PHARMACY UPDATE PULMONARYARTERYHYPERTENSION: NEW DRUG TREATMENT IN CHILDREN

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1 PHARMACY UPDATE PULMONARYARTERYHYPERTENSION: NEW DRUG TREATMENT IN CHILDREN Correspondene to: Katrina Ford, Great Ormond Street Hospital NHS Trust, London, UK; nhs.uk P Katrina Ford Arh Dis Child Edu Prat Ed 2005; 90:ep15 ep20. doi: /ad ulmonary artery hypertension (PAH) is a rare progressive disease of the pulmonary vasulature. Although it affets fewer than two adults per million population, and probably fewer hildren, the linial ourse an be one of rapid deterioration, with death ourring within three years of diagnosis for adults, and less than one year for hildren. 1 2 In the last deade, greater understanding of the disease has led to rethinking the diagnosti lassifiation of pulmonary hypertension, and the identifiation of therapeuti targets for drug development. A number of new drugs have been studied in randomised ontrolled trials, and are liensed to treat PAH. A key message from the reent World Symposium on Pulmonary Arterial Hypertension was to refer patients to a entre with expertise in managing PAH; however, paediatriians may enounter patients already ommened on these novel drugs and delivery systems. 3 This review will summarise the key trials of the new drugs reently marketed for PAH, some of whih are not yet available and none of whih are liensed for hildren in the UK. DIAGNOSTIC CLASSIFICATION AND DEFINITIONS Until reently, primary pulmonary hypertension (PPH) was the term used to desribe familial disease, or sporadi disease of unknown ause. At the World Pulmonary Arterial Hypertension Symposium in 2003, the term primary pulmonary hypertension was offiially abandoned and replaed with idiopathi pulmonary artery hypertension (IPAH). This term more aurately indiates that the diagnosis is by exlusion, and exat auses are not known. Where geneti information supports a hereditary basis, the term familial pulmonary artery hypertension (FPAH) is to be used. In this lassifiation, pulmonary artery hypertension (PAH) is differentiated from pulmonary hypertension aused by left heart disease; or hroni lung disease or hypoxaemia; or hroni thromboti or emboli disorders affeting the lungs; or other infetious or inflammatory triggers (table 1). This lassifiation system is useful in that it provides a rationale for treatment, as refleted in the approval by drug regulating authorities of new drugs for PAH. 4 The pathogenesis of PAH is omplex and not ompletely understood. Three fators are thought to be important: vasoonstrition of the pulmonary vasulature, remodelling of the pulmonary vessel wall, and thrombosis in situ. 5 Esalating pulmonary vasular resistane (PVR) leads to eventual right heart failure and death. Thus, standard drug treatment for PAH inludes vasodilators, diuretis, digoxin, and antioagulation. A detailed disussion of the pathology and linial presentation in hildren is beyond the sope of this review. The definition of PAH in hildren is the same as that for adults. It is defined as a mean pulmonary artery pressure (mpap) > 25 mm Hg at rest, or > 30 mm Hg during exerise, with a normal pulmonary artery wedge pressure, and an inreased pulmonary vasular resistane index > 3 Wood units 6 m 2. Exerise haemodynamis is important for the diagnosis in hildren, sine they may have normal-high pulmonary artery pressure at rest, but an exaggerated inrease in response to exertion. 6 RESPONDERS AND NON-RESPONDERS Aute vasodilator testing in the ardia atheter laboratory is performed to determine the appropriate treatment ourse. A response is onsidered to be a derease in mpap of at least 10 mm Hg to ( 40 mm Hg, with no hange or an inrease in ardia output (CO). A higher proportion of hildren are aute responders ompared to adults, 6 and an be effetively managed with alium hannel blokers. 7 A survival advantage was observed in both adults and hildren who were responders to aute vasodilator hallenge and were treated with nifedipine in addition to onventional anti-failure treatment that is, digoxin, diuretis, and supplemental oxygen. 78 Dihydropyridine alium hannel blokers, suh as nifedipine and amlodipine that at on vasular smooth musle, are the preferred agents. Nifedipine is preferred over amlodipine beause of its shorter half life and duration of ation, although amlodipine has been used in stabilised patients. Negative inotropi alium hannel blokers, suh as verapamil, should be avoided. 9 The optimum dose of nifedipine or amlodipine in hildren with PAH is not known. These agents should be introdued autiously and the dose titrated as tolerated. They should not be started indisriminately, sine in non-responders alium hannel ep15 Arh Dis Child Edu Prat Ed: first published as /ad on 20 May Downloaded from on 1 September 2018 by guest. Proteted by opyright.

2 FORD ep16 Table 1 Revised diagnosti lassifiation of pulmonary hypertension (2003) Pulmonary artery hypertension (PAH) Idiopathi PAH Familial PAH Related to: Collagen vasular disease Congenital systemi to pulmonary shunts Portal hypertension HIV infetion Drugs and toxins Others Assoiated with signifiant venous or apillary involvement Pulmonary veno-olusive disease Pulmonary apillary haemangiomatosis Pulmonary hypertension with left heart disease Pulmonary hypertension assoiated with lung disease and/or hypoxaemia Pulmonary hypertension aused by hroni thromboti or emboli disease Misellaneous blokers an ause worsening failure. 10 Non-responders treated with intravenous epoprostenol have shown linial improvement and inreased survival 11 indiating that a mehanism other than vasodilation is important. Children who were aute responders initially, may beome non-responders over time. 11 Periodi repeat aute vasodilator testing is reommended to maintain optimum long term treatment. 611 ANTICOAGULATION Adult studies demonstrated a survival benefit with the addition of warfarin, 12 and subsequently warfarin is ommonly given to hildren. The target international normalised ratio (INR) depends on the risk of benefit and bleeding. In general the INR range is 1.5 2, while hildren with hroni thromboemboli disease will aim for a higher INR; and ative toddlers, and hildren with thromboytopenia, would aim for INR, In some small hildren, the need for ongoing INR blood tests an be problemati for everyone involved, and warfarin is not presribed. CLINICAL STUDIES OF NEW DRUGS All studies enrolled only adults. There are a number of diffiulties assoiated with extrapolating adult data to hildren. Firstly, hildren have a longer antiipated lifespan than adults; seondly, hildren may have a more reative pulmonary irulation ompared to adults, meaning that greater responsiveness ould lead to better therapeuti outomes; and thirdly, hildren who are not treated show a worse survival ompared to adults, despite linial and pathologial studies indiating inreased vasoreativity in hildren. 13 In addition, metaboli hanges assoiated with growth and development during infany and hildhood mean that optimum drug doses for hildren may be different to those in adults. This artile will review the studies from the point of view of treating hildren. PROSTACYCLIN AND ANALOGUES Prostaylin and thromboxane A 2 are produts of the arahidoni aid pathway. They have opposing physiologial funtions: prostaylin is a short ating vasodilator produed by vasular endothelium with antiplatelet properties. Thromboxane A 2 is a vasoonstritor and has pro-platelet aggregatory effets. The balane of these two loal hormones regulates vasomotor ontrol in many tissues. In PAH, this balane is lost and may ontribute to the overall pathogenesis of PAH. 14 Epoprostenol Epoprostenol sodium is the syntheti sodium salt of naturally ourring prostaylin. It is liensed in the UK for the treatment of adults with PAH. When given as a ontinuous intravenous infusion, epoprostenol improves exerise tolerane, symptoms, haemodynamis, and survival in hildren and adults. Epoprostenol dereases PVR and improves the survival in non-responders Survival in epoprostenol treated adults at one, two, and three years was 87.8%, 76.3%, and 62.8%, respetively, and signifiantly better than that observed with historial ontrols, 58.9%, 46.3%, and 35.4%, respetively. 19 This raises the question of a mehanism of ation other than vasodilation. Antiproliferative and vasular remodelling effets are proposed. Side effets assoiated with epoprostenol treatment inlude jaw pain, diarrhoea, nausea, light headedness, and flushing. The usual starting dose in hildren is the same as in adults: 2 ng/kg/min with up titration until the maximum tolerated dose is reahed. 7 Tolerane frequently develops, and regular dosage adjustment is required to maintain therapeuti response. In hildren, the maintenane dose is generally higher than adults, and there is onsiderable interpatient variability for optimum dose. The mean dose for hildren after one year of treatment is around ng/kg/min ompared to ng/kg/min in adults. 6 Epoprostenol is the urrent standard treatment for PAH in patients who do not respond to aute vasodilator hallenge, and for those responders who have deteriorated on alium hannel blokers. However, there are risks and important onsiderations for administration, espeially with regard to hildren. The administration of epoprostenol requires the plaement of a entral venous line and a ontinuous infusion pump to be worn by the hild. Unintentional interruption of the infusion, and pump failure, an lead to life threatening hypertensive rises. Catheter related sepsis and thrombosis are life threatening ompliations. Epoprostenol is an unstable ompound that requires partiular and areful reonstitution and dilution. Parents/arers must be ompetent in the preparation of daily infusions at home. There is a lear need for an alternative mode of drug administration. Iloprost nebulised Iloprost is a stable analogue of prostaylin with a longer half life; minutes ompared to 2 3 minutes for Abbreviations AUC: area under the urve ALT: alanine aminotransferase GMP: yli guanosine monophosphate CO: ardia output ET: endothelin FPAH: familial pulmonary artery hypertension IPAH: idiopathi pulmonary artery hypertension mpap: mean pulmonary artery pressure mpvr: mean pulmonary vasular resistane NO: nitri oxide NYHA: New York Heart Assoiation PAH: pulmonary artery hypertension PPH: primary pulmonary hypertension SVR: systemi vasular resistane 6MWT: six minute walk test Arh Dis Child Edu Prat Ed: first published as /ad on 20 May Downloaded from on 1 September 2018 by guest. Proteted by opyright.

3 PHARMACY UPDATE epoprostenol. 21 The duration of ation for iloprost is about 60 minutes, thus frequent nebulisations are neessary. 22 Drug delivery diret to the lungs avoids the morbidity assoiated with a entral intravenous atheter, and may also avoid systemi side effets. However, it is not known whether the benefits seen with a ontinuous infusion will be observed with pulsed delivery. Iloprost has a liene in the UK for the treatment of adults with PAH. Clinial studies A multientre, randomised, double blind trial ompared nebulised iloprost (2.5 5 mg administered 6 9 times per day) with plaebo in 203 patients with IPAH and PAH assoiated with onnetive tissue disease or hroni thromboemboli disorder. Only patients with New York Heart Assoiation (NYHA) funtional lass III or IV disease were inluded. After 12 weeks there was no signifiant differene between groups for the primary end point of. 10% inrease in baseline walking distane and improvement in NYHA lass. However, there was a signifiant inrease in six minute walk test (6MWT) for the iloprost group ompared to plaebo (overall mean inrease 36 m in iloprost group; p = 0.004), and there was an overall signifiant improvement in NYHA lass for the iloprost group ompared to plaebo. There were signifiant improvements in haemodynami variables when measured after inhalation ompared to plaebo. Pre-inhalation values were not different from baseline. In total 17.7% of patients withdrew from the study (13.7% in the plaebo group). The most ommon reason was linial deterioration. Serious adverse effets were the same for both groups. However, there were signifiantly more episodes of synope, jaw pain, and flushing in the iloprost group. 23 Treprostinil sodium subutaneous infusion Treprostinil is also a stable analogue of prostaylin with a longer half life (approximately three hours). Unlike epoprostenol, it is stable at room temperature and has a neutral ph. It has been studied in adults as a ontinuous subutaneous infusion, and although it is not yet available in the UK, it has a liene for the treatment of adults with PAH in Europe. Clinial studies Treprostinil was ompared with plaebo in a double blind randomised, multientred, ontrolled trial enrolling 470 patients with both IPAH and PAH assoiated with onnetive tissue disease or ongenital systemi to pulmonary shunts. Patients with NYHA lass II, III, or IV disease were inluded. Subutaneous treprostinil was given at a starting dose of 1.25 ng/kg/min and inrementally inreased until the maximum tolerated dose. Exerise tolerane signifiantly improved in the ative group ompared to ontrols at 12 weeks. The median between group differene was 16 m in favour of treprostinil (p = 0.006). There were signifiant improvements in mpap, mpvr, and CO for the treprostinil group ompared to ontrols. Eighty five per ent of patients in the treprostinil group reported infusion site pain or erythema. Signifiantly more patients in the treatment group reported diarrhoea, jaw pain, vasodilation, and oedema. 24 Beraprost sodium oral Beraprost is an orally ative prostaylin analogue with a half life of one hour. Beraprost was designated orphan drug status in the European Union in It has not been extensively studied in hildren with PAH. Clinial studies There are two studies omparing beraprost to plaebo for treatment of PAH. Both studies are double blind randomised and plaebo ontrolled. The first study inluded 130 patients with NYHA lass II or III disease, with IPAH or PAH assoiated with other diseases. Beraprost was started at 20 mg four times a day, and titrated up to maximum of 480 mg per day as tolerated. After 12 weeks, there was an overall signifiant improvement in 6MWT in the beraprost group (adjusted mean differene between groups was +25 m in favour of beraprost; p = 0.036). However, there were no signifiant improvements in mpap, mpvr, or CO in the beraprost group, and hanges in NYHA lass were not signifiant. 25 The seond study was onduted over 12 months and enrolled 116 patients with NYHA lass II or III disease. The primary end point was disease progression. Signifiantly fewer patients in the beroprost group met the riteria for disease progression at six months ompared to plaebo, but this benefit was not evident beyond six months. Exerise apaity was signifiantly improved from baseline in the beraprost group up to six months ompared to plaebo. However, the treatment benefit was not sustained at follow up. 26 Limitations All the trials disussed above were randomised, double blind, and plaebo ontrolled, exept for the epoprostenol trials, where a plaebo was not used. There were no hildren inluded in any of these studies. The studies for both iloprost and treprostinil were not long enough to determine a survival advantage. Although the nebulised route is less invasive and may redue systemi side effets, small hildren and very sik hildren may not be able to manage the mask and nebuliser devie, nor the frequeny of nebulisations. The high rate of infusion site reations and pain with subutaneous treprostinil preludes this treatment option for many hildren. Cautions Iloprost is not reommended for patients with unstable disease and advaned right heart failure. The pulmonary vasodilator effet of nebulised iloprost is of short duration, thus episodes of synope may reflet therapeuti gaps or insuffiient effiay. 21 The need for dose adjustment or hanging treatment should be ontinually monitored. Iloprost may exaerbate hypotension in patients with existing low blood pressure. Iloprost is leared via the liver. In patients with liver dysfuntion, iloprost should be started at low dose and inreased autiously. The dosage interval should not be less than three hours. Parents or arers of hildren on treprostinil must be skilled in the are of the infusion site and the infusion devie. They must also be ompetent in the preparation of daily infusions at home. Treprostinil is extensively metabolised in the liver. In hildren with mild hepati insuffiieny, treprostinil sodium should be started at a lower dose and inreased autiously. Beroprost is an attrative alternative beause of its oral bioavailability. However, effiay is yet to be established in adults, and dosage information for hildren are laking. ENDOTHELIN RECEPTOR ANTAGONISTS Endothelin-1 (ET-1) is a potent vasoonstritor and smooth musle mitogen produed by vasular endothelium. 27 The ep17 Arh Dis Child Edu Prat Ed: first published as /ad on 20 May Downloaded from on 1 September 2018 by guest. Proteted by opyright.

4 FORD ep18 vasoonstritor effets of ET-1 our via ET-A reeptors, while ET-B reeptors on vasular smooth musle and endothelium are involved with learane of ET-1 or vasodilation. 28 In PAH, endothelin-1 prodution is inreased, and the ET-A vasoonstritor effet predominates, while ET-B vasodilator mehanisms on endothelium ells are impaired. ET-A reeptors and ET-B reeptors on vasular smooth musle are ativated ausing ell proliferation. 29 Bosentan Bosentan is a ompetitive ET-A and ET-B reeptor antagonist. It is the only oral agent with a liene for the treatment of adult PAH. The liene states effiay and safety have not been studied in hildren, 12 years old; however, a pharmaokineti study has been onduted whih indiates doses for hildren, 40 kg. 30 Clinial studies To date, two randomised studies have been published in adults with PAH. Both trials were multientre, double blind, and ompared bosentan with plaebo. The first study enrolled 32 adults with IPAH, or PAH assoiated with other aetiologies, with stable World Health Organization funtional lass III disease. Patients on intravenous epoprostenol were exluded. Bosentan was added to onventional treatment at a starting dose of 62.5 mg twie a day and titrated up to 125 mg twie a day after four weeks. At 12 weeks, there was a signifiant improvement in the 6MWT in the bosentan group ompared to plaebo (overall mean differene +76 m in favour of bosentan; p, 0.021). Cardiopulmonary haemodynamis and NYHA funtional lass were also signifiantly improved from baseline in the bosentan group ompared to plaebo. Two patients withdrew from the study beause of linial deterioration. Both were in the plaebo group. Adverse effets were similar in both groups. 31 An open label extension of this study enrolled 29 of the 32 patients to monitor ongoing linial improvement and adverse effets for one year. There were no deaths reported. The most ommon adverse effets reported were headahe, upper respiratory trat infetion, dyspnoea, hest pain and aggravated PAH, and sinusitis. Three patients showed elevated hepati transaminases, although no patient disontinued treatment. 32 The seond study enrolled 213 adults using the same inlusion riteria as the first study. Bosentan was started at a dose of 62.5 mg twie a day for the first four weeks, then inreased to 125 mg or 250 mg twie a day for the following 12 weeks. There was a signifiant overall improvement in the 6MWT in bosentan treated patients ompared to plaebo (mean differene +44 m in favour of bosentan; p = 0.002) for the 125 mg twie daily dose. The improvement seen with 250 mg twie daily was not signifiantly different from the lower dose. There were no signifiant improvements in NYHA lass or Borg dyspnoea sores. The most frequent adverse effets reported were headahe and dizziness, with the frequeny of eah similar in both bosentan and plaebo groups. Hepati dysfuntion was more ommon in the bosentan group ompared to plaebo, and was most ommon in the high dose group. 33 Survival has been estimated from both these studies. At 36 months, survival for patients treated with bosentan was 86% ompared with predited survival of 48%. 34 Paediatri study Bosentan has been studied in 19 hildren aged between 3 15 years with IPAH or PAH related to ongenital heart disease. All hildren were in WHO lass II or III. The study was an open label, non-ontrolled study omparing the pharmaokineti parameters of single and multiple doses of bosentan with those seen in healthy adults after 12 weeks treatment. Bosentan was added to existing treatment, inluding intravenous (iv) epoprostenol. The bosentan dosage was stratified aording to weight as follows: kg: mg daily for four weeks then inrease to 32.5 mg twie a day kg: mg twie a day for four weeks then inrease to 62.5 mg twie a day. 40 kg: 62.5 mg twie a day for four weeks then inrease to 125 mg twie a day. The end points were area under the urve (AUC) omparisons, exerise apaity, haemodynami assessment, and WHO lass. The AUC values observed in hildren were omparable with those measured in healthy adults given 125 mg of bosentan twie a day. Calulated values for the half life of bosentan were not different after single or multiple doses, and were omparable to that alulated in healthy adults. mpap and PVR index signifiantly improved for the group. However, hange in exerise apaity and WHO lass at 12 weeks was not signifiantly different from baseline. The most frequent adverse effet was flushing, headahe, and elevated liver enzymes. One hild experiened elevated ALT (alanine transaminase) values to more than three times the upper limit of normal. These resolved upon disontinuation. There were no deaths. 35 Bosentan is being used in infants and hildren with severe disease. The oral dosage form is an enormous advantage in this age group. Clinial improvement has been observed in patients as young as 9 months with severe disease. Endothelium reeptor blokers may be benefiial in patients who do not respond to aute vasodilator treatment, or who deteriorate on alium hannel blokers. 6 Limitations Paediatri pharmaokineti studies assume that if AUCs omparable to adult data are measured, omparable effiay and safety an be expeted. This may not be the ase if hildren have a different form of disease. Studies of short duration are insuffiient to observe long term adverse effets on growth and development. Cautions Bosentan is metabolised by ytohrome P450 isozymes 3A4 and 2C9. Bosentan has induible metabolism and an ative metabolite. 30 The effet of these on other drugs metabolised through these same isozymes, suh as warfarin, is not known. Table 2 Drug Drug osts for pulmonary artery hypertension Costs/year/hild Epoprostenol sodium + home are delivery osts , = * Iloprost trometamol + nebuliser * +, 500 Bosentan * Sildenafil * *Prie range reflets the dose inrease for different age groups. Arh Dis Child Edu Prat Ed: first published as /ad on 20 May Downloaded from on 1 September 2018 by guest. Proteted by opyright.

5 PHARMACY UPDATE Liver dysfuntion is reported and monitoring is important espeially in the setting of advaning right side failure. Baseline liver funtion tests should be taken, with disontinuation if liver dysfuntion ours. PHOSPHODIESTERASE INHIBITORS In PAH, synthesis of endogenous nitri oxide (NO) is impaired. 38 Phosphodiesterase inhibitors boost the effet of NO by inhibiting the breakdown of yli guanosine monophosphate (GMP). In smooth musle ells, GMP regulates alium influx and mediates vasodilation. Sildenafil, a type 5 phosphodiesterase inhibitor, has bloked rebound pulmonary hypertension assoiated with withdrawal of inhaled NO in infants and neonates. 39 In small ase series desribing hildren and adults with PAH, sildenafil is reported to improve exerise apaity, derease PAP, and improve symptoms Limitations Randomised, ontrolled studies are needed to determine the effiay and safety of sildenafil in hildren and adults with PAH. Cautions Muh of the safety data for sildenafil relates to its use on a prn basis. The optimum dosage and long term adverse effets are not known. Sildenafil is metabolised in the liver via CYP450 3A4. 43 The linial importane of drug interations with other drugs used to treat PAH, suh as bosentan, is not known. COMBINATION THERAPY Bosentan and epoprostenol ombination were assessed in adults with NYHA lass III or IV disease in a multientred, double blind trial. Epoprostenol was ommened in all patients. After two days, patients were randomised to either bosentan or plaebo. At 16 weeks, the primary end point of a 30% redution in total pulmonary resistane was not signifiantly different between groups. Haemodynami Table 3 Summary of drugs used to treat pulmonary artery hypertension parameters and distane overed in 6MWT for the epoprostenol/bosentan ombination were not signifiantly different from the epoprostenol/plaebo ombination. Four of five patients who withdrew from the study were in the epoprostenol/bosentan arm. Two patients died, one had linial deterioration, and the final patient withdrew beause of adverse effets. 44 To date, other ombinations suh as bosentan/sildenafil, sildenafil/prostaglandin analogue have been reported in ase series only There is no evidene so far that ombination therapy improves survival or quality of life. ON THE HORIZON An imbalane between thromboxane A 2 synthesis and learane may ontribute to the progression of PAH. Thromboxane A 2 inhibitors, suh as terbogrel, are in linial development. 50 Sitaxentan is a seletive ET-A reeptor antagonist urrently under investigation. 51 Arginine infusion and inhaled NO are being investigated as treatment options. 9 Lung transplantation may be an option for some hildren, 11 though the donor pool is limited. COSTS The treatment of PPH is expensive (table 2). SUMMARY The treatment of PAH is omplex and involves the use of therapeuti agents with sophistiated delivery systems, whih have not been formally studied in hildren (table 3). Evidene based linial pratie guidelines have been published for the management of PAH in adults, and the treatment of hildren tends to follow a similar strategy. 9 However, in all patients, partiularly hildren, areful onsideration must be given to the patient and their arers, sine the overall benefit of intravenous treatment will depend on their ability to aept and manage drug administration through a entral line. Oral therapies are preferable. Until randomised ontrolled studies have been onduted, the role of sildenafil in PAH is undefined. It is important that both Drug Liene Doses used in paediatri studies Epoprostenol Iloprost Treprostinil Treatment of patients with PPH in NYHA lass III or IV who have not responded to onventional treatment. Administered by ontinuous iv infusion. Limited published information on use in hildren Treatment of adults with PPH in funtional lass III by inhalation. Currently no published experiene in hildren and adolesents is available. Treatment of PAH in patients with lass II IV symptoms by ontinuous subutaneous infusion. Safety and effiay in paediatri patients has not been established* Beraprost sodium Orphan drug. Limited studies in hildren. Use is experimental NA Bosentan Treatment of PPH and PAH seondary to sleroderma in patients with grade III funtional status. Safety and effiay in patients,12 years old has not been substantially doumented Sildenafil Not liensed for PPH or PAH. Use is experimental NA 2 ng/kg/min initially. Continuous infusion via entral line. Doses inrease depending on linial ourse and tolerane. At 1 year, doses may be up to ng/kg/min for some hildren. 6 Higher doses have been used beyond 1 year 8 NA NA kg: mg daily for 4 weeks then inrease to 32.5 mg twie a day kg: mg twie a day for 4 weeks then inrease to 62.5 mg twie a day.40 kg: 62.5 mg twie a day for 4 weeks then inrease to 125 mg twie a day *Liene in the USA and Europe. Not yet liensed in the UK. NA, not available; NYHA, New York Heart Assoiation; PAH, pulmonary artery hypertension; PPH, primary pulmonary hypertension. ep19 Arh Dis Child Edu Prat Ed: first published as /ad on 20 May Downloaded from on 1 September 2018 by guest. Proteted by opyright.

6 FORD ep20 adults and hildren are referred to a entre with expertise in the management of PAH, and knowledge of the omplex drug delivery systems. ACKNOWLEDGEMENTS Thanks to Mansur Ahmed for assisting with the ost details. REFERENCES 1 D Alonso GE, Barst RJ, Ayres SM, et al. Primary pulmonary hypertension: a national prospetive study. Ann Intern Med 1991;115: Gaine SP, Rubin LJ. Primary pulmonary hypertension. Lanet 1998;352: Galie N, Rubin LJ. Introdution: new insights into a hallenging disease. A review of the Third World Symposium on Pulmonary Artery Hypertension. J Am Coll Cardiol 2004;43(12 suppl):1s. 4 Rubin LJ. Introdution: diagnosis and management of pulmonary arterial hypertension: ACCP evidene-based linial pratie guidelines. Chest 2004;126:7S 10S. 5 Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary artery hypertension. N Engl J Med 2004;351: Rosenzweig EB, Widlitz A, Barst RJ. Pulmonary arterial hypertension in hildren. 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