1 The aim of this study was to investigate, by use of spectral analysis, (1) the blood pressure (BP) variability changes in the conscious rat during blockade of nitric oxide (NO) synthesis by the L-arginine analogue N0-nitro-L-arginine methyl ester (L-NAME); (2) the involvement of the renin-angiotensin system in these modifications, by use of the angiotensin II AT,-receptor antagonist losartan.2 Blockade of NO synthesis was achieved by infusion for 1 h of a low-dose (10 jug kg-' min-', i.v., n= 10) and high-dose (100 pg kg-' min-', i.v., n= 10) of L-NAME. The same treatment was applied in two further groups (2 x n = 10) after a bolus dose of losartan (10 mg kg-', i.v.). 3 Thirty minutes after the start of the infusion of low-dose L-NAME, systolic BP (SBP) increased (+ 10 + 3 mmHg, P< 0.01), with the effect being more pronounced 5 min after the end of L-NAME administration (+ 20 + 4 mmHg, P< 0.001). With high-dose L-NAME, SBP increased immediately (5 min: + 8+2 mmHg, P<0.05) and reached a maximum after 40 min (+ 53+4 mmHg, P<0.001); a bradycardia was observed (60 min: -44+ 13 beats min'-, P<0.01). 4 Low-dose L-NAME increased the low-frequency component (LF: 0.02-0.2 Hz) of SBP variability (50 min: 6.7+ 1.7 mmHg2 vs 3.4+0.5 mmHg2, P<0.05), whereas the high dose of L-NAME not only increased the LF component (40 min: 11.7 + 2 mmHg2 vs 2.7 + 0.5 mmHg2, P<0.001) but also decreased the mid frequency (MF: 0.2-0.6 Hz) component (60 min: 1.14+0.3 mmHg2 vs 1.7+0.1 mmHg2, P<0.05) of SBP. 5 Losartan did not modify BP levels but had a tachycardic effect (+45 beats min-'). Moreover, losartan increased MF oscillations of SBP (4.26 + 0.49 mmHg2 vs 2.43 + 0.25 mmHg2, P< 0.001), prevented the BP rise provoked by the low-dose of L-NAME and delayed the BP rise provoked by the high-dose of L-NAME. Losartan also prevented the amplification of the LF oscillations of SBP induced by L-NAME; the decrease of the MF oscillations of SBP induced by L-NAME was reinforced after losartan. 6 We conclude that the renin-angiotensin system is involved in the increase in variability of SBP in the LF range which resulted from the withdrawal of the vasodilating influence of NO. We propose that NO may counterbalance LF oscillations provoked by the activity of the renin-angiotensin system.
CC‐292, a potent Bruton tyrosine kinase inhibitor, is under development for the treatment of B‐cell malignancies. An analysis was performed to develop a population pharmacokinetic model of CC‐292 and assess the influence of demographics and disease‐related covariates on CC‐292 exposure and to assess the exposure‐response (overall response rate) relationship in patients with chronic lymphocytic leukemia. Population pharmacokinetic analysis was based on a 2‐compartment base model conducted in NONMEM. Categorical exposure‐response analysis was performed using logistic regression in SAS. The population pharmacokinetic analysis results indicated that CC‐292 pharmacokinetic disposition is similar between healthy subjects and patients. CC‐292 showed a larger central compartment volume of distribution than the peripheral compartment volume of distribution (158 L and 72 L, respectively) and a faster clearance than intercompartmental clearance (134 L/h and 18.7 L/h, respectively), indicating that for CC‐292, clearance from blood occurs faster than distribution into deep tissues and organs. CC‐292 clearance is not affected by demographics or baseline clinical lab factors, except for sex. Although sex significantly reduced variation of apparent clearance, the sex effect on apparent clearance is unlikely to be clinically relevant. The exposure‐response analysis suggested that higher drug exposure is linearly correlated with higher overall response rate. A twice‐daily dose regimen showed higher overall response rate as compared to once‐daily dosing, consistent with a threshold concentration of approximately 300 ng/mL, above which the probability of overall response rate significantly increases.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.