Idiopathic Pulmonary Fibrosis (IPF) now has two licensed treatments available. Pirfenidone was the first drug to be licensed and approved for use, followed by nintedanib. We set out our real world experience with these agents in terms of their adverse events profile outside the restrictions of a clinical trial. We have demonstrated in the real world setting, that side effects are common and predominantly gastrointestinal with both therapies. Our study shows that the side effects can be effectively managed in the majority of patients with an acceptable discontinuation rate similar to that seen in the clinical trials. These findings are compelling despite the fact that the patients in our study are older, have severer disease as depicted by baseline lung function and more co-morbidities. Our data provides ongoing evidence of the safety and tolerability of both pirfenidone and nintedanib in patients who would not have met the rigorous criteria to be included in a clinical trial. Both these agents are effective in the management of IPF and slow the progression of this debilitating life limiting condition.

Abstract. Generation of reactive oxygen metabolites, thromboxane increases, and vasoconstriction have been implicated in the pathogenesis of acute edematous lung injury, such as that seen in patients with the Adult Respiratory Distress Syndrome (ARDS), but their interactions are unknown. We hypothesized that reactive 02 products would stimulate arachidonic acid metabolism in lungs and that vasoactive products of arachidonate, such as the potent vasoconstrictor thromboxane A2, might then mediate 02-metabolite-induced pulmonary vasoconstriction. We found that 02 metabolites generated by injection of purine plus xanthine oxidase caused increases in mean pulmonary artery perfusion pressures (27±4 mmHg) in isolated perfused lungs. In addition, purine plus xanthine oxidase also caused 30-fold increases in perfusate levels ofthromboxane B2 (the stable metabolite ofthromboxane A2) compared with only twofold increases in 6-keto-PGFia (the stable metabolite of prostacyclin). Moreover, prior addition of catalase inhibited both vasoconstriction and the thromboxane B2 production seen in isolated lungs following injection of purine plus xanthine oxidase. Similarly, pretreatment with cyclooxygenase inhibitors, either aspirin or indomethacin, also completely blocked thromboxane generation and markedly attenuated pressor responses usually seen after purine plus xanthine oxidase (increase in mean pulmonary artery perfusion pressures, 4.4±1.5 mmHg). Furthermore, imDr. Tate is a recipient of a Clinician-Scientist Award from the American Heart Association. Address correspondence and reprint requests to Dr.Tate, Pulmonary Division, Department of Medicine, Box 4000, Denver General Hospital, Denver, CO 80204.Received for publication 6 July 1983 and in revised form 26 April 1984. idazole, a thromboxane synthetase inhibitor, also decreased 02-metabolite-induced thromboxane generation and vasoconstriction. These results suggested that thromboxane generation might participate in 02-metaboliteinduced vasoconstriction. However, since a significant correlation between thromboxane levels and the degree ofvasoconstriction could not be demonstrated, and since addition of superoxide dismutase reduced thromboxane generation but did not affect the intensity of vasoconstriction, it is possible that thromboxane is not the only vasoactive mediator in this model. We conclude that exposing lungs to 02 metabolites results in thromboxane generation and that thromboxane is a major mediator of oxidant-induced vasoconstriction.

A B S T R A C T Macrophages, neutrophils, and platelets may play a role in acute edematous lung injury, such as that seen in the adult respiratory distress syndrome (ARDS), but their potential actions and interactions are unclear. Because stimulated human macrophages and neutrophils can release acetyl glyceryl ether phosphorylcholine (AGEPC), a potent platelet activator, we hypothesized that in ARDS, leukocyte release of AGEPC might stimulate platelets to release thromboxane A2 (TXA2), which then produces pulmonary hypertension and lung edema. In support of this premise, we found that pulmonary hypertension and edema occurred in isolated rabbit lungs perfused with human platelets and AGEPC, but not with platelets or AGEPC alone. Infusion of a vasodilator (nitroglycerin) to maintain base-line pulmonary artery pressures in lungs perfused with platelets and AGEPC prevented the development of lung edema suggesting that platelet and AGEPC-induced edema was hydrostatic in nature. Additional experiments suggested that the increased pressure was a result of TXA2 release from platelets stimulated by AGEPC. Specifically, preincubation of platelets with imidazole, a thromboxane synthetase Preliminary reports of this work

ExtractThe effects of corticosteroid treatment on growth and skeletal maturation were evaluated in 189 children with severe asthma who were referred for care a t a residential treatment center. Height age on admission was significantly retarded in 8-10% of patients who had received little corticosteroid treatment previously and in 35% of patients who had taken steroids daily for more than 2 years. Children who had been treated with steroids intermittently or on alternate days were comparable to those who had taken steroids rarely. During an average residential period of 17 months, patients whose daily steroid treatment was discontinued had a relative gain in height age of 5 months; children who were started on daily steroids had a 5-month delay in growth. Evaluation of skeletal maturation a t the time of admission revealed that skeletal age was more retarded than height age in the boys and less retarded than height age in the girls. During the period of residence, the changes in bone age paralleled the changes in height age.

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