SAFETYLIT WEEKLY UPDATE

We compile citations and summaries of about 400 new articles every week.
RSS Feed

HELP: Tutorials | FAQ
CONTACT US: Contact info

Search Results

Journal Article

Citation

van Kraaij SJW, Gal P, Borghans LGJM, Klaassen ES, Dijkstra F, Winrow C, Glasser C, Groeneveld GJ. Clin. Transl. Sci. 2023; 16(8): 1381-1395.

Copyright

(Copyright © 2023, John Wiley and Sons)

DOI

10.1111/cts.13537

PMID

37118895

PMCID

PMC10432884

Abstract

Soluble guanylate cyclase (sGC) and its product, cyclic guanosine monophosphate, play a role in learning and memory formation. Zagociguat (CY6463) is a novel stimulator of sGC being developed for the treatment of neurodegenerative disease. Single zagociguat doses of 0.3, 1, 3, 10, 20, 30, and 50 mg were administered once to healthy participants in a single-ascending-dose phase; then zagociguat 2, 5, 10, and 15 mg was administered q.d. for 14 days in a multiple-ascending-dose phase; and, finally, zagociguat 10 mg was administered once in both fed and fasted state in a food-interaction phase. Safety of zagociguat was evaluated by monitoring treatment-emergent adverse events, suicide risk, vital signs, electrocardiography, and laboratory tests. Pharmacokinetics of zagociguat were assessed through blood, urine, and cerebrospinal fluid sampling. Pharmacodynamic effects of zagociguat were evaluated with central nervous system (CNS) tests and pharmaco-electroencephalography. Zagociguat was well-tolerated across all doses evaluated. Zagociguat exposures increased in a dose-proportional manner. Median time to maximum concentration ranged from 0.8 to 5 h and mean terminal half-life from 52.8 to 67.1 h. CNS penetration of the compound was confirmed by cerebrospinal fluid sampling. Zagociguat induced up to 6.1 mmHg reduction in mean systolic and up to 7.5 mmHg reduction in mean diastolic blood pressure. No consistent pharmacodynamic (PD) effects on neurocognitive function were observed. Zagociguat was well-tolerated, CNS-penetrant, and demonstrated PD activity consistent with other sGC stimulators. The results of this study support further development of zagociguat.


Language: en

Keywords

*Neurodegenerative Diseases; Area Under Curve; Central Nervous System; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Soluble Guanylyl Cyclase; Vasodilator Agents

NEW SEARCH


All SafetyLit records are available for automatic download to Zotero & Mendeley
Print