Tim Higenbottam

Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group.

BACKGROUNDnRecently, a cluster of patients was observed in France in whom primary pulmonary hypertension developed in patients exposed to derivatives of fenfluramine in appetite suppressants (anorexic agents), which are used for weight control. We investigated the potential role of anorexic agents and other suspected risk factors for primary pulmonary hypertension.nnnMETHODSnIn a case-control study, we assessed 95 patients with primary pulmonary hypertension from 35 centers in France, Belgium, the United Kingdom, and the Netherlands and 355 controls recruited from general practices and matched to the patients sex and age.nnnRESULTSnThe use of anorexic drugs (mainly derivatives of fenfluramine) was associated with an increased risk of primary pulmonary hypertension (odds ratio with any anorexic-drug use, 6.3; 95 percent confidence interval, 3.0 to 13.2). For the use of anorexic agents in the preceding year, the odds ratio was 10.1 (95 percent confidence interval, 3.4 to 29.9). When anorexic drugs were used to a total of more than three months, the odds ratio was 23.1 (95 percent confidence interval, 6.9 to 77.7). We also confirmed an association with several previously identified risk factors: a family history of pulmonary hypertension, infection with the human immunodeficiency virus, cirrhosis, and use of cocaine or intravenous drugs.nnnCONCLUSIONSnThe use of anorexic drugs was associated with the development of primary pulmonary hypertension. Active surveillance for this disease should be considered, particularly since their use is expected to increase in the near future.

Caution with use of inhaled nitric oxide

nitrate, the remainder being excreted as urea from an unknown metabolic pathway. Nitrite is also formed when NO dissolves in aqueous solutions and is present in the plasma in concentrations ranging from 1·3 to 13 mol/L. Nitrite, unlike NO, can nitrosate sulphydryl groups, on, for example, ion channels or circulating oxyhaemoglobin. Also unlike NO, nitrite anions, by acting systemically, could contribute to neural toxicity and potential carcinogenicity of inhaled-NO. The absence of regulatory approval for inhaled-NO is unsatisfactory. Although there are guidelines for its use for research purposes, there are still no specific recommendations for gas cylinder connectors or a pin index system as for other medical gases to prevent wrong use of a cylinder. The possibility of accidental overdosing remains because there is no accepted colour coding for NO cylinders and administration systems remain complex. There is a need to learn more about the metabolism of inhaled-NO, particularly by the use of accurate measurement of nitrite and its metabolites. The lowest clinical effective dose of inhaled-NO needs to be defined for each indication. There remains uncertainty about the effects of inhaled-NO on gas exchange because, unlike what happens in ARDS, when given to chronic obstructive lung disease patients, it causes a fall in arterial oxygen tension. An explanation also is needed for the rebound pulmonary hypertension that develops when reducing the dose of inhaled-NO. There is an urgent need for a safe administration system not simply for the ventilated patient but also for the ambulatory. The routine use of inhaled-NO should not be recommended until these requirements are met.

Minimizing the Inhaled Dose of NO With Breath-by-Breath Delivery of Spikes of Concentrated Gas

BACKGROUNDnPulmonary vasodilatation with a 100 ppm concentration of NO given as a short burst of a few milliliters at the beginning of each breath (NOmin) was compared with conventionally inhaled NO, in which a full breath of 40 ppm of NO was inhaled (NOCD).nnnMETHODS AND RESULTSnNOmin was studied in 16 patients with severe pulmonary hypertension and in 16 isolated porcine lungs with experimentally induced pulmonary hypertension. We compared volumes of 8 to 38 mL of 100 ppm NO in N2 injected at the beginning of each breath with conventional inhalation of 40 ppm NO in air. NOCD and NOmin were studied in 4 pigs after inhibition of NO synthase with NG-nitro-L-arginine methyl ester (1 to 2 mg/kg IV) had raised the pulmonary vascular resistance index (PVRI) from 4.4+/-0.8 to 10. 0+/-1.6 mm Hg. L-1. min-1. kg-1. A similar comparison was made in 7 isolated porcine lungs after the thromboxane analogue U46619 (10 pmol. L-1. min-1) increased the mean PVRI from 4.6+/-0.8 to 12.2+/-1. 3 mm Hg. L-1. min-1. kg-1. Patients mean PVRI was reduced from 29. 2+/-3.7 to 24.0+/-3.1 with NOmin and 24.5+/-3.3 mm Hg. L-1. min-1. m-2 (mean+/-SEM) with NOCD. In isolated porcine lungs, there was the same reduction of PVRI for NOmin and NOCD between 12.7% and 34.8%.nnnCONCLUSIONSnA small volume of NO inhaled at the beginning of the breath was equally effective as NOCD but reduced the dose of NO per breath by 40-fold, which ranged from 1.2x10(-8) (0.4 microg) to 1. 6x10(-7) mol/L (4.8 microg) compared with 5.3x10(-7) (16 microg) to 1.2x10(-6) mol/L (36 microg) per breath with NOCD.

Effect of nitric oxide inhibition on nasal airway resistance after nasal allergen challenge in allergic rhinitis

Background Nitric oxide has been detected by chemiluminescence in the lumen of nasal airway, which is increased in nasal breathing in patients with seasonal rhinitis during a chronic exposure. The purpose of this study was to determinate the effect of a NO‐synthase inhibitor NGL‐arginine methyl ester (L‐NAME) on nasal airway resistance (NAR) in patients with seasonal allergic rhinitis after an acute challenge to the allergen.

Induction of nitric oxide synthase II does not account for excess vascular nitric oxide production in experimental cirrhosis

BACKGROUND/AIMSnExcess production of nitric oxide (NO) reduces vasoconstriction of cirrhotic rat aorta. Expression of the inducible nitric oxide synthase (NOS II) in endothelial cells or vascular smooth muscle could account for this, as described with endotoxin or lipopolysaccharide (LPS) treatment. Alternatively, the endothelial NOS enzyme (NOS III) could be activated by an as-yet undescribed mechanism. Here we describe a combined study of the basal release of NO and quantitative measurement of the mRNA for NOS II and NOS III from thoracic aorta of an animal model of cirrhosis.nnnMETHODSnThoracic aortas of six normal, six cirrhotic (secondary biliary cirrhosis) and six intra-peritoneal LPS-treated (15 mg/kg) rats were removed. Dissected aortic rings were precontracted with norepinephrine (NE; 10(-6) M) and relaxed with acetylcholine (Ach; 10(-6) M) with or without pre-incubation with the specific NOS inhibitor (L-NNA, 10(-5) M). Total RNA was extracted from aorta, reverse transcribed (RT) and used in polymerase chain reaction (PCR) amplification with primers specific for NOS II, NOS III and beta-actin. PCR products were hybridized with fluorescein labelled cDNA probes and the relative intensity on film was analyzed by densitometry.nnnRESULTSnCompared to normal, NE caused 32% less contraction in cirrhotic and 43% less contraction in LPS-treated aortic rings. This response was corrected to normal by L-NNA pre-incubation. All the contracted rings relaxed with Ach. NOS II mRNA, was expressed only in LPS-treated aorta and not in aorta from normal and cirrhotic rats. NOS III mRNA levels were the same in normal, cirrhotic and LPS-treated rats: 1176 +/- 170, 1233 +/- 626 and 979 +/- 423, in arbitrary densitometry units, respectively.nnnCONCLUSIONSnNO is overproduced by aorta from cirrhotic and LPS-treated rats. In LPS-treated rats this could result from expression of NOS II, but this was not the case in the cirrhotic rat aorta. Comparable amounts of NOS III mRNA suggest that, in cirrhosis, increased activity of this enzyme and not increased NOS III expression is responsible for the overproduction of NO.

Guidelines on Diagnosis and Treatment of Pulmonary Arterial Hypertension

ESC Committee for Practice Guidelines (CPG): Silvia G. Priori (Chairperson) (Italy), Maria Angeles Alonso Garcia (Spain), Jean-Jacques Blanc (France), Andrzej Budaj (Poland), Martin Cowie (UK), Veronica Dean (France), Jaap Deckers (The Netherlands), Enrique Fernandez Burgos (Spain), John Lekakis (Greece), Bertil Lindahl (Sweden), Gianfranco Mazzotta (Italy), Keith McGregor (France), Joao Morais (Portugal), Ali Oto (Turkey), Otto A. Smiseth (Norway)

Effects of an NO-Synthase Inhibitor L-NMMA in the Hepatopulmonary Syndrome

Increased nitric oxide (NO) levels in expired air have been reported in patients with hepatopulmonary syndrome (HPS) [1] and have been suggested to be an important mediator of hyperdynamic circulation and impaired oxygenation, which is typical in HPS patients [2]. In one patient with HPS, we have studied the effects of the intravenous administration of NG-monomethyl-L-arginine (L-NMMA), a specific NO-synthase inhibitor. A 31-year-old male nonsmoker had cryptogenic cirrhosis confirmed by liver biopsy. He was in stable clinical condition without ascites, but he had profound arterial hypoxemia, with orthodeoxia (supine PaO2 = 7.3 kPa and upright PaO2 = 4.3 kPa). The chest radiograph was normal as was the FEV1 of 3.9 litres, but he had a reduced diffusion coefficient for carbon monoxide of 30% of predicted. The lung perfusion scan revealed a shunt fraction of 13.7%. There was no evidence of an intracardiac shunt by echocardiogram. The right heart catheter study showed a mean pulmonary artery pressure of 12 mm Hg, cardiac output of 8.2 litres/min and a pulmonary vascular resistance of 0.73 IU. The patient was studied in both supine and upright positions prior to and following an intravenous infusion of L-NMMA (8 mg/kg in normal saline) over a 5-min period. Control infusion of normal saline was also performed. Cardiac output, mean arterial pressure (MAP), heart rate and transcutaneous oxygen tension were measured. NO production was recorded as mixed exhaled breath NO concentration (NO ppb) by chemiluminescence and the rate of NO production was calculated. NO measurements were made while the patient was supine and after 10 min of an upright posture at the end of the infusion of both saline solution and L-NMMA (table 1). The patient had high concentrations of exhaled NO, which increased threefold from the supine to the upright posture. L-NMMA infusion decreased the levels of NO in both postures with a persistence of greater NO levels in upright in comparison to supine. An increase in MAP and a decrease in cardiac output was shown after L-NMMA, which lasted over 1 h. Neither the impaired oxygenation nor the orthodeoxia were modified by L-NMMA administration. (All the results are reported in the table.) In conclusion, our findings indicate an increased pulmonary release of NO, which increased further in the upright posture, in this severely hypoxemic cirrhotic patient. The administration of NO-synthase inhibitors was able to restore near-normal NO expired levels and the NO decrease was associated with changes in systemic haemodynamics, without significant improvement in oxygenation and orthodeoxia. The relevance of changes in NO production to systemic and pulmonary abnormalities in HPS patients warrant further studies.

Developments in Inhaled Immunosuppressive Therapy for the Prevention of Pulmonary Graft Rejection

SummaryCyclosporin is the main immunosuppressive treatment for lung and heart-lung transplantation. When combined with azathioprine and oral corticosteroids, repeated episodes of acute rejection are limited to a minority of transplant patients. Despite early successful transplantation, many patients developed a disabling and fatal condition called obliterative bronchiolitis. This is currently thought to be a result of chronic rejection. The principal risk factor for the development of obliterative bronchiolitis is undercontrolled acute rejection in the first 3 months after transplantation. Frequent early acute rejection increases the later risk of death and disability.A new approach to immunosuppressive therapy is needed to prevent this complication. Simply increasing the dosage of cyclosporin or oral corticosteroids results in the major complications of opportunistic infection and renal failure. Targeted immunosuppressive treatment delivered to the transplanted organ may offer certain advantages, since a high topical inhaled dosage should be relatively free from systemic complications. The lung as a transplanted organ is easily accessible to targeted therapy by means of inhalation. Inhaled nebulised corticosteroids have been shown to be effective in preventing obliterative bronchiolitis in patients at risk after heart-lung transplantation. Similarly, inhaled cyclosporin has also been reported to be more effective than oral administration, with substantially lower blood concentrations.Such new approaches to targeting immunosuppressive treatment could have specific advantages in long term therapy of lung and heart-lung transplant recipients. They might also be of use in other types of solid organ transplantation.