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Colchicine (COL) is a well-known plant alkaloid long used for medical purposes due to the selective anti-inflammatory effect on acute gouty arthritis. It is also a kind of mitosis toxin with strong inhibitory effects of cell division and is therefore being applied to the treatment of various cancers. However, this product shows a variety of adverse effects that are significantly correlated with the dosage and have attracted much attention. For the first time, the present work obtained a new insight into the gastrointestinal toxicity of colchicine analogues by molecular docking analysis, which was based on the 3D structure of intestinal tight junction protein ZO-1 and the ligand library containing dozens of small-molecule compounds with the basic skeleton of COL and its metabolites. The binding energy and mode of protein–ligand interaction were investigated to better understand the structure–toxicity relationships of COL analogues and the mechanism of action as well. Cluster analysis clearly demonstrated the strong correlation between the binding energy and toxicity of ligand molecules. The interaction mode further revealed that the hydrogen bonding (via the C-7 amide or C-9 carbonyl group) and hydrophobic effect (at ring A or C) were both responsible for ZO-1-related gastrointestinal toxicity of COL analogues, while metabolic transformation via phase I and/or phase II reaction would significantly attenuate the gastrointestinal toxicity of colchicine, indicating an effective detoxication pathway through metabolism.

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Meloxicam (MLX) is a commonly used drug in the clinical treatment of osteoarthritis, but it is associated with gastrointestinal adverse reactions. Therefore, in this study, we developed a sustained-release microsphere formulation of MLX for topical administration of knee joint. The MLX-loaded PLGA microspheres (MLX-MS) were prepared by emulsion solvent evaporation method with optimization of formulation using orthogonal experimental design. Physicochemical characterization results show MLX-MS were spherical with a smooth surface, the particle size was about 100 μm, drug loading was 30%, and encapsulation efficiency was 76.8%. In addition, the in vivo pharmacokinetics, tissue distribution, and pharmacodynamics were evaluated in rats by intra-articular administration of MLX. The microspheres showed a typical long-term sustained release pattern with a low initial burst release. In contrast to oral administration, local injection of MLX-MS produced a much higher value of elimination half-life time(T 1/2 ) and peak time (T max ) in plasma, while the intestinal drug distribution was significantly decreased. MLX-MS could also cause a greater reduction in the body level of IL-6 and TNF-α, which was positively correlated with R 2 =0.981. A good linear relationship (R 2 = 0.9945) between the in vitro and in vivo drug release from MLX-MS could be observed, bivariate correlation analysis. All the findings demonstrated that local administration of MLX-MS can prolong the action time of MLX and reduce side effects, thus would be a promising preparation for the treatment of arthritis.

Background. Azithromycin (AZM) is one of the most common broad-spectrum antibiotics. However, drug resistance is increasing and combination therapy has attracted great attention. AZM is usually combined with traditional Chinese medicine (TCM) preparations with heat-clearing and detoxifying effects, including Kumu injection (KM) made from Picrasma quassioides (D. Don) Benn. Purpose. The present study aimed to investigate synergistic antimicrobial and anti-inflammatory activities of KM plus AZM with the aim of understanding the mechanism of clinical efficacy of combination regimens. Methods. Seven common bacterial clinical isolates and LPS-induced RAW 264.7 cells were used for assay of in vitro potency. The minimum inhibitory concentration (MIC) was determined for each drug, followed by synergy testing through the checkerboard method and fractional inhibitory concentration index (FICI) for quantifying combined antibacterial effects. The rat model of Klebsiella pneumoniae-induced pneumonia was developed and subjected to various drug treatments, namely, AZM, KM, or AZM plus KM, intravenously administered at 75 mg/kg once a day for one week. The combination effects then were evaluated according to pharmacodynamics and pharmacokinetic assessments. Results. KM-AZM combination synergistically inhibits in vitro growth of all the test standard strains except Pseudomonas aeruginosa and also the drug-resistant strains of Staphylococcus aureus, Streptococcus pneumoniae, Shigella dysenteriae, Klebsiella pneumoniae, and Escherichia coli. Despite an additive effect against NO, KM plus AZM at an equal dose could synergistically suppress overrelease of the inflammatory cytokines TNF-α and IL-6 by LPS-induced RAW 264.7 cells. The combination significantly inhibited the proliferation of K. pneumoniae in the rat lungs, mainly by inactivating MAPKs and NF-κB signaling pathways. KM-AZM combination caused a onefold increase in apparent distribution volume of AZM, along with a significant decrease of AZM level in the livers and heart for pharmacokinetics. Conclusion. KM-AZM combination displayed synergistic antibacterial and anti-inflammatory effects beneficial to the therapeutic potential against bacterial infection.