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Chondroprotective Effects and Mechanisms of Dextromethorphan: Repurposing Antitussive Medication for Osteoarthritis Treatment.

ABSTRACT: Osteoarthritis (OA) is the most common joint disorder and primarily affects older people. The ideal anti-OA drug should have a modest anti-inflammatory effect and only limited or no toxicity for long-term use. Because the antitussive medication dextromethorphan (DXM) is protective in atherosclerosis and neurological diseases, two common disorders in aged people, we examined whether DXM can be protective in pro-inflammatory cytokine-stimulated chondrocytes and in a collagen-induced arthritis (CIA) animal model in this study. Chondrocytes were prepared from cartilage specimens taken from pigs or OA patients. Western blotting, quantitative PCR, and immunohistochemistry were adopted to measure the expression of collagen II (Col II) and matrix metalloproteinases (MMP). DXM significantly restored tumor necrosis factor-alpha (TNF-?)-mediated reduction of collagen II and decreased TNF-?-induced MMP-13 production. To inhibit the synthesis of MMP-13, DXM blocked TNF-? downstream signaling, including I kappa B kinase (IKK)?/?-I?B?-nuclear factor-kappaB (NF-?B) and c-Jun N-terminal kinase (JNK)-activator protein-1 (AP-1) activation. Besides this, DXM protected the CIA mice from severe inflammation and cartilage destruction. DXM seemed to protect cartilage from inflammation-mediated matrix degradation, which is an irreversible status in the disease progression of osteoarthritis. The results suggested that testing DXM as an osteoarthritis therapeutic should be a focus in further research.

SUBMITTER: Chen LW

PROVIDER: S-EPMC5877686 | biostudies-other | 2018 Mar

REPOSITORIES: biostudies-other

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Chondroprotective Effects and Mechanisms of Dextromethorphan: Repurposing Antitussive Medication for Osteoarthritis Treatment.

Chen Liv Weichien LW Liu Feng-Cheng FC Hung Li-Feng LF Huang Chuan-Yueh CY Lien Shiu-Bii SB Lin Leou-Chyr LC Lai Jenn-Haung JH Ho Ling-Jun LJ

International journal of molecular sciences 20180312 3

Osteoarthritis (OA) is the most common joint disorder and primarily affects older people. The ideal anti-OA drug should have a modest anti-inflammatory effect and only limited or no toxicity for long-term use. Because the antitussive medication dextromethorphan (DXM) is protective in atherosclerosis and neurological diseases, two common disorders in aged people, we examined whether DXM can be protective in pro-inflammatory cytokine-stimulated chondrocytes and in a collagen-induced arthritis (CIA ...[more]

PMID: 29534535

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Project description:Often affecting knee joints, osteoarthritis (OA) is the most common type of arthritis and by 2020 is predicted to become the fourth leading cause of disability globally. Without cure, medication management is symptomatic, mostly with simple analgesics such as acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs), and glucosamine sulfate. Adherence to arthritis medications is generally low. Intentional non-adherence, that is deliberate decision-making about the use of analgesics, occurs in OA patients. To date, a limited number of studies have explored medication-taking decisions in people with OA nor the extent to which individuals' trade off one treatment factor for another in their decision-making using quantitative techniques. This study aimed to estimate the relative influence of medication-related factors and respondent characteristics on decisions to continue medications among people with symptomatic OA.A discrete choice experiment (DCE) was conducted among participants attending end-of-study visits in the Long-term Evaluation of Glucosamine Sulfate (LEGS) study (ClinicalTrials.gov ID: NCT00513422). The paper-based survey was used to estimate the relative importance of seven medication specific factors (pain efficacy, mode of action, dose frequency, treatment schedule, side effects, prescription, and out-of-pocket costs) and respondent characteristics on decisions to continue medications.188 (response rate 37%) completed surveys were returned. Four of the seven medication factors (side effects, out-of-pocket costs, mode of action, treatment schedule) had a significant effect on the choice to continue medication; patient characteristics did not. Assuming equivalent pain efficacy and disease-modifying properties for glucosamine, the positive relative likelihood of continuing with sustained-release acetaminophen was equivalent to glucosamine. By contrast, the negative relative likelihood of NSAID continuation was mostly driven by the side effect profile. The predicted probability of continuing with glucosamine decreased with increasing out-of-pocket costs.This study has characterised the complexity of medication-taking decisions that potentially underpin intentional non-adherent behaviour for people with symptomatic OA. In particular, medication risks and cost were important and ought to be borne into considerations in interpreting clinical trial evidence for practice. Ultimately addressing these factors may be the way forward to realising the full potential of health and economic benefits from the efficacious and safe use of OA medications.

Project description:BackgroundWe conducted an exploratory analysis of osteoarthritis progression among medication users in the Osteoarthritis Initiative to identify interventions or pathways that may be associated with disease modification and therefore of interest for future clinical trials.MethodsWe used participants from the Osteoarthritis Initiative with annual medication inventory data between the baseline and 36-month follow-up visit (n = 2938). Consistent medication users were defined for each medication classification as a participant reporting at all four annual visits that they were regularly using an oral prescription medication at the time of the visit. The exploratory analysis focused on medication classes with 40 or more users. The primary outcome measures were medial tibiofemoral joint space width change and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) knee pain score change (12-36-month visits). Within each knee, we explored eight comparisons between users and matched or unmatched nonusers (defined two ways). An effect size of each comparison was calculated. Medication classes had potential signals if (a) both knees had less progression among users compared with nonusers, or (b) there was less progression based on structure and symptoms in one knee.ResultsWe screened 28 medication classes. Six medication classes had signals for fewer structural changes and better knee pain changes: alpha-adrenergic blockers, antilipemic (excluding statins and fibric acid), anticoagulants, selective serotonin reuptake inhibitors, antihistamines, and antineoplastic agents. Four medication classes had signals for structural changes alone: anti-estrogen (median effect size = 0.28; range = -0.41-0.64), angiotensin-converting enzyme inhibitors (median effect size = 0.13; range = -0.08-0.28), beta-adrenergic blockers (median effect size = 0.09; range = 0.01-0.30), and thyroid agents (median effect size = 0.04; range = -0.05-0.14). Thiazide diuretics had evidence for symptom modification (median effect size = -0.12; range = -0.24-0.04).ConclusionsUsers of neurovascular, antilipemic, or hormonal interventions may have less disease progression compared with nonusers.

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Chondroprotective Effects and Mechanisms of Dextromethorphan: Repurposing Antitussive Medication for Osteoarthritis Treatment.

Publications

Chondroprotective Effects and Mechanisms of Dextromethorphan: Repurposing Antitussive Medication for Osteoarthritis Treatment.

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