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Lucie H Clapp - One of the best experts on this subject based on the ideXlab platform.
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Prostanoid EP2 Receptors Are Up-Regulated in Human Pulmonary Arterial Hypertension: A Key Anti-Proliferative Target for Treprostinil in Smooth Muscle Cells
'MDPI AG', 2018Co-Authors: Jigisha A. Patel, Adam M Silverstein, Lei Shen, Susan M. Hall, Chabha Benyahia, Xavier Norel, Robin J. Mcanulty, Shahin Moledina, Brendan J. Whittle, Lucie H ClappAbstract:Prostacyclins are extensively used to treat pulmonary arterial hypertension (PAH), a life-threatening disease involving the progressive thickening of small pulmonary arteries. Although these agents are considered to act therapeutically via the prostanoid IP receptor, Treprostinil is the only prostacyclin mimetic that potently binds to the prostanoid EP2 receptor, the role of which is unknown in PAH. We hypothesised that EP2 receptors contribute to the anti-proliferative effects of Treprostinil in human pulmonary arterial smooth muscle cells (PASMCs), contrasting with selexipag, a non-prostanoid selective IP agonist. Human PASMCs from PAH patients were used to assess prostanoid receptor expression, cell proliferation, and cyclic adenosine monophosphate (cAMP) levels following the addition of agonists, antagonists or EP2 receptor small interfering RNAs (siRNAs). Immunohistochemical staining was performed in lung sections from control and PAH patients. We demonstrate using selective IP (RO1138452) and EP2 (PF-04418948) antagonists that the anti-proliferative actions of Treprostinil depend largely on EP2 receptors rather than IP receptors, unlike MRE-269 (selexipag-active metabolite). Likewise, EP2 receptor knockdown selectively reduced the functional responses to Treprostinil but not MRE-269. Furthermore, EP2 receptor levels were enhanced in human PASMCs and in lung sections from PAH patients compared to controls. Thus, EP2 receptors represent a novel therapeutic target for Treprostinil, highlighting key pharmacological differences between prostacyclin mimetics used in PAH
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inotropic effects of prostacyclins on the right ventricle are abolished in isolated rat hearts with right ventricular hypertrophy and failure
Journal of Cardiovascular Pharmacology, 2017Co-Authors: Sarah Holmboe, Lucie H Clapp, Asger Andersen, Jacob Johnsen, Jan Moller Nielsen, Rikke Norregaard, Hans Erik Botker, Jens Erik NielsenkudskAbstract:BACKGROUND: Prostacyclin mimetics are vasodilatory agents used in the treatment of pulmonary arterial hypertension. The direct effects of prostanoids on right-ventricular (RV) function are unknown. We aimed to investigate the direct effects of prostacyclin mimetics on RV function in hearts with and without RV hypertrophy and failure. METHODS: Wistar rats were subjected to pulmonary trunk banding to induce compensated RV hypertrophy (n = 32) or manifest RV failure (n = 32). Rats without banding served as healthy controls (n = 30). The hearts were excised and perfused in a Langendorff system and subjected to iloprost, Treprostinil, epoprostenol, or MRE-269 in increasing concentrations. The effect on RV function was evaluated using a balloon-tipped catheter inserted into the right ventricle. RESULTS: In control hearts, iloprost, Treprostinil, and MRE-269 improved RV function. The effect was, however, absent in hearts with RV hypertrophy and failure. Treprostinil and MRE-269 even impaired RV function in hearts with manifest RV failure. CONCLUSIONS: Iloprost, Treprostinil, and MRE-269 improved RV function in the healthy rat heart. RV hypertrophy abolished the positive inotropic effect, and in the failing right ventricle, MRE-269 and Treprostinil impaired RV function. This may be related to changes in prostanoid receptor expression and reduced coronary flow reserve in the hypertrophic and failing right ventricle.
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abstract 16601 apd811 a novel and highly selective non prostanoid ip receptor agonist in smooth muscle cells from patients with pulmonary hypertension
Circulation, 2016Co-Authors: Lei Shen, Jigisha Patel, Dominic P Behan, John W Adams, Lucie H ClappAbstract:Introduction: APD811 is an oral, non-prostanoid IP receptor agonist with a long plasma half-life (~ 24 hr) in development by Arena Pharmaceuticals Inc for pulmonary arterial hypertension (PAH). Little is known about the pulmonary pharmacology of this agent. We assessed the ability of APD811 to generate cyclic AMP (cAMP) and inhibit cell proliferation in pulmonary artery smooth muscle cells (PASMCs) isolated from PAH patients. The role of the IP receptor was investigated alongside prostacyclin mimetics already licensed for PAH. Methods: Distal PASMCs were stimulated with 9% serum and treated with agonists ± RO-118452 (IP receptor antagonist; IPRA) for 1 hr or 4 days to measure cAMP (ELISA) and cell proliferation (MTS), respectively. The concentration (EC 50 ) producing the half maximal (E Max ) response was determined. Results and conclusions: Iloprost APD811, MRE 269 (selexipeg metabolite) and Treprostinil increased cAMP (EC 50 17, 252, 340, 550 nM, respectively). E Max was lower (P Max compared to Treprostinil (57% versus 89%). RO-118452 (1 μM) essentially abolished agonist-induced cAMP generation and the effects of APD811 and MRE-269 in cell proliferation assays. In contrast, the antiproliferative effects of Treprostinil and iloprost were weakly inhibited by RO-118452. In combination with other PAH therapies, APD811 produced a greater (range 0.1-10,000 nM) antiproliferative response in the presence of riociguat (100nM) and to a lesser extent with 100nM Treprostinil or the phosphodiesterase inhibitor, sildenafil but not when combined with 100nM endothelin receptor antagonists (bosentan and macitentan). Summary: In human PASMCs, APD811 and MRE-269 both behave as selective, but partial IP receptor agonists in cAMP and cell proliferation assays, with APD811 a more effective agonist than MRE-269. Iloprost and Treprostinil inhibit proliferation through IP-receptor independent pathways. Agents stimulating cyclic GMP could work better at inhibiting cell proliferation in combination with APD-811 than endothelin receptor antagonists.
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binding and activity of the prostacyclin receptor ip agonists Treprostinil and iloprost at human prostanoid receptors Treprostinil is a potent dp1 and ep2 agonist
Biochemical Pharmacology, 2012Co-Authors: Brendan J R Whittle, Adam M Silverstein, David Mottola, Lucie H ClappAbstract:The prostacyclin analogues, iloprost and Treprostinil are extensively used in treating pulmonary hypertension. Their binding profile and corresponding biochemical cellular responses on human prostanoid receptors expressed in cell lines, have now been compared. Iloprost had high binding affinity for EP1 and IP receptors (Ki 1.1 and 3.9 nM, respectively), low affinity for FP, EP3 or EP4 receptors, and very low affinity for EP2, DP1 or TP receptors. By contrast, Treprostinil had high affinity for the DP1, EP2 and IP receptors (Ki 4.4, 3.6 and 32 nM, respectively), low affinity for EP1 and EP4 receptors and even lower affinity for EP3, FP and TP receptors. In functional assays, iloprost had similar high activity in elevating cyclic AMP levels in cells expressing the human IP receptor and stimulating calcium influx in cells expressing EP1 receptors (EC50 0.37 and 0.3 nM, respectively) with the rank order of activity on the other receptors comparable to the binding assays. As with binding studies, Treprostinil elevated cyclic AMP with a similar high potency in cells expressing DP1, IP and EP2 receptors (EC50 0.6, 1.9 and 6.2 nM, respectively), but had low activity at the other receptors. Activation of IP, DP1 and EP2 receptors, as with Treprostinil, can all result in vasodilatation of human pulmonary arteries. However, activation of EP1 receptors can provoke vasoconstriction, and hence may offset the IP-receptor mediated vasodilator effects of iloprost. Treprostinil may therefore differ from iloprost in its overall beneficial pulmonary vasorelaxant profile and other pharmacological actions, especially in diseases where the IP receptor is down-regulated.
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role of prostanoid ip and ep receptors in mediating vasorelaxant responses to pgi2 analogues in rat tail artery evidence for gi o modulation via ep3 receptors
European Journal of Pharmacology, 2011Co-Authors: Nelson N Orie, Lucie H ClappAbstract:Prostanoid IP receptors coupled to Gs are thought to be the primary target for prostacyclin (PGI(2)) analogues. However, these agents also activate prostanoid EP(1-4) receptor subtypes to varying degrees, which are positively (EP(2/4)) or negatively (EP(3)) coupled to adenylate cyclase through Gs or Gi, respectively. We investigated the role of these receptors in modulating relaxation to PGI(2) analogues cicaprost, iloprost and Treprostinil in pre-contracted segments of rat tail artery. Prostanoid IP (RO1138452), EP(4) (GW627368X), EP(3) (L-798106), EP(1-3) (AH6809), and EP(1) (SC-51322) receptor antagonists were used to determine each receptor contribution. The role of G(i/o) was investigated using pertussis toxin (PTX), while dependence on cAMP was determined using adenylate cyclase (2'5'dideoxyadenosine, DDA) and protein kinase A (2'-O-monobutyryladenosine- 3',5'-cyclic monophosphorothioate, Rp- isomer, Rp-2'-O-MB-cAMPS) inhibitors, and by measurement of tissue cAMP. All analogues caused relaxation which was significantly (P<0.01) inhibited by RO1138452; with maximum response to cicaprost, iloprost and Treprostinil reduced by 51%, 66% and 37%, respectively. GW627368X had no effect when used alone, but in combination with RO1138452, caused a rightward shift of the curves for cicaprost and iloprost but not Treprostinil. PTX treatment potentiated relaxation to all 3 analogues (P<0.01), as did L798106 and AH6809 but not SC-51322. Basal cAMP levels were higher in PTX-treated tissues and DDA- and Rp-2'-O-MB-cAMPs--sensitive responses increased to analogue concentrations <0.1μM. In conclusion, prostanoid EP(3) receptors via G(i/o) negatively modulate prostanoid IP receptor-mediated relaxation to cicaprost, iloprost and Treprostinil. However, other pathways contribute to analogue-induced vasorelaxation, the nature of which remains unclear for Treprostinil.
Jean-luc Cracowski - One of the best experts on this subject based on the ideXlab platform.
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Treprostinil hydrogel iontophoresis in systemic sclerosis related digital skin ulcers a safety study
The Journal of Clinical Pharmacology, 2020Co-Authors: Alicia Guigui, Claire Cracowski, Sbastien Blaise, Matthieu Roustit, Roseline Mazet, Myrtille Beauguillaumot, Sylvain Kotzki, Jean-luc CracowskiAbstract:: Digital skin ulcers are a severe complication of systemic sclerosis. The first-line treatment is intravenous iloprost, but it induces dose-limiting adverse effects. Local administration of Treprostinil through skin iontophoresis may be a safe alternative. We conducted a 2-stage, randomized, placebo-controlled single-ascending-dose study in healthy volunteers and patients with systemic sclerosis-related digital ulcer. We further explored the effect of the procedure on skin blood flux. In a first group of healthy subjects, Treprostinil and placebo iontophoresis were performed at 3 locations (ie, 6 skin sites): the sole of the foot, the leg, and the fingers. We used a 1-mg/mL hydrogel of Treprostinil. We then randomly treated systemic sclerosis-related digital ulcers in a 3:1 ratio of Treprostinil or placebo. We used concentrations from 0.1 to 1 mg/mL. All adverse events were recorded and rated according to the Common Terminology Criteria for Adverse Events (CTCAE), whereas skin microvascular blood flux was recorded with laser speckle contrast imaging. Among the 12 healthy volunteers, we observed 60 local adverse effects: burns, skin pain, erythema, and pruritus, graded 1 or 2 on the 5-point CTCAE scale. Treprostinil iontophoresis significantly increased skin blood flux on the leg (AUC0-4 h at 88 460% ± 6436% versus 12 730% ± 3397% baseline flux.min respectively; P < .001) and on the sole of the foot (AUC0-3 h at 20 124% ± 6119% versus 3142% ± 3036% baseline flux.min, respectively; P = .018) with a trend on the finger. Among 5 patients with systemic sclerosis-related digital ulcer, 2 resolutive local adverse effects were reported. Iontophoresis of Treprostinil hydrogel was safe in systemic sclerosis patients with digital ulcer.
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Treprostinil iontophoresis improves digital blood flow during local cooling in systemic sclerosis
Microcirculation, 2016Co-Authors: Florence Gaillardbigot, Claire Cracowski, Sbastien Blaise, Christophe Seinturier, P Carpentier, Bruce Imbert, Matthieu Roustit, Jean-luc CracowskiAbstract:Introduction Severe Raynaud's syndrome and DUs are the most prevalent manifestations of SSc peripheral microvascular disease. We tested whether Treprostinil iontophoresis on the finger pad of patients with SSc would improve digital blood flow during hand cooling. Methods Eleven patients with limited cutaneous SSc underwent a double-blinded iontophoresis of Treprostinil (2.56 × 10−4 M during two hours) and placebo (NaCl 0.9%) on two finger pads. Then, the hand was inserted for 30 minutes in a fenestrated cooling box at 8°C, and skin blood flow was recorded continuously using LSCI. Results During the local cooling, CVC was significantly higher at the Treprostinil site than at the placebo site and remained higher 30 minutes after the test. Conclusions In patients with SSc, digital Treprostinil iontophoresis shifts skin blood flow upward during local cooling of the hand and during the initial rewarming phase. Digital Treprostinil iontophoresis should now be tested in larger scale studies.
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Treprostinil iontophoresis improves digital blood flow during local cooling in systemic sclerosis
Microcirculation, 2016Co-Authors: Florence Gaillardbigot, Claire Cracowski, Sbastien Blaise, Christophe Seinturier, P Carpentier, Bruce Imbert, Matthieu Roustit, Jean-luc CracowskiAbstract:Introduction Severe Raynaud's syndrome and DUs are the most prevalent manifestations of SSc peripheral microvascular disease. We tested whether Treprostinil iontophoresis on the finger pad of patients with SSc would improve digital blood flow during hand cooling. Methods Eleven patients with limited cutaneous SSc underwent a double-blinded iontophoresis of Treprostinil (2.56 × 10−4 M during two hours) and placebo (NaCl 0.9%) on two finger pads. Then, the hand was inserted for 30 minutes in a fenestrated cooling box at 8°C, and skin blood flow was recorded continuously using LSCI. Results During the local cooling, CVC was significantly higher at the Treprostinil site than at the placebo site and remained higher 30 minutes after the test. Conclusions In patients with SSc, digital Treprostinil iontophoresis shifts skin blood flow upward during local cooling of the hand and during the initial rewarming phase. Digital Treprostinil iontophoresis should now be tested in larger scale studies.
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cutaneous iontophoresis of Treprostinil a prostacyclin analog increases microvascular blood flux in diabetic malleolus area
European Journal of Pharmacology, 2015Co-Authors: Marcin Hellmann, Florence Gaillardbigot, Matthieu Roustit, Jean-luc CracowskiAbstract:Abstract Diabetic foot ulcers are one of the most common and serious complications of diabetes mellitus. Few drugs are effective in enhancing the healing of microvascular skin ulcers. The main objective of the present study was to determine whether iontophoresis of Treprostinil, a prostacyclin analog, increases skin microvascular blood flux in the malleolus area of healthy subjects and diabetic patients. We recruited 12 healthy subjects and 12 type 2 diabetic patients. Cathodal iontophoresis (40 mC/cm²) of Treprostinil 250 µM and NaCl 0.9% was performed in the malleolus area. Skin hyperemia was quantified using non-invasive laser speckle contrast imaging, and expressed as the area under the curve (AUC) of cutaneous vascular conductance (CVC). In healthy controls and diabetic patients, Treprostinil 250 µM induced a significant increase in CVC compared with NaCl (for diabetic patients, AUC 0–6 h was 19970±8697; versus 2893±5481%BL.min, respectively; P =0.002). In both groups, the peak flux was obtained between 30 min and 1 h after the end of Treprostinil iontophoresis and flux remained higher than baseline up to 6 h after ending of iontophoresis. No significant side-effect occurred. Cutaneous iontophoresis of 250 µM Treprostinil increases microvascular blood flux in the malleolus area in healthy volunteers and diabetic patients, without inducing systemic or local side-effects. Treprostinil cathodal iontophoresis should be further investigated as a new local therapy for diabetic ulcers.
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cathodal iontophoresis of Treprostinil and iloprost induces a sustained increase in cutaneous flux in rats
British Journal of Pharmacology, 2011Co-Authors: Claire Millet, Christophe Ribuot, Sbastien Blaise, Jean Boutonnat, Matthieu Roustit, Jean-luc CracowskiAbstract:BACKGROUND AND PURPOSE The treatment of scleroderma-related digital ulcers is still a therapeutic challenge. The most effective drugs are prostacyclin analogues. However, their usage is limited to an intravenous route of administration and by their frequent side effects. The objective of this study was to test whether Treprostinil, iloprost and epoprostenol can induce sustained vasodilatation in rats when delivered locally using cutaneous iontophoresis. EXPERIMENTAL APPROACH Treprostinil, iloprost and epoprostenol were delivered by cathodal and anodal iontophoresis onto the hindquarters of anaesthesized rats (n= 8 for each group). Skin blood flow was quantified using laser Doppler imaging and cutaneous tolerance was assessed from day 0 to day 3. KEY RESULTS Cathodal but not anodal iontophoresis of Treprostinil (6.4 mM), iloprost (0.2 mM) and epoprostenol (1.4 mM) induced a significant and sustained increase in cutaneous blood flow. The effects of Treprostinil and iloprost were significantly different from those of Treprostinil vehicle. Only weak effects were observed when both drugs were applied locally without current. Skin resistance was unchanged in areas treated with prostacyclin analogues. Finally, skin tolerance was good, with no evidence of epidermal damage. CONCLUSIONS AND IMPLICATIONS Cathodal iontophoresis of Treprostinil and iloprost increases cutaneous blood flow with a good local tolerance. The effects of cathodal iontophoresis of these drugs should be investigated in humans, as they could have potential as new local therapies for digital ulcers in patients with scleroderma.
Kevin Laliberte - One of the best experts on this subject based on the ideXlab platform.
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A Comprehensive Review of Treprostinil Pharmacokinetics via Four Routes of Administration
Clinical Pharmacokinetics, 2016Co-Authors: Parag Kumar, Emily Thudium, Kevin Laliberte, David Zaccardelli, Andrew NelsenAbstract:Treprostinil is available in three different formulations and four different routes of administration: Remodulin^® (Treprostinil sodium, intravenous and subcutaneous administration), Tyvaso^® (Treprostinil sodium, inhaled administration), and Orenitram^® (Treprostinil diolamine, oral administration) for the treatment of pulmonary arterial hypertension (PAH). Pharmacokinetic studies have been performed in healthy volunteers and patients with PAH. The intent of this review is to outline pharmacokinetic considerations of the three Treprostinil formulations and provide clinicians with a resource that may support clinical decisions in treating patients with PAH.
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oral Treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and or phosphodiesterase type 5 inhibitor therapy the freedom c study a randomized controlled trial
Chest, 2012Co-Authors: Victor F Tapson, Fernando Torres, A Keogh, David B Badesch, Robert P Frantz, F Kermeen, Roblee P Allen, Shelley M Shapiro, Kevin LaliberteAbstract:Background Treprostinil is a stable prostacyclin analog approved for the treatment of pulmonary arterial hypertension (PAH) as parenteral or inhaled therapy. Treprostinil diolamine, a sustained-release oral formulation of Treprostinil, was studied to determine whether it could provide a more convenient prostacyclin treatment option for patients with less severe PAH. The objective of this study was to evaluate the efficacy and safety of oral Treprostinil in patients with PAH receiving stable background endothelin receptor antagonist (ERA), phosphodiesterase type 5 inhibitor (PDE-5I) therapy, or both. Methods A 16-week, multicenter, double-blind, placebo-controlled study in 310 patients with PAH compared bid administration of oral Treprostinil (n = 157) with placebo (n = 153). The primary end point was change in 6-min walk distance at week 16. Secondary efficacy end points were World Health Organization functional class, Borg dyspnea score, dyspnea-fatigue index, signs and symptoms of PAH, and clinical worsening. Results One hundred thirty-two patients (84%) receiving oral Treprostinil and 138 (90%) receiving placebo completed the study. The mean ± SD dose of oral Treprostinil at week 16 was 3.1 ± 1.9 mg bid. The Hodges-Lehmann placebo-corrected median difference in 6MWD at week 16 was 10.0 m (95% CI, −2 to 22 m; P = .089). There were no significant changes in secondary end points. The most common adverse events associated with oral Treprostinil were headache (71%), diarrhea (55%), nausea (46%), flushing (35%), and jaw pain (25%). Conclusions The addition of oral Treprostinil to background ERA and PDE-5I therapy did not result in a statistically significant improvement in exercise capacity. Side effects were common but tolerated by most subjects. Trial registry ClinicalTrials.gov; No.: NCT00887978; URL: www.clinicaltrials.gov
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pharmacokinetics and steady state bioequivalence of Treprostinil sodium remodulin administered by the intravenous and subcutaneous route to normal volunteers
Journal of Cardiovascular Pharmacology, 2004Co-Authors: Kevin Laliberte, Carl Arneson, Roger Jeffs, Thomas L Hunt, Michael WadeAbstract:Treprostinil sodium is a chemically stable analogue of prostacyclin administered as a chronic, continuous subcutaneous infusion for the treatment of pulmonary arterial hypertension (PAH). There has been significant clinical interest in determining the feasibility of delivering Treprostinil by intravenous infusion. Therefore, a bioequivalence and comparative pharmacokinetics study of the two routes of administration was conducted in normal volunteers. A randomized, two-period, crossover study design was employed. Each subject was dosed at 10 ng/kg/min for 72 hours by each route, with the infusions separated by a 4-day wash-out period. In the 51 subjects who received at least 24 hours of Treprostinil administered subcutaneously and intravenously, the steady-state ratios of the geometric means (i.v./s.c.) and 90% confidence intervals for AUCss and Cmaxss were 92.9% (89.8-96.1%) and 106% (99.4-113%), respectively. Secondary pharmacokinetic assessments confirmed the comparability of the two routes of administration at steady state, and also demonstrated that the elimination half-life of Treprostinil was 4.4 and 4.6 hours following intravenous and subcutaneous administration, respectively. Based on these findings it was concluded that intravenously and subcutaneously administered Treprostinil are bioequivalent at steady state.
Sbastien Blaise - One of the best experts on this subject based on the ideXlab platform.
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Treprostinil hydrogel iontophoresis in systemic sclerosis related digital skin ulcers a safety study
The Journal of Clinical Pharmacology, 2020Co-Authors: Alicia Guigui, Claire Cracowski, Sbastien Blaise, Matthieu Roustit, Roseline Mazet, Myrtille Beauguillaumot, Sylvain Kotzki, Jean-luc CracowskiAbstract:: Digital skin ulcers are a severe complication of systemic sclerosis. The first-line treatment is intravenous iloprost, but it induces dose-limiting adverse effects. Local administration of Treprostinil through skin iontophoresis may be a safe alternative. We conducted a 2-stage, randomized, placebo-controlled single-ascending-dose study in healthy volunteers and patients with systemic sclerosis-related digital ulcer. We further explored the effect of the procedure on skin blood flux. In a first group of healthy subjects, Treprostinil and placebo iontophoresis were performed at 3 locations (ie, 6 skin sites): the sole of the foot, the leg, and the fingers. We used a 1-mg/mL hydrogel of Treprostinil. We then randomly treated systemic sclerosis-related digital ulcers in a 3:1 ratio of Treprostinil or placebo. We used concentrations from 0.1 to 1 mg/mL. All adverse events were recorded and rated according to the Common Terminology Criteria for Adverse Events (CTCAE), whereas skin microvascular blood flux was recorded with laser speckle contrast imaging. Among the 12 healthy volunteers, we observed 60 local adverse effects: burns, skin pain, erythema, and pruritus, graded 1 or 2 on the 5-point CTCAE scale. Treprostinil iontophoresis significantly increased skin blood flux on the leg (AUC0-4 h at 88 460% ± 6436% versus 12 730% ± 3397% baseline flux.min respectively; P < .001) and on the sole of the foot (AUC0-3 h at 20 124% ± 6119% versus 3142% ± 3036% baseline flux.min, respectively; P = .018) with a trend on the finger. Among 5 patients with systemic sclerosis-related digital ulcer, 2 resolutive local adverse effects were reported. Iontophoresis of Treprostinil hydrogel was safe in systemic sclerosis patients with digital ulcer.
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Treprostinil iontophoresis improves digital blood flow during local cooling in systemic sclerosis
Microcirculation, 2016Co-Authors: Florence Gaillardbigot, Claire Cracowski, Sbastien Blaise, Christophe Seinturier, P Carpentier, Bruce Imbert, Matthieu Roustit, Jean-luc CracowskiAbstract:Introduction Severe Raynaud's syndrome and DUs are the most prevalent manifestations of SSc peripheral microvascular disease. We tested whether Treprostinil iontophoresis on the finger pad of patients with SSc would improve digital blood flow during hand cooling. Methods Eleven patients with limited cutaneous SSc underwent a double-blinded iontophoresis of Treprostinil (2.56 × 10−4 M during two hours) and placebo (NaCl 0.9%) on two finger pads. Then, the hand was inserted for 30 minutes in a fenestrated cooling box at 8°C, and skin blood flow was recorded continuously using LSCI. Results During the local cooling, CVC was significantly higher at the Treprostinil site than at the placebo site and remained higher 30 minutes after the test. Conclusions In patients with SSc, digital Treprostinil iontophoresis shifts skin blood flow upward during local cooling of the hand and during the initial rewarming phase. Digital Treprostinil iontophoresis should now be tested in larger scale studies.
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Treprostinil iontophoresis improves digital blood flow during local cooling in systemic sclerosis
Microcirculation, 2016Co-Authors: Florence Gaillardbigot, Claire Cracowski, Sbastien Blaise, Christophe Seinturier, P Carpentier, Bruce Imbert, Matthieu Roustit, Jean-luc CracowskiAbstract:Introduction Severe Raynaud's syndrome and DUs are the most prevalent manifestations of SSc peripheral microvascular disease. We tested whether Treprostinil iontophoresis on the finger pad of patients with SSc would improve digital blood flow during hand cooling. Methods Eleven patients with limited cutaneous SSc underwent a double-blinded iontophoresis of Treprostinil (2.56 × 10−4 M during two hours) and placebo (NaCl 0.9%) on two finger pads. Then, the hand was inserted for 30 minutes in a fenestrated cooling box at 8°C, and skin blood flow was recorded continuously using LSCI. Results During the local cooling, CVC was significantly higher at the Treprostinil site than at the placebo site and remained higher 30 minutes after the test. Conclusions In patients with SSc, digital Treprostinil iontophoresis shifts skin blood flow upward during local cooling of the hand and during the initial rewarming phase. Digital Treprostinil iontophoresis should now be tested in larger scale studies.
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cathodal iontophoresis of Treprostinil and iloprost induces a sustained increase in cutaneous flux in rats
British Journal of Pharmacology, 2011Co-Authors: Claire Millet, Christophe Ribuot, Sbastien Blaise, Jean Boutonnat, Matthieu Roustit, Jean-luc CracowskiAbstract:BACKGROUND AND PURPOSE The treatment of scleroderma-related digital ulcers is still a therapeutic challenge. The most effective drugs are prostacyclin analogues. However, their usage is limited to an intravenous route of administration and by their frequent side effects. The objective of this study was to test whether Treprostinil, iloprost and epoprostenol can induce sustained vasodilatation in rats when delivered locally using cutaneous iontophoresis. EXPERIMENTAL APPROACH Treprostinil, iloprost and epoprostenol were delivered by cathodal and anodal iontophoresis onto the hindquarters of anaesthesized rats (n= 8 for each group). Skin blood flow was quantified using laser Doppler imaging and cutaneous tolerance was assessed from day 0 to day 3. KEY RESULTS Cathodal but not anodal iontophoresis of Treprostinil (6.4 mM), iloprost (0.2 mM) and epoprostenol (1.4 mM) induced a significant and sustained increase in cutaneous blood flow. The effects of Treprostinil and iloprost were significantly different from those of Treprostinil vehicle. Only weak effects were observed when both drugs were applied locally without current. Skin resistance was unchanged in areas treated with prostacyclin analogues. Finally, skin tolerance was good, with no evidence of epidermal damage. CONCLUSIONS AND IMPLICATIONS Cathodal iontophoresis of Treprostinil and iloprost increases cutaneous blood flow with a good local tolerance. The effects of cathodal iontophoresis of these drugs should be investigated in humans, as they could have potential as new local therapies for digital ulcers in patients with scleroderma.
Robert P Frantz - One of the best experts on this subject based on the ideXlab platform.
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transition of intravenous Treprostinil to oral therapy in a patient with functional class iv chronic thromboembolic pulmonary hypertension
Pharmacotherapy, 2017Co-Authors: Kristina M Thurber, Breann M Williams, Ruth E Bates, Robert P FrantzAbstract:Chronic thromboembolic pulmonary hypertension (CTEPH) occurs when pulmonary emboli fail to resolve with anticoagulation. For patients with inoperable or residual CTEPH, riociguat is currently the only therapy approved by the United States Food and Drug Administration. However, some patients with CTEPH may require therapy beyond riociguat, such as intravenous prostacyclins, which can present significant administration challenges in patients with complex comorbid conditions. We describe a 42-year-old man with T12 paraplegia complicated by CTEPH (functional class IV with substantial right ventricular dysfunction) and severe pressure ulcers. In order to facilitate goals of care (hospital discharge to a skilled nursing facility where parenteral prostanoids could not be administered), he underwent rapid transition from intravenous Treprostinil to oral selexipag in the form of a cross-taper over 6 days. The patient required readmission due to worsening symptoms and was transitioned back to intravenous Treprostinil; he tolerated conversion to oral Treprostinil for approximately 4 months, but it was subsequently discontinued due to nausea and modified goals of care. The patient underwent transition to hospice care 3 months later and eventually died from clinical deterioration. To our knowledge, this is the first report to describe transition from intravenous Treprostinil to selexipag as well as conversion from parenteral Treprostinil to oral Treprostinil in a patient with CTEPH and illustrates the approaches to and potential issues with prostanoid transitions. Additional observations are necessary to better understand the relative roles of selexipag and oral Treprostinil regarding comparative efficacy and tolerability.
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oral Treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and or phosphodiesterase type 5 inhibitor therapy the freedom c study a randomized controlled trial
Chest, 2012Co-Authors: Victor F Tapson, Fernando Torres, A Keogh, David B Badesch, Robert P Frantz, F Kermeen, Roblee P Allen, Shelley M Shapiro, Kevin LaliberteAbstract:Background Treprostinil is a stable prostacyclin analog approved for the treatment of pulmonary arterial hypertension (PAH) as parenteral or inhaled therapy. Treprostinil diolamine, a sustained-release oral formulation of Treprostinil, was studied to determine whether it could provide a more convenient prostacyclin treatment option for patients with less severe PAH. The objective of this study was to evaluate the efficacy and safety of oral Treprostinil in patients with PAH receiving stable background endothelin receptor antagonist (ERA), phosphodiesterase type 5 inhibitor (PDE-5I) therapy, or both. Methods A 16-week, multicenter, double-blind, placebo-controlled study in 310 patients with PAH compared bid administration of oral Treprostinil (n = 157) with placebo (n = 153). The primary end point was change in 6-min walk distance at week 16. Secondary efficacy end points were World Health Organization functional class, Borg dyspnea score, dyspnea-fatigue index, signs and symptoms of PAH, and clinical worsening. Results One hundred thirty-two patients (84%) receiving oral Treprostinil and 138 (90%) receiving placebo completed the study. The mean ± SD dose of oral Treprostinil at week 16 was 3.1 ± 1.9 mg bid. The Hodges-Lehmann placebo-corrected median difference in 6MWD at week 16 was 10.0 m (95% CI, −2 to 22 m; P = .089). There were no significant changes in secondary end points. The most common adverse events associated with oral Treprostinil were headache (71%), diarrhea (55%), nausea (46%), flushing (35%), and jaw pain (25%). Conclusions The addition of oral Treprostinil to background ERA and PDE-5I therapy did not result in a statistically significant improvement in exercise capacity. Side effects were common but tolerated by most subjects. Trial registry ClinicalTrials.gov; No.: NCT00887978; URL: www.clinicaltrials.gov
