Infusion of iloprost, a prostacyclin analogue, for treatment of Raynaud's phenomenon in systemic sclerosis.

McHugh, Neil; Csuka, Mary Ellen; Watson, H.R.; Belcher, G.; Amadi, Aham; Ring, E. F. J.; Black, Carol M.; Maddison, P. J.

doi:10.1136/ard.47.1.43

Cited by 84 publications

(42 citation statements)

References 12 publications

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“…Iloprost infusion is used clinically to treat severe refractory Raynaud's phenomenon, in particular Raynaud's phenomenon associated with the connective tissue disease scleroderma, and appears safe and well tolerated in such patients (11). The results of the present study suggest that Iloprost infusion could have beneficial effects in addition to its properties as a vasodilator.…”

Section: Figurementioning

confidence: 56%

“…Infusion of Iloprost, a synthetic prostacyclin analogue (10), has a beneficial effect in Raynaud's phenomenon and as a treatment for pulmonary hypertension in these patients (11,12). Scleroderma patients receiving Iloprost infusions frequently report an improvement in skin tightness consistent with an inhibitory effect on scar tissue formation by skin fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

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Iloprost suppresses connective tissue growth factor production in fibroblasts and in the skin of scleroderma patients

Stratton¹,

Xu²,

Martini³

et al. 2001

J. Clin. Invest.

182

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Patients with scleroderma receiving Iloprost as a treatment for severe Raynaud's phenomenon report a reduction in skin tightness, suggesting that this drug inhibits skin fibrosis. Connective tissue growth factor (CTGF), a recently described profibrotic cytokine, acts downstream and in concert with TGF-β to stimulate the fibrotic process and is involved in the fibrosis seen in scleroderma. Here we show that Iloprost, acting by elevation of cAMP, blocks the induction of CTGF and the increase in collagen synthesis in fibroblasts exposed to TGF-β. The potency of Iloprost with respect to suppression of CTGF far exceeds that of other prostanoid receptor agonists, suggesting that its effect is mediated by the prostacyclin receptor IP. By sampling dermal interstitial fluid using a suction blister device, we show that CTGF levels are greatly elevated in the dermis of scleroderma patients compared with healthy controls and that Iloprost infusion causes a marked decrease in dermal CTGF levels. These studies suggest that Iloprost could be reducing the level of a key profibrotic cytokine in scleroderma patients and that endogenous production of eicosanoids may limit the fibrotic response to TGF-β.

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Section: Figurementioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Iloprost suppresses connective tissue growth factor production in fibroblasts and in the skin of scleroderma patients

Stratton¹,

Xu²,

Martini³

et al. 2001

J. Clin. Invest.

182

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“…Several candidate proteins and compounds that have potential as collagen antagonists have been identified in recent years. For example, iloprost, a synthetic prostacyclin analog (48), has been reported to improve skin tightness in scleroderma patients (49,50), probably because of its ability to reduce the expression of type I collagen and connective tissue growth factor in fibroblasts (50). In addition, relaxin, a hormone produced by the corpus luteum in high concentrations during pregnancy (51,52), was found to significantly reduce collagen synthesis in fibroblasts; this effect could be amplified by the addition of interferon-␥, a cytokine that down-regulates the expression of collagen genes (53).…”

Section: Discussionmentioning

confidence: 99%

Halofuginone inhibition of COL1A2 promoter activity via a c‐Jun–dependent mechanism

McGaha¹,

Kodera²,

Spiera³

et al. 2002

Arthritis & Rheumatism

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Objective. The naturally occurring compound halofuginone has been shown to antagonize collagen synthesis by fibroblasts both in vitro and in vivo. We previously demonstrated that this inhibitory property was related to the ability of halofuginone to disrupt transforming growth factor ␤ signal transduction. The present study further analyzed the ability of halofuginone to affect transcription factors that can regulate type I collagen gene expression by examining its effect on c-Jun, the negative regulator of collagen gene transcription.Methods. The phosphorylation state of c-Jun in the presence of halofuginone was examined via direct Western blotting, and the transcriptional activity of the activator protein 1 (AP-1) binding element via electrophoretic mobility shift assay and luciferase reporter assay. We determined whether the effect of halofuginone on collagen synthesis was dependent on the presence of c-Jun by ectopic expression of a wild-type or dominantnegative c-Jun construct in the presence of halofuginone and assaying ␣2(I) collagen promoter strength via luciferase reporter assay. The effect of halofuginone on ␣2(I) collagen message levels in fibroblasts when wildtype or dominant-negative c-Jun was overexpressed was determined. We also determined whether halofuginone Extracellular matrix (ECM) protein turnover is an important process in the maintenance of connective tissue structure. Consequently, there is a constant low level of collagen synthesis by fibroblasts to maintain the integrity of the ECM. During wound healing, there is a shift in the balance of ECM protein synthesis/degradation that favors an increased deposition of fibrotic material. In the normal state, this shift in the balance is short-lived. In fibrotic disease, however, there appears to

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“…Iloprost is a chemically stable analog of prostacyclin and mimics its pharmacological properties, namely inhibition of platelet aggregation and vasodilatation, rendering this substance appropriate for therapeutic use. Clinical benefits of iloprost infusion were reported for patients with peripheral arterial occlusive disease, thromboangiitis obliterans, and Raynaud's phenomenon (Fitscha et al, 1987;McHugh et al, 1988;Fiessinger and Schafer, 1990).…”

mentioning

confidence: 99%

Pharmacokinetics and Metabolism of Infused versus Inhaled Iloprost in Isolated Rabbit Lungs

Schermuly

Schulz²,

Ghofrani³

et al. 2002

J Pharmacol Exp Ther

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Iloprost is a potent prostacyclin analog, which has been shown to exert beneficial effects in several vascular disorders. Inhalation of aerosolized iloprost was found to cause selective pulmonary vasodilatation, and this approach is under current investigation for treatment of chronic pulmonary hypertension. The present study investigated pharmacokinetics and metabolism of aerosolized iloprost in isolated buffer-perfused rabbit lungs, compared with intravascular administration of the prostanoid. After buffer admixture of iloprost, a steady decline of perfusate concentrations of the intact prostanoid was noted (half-life ϳ3.5 h), mostly attributable to progressive metabolism to dinor-and tetranoriloprost. Inhaled iloprost rapidly entered the intravascular compartment, with peak buffer concentrations being noted after 30 min (bioavailability ϳ63%). Compared with infused iloprost, significantly more rapid metabolism to dinorand tetranoriloprost was noted for iloprost administered via the inhalative route of application. However, the percentage of the nebulized agent that enters the intravascular space as intact iloprost displays the same clearance rate as directly perfusateadmixed prostanoid. We conclude that a high percentage of inhaled iloprost rapidly enters the intravascular compartment in intact rabbit lungs. The lung is capable of metabolizing iloprost via ␤-oxidation, and more rapid appearance of dinor-and tetranoriloprost is noted for the inhalative as compared with the intravascular route of iloprost administration.

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Infusion of iloprost, a prostacyclin analogue, for treatment of Raynaud's phenomenon in systemic sclerosis.

Cited by 84 publications

References 12 publications

Iloprost suppresses connective tissue growth factor production in fibroblasts and in the skin of scleroderma patients

Iloprost suppresses connective tissue growth factor production in fibroblasts and in the skin of scleroderma patients

Halofuginone inhibition of COL1A2 promoter activity via a c‐Jun–dependent mechanism

Pharmacokinetics and Metabolism of Infused versus Inhaled Iloprost in Isolated Rabbit Lungs

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