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Biomedical subjects

U R Juergens

Publications and source records attributed to U R Juergens.

17 recordsLinked to original sources

[Early diagnosis of chronic obstructive pulmonary disease (COPD)].

Since the early detection of COPD is problematic, nonobstructed smokers with a chronic productive cough are initially assigned to the COPD risk group o. Although there is still a lack of evidence that early pharmacological intervention is associated with benefits in terms of disease progression, the earliest possible diagnosis is still considered a desirable goal. For the sooner triggering noxae, such as cigarette smoke, are eliminated, the more positive are the effects on the subsequent course of the illness. When establishing the diagnosis, a careful case history is of particular importance. With the aid of various diagnostic pulmonary function tests, degrees of severity can be differentiated and the course of COPD can be determined. Since the end of 2004, structured therapeutic programs for COPD have become available.

Bronchitis, Chronic↗

[A connection between allergic rhinitis and allergic asthma? The "one-airway-one-disease"-hypothesis].

The nose and the lungs are anatomically and physiologically divided which lead to separated strategies in diagnostic and therapy. The upper airways, from the nose and lungs may account for the traditional division in upper and lower airways. Nonetheless a link between upper and lower respiratory tracts has been repeatedly observed in the past decades making the current division in two separate entities an arbitrary dichotomy. Once allergic rhinitis and asthma are two manifestation of the atopic syndrome it is logical to expect that allergy is not a disease confined to specific target organ rather to a broad spectrum of clinical manifestations. This hypothesis has been supported from various observations: Both, allergic asthma and allergic rhinitis are characterized by a similar if not an identical inflammatory process in which mast cells and eosinophils appear to be the major effector cells, high comorbidity of both allergic manifestations as shown in epidemiologic studies. Both diseases are caused by the interaction of genetic susceptibility with environmental factors. In this review, the latest developments in epidemiology and pathophysiology with regard to nasobronchial interaction in allergic airway disease will be discussed.

Asthma↗

[A connection between allergic rhinitis and allergic asthma? The "one-airway-one-disease"-hypothesis].

As outlined in part 1, numerous data from immunologic, genetic and epidemiologic studies point to a systemic link between allergic asthma and rhinitis which can be seen as manifestations of a common atopic syndrome. In part 2 clinical manifestations, diagnostics and most importantly therapeutic options effecting on both nasal and bronchial symptoms will be discussed. Allergen avoidance is the first step in therapeutic management of allergic diseases. Specific immunotherapy (SIT), leukotriene modifying compounds (in Germany exclusively Montelukast), and corticosteroids inhibit inflammation in the epithelium of the upper and the lower airways. Although SIT has a widely accepted indication in the treatment of allergic rhinitis, it is just provisionally recommended for the treatment of asthmatic patients. Most recently Montelukast, a potent leukotriene receptor inhibitor, has been approved for the treatment of asthma as well as for allergic rhinitis. Local administration of corticosteroids requires that they be given both nasally and bronchially. Just on the i. v. or oral route corticosteroids may inhibit the allergic inflammation in both compartments. Newly developed IgE-inhibitor Omalizumab, which has no approval in Germany yet, has been reported to have similar effects. Thus, various therapeutic options are available to treat asthma and rhinitis at the same time. Furthermore, multilateral clinical efficacy of antiinflammatory drugs support the "One-Airway-One-Disease" hypothesis.

Asthma↗

Anti-inflammatory activity of 1.8-cineol (eucalyptol) in bronchial asthma: a double-blind placebo-controlled trial.

Airway hypersecretion is mediated by increased release of inflammatory mediators and can be improved by inhibition of mediator production. We have recently reported that 1.8-cineol (eucalyptol) which is known as the major monoterpene of eucalyptus oil suppressed arachidonic acid metabolism and cytokine production in human monocytes. Therefore, the aim of this study was to evaluate the anti-inflammatory efficacy of 1.8-cineol by determining its prednisolone equivalent potency in patients with severe asthma. Thirty-two patients with steroid-dependent bronchial asthma were enrolled in a double-blind, placebo-controlled trial. After determining the effective oral steroid dosage during a 2 month run-in phase, subjects were randomly allocated to receive either 200 mg 1.8-cineol t. i.d. or placebo in small gut soluble capsules for 12 weeks. Oral glucocorticosteroids were reduced by 2.5 mg increments every 3 weeks. The primary end point of this investigation was to establish the oral glucocorticosteroid-sparing capacity of 1.8-cineol in severe asthma. Reductions in daily prednisolone dosage of 36% with active treatment (range 2.5-10 mg, mean: 3.75 mg) vs. a decrease of only 7% (2.5-5 mg, mean: 0.91 mg) in the placebo group (P = 0.006) were tolerated. Twelve of 16 cineol vs. four out of 16 placebo patients achieved a reduction of oral steroids (P = 0.012). Long-term systemic therapy with 1.8-cineol has asignificant steroid-saving effect in steroid-depending asthma. This is the first evidence suggesting an anti-inflammatory activity of the monoterpene 1.8-cineol in asthma and a new rational for its use as mucolytic agent in upper and lower airway diseases.

Adult↗

Human and rat alveolar macrophages express multiple EDG receptors.

Endothelial differentiation gene (EDG) receptors are a new family of eight G protein-coupled receptors for the lysophospholipids lysophosphatitic acid and sphingosine-1-phosphate. In the present experiments, the expression of EDG receptors in rat and human alveolar macrophages was studied by reverse transcription-polymerase chain reaction (RT-PCR). In alveolar macrophages of both species, mRNA for multiple EDG receptors could be detected, but the pattern of expression was different in both species. In human alveolar macrophages, mRNA for EDG1, EDG2, EDG4, EDG7 receptors and, to a lesser extent, for the EDG7 receptor was detected, whereas in rat macrophages, mRNA for EDG2, EDG5 receptors and, to a lesser extent, for the EDG6 receptor was found. In functional experiments, it was observed that lysophosphatitic acid and sphingosine-1-phosphate can stimulate O(2)(-) generation in rat and human alveolar macrophages suggesting that lysophosphatitic acid and sphingosine-1-phosphate possibly acting via EDG receptors may play a role in controlling the activation of macrophages.

Animals↗

Potential role of EDG receptors and lysophospholipids as their endogenous ligands in the respiratory tract.

The role of lipid mediators derived from membrane glycerophospholipids and sphingolipids as intracellular messenger has been studied intensively during the last two decades, but with the recent discovery of high affinity G-protein coupled receptors for the lysophospholipids lysophosphatidic acid (LPA), sphingosine-1-phosphate (S1P) and sphingosylphosphorylcholine (SPC), increasing attention has been paid to the role of these lipid mediators as extracellular mediators. This review will summarize the biosynthesis and metabolism of lysophospholipids and describe the family of endothelial differentiation gene (EDG) receptors as high affinity receptors for lysophospholipids. Furthermore, an overview of the numerous biological effects of lysophospholipids which might be mediated by EDG receptors will be given together with an outlook on the potential role of such mechanisms in pulmonary physiology and pathophysiology.

Animals↗

Respimat (a new soft mist inhaler) delivering fenoterol plus ipratropium bromide provides equivalent bronchodilation at half the cumulative dose compared with a conventional metered dose inhaler in asthmatic patients.

BACKGROUND: Respimat, a possible alternative to the conventional metered dose inhaler (MDI), is a novel, reusable, propellant-free, multidose soft mist inhaler. Respimat slowly releases a metered dose of active substance as a soft mist with a high proportion of the dose in the fine particle fraction, leading to improved lung deposition following inhalation when compared with the conventional MDI. OBJECTIVES AND METHODS: The equipotent bronchodilating efficacy and safety of a combination of fenoterol hydrobromide and ipratropium bromide (F/I) in cumulative doses delivered by either Respimat or pressurised MDI was assessed in a randomised, controlled, double-blind (within device) 4-way crossover study. Forty-three patients with stable asthma (mean FEV(1) 62% predicted) responsive to F/I inhaled cumulatively 16 puffs on each of 4 test days (1 + 1 + 2 + 4 + 8 puffs at 50-min intervals) via Respimat delivering 50/20, 25/20 or 25/10 microg F/I per puff or via MDI delivering 50/20 microg F/I per puff. RESULTS: Cumulative doses of 400/160 and 400/320 microg F/I via Respimat produced bronchodilation (evaluated by average increase in FEV(1) 45-245 min after first inhalation) equivalent to that achieved with a cumulative 800/320 microg F/I via MDI (mean increase in FEV(1) above baseline 0.76, 0.73 and 0.71 litres, respectively). The tolerability of the F/I combination via Respimat was also comparable to that of twice the dose delivered via MDI. CONCLUSION: Therefore, a fenoterol hydrobromide/ipratropium bromide combination delivered by Respimat is as safe and effective as the MDI at half the cumulative dose, on acute administration to patients with asthma.

Administration, Inhalation↗

New insights in the bronchodilatory and anti-inflammatory mechanisms of action of theophylline.

Phosphodiesterase (PDE) inhibition and adenosine antagonism have been identified as important underlying mechanisms for the bronchodilating and anti-inflammatory action of theophylline (CAS 58-55-9). The aim of the present study was to determine the effects of PDE inhibition by theophylline on cAMP and arachidonic acid (AA) metabolism, namely leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) production, in cultured monocytes in vitro. Monocytes obtained from healthy non-smoking subjects were incubated in adherence at 37 degrees C for 4 h in the presence of theophylline (0.18, 1.8 and 18 micrograms/ml, respectively) and stimulated with LPS (10 micrograms/ml). LTB4, PGE2 and cAMP were measured in the same culture supernatants by direct enzyme immunoassay. LPS-stimulated generation of cAMP increased significantly (+162%) in the presence of theophylline (18 micrograms/ml); production of LTB4 was suppressed (-42%) compared to the baseline, whereas PGE2 production increased significantly (+39%). Production of cAMP correlated with increased PGE2 production (r = 0.73, p = 0.025) and with suppression of LTB4 (r = 0.67, p = 0.016). These effects were mimicked by cell permeant nucleotides, such as dibutyryl-cAMP but not by dibutyryl-cGMP and could be abolished by ibuprofen. These results provide the first evidence that the clinical efficacy of theophylline may result from inhibition of leukotriene production and its capacity to stimulate PGE2 production. The underlying mechanism is suggested as feedback regulatory induction of COX-2 by a prostaglandin driven cAMP-mediated process.

Adult↗

Reproterol--A monomolecular combination of orciprenaline and theophylline: novel aspects of its mode of action in asthma.

BACKGROUND AND OBJECTIVE: Reproterol is a monomolecular combination of orciprenaline and theophylline used as beta-adrenergic agonist to induce bronchodilation in bronchial asthma. Since the mechanism of action of reproterol has not been investigated so far, its potential anti-inflammatory activity in asthma remains still unknown. Therefore, we have studied in vitro whether the theophylline component of the reproterol molecule might enhance the stimulatory effect of the beta-adrenoceptor on cAMP production resulting in suppression of inflammatory mediator production. METHODS: The effects of reproterol, orciprenaline and theophylline (10(-9)-10(-5) M) on spontaneous cAMP (5 x 10(4) cells/30 min)- and on LPS (10 microg/ml)-stimulated LTB4 production (10(5) cells/4 h) were determined in normal monocytes in vitro. RESULTS: Production of cAMP (n = 9) was significantly augmented in a dose-dependent manner by orciprenaline (30 +/- 8%) and theophylline (28 +/- 10%), but mostly by reproterol (127 +/- 8%) at 10(-5) M. Despite incubation with propranolol, significant stimulation of cAMP production was notable following reproterol therapy. Production of LTB4 was significantly inhibited by reproterol (-48 +/- 14%) and less by theophylline (-28 +/- 10%), but was stimulated by orciprenaline (+20 +/- 8%) at 10(-5) M. CONCLUSION: We conclude that reproterol exerts a strong stimulatory effect on monocyte cAMP production and a suppressive effect on LTB4 production possibly due to a synergistic mode of action on adenylate cyclase activity and inhibition of phosphodiesterases. More clinical studies in bronchial asthma will be needed to determine whether these results may translate into clinically relevant effects.

Adrenergic beta-Agonists↗

The anti-inflammatory activity of L-menthol compared to mint oil in human monocytes in vitro: a novel perspective for its therapeutic use in inflammatory diseases.

The anti-inflammatory efficacy of monoterpenes is still unknown. In order to evaluate the potential role of L-menthol and mint oil as an anti-inflammatory drug, preclinical in vitro-investigations were performed using LPS-stimulated monocytes from healthy volunteers. Arachidonic acid metabolism was assessed by measuring LTB subset4 and PGE subset2 as indicators for both the lipoxygenase and the cyclooxygenase pathways respectively. In addition, the anti-inflammatory effects of the two terpenes on IL-1beta production were analysed. - L-menthol significantly suppressed the production of each of the three inflammation mediators by monocytes in vitro. LTB subset4 decreased by -64.4 +/- 10%, PGE subset2 by -56.6 +/- 8%, and IL-1beta by -64.2 +/- 7% respectively at L-menthol concentrations within the presumed therapeutic range of about 10 superset-7 g/ml. In contrast, mint oil had a bimodal effect on PGE subset2 production: lower concentrations of 10 superset-10 to 10 superset-8 g/ml increased PGE subset2 up to 6-fold compared to baseline but concentrations of 10 superset-7 g/ml suppressed PGE subset2 production by approximately 50%. Mint oil had similar effects on LTB subset4 and IL-1beta as its main constituent, L-menthol, although the degree of suppression was by comparison smaller at lower concentrations. Paraffin oil, which served as a solvent, did not affect arachidonic acid metabolism and IL-1beta production. - These results obtained with human monocytes suggest preferable anti-inflammatory effects of L-menthol compared to mint oil at therapeutically relevant concentrations supplied in enteric coated capsules. Therefore, clinical trials investigating the potential therapeutic efficacy of L-menthol for treatment of chronic inflammatory disorders such as bronchial asthma, colitis and allergic rhinitis seem worthwhile.

Anti-Inflammatory Agents, Non-Steroidal↗

Inhibition of cytokine production and arachidonic acid metabolism by eucalyptol (1.8-cineole) in human blood monocytes in vitro.

Cineole (eucalyptol) is the isolated active agent of eucalyptus oil. Traditionally, it is recommended for treating the symptoms of airway diseases exacerbated by infection. We have examined the inhibitory effect of 1.8-cineole on LPS-and IL1beta-stimulated mediator production by human monocytes in vitro. For the first time, we report on a dose-dependent and highly significant inhibition of production of tumor necrosis factor-alpha, interleukin-1beta, leukotriene B4 and thromboxane B2 by 1.8-cineole. In summary, this is the first report on a new mechanism of action of monoterpenes suggesting 1.8-cineole as a strong inhibitor of cytokines that might be suitable for longterm treatment of airway inflammation in bronchial asthma and other steroid-sensitive disorders.

Adult↗

Antiinflammatory effects of euclyptol (1.8-cineole) in bronchial asthma: inhibition of arachidonic acid metabolism in human blood monocytes ex vivo.

Monoterpenes are prescribed to treat chronic obstructive airway disorders mainly because of their familiar secretolytic properties. The aim of this study was to investigate the effect of 1.8-cineole (Soledum) on arachidonic acid (AA) metabolism in blood monocytes of patients with bronchial asthma. Patients with bronchial asthma (n = 10) and healthy test subjects (n = 12) were included in the study. Production of the representative AA-metabolites LTB4 and PGE2 from isolated monocytes stimulated with the calcium ionophore A23187 were measured ex vivo before therapy with 1.8-cineole (3 x 200 mg/day), after three days of treatment (day 4) and four days after discontinuation of 1. 8-cineole (day 8). The production of LTB4 and PGE2 from monocytes ex vivo was significantly inhibited on day 4 in patients with bronchial asthma (-40.3%, n = 10 and -31.3%, p = 0.1, n = 3 respectively) as well as in healthy volunteers (-57.9%, n = 12 and -42.7%, n = 8 respectively). In conclusion, 1.8-cineole was shown to inhibit LTB4 and PGE2, both pathways of AA-metabolism. Further studies are needed to show that 1.8-cineole is suitable in the treatment of bronchial asthma.

Anti-Inflammatory Agents, Non-Steroidal↗

Inhibition of monocyte leukotriene B4 production after aspirin desensitization.

Aspirin-sensitive patients may be desensitized through a graded series of exposures to aspirin. We investigated the underlying mechanism of aspirin desensitization by measuring the release of leukotrienes B4 and C4 from calcium ionophore-stimulated peripheral blood monocytes. Compared with monocytes from normal volunteers (n = 5), monocytes from patients with aspirin-sensitive asthma (n = 10) released increased amounts of thromboxane B2 (1060 +/- 245 pg/ml vs 456 +/- 62 pg/ml), leukotriene B4 (861 +/- 139 pg/ml vs 341 +/- 44 pg/ml), and leukotriene C4 (147 +/- 31 pg/ml vs 56 +/- 6 pg/ml) at baseline. After aspirin desensitization, thromboxane B2 release was almost completely suppressed in both groups. Leukotriene B4 release was significantly decreased in the aspirin-sensitive group (484 +/- 85 pg/ml) but not in the normal subject group (466 +/- 55 pg/ml). The need for prednisone decreased significantly after patients were desensitized to aspirin (10.4 +/- 2.2 mg/day to 1.6 +/- 2.8 mg/day). These results demonstrate that desensitization to aspirin results in decreased monocyte leukotriene B4 release. On the basis of the bronchospastic and inflammatory potential of leukotrienes, the decrease in leukotriene release may contribute to the clinical improvement seen after aspirin desensitization.

Adult↗

Arachidonic acid metabolism in monocytes of aspirin-sensitive asthmatic patients before and after oral aspirin challenge.

Aspirin and nonsteroidal antiinflammatory drugs induce bronchospastic reactions in patients with aspirin-sensitive respiratory disease. Although the mechanism of this reaction is unknown, all drugs that induce the respiratory reaction also inhibit the cyclooxygenase enzyme. The ensuing changes in arachidonate metabolism are presumed to play a role in the pathogenesis of the reaction. We measured generation of leukotrienes and thromboxane by calcium ionophore stimulated blood monocytes. Before aspirin challenge, monocytes released significantly more thromboxane B2 in patients with aspirin sensitivity than in patients without aspirin sensitivity or in healthy control subjects (p < 0.02). During aspirin-induced bronchospasm, release of leukotriene B4 increased significantly (45.5%, p = 0.018), whereas release of thromboxane B2 decreased (-46.9%, p = 0.028). Two hours after ingestion of 60 mg aspirin, normal monocyte release of thromboxane B2 did not drop, whereas leukotriene B4 release increased. Monocytes formed only minimal amounts of leukotriene C4. We conclude that the profile of released eicosanoids from aspirin-sensitive monocytes is distinct from non-aspirin-sensitive subjects, and that these differences could contribute to the development of bronchospasm after aspirin ingestion.

Administration, Oral↗

[Dyspnea, fever].

A 28-year-old female with known allergic bronchial asthma complained about increasing dyspnea, white sputum and fever. Pulmonary infiltrates progressed in spite of tetracycline administration. An increased leucocyte count, eosinophilia and an elevated sedimentation rate were found. Bronchoscopy was unrevealing except for signs of mild bronchitis. Eosinophils were abundant in the bronchial lavage. Eosinophilic pneumonia was diagnosed in a biopsy specimen. Prednisolone (100 mg/die initially, decreasing doses thereafter) led to significant reduction of infiltrates and eosinophilia. After 8 weeks of treatment the patient had completely recovered.

Adult↗

[Urticaria, pruritus].

A 53-year old patient was admitted because of severe urticaria and itching aggravating since 9 months. Laboratory findings like increased sedimentation rate and leucocytosis were suspicious for an infection-associated allergy or a paraneoplastic syndrome. After exclusion of a gastro-intestinal tumor search for the source of a possible infection was intensified by several fecal analyses and trophozoites were found indicating an infestation of the small bowel by Giardia lamblia. Finally lamblia were detected in duodenal aspirate. After therapy with metronidazole 3 x 400 mg/die for 10 days all parameters of infection were normalized and the patient was permanently relieved from symptoms.

Giardiasis↗