WO2004017993A1 - Combination of prostacyclin or prostacyclin analogues and endothelin receptor antagonists for the treatment of pulmonary arterial hypertension - Google Patents
Combination of prostacyclin or prostacyclin analogues and endothelin receptor antagonists for the treatment of pulmonary arterial hypertension Download PDFInfo
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- WO2004017993A1 WO2004017993A1 PCT/EP2003/008122 EP0308122W WO2004017993A1 WO 2004017993 A1 WO2004017993 A1 WO 2004017993A1 EP 0308122 W EP0308122 W EP 0308122W WO 2004017993 A1 WO2004017993 A1 WO 2004017993A1
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- WIPO (PCT)
- Prior art keywords
- prostacyclin
- epoprostenol
- bosentan
- endothelin receptor
- pulmonary arterial
- Prior art date
Links
- 229960001123 epoprostenol Drugs 0.000 title claims abstract description 59
- 150000003815 prostacyclins Chemical class 0.000 title claims abstract description 20
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 title claims abstract description 15
- 239000002308 endothelin receptor antagonist Substances 0.000 title claims abstract description 15
- 229940118365 Endothelin receptor antagonist Drugs 0.000 title claims abstract description 12
- 238000011282 treatment Methods 0.000 title claims abstract description 12
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 title claims abstract 15
- GJPICJJJRGTNOD-UHFFFAOYSA-N bosentan Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2N=CC=CN=2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 GJPICJJJRGTNOD-UHFFFAOYSA-N 0.000 claims abstract description 31
- 229960003065 bosentan Drugs 0.000 claims abstract description 30
- 230000000694 effects Effects 0.000 claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims description 6
- 230000037396 body weight Effects 0.000 claims description 5
- 239000000203 mixture Substances 0.000 abstract 1
- KAQKFAOMNZTLHT-OZUDYXHBSA-N prostaglandin I2 Chemical compound O1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-OZUDYXHBSA-N 0.000 description 46
- 230000000004 hemodynamic effect Effects 0.000 description 8
- 230000007423 decrease Effects 0.000 description 7
- 230000004872 arterial blood pressure Effects 0.000 description 5
- 230000002685 pulmonary effect Effects 0.000 description 5
- 208000001953 Hypotension Diseases 0.000 description 4
- 206010033433 Pain in jaw Diseases 0.000 description 4
- 231100000869 headache Toxicity 0.000 description 4
- 230000036543 hypotension Effects 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- 239000000902 placebo Substances 0.000 description 4
- 229940068196 placebo Drugs 0.000 description 4
- 230000036593 pulmonary vascular resistance Effects 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 206010019233 Headaches Diseases 0.000 description 3
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 3
- 230000000747 cardiac effect Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000011010 flushing procedure Methods 0.000 description 3
- 101800004490 Endothelin-1 Proteins 0.000 description 2
- 208000001871 Tachycardia Diseases 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 230000001746 atrial effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 210000001147 pulmonary artery Anatomy 0.000 description 2
- 208000002815 pulmonary hypertension Diseases 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 230000006794 tachycardia Effects 0.000 description 2
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 206010048554 Endothelial dysfunction Diseases 0.000 description 1
- 108050009340 Endothelin Proteins 0.000 description 1
- 102000002045 Endothelin Human genes 0.000 description 1
- 102000010180 Endothelin receptor Human genes 0.000 description 1
- 108050001739 Endothelin receptor Proteins 0.000 description 1
- 102100033902 Endothelin-1 Human genes 0.000 description 1
- 102400000686 Endothelin-1 Human genes 0.000 description 1
- 206010039163 Right ventricular failure Diseases 0.000 description 1
- 206010043269 Tension headache Diseases 0.000 description 1
- 206010072810 Vascular wall hypertrophy Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 229960002890 beraprost Drugs 0.000 description 1
- CTPOHARTNNSRSR-APJZLKAGSA-N beraprost Chemical compound O([C@H]1C[C@@H](O)[C@@H]([C@@H]21)/C=C/[C@@H](O)C(C)CC#CC)C1=C2C=CC=C1CCCC(O)=O CTPOHARTNNSRSR-APJZLKAGSA-N 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000008694 endothelial dysfunction Effects 0.000 description 1
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 229960002240 iloprost Drugs 0.000 description 1
- HIFJCPQKFCZDDL-ACWOEMLNSA-N iloprost Chemical compound C1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)C(C)CC#CC)[C@H](O)C[C@@H]21 HIFJCPQKFCZDDL-ACWOEMLNSA-N 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000008035 nerve activity Effects 0.000 description 1
- 230000002644 neurohormonal effect Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 229940127293 prostanoid Drugs 0.000 description 1
- 150000003814 prostanoids Chemical class 0.000 description 1
- 230000008695 pulmonary vasoconstriction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 229960005032 treprostinil Drugs 0.000 description 1
- PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical compound C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 PAJMKGZZBBTTOY-ZFORQUDYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000003639 vasoconstrictive effect Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
Definitions
- the invention relates to pharmaceutical compositions for the treatment of pulmonary arterial hypertension one containing a prostacyclin or a prostacyclin analogue and the other an endothelin receptor antagonist, characterised in that the side effects of the prostacyclin or the prostacyclin analogue are strongly reduced by the concomitant administration of the prostacyclin or the prostacyclin analogue and the endothelin receptor antagonist.
- Pulmonary hypertension is a disease defined by a progressive elevation of pulmonary artery pressure and pulmonary vascular resistance, leading to right ventricular failure and death. Pulmonary hypertension is associated with endothelial dysfunction, characterized by a decreased expression of the vasodilators nitric oxide and prostacyclin, and by an increased expression of the growth factor and vasoconstrictive substance endothelin-1 and its receptors.
- Prostacyclin and prostacyclin analogues such as epoprostenol, treprostinil, iloprost, beraprost significantly improve hemodynamic parameters and clinical cyrr.ptoms in patients with pulmonary arterial hypertension.
- the major mechanism of action of prostacyclin and prostacyclin analogues is vasodilation, whereas improvement in pulmonary vascular hypertrophy and inhibition of platelet aggregation may also play a role.
- the use of prostacyclin or prostacyclin analogues is associated with a number of side effects such as jaw pain, headaches, flushing, tachycardia and systemic hypotension.
- Endothelin receptor antagonists such as bosentan (4-tert-butyl-N-[6-(2- hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl]-benzene- sulfonamide) are also efficacious in the treatment of pulmonary arterial hypertension.
- Bosentan improves hemodynamic parameters (cardiac index, pulmonary artery pressure, pulmonary vascular resistance), increases exercise capacity, improves WHO functional class, and decreases the rate of clinical worsening in patients with pulmonary arterial hypertension.
- Bosentan does not significantly modify heart rate or mean arterial blood pressure in patients with pulmonary arterial hypertension.
- Endothelin receptor antagonists are competitive antagonism of the binding of ET-1 on ET receptors, thereby decreasing pulmonary vasoconstriction and vascular remodelling.
- Endothelin receptor _ ⁇ tagonists by their inhibition of the endothelin system, further inhibit the activation of other neurohormonal systems, and in particular reduce sympathetic nerve activity, decrease catecholamine concentrations and blunt reactive tachycardia in response to a decrease in blood pressure.
- bosentan and a prostacyclin especially epoprostenol (5Z, 9 alpha, 11alpha, 13E, 15S)-6,9-Epoxy-11 ,15-dihydroxyprosta-5,13-dien-1-oic acid, sodium salt [compare also US Patent 4,539,333], has been evaluated in a clinical study.
- the authors, (compare Am J Respir Crit Care Med Vol 165. pp1209-1216, 2002), who were running on behalf of Actelion Pharmaceuticals Ltd the clinical trials of the combination of these two drugs, speculated that tnis combination may have additional efficacy. The outcome of the trial was, however, entirely unexpected.
- the basis of the present application is the unexpected finding in the clinical trial initiated and supervised by Actelion Pharmaceuticals Ltd that the combination of bosentan with epoprostenol not only has additional efficacy, but also decreases the risk of side effects related to epoprostenol considerably. Indeed, in patients treated with bosentan and epoprostenol, there were fewer reported cases of jaw pain, headaches and systemic hypotension, a lesser decrease in blood pressure and a lesser increase in heart rate as compared to patients treated with epoprostenol alone.
- compositions for the treatment of pulmonary arterial hypertension one containing epoprostenol and the other bosentan, characterised in that the side effects of epoprostenol are strongly reduced by the concomitant administration of epoprostenol and bosentan or by preferably administering bosentan within a time frame of ninety six hours after epoprostenol has been administered.
- the dose of the prostacyclin may vary between 1 ng/kg/min and 250 ng/kg/min depending on the length it has been already administered.A preferred dose range is 2 ng/kg/min. With increasing time the dose is increased.
- a preferred use of the pharmaceutical compositions resides in administering for two days 2 ng/kg/min, then increasing every two weeks the dose by 2 ng/kg/min up to the preferred target dose of 14 ⁇ 2 ng/kg/min. After the first two days of treatment with prostacyclin or an analogue bosentan is administered twice a day at a dose of either 62,5 mg or 125 mg.
- a dose range for the prostacyclin of 0,01 to 200 mg per kilogram bodyweight, conveniently 0,01 to 10 mg per kilogram, is used.
- the dose range for the endothelin antagonist may be 0,01 mg to 10 mg per kilogram bodyweight, conveniently 0,5 mg to 3,0 mg per kilogram bodyweight.
- the preparation of a pharmaceutical composition containing a prostacyclin has been described in US Patent No. 4,539,333 and is incorporated by reference.
- Study design The duration of the study was 16 weeks, 2:1 bosentan:placebo randomization. All patients received the starting epoprostenol dose of 2 ng/kg/min for 2 days, then they were randomized i ⁇ either bosentan or placebo. Every 2 weeks thereafter, epoprostenol was increased 2 ng/kg/min up to the target dose of 14 ⁇ 2 ng/kg/min by week 16. All patients received epoprostenol together with either bosentan or placebo for 16 weeks. Hemodynamic assessments were performed at baseline (prior to start of therapy) and again after 16 weeks of therapy. Safety monitoring was performed throughout the study duration.
- TPR total pulmonary resistance
- Secondary endpoints Changes from baseline to week 16 in Cl (Cardiac Index), PVR (Pulmonary Vascular Resistance), mPAP (mean pulmonary arterial pressure), and mRAP (mean right atrial pressure); changes from baseline to week 16 in walk distance (6-min walk test), dyspnea fatigue rating, WHO functional class; and safety and tolerability.
- the results show a positive trend toward an improvement in hemodynamic parameters, specifically increase in Cardiac Index (Cl) and decreases in Total Pulmonary Resistance (TPR), mean Pulmonary Arterial Pressure (mPAP) and mean Right Atrial Pressure (mRAP), in patients who received bosentan with epoprostenol compared to those who received epoprostenol alone.
- TPR Total Pulmonary Resistance
- mPAP mean Pulmonary Arterial Pressure
- mRAP mean Right Atrial Pressure
- HYPOTENSION 2 18.2% - The combination of bosentan with epoprostenol or any other prostacyclin analogs leads to an additional efficacy and less prostanoid-related side effects.
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to pharmaceutical compositions for the treatment of pulmonary arterial hypertension one containing a prostacyclin or a prostacyclin analogue, preferably epoprostenol, and the other an endothelin receptor antagonist, preferably bosentan, and to the concomitant use of these compositions to reduce the side effects of the prostcyclin or prostacyclin analogues.
Description
COMBINATION OF PROSTACYCLIN OR PROSTACYCLIN ANALOGUES AND ENDOTHELIN RECEPTOR ANTAGONISTS FOR THE TREATMENT OF PULMONARY ARTERIAL HYPERTENSION
The invention relates to pharmaceutical compositions for the treatment of pulmonary arterial hypertension one containing a prostacyclin or a prostacyclin analogue and the other an endothelin receptor antagonist, characterised in that the side effects of the prostacyclin or the prostacyclin analogue are strongly reduced by the concomitant administration of the prostacyclin or the prostacyclin analogue and the endothelin receptor antagonist.
Pulmonary hypertension is a disease defined by a progressive elevation of pulmonary artery pressure and pulmonary vascular resistance, leading to right ventricular failure and death. Pulmonary hypertension is associated with endothelial dysfunction, characterized by a decreased expression of the vasodilators nitric oxide and prostacyclin, and by an increased expression of the growth factor and vasoconstrictive substance endothelin-1 and its receptors.
Prostacyclin and prostacyclin analogues such as epoprostenol, treprostinil, iloprost, beraprost significantly improve hemodynamic parameters and clinical cyrr.ptoms in patients with pulmonary arterial hypertension. The major mechanism of action of prostacyclin and prostacyclin analogues is vasodilation, whereas improvement in pulmonary vascular hypertrophy and inhibition of platelet aggregation may also play a role. However, the use of prostacyclin or prostacyclin analogues is associated with a number of side effects such as jaw pain, headaches, flushing, tachycardia and systemic hypotension.
Endothelin receptor antagonists such as bosentan (4-tert-butyl-N-[6-(2- hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl]-benzene- sulfonamide) are also efficacious in the treatment of pulmonary arterial
hypertension. Bosentan improves hemodynamic parameters (cardiac index, pulmonary artery pressure, pulmonary vascular resistance), increases exercise capacity, improves WHO functional class, and decreases the rate of clinical worsening in patients with pulmonary arterial hypertension. Bosentan does not significantly modify heart rate or mean arterial blood pressure in patients with pulmonary arterial hypertension.
The mechanism of action of endothelin receptor antagonists is competitive antagonism of the binding of ET-1 on ET receptors, thereby decreasing pulmonary vasoconstriction and vascular remodelling. Endothelin receptor _ ■ tagonists, by their inhibition of the endothelin system, further inhibit the activation of other neurohormonal systems, and in particular reduce sympathetic nerve activity, decrease catecholamine concentrations and blunt reactive tachycardia in response to a decrease in blood pressure.
The combination of bosentan and a prostacyclin, especially epoprostenol (5Z, 9 alpha, 11alpha, 13E, 15S)-6,9-Epoxy-11 ,15-dihydroxyprosta-5,13-dien-1-oic acid, sodium salt [compare also US Patent 4,539,333], has been evaluated in a clinical study. The authors, (compare Am J Respir Crit Care Med Vol 165. pp1209-1216, 2002), who were running on behalf of Actelion Pharmaceuticals Ltd the clinical trials of the combination of these two drugs, speculated that tnis combination may have additional efficacy. The outcome of the trial was, however, entirely unexpected.
The basis of the present application is the unexpected finding in the clinical trial initiated and supervised by Actelion Pharmaceuticals Ltd that the combination of bosentan with epoprostenol not only has additional efficacy, but also decreases the risk of side effects related to epoprostenol considerably. Indeed, in patients treated with bosentan and epoprostenol, there were fewer reported cases of jaw pain, headaches and systemic hypotension, a lesser decrease in blood pressure and a lesser increase in heart rate as compared to patients treated with epoprostenol alone. This may
allow to combine two efficacious treatments with a better safety profile as compared to a prostacyclin or prostacyclin analogue alone, and also to decrease the risk of exaggeration of side effects upon stopping the administration of a prostacyclin or prostacyclin analogue.
Especially preferred are pharmaceutical compositions for the treatment of pulmonary arterial hypertension one containing epoprostenol and the other bosentan, characterised in that the side effects of epoprostenol are strongly reduced by the concomitant administration of epoprostenol and bosentan or by preferably administering bosentan within a time frame of ninety six hours after epoprostenol has been administered.
The use of the pharmaceutical compositions mentioned above is leading to an improvement of the patients as compared to the use of prostacyclin or prostacyclin analogues alone. Therefore, a new method of treating patients with epoprostenol and bosentan has been established or in a more general manner a method of treating patients suffering from pulmonary arterial hypertension with a prostacyclin or a prostacyclin analogue followed by administering an endothelin antagonist has been found.
The dose of the prostacyclin may vary between 1 ng/kg/min and 250 ng/kg/min depending on the length it has been already administered.A preferred dose range is 2 ng/kg/min. With increasing time the dose is increased. A preferred use of the pharmaceutical compositions resides in administering for two days 2 ng/kg/min, then increasing every two weeks the dose by 2 ng/kg/min up to the preferred target dose of 14± 2 ng/kg/min. After the first two days of treatment with prostacyclin or an analogue bosentan is administered twice a day at a dose of either 62,5 mg or
125 mg. The resulting advantages and benefits are disclosed in the following description of a clinical trial, which illustrates the invention. In general a dose range for the prostacyclin of 0,01 to 200 mg per kilogram bodyweight, conveniently 0,01 to 10 mg per kilogram, is used. The dose range for the endothelin antagonist may be 0,01 mg to 10 mg per kilogram bodyweight, conveniently 0,5 mg to 3,0 mg per kilogram bodyweight. The preparation of a pharmaceutical composition containing a prostacyclin has been described in US Patent No. 4,539,333 and is incorporated by reference.
The preparation of a pharmaceutical composition containing an endothelin antagonist, e.g. bosentan, is described in US Patent No. 5,292,740 and is ls incorporated by reference.
Summary of a clinical trial (protocol AC-052-355)
This was a double-blind, randomized, placebo-controlled study to assess the effects of bosentan on hemodynamics, safety and tolerability in patients with severe pulmonary arterial hypertension when combined with the initiation of epoprostenol therapy.
Study design: The duration of the study was 16 weeks, 2:1 bosentan:placebo randomization. All patients received the starting epoprostenol dose of 2 ng/kg/min for 2 days, then they were randomized iυ either bosentan or placebo. Every 2 weeks thereafter, epoprostenol was increased 2 ng/kg/min up to the target dose of 14 ± 2 ng/kg/min by week 16. All patients received epoprostenol together with either bosentan or placebo for 16 weeks. Hemodynamic assessments were performed at baseline (prior to start of therapy) and again after 16 weeks of therapy. Safety monitoring was performed throughout the study duration.
Primary endpoint: Percent change from baseline in total pulmonary resistance (TPR) to week 16. The sample size was estimated for an expected mean difference in TPR of 28%.
Secondary endpoints: Changes from baseline to week 16 in Cl (Cardiac Index), PVR (Pulmonary Vascular Resistance), mPAP (mean pulmonary arterial pressure), and mRAP (mean right atrial pressure); changes from baseline to week 16 in walk distance (6-min walk test), dyspnea fatigue rating, WHO functional class; and safety and tolerability.
Results:
Thirty-three patients entered the study: 11 patients received epoprostenol alone, while 22 patients received bosentan with epoprostenol. The results are summarized in Table 1 below.
Hemodynamic Efficacy:
The results show a positive trend toward an improvement in hemodynamic parameters, specifically increase in Cardiac Index (Cl) and decreases in Total Pulmonary Resistance (TPR), mean Pulmonary Arterial Pressure (mPAP) and mean Right Atrial Pressure (mRAP), in patients who received bosentan with epoprostenol compared to those who received epoprostenol alone. The Hemodynamic efficacy data are summarized in Table 1 below.
Table 1
Hemodynamic Efficacy Results:
Safety and Tolerability
Vital signs
Concomitant administration of bosentan with epoprostenol reduced the fall in systolic blood pressure resulting from monotherapy with epoprostenol and also prevented the epoprostenol-induced increase in heart rate.
Table 2 Mean and median changes from baseline to week 16:
Symptomatic Adverse Events:
The frequency of epoprostenol related side effects (jaw pain, flushing, headache and hypotension) was lower in patients receiving the combined bosentan and epoprostenol therapy compared to those receiving epoprostenol alone.
Summary of treatment emergent adverse events
Epoprostenol alone Bosentan + Epo
Adverse event
No. % No. %
PAIN IN JAW 10 90.9% 13 59.1%
FLUSHING 5 45.5% 6 27.3%
HEADACHE 4 36.4% 6 27.3%
HYPOTENSION 2 18.2% -
The combination of bosentan with epoprostenol or any other prostacyclin analogs leads to an additional efficacy and less prostanoid-related side effects.
Results: In addition to the improvement in efficacy, there were less side effects related to prostacyclin analogues when bosentan is added to a prostacyclin analog.
Claims
1. Pharmaceutical compositions for the treatment of pulmonary arterial hypertension one containing a prostacyclin or a prostacyclin analogue and the other an endothelin receptor antagonist, characterised in that the side effects of the prostacyclin or the prostacyclin analogue are strongly reduced by the concomitant administration of the prostacyclin or the prostacyclin analogue and the endothelin receptor antagonist or by administering the endothelin receptor antagonist within a time frame of ninety six hours after the prostacyclin or the prostacyclin analogue has been administered.
2. Pharmaceutical compositions according to claiml for the treatment of pulmonary arterial hypertension containing epoprostenol and bosentan, characterised in that the side effects of epoprostenol are strongly reduced by the concomitant administration of epoprostenol and bosentan or by administering bosentan within a time frame of ninety six hours after epoprostenol has been administered.
3. Use of pharmaceutical compositions according to any one of claims 1 or 2 for the treatment of pulmonary arterial hypertension to reduce the side effects of the prostacyclin.
4. Method of treating a patient suffering from pulmonary arterial hypertension by administering pharmaceutical compositions according to any one of claims 1 or 2.
5. Method according to claim 4 by administering a dose of prostacyclin between 1 ng/kg/min and 25 ng/kg/min and a dose of endothelin receptor antagonist between 0,01 mg and 10 mg per kilogram bodyweight.
6. Method according to claim 4 by administering a dose of prostacyclin between 2 ng/kg/min and 14 ng/kg/min and a dose of endothelin receptor antagonist between 0,5 mg and 3,0 mg per kilogram bodyweight.
7. Method according to any one of claims 4 to 6 by administering to a patient for two days 2ng/kg/min of epoprostenol followed by increasing the dose every two weeks by 2 ng/kg/min up to the target dose of 14± 2ng/kg/min and administering in addition after the first two days twice a day 62,5 mg or twice a day 125 mg bosentan.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP0209024 | 2002-08-12 | ||
| EPPCT/EP02/09024 | 2002-08-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2004017993A1 true WO2004017993A1 (en) | 2004-03-04 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2003/008122 WO2004017993A1 (en) | 2002-08-12 | 2003-07-24 | Combination of prostacyclin or prostacyclin analogues and endothelin receptor antagonists for the treatment of pulmonary arterial hypertension |
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| WO (1) | WO2004017993A1 (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008088617A1 (en) * | 2006-12-04 | 2008-07-24 | Regents Of The University Of Colorado | Treatment of copd |
| WO2009009561A1 (en) * | 2007-07-11 | 2009-01-15 | Lexicon Pharmaceuticals, Inc. | Methods and compositions for treating pulmonary hypertension and related diseases and disorders |
| WO2009152160A1 (en) * | 2008-06-10 | 2009-12-17 | Gilead Sciences, Inc. | Inhaled carbaprostacyclin and prostacyclin prodrugs for the treatment of pulmonary arterial hypertension |
| WO2010018549A3 (en) * | 2008-08-13 | 2010-07-29 | Actelion Pharmaceuticals Ltd | Therapeutic compositions containing macitentan |
| US8071596B2 (en) | 2007-01-12 | 2011-12-06 | Concert Pharmaceuticals, Inc. | Endothelin receptor antagonists |
| US8080549B2 (en) | 2007-01-12 | 2011-12-20 | Concert Pharmaceuticals, Inc. | Endothelin receptor antagonists |
| US8623917B2 (en) | 2005-06-02 | 2014-01-07 | The Regents Of The University Of Colorado, A Body Corporate | Uses of prostacyclin analogs |
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| US8623917B2 (en) | 2005-06-02 | 2014-01-07 | The Regents Of The University Of Colorado, A Body Corporate | Uses of prostacyclin analogs |
| WO2008088617A1 (en) * | 2006-12-04 | 2008-07-24 | Regents Of The University Of Colorado | Treatment of copd |
| US8071596B2 (en) | 2007-01-12 | 2011-12-06 | Concert Pharmaceuticals, Inc. | Endothelin receptor antagonists |
| US8080549B2 (en) | 2007-01-12 | 2011-12-20 | Concert Pharmaceuticals, Inc. | Endothelin receptor antagonists |
| US8410121B2 (en) | 2007-07-11 | 2013-04-02 | Lexicon Pharmaceuticals, Inc. | Methods of treating pulmonary hypertension |
| AU2008275179B2 (en) * | 2007-07-11 | 2013-09-12 | Lexicon Pharmaceuticals, Inc. | Methods and compositions for treating pulmonary hypertension and related diseases and disorders |
| US7875622B2 (en) | 2007-07-11 | 2011-01-25 | Lexicon Pharmaceuticals, Inc. | Methods and compositions for treating pulmonary hypertension and related diseases and disorders |
| WO2009009561A1 (en) * | 2007-07-11 | 2009-01-15 | Lexicon Pharmaceuticals, Inc. | Methods and compositions for treating pulmonary hypertension and related diseases and disorders |
| WO2009152160A1 (en) * | 2008-06-10 | 2009-12-17 | Gilead Sciences, Inc. | Inhaled carbaprostacyclin and prostacyclin prodrugs for the treatment of pulmonary arterial hypertension |
| TWI446911B (en) * | 2008-08-13 | 2014-08-01 | Actelion Pharmaceuticals Ltd | Therapeutic composition containing MACITENTAN |
| WO2010018549A3 (en) * | 2008-08-13 | 2010-07-29 | Actelion Pharmaceuticals Ltd | Therapeutic compositions containing macitentan |
| US20110136818A1 (en) * | 2008-08-13 | 2011-06-09 | Martine Clozel | Therapeutic compositions containing macitentan |
| US8809334B2 (en) * | 2008-08-13 | 2014-08-19 | Actelion Pharmaceuticals Ltd. | Therapeutic compositions containing macitentan |
| AU2009280843B2 (en) * | 2008-08-13 | 2015-03-05 | Actelion Pharmaceuticals Ltd | Therapeutic compositions containing macitentan |
| US9173881B2 (en) | 2008-08-13 | 2015-11-03 | Actelion Pharmaceuticals Ltd. | Therapeutic compositions containing macitentan |
| US9597331B2 (en) | 2008-08-13 | 2017-03-21 | Actelion Pharmaceuticals Ltd. | Therapeutic compositions containing macitentan |
| EP2315587B1 (en) | 2008-08-13 | 2017-10-25 | Actelion Pharmaceuticals Ltd. | Therapeutic compositions containing macitentan |
| EP3300729A1 (en) | 2008-08-13 | 2018-04-04 | Actelion Pharmaceuticals Ltd | Therapeutic compositions containing macitentan |
| US11069054B2 (en) | 2015-12-30 | 2021-07-20 | Visiongate, Inc. | System and method for automated detection and monitoring of dysplasia and administration of immunotherapy and chemotherapy |
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