Mechanistic insights into synergistic effects using coupled PK-PD modeling

Develop a novel coupled PK-PD model and apply it to quantitatively evaluate the synergistic effects of Hydroxysafflor Yellow A (HSYA) combined with Calycosin (CA) in the treatment of ischemic stroke. A total of 6 rats were modelled for middle cerebral artery occlusion (MCAO). Plasma was collected fr...

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Veröffentlicht in:Scientific reports Jg. 15; H. 1; S. 15631 - 14
Hauptverfasser: Sun, Jinzhou, Chen, Qianqian, Zhuang, Chumeng, Li, Xiaohong, Yu, Li, Jin, Weifeng
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 05.05.2025
Nature Publishing Group
Nature Portfolio
Schlagworte:
631/114/2164
631/154/436/1729
Animals
Anthraquinones - pharmacokinetics
Anthraquinones - pharmacology
Calycosin
Caspase-9
Cerebral blood flow
Chalcone - analogs & derivatives
Coupled PK-PD
Disease Models, Animal
Drug interaction
Drug Synergism
Humanities and Social Sciences
Hydroxysafflor yellow A
Infarction, Middle Cerebral Artery - drug therapy
Interleukin-1beta - blood
Ischemia
Isoflavones - pharmacokinetics
Isoflavones - pharmacology
Male
Metabolic rate
Models, Biological
multidisciplinary
Pharmacodynamics
Quinones - pharmacokinetics
Quinones - pharmacology
Rats
Rats, Sprague-Dawley
Retention time
Science
Science (multidisciplinary)
Stroke
Synergistic effect
Synergistic effects
Hydroxysafflor yellow A
Coupled PK-PD
Synergistic effects
Calycosin
ISSN:2045-2322, 2045-2322
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Zusammenfassung:Develop a novel coupled PK-PD model and apply it to quantitatively evaluate the synergistic effects of Hydroxysafflor Yellow A (HSYA) combined with Calycosin (CA) in the treatment of ischemic stroke. A total of 6 rats were modelled for middle cerebral artery occlusion (MCAO). Plasma was collected from the submandibular venous plexus of rats after the administration of HSYA and CA, and was detected and analyzed by LC-MS method. The plasma expression levels of Caspase-9, IL-1β and SOD in rats were also determined by ELISA kit. Meanwhile, a coupled PK-PD model was proposed, incorporating interaction terms between drugs and coupling of pharmacodynamic effects, to quantitatively reveal their interactions. Moreover, a numerical solution technique based on optimization methods was proposed, enabling the model to be effectively applied to experimental data. Based on the coupled PK model, HSYA and CA significantly increased each other’s metabolic rates. The model also showed that CA had a larger apparent volume of distribution and clearance in rats, while HSYA had a shorter mean retention time and elimination half-life. The coupled PK-PD model indicated a synergistic effect between HSYA and CA on all three pharmacodynamic markers, with HSYA contributing more significantly. Despite individual variability among the six rats, the parameter interpretations remained consistent. The proposed coupled PK-PD model and its numerical solution algorithm successfully revealed the synergistic effects of HSYA and CA in the treatment of ischemic stroke. This model lays the foundation for future models with more complex interactions and effects.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-025-00182-4