Inhibition of acetylcholine-induced bronchoconstriction in asthmatics by nifedipine

The calcium-dependent constriction of bronchial smooth muscle cells and release of mediators derived from mast cells is important in the pathophysiology of asthma. We hypothesized that nifedipine, a slow calcium channel blocker, would inhibit or attenuate acetylcholine-induced bronchoconstriction in asthmatics. Because one consequence of mast cell activation is the release of platelet-activating factor, we wondered whether thromboxane levels would be increased during acute bronchial constriction in asthmatics. Bronchoconstriction was induced in 8 asthmatics (6 men, 2 women) by acetylcholine; each subject was pretreated either with placebo or nifedipine (20 mg sublingually) on 2 separate days. Vital capacity, forced expiratory volume in 1 s, peak expiratory flow rates and oscillatory resistance were measured prior to and after the intake of placebo or nifedipine as well as after an acetylcholine challenge. Pretreatment with nifedipine significantly attenuated acetylcholine-induced changes in all four lung function parameters studied, but did not significantly influence the increase in thromboxane B2 plasma concentrations observed after the acetylcholine challenge. From these data we conclude that nifedipine inhibits the acetylcholine-induced bronchoconstriction in asthmatics. This effect may be either a direct action on bronchial smooth muscle or may be due to the inhibition of mediators other than thromboxane.     

Longitudinal analysis of perfusion lung scintigrams of patients with unoperated chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is the result of single or recurrent pulmonary thromboemboli that are thought to develop into organized pulmonary arterial obstructions by recurrent embolism and in situ thrombosis. Radioisotopic ventilation-perfusion scanning (V/Q scan) is a safe and highly sensitive test for pulmonary thromboembolic disease. The aim was to assess the natural history of thrombus expansion. We performed a prospective quantitative evaluation of ventilation/perfusion scintigrams (V/Q scans) in 20 patients with severe unoperated CTEPH.The baseline V/Q scan of each patient served as a reference for the second scan 21.7 +/- 8.2 months later. Planar images with intravenous 99mTc-labeled human albumin macroaggregates were reconstructed in six standard projections. Perfusion scans were analyzed by a semi-quantitative evaluation. In parallel, hemodynamics and clinical condition were prospectively observed. Lung perfusion scintigrams analyzed by a semi-quantitative method in patients with severe unoperated CTEPH show an apparent decrease of segmental flow abnormalities over time, paralleling right ventricular decline.     

Signal recognition particle (SRP) positive myositis in a patient with cryptogenic organizing pneumonia (COP)

We report of a 46-year-old female patient with cryptogen organizing pneumonia preceeding the rare SRP positive necrotising myositis without cardiac involvement and no sign of dysphagia. Myositis showed full regression without oral immune suppression but with extracorporeal treatment, performed as a combined therapy of plasmaexchange and immunoadsorption. After 33-month of treatment, anti-SRP antibodies were not detectable any more.     

Long-term treatment of pulmonary hypertension with aerosolized iloprost.

Pulmonary arterial hypertension (PAH), defined as elevated pulmonary arterial pressure and pulmonary vascular resistance, is an end-point of a variety of conditions. The only therapy that has been shown to improve both quality of life and survival is intravenous prostacyclin (prostaglandin I2 (PGI2), epoprostenol). The effect of long-term aerosolized iloprost (Ilomedin, Schering, Berlin, Germany and Vienna, Austria), a stable prostacyclin analogue and potent vasodilator, on haemodynamics and functional status was investigated in 12 patients with severe pulmonary hypertension. Haemodynamic measurements and vasodilator testing by right heart catheterization were performed prior to and after long-term iloprost inhalation therapy. Haemodynamic improvement or increased exercise tolerance was not observed in any of the patients. After a mean+/-SD treatment period of 10+/-5 months, mean+/-SD pulmonary vascular resistance had increased from 11+/-3 Wood Units (mmHg.L(-1).min) to 13+/-4 Wood Units, with unchanged arterial oxygen saturation (92+/-4%, versus 91+/-4%). Within the study period, three patients went into right heart failure and had to be placed on intravenous epoprostenol. The authors conclude that inhaled iloprost in addition to conventional therapy in the presently recommended dose of 100 microg.day(-1) delivered in 8-10 2 h portions, is not an efficient vasodilator therapy in severe pulmonary hypertension. It remains to be shown whether dose increases and/or combination protocols will be effective, or whether inhalation of iloprost may be safe for selected cases of pulmonary hypertension.     

The ADMIT series - issues in inhalation therapy. 1) The goals of asthma treatment: can they be achieved?

The widespread use of inhaled corticosteroids (ICS) since the early 1970's has meant that asthma is generally better controlled in comparison with previous decades. Nevertheless, recent patient interview surveys indicate that there is still a lot to gain in terms of abolishing daytime and nocturnal symptoms, and asthma exacerbations. It is important to use the terms asthma 'control' and asthma 'severity' in a correct way. Whereas asthma control reflects fluctuation in symptoms and lung function (or lack of them) over time, asthma severity reflects both asthma control and the need for medication. Thus, 'severity' is a property of the disease which reflects the degree of pathophysiological abnormality, whereas 'control' refers to the reduction of the clinical manifestations of disease achieved by treatment - thereby reflecting the adequacy of treatment. This introductory review, the first of a series of review papers to be published in this journal by the ADMIT team (see Appendix), discusses briefly our present knowledge of asthma control, its components, factors that may limit patients' ability to achieve optimal asthma control, and instruments to measure asthma control.     

Pulmonary hypertension in rheumatic diseases

Pulmonary hypertension (PH) is a progressive disease of the pulmonary vasculature characterized by increased vascular resistance and pressure overload of the right ventricle. Histologically, PH lungs demonstrate medial hypertrophy of small pulmonary arteries and proliferation of endothelial cells resulting in plexiform lesions. Recent studies have identified mutations of the bone morphogenetic protein receptor 2 (BMPR2) gene and the activin-receptor-like kinase 1 (ALK1) gene, that affect the transforming growth factor beta (TGF-beta) receptor superfamily, a group of transmembrane signaling molecules with serine-threonine kinase activity that are involved in the regulation of cell growth. Several lines of evidence indicate that the development of PH is a multi-hit process, where one of the events is having a gene mutation and another might be a circumstantial condition or other disease-modifying genes. It is unknown which mechanism that is critical in rheumatic diseases causes pulmonary vascular disease. PH is most frequently associated with systemic sclerosis (SS), systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD), however, it is still a rare manifestation of these disorders. For example, approximately 10% of SS cases manifest pulmonary vascular disease. In recent years symptomatic vasodilator therapies have been employed and have been able to improve exercise capacity and survival in these patients.     

Effects of the thromboxane synthetase inhibitor and receptor antagonist terbogrel in patients with primary pulmonary hypertension

Background Circulating mediators, including thromboxane A2, the vasoconstrictor, platelet aggregant, and smooth muscle mitogen, may contribute to the progression of vascular narrowing in primary pulmonary hypertension (PPH). Methods To further understand the contribution of thromboxane and to provide novel therapy for PPH, we administered the potent orally active thromboxane synthetase inhibitor and thromboxane receptor antagonist terbogrel for 12 weeks to patients with New York Heart Association functional classification II and III PPH. The study had a multicenter randomized placebo-controlled design. The primary endpoint was a change in the distance walked during 6 minutes. The pharmacologic effects of terbogrel on thromboxane and prostacyclin metabolism also were studied. Results Although the planned enrollment was 135 patients, the study was halted after only 71 patients had been randomized because of the unforeseen side effect of leg pain, which occurred almost exclusively in patients with terbogrel treatment. Only 52 patients completed the 12-week study, and only 22 patients (31%) were fully compliant with the study medication. The leg pain confounded the primary endpoint of walking distance. On an intention-to-treat analysis, no improvements in 6-minute walk distance or in hemodynamics in patients with terbogrel treatment were seen. However, terbogrel was effective from a pharmacologic standpoint, reducing thromboxane metabolites by as much as 98% (P < .0001), with a modest but statistically insignificant (39%) rise in prostacyclin metabolites. Conclusion Inhibition of thromboxane with an orally active agent is feasible in PPH, but the incidence of severe leg pain with terbogrel precludes its use in this disorder. Similar therapeutic efforts, with other thromboxane inhibitors, should be considered. (Am Heart J 2002;143:e4)     

Aerodynamic measurements in medialization thyroplasty

OBJECTIVE: External vocal fold medialization thyroplasty is a standard technique for improving voice, swallowing and breathing impairments due to insufficient glottal closure caused by either unilateral vocal fold paralysis or deficit of vocal fold tissue (i.e. as a result of cordectomy, scarring processes or sulcus glottidis). However, only scant information is available concerning the effect of the medialization thyroplasty on aerodynamic parameters. The aim of this study was to investigate the effect of vocal fold medialization thyroplasty on the degree of laryngeal stenosis using selected aerodynamic parameters. MATERIAL AND METHODS: Thirty patients (12 female, 18 male) underwent external vocal fold medialization with a titanium vocal fold medialization implant under local anesthesia supplemented by i.v. sedation. Pulmonary function tests were performed pre- and postoperatively and selected parameters were analyzed statistically. RESULTS: All patients reported improved self-control of breathing during speaking, laughing, coughing and physical activity. The postoperative values of the parameters tested showed no significant alteration in comparison to the preoperative data. CONCLUSIONS: The analysis of the aerodynamic findings indicated that the medialization procedure using an implant did not cause an increase in the laryngeal resistance.