Epinephrine Levels Research Articles

Impact of Aerobic Exercise on Brain Metabolism: Insights from Spatial Metabolomic Analysis.

Exercise is acknowledged for its beneficial effects on brain health; however, the intricate underlying molecular mechanisms remain poorly understood. This study aimed to explore aerobic exercise-induced metabolic alterations in the brain. We conducted an eight-week treadmill running exercise program in two-month-old male C57/BL6J mice. Body weight, serum lipid, glucose levels, and spatial cognition were measured. Spatial metabolomic analysis was performed to compare the metabolomic profiles across different brain regions. Immunohistochemical methods were used to compare the expression of carnitine palmitoyltransferase 1c (CPT1c). Exercise induced significant changes in the analysed metabolomic profiles. There were 904 differentially expressed metabolites (DEMs) detected in the whole brain section. Notable alterations in lipid profiles were observed, and among the 292 lipids detected, there were 74 (25.34%), 85 (29.11%), and 78 (26.71%) lipids differentially expressed in the hippocampus, thalamus, and hypothalamus of the Exe group, respectively. Lipid metabolism related pathways and enzymes were also altered, with L-carnitine and CPT1c upregulated in the three regions (p<0.05), and epinephrine levels decreased in the hippocampus (p<0.05). Furthermore, the vitamin B6 metabolism pathway was altered in the hypothalamus. This study highlighted the significant changes in lipid metabolism induced by involuntary exercise in the brains of young male mice. Exercise also altered epinephrine levels and the vitamin B12 metabolic pathway in specific brain regions, which indicated the multifaceted effects of exercise on the brain.

Effects of circuit weight training by intensity on stress hormones and antioxidant capacity in high-school wrestlers.

We aimed to investigate the effects of 8-week circuit weight training by intensity on blood stress hormones and antioxidant capacity in high-school wrestlers. This study involved 27 male wrestlers with >2 years of wrestling experience who were randomly assigned to either a low intensity (n=13) or a high-intensity circuit weight training group (n=14). The participants performed circuit weight training for 60 min per session, 3 times per week for 8 weeks. The low- and high-intensity circuit weight training exercises were performed at 50%-60% and 70%-80% of one-repetition maximum for 10 stations, respectively, and 8-15 repeated sessions per station were performed in order. No changes were observed in adrenocorticotropic hormone (ACTH), cortisol, epinephrine, and norepinephrine levels between the two training groups. When compared to levels before the training, ACTH and epinephrine levels decreased, whereas cortisol levels increased. However, no difference was observed in norepinephrine levels. Further, no differences were observed in malondialdehyde (MDA) and glutathione peroxidase (GPX) levels between the two groups. However, MDA and GPX levels were increased from those before training. Changes in superoxide dismutase levels were observed between the two groups, but the change was significant only in the high-intensity circuit weight training group. Long-term training did not increase lipid peroxidation, but increased the activity of antioxidant enzymes that defend against oxidative stress. The antioxidant defense system in tissues can be regulated by exercise intensity as well as physical training status.

Effects of Multimodal Analgesia Combined with Comfort Management on Pain and Stress Indexes in Patients with Orthopedic Trauma after Intervention: A Retrospective Study.

This study aims to assess the impact of combining multimodal analgesia with comfort care on pain levels, stress, negative emotions, and quality of life in individuals recovering from traumatic fractures. This retrospective study analyzed clinical data from traumatic fracture patients who underwent emergency operations at our hospital between June 2022 and February 2024. Patients were divided into two groups based on their postoperative pain management: the control group, which received standard measures, and the exposure group, which received a combination of multimodal analgesia and comfort-based care. We compared these groups for pain intensity (baseline and activity Visual Analog Scale (VAS) scores), serum stress biomarkers (norepinephrine, adrenaline, cortisol), emotional distress (self-rating depression scale (SDS), and the self-rating anxiety scale (SAS)), and overall quality of life (Comprehensive Quality of Life Assessment Questionnaire (GQOLI-74) score). Overall, this study evaluated differences in postoperative complications between the two pain management approaches. In this study, we included 101 participants, 41 in the exposed group and 60 in the control group. Before the intervention, baseline characteristics were similar between the two groups (p > 0.05). However, one week after the intervention, the resting and active VAS scores were significantly reduced in the exposed group than in the control group (p < 0.05). Furthermore, one week after the intervention, the exposed group had lower levels of serum sodium, epinephrine, cortisol, stress, and anxiety, as well as higher physical and mental health scores on the GQOLI-74 scale. During the intervention period, there was no significant difference in postoperative complications between the two groups (p > 0.05). Combining multi-mode analgesia with comfort management for patients with traumatic fractures significantly reduces postoperative pain and stress levels. Additionally, this approach can effectively enhance patients' negative emotions and improve their quality of life. This approach holds significant promise for practical use in clinical settings.

Endotracheal Tube Cuff Deflation Methods Reduce Stress Response and Incidence of Postoperative Pharyngeal Complications in Patients Treated with Gynecological Laparoscopic Surgery.

This study aims to explore the impact of endotracheal tube cuff deflation methods on extubation stress responses and postoperative pharyngeal complications in patients treated with gynecological laparoscopic surgery. In this study, retrospective clinical data of 94 patients treated with gynecological laparoscopic surgery under general anesthesia in Northwest Women's and Children's Hospital from June 2023 to June 2024 were collected and analyzed. Patients were assigned into two groups based on the cuff deflation methods used after anesthesia: Group A (45 patients) adopted a one-time deflation method, while Group B (49 patients) employed a gradual deflation method. Surgery-associated indicators were recorded, with heart rate (HR), mean arterial pressure (MAP), rate pressure product (RPP), epinephrine (E), norepinephrine (NE), and cortisol (Cor) levels monitored at selected time points: before cuff (T0), immediately after extubation (T1), 1 minute post-extubation (T2), 5 minutes post-extubation (T3), and 10 minutes post-extubation (T4). The incidence of pharyngeal complications was also compared between the two groups. Compared with Group A, Group B displayed smaller variations in HR, MAP, and RPP at T1, T2, and T3 (p < 0.05). Group B also showed smaller variations in E, NE, and Cor levels at T2, T3, and T4 in contrast with Group A (p < 0.05). The incidence of complications such as coughing, sore throat, and hoarseness was conspicuously attenuated in Group B compared to Group A (6.12% vs 22.22%, p < 0.05). Gradual deflation of the endotracheal tube cuff dramatically ameliorates extubation stress responses, stabilizes hemodynamics, and alleviates pharyngeal discomfort in patients treated with gynecological laparoscopic surgery.

Comparative analysis of the therapeutic efficacy of remimazolam tosylate and propofol in older adults undergoing painless endoscopic retrograde cholangiopancreatography.

The aim of this study is to conduct a comparative analysis of the therapeutic outcomes associated with the administration of remimazolam and propofol during painless endoscopic retrograde cholangiopancreatography (ERCP) procedures in older adults. A total of 140 older adults who underwent elective painless ERCP were randomly assigned to two groups using the random number table method: the remimazolam group and the propofol group, each consisting of 70 patients. In the remimazolam group, anesthesia was administered using a combination of remimazolam and opioids, while in the propofol group, a combination of propofol and opioids was used. Comparative assessments between the two groups included anesthesia induction time, first induction success rate, intraoperative hemodynamics, awakening duration, stress response index, and the incidence of adverse reactions. The remimazolam group exhibited a prolonged anesthesia induction time compared to the propofol group and a lower success rate of first induction (P < 0.05). At the point of endoscope entry (T2) and 10min post-operation (T3), patients in the remimazolam group demonstrated higher mean arterial pressure (MAP), heart rate (HR), and bispectral index (BIS) values compared to those in the propofol group (P < 0.05). Furthermore, the remimazolam group had shorter durations for eye-opening, consciousness recovery, and residence in the recovery room compared to the propofol group (P < 0.05). Post-surgery levels of epinephrine (E), norepinephrine (NE), and cortisol (Cor) at 24h were lower in the remimazolam group than in the propofol group (P < 0.05). The incidence of adverse reactions was significantly lower in the remimazolam group (18.57%) compared to the propofol group (31.43%) (P < 0.05). Remimazolam exhibits a longer induction time compared to propofol in the painless diagnosis and treatment of ERCP in older adults. However, it provides a more stable circulatory state post-induction and throughout the operation, reduces stress response, enables rapid recovery, and has a lower incidence of serious adverse reactions. These attributes suggest that remimazolam has potential for widespread clinical application and adoption. clinicaltrials.gov, identifier ChiCTR2400080926.

Adrenaline Auto-Injectors for Preventing Fatal Anaphylaxis.

Anaphylaxis affects up to 5% of people during their lifetime. Although anaphylaxis usually resolves without long-term physical consequences, it can result in anxiety and quality of life impairment. Rarely and unpredictably, community anaphylaxis can cause rapid physiological decompensation and death. Adrenaline (epinephrine) is the cornerstone of anaphylaxis treatment, and provision of adrenaline autoinjectors (AAI) has become a standard of care for people at risk of anaphylaxis in the community. In this article, we explore the effectiveness of AAIs for preventing fatal outcomes in anaphylaxis, using information drawn from animal and human invivo studies and epidemiology. We find that data support the effectiveness of intravenous adrenaline infusions for reversing physiological features of anaphylaxis, typically at doses from 0.05 to 0.5 μg/kg/min for 1-2 h, or ~ 10 μg/kg total dose. Intramuscular injection of doses approximating 10 μg/kg in humans can result in similar peak plasma adrenaline levels to intravenous infusions, at 100-500 pg/mL. However, these levels are typically short-lived following intramuscular adrenaline, and pharmacokinetic and pharmacodynamic outcomes can be unpredictable. Epidemiological data do not support an association between increasing AAI prescriptions and reduced fatal anaphylaxis, although carriage and activation rates remain low. Taken together, these data suggest that current AAIs have little impact on rates of fatal anaphylaxis, perhaps due to a lack of sustained and sufficient plasma adrenaline concentration. Effects of AAI prescription on quality of life may be variable. There is a need to consider alternatives, which can safely deliver a sustained adrenaline infusion via an appropriate route.

Alterations and clinical value of peripheral lymphocyte subsets and inflammatory factors in paragangliomas.

Given the pivotal role of immune and inflammatory responses in tumor patients, the present study aimed to explore alterations and the clinical value of peripheral lymphocyte subsets and inflammatory factors in pheochromocytomas/paragangliomas (PPGLs). The clinical data of 327 patients, including 102 patients with metastatic PPGLs, were retrospectively analysed. Peripheral lymphocyte subsets were determined by flow cytometry. Relationships between immune and inflammatory parameters and clinicopathological characteristics were evaluated by intergroup comparisons and correlation analyses. Univariate and multivariate logistic regression analyses were employed to identify metastatic indicators. The corresponding nomogram was constructed and evaluated for discrimination and calibration. The median age at diagnosis was 45.0 years, and duration of follow-up was 3.0 years. Compared with those in younger patients (<45.0 years), most lymphocyte subsets were significantly reduced in older patients (≥45 years) (P<0.05). The count of lymphocytes, CD3+T cells and CD4+T cells were negatively correlated with 24h-urinary epinephrine and plasma metanephrine levels (R=-0.2∼-0.1, P<0.05). In addition, patients with lymph node (n=37) or bone metastases (n=41) had a lower percentage of CD4+T cells (P<0.05). Multivariate analysis revealed that CD3+T cell≥1446.50/μl, CD4+T cell%<39.95%, CD8+T cell%<24.95%, CD4+/CD8+T cell ratio<2.88, B cell%≥8.65%, TNF-alpha<12.45pg/ml, IL8<30.50pg/ml and PLT≥269.50*109/L were significant indicators of metastatic PPGLs. The area under the curve (AUC) of the nomogram was 0.800 (95% CI: 0.736-0.865). Immunesenescence, characterized by immune dysfunction with aging, was observed in PPGLs. Higher epinephrine and metanephrine levels might impair host's immune response. Monitoring changes in peripheral lymphocyte subsets and serum cytokines could indicate patients' conditions, especially the occurrence of metastasis.

8358 A Diagnostic Challenge: Occult Paraganglioma Misdiagnosed as Pheochromocytoma Leading to Unnecessary Adrenalectomy

Abstract Disclosure: A.R. Kasireddy: None. S. Alshami: None. S. Gummalla: None. C. Balasubramaniapandian: None. J.A. Henske: None. A. Albashaireh: None. Background: Pheochromocytomas and paragangliomas are rare neuroendocrine tumors. Catecholamine-secreting paragangliomas, like pheochromocytomas, can present with hypertension, sweating and episodic headaches. Thoughtful consideration must be given to distinguish between the two and potentially avoid a critical misdiagnosis. Case: A 61-year-old woman with hypertension and diabetes presented for evaluation of glomus jugulare discovered on CT of the head during evaluation of worsening hearing loss and tinnitus. She reported a longstanding history of episodic headaches, palpitations, anxiety spells and excessive sweating with more recent onset of ear fullness. When symptoms first presented, she had a left adrenalectomy 3 years prior. CT abdomen at that time showed 1.8 x 2.2 cm left adrenal nodule with a density of 12.2 HU and early contrast washout. Plasma metanephrines were normal but normetanephrines were elevated at 5.1 nmol/L (nl: less than 0.9 nmol/L). 24-hour urine metanephrines were normal but normetanephrines were elevated to 892mcg/24h (nl: 122-676 mcg/24h). MIBG scan was done and showed increased activity in the left adrenal nodule. Decision was made to proceed with left adrenalectomy. Surgical pathology was benign. Present evaluation after discovery of the glomus tumour with worsening symptoms showed normal plasma metanephrines, elevated plasma normetanephrines at 1529.9 pg/ml (0- 285.2 pg/ml), elevated plasma norepinephrine at 3280 pg/ml (0-874 pg/ml), with normal dopamine and epinephrine levels. CT head showed a 3 x 2.7 x 2.1 cm lytic destructive mass within the petrous temporal bone at the left skull base containing multiple internal calcifications. Given the lab and imaging findings, paraganglioma was diagnosed. Genetic testing revealed SDHB mutation. Neurosurgery consultants determined that the tumour was not amenable to resection. She was treated with radiation therapy, alpha blockade, and close blood pressure monitoring. Discussion: This case highlights the importance of reviewing the degree of hormonal elevations as well as the pattern of elevation to obtain a correct diagnosis. Paragangliomas commonly secrete normetanephrines rather than metanephrines and are often not immediately localized. Understanding the most likely genetic mutations when a paraganglioma is suspected can direct appropriate choice of radionuclide scanning agents. In this case, an earlier diagnostic scan may have prevented unnecessary adrenalectomy and facilitated earlier discovery of the paraganglioma. Presentation: 6/2/2024

6701 Bilateral Adrenal Hematomas As Initial Presenting Sign Of Lung Adenocarcinoma

Abstract Disclosure: S. Gumireddy: None. R. Panta: None. Y. Shaikh: None. Introduction: Lung cancer typically presents with dyspnea, chest pain, hemoptysis, weight loss, or recurrent pulmonary infections. This case illustrates primary lung adenocarcinoma presenting with abdominal pain and bilateral adrenal hematomas. Clinical Case: 51-year-old male presented to the emergency department with left sided abdominal pain persisting for one week. CT abdomen showed a left suprarenal mass measuring 4.5 x 5 x 4.3cm indicating an acute adrenal hematoma. An MRI showed a partially solid left adrenal lesion that had hemorrhaged and a 1.3cm hemorrhagic nodule in the right adrenal gland. The patient remained hemodynamically stable. Hormonal evaluation done while patient was in the hospital showed renin level 0.417ng/mL/hr, aldosterone level &amp;lt;1.0ng/dL, epinephrine level 312pg/mL, norepinephrine level 333pg/mL, cortisol 11.3, ACTH level 13, plasma metanephrine levels 93pg/mL, plasma normetanephrine levels 111.7pg/mL, DHEA-S 151mcg/dL, potassium 4.1mmol/L, raising concern for hypersecretion. Patient was discharged with plans for outpatient follow-up but was readmitted in two months due to worsening abdominal pain. Repeat imaging revealed an increase in size of adrenal lesions, measuring 3.3 x 3.6 cm within the right adrenal gland and a 6.7 x 6.3 cm heterogeneously enhancing lesion within the left adrenal gland concerning for metastatic disease to bilateral adrenals and to the ileum causing small bowel obstruction. Chest imaging showed a 2.2cm irregular right apical nodule. Subsequent hormonal evaluation showed normalization of plasma metanephrine levels at 15.8pg/mL, renin level 3.314ng/mL/hr, aldosterone level 4.3ng/dL, deoxycorticosterone level 4.8ng/dL, androstenedione level 40ng/dL, plasma normetanephrines 146.4pg/mL. The patient underwent left adrenal gland mass biopsy which showed metastatic poorly differentiated adenocarcinoma of pulmonary origin. Tumor cells were positive for keratin cocktail, TTF1 and synaptophysin supporting the morphologic interpretation. Patient is currently receiving treatment with carboplatin, pemetrexed, and pembrolizumab. Conclusion: Adrenal masses can be unilateral (85%) or bilateral (15%). While most unilateral adrenal masses are benign and nonfunctional, bilateral adrenal masses are likely to be metastatic disease, hemorrhage, infiltrative disease, congenital adrenal hyperplasia, macronodular Cushing’s syndrome, or bilateral cortical adenomas. Although uncommon, our case highlights the importance of considering metastatic disease to the adrenal glands as a potential initial manifestation of primary cancers. The most likely primary cancers to metastasize to the adrenal glands are breast, lung, colon, kidney, and esophagus. Presentation: 6/1/2024

12394 "Sugar And Tumors: A Case Report On New-onset Diabetes In Metastatic Pheochromocytoma With Elevated Dopamine Levels"

Abstract Disclosure: B. Agrawal: None. V. mehta: None. R. naseem: None. M. Renzu: None. R. rashid: None. Introduction: Metastatic pheochromocytoma is a rare neuroendocrine tumor with potential complication of new-onset diabetes mellitus (DM). We present a case highlighting the challenges in managing a patient with metastatic pheochromocytoma and concurrent DM. Case presentation: A 66-year-old male with a history of hypertension and gout initially presented in 2010 with an adrenal mass, later identified as pheochromocytoma and resected. In 2018, he presented with bilateral leg pain, revealing metastatic disease-causing spinal cord compression along with metastatic lung nodules and metastasis in adrenalectomy bed. Despite interventions including T6,7,8 laminectomy in 2020 and radiation therapy, metastases persisted. In 2024, he presented with polyuria, polydipsia, and hyperglycemia (blood glucose &amp;gt;500 mg/dL). Laboratory findings showed elevated a1c of 15 in addition to elevated normetanephrines, metanephrines, and dopamine with levels of 3880, 48 and 488 respectively. He was diagnosed with new-onset DM and started on insulin therapy in addition to metformin and jardiance. Discussion: Secondary diabetes mellitus (DM) in secretory pheochromocytoma occurs in approximately 50% of cases, manifesting from mild insulin resistance to severe presentation like DKA. Epinephrine-secreting tumors contribute to glucose intolerance by activating beta receptors, thereby stimulating gluconeogenesis. Patients with higher levels of epinephrine and preoperative glucose intolerance were more prone to developing postoperative hypoglycemia, requiring close monitoring during the postoperative period. Additionally, research by DiSalvo et al. Epinephrine-secreting tumors have a more significant impact on hyperglycemia by impairing insulin secretion and stimulation GLP-1. Tumor resection has been found to be more effective effective in restoring normal glucose homeostasis in these patients. Dopamine-secreting pheochromocytomas are rare neoplasms characterized by the presence of immature catecholamine vesicles that inhibit dopamine conversio owing to localized dopamine beta hydroxylase. Typically presenting around the age of 48, these tumors often lack excess catecholamines, leading to atypical symptoms such as local discomfort or pain from tumor compression. These neoplasms are less detectable on metaiodobenzylguanidine (MIBG) scans, necessitating positron emission tomography (PET) for accurate diagnosis. Surgical resection is the treatment, with preoperative management involving metyrosine instead of alpha blockers. These tumors are frequently diagnosed late, often in a malignant stage, contributing to poor prognosis Conclusion: Overall, understanding the complex interplay between catecholamines and glucose metabolism is crucial for the comprehensive management of patients with pheochromocytoma and secondary DM. Presentation: 6/1/2024

6606 Connshing Syndrome: An Uncommon Presentation Of Bilateral Adrenal Mass

Abstract Disclosure: C.S. Botero Suarez: None. N. Meda: None. K. Lamar: None. S.K. Suryanarayanan: None. Introduction: Mild autonomous hypersecretion of cortisol in the underlying setting of hyperaldosteronism has been described before and coined the term Connshing Syndrome. Even though it was described in 1979, recently W. Arlt et al in 2017 revived interest in the topic of Connshing Syndrome represents a distinct entity among PA (primary hyperaldosteronisms). We present a case of bilateral adrenal mass associated with mild autonomous hypersecretion of cortisol as well as the development of primary aldosteronism. Case Description: A 62-year-old male with a medical history of hyperlipidemia, hypertension, spontaneous hypokalemia, and T2DM was referred to the clinic due to concerns for hyperaldosteronism. Exam was unremarkable for signs of hypercortisolism. Blood pressure in the clinic was 143/88 mmHg, pulse 81 bpm, weight 105.4 Kg (231.8 lbs.), and a BMI of 28 kg/m2. A non-contrast abdominal CT performed, showed a 2.9 x.1.4 cm right adrenal lipid-rich adenoma with -3.7 HU, as well as a left adrenal lipid-rich adenoma of 1.8 x 1.3 x cm and -7.7 HU. A hormonal workup showed normal plasma metanephrines, an aldosterone of 39 ng/dL, plasma renin activity 0.16 ng/mL/h, and aldosterone/PRA ratio of 243. The patient underwent 1 mg dexamethasone suppression test which resulted in an ACTH &amp;lt;5 pg/mL, dexamethasone level of 288 ng/dL, and cortisol of 1.9 mcg/dL. AVS with Cosyntropin was performed (see Table 1). Right sided adrenalectomy is being considered but the identification of possible lateralization of cortisol is being considered. Discussion: Surgical management is usually preferred treatment modality for both unilateral PA and MACS, but identification of lateralization of both cortisol and aldosterone can be difficult. Although identifying lateralization of aldosterone with Cosyntropin-stimulated AVS is well understood, lateralization of cortisol production is not well understood. Johnson et. all have suggested the use of adrenal venous sampling with dexamethasone suppression as well as measurement of epinephrine levels to identify the source of hypercortisolism. They demonstrated identification of cortisol lateralization with adrenal vein sampling with specificity of 95 – 100% for unilateral disease utilizing a AV/IVC cortisol ratio &amp;gt; 9 and a cortisol lateralization ratio (CLR) of &amp;gt; 2.3. Although our case had a Cosyntropin-stimulated AVS showing clear lateralization of aldosterone production to the right adrenal, the lateralization of cortisol production is yet unknown and AVS with dexamethasone suppression is being considered. Although the treatment considerations are traditionally utilizing the guidelines for both PA and Cushing Syndrome guidelines respectively, very little is known when there are divergence of autonomous secretion amongst the bilateral adrenal masses and more studies are needed to clarify the long-term treatment considerations. 1 Presentation: 6/3/2024

Hand cooling induces changes in the kinetics of oxygen uptake

The objective of this investigation was to assess the impact of elevated catecholamine concentrations, induced through cold-water hand immersion, on the oxygen consumption (V̇O2) kinetics during intense exercise, and to contrast this effect with that of the priming effect. Ten active participants underwent three 8-minute constant work rate exercises (CWR) at ∆25%, with one CWR preceded by hand cooling (2 min at 0 °C, HC) and two consecutive CWR to induced priming effect on the second bout (SB). Pulmonary gas exchange and blood samples were analyzed to measure levels of epinephrine (E) and norepinephrine (NE). Results demonstrated a significant increase in the primary phase amplitude of V̇O2 kinetics in response to both hand HC (33.9 mL.min−1.kg−1; CI [32.2;35.7], p < 0.001) and SB (34.6 mL.min−1.kg−1; CI [33.0;36.3], p < 0.001) relative to the control (32.7 mL.min−1.kg−1; CI [31.5;35.1]). Additionally, the amplitude of the V̇O2 slow component was reduced for both HC (3.2 mL.min−1.kg−1; CI [2.2;4.1], p = 0.018) and SB (2.9 mL.min−1.kg−1; CI [1.8;4.2], p = 0.009) in comparison to control (3.9 mL.min−1.kg−1; CI [2.9;4.2]). These findings suggest that the increase in E and NE induced by hand cooling prior to exercise modifies V̇O2 kinetics in a manner akin to the priming effect. This research underscores the potential role of catecholamines in facilitating the priming effect and its subsequent impact on V̇O2 kinetics. However, further studies are necessary to clearly establish this link.

Pharmacokinetic and Pharmacodynamic Profile of Epinephrine Nasal Spray Versus Intramuscular Epinephrine Autoinjector in Healthy Adults

BackgroundStandard of care for anaphylaxis treatment is intramuscular (IM) epinephrine. An epinephrine nasal spray (ENS) is under development as an alternative form of administration. ObjectiveTo compare the pharmacokinetic (PK) and pharmacodynamic (PD) profile of 13.2 mg ENS with 0.3 mg IM epinephrine auto-injector. MethodsData from 4 open-label phase 1 crossover studies conducted in healthy adults were pooled to determine the PK and PD profile of a single 13.2 mg ENS dose delivered by 2 consecutive sprays of 6.6 mg each in opposite (n=224 doses) or the same nostril (n=75 doses) compared with the 0.3 mg IM auto-injector (n=215 doses). Each participant served as their own control. Blood samples and vital signs were collected pre-dose and at multiple intervals from 0-360 minutes post-dose. ResultsENS rapidly increased the plasma epinephrine concentration, with levels that were overall greater than IM auto-injector. Median (range) time to maximum plasma epinephrine concentration with ENS opposite nostrils, ENS same nostril, and IM auto-injector was 25.1 (1.3, 362.1), 20.1 (3.0, 120.2), and 20.0 (1.0, 121.3) minutes, respectively. The area under the plasma concentration–time curve for 0-360 minutes was significantly higher with ENS than the IM auto-injector (geometric mean ratio [90% CI]=155% [140%, 172%] with ENS opposite nostrils, 159% [138%, 182%] with ENS same nostril). The PD effects on heart rate and blood pressure were similar in pattern and magnitude among all 3 treatment groups. ConclusionsENS rapidly achieved plasma epinephrine levels greater and more sustained than the IM auto-injector and with a similar PD effect.

Development and Validation of Stability Indicating HPLC Method for the Determination of Related Substances in Droxidopa Drug Substance.

Droxidopa, a synthetic amino acid precursor to norepinephrine, was licensed by the FDA in 2014 to treat neurogenic OH. The enzyme L-amino acid decarboxylase in sympathetic neurons converts Droxidopa to norepinephrine, which raises the amount of norepinephrine in the blood.1 Because noradrenaline crosses the blood-brain barrier poorly. Droxidopa is used to raise the concentration of noradrenaline in the brain instead of noradrenaline itself. It is recommended for the treatment of dopamine beta-hydroxylase deficiency, non-diabetic autonomic neuropathy, orthostatic dizziness, and lightheadedness in adult patients with symptomatic neurogenic orthostatic hypotension resulting from primary autonomic failure (Parkinson’s disease, multiple system atrophy, and pure autonomic failure.2-5 It is a synthetic analog of catecholamine acid that raises norepinephrine and epinephrine levels throughout the body by being immediately metabolized by dopa-decarboxylase. In the CNS, it also penetrates the blood-brain barrier to carry out its pharmacological actions. Through the induction of peripheral arterial and venous vasoconstriction, it raises blood pressure peripherally and causes slight, momentary increases in plasma norepinephrin.

Hypertension and its correlation with autonomic nervous system dysfunction, heart rate variability and chronic inflammation

Objective This study investigates the relationship between hypertension, dysregulation of the autonomic nervous system, heart rate variability (HRV), and chronic inflammation. Methods We analysed a cohort of 50 hypertensive patients treated at the affiliated Hospital of Jianghan University. The average systolic and diastolic blood pressures (BPs) in this group were 155.26 and 95.32 mmHg, respectively. A control group of 50 healthy volunteers, undergoing routine physical examinations at the same hospital, was also analysed. Results The average systolic BP of the control group was 115.64 ± 10.27 mmHg, and the average diastolic BP was 75.33 ± 8.25 mmHg. In contrast, the experimental group exhibited an average systolic BP of 155.26 ± 20.13 mmHg and an average diastolic BP of 95.32 ± 12.16 mmHg. Both systolic and diastolic BPs were significantly higher in the hypertensive group (p < 0.05). The experimental group also demonstrated reduced HRV and skin conductance response, alongside increased BP variability (BPV), urinary epinephrine levels and prolonged pupillary light reaction time compared to controls (p < 0.05). Notably, Standard Deviation of Normal to Normal Intervals (SDNN) and Root Mean Square of Successive Differences (RMSSD) values were significantly lower in the experimental group (p < 0.05). Furthermore, levels of inflammatory markers such as CRP, TNF-α, IL-6 and IL-1β were markedly elevated in hypertensive patients (p < 0.05). Negative correlations were observed between systolic and diastolic BP with HRV metrics, while positive correlations were found between BP and BPV as well as urinary adrenaline levels. Conclusions The findings indicate that hypertension is closely associated with autonomic nervous system dysfunction, reduced HRV and increased chronic inflammation. A comprehensive approach to hypertension management should integrate these interrelated physiological and pathological mechanisms, with potential therapeutic interventions targeting autonomic function and inflammatory states.

The protective effects of chitosan and curcumin nanoparticles against the hydroxyapatite nanoparticles-induced neurotoxicity in rats

Hydroxyapatite nanoparticles (HANPs) have extensive applications in biomedicine and tissue engineering. However, little information is known about their toxicity. Here, we aim to investigate the possible neurotoxicity of HANPs and the possible protective role of chitosan nanoparticles (CNPs) and curcumin nanoparticles (CUNPs) against this toxicity. In our study, HANPs significantly reduced the levels of neurotransmitters, including acetylcholine (Ach), dopamine (DA), serotonin (SER), epinephrine (EPI), and norepinephrine (NOR). HANPs significantly suppressed cortical expression of the genes controlling mitochondrial biogenesis such as peroxisome proliferator activator receptor gamma coactivator 1α (PGC-1α) and mitochondrial transcription factor A (mTFA). Our findings revealed significant neuroinflammation associated with elevated apoptosis, lipid peroxidation, oxidative DNA damage and nitric oxide levels with significant decline in the antioxidant enzymes activities and glutathione (GSH) levels in HANPs-exposed rats. Meanwhile, co-supplementation of HANP-rats with CNPs and/or CUNPs significantly showed improvement in levels of neurotransmitters, mitochondrial biogenesis, oxidative stress, DNA damage, and neuroinflammation. The co-supplementation with both CNPs and CUNPs was more effective to ameliorate HANPs-induced neurotoxicity than each one alone. So, CNPs and CUNPs could be promising protective agents for prevention of HANPs-induced neurotoxicity.

Impact of Dexmedetomidine on Hemodynamics, Plasma Catecholamine Levels, and Delirium Incidence Among Intubated Patients in the ICU--A Randomized Controlled Trial.

To investigate the impact of various sedative medications on hemodynamics and plasma levels of epinephrine (E) and norepinephrine (NE) in mechanically ventilated patients postoperatively in the intensive care unit (ICU). Ninety-seven patients admitted to the ICU undergoing postoperative mechanical ventilation with tracheal intubation and continuous analgesic sedation following general anesthesia were randomly assigned to either the observation group (dexmedetomidine) (n = 49) or the control group (propofol) (n = 48) in this randomized controlled trial. Upon transfer to the ICU, vital signs (heart rate [HR], respiratory rate [RR], mean arterial pressure [MAP]) were recorded prior to the initiation of the sedation treatment (T0), at one-hour post sedation (T1) and two hours following tracheal extubation (T2), plasma levels of epinephrine (E) and norepinephrine (NE) were measured at these time points. The incidence of delirium was recorded in both groups. MAP between the two groups at both T0 and T1 At T2 plasma NE and HR were found to be lower in the observation group compared to the control group (P < 0.001). Among the patients receiving antihypertensive medication in the ICU, NE levels were significantly lower in the observation group compared to the control group (P = 0.019) Among the patients not receiving antihypertensive medication, both NE (P < 0.001) and MAP (P = 0.001) levels were lower in the observation group compared to the control group. The incidence of delirium in the observation group (dexmedetomidine) was not significantly different from that in the control group (propofol). With dexmedetomidine sedation, blood pressure fluctuated less, plasma catecholamine levels were lower, and sympathetic inhibition was stronger in patients before and after extubation. However, it did not significantly reduce the incidence of postoperative delirium.

Circulating factors, in both donor and ex-vivo heart perfusion, correlate with heart recovery in a pig model of DCD

BackgroundHeart transplantation with donation after circulatory death and ex-situ heart perfusion offers excellent outcomes and increased transplantation rates. However, improved graft evaluation techniques are required to ensure effective utilization of grafts. Therefore, we investigated circulating factors, both in-situ and ex-situ, as potential biomarkers for cardiac graft quality. MethodsCirculatory death was simulated in anesthetized male pigs with warm ischemic durations of 0, 10, 20, or 30 min. Hearts were explanted and underwent ex-situ perfusion for 3h in an unloaded mode, followed by left ventricular loading for 1h, to evaluate cardiac recovery (outcomes). Multiple donor blood and ex-situ perfusate samples were used for biomarker evaluation with either standard biochemical techniques or nuclear magnetic resonance spectroscopy. ResultsCirculating adrenaline, both in the donor and at 10 min ex-situ heart perfusion, negatively correlated with cardiac recovery (p <0.05 for all). We identified several new potential biomarkers for cardiac graft quality that can be measured rapidly and simultaneously with nuclear magnetic resonance spectroscopy. At multiple timepoints during unloaded ex-situ heart perfusion, perfusate levels of acetone, betaine, creatine, creatinine, fumarate, hypoxanthine, lactate, pyruvate and succinate (p <0.05 for all) significantly correlated with outcomes; the optimal timepoint being 60 min. ConclusionsIn heart donation after circulatory death, circulating adrenaline levels are valuable for cardiac graft evaluation. Nuclear magnetic resonance spectroscopy is of particular interest, as it measures multiple metabolites in a short timeframe. Improved biomarkers may allow more precision and therefore better support clinical decisions about transplantation suitability.

Comparison of Systemic Exposure Between Epinephrine Delivered via Metered-Dose Inhalation and Intramuscular Injection.

Background: Primatene® MIST, an epinephrine metered-dose inhaler (MDI), has long been questioned by some medical professionals for asthma treatment despite having been approved by the Food and Drug Administration. One of the primary reasons for their concerns stemmed from potential cardiovascular complications following epinephrine administration. However, the majority of documented cardiovascular complications seemed to occur following the injection route of the epinephrine. The aim of this study was to evaluate the systemic exposure of epinephrine delivered through different administration routes and to understand its relationship with cardiovascular effects. Since albuterol inhalers are commonly recommended for asthma, albuterol was also studied as a comparator drug. Method: A randomized, evaluator-blinded, three-arm crossover study was conducted in 28 healthy adult subjects to compare the profiles of systemic exposure for epinephrine delivered by MDI versus epinephrine intramuscular (IM) injection and albuterol MDI. Serially sampled plasma epinephrine and albuterol levels were measured and compared between treatment groups. Safety was assessed by adverse events, serial vital signs, electrocardiograms (ECGs), and clinical laboratory tests obtained at each crossover dosing visit. Results: Systemic exogenous drug exposure for inhaled epinephrine MDI (39 pg/mL × hour) was ∼9 times lower than that of epinephrine IM (435 pg/mL × hour) and 122 times lower than that of albuterol MDI (3453 pg/mL × hour) after dose normalization. The Cmax in epinephrine MDI (345 pg/mL) was approximately half of that of epinephrine IM (816 pg/mL) and that of albuterol MDI (681 pg/mL). Plasma drug concentrations for epinephrine MDI dropped rapidly to baseline (∼0.6 hour), while epinephrine IM took ∼8 hours, and albuterol MDI required more than 24 hours. Epinephrine MDI and albuterol MDI resulted in minimal, clinically insignificant changes in vital signs and ECGs, whereas epinephrine IM led to mild transient increases in systolic blood pressure, heart rate, and corrected QT interval. Conclusion: Epinephrine MDI (Primatene MIST) had ∼9 times lower systemic drug exposure (SDE) than that of epinephrine IM and ∼122 times lower than that of albuterol MDI. The lower SDE of inhaled epinephrine also correlated with reassuring safety findings, with no significant cardiovascular adverse effects found, compared with transient effects seen after IM epinephrine. Clinical trial registration number: NCT04207840.

Effects of Music Therapy on Postoperative Pain Perception in Patients Undergoing Abdominal Surgeries Under General Anesthesia: A Prospective Controlled Randomized Comparative Clinical Study.

Background Music therapy has been shown to reduce the need for sedation and analgesics, as well as lower plasma cortisol and epinephrine levels in patients undergoing regional anesthesia. This study evaluates the efficacy of perioperative music therapy in reducing pain perception and its impact on cortisol levels. Materials and methods This prospective randomized control trial was conducted at the tertiary care center in Western Maharashtra. Sixty adult patients (males/females) undergoing elective lower abdomen surgery were included and randomized equally into two groups to listen to music using headphones at a preselected volume (Group M) or to use only headphones without any music played (Group C) for 2 hours in the preoperative, intraoperative, and postoperative periods. Demographic information, anthropometric (height, weight), and biochemical (serum cortisol) measurements were performed. American Society of Anesthesiologists (ASA) grades 1 and 2, and patients aged 18 to 65 years were included. Pain perception was assessed using the Visual Analog Scale (VAS). Results The demographic data, including mean age, BMI, ASA status, average duration of anesthesia, and average duration of surgery, were comparable between the two groups. Group M showed improved control of systolic blood pressure (SBP) at 10- and 30-minutepost-induction of general anesthesia and had a significantly lower VAS score (p < 0.05). Additionally, patient satisfaction was higher in Group M (81.4%) compared to Group C (51.4%) with a p-value of < 0.05. Intraoperative awareness was non-significant between the groups. Conclusion Music therapy is a safe, cost-effective, and efficacious method for reducing pain perception and can be used in conjunction with other treatments for postoperative pain management.