An open-label, single-arm pilot study in patients with severe plaque-type psoriasis treated with an oral anti-inflammatory agent, apremilast

Gottlieb, Alice B.; Strober, Bruce; Krueger, James G.; Rohane, Patricia; Zeldis, Jerry; Hu, C.; Kipnis, Cindy D.

doi:10.1185/030079908x301866

Cited by 116 publications

(70 citation statements)

References 9 publications

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“…3,6,11 In healthy patients, apremilast plasma clearance is about 10 L/h, and the terminal elimination halflife is 6 to 9 hours. 1,7,9,12 The half-life of apremilast metabolites is 11 to 16 hours. 9 Following oral administration of radiolabeled apremilast, about 58% and 39% of the radioactivity and about 3% and 7% of unchanged radioactive apremilast is recovered in urine and feces, respectively.…”

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confidence: 99%

Apremilast

2014

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Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are sent in print and are also available on-line. Monographs can be customized to meet the needs of a facility. A drug class review is now published monthly with The Formulary Monograph Service. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, call The Formulary at 800-322-4349. The September 2014 monograph topics are tedizolid phosphate, ceritinib, omega-3-carboxylic acids, umeclidinium bromide inhalation powder, and siltuximab. The DUE/MUE is on avoidance of insulin use errors.

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confidence: 99%

Apremilast

2014

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“…19 Celgene's PDE4 inhibitors have been shown to be nonteratogenic and well tolerated by humans as an anti-inflammatory agent in phase 1 clinical studies. 20 CC-3052 is one of these PDE4 inhibitors; it is approximately 200-fold more potent than thalidomide in inhibiting TNF-␣ production by activated macrophages in vitro. 21 We have previously established a model of progressive pulmonary TB in the rabbit by infecting animals via the respiratory route with the M. tuberculosis strain HN878.…”

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confidence: 99%

Phosphodiesterase-4 Inhibition Combined with Isoniazid Treatment of Rabbits with Pulmonary Tuberculosis Reduces Macrophage Activation and Lung Pathology

Subbian¹,

Tsenova

O'Brien

et al. 2011

The American Journal of Pathology

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Tuberculosis (TB) is responsible for significant morbidity and mortality worldwide. Even after successful microbiological cure of TB, many patients are left with residual pulmonary damage that can lead to chronic respiratory impairment and greater risk of additional TB episodes due to reinfection with Mycobacterium tuberculosis. Elevated levels of the proinflammatory cytokine tumor necrosis factor-␣ and several other markers of inflammation, together with expression of matrix metalloproteinases, have been associated with increased risk of pulmonary fibrosis, tissue damage, and poor treatment outcomes in TB patients. In this study, we used a rabbit model of pulmonary TB to evaluate the impact of adjunctive immune modulation, using a phosphodiesterase-4 inhibitor that dampens the innate immune response, on the outcome of treatment with the antibiotic isoniazid. Our data show that cotreatment of M. tuberculosis infected rabbits with the phosphodiesterase-4 inhibitor CC-3052 plus isoniazid significantly reduced the extent of immune pathogenesis, compared with antibiotic alone, as determined by histologic analysis of infected tissues and the expression of genes involved in inflammation, fibrosis, and wound healing in the lungs. Combined treatment with an antibiotic and CC-3052 not only lessened disease but also improved bacterial clearance from the lungs. These findings support the potential for adjunctive immune modulation to improve the treatment of pulmonary TB and reduce the risk of chronic respiratory impairment. Tuberculosis (TB), caused by Mycobacterium tuberculosis, is one of the leading infectious disease causes of morbidity and mortality worldwide. Although current multidrug regimens are generally effective, treatment is lengthy, requiring a minimum of 6 months and sometimes more than 1 year, for patients with drug-resistant TB or other clinical complications.1 Even after successful microbiological cure, pulmonary TB patients are often left with residual lung damage.2-5 Pulmonary impairment after TB treatment has been observed as changes in the structure and function of bronchial parenchymal tissue and the persistence of fibrocavitary lung damage.6,7 The risk and the extent of chronic respiratory dysfunction in individuals after curative therapy have been shown to increase with the number of previous TB episodes. 8 Most importantly, one recent study in South Africa found a fourfold higher risk of TB due to reinfection in previously treated patients compared with incidence rates among new TB cases.

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“…A selective PDE4 inhibitor, apremilast has been shown to block pro-inflammatory cytokines including TNF-α, Interferon-γ, IL-12, IL-17 and IL-23 with a reduction in psoriasiform biology in humans [113]. By binding to the catalytic site and blocking PDE4 mediated enzymatic degradation of cAMP, apremilast leads to increased cAMP mediated PKA activation and subsequent phosphorylation of CREB.…”

Section: A Pde4 Inhibitor For the Treatment Of Psoriasismentioning

confidence: 99%

Cyclic Adenosine Monophosphate Signalling in Inflammatory Skin Disease

Levy¹,

Zhou²

2015

J Clin Exp Dermatol Res

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The second messenger cyclic adenosine monophosphate (cAMP) regulates numerous key pathways that impact the immune system. Distinct cellular cAMP signaling pathways can lead to both pro-and anti-inflammatory effects depending upon the cell type. When dysregulated, these cAMP pathways can influence the pathogenesis of inflammatory cutaneous diseases, such as atopic dermatitis and psoriasis. In psoriasis and atopic dermatitis, cAMP and/or its effector proteins (e.g., protein kinase A) are downregulated suggesting that elevation of cAMP might be a therapeutic option. cAMP levels are the result of balance between synthesis by adenylyl cyclases and degradation by phosphodiesterases (PDEs). Pharmacologically inhibiting PDEs represents one effective mechanism to raise intracellular cAMP levels perhaps leading to targeted immune suppression. Several drugs have been developed to target PDEs and while some toxicities (e.g., nausea and emesis) exist these drugs are generally well tolerated. Perhaps the best characterized is Apremilast, a PDE4 specific inhibitor, which has been FDA approved for the treatment of psoriasis and shows great promise as a safe and novel immunosuppressive medication. Following on the heels of Apremilast are numerous oral and topical PDE inhibitors in various stages of clinical trials. In this review, we examine the role of cAMP signaling in inflammatory cutaneous diseases and the development of PDE inhibitors as therapeutics.

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An open-label, single-arm pilot study in patients with severe plaque-type psoriasis treated with an oral anti-inflammatory agent, apremilast

Cited by 116 publications

References 9 publications

Apremilast

Apremilast

Phosphodiesterase-4 Inhibition Combined with Isoniazid Treatment of Rabbits with Pulmonary Tuberculosis Reduces Macrophage Activation and Lung Pathology

Cyclic Adenosine Monophosphate Signalling in Inflammatory Skin Disease

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