Drugs and Polymers for Delivery Systems in OA Joints: Clinical Needs and Opportunities

Janssen, M; Mihov, George; Welting, Tim J. M.; Thies, Jens; Emans, Pieter J.

doi:10.3390/polym6030799

Cited by 42 publications

(30 citation statements)

References 91 publications

(118 reference statements)

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“…Therefore, even if MTX were available to treat a chronic disease like OA, there would be serious concerns about its safety aspects. Moreover, an oral treatment such as MTX is not appropriate to treat OA, which is usually regarded as a localized disease, for which the optimal treatment is a therapy applied directly to the affected joint [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Novel hyaluronic acid–methotrexate conjugate suppresses joint inflammation in the rat knee: efficacy and safety evaluation in two rat arthritis models

Tamura¹,

Higuchi²,

Kitamura³

et al. 2016

Arthritis Res Ther

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BackgroundMethotrexate (MTX) is one of the most widely used medications to treat rheumatoid arthritis (RA), and recent studies have also suggested the potential benefit of the drug for the treatment of osteoarthritis (OA) of the knee. MTX is commonly administered in oral formulations, but is often associated with systemic adverse reactions. In an attempt to address this issue, we have shown previously that a conjugate of hyaluronic acid (HA) and MTX exhibits potential as a drug candidate for intra-articular treatment of inflammatory arthritis. In this study, we compare the efficacy and safety of an optimized HA-MTX conjugate, DK226, with that of MTX in inflammatory arthritis rat models.MethodsIn vitro activity of DK226 was assessed in human fibroblast-like synoviocytes (HFLS) and a synovial sarcoma cell line, SW982. Release of MTX from DK226 was investigated after incubation with rabbit synovial tissue homogenate or synovial fluid. In vivo efficacy of DK226 was evaluated in antigen-induced arthritis (AIA) and collagen-induced arthritis (CIA) in the rat knee. Pharmacokinetics and hematological toxicity after treatment with oral MTX or an intra-articular injection of DK226 were compared in AIA.ResultsProliferation of HFLS and SW982 cells was inhibited by DK226, and the inhibitory activity was reversed by cotreatment with excess HA or anti-CD44 antibody. MTX was released from DK226 by incubation with rabbit synovial tissue homogenate or synovial fluid at pH 4.0, but not at pH 7.4. AIA was ameliorated by intra-articular DK226, but not by HA, as potently as oral MTX. Hematological toxicity was induced by oral MTX, but not by DK226. The maximum plasma concentration of MTX after oral MTX was 40 times higher than the concentration of MTX after an intra-articular injection of DK226. Knee swelling in AIA was inhibited by intra-articular injections of DK226, but not by free MTX or a mixture of HA and MTX. In CIA, an injection of DK226 into the right knee joint significantly reduced swelling and synovial inflammation of the treated knee joint, but had no effect on the untreated contralateral knee joint.ConclusionsDK226 exerted anti-arthritic effects in two different models of arthritis. The conjugate had a wider therapeutic window than oral MTX, and could be a future drug for treatment of arthritic disorders, including inflammatory OA.

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Section: Introductionmentioning

confidence: 99%

Novel hyaluronic acid–methotrexate conjugate suppresses joint inflammation in the rat knee: efficacy and safety evaluation in two rat arthritis models

Tamura¹,

Higuchi²,

Kitamura³

et al. 2016

Arthritis Res Ther

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“…To decrease systemic and IA peak levels of corticosteroids, drug delivery systems for local application, in particular microspheres (MSs), are promising alternatives. These provide prolonged low‐level drug exposure with a lower risk of IA and systemic side effects (Janssen, Mihov, Welting, Thies, & Emans, ). The MSs are injected into the joint and, given their size, cannot leave this location.…”

Section: Introductionmentioning

confidence: 99%

Local controlled release of corticosteroids extends surgically induced joint instability by inhibiting tissue healing

Rudnik-Jansen

Tellegen

Pouran

et al. 2019

British J Pharmacology

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Background and PurposeCorticosteroids are intra‐articularly injected to relieve pain in joints with osteoarthritis (OA) or acute tissue damage such as ligament or tendon tears, despite its unverified contraindication in unstable joints. Biomaterial‐based sustained delivery may prolong reduction of inflammatory pain, while avoiding harmful peak drug concentrations.Experimental ApproachThe applicability of prolonged corticosteroid exposure was examined in a rat model of anterior cruciate ligament and medial meniscus transection (ACLT + pMMx) with ensuing degenerative changes.Key ResultsIntra‐articular injection of a bolus of the corticosteroid triamcinolone acetonide (TAA) resulted in enhanced joint instability in 50% of the joints, but neither instability‐induced OA cartilage degeneration, synovitis, nor the OA‐related bone phenotype was affected. However, biomaterial microsphere‐based extended TAA release enhanced instability in 94% of the animals and induced dystrophic calcification and exacerbation of cartilage degeneration. In healthy joints, injection with TAA releasing microspheres had no effect at all. In vitro, TAA inhibited cell migration out of joint tissue explants, suggesting inhibited tissue healing in vivo as mechanisms for enhanced instability and subsequent cartilage degeneration.Conclusions and ImplicationsWe conclude that short‐term TAA exposure has minor effects on surgically induced unstable joints, but its extended presence is detrimental by extending instability and associated joint degeneration through compromised healing. This supports a contraindication of prolonged corticosteroid exposure in tissue damage‐associated joint instability, but not of brief exposure.

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“…Delivering drugs through oral administration to the targeted site takes long (1–5 h) and leads to the decrease of drug efficiency due to their gastrointestinal adsorption and systemic circulation. 59 , 60 Corticosteroid injection has a palliative (not curative) effect, is only used in severe acute pain, and generally for limited doses only. The effect of steroid on the disk is widely reported to irritate.…”

Section: Delivery Vehicles Of Therapeutic Moleculesmentioning

confidence: 99%

Intra-articular biomaterials-assisted delivery to treat temporomandibular joint disorders

et al. 2018

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The temporomandibular joint disorder, also known as myofascial pain syndrome, is considered one of the prevalent chronic pain diseases caused by muscle inflammation and cartilage degradation in head and neck, and thus influences even biopsychosocial conditions in a lifetime. There are several current treatment methodologies relieving inflammation and preventing degradation of the joint complex. One of the promising non-surgical treatment methods is an intra-articular injection of drugs such as corticosteroids, analgesics, and anti-depressants. However, the side effects of drugs due to frequent injections and over-doses, including dizziness, dry mouth, and possible drug dependency are considered limitations. Thus, the delivery of therapeutic molecules through the use of nano/microparticles is currently considered as a promising strategy primarily due to the controlled release. This review highlights the nano/microparticle systems for effective intra-articular therapeutics delivery to prevent cartilage degradation and protect subchondral bone in a temporomandibular joint.

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Drugs and Polymers for Delivery Systems in OA Joints: Clinical Needs and Opportunities

Cited by 42 publications

References 91 publications

Novel hyaluronic acid–methotrexate conjugate suppresses joint inflammation in the rat knee: efficacy and safety evaluation in two rat arthritis models

Novel hyaluronic acid–methotrexate conjugate suppresses joint inflammation in the rat knee: efficacy and safety evaluation in two rat arthritis models

Local controlled release of corticosteroids extends surgically induced joint instability by inhibiting tissue healing

Intra-articular biomaterials-assisted delivery to treat temporomandibular joint disorders

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