The present study was designed to characterize the in vivo pharmacology of L-159,913 (4-[[2'-(N-benzoylsulfamoyl)biphenyl-4-yl]-5butyl-2,4-dihydr o-2- [2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one); a potent All receptor antagonist. In normotensive rats, dogs, rhesus monkeys, and chimpanzees, L-159,913 inhibited All-induced elevations in blood pressure. In conscious rats, the relative potencies (ED50) were 0.51 mg/kg i.v. and 0.72 mg/kg p.o. Duration of action with single i.v. or p.o. doses exceeded 6 hr in rats. L-159,913 was 3 times less potent than losartan in rats and equipotent to losartan in monkeys. All induced elevation of plasma aldosterone in rats was also inhibited by L-159,913. L-159,913 was antihypertensive in high renin hypertensive rats (aortic coarctation). The maximum hypotensive response to an acute dose of L-159,913 (10 mg/kg, po) was equal to that of enalaprilat (0.3 mg/kg, iv) in this renin dependent animal model. In conscious normotensive dogs, L-159,913 had a moderate diuretic, natriuretic and kaliuretic response with no effect on glomerular filtration rate, effective renal plasma flow or filtration fraction, suggesting a tubular site of action. L-159,913 is a selective and potent All receptor antagonist with good oral activity, long duration of action and antihypertensive efficacy.
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http://dx.doi.org/10.3109/10641969509033644 | DOI Listing |
Background: Alzheimer's disease (AD) agitation is a distressing neuropsychiatric symptom characterized by excessive motor activity, verbal aggression, or physical aggression. Agitation is one of the causes of caregiver distress, increased morbidity and mortality, and early institutionalization in patients with AD. Current medications used for the management of agitation have modest efficacy and have substantial side effects.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
Department of Bioengineering, University of California, Los Angeles, CA, USA, Los Angeles, CA, USA.
Background: The initiation of amyloid plaque deposition signifies a crucial stage in Alzheimer's disease (AD) progression, which often coincides with the disruption of neural circuits and cognitive decline. While the role of excitatory-inhibitory balance is increasingly recognized in AD pathophysiology, targeted therapies to modulate this balance remain underexplored. This study investigates the effect of perampanel, a selective non-competitive AMPA receptor antagonist, in modulating neurophysiological changes in hAPP-J20 transgenic Alzheimer's mice.
View Article and Find Full Text PDFBackground: Alzheimer's disease (AD) is a neurodegenerative disorder without a cure. Targeting this multifactorial disease by repurposing FDA approved drugs serves as a faster mode of treatment due to its pre-established human safety. We tested terazosin (TZ), an a-1 adrenergic receptor (AR) antagonist and phosphoglycerate kinase-1 (PGK1) activator as having potential to treat AD.
View Article and Find Full Text PDFBackground: Patients with Alzheimer's disease (AD) often experience burdensome neuropsychiatric symptoms, including agitation which occurs in both home and long-term care (LTC) facilities, and is associated with substantial increases in caregiver burden and LTC placements. AXS-05 (45-mg dextromethorphan/105-mg bupropion), a novel, oral NMDA receptor antagonist and sigma-1 receptor agonist, approved by the FDA for major depressive disorder, is being investigated for treatment of AD agitation (ADA). AXS-05 has been evaluated in 2 randomized, double-blind studies: Phase 2 ADVANCE-1 (NCT03226522); Phase 3 ACCORD (NCT04797715).
View Article and Find Full Text PDFInt J Med Sci
January 2025
Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, People's Republic of China.
Elevated lipoprotein(a) [Lp(a)] levels are increasingly recognized as a significant risk factor for cardiovascular diseases and may also contribute to atrial fibrillation (AF). This review investigated the indirect mechanisms through which Lp(a) may influence AF, including proatherogenic, prothrombotic, and proinflammatory pathways. Traditional lipid-lowering therapies, such as lifestyle modifications and statins, have limited effects on Lp(a) levels.
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