Prednisolone and dexamethasone are systemically absorbed after topical application of ophthalmic suspensions in healthy dogs

OBJECTIVE To quantify plasma concentrations of prednisolone and dexamethasone (peripheral and jugular) and cortisol following topical ophthalmic application of 1% prednisolone acetate and 0.1% dexamethasone to healthy adult dogs. ANIMALS 12 purpose-bred Beagles. PROCEDURES Dogs received 1 drop of 1% prednisolone acetate (n = 6) or neomycin polymyxin B dexamethasone (ie, 0.1% dexamethasone; 6) ophthalmic suspension in both eyes every 6 hours for 14 days. Blood samples (peripheral and jugular) were collected on days 0, 1, 7, and 14 and analyzed for plasma prednisolone and dexamethasone concentrations. Plasma cortisol concentrations were measured at the beginning of the study and following topical drug administration. RESULTS Both drugs demonstrated systemic absorption. Prednisolone was detected on days 1, 7, and 14 (median plasma concentration, 24.80 ng/mL; range, 6.20 to 74.00 ng/mL), and dexamethasone was detected on days 1, 7, and 14 (2.30 ng/mL; 0 to 17.70 ng/mL). Neither prednisolone nor dexamethasone were detected in plasma samples on day 0 (baseline). Sampling from the jugular vein resulted in higher plasma drug concentrations than from a peripheral vein when samples from each day were combined. Plasma cortisol concentrations were significantly lower than baseline following 14 days of treatment with topical prednisolone acetate and dexamethasone. CLINICAL RELEVANCE Prednisolone and dexamethasone are detected in the plasma of healthy dogs following topical ophthalmic administration 4 times/d with prednisolone concentrations being close to a physiologic dose of orally administered prednisolone. Additional research is needed to evaluate the systemic absorption of these medications in dogs with ocular inflammation.

The Role of Morning Plasma Cortisol in Obesity: A Bi-directional Mendelian Randomization Study

Context Cortisol, an important hormone regulated by the hypothalamic-pituitary-adrenal (HPA) axis, is associated with obesity. However, it is unclear whether the relationship between cortisol and obesity is causal or could be explained by reverse causality. Objective This work aims to assess the role of morning plasma cortisol in clinical classes of obesity. Methods In this bi-directional two-sample Mendelian Randomization (MR) study, cortisol-associated genetic variants were obtained from the CORtisol NETwork consortium (n = 12,597). The primary outcomes were obesity class I (BMI ≥ 30 kg/m 2), class II (BMI ≥ 35 kg/m 2), and class III (BMI ≥ 40kg/m 2). Inverse variance weighting (IVW) method was used as the main analysis, with weighted median, MR-Egger, and MR-PRESSO as sensitivity analyses. Conversely, genetic variants predicting clinical classes of obesity were applied to the cortisol GWAS. Results Genetically predicted cortisol was associated with reduced risk of obesity class I (OR = 0.905; 95% CI, 0.865-0.946; p < 0.001). Evidence from bi-directional MR showed that obesity class II and class III were associated with lower cortisol levels ((class II-cortisol OR = 0.953; 95% CI, 0.923-0.983; p = 0.002); (class III-cortisol OR = 0.955; 95% CI, 0.942-0.967; p < 0.001)), indicating reverse causality between cortisol and obesity. Conclusions This study demonstrates that cortisol is negatively associated with obesity and vice versa. Together, these findings suggest that blunted morning plasma cortisol secretion may be responsible for severe obesity. Regulating morning plasma secretion might be a prevention measure for obese people.

Preemptive Ketorolac is as Effective as Oxycodone Decreasing Plasma Cortisol Levels in Patients Undergoing Spinal Anesthesia

Introduction: Post-surgical pain is a complex problem, if not treated properly it can have multisystem negative effects. Hormone cortisol can be increased in stressful situations. A study on the effectiveness of ketorolac and another opioid on cortisol levels has been shown. However, a study about the effect of oxycodone on cortisol levels and its comparison with Ketorolac has never been done before. This study aimed to compare the effect of preemptive administration of 30 mg ketorolac and 5 mg oxycodone on plasma cortisol levels in patients undergoing spinal anesthesia. Methods: A double-blind randomized clinical trial was carried out between October and December 2020 in the central operating room of dr. Mohammad Hoesin Palembang. Surgical patients according to the inclusion criteria who received spinal anesthesia were randomly given 5 mg oxycodone and 30 mg ketorolac intravenously shortly after spinal anesthesia. Cortisol levels were measured before and after the intervention. Data analysis using SPSS ver. 20 Windows with a 95% confidence interval. Result: In total, 56 subjects were included. 29 samples in the ketorolac group and 27 samples in the oxycodone group. There were no significant differences in age, sex, nutritional status, blood sugar, and VAS score. There was no significant difference in the mean of cortisol levels before the intervention in the ketorolac group 12.9421 + 6.096 m/dL and the oxycodone group 14.033 + 4.315 m/dL (p = 0.446). The mean value of cortisol levels after intervention in the ketorolac group was 12.979 + 6.280 m/dL and oxycodone 15.353 + 11.704 m/dL, there was no significant difference in changes in cortisol before and after intervention in the Ketorolac group (p = 0.692) and Oxycodone (p = 0.552). The comparison level of cortisol changes between the two groups was not significantly different (p = 0.267). Conclusion: There was no difference in the comparison of the effect of preemptive administration of 30 mg IV ketorolac and 5 mg IV oxycodone on plasma cortisol levels in patients undergoing spinal anesthesia.

Bilateral adrenal masses due to tuberculosis: how to diagnose without extra-adrenal tuberculosis

Summary Primary adrenal insufficiency is a rare disease and can masquerade as other conditions; therefore, it is sometimes incorrectly diagnosed. Herein, we reported the case of a 39-year-old Vietnamese male with primary adrenal insufficiency due to bilateral adrenal tuberculosis. The patient presented to the emergency room with acute adrenal crisis and a 3-day history of nausea, vomiting, epigastric pain, and diarrhoea with a background of 6 months of fatigue, weight loss, and anorexia. Abdominal CT revealed bilateral adrenal masses. Biochemically, unequivocal low morning plasma cortisol (<83 nmol/L) and high plasma adrenocorticotropic hormone levels were consistent with primary adrenal insufficiency. There was no evidence of malignancy or lymphoma. As the patient was from a tuberculosis-endemic area, extra-adrenal tuberculosis was excluded during the work up. A retroperitoneal laparoscopic left adrenalectomy was performed, and tuberculous adrenalitis was confirmed by the histopathological results. The patient was started on antituberculous therapy, in addition to glucocorticoid replacement. In conclusion, even without evidence of extra-adrenal tuberculosis, a diagnosis of bilateral adrenal tuberculosis is required. A histopathological examination has a significant role along with clinical judgement and hormonal workup in establishing a definitive diagnosis of adrenal tuberculosis without evidence of active extra-adrenal involvement. Learning points Primary adrenal insufficiency can be misdiagnosed as other mimicking diseases, such as gastrointestinal illness, leading to diagnostic pitfalls. Adrenal insufficiency can be confirmed with significantly low morning plasma cortisol levels of <83 nmol/L without a dynamic short cosyntropin stimulation test. Tuberculous adrenalitis is an uncommon treatable condition; however, it remains an important cause of primary adrenal insufficiency, especially in developing countries. In the absence of extra-adrenal involvement, adrenal biopsy plays a key role in the diagnostic process. Alternatively, adrenalectomy for histopathological purposes should be considered if CT scan-guided fine needle aspiration is infeasible in cases of small adrenal masses.

Differential Metabolic and Transcriptional Responses of Gilthead Seabream (Sparus aurata) Administered with Cortisol or Cortisol-BSA

Cortisol is the main glucocorticoid hormone promoting compensatory metabolic responses of stress in teleosts. This hormone acts through genomic and membrane-initiated actions to exert its functions inside the cell. Experimental approaches, using exogenous cortisol administration, confirm the role of this hormone during short (minutes to hours)- and long-term (days to weeks) responses to stress. The role of membrane-initiated cortisol signaling during long-term responses has been recently explored. In this study, Sparus aurata were intraperitoneally injected with coconut oil alone or coconut oil containing cortisol, cortisol-BSA, or BSA. After 3 days of treatment, plasma, liver, and skeletal muscle were extracted. Plasma cortisol, as well as metabolic indicators in the plasma and tissues collected, and metabolism-related gene expression, were measured. Our results showed that artificially increased plasma cortisol levels in S. aurata enhanced plasma glucose and triacylglycerols values as well as hepatic substrate energy mobilization. Additionally, cortisol stimulated hepatic carbohydrates metabolism, as seen by the increased expression of metabolism-related genes. All of these responses, observed in cortisol-administered fish, were not detected by replicating the same protocol and instead using cortisol-BSA, which exclusively induces membrane-initiated effects. Therefore, we suggest that after three days of cortisol administration, only genomic actions are involved in the metabolic responses in S. aurata.

Endoplasmic reticulum stress as a key mechanism in stunted growth of seawater rainbow trout (Oncorhynchus mykiss)

Background Rainbow trout (Oncorhynchus mykiss) is a salmonid species with a complex life-history. Wild populations are naturally divided into freshwater residents and sea-run migrants. Migrants undergo an energy-demanding adaptation for life in seawater, known as smoltification, while freshwater residents display these changes in an attenuated magnitude and rate. Despite this, in seawater rainbow trout farming all fish are transferred to seawater. Under these circumstances, weeks after seawater transfer, a significant portion of the fish die (around 10%) or experience growth stunting (GS; around 10%), which represents an important profitability and welfare issue. The underlying causes leading to GS in seawater-transferred rainbow trout remain unknown. In this study, we aimed at characterising the GS phenotype in seawater-transferred rainbow trout using untargeted and targeted approaches. To this end, the liver proteome (LC-MS/MS) and lipidome (LC-MS) of GS and fast-growing phenotypes were profiled to identify molecules and processes that are characteristic of the GS phenotype. Moreover, the transcription, abundance or activity of key proteins and hormones related to osmoregulation (Gill Na+, K + –ATPase activity), growth (plasma IGF-I, and liver igf1, igfbp1b, ghr1 and ctsl) and stress (plasma cortisol) were measured using targeted approaches. Results No differences in Gill Na+, K + –ATPase activity and plasma cortisol were detected between the two groups. However, a significant downregulation in plasma IGF-I and liver igf1 transcription pointed at this growth factor as an important pathomechanism for GS. Changes in the liver proteome revealed reactive-oxygen-species-mediated endoplasmic reticulum stress as a key mechanism underlying the GS phenotype. From the lipidomic analysis, key observations include a reduction in triacylglycerols and elevated amounts of cardiolipins, a characteristic lipid class associated with oxidative stress, in GS phenotype. Conclusion While the triggers to the activation of endoplasmic reticulum stress are still unknown, data from this study point towards a nutritional deficiency as an underlying driver of this phenotype.

Impact of hydrocortisone and of CRH infusion on the hypothalamus-pituitary-adrenocortical axis of septic male mice

Purpose Sepsis is hallmarked by high plasma cortisol/corticosterone (CORT), low adrenocorticotropic hormone (ACTH) and high pro-opiomelanocortin (POMC). While corticotropin-releasing hormone-(CRH) and arginine-vasopressin-(AVP) driven pituitary POMC expression remains active, POMC processing into ACTH becomes impaired. Low ACTH is accompanied by loss of adrenocortical structure, although steroidogenic enzymes remain expressed. We hypothesized that treatment of sepsis with hydrocortisone (HC) aggravates this phenotype whereas CRH infusion safeguards ACTH-driven adrenocortical structure. Methods In a fluid-resuscitated, antibiotics-treated mouse model of prolonged sepsis, we compared the effects of HC and CRH infusion with placebo, on plasma ACTH, POMC and CORT and on markers of hypothalamic CRH and AVP signaling and pituitary POMC processing, and on the adrenocortical structure and markers of steroidogenesis. In adrenal explants, we studied the steroidogenic capacity of POMC. Results During sepsis, HC further suppressed plasma ACTH, but not POMC, predominantly by suppressing sepsis-activated CRH/AVP-signaling pathways. In contrast, in CRH-treated sepsis, plasma ACTH was normalized following restoration of pituitary POMC processing. The sepsis-induced rise in markers of adrenocortical steroidogenesis was unaltered by CRH and suppressed partially by HC which also increased adrenal markers of inflammation. Ex vivo stimulation of adrenal explants with POMC increased CORT as effectively as an equimolar dose of ACTH. Conclusions Treatment of sepsis with HC impaired integrity and function of the HPA axis at the level of the pituitary and the adrenal cortex while CRH restored pituitary POMC processing without affecting the adrenal cortex. Sepsis-induced high circulating POMC may be responsible for ongoing adrenocortical steroidogenesis despite low ACTH.

Efficacy of Nx4 to Reduce Plasma Cortisol and Gastrin Levels in Norwegian Sled Dogs During an Exercise Induced Stress Response: A Prospective, Randomized, Double Blinded, Placebo-Controlled Cohort Study

Introduction: An exercise induced stress response is commonly seen in high performance sled dogs, resulting in increased plasma cortisol. A stress induced rise of cortisol might result in increased prevalence of gastritis and gastric ulcers mediated by an increase of gastrin. Neurexan® (Nx4) is a medicinal product used for stress relief by reduction of cortisol. The aim of the study was to show that Nx4 reduces plasma cortisol and plasma gastrin in high performance sled dogs and to show tolerability of Nx4 in dogs.Material and Methods: First, a pilot study was done to validate the increase of cortisol by performance. The data from the pilot study was used for sample size estimation via an adapted power analysis as well as the identification of important variables. These were then used in the randomization procedure of the main study. Second, a prospective randomized, double blinded, placebo-controlled cohort study was conducted. The main study included 45 sled dogs, assigning 23 dogs to the Nx4 group, and 22 dogs to the placebo group, to analyze plasma cortisol and plasma gastrin at four time points: before, directly after and 30 and 120 min after performance.Results: For the main target variable, area under the curve (AUC) of plasma cortisol, a significantly lower adjusted mean value in the Nx4 group compared to the placebo group (p = 0.031) was found. Plasma gastrin was also significantly reduced in the Nx4 group 30 min after performance (p = 0.023), resulting in a significantly reduced plasma gastrin AUC in the Nx4 group compared to the placebo group (p = 0.049).Discussion: Within the limitation of the study, the results carry implications for the usefulness of Nx4 to reduce exercise induced plasma cortisol and gastrin levels. The reduction of the exercise induced stress response could help to improve the welfare of high-performance sled dogs. Since activation of the hypothalamic-pituitary-adrenal axis resulting in increased cortisol is similar for exercise induced stress and psychologic stress, the same might be true independent of the stressor, making Nx4 potentially useful in any stressful situation for dogs.

Adaptogens as anti-stress agents in reducing increased plasma cortisol level during stress

The stress response involves the activation of both the sympathetic-adrenal response and the hypothalamic-pituitary-adrenal axis. During times of increased stress, the adrenal gland is stimulated to produce increased levels of hormones. Cortisol, the main hormone involved in the stress response, is secreted in increased amounts within minutes of a perceived stressor. Cortisol secretion can increase as much as 20-fold and has several important physiological effects. Short-term surges in cortisol levels can suppress inflammation and at the same time suppress immune function. Though inflammation control is important, surges of sustained levels of cortisol are not healthy and ultimately lead to premature aging, degenerative disease, and increased susceptibility to cancer. Studies show that psycho-social stress activates the hypothalamus-pituitary-adrenal axis causing an increase in morning cortisol levels, which correlated to the subjects reports of increased fatigue and anxiety. Although this stress response is important for survival during an acute stressor, prolonged activation of the stress response may lead to adrenal exhaustion in which cortisol levels drop to insufficient levels resulting in fatigue or illness. Many herbs have been shown to impact adrenal function. Adaptogens are plants that produce a non-specific response improving the physiological resistance to stressors. These herbs are often used in the context of adrenal support formulas to balance adrenal hormone levels. It is believed that adaptogenic herbs can increase low levels of adrenal hormone or decrease levels that are elevated. Additionally, these herbs provide balancing activity on many body systems that are impacted by stress, such as the immune response and blood sugar control.In the present study, we have evaluated the efficacy of ethanolic extract of Ocimum sanctum 47mg/kg p.o, Withania somnifera 23 mg/kg p.o and Bacopa monnieri 23 mg/kg p.o on plasma cortisol level in mice subjected to swim endurance test and cold restraint stress. The standard group was administered water-soluble root powder of Panax ginseng 100 mg/kg p.o and the stress control group was administered distilled water orally for 7 days. It was found that mice pretreated with ethanolic extracts of Ocimum sanctum, Withania somnifera and Bacopa monnieri showed a fall in the plasma cortisol level. The standard group also showed a significant decrease in the plasma cortisol level compared to the stress and normal control groups.

245 Prenatal Transportation Stress Does Not Impact Ovarian Follicle Count in Brahman Offspring

Calves from transported dams had greater concentrations of plasma cortisol when restrained and cleared plasma cortisol at a slower rate than calves from non-transported dams. Considering this hypothalamic-pituitary-adrenal axis effect, investigation of other parameters influencing reproduction is warranted in offspring exposed to prenatal transportation stress. The purpose was to determine impact of prenatal transportation stress on offspring ovarian follicle count. Brahman cows were transported for 2 h on d 60, 80, 120, and 140 (± 5 d) of gestation. Offspring from transported (Stressed, n = 19) or non-transported (Control, n = 15) dams were slaughtered at 5 yr (Replication 1, n = 14) or ovariectomized at 8 yr (Replication 2, n = 20). A cross-section of ovary was collected, serially sectioned, and stained. Numbers of total, primordial, primary, secondary, and antral follicles were determined per section. Total ovarian follicle count for each stage was calculated using ovary dimensions. The MIXED procedure of SAS was used to analyze ovarian follicle count with treatment, replicate, and the interaction as fixed effects. Total ovarian follicle count decreased with age (P &lt; 0.01; R1 = 383,663, R2 = 154,560); however, there was no difference in total ovarian follicle count between offspring due to treatment (P = 0.17; S = 221,813, C = 316,409). Similarly, there was no difference in primordial (P = 0.22; S = 127,300, C = 188,304), primary (P = 0.28; S = 58,610, C = 77,237), or antral (P = 0.48; S = 23,202, C = 28,695) follicle count between offspring due to treatment. Fewer secondary follicles were observed in Stressed offspring compared to Control offspring (P = 0.03). These results suggest that the ovarian follicular reserve, AFC, and potential fertility of cows may not be impacted by exposure to prenatal transportation stress. USDA is an equal opportunity provider and employer.