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Clinical Medicine (London, England) Mar 2023Adrenal insufficiency is the inadequate secretion of glucocorticoid and/or mineralocorticoid secretion from the adrenal cortex. Primary adrenal insufficiency is the...
Adrenal insufficiency is the inadequate secretion of glucocorticoid and/or mineralocorticoid secretion from the adrenal cortex. Primary adrenal insufficiency is the result of failure of the adrenal gland and secondary adrenal insufficiency is due to a lack of stimulation via pituitary adrenocorticotropic hormone or hypothalamic corticotropin-releasing hormone. Adrenal insufficiency may cause non-specific symptoms. Early detection and testing based on clinical suspicion may prevent subsequent presentation with adrenal crisis. Once identified, a low baseline cortisol (often <100 nmol/L) alongside raised adrenocorticotropic hormone (ACTH) can be enough to diagnose primary adrenal insufficiency. However, confirmatory testing can be done using the cosyntopin (Synacthen®) stimulation test or the insulin tolerance test, which is the gold standard for secondary adrenal insufficiency. The underlying cause of adrenal insufficiency can often be identified via a strategic approach to investigation. Adrenal crisis is a life-threatening medical emergency which must be treated immediately if there is strong clinical suspicion with fluids and corticosteroids otherwise can be fatal. Patients must be educated and empowered to take control of their own medical management.
Topics: Humans; Hydrocortisone; Addison Disease; Adrenal Insufficiency; Adrenocorticotropic Hormone; Corticotropin-Releasing Hormone
PubMed: 36958832
DOI: 10.7861/clinmed.2023-0067 -
Advances in Therapy Jul 2022Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that affects multiple organ systems. The most prevalent manifestations include constitutional... (Review)
Review
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that affects multiple organ systems. The most prevalent manifestations include constitutional symptoms, arthritis, and rash. An SLE flare is defined as a measurable increase in disease activity that may prompt a change in treatment. According to the European Alliance of Associations for Rheumatology guidance, SLE treatments should be aimed at reducing disease activity and flares, as well as preventing organ damage. Standard-of-care treatment of SLE includes glucocorticoids, but their long-term use is associated with damage accrual. Repository corticotropin injection (RCI; Acthar Gel) is a naturally sourced complex mixture of adrenocorticotropic hormone analogs and other pituitary peptides that has anti-inflammatory and immunomodulatory effects beyond its steroidogenic effect, and has been US Food and Drug Administration-approved for the treatment of SLE flares and as a maintenance therapy. This review summarizes data from three clinical trials that evaluated the efficacy and safety of RCI in the treatment of patients with moderate-severe refractory SLE. These clinical trials confirmed that RCI improved global disease activity scores and some SLE clinical manifestations. Analysis of pooled data from these trials showed that RCI treatment significantly improved the British Isles Lupus Assessment Group 2004 (BILAG-2004) index scores after 8 weeks of treatment, and tender and swollen joint counts after 4 weeks. These clinical trials demonstrated an acceptable safety profile with few serious adverse events reported. The distinct mechanisms of action from standard-of-care therapies and the favorable safety and good efficacy profiles support the use of RCI as therapy for patients with refractory SLE.
Topics: Adrenocorticotropic Hormone; Autoimmune Diseases; Glucocorticoids; Humans; Lupus Erythematosus, Systemic; Rheumatology
PubMed: 35641860
DOI: 10.1007/s12325-022-02160-y -
International Journal of Molecular... Nov 2021This review addresses the molecular mechanisms of corticotropin-releasing factor (CRF) regulation in the hypothalamus under stress and stress resilience. CRF in the... (Review)
Review
This review addresses the molecular mechanisms of corticotropin-releasing factor (CRF) regulation in the hypothalamus under stress and stress resilience. CRF in the hypothalamus plays a central role in regulating the stress response. CRF stimulates adrenocorticotropic hormone (ACTH) release from the anterior pituitary. ACTH stimulates glucocorticoid secretion from the adrenal glands. Glucocorticoids are essential for stress coping, stress resilience, and homeostasis. The activated hypothalamic-pituitary-adrenal axis is suppressed by the negative feedback from glucocorticoids. Glucocorticoid-dependent repression of cAMP-stimulated promoter activity is mediated by both the negative glucocorticoid response element and the serum response element. Conversely, the inducible cAMP-early repressor can suppress the stress response via inhibition of the cAMP-dependent gene, as can the suppressor of cytokine signaling-3 in the hypothalamus. CRF receptor type 1 is mainly involved in a stress response, depression, anorexia, and seizure, while CRF receptor type 2 mediates "stress coping" mechanisms such as anxiolysis in the brain. Differential effects of FK506-binding immunophilins, FKBP4 and FKBP5, contribute to the efficiency of glucocorticoids under stress resilience. Together, a variety of factors contribute to stress resilience. All these factors would have the differential roles under stress resilience.
Topics: Adaptation, Physiological; Adrenocorticotropic Hormone; Animals; Corticotropin-Releasing Hormone; Humans; Hypothalamo-Hypophyseal System; Hypothalamus; Models, Biological; Pituitary-Adrenal System; Stress, Physiological
PubMed: 34830130
DOI: 10.3390/ijms222212242 -
Endocrinology Dec 2022Preterm birth worldwide remains a significant cause of neonatal morbidity and mortality, yet the exact mechanisms of preterm parturition remain unclear. Preterm birth is... (Review)
Review
Preterm birth worldwide remains a significant cause of neonatal morbidity and mortality, yet the exact mechanisms of preterm parturition remain unclear. Preterm birth is not a single condition, but rather a syndrome with a multifactorial etiology. This multifactorial nature explains why individual predictive measures for preterm birth have had limited sensitivity and specificity. One proposed pathway for preterm birth is via placentally synthesized corticotrophin-releasing hormone (CRH). CRH is a peptide hormone that increases exponentially in pregnancy and has been implicated in preterm birth because of its endocrine, autocrine, and paracrine roles. CRH has actions that increase placental production of estriol and of the transcription factor nuclear factor-κB, that likely play a key role in activating the myometrium. CRH has been proposed as part of a placental clock, with early activation of placental production resulting in preterm birth. This article will review the current understanding of preterm birth, CRH as an initiator of human parturition, and the evidence regarding the use of CRH in the prediction of preterm birth.
Topics: Pregnancy; Female; Infant, Newborn; Humans; Placenta; Corticotropin-Releasing Hormone; Premature Birth; Parturition; Adrenocorticotropic Hormone
PubMed: 36478045
DOI: 10.1210/endocr/bqac206 -
International Journal of Molecular... Mar 2018The Hypothalamic-Pituitary-adrenal (HPA) axis describes a complex set of positive and negative feedback influences between the hypothalamus, pituitary gland, and adrenal...
The Hypothalamic-Pituitary-adrenal (HPA) axis describes a complex set of positive and negative feedback influences between the hypothalamus, pituitary gland, and adrenal gland.[...].
Topics: Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Animals; Corticotropin-Releasing Hormone; Feedback, Physiological; Humans; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System
PubMed: 29587417
DOI: 10.3390/ijms19040986 -
Clinical Pharmacology in Drug... Apr 2022Repository corticotropin injection (RCI; Acthar Gel) is a naturally sourced complex mixture of adrenocorticotropic hormone (ACTH) analogs and other pituitary peptides.... (Randomized Controlled Trial)
Randomized Controlled Trial
Repository corticotropin injection (RCI; Acthar Gel) is a naturally sourced complex mixture of adrenocorticotropic hormone (ACTH) analogs and other pituitary peptides. This phase 1, single-center, open-label, randomized parallel study directly compared the pharmacokinetics and pharmacodynamics of RCI and synthetic ACTH depot. Methylprednisolone was included to estimate the steroidogenic exposure of RCI and synthetic ACTH depot when used to treat nephrotic syndrome. A total of 48 healthy subjects aged 18 to 50 years were randomly assigned 1:1:1 to RCI (80 IU subcutaneously twice weekly on study days 1 and 4), synthetic ACTH depot (1 mg subcutaneously twice weekly on study days 1 and 4), or methylprednisolone (32 mg orally once daily on study days 1 through 6). After 2 doses, RCI induced about 5-fold lower free cortisol exposure and an estimated 4-fold lower steroidogenic exposure than synthetic ACTH depot. The lower endogenous cortisol response of RCI was achieved despite higher observed mean plasma concentrations of N25-deamidated porcine ACTH (the pharmacokinetic marker for RCI) than of ACTH . The different pharmacodynamic properties demonstrated by RCI and synthetic ACTH depot in this study suggest that these products in the ACTH class are not interchangeable.
Topics: Adrenocorticotropic Hormone; Animals; Cosyntropin; Healthy Volunteers; Humans; Hydrocortisone; Methylprednisolone; Swine
PubMed: 34528408
DOI: 10.1002/cpdd.1020 -
Clinical Chemistry and Laboratory... Jan 2022Corticotropin is notorious for its instability. Whereas several studies have investigated its short-term stability in plasma following venous blood sampling, studies on...
OBJECTIVES
Corticotropin is notorious for its instability. Whereas several studies have investigated its short-term stability in plasma following venous blood sampling, studies on long-term stability are lacking. Here we investigated the long-term storage stability of corticotropin in ethylenediaminetetraacetic acid containing plasma.
METHODS
Specimens from healthy volunteers (neat, spiked) were stored in polypropylene microcentrifuge tubes with socket screw-caps at -20 °C and -70 °C for up to one and a half years. Corticotropin in plasma was measured using an Abbott research only immunoassay. Separately, specimens from patients were collected during diagnostic routine testing and stored in polystyrene tubes with push-caps at -20 °C for up to 6 years. In these samples corticotropin hormone was measured using the Diasorin corticotropin immunoassay.
RESULTS
Storage of specimens at -20 °C or -70 °C for up to one and a half years showed minimal changes (<11%) in corticotropin levels, while storage of patient samples at -20 °C for up to 6 years showed a significant (54%) reduction in corticotropin levels.
CONCLUSIONS
Corticotropin levels are stable in plasma when stored at -20 °C for one and a half years using the Abbott research only assay, but with longer storage time a significant reduction in corticotropin levels can be expected. Once specimens are stored for future corticotropin measurements, one should consider storage time, storage temperature and assay differences.
Topics: Adrenocorticotropic Hormone; Edetic Acid; Humans; Plasma; Protein Stability; Specimen Handling; Temperature
PubMed: 34643074
DOI: 10.1515/cclm-2021-0818 -
Gut Feb 1997
Topics: Adrenocorticotropic Hormone; Animals; Cortisone; Dogs; History, 20th Century; Stomach Ulcer
PubMed: 9071951
DOI: 10.1136/gut.40.2.289-b -
British Medical Journal Mar 1953
Topics: Adrenocorticotropic Hormone; Agranulocytosis; Cortisone
PubMed: 13019118
DOI: No ID Found -
Advances in Therapy Aug 2017Repository corticotropin injection (RCI; H.P. Acthar Gel; Mallinckrodt Pharmaceuticals Inc., Hampton, NJ) is a highly purified, prolonged-release porcine preparation of... (Review)
Review
Clinical and Economic Evaluation of Repository Corticotropin Injection: A Narrative Literature Review of Treatment Efficacy and Healthcare Resource Utilization for Seven Key Indications.
INTRODUCTION
Repository corticotropin injection (RCI; H.P. Acthar Gel; Mallinckrodt Pharmaceuticals Inc., Hampton, NJ) is a highly purified, prolonged-release porcine preparation of adrenocorticotropic hormone (ACTH) analogue that is FDA-approved for treatment of 19 autoimmune and inflammatory disorders. The diverse physiological actions of RCI at the melanocortin receptors (MCRs) affect processes involved in inflammation, pigmentation, steroidogenesis, and immunomodulation. Although RCI has been approved to treat inflammatory and autoimmune diseases for more than 60 years, recent progress in understanding both MCRs and the effects of RCI in modulating immune responses has led to increased interest in RCI as a therapeutic choice. The objective of this narrative literature review is to summarize key clinical and economic data on RCI treatment of seven disorders: infantile spasms (IS), multiple sclerosis (MS) relapses, proteinuria in nephrotic syndrome, rheumatoid arthritis (RA), dermatomyositis/polymyositis (DM/PM), systemic lupus erythematosus (SLE), and symptomatic sarcoidosis based on published literature and product information. An extended report is available as the Academy of Managed Care Pharmacy (AMCP) Formulary dossier for H.P. Acthar Gel.
METHODS
Key studies of clinical efficacy and healthcare utilization and cost from 1956 to 2016 are summarized.
RESULTS
The evidence supports the efficacy of RCI across the seven indications. RCI is effective as a first-line therapy for IS. For the other six conditions, RCI may improve clinical outcomes during exacerbations or when the condition is resistant to conventional treatments. Use of RCI is associated with reduced use of biologics, corticosteroids, and disease-modifying antirheumatic drugs. Initiation of RCI therapy in patients with IS, MS, RA, SLE, or DM/PM has been associated with lower post-therapy healthcare utilization and medical costs, including decreases in hospitalizations, hospital length of stay, outpatient visits, and emergency department visits.
CONCLUSION
The evidence suggests that RCI may improve inflammatory and autoimmune disease control and patient quality of life, particularly in complex patients, and yield healthcare cost savings that demonstrate the medicine's value.
FUNDING
Mallinckrodt Pharmaceuticals Inc.
Topics: Adrenocorticotropic Hormone; Arthritis, Rheumatoid; Autoimmune Diseases; Cost-Benefit Analysis; Hospitalization; Humans; Inflammation; Lupus Erythematosus, Systemic; Managed Care Programs; Multiple Sclerosis; Treatment Outcome
PubMed: 28660550
DOI: 10.1007/s12325-017-0569-9