Appendix C Section Comparators continued ; Consultees Pfizer Ltd Comments No also see comment above population ; . The therapies listed in the draft scope can not be considered standard comparators. CCBs are only appropriate for those patients who have a positive adenosine test approximately 10% ; 1.Humbert M, et al. Treatment of Pulmonary Hypertension NEJM 2004 351: 1425-1436. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. link provided in covering E-mail as your formatting does not permit inclusion here. ; . Diuretics are useful in patients with right heart failure. In the clinical trials of epoprostenol, sildenafil, bosentan and iloprost 47 to 70% of paitents were on diuretics. Warfarin is given as an anti-coagulant to avoid thrombo-embolic complications. It is the expectation that by the time patients achieve Functional Class III usually at diagnosis ; that they will require oxygen therapy for symptom relief. The licensed therapies described as the technology intervention in this scope are the comparators that should be identified for patients with PAH. For patients with PAH Functional Class III the comparator is each of the other licensed therapies. The expectation would therefore be where data exists ; for a pairwise comparison of all therapies licensed for symptom relief in patients with severe PAH at the time of the appraisal. In the absence of head to head data an adjusted indirect comparison using an approach that preserves the random allocation of the original trials should be considered. Pfizer is aware that combinations of sildenaifil, and or bosentan and or epoprostenol iloprost have been used in clinical practice. Pfizer is unaware of any such combination being recomended as an appropriate regimen within a product label or a clnical guideline. Action Calcium channel blockers will not be considered as comparators and the population to be considered has also been amended. Comparisons with prostaglandins will be covered in addition to comparisons with supportive care. Combination therapy will be considered if the evidence allows.

This set of experiments was performed to verify that Ang II can acutely induce collagen type I gene activation in the renal tissue in vivo and to test the role of endothelin as mediator of this action. To this end, Ang II alone or mixed with losartan or bosentan was injected intraperitoneally into control animals. Exogenous Ang II slightly increased luciferase activity in renal cortical slices 4 hours after the injections. Luciferase activity was further increased 24 or 48 hours after Ang II administration 147 10 versus 185 22, 387 and. Our study confirms the favorable effect of bosentan therapy to improve pulmonary haemodynamics and exercise capacity in CTEPH not eligible for PEA. In addition, a positive effect on quality of life could be demonstrated. Although PEA is the only curative therapy for patients with CTEPH, many patients do not qualify for this surgical option due to distal pulmonary vascular.

Weight, heart rate, and blood pressure were measured once a week. To analyze the paracrine cardiac endothelin system, we studied rats with renovascular hypertension 10 days, 4 weeks, and 12 weeks after the artery was clipped and compared them with corresponding sham-operated controls. After decapitation, the left ventricle was prepared and separated into 2 equal parts by longitudinal sectioning and frozen in LN2. One part was used for measurement of tissue ET-1 and big ET-1 and the other was used for binding studies. Five additional groups of rats were established for analyzing the effects of treatment with ETA, ETB, and combined ETA ETB receptor antagonists: 1 ; a sham-operated group treated for 44 days with intraperitoneal placebo solvent for BQ 123 and IRL 1038 2 ; a group with renovascular 2K1C ; hypertension treated for 44 days with intraperitoneal placebo solvent for BQ 123 and IRL 1038 3 ; a group with renovascular 2K1C ; hypertension treated for 44 days with the ETA antagonist BQ 123 30 mg kg 1 d 1 group with renovascular 2K1C ; hypertension treated for 44 days with the ETB antagonist IRL 1038 22 mg kg 1 d 1 and 5 ; a group with renovascular 2K1C ; hypertension treated for 44 days with the combined ETA ETB antagonist bosentan 100 mg kg 1 d 1 and intraperitoneal placebo see above ; . Bosentan was given by gavage. Treatment was started 24 hours after clipping. The drugs were given at 8 AM. Blood pressure measurement was performed once a week at noon. The antagonists were given without any interruption. The ETA antagonist BQ 123 and the ETB antagonist IRL 1038 were given by intraperitoneal injection. The solvent for both drugs consisted of 140 mmol L NaCl and 20 mmol L Tris, pH 8.4. No signs of peritonitis or any other infectious disease were seen. The animals tolerated the treatment very well.

Klemm P, Warner T, Hohlfeld T, Corder R, Vane J. Endothelin 1 mediates ex vivo cornary vasoconstriction caused by exogenous and endogenous cytokines. Proc Natl Acad Sci USA 1994; 92: 26912695. Kiowski W, Sutsch G, Hunziker P, et al. Evidence of ET 1-mediated vasoconstriction in severe chronic heart failure. Lancet 1995; 346: 732736. Zuccarello M, Soattin G, Lewis I, Breu V, Hallak H, Rapoport R. Prevention of subarachnoid hemorrhage-induced cerebral vasospasm by oral administration of endothelin receptor antagonists. J Neurosurg 1996; 84: 503507. Eichacker PQ, Hoffman WD, Danner RL, et al. Serial measures of total body oxygen consumption in an awake canine model of septic shock. J Respir Crit Care Med 1996; 154: 6875. Oldner A, Wanecek M, Goiny M, et al. The endothelin receptor antagonist bosentan restores gut oxygen delivery and reverses mucosal acidosis in porcine endotoxin shock. Gut 1998; 42: 696702. Sugiura M, Inagami T, Kon V. Endotoxin stimulates endothelin-release in vivo and in vitro as determined by radioimmunoassay. Biochem Biophys Res Commun 1989; 161: 12201227. Maemura K, Kurihara H, Morita T, Oh-hashi Y, Yazaki Y. Production of endothelin-1 in vascular endothelial cells is regulated by factors associated with vascular injury. Gerontology 1992; 35: Suppl. 1, 2935. Hemsen A, Modin A, Wanecek M, Malmstrom R, Weitzberg E. Effects of Ro-47-0203 and PD 155080 on the plasma kinetics, receptor binding and vascular effects of endothelin in the pig. Eur J Pharmacol 1996; 318: 369376. Dupuis J, Goresky CA, Fournier A. Pulmonary clearance of circulating endothelin-1 in dogs in vivo: exclusive role of ETB. J Appl Physiol 1996; 81: 15101515. 1. Nomenclature Committee. Nomenclature and Classification of Pulmonary Hypertension. Rich S. Primary pulmonary hypertension: executive summary from the World Symposium-Primary Pulmonary Hypertension 1998, 2527. World Health Organization. Available at: : who.int ncd cvd pph . 2. Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997; 336: 1117. MacGregor AJ, Canavan R, Knight C, et al. Pulmonary hypertension in systemic sclerosis: risk factors for progression and consequences for survival. Rheumatology Oxford ; 2001; 40: 4539. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001; 358: 1119 Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346: 896 Guyatt GH, Sullivan MJ, Thompson PJ, et al. The 6-minute walk: a new measure of exercise capacity in patients with chronic failure. Can Med Assoc J 1985; 132: 919 Miyamoto S, Nagaya N, Satoh T, et al. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing. J Respir Crit Care Med 2000; 161: 48792. Naeije R, Torbicki A. More on the noninvasive diagnosis of pulmonary hypertension: Doppler echocardography revisited. Eur Respir J 1995; 8: 1449. Bossone E, Duong Wagner TH, Paciocco G, et al. Echocardiographic features of primary pulmonary hypertension. J Soc Echocardiogr 1999; 12: 65562. Hinderliter AL, Willis PW, Barst RJ, et al. Effects of long-term infusion of prostacyclin epoprostenol ; on echocardiographic measures of right ventricular structure and function in primary pulmonary hypertension. Primary Pulmonary Hypertension Study Group. Circulation 1997; 95: 1479 Ritchie M, Waggoner AD, Davila RV, Barzilai B, Trulock EP, Eisenberg PR. Echocardiographic characterization of the improvement in right ventricular function in patients with severe pulmonary and bumetanide.

Effects of Long-Term Bosentan in Children With Pulmonary Arterial Hypertension Erika Berman Rosenzweig, D. Dunbar Ivy, Allison Widlitz, Aimee Doran, Lori R. Claussen, Delphine Yung, Steven H. Abman, Adele Morganti, Ngoc Nguyen, and Robyn J. Barst J. Am. Coll. Cardiol. 2005; 46; 697-704; originally published online Jul 20, 2005; doi: 10.1016 j.jacc.2005.01.066. Bosentan is the first oral endothelin antagonist approved recently for the treatment of pph and pah and buspirone. To phase the cost of an installation, a conversion kit can be fitted to an existing coal fired heat exchanger and two or so years subject to life left in heat exchanger ; later the existing heat exchanger can be replaced with a new one. Lipopolysaccharide LPS ; in conscious rats. The contribution of ETB receptor-mediated mechanisms to fever triggered by i.c.v. interleukin IL ; -6, prostaglandin PG ; E2, PGF2 , corticotropin-releasing factor CRF ; and pre-formed pyrogenic factor derived from LPS-stimulated macrophages PFPF ; was examined. The influence of natural IL-1 receptor antagonist IL-1ra ; or soluble tumor necrosis factor receptor I sTNFRI ; on endothelin ET ; -1-induced fever was also assessed. The selective ETB receptor antagonist BQ-788 3 pmol, i.c.v. ; abolished fever induced by i.c.v. ET-1 1 pmol ; or PFPF 200 ng ; and reduced that caused by i.c.v. CRF 1 nmol ; , but not by IL-6 14.6 pmol ; , PGE2 1.4 nmol ; or PGF2 2 nmol ; . CRF-induced fever was also attenuated by bosentan dual ETA ETB receptor antagonist; 10 mg kg, i.v. ; , but unaffected by BQ-123 selective ETA receptor antagonist; 3 pmol, i.c.v. ; . -helical CRF9-41 dual CRF1 CRF2 receptor antagonist; 6.5 nmol, i.c.v. ; attenuated fever induced by CRF, but not by ET-1. Human IL-1ra 9.1 pmol ; markedly reduced fever to IL-1 180 fmol ; or ET-1, and attenuated that caused by PFPF or CRF. Murine sTNFRI 23.8 pmol ; reduced fever to TNF- 14.7 pmol ; , but not to ET-1. The results of the present study suggest that PFPF and CRF recruit the brain ET system to cause ETB receptor-mediated IL-1-dependent fever and busulfan.

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