PMID- 34873316
OWN - NLM
STAT- MEDLINE
DCOM- 20220803
LR  - 20230802
IS  - 1745-7254 (Electronic)
IS  - 1671-4083 (Print)
IS  - 1671-4083 (Linking)
VI  - 43
IP  - 8
DP  - 2022 Aug
TI  - Novel treatment for refractory rheumatoid arthritis with total glucosides of 
      paeony and nobiletin codelivered in a self-nanoemulsifying drug delivery system.
PG  - 2094-2108
LID - 10.1038/s41401-021-00801-6 [doi]
AB  - Patients with refractory rheumatoid arthritis (RA) remain a substantial clinical 
      problem, while the overexpression of P-glycoprotein (P-gp) on their lymphocytes 
      may contribute to resistance to anti-rheumatic drugs. This study aims to develop 
      a novel treatment for refractory RA consisting of the combination of total 
      glucosides of paeony (TGPs) and the P-gp inhibitor nobiletin (N), which are 
      codelivered in a self-nanoemulsifying drug delivery system (SNEDDS). Based on the 
      solubility, compatibility, and pseudoternary phase diagram tests, a nano-SNEDDS 
      formulation composed of capryol 90-cremophor EL35-tcranscutol HP (CET) to 
      codeliver TGP and N was developed, and this formulation increased the 
      bioavailability of TGP by 435.04% (indicated with paeoniflorin). A modified 
      adjuvant-induced arthritis (AIA) rat model was verified for the overexpression of 
      P-gp in lymphocytes and resistance to methotrexate (MTX) treatment at the 
      reported anti-inflammatory dosage. CET formulation not only increased the 
      solubility and permeability of TGP but also inhibited the function and expression 
      of P-gp, leading to enhanced bioavailability and intracellular concentration in 
      the lymphocytes of AIA rats and consequently boosting the anti-arthritic effects 
      of TGP. Moreover, TGP and N coloaded CET reduced the expression of P-gp in AIA 
      rats partly by inhibiting the phosphorylated AKT and HIF-1alpha pathways. In summary, 
      TGP-N coloaded SNEDDS is a novel and effective treatment for refractory RA.
CI  - (c) 2021. The Author(s), under exclusive licence to CPS and SIMM.
FAU - Qu, Biao
AU  - Qu B
AD  - State Key Laboratory of Quality Research in Chinese Medicines, Macau University 
      of Science and Technology, Taipa, Macao SAR, China.
AD  - Faculty of Chinese Medicines, Macau University of Science and Technology, Taipa, 
      Macao SAR, China.
FAU - Wang, Xiao-Lin
AU  - Wang XL
AD  - State Key Laboratory of Quality Research in Chinese Medicines, Macau University 
      of Science and Technology, Taipa, Macao SAR, China.
AD  - School of Pharmacy, Macau University of Science and Technology, Taipa, Macao SAR, 
      China.
FAU - Zheng, De-Chong
AU  - Zheng DC
AD  - State Key Laboratory of Quality Research in Chinese Medicines, Macau University 
      of Science and Technology, Taipa, Macao SAR, China.
AD  - Faculty of Chinese Medicines, Macau University of Science and Technology, Taipa, 
      Macao SAR, China.
FAU - Mai, Chu-Tian
AU  - Mai CT
AD  - State Key Laboratory of Quality Research in Chinese Medicines, Macau University 
      of Science and Technology, Taipa, Macao SAR, China.
AD  - Faculty of Chinese Medicines, Macau University of Science and Technology, Taipa, 
      Macao SAR, China.
FAU - Liu, Zhong-Qiu
AU  - Liu ZQ
AD  - Joint Laboratory for Translational Cancer Research of Chinese Medicine of the 
      Ministry of Education of the People's Republic of China, School of Chinese 
      Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
FAU - Zhou, Hua
AU  - Zhou H
AD  - State Key Laboratory of Quality Research in Chinese Medicines, Macau University 
      of Science and Technology, Taipa, Macao SAR, China. hzhou@must.edu.mo.
AD  - Faculty of Chinese Medicines, Macau University of Science and Technology, Taipa, 
      Macao SAR, China. hzhou@must.edu.mo.
FAU - Xie, Ying
AU  - Xie Y
AD  - State Key Laboratory of Quality Research in Chinese Medicines, Macau University 
      of Science and Technology, Taipa, Macao SAR, China. yxie@must.edu.mo.
AD  - School of Pharmacy, Macau University of Science and Technology, Taipa, Macao SAR, 
      China. yxie@must.edu.mo.
LA  - eng
PT  - Journal Article
DEP - 20211206
PL  - United States
TA  - Acta Pharmacol Sin
JT  - Acta pharmacologica Sinica
JID - 100956087
RN  - 0 (Flavones)
RN  - 0 (Glucosides)
RN  - D65ILJ7WLY (nobiletin)
SB  - IM
MH  - Animals
MH  - *Arthritis, Rheumatoid/drug therapy
MH  - Drug Delivery Systems
MH  - Flavones
MH  - Glucosides/pharmacology
MH  - *Paeonia
MH  - Rats
PMC - PMC9343439
OTO - NOTNLM
OT  - P-glycoprotein
OT  - nobiletin
OT  - refractory rheumatoid arthritis
OT  - self-nanoemulsifying drug delivery systems
OT  - total glucosides of paeony
COIS- The authors declare no competing interests.
EDAT- 2021/12/08 06:00
MHDA- 2022/08/04 06:00
PMCR- 2023/08/01
CRDT- 2021/12/07 06:40
PHST- 2021/08/18 00:00 [received]
PHST- 2021/10/19 00:00 [accepted]
PHST- 2021/12/08 06:00 [pubmed]
PHST- 2022/08/04 06:00 [medline]
PHST- 2021/12/07 06:40 [entrez]
PHST- 2023/08/01 00:00 [pmc-release]
AID - 10.1038/s41401-021-00801-6 [pii]
AID - 801 [pii]
AID - 10.1038/s41401-021-00801-6 [doi]
PST - ppublish
SO  - Acta Pharmacol Sin. 2022 Aug;43(8):2094-2108. doi: 10.1038/s41401-021-00801-6. 
      Epub 2021 Dec 6.