Self-Nanoemulsifying Drug Delivery System (SNEDDS) of Apremilast: In Vitro Evaluation and Pharmacokinetics Studies

Psoriatic arthritis is an autoimmune disease of the joints that can lead to persistent inflammation, irreversible joint damage and disability. The current treatments are of limited efficacy and inconvenient. Apremilast (APR) immediate release tablets Otezla^® have 20–33% bioavailability compared to the APR absolute bioavailability of 73%. As a result, self-nanoemulsifying drug delivery systems (SNEDDS) of APR were formulated to enhance APR’s solubility, dissolution, and oral bioavailability. The drug assay was carried out using a developed and validated HPLC method. Various thermodynamic tests were carried out on APR-SNEDDS. Stable SNEDDS were characterized then subjected to in vitro drug release studies via dialysis membrane. The optimum formulation was F9, which showed the maximum in vitro drug release (94.9%) over 24 h, and this was further investigated in in vivo studies. F9 was composed of 15% oil, 60% S_mix, and 25% water and had the lowest droplet size (17.505 ± 0.247 nm), low PDI (0.147 ± 0.014), low ZP (−13.35 mV), highest %T (99.15 ± 0.131) and optimum increases in the relative bioavailability (703.66%) compared to APR suspension (100%) over 24 h. These findings showed that APR-SNEDDS is a possible alternative delivery system for APR. Further studies are warranted to evaluate the major factors that influence the encapsulation efficiency and stability of APR-containing SNEDDS.     

英平诸痹灵药酒中铜锰镍含量的分析

采用火争原子吸收分光度法测定了5种英平诸痹灵药酒中铜,锰,镍的含量,结果表明,该类药酒中镍,锰的含量较丰富,以锰的含量为最高,镍的含量次之,铜的含量相对最低。     

Investigating Antiarthritic Potential of Nanostructured Clove Oil (Syzygium aromaticum) in FCA-Induced Arthritic Rats: Pharmaceutical Action and Delivery Strategies

The combined application of clove oil in a lipid nanocarrier opens a promising avenue for bone and joints therapy. In this study, we successfully developed a tunable controlled-release lipid platform for the efficient delivery of clove oil (CO) for the treatment of rheumatoid arthritis (RA). The ultra-small nanostructured lipid carriers co-loaded with CO (CONCs) were developed through an aqueous titration method followed by microfluidization. The CONCs appeared to be spherical (particle size of 120 nm), stable (zeta potential of −27 mV), and entrapped efficiently (84.5%). In toluene:acetone:glacial acetic acid (90:9:1 percent v/v/v) solvent systems, high-performance thin layer chromatography (HPTLC) analysis revealed the primary components in CO as eugenol (R_F = 0.58). The CONCs greatly increased the therapeutic impact of CO in both in vitro and in vivo biological tests, which was further supported by excellent antiarthritic action. The CONC had an antiarthritic activity that was slightly higher than neat CO and slightly lower than standard, according to our data. The improved formulation inhibited serum lysosomal enzymes and proinflammatory cytokines while also improving hind leg function. This study provides a proof of concept to treat RA with a new strategy utilizing essential oils via nanodelivery.     

风湿性关节炎动物模型中血啉甲醚荧光强度的同步检测研究

光动力疗法的疗效依赖于治疗过程中靶组织中光敏剂的含量或浓度 ,而药物在组织中的分布特性是受动物机体调控的 ,因此 ,同一个体不同组织对光敏剂吸收的时间特性需要同时进行检测才能排除个体之间的差异。建立了一套空间三通道激光诱导荧光同步检测装置 ,并用该装置研究了活体大耳白兔风湿性关节炎模型滑膜、软骨和皮肤对血啉甲醚吸收的时间特性。研究结果表明 ,炎性滑膜组织对血啉甲醚的吸收量远大于软骨和皮肤 ,这一差别在静脉给药即刻就很明显 ,在静脉给药后 2 0min内 ,滑膜中的光敏剂药物含量约为软骨和皮肤中的 6倍。因此 ,对于借助血啉甲醚 ,用光动力疗法治疗风湿性关节炎并采用体外照射治疗方案时 ,从注药即刻开始 ,前 2 0min左右进行光照治疗可能是较好的选择。     

A new morphinandienone alkaloid from the stems of Fissistigma tungfangense

A new morphinandienone alkaloid, fissistigmine A (1), together with three known alkaloids (2?4), were isolated and identified from the stems of Fissistigma tungfangense. Among them, fissistigmine A (1) represents the first example of a novel naturally occurring morphinandienone alkaloid with a unique cleavage of the C-9?N-17 bond. All isolated compounds were evaluated for their anti-rheumatoid arthritis activities via examining their anti-proliferative effects on synoviocytes in vitro. Compound 1 exhibited inhibitory effect on the proliferation of synoviocytes with an IC₅₀ value of 114.6 ± 2.2 μM.     

基于气相色谱-飞行时间质谱技术的佐剂性关节炎大鼠尿液代谢组学的研究

采用弗氏完全佐剂(FCA)诱导佐剂性关节炎(AA)大鼠模型,观察大鼠足趾肿胀度和踝关节组织的病理学形态变化。应用气相色谱-飞行时间质谱(GC-TOF MS)技术检测AA大鼠尿液代谢物谱,并对数据进行主成分分析(PCA)、偏最小二乘法-判别分析(PLS-DA)及正交偏最小二乘法-判别分析(OPLS-DA),探讨可能的发病机制。通过变量重要性投影值(VIP>1)和P值(<0.05),筛选出尿液中的差异代谢物。在模型组大鼠的尿液中共发现异柠檬酸、α-酮戊二酸、柠康酸、肌酸、3-羟基丁酸等20种差异代谢物。推断AA代谢组学的发病机制可能与能量代谢、氨基酸代谢、脂肪酸代谢途径有关。     

The Protective Effects of Neoastilbin on Monosodium Urate Stimulated THP-1-Derived Macrophages and Gouty Arthritis in Mice through NF-κB and NLRP3 Inflammasome Pathways

Gouty arthritis (GA) is a frequent inflammatory disease characterized by pain, swelling, and stiffness of joints. Neoastilbin is a flavonoid isolated from the rhizome of Smilax glabra, which possesses various anti-inflammatory effects. However, the mechanism of neoastilbin in treating GA has not yet been clarified. Thus, this study was to investigate the protective effects of neoastilbin in both monosodium urate (MSU) stimulated THP-1-derived macrophages and the animal model of GA by injecting MSU into the ankle joints of mice. The levels of key inflammatory cytokines in MSU stimulated THP-1-derived macrophages were detected by enzyme-linked immunosorbent assay (ELISA) kits. Protein expressions of nuclear factor kappa B (NF-κB) and NOD-like receptor protein 3 (NLRP3) inflammasome pathways were further detected by Western blotting. In addition, swelling degree of ankle joints, the levels of inflammatory factors, infiltration of inflammatory cells and the expressions of related proteins were determined. Swelling degree and histopathological injury in ankle joints of MSU-injected mice were significantly decreased after being treated with neoastilbin. Moreover, neoastilbin significantly diminished the secretion of interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), suppressing the activation of NF-κB and NLRP3 inflammasome pathways in both MSU stimulated THP-1-derived macrophages and the mouse model of GA. In summary, neoastilbin could alleviate GA by inhibiting the NF-κB and NLRP3 inflammasome pathways, which provided some evidence for neoastilbin as a promising therapeutic agent for GA treatment.     

An Overview of PDE4 Inhibitors in Clinical Trials: 2010 to Early 2022

Since the early 1980s, phosphodiesterase 4 (PDE4) has been an attractive target for the treatment of inflammation-based diseases. Several scientific advancements, by both academia and pharmaceutical companies, have enabled the identification of many synthetic ligands for this target, along with the acquisition of precise information on biological requirements and linked therapeutic opportunities. The transition from pre-clinical to clinical phase was not easy for the majority of these compounds, mainly due to their significant side effects, and it took almost thirty years for a PDE4 inhibitor to become a drug i.e., Roflumilast, used in the clinics for the treatment of chronic obstructive pulmonary disease. Since then, three additional compounds have reached the market a few years later: Crisaborole for atopic dermatitis, Apremilast for psoriatic arthritis and Ibudilast for Krabbe disease. The aim of this review is to provide an overview of the compounds that have reached clinical trials in the last ten years, with a focus on those most recently developed for respiratory, skin and neurological disorders.     

Synthesis,reactivity, in vitro boron neutron capture therapy assay,and molecular docking of fluorocyclocarboxyboranylamine

The one-pot reaction of Me₃NBH₂CN with Et₃O⁺BF₄⁻ followed by addition of BF₃·Et₂O and water produces a trimethylamine derivative of fluorocyclocarboxyboranylamine, Me₃NBH₂C(O₂BF₂NH₂) ( 1 ) in 36.0% yield. Compound 1 undergoes exchange reaction between the exo-Me₃N moiety and piperidine or pyridine to produce the corresponding piperidine-substituted fluorocyclocarboxyboranylamine ( 2 ) or pyridine-substituted fluorocyclocarboxyboranylamine ( 3 ) in 51.2% or 42.4% yields, respectively. The new compounds were characterized by ¹H, ¹³C, ¹¹B, and ¹⁹F nuclear magnetic resonance spectroscopy; Fourier-transform infrared spectroscopy; and elemental analyses and the crystal structure of 1 was determined to confirm its molecular geometry. The in vitro killing effects of 1 , along with its toxicity measurements and molecular docking interactions with matrix metalloproteinases showed a potential promise of such species as both boron neutron capture therapy and boron neutron capture synovectomy agents in the treatment of tumors and rheumatoid arthritis, respectively, in the presence of slow neutrons.     

Synovial fluid of patients with rheumatoid arthritis induces ��-smooth muscle actin in human adipose tissue-derived mesenchymal stem cells through a TGF-��1-dependent mechanism

Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disorder that causes the immune system to attack the joints. Transforming growth factor-β1 (TGF-β1) is a secreted protein that promotes differentiation of synovial fibroblasts to α-smooth muscle actin (α-SMA)-positive myofibroblasts to repair the damaged joints. Synovial fluid from patients with RA (RA-SF) induced expression of α-SMA in human adipose tissue-derived mesenchymal stem cells (hASCs). RA-SF-induced α-SMA expression was abrogated by immunodepletion of TGF-β1 from RA-SF with anti-TGF-β1 antibody. Furthermore, pretreatment of hASCs with the TGF-β type I receptor inhibitor SB431542 or lentiviral small hairpin RNA-mediated silencing of TGF-β type I receptor expression in hASCs blocked RA-SF-induced α-SMA expression. Small interfering RNA-mediated silencing of Smad2 or adenoviral overexpression of Smad7 (an inhibitory Smad isoform) completely inhibited RA-SF-stimulated α-SMA expression. These results suggest that TGF-β1 plays a pivotal role in RA-SF-induced differentiation of hASCs to α-SMA-positive cells.