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Cytochrome P450 2C9-natural antiarthritic interactions: Evaluation of inhibition magnitude and prediction from in vitro data

Tan BH, Ahemad N, Pan Y, Palanisamy UD, Othman I, Yiap BC, et al.

Biopharm Drug Dispos, 2018 Apr;39(4):205-217.
PMID: 29488228 DOI: 10.1002/bdd.2127

Many dietary supplements are promoted to patients with osteoarthritis (OA) including the three naturally derived compounds, glucosamine, chondroitin and diacerein. Despite their wide spread use, research on interaction of these antiarthritic compounds with human hepatic cytochrome P450 (CYP) enzymes is limited. This study aimed to examine the modulatory effects of these compounds on CYP2C9, a major CYP isoform, using in vitro biochemical assay and in silico models. Utilizing valsartan hydroxylase assay as probe, all forms of glucosamine and chondroitin exhibited IC50 values beyond 1000 μM, indicating very weak potential in inhibiting CYP2C9. In silico docking postulated no interaction with CYP2C9 for chondroitin and weak bonding for glucosamine. On the other hand, diacerein exhibited mixed-type inhibition with IC50 value of 32.23 μM and Ki value of 30.80 μM, indicating moderately weak inhibition. Diacerein's main metabolite, rhein, demonstrated the same mode of inhibition as diacerein but stronger potency, with IC50 of 6.08 μM and Ki of 1.16 μM. The docking of both compounds acquired lower CDOCKER interaction energy values, with interactions dominated by hydrogen and hydrophobic bondings. The ranking with respect to inhibition potency for the investigated compounds was generally the same in both in vitro enzyme assay and in silico modeling with order of potency being diacerein/rhein > various glucosamine/chondroitin forms. In vitro-in vivo extrapolation of inhibition kinetics (using 1 + [I]/Ki ratio) demonstrated negligible potential of diacerein to cause interaction in vivo, whereas rhein was predicted to cause in vivo interaction, suggesting potential interaction risk with the CYP2C9 drug substrates.

Matched MeSH terms: Arthritis/drug therapy
Anti-inflammatory, analgesic and anti-ulcerogenic effect of total alkaloidal extract from Murraya koenigii leaves in animal models

Mani V, Ramasamy K, Abdul Majeed AB

Food Funct, 2013 Apr 25;4(4):557-67.
PMID: 23360913 DOI: 10.1039/c3fo30356j

The fresh leaves of Murraya koenigii are often added to various dishes in Asian countries due to the delicious taste and flavour that they impart. In the present study, the effect of the total alkaloidal extract from Murraya koenigii leaves (MKA) with respect to anti-inflammatory, analgesic and anti-ulcerogenic effects were evaluated using different experimental animal models. Oral supplementation of MKA at 10, 20 and 40 mg kg(-1) body weight successfully and dose-dependently reduced the formation of oedema induced by carrageenan, histamine and serotonin as well as formaldehyde-induced arthritis. In addition, the extract (10, 20 and 40 mg kg(-1), p.o.) attenuated the writhing responses induced by an intraperitoneal injection of acetic acid and late phase of pain response induced by a subplantar injection of formalin in mice. MKA at higher doses (20 and 40 mg kg(-1), p.o) reduced the early phase response induced by formalin as well as reaction time on hot plate models. Interestingly, there was no ulcer score with the ulcerogenic effect of MKA. Moreover, all the doses of MKA (10, 20 and 40 mg kg(-1), p.o) showed promising anti-ulcerogenic activity with protection against acute gastric ulcers induced by ethanol plus hydrochloric acid and aspirin models in a dose dependent manner.

Matched MeSH terms: Arthritis/drug therapy*
Chronic nephrotoxicity of anti-inflammatory drugs used in the treatment of arthritis

Segasothy M, Chin GL, Sia KK, Zulfiqar A, Samad SA

Br J Rheumatol, 1995 Feb;34(2):162-5.
PMID: 7704463

We determined the consumption of non-steroidal anti-inflammatory drugs (NSAIDs) and the prevalence of chronic renal impairment and renal papillary necrosis (RPN) in patients with various types of arthritis. Ninety-four patients with chronic arthritis who had consumed more than 1000 capsules and/or tablets of NSAIDs were studied. Renal profiles and radiological investigations such as intravenous urogram (IVU), ultrasonography (US) and computed tomography (CT) were performed to look for evidence of RPN. Twelve patients did not complete the study. Ten of the 82 patients who had completed the study (12.2%) had radiologic evidence of RPN. Five out of 53 patients (9.4%) with rheumatoid arthritis, three out of 11 patients (27.3%) with gouty arthritis and two out of seven patients (28.6%) with osteoarthritis had RPN. Renal impairment (serum creatinine levels of 125-451 mumol/l) was found in 20 patients (24.4%). The patients had consumed 1000-26,300 capsules and/or tablets over a period ranging from 1 yr to more than 30 yr. Patients with chronic arthritis who consume excessive amount of NSAIDs are at risk of developing RPN and chronic renal impairment.

Matched MeSH terms: Arthritis/drug therapy*
The role of the kallikrein-kinin system in joint inflammatory disease

Sharma JN

Pharmacol Res, 1991 Feb;23(2):105-12.
PMID: 1648214

Components of kallikrein-kininogen-kinin are activated in response to noxious stimuli (chemical, physical or bacterial), which may lead to excessive release of kinins in the synovial joints that may produce inflammatory joint disease. The inflammatory changes observed in synovial tissue may be due to activation of B2 receptors. Kinins also stimulate the synthesis of other pro-inflammatory agents (PGs, LTs, histamine, EDRF, PGI2 and PAF) in the inflamed joint. B2 receptor antagonists may provide valuable new analgesic drugs. The mode of excessive kinin release in inflamed synovial joints leads to stimulation of pro-inflammatory actions of B2 kinin receptors. These properties could be antagonized by novel B2 receptor antagonists (see Fig. 4). Further, it is suggested that substances directed to reduce the activation of KKS may provide a pharmacological basis for the synthesis of novel antirheumatic or anti-inflammatory drugs.

Matched MeSH terms: Arthritis/drug therapy
Fulltext Anti-TNF Treatment for Extraintestinal Manifestations of Inflammatory Bowel Disease in the Swiss IBD Cohort Study

Vavricka SR, Gubler M, Gantenbein C, Spoerri M, Froehlich F, Seibold F, et al.

Inflamm Bowel Dis, 2017 07;23(7):1174-1181.
PMID: 28452862 DOI: 10.1097/MIB.0000000000001109

BACKGROUND: Extraintestinal manifestations (EIMs) in patients with inflammatory bowel disease (IBD) are frequently observed. Little is known about the efficacy of anti-tumor necrosis factor (TNF) in EIM management. We assessed the effect of 3 anti-TNF agents (infliximab, adalimumab, and certolizumab pegol) on EIM evolution.
METHODS: Data on 1249 patients from the Swiss IBD Cohort Study (SIBDCS) were analyzed. All EIMs were diagnosed by relevant specialists. Response was classified into improvement, stable disease, and clinical worsening based on the physician's interpretation.
RESULTS: Of the 366 patients with at least 1 EIM, 213 (58.2%) were ever treated with an anti-TNF. A total of 299 treatments were started for 355 EIMs. Patients with EIM were significantly more often treated with anti-TNF compared with those without EIM (58.2% versus 21.0%, P < 0.001). Infliximab was the most frequently used drug (63.2%). In more than 71.8%, a clinical response of the underlying EIM to anti-TNF therapy was observed. In 92 patients (43.2%), anti-TNF treatments were started for the purpose of treating EIM rather than IBD. Response rates to anti-TNF were generally good and best for psoriasis, aphthous stomatitis, uveitis, and peripheral arthritis. In 11 patients, 14 EIM occurred under anti-TNF treatment.
CONCLUSIONS: Anti-TNF was frequently used among patients with EIM. In more than 40%, anti-TNF treatments are started to treat EIM rather than IBD. Given the good response rates, anti-TNF seems to be a valuable option in the treatment of EIM, whereas appearance of EIM under anti-TNF does not seem to be a source of considerable concern.

Matched MeSH terms: Arthritis/drug therapy*
Fulltext Brief Report: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Multiple-Dose Study to Evaluate AMG 557 in Patients With Systemic Lupus Erythematosus and Active Lupus Arthritis

Cheng LE, Amoura Z, Cheah B, Hiepe F, Sullivan BA, Zhou L, et al.

Arthritis Rheumatol, 2018 07;70(7):1071-1076.
PMID: 29513931 DOI: 10.1002/art.40479

OBJECTIVE: To evaluate the safety and potential efficacy of AMG 557, a fully human antibody directed against the inducible T cell costimulator ligand (ICOSL) in patients with systemic lupus erythematosus (SLE) with arthritis.
METHODS: In this phase Ib, randomized, double-blind, placebo-controlled study, patients received AMG 557 210 mg (n = 10) or placebo (n = 10) weekly for 3 weeks, then every other week for 10 additional doses. The corticosteroid dosage was tapered to ≤7.5 mg/day by day 85, and immunosuppressants were discontinued by day 29. Primary end points on day 169 were safety, immunogenicity, the Lupus Arthritis Response Index (LARI; defined by a reduction in the tender and swollen joint counts), ≥1-letter improvement in the musculoskeletal domain of the British Isles Lupus Assessment Group (BILAG) index, and medication discontinuation. The secondary/exploratory end points were changes in the tender and swollen joint counts, BILAG index scores (musculoskeletal, global), and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).
RESULTS: The incidence of adverse events, most of which were mild, was similar between groups. LARI responses occurred in 3 of 10 patients receiving AMG 557 and 1 of 10 patients receiving placebo (P = 0.58). More patients in the AMG 557 group achieved a ≥4-point improvement in the SLEDAI score on day 169 (7 of 10 patients) compared with the placebo group (2 of 10 patients) (P = 0.07). Patients treated with AMG 557 (versus placebo) had greater improvements from baseline in the global BILAG index scores (-36.3% versus -24.7%) and the SLEDAI score (-47.8% versus -10.7%) and in tender (-22.8% versus -13.5%) and swollen (-62.1% versus -7.8%) joint counts on day 169.
CONCLUSION: AMG 557 showed safety and potential efficacy, supporting further evaluation of the clinical efficacy of ICOSL blockade in patients with SLE.

Matched MeSH terms: Arthritis/drug therapy*