Pharmacokinetics-Based Chronoefficacy of Semen Strychni and Tripterygium Glycoside Tablet Against Rheumatoid Arthritis

Abstract

Rheumatoid arthritis is a systemic autoimmune disease characterized by synovial inflammation and bone destruction. Identifying drugs with time-varying efficacy and toxicity, and elucidating the mechanisms would help to improve treatment efficacy and reduce adverse effects. Here, we aimed to determine the chronoefficacy of semen strychni (SS) and tripterygium glycoside tablet (TGT) against rheumatoid arthritis in mice, and to investigate a potential role of circadian pharmacokinetics in generating chronoefficacy. SS extract and TGT suspension were prepared with ultrasonication. Effects of SS and TGT on collagen-induced arthritis (CIA) were evaluated by measuring TNF-α and IL-6 levels. SS dosed at ZT18 was more effective in protecting against CIA than drug dosed at ZT6 (i.e., lower levels of key inflammatory factors at ZT18 than at ZT6). This was accompanied by higher systemic exposure levels of strychnine and brucine (two main putative active ingredients of SS) in ZT18-treated than in ZT6-treated CIA mice. TGT dosing at ZT2 showed a better efficacy against CIA as compared to herb doing at ZT14. Consistently, ZT2 dosing generated a higher exposure of triptolide (a main putative active ingredient of TGT) as compared to ZT14 dosing in CIA mice. Moreover, strychnine, brucine, and triptolide significantly inhibited the proliferation of fibroblast-like synoviocytes, and reduced the production of TNF-α and IL-6 and the mRNAs of TNF-α, IL-6, COX-2, and iNOS, suggesting that they possessed an anti-arthritis activity. In conclusion, SS and TGT display chronoefficacy against rheumatoid arthritis in mice, that is attributed to circadian pharmacokinetics of main active ingredients. Our findings have implications for improving treatment outcomes of SS and TGT via timed delivery.

Study on the Potential Mechanism of Semen Strychni against Myasthenia Gravis Based on Network Pharmacology and Molecular Docking with Experimental Verification

“…Clinical practice indicates that SS has an apparent effect on MG. Studies demonstrated that treatment with SS decreased the production of proinflammatory cytokines and inhibited the TLR-4/NF-kB signaling pathway in EAMG rats [ 9 ]. Although many studies have focused on the anti-inflammatory and neurotransmitter-regulating effects of SS [ 16 , 17 ], the underlying mechanisms have not been systematically uncovered. Our team desired to further investigate the mechanism of SS in the treatment of MG.…”

Differences in Multicomponent Pharmacokinetics, Tissue Distribution, and Excretion of Tripterygium Glycosides Tablets in Normal and Adriamycin–Induced Nephrotic Syndrome Rat Models and Correlations With Efficacy and Hepatotoxicity

“…Previous studies on TGT pharmacokinetics have mainly focused on healthy animals, or animals with rheumatoid arthritis. Of note, the severity of rheumatoid arthritis was positively correlated with plasma exposure to WFG and WFR in rats after TGT administration ( Su et al, 2015a ; Lin et al, 2021 ; Zhao et al, 2021 ). Thus, it is rational to investigate the influence of NS on the key TGT components, as NS is another clinical indication for TGT.…”

Exploring the molecular mechanism of Nux Vomica in treating ischemic stroke using network pharmacology and molecular docking methods

“…According to the Chinese Pharmacopoeia, [ 17 ] NV has the effect of promoting pain, dispersing nodules and, reducing swelling, and can be used to treat rheumatic paralysis and numbness and paralysis. Current studies point out that NV can excite spinal cord reflex functions, stimulate the medullary respiratory and vasomotor centers, and increase the excitability of the sensory center of the cerebral cortex, [ 7 , 18 ] but the underlying mechanism is unclear. Notably, Strychnine and brucine are the main components and the main toxic components of NV, which must be strictly controlled in dosage.…”

“…center of the cerebral cortex, [7,18] but the underlying mechanism is unclear. Notably, Strychnine and brucine are the main components and the main toxic components of NV, which must be strictly controlled in dosage.…”