The extent of involvement of ouabain, hippocampal expression of Na+/K+-ATPase, and corticosterone/melatonin receptors ratio in modifying stress-induced behavior differs according to the stressor in context.

The aim of this study was to assess the effect of two types of stressors, regarding the extent of involvement of ouabain (OUA), hippocampal sodium/potassium ATPase (NKA) expression, and the hippocampal corticosterone receptors (CR)/melatonin receptors (MR) expression ratio, on the behavioral and cardiovascular responses and on the hippocampal cornu ammonis zone 3 (CA3) and dentate gyrus (DG). Thirty adult male Wistar albino rats aged 7-8 months were exposed to either chronic immobilization or a disturbed dark/light cycle and treated with either ouabain or vehicle. In the immobilized group, in the absence of hippocampal corticosterone (CORT) changes, rats were non-responsive to stress, despite experiencing increased pulse rate, downregulated hippocampal sodium/potassium pump, and enhanced hippocampal CR/MR expression ratio. Prolonged darkness precipitated a reduced upright attack posture, with elevated CORT against hippocampal MR downregulation. Both immobilization and, to a lesser extent, prolonged darkness stress resulted in histopathological and ultrastructural neurodegenerative changes in the hippocampus. OUA administration did not change the behavioral resilience in restrained rats, despite persistence of the underlying biochemical derangements, added to decreased CORT. On the contrary, with exposure to short photoperiods, OUA reverted the behavior towards a combative reduction of inactivity, with unvaried CR/MR and CORT, while ameliorating hippocampal neuro-regeneration, with co-existing NKA and MR repressions. Therefore, the extent of OUA, hippocampal NKA expression, and CR/MR expression, and subsequent behavioral and cardiac responses and hippocampal histopathology, differ according to the type of stressor, whether immobilization or prolonged darkness.

Postmarketing safety of anaplastic lymphoma kinase (ALK) inhibitors: an analysis of the FDA Adverse Event Reporting System (FAERS).

BACKGROUND: Inhibitors of the anaplastic lymphoma kinase (ALK) gene mutation are highly effective treatments for ALK-positive lung cancer. We conducted this pharmacovigilance analysis using the Food and Drug Administration Adverse Event Reporting System (FAERS). PATIENTS AND METHODS: FAERS files from 2012 to 2020 were used. Reports for crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib were filtered. We used the Medical Dictionary for Regulatory Activities (MedDRA version 22.1). Further, we searched for adverse events on the preferred term (PT) level based on case reports in the literature. After filtering duplicate reports, disproportionality analysis was used to detect safety signals by calculating proportional reporting ratios (PRRs), reporting odds ratios (RORs), empirical Bayesian geometric mean, and information component. Reports were considered statistically significant if the 95% confidence interval did not contain the null value. RESULTS: Within the system organ classes, significant safety signals were found, including those for crizotinib [eye disorders (PRR 2.09, ROR 2.12)], ceritinib [gastrointestinal disorders (PRR 2.19, ROR 2.41), hepatobiliary disorders (PRR 4.4, ROR 4.52), respiratory disorders (PRR 1.96, ROR 2.08)], alectinib [hepatobiliary disorders (PRR 2.60, ROR 2.63)], brigatinib [respiratory disorders (PRR 2.15, ROR 2.31)], and lorlatinib [metabolism disorders (PRR 3.34, ROR 3.53)]. For adverse events on the PT level, we found several significant signals, including pneumothorax with crizotinib (PRR 3.29, ROR 3.29), ceritinib (PRR 3.13, ROR 3.13), and alectinib (PRR 4.88, ROR 4.89); myasthenia gravis with lorlatinib (PRR 6.05, ROR 6.05); photosensitivity reactions with crizotinib (PRR 2.20, ROR 2.20), ceritinib (PRR 4.30, ROR 4.31), alectinib (PRR 20.43, ROR 20.51), and brigatinib (PRR 20.97, ROR 21.05); pulmonary arterial hypertension with brigatinib (PRR 2.92, ROR 2.92) and lorlatinib (PRR 9.2, ROR 9.24); and rectal perforation with crizotinib (PRR 7.83, ROR 7.83). All the detected safety signals were confirmed using Bayesian methods. CONCLUSION: ALK inhibitors differed in their safety profile reports. We found several significant safety signals that matched previously published case reports, including pulmonary arterial hypertension, rectal perforation, myasthenia gravis, and photosensitivity. These signals require further regulatory investigation to determine their significance and potentially update the product labels to inform patients and clinicians.

The effect of nitro-oleic versus losartan in diabetic nephropathy: modulation of parathyroid hormone-related protein.

BACKGROUND: Parathyroid hormone-related protein (PTHrP) involvement in the mechanisms related to angiotensin II (AngII)-induced renal injury has become an emerging concern. The current study was thus designed to compare the possible preventive and therapeutic effect of AngII antagonists, losartan and nitro-oleic (NO2-OA) acid, on diabetic nephropathy (DN) and evaluate their effect on PTHrP modulation as well as on the functional and histopathological parameters in the kidney of diabetic rats. MATERIALS AND METHODS: Forty eight adult male Sprague Dawley rats were divided into control group, DN group, pre-diabetic nephropathy (pre-DN) losartan group, pre-diabetic nephropathy nitro-oleic acid (pre-DN NO2-OA) group, post-diabetic nephropathy (post-DN) losartan and post-diabetic nephropathy nitro-oleic acid (post-DN NO2-OA) groups. At the end of the study, systolic blood pressure (SBP), serum fasting glucose, glomerular filtration rate (GFR), urea, urea albumin excretion (UAE), serum angiotensin, renal PTHrP gene expression and correlations between PTHrP and SBP, serum glucose, AngII and kidney functions were evaluated. Histo- logical examination, Masson's trichrome, periodic acid-Schiff staining as well as morphometric analysis and histopathological scoring for tubular and glomerular parameters have been carried out. RESULTS: Prophylactic losartan and NO2-OA were associated with improvement in SBP, serum glucose, urea, GFR, UAE, with reduction in serum AngII and PTHrP overexpression observed in diabetic kidney. Treatment with losartan and NO2-OA showed the same effect except that post-DN NO2-OA showed no significant effect regarding kidney function. Strong correlations were observed between PTHrP and SBP, serum glucose, AngII and kidney functions. Histopathological results revealed obvious improvement in glomerulosclerosis, vascular and tubular injury parameters in prophylactic groups especially with losartan. CONCLUSIONS: Both pre and post-DN losartan, NO2-OA may have a potential role in protection and regression of DN through reduction of PTHrP overexpression.

The extent of involvement of ouabain, hippocampal expression of Na+/K+-ATPase, and corticosterone/melatonin receptors ratio in modifying stress-induced behavior differs according to the stressor in context

The aim of this study was to assess the effect of two types of stressors, regarding the extent of involvement of ouabain (OUA), hippocampal sodium/potassium ATPase (NKA) expression, and the hippocampal corticosterone receptors (CR)/melatonin receptors (MR) expression ratio, on the behavioral and cardiovascular responses and on the hippocampal cornu ammonis zone 3 (CA3) and dentate gyrus (DG). Thirty adult male Wistar albino rats aged 7-8 months were exposed to either chronic immobilization or a disturbed dark/light cycle and treated with either ouabain or vehicle. In the immobilized group, in the absence of hippocampal corticosterone (CORT) changes, rats were non-responsive to stress, despite experiencing increased pulse rate, downregulated hippocampal sodium/potassium pump, and enhanced hippocampal CR/MR expression ratio. Prolonged darkness precipitated a reduced upright attack posture, with elevated CORT against hippocampal MR downregulation. Both immobilization and, to a lesser extent, prolonged darkness stress resulted in histopathological and ultrastructural neurodegenerative changes in the hippocampus. OUA administration did not change the behavioral resilience in restrained rats, despite persistence of the underlying biochemical derangements, added to decreased CORT. On the contrary, with exposure to short photoperiods, OUA reverted the behavior towards a combative reduction of inactivity, with unvaried CR/MR and CORT, while ameliorating hippocampal neuro-regeneration, with co-existing NKA and MR repressions. Therefore, the extent of OUA, hippocampal NKA expression, and CR/MR expression, and subsequent behavioral and cardiac responses and hippocampal histopathology, differ according to the type of stressor, whether immobilization or prolonged darkness.