Editorials Effective police interventions include patrols targeted at known hotspots of violence and arrest of serious repeat offenders, drunk drivers, and employed suspects of domestic violence. In terms of rehabilitation programmes, intensive targeting of specific offender problems, prison based community treatment of offender drug misuse, cognitive behavioural therapy, and sex offender treatment outside prisons have all been found to be effective. 11 13 Nowhere are the impacts of antisocial lifestyle on health more apparent than in prisons. Although a captive population provides unique opportunities for treatment, problems related to prisoner health are often established and intransigent. The recent transfer of responsibility for prison health services in England 1 2
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Shepherd JP, Farrington DP, Potts AJC. Relations between offending, injury and illness. J R Soc Med 2002;95:539-44. Farrington DP. Key results from the first forty years of the Cambridge study in delinquent development. In: Thornberry TP and Krohn MD, eds. Taking stock of delinquency. New York: Kluwer/Plenum, 2002. Laub JH, Sampson RJ. Understanding desistance from crime. In: Tonry M. Crime and Justice. Vol 28. Chicago: University of Chicago, 2001. Farrington DP. Individual differences and offending. In: Tonry M, ed. Handbook of crime and punishment. Oxford: Oxford University Press, 1998. Sutherland I, Shepherd JP. Social dimensions of adolescent substance use. Addiction 2001;96:445-8. Vaillant GE. A twenty year follow-up of New York narcotic addicts. Arch Gen Psychiatr 1987;29:237-41. Caspi A, Begg D, Dickson N, et al. Identification of personality types at risk for poor health and injury in late adolescence. Crim Behav Ment Health 1995;5:330-5.
and Wales from the Home Office to the Department of Health, however, is logical, and a prompt both to acknowledge relationships between crime, injury, and illness and to develop integrated prevention and treatment. While links between deprivation and health have been widely studied, links between antisocial lifestyle and health have been neglected. Jonathan Shepherd professor of oral and maxillofacial surgery University of Wales College of Medicine, Cardiff CF14 4XY (
[email protected])
David Farrington professor of psychological criminology University of Cambridge, Cambridge CB3 9DT
Competing interests: None declared. 8 9 10
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Shepherd JP, Farrington DP, Potts AJC. The relation between injury, offending and illness. J Dent Res 2001;80:649. Junger M, Terlouw GJ, Van der Heijden PGM. Crime, accidents and social control. Crim Behav Ment Health 1995;5:386-410. Shepherd JP, Peak JD, Haria S, Sleeman D. Characteristic illness behaviour in assault patients: DATES syndrome. J R Soc Med 1995;88:85-7. Welsh BC, Farrington DP. What works, what doesn’t, what’s promising, and future directions. In: Sherman LW, Farrington DP, Welsh BC, Mckenzie DL. eds. Evidence-based crime prevention. London: Routledge, 2002. Scheweinhart L, Barnes H, Weikart D, Garnett WS, Epstein AS. Significant benefits: the High/Scope Perry Preschool Study through age 27. Monographs of the High/Scope Educational Research Foundation. Number 10. Ypsilanti: The High/Scope Press, 1993. Shepherd JP. Criminal deterrence as a public health strategy. Lancet 2001;358:1717-22.
Treatment of pulmonary hypertension Several options exist, but they are expensive and necessitate specialist care
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or understandable reasons, the pulmonary circulation remains an enigma to most doctors. This is because the cardinal symptom, dyspnoea, is shared with many more common diseases, and the signs of pulmonary hypertension are difficult to elicit for the non-specialist. Consequently, the delay between onset of symptoms and diagnosis is two years, and the mean survival from the time of diagnosis is only another two years in untreated patients with severe hypertension of the pulmonary artery. In the past, pulmonary hypertension was not treatable, but now several treatments are available. Severe pulmonary hypertension, with a total prevalence of about 30-50/million, can be primary or associated with apparently disparate conditions including connective tissue disease, congenital heart disease, chronic pulmonary thromboembolism, HIV infection, use of an appetite suppressant, and liver disease. Surprisingly, nearly all these conditions have a similar histological picture of vascular remodelling. The pathobiology of pulmonary artery hypertension is now better understood. A gene for familial pulmonary arterial hypertension, which codes for BMPR2 a receptor in the transforming growth factor (TGF-) family, has been discovered.1 2 This gene is also found in up to 26% of patients with so called sporadic pulmonary hypertension. The genetic abnormality perhaps must be accompanied by some additional environmental factor to cause pulmonary artery hypertension (“the double hit hypothesis”), and the remodelling occurs because that factor (or factors) acts in concert with dis19 APRIL 2003
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turbed BMPR signalling to cause an increase in production of cytokines and other factors. In the past pulmonary artery hypertension was considered untreatable unless the underlying cause could be treated (for example, HIV infection), and patients could be offered only oxygen and transplantation. It was later realised that oral anticoagulants alone improved survival, which implies a thrombotic component to the cause or progression of the disease. Furthermore, in patients with an acute response to vasodilators, a high dose of calcium channel blockers resulted in a five year survival of more than 90%.3 Unfortunately only 10-15% of patients fall into this “responder” category, and therefore a need for other forms of treatment existed. The breakthrough came in the early 1980s when it was shown that patients could be maintained on continuous intravenous epoprostenol, which improves both exercise capacity and haemodynamics.4 Subsequently it was also shown that long term treatment with intravenous epoprostenol improved survival.5 Unfortunately, because of its short half life, epoprostenol must be given continuously intravenously, with the attendant risks of air embolism and sepsis. This difficulty and the need for treatments working through alternative mechanisms prompted several trials. No placebo controlled trials were conducted before 1999, but since 2000 over 1000 patients worldwide have been enrolled in trials, all of which have examined similar end points and studied similar patients. Most of the trials studied patients in WHO functional classes 2-4 and lasted 835
Editorials between 12 and 16 weeks. Their primary end point was a measurement of exercise capacity as defined by the six minute walk test (which measures how far someone can walk in six minutes), and the main secondary end points were improvements in pulmonary haemodynamics and breathlessness. Three epoprostenol analogues were studied— treprostinol, beraprost, and iloprost. Treprostinol is a stable analogue of epoprostenol, which is given continuously subcutaneously. Escalation of dosage was limited by the protocol to avoid pain at the site of infusion. Thus many patients did not receive therapeutic doses, but a significant improvement was found in the six minute walk test, which was greater in those taking the higher doses.6 Beraprost is active orally and was given to generally less sick patients (WHO classes 2-3). An improvement in the six minute walk test occurred in all patients, but, patients with primary pulmonary hypertension improved more.7 Iloprost can be given intravenously or by nebuliser, but in this trial it was given by inhalation. The rationale for this method of delivery is that less of the substance reaches the systemic circulation (a “pseudoselective” pulmonary vasodilator). The six minute walk test improved in all categories, but once again improvement was greater in those with primary pulmonary hypertension. An improvement in haemodynamics also occurred.8 Iloprost must be given six to nine times a day, which may disrupt the patient’s lifestyle, but this may be helped by the new portable nebulisers. The other main approach to pulmonary hypertension has been the blockade of endothelin receptors, the rationale being that plasma endothelin is raised in patients with various types of pulmonary hypertension. Two placebo controlled trials of bosentan (an endothelin receptor A and B antagonist) have been conducted.9 10 The six minute walk test improved in the whole group, but the improvement was greater when the drug was used in higher doses. However, problems with liver function occurred with the higher dose. There is an argument for using a pure endothelin A antagonist, and sitaxsentan has been used in an open pilot study. This showed an improvement in the six minute walk test and a decrease in pulmonary vascular resistance of 30%.11 Endothelial production of nitric oxide is diminished with pulmonary hypertension, prompting attempts to reverse this defect either by giving continuous inhaled nitric oxide, which is effective but difficult to administer, or by increasing the substrate for nitric oxide l-arginine.12 A trial of supplementation with l-arginine is currently under way. In addition to increasing the supply of nitric oxide, attempts to increase directly cyclic GMP in the smooth muscle cells have been made. Sildenafil used for erectile dysfunction blocks the enzyme phosphodiesterase type 5 present in the corpus cavernosum of the penis and also the lungs. This raises the possibility that a phosphodiesterase type 5 inhibitor such as sildenafil could be a relatively selective pulmonary vasodilator. There is some evidence for this belief.13 14 A large placebo controlled trial of sildenafil is now in progress. Several treatments are now available for severe pulmonary arterial hypertension. Most of the experience concerns adults, but the same principles of management apply even to very young children. We have good 836
evidence that these drugs improve exercise tolerance and haemodynamics, but we must await evidence for an improvement in survival, which so far has been shown only with epoprostenol. These drugs are expensive, the patients sick, and the appropriate investigations difficult and potentially dangerous. For these reasons, the care in the United Kingdom and Ireland has been organised into designated pulmonary hypertension units with published standards of care. Currently only epoprostenol and bosentan are licensed treatments for pulmonary arterial hypertension, but we hope that other drugs will be licensed shortly. If these drugs show synergy, they may be used in combination in the future. Eventually with greater understanding of the genetics and pathobiology of pulmonary hypertension we may even have a series of drugs, which attack the problem at its molecular roots. Andrew J Peacock director Scottish Pulmonary Vascular Unit, Western Infirmary, Glasgow G11 6NT (
[email protected])
On behalf of the National Pulmonary Hypertension Services of UK and Ireland: Ireland, Dublin, Sean Gaine (Mater Misericordiae); London, Gerry Coghlan and Carol Black (Royal Free); London, Simon Gibbs (Hammersmith, Royal Brompton, and Harefield), and Michael Gatzoulis and Timothy Evans (Royal Brompton and Harefield); London (children) Glennis Haworth (Great Ormond Street); Sheffield, David Kiely (Royal Hallamshire); Newcastle, Paul Corris (Freeman Hospital); Cambridge, Joanna Pepke-Zaba and Nicholas Morell (Papworth); Scotland, Glasgow, Andrew Peacock (Western Infirmary). Competing interests: AJP has received support to attend conferences and occasional consultation fees from Glaxo (UK), Actelion (UK), and Schering (Germany). 1
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Newman JH, Wheeler L, Lane KB, Loyd E, Gaddipati R, Phillips JA, et al. Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred. N Engl J Med 2001;345:319-24. Machado RD, Paucilo MW, Thomson JR, Lane KB, Morgan NV, Wheeler L, et al. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am J Hum Genet 2001;68:92-102. Rich S, Kaufmann E, Levy PS. The effects of high doses of calcium channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992;327:76-81. Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesh DB, et al. A comparison of continuous intravenous epoprostenol (epoprostenol) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996;334:296-302. McLaughlin VV, Genthner DE, Panella MM, Rich S. Reduction in pulmonary vascular resistance with long term epoprostenol (epoprostenol) therapy in primary pulmonary hypertension. N Engl J Med 1998;338:273-7. Simmoneau G, Barst RJ, Galie N, Naeije R, Rich S, Bourge RC, et al. Continuous subcutaneous infusion of teprostinil, a epoprostenol analogue, in patients with pulmonary arterial hypertension: a double-blind randomized controlled trial. Am J Respir Crit Care Med 2002;165:800-4. Galie N, Humbert M, Vachiery JL, Vizza CD, Kneussi M, Manes A, et al. Effect of beraprost sodium, an oral epoprostenol analogue, in patients with pulmonary arterial hypertension: a randomised, double-blind, placebo-controlled trial. J Am Coll Cardiol 2002;39:1496-502. Olschewski H, Simonneau G, Galie N, Higenbottam T, Naeije R, Rubin L et al. Inhaled iloprost for severe pulmonary hypertension. New Engl J Med 2002;347:322-9. Channick RN, Simmoneau G, Sitbon O, Robbins I, Frost A, Tapson VF, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001;358:1119-23. Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, et al. Bosentan in patients with pulmonary artery hypertension: a randomised placebo controlled, multicenter study. N Engl J Med 2002;346:896-903. Barst RJ, Rich S, Horn EM, McLaughlin VV, Kerstein D, Widlitz, et al. Efficacy and safety of chronic treatment with the oral selective endothelin A receptor blocker sitaxsentan in pulmonary arterial hypertension. Circulation 2000;102:II-427. Nagaya N, Uematsu M, Oya H, Sato N, Sakamaki F, Kyotani S, et al Short term oral administration of L-arginine improves haemodynamics and exercise capacity in patients with precapillary pulmonary hypertension. Am J Respir Crit Care Med 2001;163:887-91. Michelakis E, Tymchak W, Lien D, Webster L, Hashimoto K, Archer S. Oral sildenafil is an effective and specific vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation 2002;105:2398-403. Ghofrani H, Wiedemann R, Rose F, Schermuly R, Olschewski H, Weissman H. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet 2002;360:895-900.
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