Opioid-induced adrenal insufficiency in transdermal fentanyl treatment: a revisited diagnosis in clinical setting.

Opioids are widely used for treatment of acute and chronic pain. However, opioids have several well-known clinical adverse effects such as constipation, nausea, respiratory depression and drowsiness. Endocrine dysfunctions are also opioid-induced adverse effects but remain under-diagnosed in clinical settings, especially opioid-induced adrenal insufficiency (OIAI). A 46-year-old woman was treated with transdermal fentanyl at a dose of 90-120 mg daily morphine milligram equivalent for non-malignant chronic pain for four years. Fatigue, loss of appetite and decrease in vitality began about two years after starting fentanyl. Subsequently, constipation and abdominal pain appeared and became worse, which led to suspicion of adrenal insufficiency. Clinical diagnosis of OIAI was established based on laboratory findings of secondary adrenal insufficiency, including corticotropin-releasing hormone stimulation test, clinical history of long-term fentanyl use, and exclusion of other hypothalamic-pituitary diseases. Oral corticosteroid replacement therapy was unable to relieve her abdominal pain and constipation; opioid-rotation and dose-reduction of fentanyl were not feasible because of her persistent pain and severe anxiety. While her clinical course clearly suggested that long-term, relatively high-dose transdermal fentanyl treatment may have contributed to the development of secondary adrenal insufficiency, the symptoms associated with OIAI are generally non-specific and complex. Together with under-recognition of OIAI as a clinical entity, the non-specific, wide range of symptoms can impede prompt diagnosis. Thus, vigilance for early symptoms enabling treatments including corticosteroid replacement therapy is necessary for patients taking long-term and/or high dose opioid treatment.

Exogenous C-type natriuretic peptide restores normal growth and prevents early growth plate closure in its deficient rats.

Signaling by C-type natriuretic peptide (CNP) and its receptor, natriuretic peptide receptor-B, is a pivotal stimulator of endochondral bone growth. We recently developed CNP knockout (KO) rats that exhibit impaired skeletal growth with early growth plate closure. In the current study, we further characterized the phenotype and growth plate morphology in CNP-KO rats, and the effects of exogenous CNP in rats. We used CNP-53, an endogenous form of CNP consisting of 53 amino acids, and administered it for four weeks by continuous subcutaneous infusion at 0.15 or 0.5 mg/kg/day to four-week old CNP-KO and littermate wild type (WT) rats. We demonstrated that CNP-KO rats were useful as a reproducible animal model for skeletal dysplasia, due to their impairment in endochondral bone growth. There was no significant difference in plasma bone-turnover markers between the CNP-KO and WT rats. At eight weeks of age, growth plate closure was observed in the distal end of the tibia and the calcaneus of CNP-KO rats. Continuous subcutaneous infusion of CNP-53 significantly, and in a dose-dependent manner, stimulated skeletal growth in CNP-KO and WT rats, with CNP-KO rats being more sensitive to the treatment. CNP-53 also normalized the length of long bones and the growth plate thickness, and prevented growth plate closure in the CNP-KO rats. Using organ culture experiment of fetal rat tibia, gene set enrichment analysis indicated that CNP might have a negative influence on mitogen activated protein kinase signaling cascades in chondrocyte. Our results indicated that CNP-KO rats might be a valuable animal model for investigating growth plate physiology and the mechanism of growth plate closure, and that CNP-53, or its analog, may have the potential to promote growth and to prevent early growth plate closure in the short stature.

Overall safety and efficacy of high-dose and low-dose intravenous glucocorticoid therapy in patients with moderate-to-severe active Graves' ophthalmopathy.

The objective of this study was to compare the safety and efficacy of high-dose and low-dose intravenous (iv) glucocorticoid (GC) therapy in patients with Graves' ophthalmopathy (GO) and to investigate which factors may help determine appropriate iv GC doses. The medical records of 43 patients who received different doses of iv GCs for GO were retrospectively reviewed. Twenty patients received high-dose iv GCs (HD group, cumulative dose 9.0-12.0 g) and 18 received low-dose iv GCs (LD group, cumulative dose 4.5 g). Five patients with previous treatment for GO were excluded. Changes in ophthalmic parameters after treatment and frequencies of adverse effects due to GCs of the 2 groups were compared. We also reviewed the incidence of GO progression and hepatic dysfunction after patients were discharged. We evaluated correlations among pretreatment (before treatment) ophthalmic parameters and investigated useful predictive factors for determining iv GC doses. There were no significant differences in ophthalmic parameters reflecting treatment efficacy or overall safety between the groups. Among baseline ophthalmic parameters, corrected signal intensity ratio (cSIR) correlated well with magnetic resonance imaging findings and were more strongly associated with changes in ophthalmic parameters after treatment in the HD group than in the LD group, indicating that pretreatment cSIR might be useful for determining iv GC doses. In conclusion, there were no significant differences in overall safety and efficacy between high-dose and low-dose iv GC therapy in patients with active GO. Further randomized clinical trials with longer observation periods are required to establish the optimal treatment regimen of GO.

Increased Bone Turnover and Possible Accelerated Fracture Healing in a Murine Model With an Increased Circulating C-Type Natriuretic Peptide.

Recent studies have revealed that C-type natriuretic peptide (CNP) is a potent stimulator of endochondral bone growth. Nevertheless, the effect of CNP on bone turnover has not yet been well studied. To elucidate this issue, we investigated the bone phenotype of a mouse model with elevated plasma CNP concentrations (SAP-CNP-Tg mice) in the present study. Microcomputed tomography (CT) analysis revealed less bone in femurs, but not in lumber vertebrae, of young adult SAP-CNP-Tg mice than that of wild-type mice. Bone histomorphometry of the tibiae from 8-week-old SAP-CNP-Tg mice showed enhanced osteoblastic and osteoclastic activities, in accordance with elevated serum levels of osteocalcin and tartrate-resistant acid phosphatase-5b, respectively. Next we performed an open and stabilized femoral fracture using 8-week-old SAP-CNP-Tg mice and compared the healing process with age-matched wild-type mice. An immunohistochemical study revealed that CNP and its receptors, natriuretic peptide receptor-B and natriuretic peptide clearance receptor, are expressed in hard calluses of wild-type mice, suggesting a possible role of CNP/natriuretic peptide receptor-B signaling in fracture repair, especially in bone remodeling stage. On micro-CT analysis, a rapid decrease in callus volume was observed in SAP-CNP-Tg mice, followed by a generation of significantly higher new bone volume with a tendency of increased bone strength. In addition, a micro-CT analysis also showed that bone remodeling was accelerated in SAP-CNP-Tg mice, which was also evident from increased serum osteocalcin and tartrate-resistant acid phosphatase-5b levels in SAP-CNP-Tg mice at the remodeling stage of fracture repair. These results indicate that CNP activates bone turnover and remodeling in vivo and possibly accelerates fracture healing in our mouse model.

Forkhead box A1 (FOXA1) and A2 (FOXA2) oppositely regulate human type 1 iodothyronine deiodinase gene in liver.

Type 1 iodothyronine deiodinase (D1), a selenoenzyme that catalyzes the bioactivation of thyroid hormone, is expressed mainly in the liver. Its expression and activity are modulated by several factors, but the precise mechanism of its transcriptional regulation remains unclear. In the present study, we have analyzed the promoter of human D1 gene (hDIO1) to identify factors that prevalently increase D1 activity in the human liver. Deletion and mutation analyses demonstrated that a forkhead box (FOX)A binding site and an E-box site within the region between nucleotides -187 and -132 are important for hDIO1 promoter activity in the liver. EMSA demonstrated that FOXA1 and FOXA2 specifically bind to the FOXA binding site and that upstream stimulatory factor (USF) specifically binds to the E-box element. Overexpression of FOXA2 decreased hDIO1 promoter activity, and short interfering RNA-mediated knockdown of FOXA2 increased the expression of hDIO1 mRNA. In contrast, overexpression of USF1/2 increased hDIO1 promoter activity. Short interfering RNA-mediated knockdown of FOXA1 decreased the expression of hDIO1 mRNA, but knockdown of both FOXA1 and FOXA2 restored it. The response of the hDIO1 promoter to USF was greatly attenuated in the absence of FOXA1. Taken together, these results indicate that a balance of FOXA1 and FOXA2 expression modulates hDIO1 expression in the liver.