Inhibition of JAK kinases in patients with rheumatoid arthritis: scientific rationale and clinical outcomes

Riese, Richard J.; Krishnaswami, Sriram; Kremer, Joel M.

doi:10.1016/j.berh.2010.02.003

Cited by 104 publications

(79 citation statements)

References 25 publications

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“…Small-molecule inhibitors of JAKs are emerging as promising therapies for RA. Two compounds, tofacitinib (JAK1/2/3 inhibitor) and LY3009104 (JAK1/2 inhibitor), are undergoing late-stage clinical trials or nearing U.S. Food and Drug Administration approval for marketing (45,53,54). The combination of activities of SB1578 against JAK2, c-Fms, and FLT3, with selectivity for JAK2 within the JAK family, is unique.…”

Section: Discussionmentioning

confidence: 99%

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

Madan¹,

Goh²,

Hart³

et al. 2012

The Journal of Immunology

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SB1578 is a novel, orally bioavailable JAK2 inhibitor with specificity for JAK2 within the JAK family and also potent activity against FLT3 and c-Fms. These three tyrosine kinases play a pivotal role in activation of pathways that underlie the pathogenesis of rheumatoid arthritis. SB1578 blocks the activation of these kinases and their downstream signaling in pertinent cells, leading to inhibition of pathological cellular responses. The biochemical and cellular activities of SB1578 translate into its high efficacy in two rodent models of arthritis. SB1578 not only prevents the onset of arthritis but is also potent in treating established disease in collagen-induced arthritis mice with beneficial effects on histopathological parameters of bone resorption and cartilage damage. SB1578 abrogates the inflammatory response and prevents the infiltration of macrophages and neutrophils into affected joints. It also leads to inhibition of Ag-presenting dendritic cells and inhibits the autoimmune component of the disease. In summary, SB1578 has a unique kinase spectrum, and its pharmacological profile provides a strong rationale for the ongoing clinical development in autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

Madan¹,

Goh²,

Hart³

et al. 2012

The Journal of Immunology

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“…4 Tofacitinib is administered orally at 50 mg/kg 5 or using osmotic minipump infusion at doses of 1.5, 5, and 15 mg/kg. 6 Competitive inhibition of dihydrofolate reductase that plays an important role in tetrahydrofolate synthesis can be achieved by MTX. 7 Other multiple mechanisms are involved apart from the inhibition of dihydrofolate reductase that include inhibition of 1) enzymes that play a role in purine metabolism 8 and 2) binding of IL-1 beta to its cell-surface receptor.…”

Section: Available Treatments For Arthritismentioning

confidence: 99%

Molecular targets in arthritis and recent trends in nanotherapy

Roy¹,

Kanwar²,

Kanwar³

2015

IJN

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Due to its severity and increasing epidemiology, arthritis needs no description. There are various forms of arthritis most of which are disabling, very painful, and common. In spite of breakthroughs in the field of drug discovery, there is no cure for arthritis that can eliminate the disease permanently and ease the pain. The present review focuses on some of the most successful drugs in arthritis therapy and their side effects. Potential new targets in arthritis therapy such as interleukin-1β, interleukin-17A, tumor necrosis factor alpha, osteopontin, and several others have been discussed here, which can lead to refinement of current therapeutic modalities. Mechanisms for different forms of arthritis have been discussed along with the molecules that act as potential biomarkers for arthritis. Due to the difficulty in monitoring the disease progression to detect the advanced manifestations of the diseases, drug-induced cytotoxicity, and problems with drug delivery; nanoparticle therapy has gained the attention of the researchers. The unique properties of nanoparticles make them highly attractive for the design of novel therapeutics or diagnostic agents for arthritis. The review also focuses on the recent trends in nanoformulation development used for arthritis therapy. This review is, therefore, important because it describes the relevance and need for more arthritis research, it brings forth a critical discussion of successful drugs in arthritis and analyses the key molecular targets. The review also identifies several knowledge gaps in the published research so far along with the proposal of new ideas and future directions in arthritis therapy.

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“…6,7 Jak3 interacts with the interleukin (IL)-2 receptor common gamma chain shared by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. 3,7,8 These cytokines bind to type I and II cytokine receptors and signal via the Jak-signal transducers, resulting in the activation of transcription of genes for lymphopoiesis and homeostasis. 4 The function of Jak signaling illustrates the vital role it plays in mediation of inflammatory immune responses and presents a novel approach to influence the pathophysiology of inflammatory autoimmune diseases, such as RA.…”

Section: Indicationsmentioning

confidence: 99%

“…1,3,13 In vivo kinase assays have demonstrated the greatest potency of inhibition of Jak3, followed by Jak1, Jak2, and Tyk2. 3,13 …”

Section: Clinical Pharmacologymentioning

confidence: 99%

“…8 The tofacitinib pharmacokinetic profile is best characterized by a 1-compartment open model with first-order absorption. 3,14 Tofacitinib is well absorbed following oral administration, with an absolute bioavailability of 74% in healthy subjects. 1,15 Coadministration with a highfat meal reduces peak plasma concentrations (C max ) by 32%; however, the manufacturer states the drug can be administered without regard to meals.…”

Section: Pharmacokineticsmentioning

confidence: 99%

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Tofacitinib

et al. 2013

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Inhibition of JAK kinases in patients with rheumatoid arthritis: scientific rationale and clinical outcomes

Cited by 104 publications

References 25 publications

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

Molecular targets in arthritis and recent trends in nanotherapy

Tofacitinib

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Inhibition of JAK kinases in patients with rheumatoid arthritis: scientific rationale and clinical outcomes

Cited by 104 publications

References 25 publications

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

SB1578, a Novel Inhibitor of JAK2, FLT3, and c-Fms for the Treatment of Rheumatoid Arthritis

Molecular targets in arthritis and recent trends in&nbsp;nanotherapy

Tofacitinib

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Molecular targets in arthritis and recent trends in nanotherapy