Category Ranking
98%
Total Visits
921
Avg Visit Duration
2 minutes
Citations
20
Article Abstract
A liquid chromatography-tandem mass spectrometry assay was developed and qualified for the multiplexed quantitation of a small molecule stimulator of soluble guanylate cyclase (sGC) and its target engagement biomarker, 3',5'-cyclic guanosine monophosphate (cGMP), in ocular tissues and plasma from a single surrogate matrix calibration curve. A surrogate matrix approach was used in this assay due to the limited quantities of blank ocular matrices in a discovery research setting. After optimization, the assay showed high accuracy, precision, and recovery as well as parallelism between the surrogate matrix and the biological matrices (rabbit plasma, vitreous, and retina-choroid). This assay provided pharmacokinetic and target engagement data after intravitreal administration of the sGC stimulator. The nitric oxide-sGC-cGMP pathway is a potential target to address glaucoma. Increasing sGC-mediated production of cGMP could improve aqueous humor outflow and ocular blood flow. The sGC stimulator showed dose-dependent exposure in rabbit vitreous, retina-choroid, and plasma. The cGMP exhibited a delayed yet sustained increase in vitreous humor but not retina-choroid. Multiplexed measurement of both pharmacokinetic and target engagement analytes reduced animal usage and provided improved context for interpreting PK and PD relationships.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1177/0192623320948836 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
The Role of Vericiguat in Heart Failure Therapy: From Clinical Trials to Clinical Practice.
Rev Cardiovasc Med
August 2025
Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy.
Heart failure with reduced ejection fraction (HFrEF) is a progressive condition that is associated with high rates of morbidity, frequent hospitalizations, and significant mortality. Despite advancements in guideline-directed medical therapy (GDMT), many patients continue to be at risk for worsening heart failure (WHF). Vericiguat is a novel soluble guanylate cyclase (sGC) stimulator that targets the impaired nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) pathway.
View Article and Find Full Text PDFCO and NO Coordinate Developmental Neuron Migration.
Int J Mol Sci
August 2025
Institute of Physiology and Cell Biology, University of Veterinary Medicine Hannover, Bischofsholer Damm 15/102, 30125 Hannover, Germany.
Similarly to the short-lived messenger nitric oxide (NO), the more stable carbon monoxide (CO) molecule can also activate soluble guanylyl cyclase (sGC) to increase cGMP levels. However, CO-induced cGMP production is much less efficient. Using an accessible invertebrate model, we dissect a potential interaction between the canonical NO/sGC/cGMP and CO signalling pathways during development.
View Article and Find Full Text PDFPredictive value of subgenual cingulate normative connectivity to TMS treatment site for antidepressant response in routine clinical practice: a prospective, multisite cohort study.
Mol Psychiatry
August 2025
Center for Brain Circuit Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Small single-site studies found that transcranial magnetic stimulation (TMS) targets with better antidepressant response were more negatively functionally connected to the subgenual cingulate cortex (SGC). These led to "anti-subgenual" TMS targeting in recent clinical trials. We conducted a larger prospective multi-site observational study to test the robustness of this observation in more diverse clinical populations.
View Article and Find Full Text PDFProximity to an SGC-DLPFC Individualized Functional Target and outcomes in large rTMS clinical trials for Treatment-Resistant Depression.
bioRxiv
July 2025
Non-Invasive Neurostimulation Therapies (NINET) Laboratory, Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada.
Background: Targeting methods for repetitive transcranial magnetic stimulation (rTMS) in patients with depression now include the use of individual functional scans to target specific functional connectivity (FC) patterns obtained from functional magnetic resonance imaging (fMRI). Potential biomarkers of rTMS response include target FC with the subgenual anterior cingulate cortex (SGC) or the causal depression circuit (CDC), each of which may be candidates for individualized functional targets (iFTs). We assessed the relationship of these two approaches to clinical outcomes in two large rTMS clinical trials.
View Article and Find Full Text PDFZagociguat prevented stressor-induced neuromuscular dysfunction, improved mitochondrial physiology, and increased exercise capacity in diverse mitochondrial respiratory chain disease zebrafish models.
Front Pharmacol
July 2025
Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States.
Background: Zagociguat (zag) is a CNS-penetrant, soluble guanylate cyclase (sGC) stimulator that has been evaluated in phase 2a, with phase 2b ongoing, clinical studies of primary mitochondrial disease (PMD) subjects with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS). To explore its utility in a broader array of PMDs and secondary mitochondrial disorders, we performed prfeclinical modeling of zag across larval and adult zebrafish models with biochemical deficiencies in diverse respiratory chain (RC) complexes or dihydrolipoamide dehydrogenase (Dldh).
Methods: Zag was evaluated for tissue uptake, gross toxicity, protection from RC toxin-induced brain death, neuromuscular dysfunction, heartbeat loss, and biochemical dysfunction in transgenic or toxin-exposed zebrafish with mitochondrial enzyme deficiencies in complex I ( or rotenone-exposed wild type (WT)), complex IV ( or azide-exposed WT), multiple RC complexes ( ), or pyruvate dehydrogenase complex ( ).