Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD.

The aim of this study was to test the hypothesis that use of tiotropium, a new long-acting anticholinergic bronchodilator, would be associated with sustained reduction in lung hyperinflation and, thereby, would improve exertional dyspnoea and exercise performance in patients with chronic obstructive pulmonary disease. A randomised, double-blind, placebo-controlled, parallel-group study was conducted in 187 patients (forced expiratory volume in one second 44 +/- 13% pred): 96 patients received 18 microg tiotropium and 91 patients received placebo once daily for 42 days. Spirometry, plethysmographic lung volumes, cycle exercise endurance and exertional dyspnoea intensity at 75% of each patient's maximal work capacity were compared. On day 42, the use of tiotropium was associated with the following effects at pre-dose and post-dose measurements as compared to placebo: vital capacity and inspiratory capacity (IC) increased, with inverse decreases in residual volume and functional residual capacity. Tiotropium increased post-dose exercise endurance time by 105 +/- 40 s (21%) as compared to placebo on day 42. At a standardised time near end-exercise (isotime), IC, tidal volume and minute ventilation all increased, whilst dyspnoea decreased by 0.9 +/- 0.3 Borg scale units. In conclusion, the use of tiotropium was associated with sustained reductions of lung hyperinflation at rest and during exercise. Resultant increases in inspiratory capacity permitted greater expansion of tidal volume and contributed to improvements in both exertional dyspnoea and exercise endurance.

Bronchodilation using combined urodilatin - albuterol administration in asthma: a randomized, double-blind, placebo-controlled trial.

Urodilatin, the renal form of natriuretic peptide type A, induces bronchodilation, increasing intracellular cyclic guanosine monophosphate (cGMP), whereas the bronchorelaxant effect by b2-agonists is triggered by cyclic adenosine monophosphate (cAMP). The objective of this investigation is to demonstrate the efficacy of urodilatin in inducing bronchodilation, and to show this activity alone or in combination with albuterol. Therefore, a randomized, double-blind, placebo-controlled, dose-finding study with cross-over design was carried out including 12 stable, mild to severe (step 2 to 4, definition by NIH/NHLBI guideline 1997) asthmatics. 96 treatments were thus performed. The intervention was comprised of an intravenous infusion of urodilatin (0, 10, 30, or 60 ng/kg/min) combined with inhaled albuterol (0 or 200 microg). As primary objective, the increase in forced expiratory volume in one second (FEV subset1) was measured. - The trial shows that urodilatin at all applied doses or 200 microg albuterol significantly increases FEV subset1 (p < 0.05). Combination of urodilatin and albuterol treament significantly improves FEV subset1 (p < 0.05) compared to either monotherapy and results in maximum bronchodilation. - From the results, the following conclusions can be drawn. In stable asthmatics, the combined activation of cGMP- and cAMP-mediated pathways results in a significantly improved, maximal bronchodilation in comparison to either type of monotherapy. This shows that urodilatin combined with albuterol improves lung function and ameliorates the therapy in asthmatics.

Therapeutic use of the natriuretic peptide ularitide in acute renal failure.

BACKGROUND: Ularitide is a member of the natriuretic peptide family. This hormone exhibits an N-terminal extension by four amino acids compared with atrial natriuretic peptide. Ularitide was shown to exert strong diuretic and natriuretic effects when infused intravenously. Its main action sites are the glomerulum, inducing preglomerular vasodilation and postglomerular vasoconstriction and thereby elevating the glomerular filtration rate, and the tubular system inhibiting Na(+)-reabsorption. In initial uncontrolled clinical trials, this peptide was shown to have beneficial effects in patients suffering from oliguric acute renal failure. METHODS: We conducted a double-blind, placebo-controlled, multicenter, dose-finding trial recruiting 176 patients randomized into 4 different Ularitide doses groups (U5, U20, U40, and U80 ng/kg/min) and a placebo group (U0). Ularitide/placebo infusion was performed for 5 days with half the originally infused dose on day 5. The primary objective of the study was to test various doses of Ularitide in patients suffering from oliguric acute renal failure to avoid mechanical renal replacement therapy during the first 12 hours. FINDINGS: The results indicate that Ularitide does not reduce the incidence of mechanical renal replacement therapy compared with placebo-treated patients during the first 12 h of treatment (U0: 36 (20), U5: 35 (11), U20: 36 (9), U40: 28 (8), U80: 41 (12), (% (n) (p = 0.87)). Diuresis increased in the Ularitide-treated groups and the placebo group after onset of infusion and did not show any significant difference in the first 12 h collection period (U0: 576, U5: 514, U20: 500, U40: 360, U80: 158 ML/12h (Median), (p = 0.16)). INTERPRETATION: In summary, the incidence of mechanical renal replacement therapy in critically ill patients suffering from oliguric acute renal failure could not be altered positively by Ularitide administration according to our protocol. Further prospective clinical trials are needed to answer the question whether a different patient collective or a prophylactic administration of Ularitide are more promising approaches in the clinical setting of oliguric acute renal failure.

Bronchodilating effects of natriuretic and vasorelaxant peptides compared to salbutamol in asthmatics.

In animal studies, the bronchial effects of urodilatin (URO, CDD/ANP-95-126, INN: ularitide) were superior to those of cardiodilatin/atrial natriuretic peptide (CDD, CDD/ANP-99-126). We compared the bronchodilating properties of intravenous URO and CDD in 36 clinically stable asthmatics showing a beta 2-agonist-induced increase of the FEV1 by > or = 15%. Any aerosol medication was discontinued for at least 8 h prior to the study. After baseline measurements of lung function parameters (FEV1, VC, PEF, MEF75, MEF50, MEF25) an intravenous infusion of 5.7, 11.4 or 17.1 pmol/kg/min URO or CDD was administered for 40 min in the morning. All measurements were repeated every 10 min during the infusion, for 30 min thereafter, and after the inhalation of 1.25 mg salbutamol (SALB). Both peptides had significant effects. While 11.4 pmol/kg/min URO dilated the central airways (FEV1, PEF, MEF75) slightly more potently than the peripheral bronchioles (MEF50, MEF25), 17.1 pmol/kg/min URO was as effective as SALB at all levels of the tracheobronchial tree. CDD reached only 50% of the SALB effect without a predominant localization of its action. The cardiovascular parameters revealed a significantly stronger vasorelaxant activity of CDD. In conclusion, the dose-dependent bronchodilating properties of intravenous URO were significantly superior to those of CDD.

Urodilatin (ularitide, INN): a potent bronchodilator in asthmatic subjects.

Atrial natriuretic peptide (CDD/ANP-99-126) has been identified as a bronchodilator in various species including humans. We investigated the effect of urodilatin (CDD/ANP-95-126) in 18 clinically stable asthmatics showing an increase of the FEV1 by > or = 15% after salbutamol inhalation. Prior to the study inhaled beta 2-agonists were withheld for 8 h. After baseline measurements of lung function parameters (FEV1, VC, PEF, MEF75, MEF50, MEF25), blood pressure, and heart rate in intravenous infusion of 20, 40 or 60 ng kg-1 min-1 urodilatin was administered for 40 min in the morning. All measurements were repeated every 10 min during the infusion, for 30 min thereafter, and after the inhalation of 1.25 mg salbutamol. Forty and 60 ng kg-1 min-1 urodilatin showed a significant effect on the central (FEV1, PEF, MEF75) and peripheral airways (MEF50, MEF25) after 10 min infusion (P < 0.05). A bronchodilation not significantly different from 1.25 mg salbutamol was induced by 40 ng kg-1 min-1 in the central airways only, while 60 ng kg-1 min-1 led to a similar effect at all levels of the bronchial tree. Lung function parameters returned to baseline within 30 min after cessation of the urodilatin infusion. Heart rate showed a tendency to increase after 40 min infusion (P < 0.05), but blood pressure did not change significantly. In conclusion, the maximal bronchodilating effect of intravenous urodilatin in clinically stable asthmatics was comparable to 1.25 mg salbutamol.

Beta-endorphin, but not substance-P, is increased by acute stress in humans.

The role of neuropeptides in the psychoneuroendocrinological stress response is largely unknown. In this study the effect of acute psychological stress on beta-endorphin and substance-P plasma concentrations was investigated and further the effect of different anxiety levels or control attributions on beta-endorphin or substance-P levels were determined. Blood samples were obtained from 47 inexperienced tandem-parachutists 2 h before, immediately after, and 1 h after a parachute jump and plasma concentrations of beta-endorphin and substance-P were analysed. Anxiety levels and control attributions were assessed by psychometric scales. Whereas substance-P concentrations seemed to be unaffected by the jump stress, there was a transient but significant increase in beta-endorphin levels immediately after jumping. However, subjects higher in state-anxiety at the point of jumping (exit) displayed higher substance-P values at all three time points compared to the "low-anxiety" jumpers. In addition, stress-induced beta-endorphin secretion was dependent on subjective control attributions.

Type A natriuretic peptides exhibit different bronchoprotective effects in rats.

The protective effect of 11.4, 22.8 or 45.6 pmol/kg/min cardiodilatin/atrial natriuretic peptide (CDD/ANP-(99-126)), urodilatin (CDD/ANP-(95-126)) or vehicle intravenously against acetylcholine-induced bronchoconstriction was compared in spontaneously breathing, halothane-anesthetized Wistar rats. The inhalation of acetylcholine induced significant alterations of the spontaneous breathing parameters evaluated by whole-body plethysmography without significant differences between the treatment groups. Forced parameters detect airflow changes with a greater sensitivity and were measured in hyperventilation-induced temporary apnoea after the challenge. The forced expiratory volume in 0.1 s revealed a significant protective effect of 11.4 pmol/kg/min urodilatin compared to the controls whereas the parameters of the forced expiratory flow-volume curve were significantly preserved by 11.4 and 22.8 pmol/kg/min urodilatin (P < 0.05). Urodilatin showed protective effects against an acetylcholine challenge whereas CDD/ANP-(99-126) was without significant influence.

Localization of the bronchodilator effect induced by type A natriuretic peptide in asthmatic subjects.

Type A natriuretic peptide (CDD/ANP-99-126) in its circulating form was analyzed with respect to the localization of its bronchodilating effects in asthmatic subjects in vivo. The intravenous infusion of 5.7, 11.4, and 17.1 pmol kg-1 min-1 CDD/ANP-99-126 caused a significant bronchodilation of both central and peripheral airways. While the localization of the bronchodilating effects was similar to beta 2-agonists, an improvement in lung function parameters comparable to these substances was not observed. But other members of the natriuretic peptide family may reveal a stronger bronchodilating potency.

[Long-term effects of breathing exercises and yoga in patients with bronchial asthma]. / Langzeiteffekte von Atemgymnastik und Yoga bei Patienten mit Asthma bronchiale.

To compare the effects of breathing exercises (BE) or Yoga (Y) on the course of bronchial asthma we studied 36 subjects with a mild disease. The patients were randomly divided into 3 groups. 2 of them participated in a 3 weeks training program of BE or Y while the third group rested without any additional treatment (control group, C). At the end of the training period the patients were asked to practise BE or Y on their own. Drug therapy and lung function parameters before and after a beta 2-agonist metered dose inhaler (albuterol, ALB) were recorded prior to the training program and in 4 weeks intervals for 4 months thereafter. The response to the beta 2-agonist was documented continuously in 28 patients. The mental state of the patients was elucidated by questionnaires.--Prior to the study a significant effect of inhaled ALB on the FEV1 was shown without any significant between group differences. Both, BE and Y, caused a significant amelioration of the mental state but only the BE induced a significant improvement of lung function parameters compared to the individual baseline values. The FEV1 increased significantly by 356.3 +/- 146.2 ml (p < 0.05) and the VC by 225.0 +/- 65.5 ml (p < 0.01). These long-term changes were not significantly different from the actual response to ALB. BE decreased the RV significantly by 306.3 +/- 111.6 ml (p < 0.05), an effect significantly higher compared to the beta 2-agonist (p < 0.01). BE in combination with ALB caused an additive effect.(ABSTRACT TRUNCATED AT 250 WORDS)

[The significance of endocrine, neurocrine and paracrine mediators in the regulation of bronchial reactivity]. / Die Bedeutung endokriner, neurokriner und parakriner Mediatoren in der Regulation der bronchialen Reagibilität.

Sympathetic and parasympathetic influences on the airway resistance under physiological and pathophysiological conditions have long been known. In recent years, this classical view had to be extended due to mounting evidence of neurocrine and paracrine peptide mediators. The term non-adrenergic non-cholinergic (NANC) nervous system was coined. Besides other effects the non-adrenergic mediators (e.g. VIP and PHI/PHM) give rise to bronchodilation, while the non-cholinergic modulators (SP, neurokinin A, and CGRP) induce bronchospasm. The axon-reflex theory postulates liberation of non-cholinergic peptide substances by afferent C-fibers exposed by bronchial epithelial cell damage as one important cause of bronchial obstruction. In addition to biogenic amines, such peptides as bombesin, leu-encephalin, beta-endorphin, calcitonin, doctrine cells of the bronchial epithelium. Our knowledge of the biological relevance of these mediators is at present very sketchy. Platelet activating factor (PAF) is released by alveolar macrophages, granulocytes, blood vessel endothelium, and platelets. The inhalation of PAF induces bronchospasm in healthy subjects and asthmatics and also prolonged bronchial hyperreactivity. The many factors influencing bronchial reactivity need to be classified by further investigations of the mode of interaction and interdependence of known and new mediators.