10 research outputs found
Salt-induced hypertension: Central regulation by ouabain-like compounds and angiotensin II.
No full textWe hypothesized that the ventral anteroventral third ventricle region (vAV3V), which mainly comprises the organum vasculosum laminae terminalis (OVLT) and extends ∼100 mum into the median preoptic nucleus, mediates salt-induced sympathoexcitation and hypertension via AT1 receptor activation. We utilized ibotenic acid lesions of the vAV3V to determine a role of neurons in this area in pressor responses to intracerebroventricular (icv) administration of hypertonic saline (0.3M NaCl, 2 mul/min for 10 min), ouabain (0.3 and 0.6 mug) and angiotensin II (Ang II; 10 and 30 ng), and in two rat models of hypertension in which mechanisms of salt-sensitive hypertension are mimicked: chronic icv hypertonic, saline (0.8 M NaC1, 5 mul/h icv for 2 weeks) to increase CSF [Na+] and chronic subcutaneous (sc) ouabain (50 mug/d sc for 3 weeks) to mimick increases in central ouabain-like compound content. 125I-Sar1Ile8-Ang II binding to AT1 receptors was determined by in vitro receptor autoradiography to determine if changes in AT1 receptor density accompany the development of salt-induced hypertension in Dahl salt-sensitive (S) rats. In conscious vAV3V lesioned Wistar rats with systemic vasopressin receptor blockade, pressor and tachycardic responses to 0.3 M NaCl and ouabain, were significantly attenuated by 26--32% whereas responses to Ang II were unaffected. Resting mean arterial pressure (MAP) in sham-operated rats that received chronic hypertonic saline infusions or ouabain treatment was significantly higher (17--19%) than in aCSF or placebo treated controls. vAV3V lesions abolished the chronic hypertonic saline or ouabain induced increases in MAP and the enhanced depressor responses to ganglionic blockade with hexamethonium. AT1 binding in the OVLT, the suprachaismatic nucleus and the paraventricular nucleus did not differ between Dahl S and R rats on regular salt diet, and was decreased similarly on high salt diet. Within the subfornical organ AT1 receptor binding did not differ between Dahl S and R rats on regular salt diet and decreased in both strains on the high salt diet, but decreased more in hypertensive Dahl S versus the normotensive Dahl R rats (50% versus 23%). In conclusion, the vAV3V area appears to play a crucial role in mediating salt-induced hypertension, possibly via sympathetic activation, but autoradiography did not provide evidence for differential AT1 stimulation in the vAV3V
Excitotoxic lesions of the ventral anteroventral third ventricle and pressor responses to central sodium, ouabain and angiotensin II
No full text
Ouabain- and central sodium-induced hypertension depend on the ventral anteroventral third ventricle region
No full textTo examine the role of the ventral anteroventral third ventricle (vAV3V) in the hypertension induced by chronic subcutaneous ouabain and intracerebroventricular hypertonic saline, neurons in this area were destroyed by microinjection of an excitotoxin, ibotenic acid. Sham-operated or lesioned Wistar rats were administered ouabain (50 μg/day) or placebo for 3 wk from subcutaneously implanted controlled release pellets or artificial cerebrospinal fluid (CSF) or CSF containing 0.8 mol/l NaCl (5 μl/h) infused intracerebroventricularly for 2 wk. At the end of the experiment, mean arterial pressure (MAP) and heart rate at rest and in response to ganglionic blockade by intravenous hexamethonium (30 mg/kg) were assessed. In rats infused with hypertonic saline, responses to air jet stress were also assessed. Baseline MAP in sham-operated rats receiving intracerebroventricular hypertonic saline or subcutaneous ouabain was significantly higher than in control rats (115 ± 1 vs. 97 ± 3 and 121 ± 3 vs. 103 ± 3 mmHg, respectively). vAV3V lesions abolished the increase in MAP elicited by chronic infusion of hypertonic saline or administration of ouabain. Sham-operated rats treated with hypertonic saline or ouabain exhibited significantly enhanced decreases in MAP to hexamethonium, but lesioned rats did not. Rats infused with hypertonic saline demonstrated enhanced responses to air jet stress that were similar in sham-operated and lesioned rats. These results demonstrate that neurons in the vAV3V are essential for the hypertension induced by intracerebroventricular hypertonic saline and subcutaneous ouabain, possibly by increasing sympathetic tone. Cardiovascular responses to air jet stress appear not to be mediated by the vAV3V.</jats:p
Brain “ouabain,” ANG II, and sympathoexcitation by chronic central sodium loading in rats
No full text Both brain ouabain-like activity (“ouabain”) and brain angiotensin II (ANG II) contribute to the sympathoexcitatory and pressor responses to high sodium intake in spontaneously hypertensive (SHR) and Dahl salt-sensitive (Dahl S) rats. To assess whether increases in cerebrospinal fluid (CSF) sodium can mimic this pattern of changes, Wistar rats were chronically infused with artificial CSF (aCSF) or sodium-rich aCSF (0.8 or 1.2 M sodium) intracerebroventricularly through osmotic minipumps for 14 days. Sodium-rich aCSF (0.8 M) was also infused intracerebroventricularly for 2 wk concomitantly with either antibody Fab fragments that bind ouabain and related steroids with high affinity, γ-globulins as control (200 μg/day for both), or the AT1blocker losartan (1 mg ⋅ kg−1 ⋅ day−1). Sodium-rich aCSF increased CSF sodium from 146 ± 2 to 152 ± 2 (0.8 M) and 160 ± 3 (1.2 M) mmol/l, and increased brain “ouabain” in the hypothalamus, pituitary, and pons. In conscious rats, sodium-rich aCSF increased baseline mean arterial pressure (MAP), enhanced MAP, heart rate (HR), and renal sympathetic nerve activity (RSNA) responses to intracerebroventricular α2-adrenoceptor agonist guanabenz and air stress, and desensitized arterial and cardiopulmonary baroreflex control of HR and RSNA. These effects were largely prevented by intracerebroventricular Fab fragments or losartan. Thus, in Wistar rats, both brain “ouabain” and the brain renin-angiotensin system contribute to sympathoexcitation, impairment of baroreflexes, and hypertension caused by chronically increased CSF sodium. The similar patterns of changes caused by CSF sodium in Wistar rats and by high sodium intake in SHR and Dahl S rats indicate that if high sodium intake increases central sodium, such changes may contribute to sympathoexcitation and hypertension. </jats:p
Drug Permeability - Best Practices for Biopharmaceutics Classification System (BCS)-Based Biowaivers: A workshop Summary Report
No full text17491762The workshop “Drug Permeability - Best Practices for Biopharmaceutics Classification System (BCS) Based Biowaivers” was held virtually on December 6, 2021, organized by the University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI), and the Food and Drug Administration (FDA). The workshop focused on the industrial, academic, and regulatory experiences in generating and evaluating permeability data, with the aim to further facilitate implementation of the BCS and efficient development of high-quality drug products globally. As the first international permeability workshop since the BCS based biowaivers was finalized as the ICH M9 guideline, the workshop included lectures, panel discussions, and breakout sessions. Lecture and panel discussion topics covered case studies at IND, NDA, and ANDA stages, typical deficiencies relating to permeability assessment supporting BCS biowaiver, types of evidence that are available to demonstrate high permeability, method suitability of a permeability assay, impact of excipients, importance of global acceptance of permeability methods, opportunities to expand the use of biowaivers (e.g. non-Caco-2 cell lines, totality-of-evidence approach to demonstrate high permeability) and future of permeability testing. Breakout sessions focused on 1) in vitro and in silico intestinal permeability methods; 2) potential excipient effects on permeability and; 3) use of label and literature data to designate permeability class.112
Current State and New Horizons in Applications of Physiologically Based Biopharmaceutics Modeling (PBBM) : A Workshop Report
No full textThis report summarizes the proceedings for Day 3 of the workshop titled “Physiologically Based Biopharmaceutics Modeling (PBBM) Best Practices for Drug Product Quality: Regulatory and Industry Perspectives”. This day focused on the current and future drug product quality applications of PBBM from the innovator and generic industries as well as the regulatory agencies perspectives. The presentations, which included several case studies, covered the applications of PBBM in generic drug product development, applications of virtual bioequivalence trials to support formulation bridging and the utility of absorption modeling in clinical pharmacology assessments. In addition, recent progress in the prediction of colon absorption and in vivo performance of extended-release drug products was shared. The morning session was concluded by representatives from FDA, ANVISA, MHRA, Health Canada, EMA, and PMDA giving their perspectives on the application of PBBM in regulatory submissions. The afternoon breakout sessions focused on four parallel topics: 1) PBBM in generic drug product development; 2) virtual bioequivalence trials applications; 3) safe space and extrapolation; and 4) regional absorption and modified release PBBM applications. This allowed the participants to engage in in-depth discussions of best practices as well to identify key points of consideration to allow further progress on the applications of PBBM
Parameterization of Physiologically Based Biopharmaceutics Models: Workshop Summary Report
No full text36973731This Article shares the proceedings from the August 29th, 2023 (day 1) workshop “Physiologically Based Biopharmaceutics Modeling (PBBM) Best Practices for Drug Product Quality: Regulatory and Industry Perspectives”. The focus of the day was on model parametrization; regulatory authorities from Canada, the USA, Sweden, Belgium, and Norway presented their views on PBBM case studies submitted by industry members of the IQ consortium. The presentations shared key questions raised by regulators during the mock exercise, regarding the PBBM input parameters and their justification. These presentations also shed light on the regulatory assessment processes, content, and format requirements for future PBBM regulatory submissions. In addition, the day 1 breakout presentations and discussions gave the opportunity to share best practices around key questions faced by scientists when parametrizing PBBMs. Key questions included measurement and integration of drug substance solubility for crystalline vs amorphous drugs; impact of excipients on apparent drug solubility/supersaturation; modeling of acid-base reactions at the surface of the dissolving drug; choice of dissolution methods according to the formulation and drug properties with a view to predict the in vivo performance; mechanistic modeling of in vitro product dissolution data to predict in vivo dissolution for various patient populations/species; best practices for characterization of drug precipitation from simple or complex formulations and integration of the data in PBBM; incorporation of drug permeability into PBBM for various routes of uptake and prediction of permeability along the GI tract.21
Parameterization of Physiologically Based Biopharmaceutics Models : Workshop Summary Report
No full textThis Article shares the proceedings from the August 29th, 2023 (day 1) workshop "Physiologically Based Biopharmaceutics Modeling (PBBM) Best Practices for Drug Product Quality: Regulatory and Industry Perspectives". The focus of the day was on model parametrization; regulatory authorities from Canada, the USA, Sweden, Belgium, and Norway presented their views on PBBM case studies submitted by industry members of the IQ consortium. The presentations shared key questions raised by regulators during the mock exercise, regarding the PBBM input parameters and their justification. These presentations also shed light on the regulatory assessment processes, content, and format requirements for future PBBM regulatory submissions. In addition, the day 1 breakout presentations and discussions gave the opportunity to share best practices around key questions faced by scientists when parametrizing PBBMs. Key questions included measurement and integration of drug substance solubility for crystalline vs amorphous drugs; impact of excipients on apparent drug solubility/supersaturation; modeling of acid-base reactions at the surface of the dissolving drug; choice of dissolution methods according to the formulation and drug properties with a view to predict the in vivo performance; mechanistic modeling of in vitro product dissolution data to predict in vivo dissolution for various patient populations/species; best practices for characterization of drug precipitation from simple or complex formulations and integration of the data in PBBM; incorporation of drug permeability into PBBM for various routes of uptake and prediction of permeability along the GI tract
