161 was statistically superior to untreated controls in fungal burden reduction (P< 0.001) and improvement in clinical scores (P< 0.001). The efficacy profile of VT-1161 was equivalent to those for doses and regimens of itraconazole and terbinafine except that VT-1161 was superior to itraconazole when each drug was dosed once weekly (P< 0.05). VT-1161 was distributed into skin and hair, with plasma and tissue concentrations in all treatment and regimen groups ranging from 0.8 to 40 μg/ml (or μg/g), at or above the MIC against the isolate used in the model (0.5 μg/ml). These data strongly support the clinical development of VT-1161 for the oral treatment of onychomycosis using either once-daily or once-weekly dosing regimens.

Naloxone affects the release of cortisol, but not of vasopressin or oxytocin, in dehydrated sheep

1989 ◽  
Vol 120 (1) ◽  
pp. 50-54 ◽  
Author(s):  
S. N. Thornton ◽  
R. F. Parrott
Keyword(s):  
Plasma Cortisol ◽  
Plasma Concentrations ◽  
Sampling Procedure ◽  
Blood Samples ◽  
Before And After ◽  
Consistent Change ◽  
Naloxone Hydrochloride ◽  
Cortisol Levels ◽  
Saline Vehicle ◽  
Naloxone Treatment

Abstract. Ovariectomized ewes (N = 7) were dehydrated for 24 h and then given iv injections of saline vehicle or 8 or 64 mg naloxone hydrochloride in saline. Blood samples were taken by jugular venepuncture before and after dehydration and at intervals during the 90 min period directly following naloxone treatment. Plasma concentrations of AVP, OT and cortisol were measured by radioimmunoassay. Plasma AVP levels and osmolality increased with dehydration, OT concentrations showed no consistent change, and cortisol levels were unaffected. After administration of naloxone, AVP and OT concentrations did not alter. The sampling procedure increased plasma cortisol levels and the duration of this response was prolonged by the 64 mg dose of naloxone.

Some biochemical and hormonal aspects of experimental ovine pregnancy toxaemia

1966 ◽  
Vol 67 (1) ◽  
pp. 129-138 ◽  
Author(s):  
N. Saba ◽  
K. N. Burns ◽  
N. F. Cunningham ◽  
C. Nancy Hebert ◽  
D. S. P. Patterson
Keyword(s):  
Plasma Cortisol ◽  
Severe Hypoglycaemia ◽  
Plasma Concentrations ◽  
Fourfold Increase ◽  
Mild Hypoglycaemia ◽  
Stress Levels ◽  
Cortisol Levels ◽  
Effects Of Stress ◽  
Slight Rise ◽  
Pregnancy Toxaemia

1. Some of the effects of stress, fasting and ACTH injections in pregnant ewes were investigated.2. A 6-day fast produced a relatively mild hypoglycaemia and hyperketonaemia without inducing pregnancy toxaemia.3. Stress of transport produced an immediate slight rise in plasma cortisol; 4 hr. later the plasma cortisol had returned to the pre-stress levels.4. A combination of stress and fasting produced severe hypoglycaemia, hyperketonaemia and subacute pregnancy toxaemia, but there was no increase in plasma cortisol levels.5. Daily injections of ACTH resulted in a fourfold increase in plasma cortisol and prevented the development of hypoglycaemia, severe hyperketonaemia, and pregnancy toxaemia in pregnant ewes subjected to stress and fasting.6. Changes in plasma concentrations of NEFA, urea, proteins, catecholamines and insulin were also investigated.

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