Teroxirone

Tripterygiumwilfordii, a traditional Chinese herbal medicine, has been used for treating autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus. Tripterygium glycoside tablets (TGT), derived from this herb, is widely used in clinical practice in China. However, the therapeutic effects of TGT on Multiple sclerosis (MS), particularly through its active component triptolide (TP), remain insufficiently understood.

This study aimed to investigate the therapeutic effects of TGT and TP on experimental autoimmune encephalomyelitis (EAE) and elucidate the underlying molecular mechanisms.

TGT and TWPT were chemically characterized using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. The therapeutic effect of TGT, TWPT, and TP was evaluated in the EAE model. Proteomics analysis and Western blot analysis were validated the signaling pathways.

TGT and TP significantly alleviated EAE symptoms in mice, including reduced weight loss and neurological deficits, whereas TWPT (TGT without triptolide) shows no significant therapeutic effect. Histological analysis revealed that TGT and TP reduced demyelination and inflammatory cell infiltration in the spinal cord. TGT and TP decreased systemic inflammatory cytokines (IL-17A, IFN-γ, TNF-α, and IL-6) and the mRNA expression of the transcription factors T-bet and ROR-γt in the spinal cord. Proteomic analysis indicated that TP significantly upregulated the expression of PACAP and activated the cAMP signaling pathway. Furthermore, TGT and TP modulate PKA, PI3K-AKT, NF-κB, and apoptosis-related signaling pathways, contributing to the reducing inflammation, apoptosis and demyelination in EAE mice.

TGT and TP exert anti-inflammatory and demyelination-improving effects to alleviate both clinical and pathological manifestations of EAE in mice via the PACAP/cAMP signaling axis, suggesting TGT as promising therapeutic strategies for MS.

Total glucosides of paeony (TGP) capsules, tripterygium glycoside tablets (TGT), and celecoxib are commonly used drugs in clinical practice for the treatment of Rheumatoid arthritis (RA). An UPLC-MS/MS method for the analysis of celecoxib in beagle dogs was developed, the herb-drug interactions (HDIs) between TGP and TGT with celecoxib were studied based on pharmacokinetics.

The method of acetonitrile precipitation was applied to process plasma samples. Celecoxib and furosemide (internal standard, IS) was separated by gradient elution, and detected using multiple reaction monitoring mode under the positive ion. The ion reactions used for quantitative analysis were m/z 379.82 → 315.82 for celecoxib, and m/z 328.74 → 204.88 for IS. HDIs experiments adopt a three-stage experimental design. In the first period, six beagle dogs was orally administered 6.67 mg/kg celecoxib. In the second period, TGP 20 mg/kg was given orally twice a day for 7 consecutive days, then celecoxib was orally administered. And, in the third period, TGT 1.5 mg/kg was orally given, twice a day for 7 consecutive days, then celecoxib was orally administered. The concentration of celecoxib in the three periods was detected, and HDIs were evaluated based on pharmacokinetics.

Celecoxib exhibited good linearity in the range of 10-2000 ng/mL. The accuracy, precision, recoveries, matrix effects, and stability all met the standards. When celecoxib was used in combination with TGPC or TGT, the main pharmacokinetic parameters of celecoxib changed, C_max, AUC_(0-t) and AUC_(0-∞) increased, t_½ was prolonged, and CL and V_d decreased.

A novel UPLC-MS/MS approach was successfully performed and applied to measure celecoxib in beagle dog plasma. TGP and TGT could inhibit the metabolism of celecoxib in beagle dogs, thereby affecting the pharmacokinetic parameters of celecoxib and increasing plasma exposure to celecoxib.