Biomedical subjects

K M Beeh

Publications and source records attributed to K M Beeh.

At least 19 recordsLinked to original sources

PubMed2006

[Efficacy of tiotropium bromide (Spiriva) in patients with chronic-obstructive pulmonary disease (COPD) of different severities].

BACKGROUND: Aim of this study was to evaluate the efficacy of inhaled Tiotropium bromide in COPD patients of different severities in pneumological practices during a three months clinical trial. METHODS: A randomized, double blind, placebo controlled study including COPD-patients (FEV1/FVC < 70 %, FEV1 < or = 70 % predicted; age > or = 40 years; > or = 10 pack years) of different severities was performed. The efficacy of 18 microg Tiotropium bromide once daily on lung function and exacerbations over 12 weeks was evaluated by respective pulmonary function tests (spirometry) before (trough value) and 2 hours after inhalation of study medication. RESULTS: 1639 patients (1236 Tiotropium bromide, 403 placebo; FEV1 reversibility after 200 microg Ipratropium bromide + 200 microg Fenoterol: 7.9 +/- 7.5 % predicted [mean +/- sd]) were randomized. After 12 weeks of treatment Tiotropium bromide led to significant increases of trough FEV1 (23 - 24 h after last inhalation; + 79 +/- 17 ml), and 2 h after Tiotropium bromide inhalation (+ 128 +/- 19 ml) (all values vs. placebo, adjusted mean +/- se, p < 0.0001). FVC and IVC were also improved significantly. In mild COPD (FEV1 > or = 50 - 70 %) improvements were most pronounced (trough FEV1 + 113 +/- 29 ml, 2 h post-inhalation + 181 +/- 33 ml; all values vs. placebo., p < 0.0001). 14.6 % of patients treated with Tiotropium bromide had a COPD exacerbation vs. 19.9 % of patients treated with placebo (p = 0.0151). The time to first exacerbation was prolonged (p = 0.0092 vs. placebo). CONCLUSION: Tiotropium bromide 18 microg once daily led to a persistent improvement of lung function and a reduction of exacerbations in patients with COPD of different severities.

Adult↗

PubMed2006

Handle with care: targeting neutrophils in chronic obstructive pulmonary disease and severe asthma?

Neutrophils play an important role in the pathogenesis of airway inflammation in both chronic obstructive pulmonary disease (COPD) and severe asthma. Currently available drugs have only limited effects on neutrophilic airway inflammation, particularily in COPD. Therefore, great efforts are undertaken to address neutrophilic inflammation in chronic respiratory disorders, in particular COPD. This review summarizes the rationale for anti-neutrophilic treatment in COPD and asthma and gives a critical overview of current developments in drug therapy. Moreover, unanswered questions and limitations of clinical trial design and choice of outcome parameters for proof-of-concept studies with novel anti-neutrophilic drugs are discussed as well as potential safety issues.

Anti-Inflammatory Agents↗

PubMed2005

[Novel perspectives of COPD pharmacotherapy: focus on neutrophils].

Inflammation in COPD is characterized by an increased presence and activation of airway neutrophils. However, since currently available treatment options have only limited effects on neutrophilic airway inflammation, great efforts are undertaken to develop novel therapies targeting the neutrophilic component of inflammation in COPD. The present review discusses the rationale for anti-neutrophilic treatment in COPD and provides a critical overview of recent developments in drug therapy. Moreover, open questions and limitations of clinical trials including choice of adequate outcome parameters for proof-of-concept studies with putative anti-neutrophilic drugs and potential safety issues are summarized.

Antioxidants↗

PubMed2004

[Seasonal variations of serum-IgE and potential impact on dose-calculation of omalizumab (rhuMab-E25, anti-IgE)].

BACKGROUND: The anti-IgE antibody Omalizumab has been approved for the treatment of perennial allergic asthma. Dosing of omalizumab is adjusted according to total IgE levels and body weight, and a near complete suppression of free IgE is deemed to be necessary for optimal efficacy. Many asthmatics, however, have additional sensitisations against seasonal allergens, e. g. pollen, and seasonal exposure may increase total and specific IgE levels ("boost"), thus leading to an imbalance between IgE levels and omalizumab with possible impact on therapeutic outcome. METHODS: We studied serum total and specific (timothy grass) IgE levels in 17 patients with seasonal allergic rhinitis and/or asthma prior to and during the grass pollen season. Based on total IgE levels, we then calculated hypothetical doses of omalizumab required for treatment at each time point. RESULTS: During the pollen season, total IgE increased significantly from a pre-seasonal mean of 89 (50 - 178) kU/l (geom. mean with 95 % confidence interval) to 126 (63 - 251) kU/l (p = 0.0006). Accordingly, specific IgE increased from 11 (6.3 - 19) kU/l to 15.1 (8.3 - 29) kU/l (p = 0.0013). Calculated doses of omalizumab based on pre-seasonal IgE levels were: no dosing (IgE < 30 kU/l): n = 2; 150 mg 4-weekly: n = 7; 300 mg 4-weekly: n = 2; 225 mg 2-weekly: n = 4; 300 mg 2-weekly: n = 1; 375 mg 2-weekly: n = 1. Based on seasonal IgE levels, doses of omalizumab would have changed in 5/17 patients requiring the next possible dosing step. Of these, two patients would have fallen out of the current dosing scheme. CONCLUSIONS: A seasonal increase of serum total and specific IgE can be observed in patients with pollen allergy, although this increase would have no impact on omalizumab doses in the majority of patient. Individual variations, however, can be large and necessitate a dose correction. Therefore, therapeutic monitoring of free IgE levels during anti-IgE treatment appears as desirable tool.

Adult↗

PubMed2003

A single nasal allergen challenge increases induced sputum inflammatory markers in non-asthmatic subjects with seasonal allergic rhinitis: correlation with plasma interleukin-5.

BACKGROUND: Seasonal allergic rhinitis (SAR) is a risk factor for asthma in affected individuals. Nasal allergic inflammation enhances bone-marrow eosinophil production, mainly via IL-5, and rhinitis patients have increased airway inflammation during the pollen season. OBJECTIVE: To assess the impact of nasal allergy on sputum inflammatory markers. METHODS: In an open-labelled, randomized, placebo-controlled cross-over study with 16 non-asthmatic SAR patients (median age 25 years, 56% males), the effect of a single nasal allergen challenge performed out of season on induced sputum inflammatory parameters was evaluated. SAR patients were identified by history, skin-prick test and specific IgE. All patients had normal lung function/bronchial hyper-responsiveness out of season and a negative asthma/wheezing history. Sputum cells and supernatant levels of ECP, sICAM, IL-5 and IL-10, and plasma levels of IL-5 and ECP, were measured before and 24 h after nasal allergen challenge. After a washout period of at least 4 weeks, the procedure was repeated with placebo challenge (diluent). RESULTS: Nasal allergen challenge led to an increase in sputum ECP (pre = 60 +/- 12, post = 212 +/- 63 micro g/L, P = 0.02 vs. placebo), and sICAM (4.8 +/- 2.7 to 6.5 +/- 2.9 ng/mL, P = 0.02 vs. placebo), whereas IL-10 decreased after provocation (44 +/- 11 to 29 +/- 6 pg/mL, P = 0.06 vs. placebo). Sputum IL-5 was undetectable in all patients. The absolute number of blood and sputum eosinophils did not change significantly after allergen or placebo challenge (P > 0.07, both comparisons). Plasma levels of IL-5 increased after allergen challenge (8.7 +/- 2.9 to 14.5 +/- 3.9 pg/mL, P = 0.001), and the increase in plasma IL-5 was positively correlated with the rise in sputum ECP in a subgroup of 'responders' (n = 12, r = 0.71, P = 0.01). CONCLUSIONS: A single nasal allergen challenge in SAR patients increased markers of allergic inflammation in the lower respiratory tract, possibly via pronounced activation of inflammatory cells through circulating immediate-type reaction cytokines like IL-5. These findings may provide additional explanatory data for the high susceptibility of SAR patients to incident asthma.

Administration, Intranasal↗

PubMed2003

Sputum matrix metalloproteinase-9, tissue inhibitor of metalloprotinease-1, and their molar ratio in patients with chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and healthy subjects.

BACKGROUND: Matrix-metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), are involved in the turnover of extracellular matrix. Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are inflammatory diseases characterized by excessive matrix degradation and tissue fibrosis. We have compared sputum concentrations of MMP-9, TIMP-1 and the controlling cytokine tumor necrosis factor (TNF)-alpha in patients with COPD, IPF and healthy subjects. METHODS: In a cross-sectional analysis, 12 patients with stable COPD, 15 patients with IPF and 14 healthy subjects underwent sputum induction. Induced sputum cells were counted and concentrations of MMP-9, TIMP-1 and TNF were measured by enzyme immunoassays. RESULTS: Sputum neutrophils were markedly elevated in COPD and IPF patients compared with controls (P<0.001, both comparisons). Concentrations of MMP-9 and the MMP-9:TIMP-1 ratio were increased in COPD (P<0.001 vs. IPF and controls), whereas sputum TIMP-1 levels were both elevated in COPD and IPF (P<0.01 vs. controls, both comparisons). TNF levels were similar in all three groups (P>0.2, all comparisons). MMP-9 concentrations were negatively correlated with airway obstruction (FEV1 FVC) in COPD (rho=-0.62, P=0.03), but not with diffusion capacity or vital capacity (% predicted) in IPF (rho=-0.06, P=0.85, and rho=-0.3, P=0.29, respectively). MMP-9 was positively correlated with sputum neutrophils in all patients (rho=0.68, P<0.0001), and with TNF in COPD patients (rho=0.76, P=0.004). CONCLUSIONS: These data underline the significance of protease/antiprotease imbalance for the pathogenesis of inflammatory lung diseases. Despite similar cellular inflammatory patterns both in COPD and IPF sputa, marked differences were observed with regard to MMP-9:TIMP-1 balance.

Aged↗

PubMed2003

Randomised controlled trial of montelukast plus inhaled budesonide versus double dose inhaled budesonide in adult patients with asthma.

BACKGROUND: Inhaled corticosteroids (ICS) affect many inflammatory pathways in asthma but have little impact on cysteinyl leukotrienes. This may partly explain persistent airway inflammation during chronic ICS treatment and failure to achieve adequate asthma control in some patients. This double blind, randomised, parallel group, non-inferiority, multicentre 16 week study compared the clinical benefits of adding montelukast to budesonide with doubling the budesonide dose in adults with asthma. METHODS: After a 1 month single blind run in period, patients inadequately controlled on inhaled budesonide (800 microg/day) were randomised to receive montelukast 10 mg + inhaled budesonide 800 microg/day (n=448) or budesonide 1600 microg/day (n=441) for 12 weeks. RESULTS: Both groups showed progressive improvement in several measures of asthma control compared with baseline. Mean morning peak expiratory flow (AM PEF) improved similarly in the last 10 weeks of treatment compared with baseline in both the montelukast + budesonide group and in the double dose budesonide group (33.5 v 30.1 l/min). During days 1-3 after start of treatment, the change in AM PEF from baseline was significantly greater in the montelukast + budesonide group than in the double dose budesonide group (20.1 v 9.6 l/min, p<0.001), indicating faster onset of action in the montelukast group. Both groups showed similar improvements with respect to "as needed" beta agonist use, mean daytime symptom score, nocturnal awakenings, exacerbations, asthma free days, peripheral eosinophil counts, and asthma specific quality of life. Both montelukast + budesonide and double dose budesonide were generally well tolerated. CONCLUSION: The addition of montelukast to inhaled budesonide is an effective and well tolerated alternative to doubling the dose of inhaled budesonide in adult asthma patients experiencing symptoms and inadequate control on budesonide alone.

Acetates↗

PubMed2003

Sputum induction leads to a decrease of exhaled nitric oxide unrelated to airflow.

Measurement of exhaled nitric oxide (eNO) and analysis of induced sputum are both established noninvasive methods for studying airway inflammation in asthma. Both methods are often used sequentially within short time frames. The aim of the present study was to evaluate the influence of sputum induction on eNO in adults and to follow the kinetics of airway eNO production after induction in relation to forced expiratory volume in one second (FEV1). eNO and FEV1 were measured in 41 adult patients (aged 29 (range 23-50) yrs, 56% male) with asymptomatic atopy or mild asthma (mean FEV1 97.2+/-3% predicted) prior to and immediately after sputum induction with hypertonic saline (4%). Sputum induction with isotonic saline was also performed in 13 subjects (control group). Repeatability of eNO decrease after sputum induction was also studied in 27 patients on separate occasions and kinetics of eNO production after sputum induction were followed over 24 h in another 10 patients. Sputum induction with hypertonic, but not isotonic, saline led to a marked decrease in eNO (log) immediately after the procedure (pre: 3.85+/-0.13 parts per billion (ppb); post: 3.24+/-0.14 ppb). This decrease was shown to be highly reproducible and not related to a fall in FEV1 following sputum induction. While FEV1 returned to baseline within 1 h, decreased eNO levels were observed over 4 h and returned to baseline after 24 h. Hypertonic saline sputum induction leads to a prolonged reduction in exhaled nitric oxide in adult atopics that is reproducible within subjects and not related to a reduction in airflow following sputum induction. This methodological interference should be taken into account when sputum induction and exhaled nitric oxide measurements are performed in the same subject.

Adult↗

PubMed2002

Effects of long-term supplementation with whey proteins on plasma glutathione levels of HIV-infected patients.

BACKGROUND: HIV infection is characterized by an enhanced oxidant burden and a systemic deficiency of the tripeptide glutathione (GSH), a major antioxidant. The semi-essential amino acid cysteine is the main source of the free sulfhydryl group of GSH and limits its synthesis. Whey proteins are rich in cysteine as well as in GSH precursor peptides. AIM OF THE STUDY: In order to evaluate the effects of whey supplementation on plasma GSH levels, HIV-infected patients were treated with whey proteins for a period of six months. METHODS: In a double blind clinical trial, 30 patients were randomized to a daily dose of 45 g whey proteins of either Protectamin (Fresenius Kabi, Germany) or Immunocal (Immunotec, Europe) for 2 weeks. Eighteen patients (16 male, 42 +/- 9.4 yr, 249 +/- 99 CD4+ lymphocytes/l) continued the trial with a daily dose of 45 g of Protectamin for six months. RESULTS: Pre-therapy, total plasma GSH levels (Protectamin: 1.92 +/- 0.6 microM; Immunocal: 1.99 +/- 0.9 microM) were less than normal (2.64 +/- 0.7 microM, p = 0.03). After two weeks of whey protein supplementation, plasma total GSH levels increased in the Protectamin group by 44 +/- 56% (2.79 +/- 1.1 microM, p = 0.004), while the difference in the Immunocal group did not reach significance (+24.5 +/- 59 %, 2.51 +/- 1.48 microM, p = 0.43). Consequently, all patients continuing the trial were openly switched to Protectamin. After six months, total GSH plasma levels were still significantly elevated compared to baseline (day 1: 1.95 +/- 0.8 microM vs. month 1: 2.18 +/- 0.8 microM, p = 0.19; month 3: 2.39 +/- 0.9 microM, p = 0.056; month 6: 2.47 +/- 0.8 microM, p = 0.033). Body weight, T-cell counts, and other clinical parameters did not change. The most common mild side effect was intestinal disturbance; severe adverse events did not occur. CONCLUSION: Supplementation with whey proteins persistently increased plasma glutathione levels in patients with advanced HIV-infection. The treatment was well tolerated. A larger long-term trial is clearly warranted to evaluate whether this positive influence on the glutathione metabolism translates into a more favorable course of the disease.

Adult↗

PubMed2002

[Efficacy and safety of salmeterol (50 microgram) and fluticasone (250 microgram) in a single inhaler device (diskus) in patients with mild to moderate asthma].

BACKGROUND: Inhaled corticosteroids and long-acting beta-agonists are first-line agents for the treatment of patients with persisting bronchial asthma. Several lines of evidence have shown, that inhaled corticosteroids and long-acting beta-agonist have multiple synergisms both in vivo and in vitro, leading to improved clinical asthma control. METHODS: A prospective, open, multi-centre study was performed to evaluate the efficacy and safety of a fixed combination of inhaled Fluticasone (250 microgram BID) and Salmeterol (50 microgram BID) in a single inhaler device (Diskus). 3345 patients (48 % male, mean age 52 years, range 17 - 90 years) with mild to moderate asthma were treated over a period of 8 weeks. Lung function, quality of life and adverse events were evaluated as primary outcome variables. RESULTS: After 8 weeks of treatment, forced expiratory volume in one second (FEV1) improved from 2.37 +/- 0.86 l to 2.7 +/- 0.96 l (p < 0.001). Accordingly, morning peak expiratory flow (PEF) increased from 4.9 +/- 2.1 l/s to 5.6 +/- 2.2 l/s (p < 0.001). Quality of life improved in 90 % of all patients, with an overall increase of 1.1. points. Frequent adverse events included symptoms of asthma (5.3 % of all adverse events) and infections (2.7 %). Typical side-effects of the study medication, e. g. oral candidiasis or tachycardia were observed in less than 2 % of all patients. CONCLUSIONS: These results confirm the efficacy and tolerability of a fixed combination of salmeterol and fluticasone in a single inhaler device (Diskus). Lung function and quality of life were significantly improved in mild to moderate asthmatics. A fixed combination of long-acting beta-agonists and inhaled corticosteroids is therefore considered as a valuable therapeutic option for the treatment of patients with asthma.

Adolescent↗

PubMed2002

[Onset of action of formoterol in patients with moderate to severe, partially reversible airflow obstruction assessed by bodyplethysmography].

BACKGROUND: Formoterol is a long acting beta2-agonist used for the treatment of obstructive airway diseases. Compared with Salmeterol, Formoterol has a rapid onset of bronchodilation. There are only scant data regarding the comparative onset of action using bodyplethysmography in moderate to severely obstructive patients. METHODS: In a mono-center, single-blinded parallel group study 60 patients (age: 61.9 +/- 12.8 years, 65 % male) with moderate to severe (mean FEV(1) 40.6 +/- 15.3 % of predicted), partially reversible (FEV(1) post bronchodilator > 15 % from baseline) airway obstruction were treated with either formoterol 12 microg bid or salmeterol 50 microg bid over a period of two weeks. Onset of action was measured by airway resistance (sRaw) before and after two weeks of treatment. RESULTS: Compared with Salmeterol, Formoterol had a significantly faster onset of action (10 % decrease of Raw) at baseline (F: 1.4 +/- 0.9 vs. S: 15.1 +/- 34.5 min., p < 0.0001) and after two weeks of treatment (F: 6.2 +/- 21.6 vs. S: 51 +/- 135 min., p < 0.0001). Morning FEV(1) improved similarily during treatment in both study groups, when compared with baseline lung function (F: 1.38 +/- 0.64 vs. 1 +/- 0.41 l; S: 1.43 +/- 0.67 vs. 1 +/- 0.4 l, p < 0.05, both comparisons). Both treatments were well tolerated. CONCLUSION: Formoterol produces a rapid improvement of airway resistance in patients with moderate to severe, partially reversible airway obstruction. The onset of bronchodilation was significantly faster for Formoterol compared with Salmeterol. Both drugs improved lung function similarily after two weeks of treatment. It is important to distinguish beta2-agonists not only into short- and long-acting but also into fast- and slow-acting.

Bronchodilator Agents↗

PubMed2002

Glutathione deficiency of the lower respiratory tract in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown aetiology. Increased oxidant burden and antioxidant, e.g. glutathione (GSH), deficiency in the lower respiratory tract have been thought to play a role in the progression of IPF. Sputum induction is a safe noninvasive tool to study inflammation in the respiratory tract. The aim of the present study was to evaluate the direct measurement of GSH in induced sputum supernatant. Sixteen IPF patients and 15 healthy, nonsmoking subjects underwent sputum induction. Total GSH in sputum, saliva and plasma was measured spectrophotometrically. Sputum GSH was decreased more then four-fold in IPF patients when compared to healthy subjects (mean GSH 1.4+/-0.34 microM versus 5.8+/-0.98 microM). Salivary GSH was generally low or undetectable in all subjects. Plasma GSH levels were lower in IPF patients (0.26+/-0.1 versus 0.74+/-0.16 microM). In IPF patients, there was a borderline correlation of sputum GSH levels with disease duration and lung-function impairment. These data confirm the established role of oxidant/antioxidant imbalance in the pathogenesis of idiopathic pulmonary fibrosis, and show the potential of induced sputum to directly study inflammatory processes and surrogate markers in interstitial lung diseases like idiopathic pulmonary fibrosis.

Adult↗

PubMed2001

c-erbB-2 expression in small-cell lung cancer is associated with poor prognosis.

Small-cell lung cancer (SCLC) carries a bad prognosis despite good initial response to chemotherapy. It is therefore important to identify molecular markers that influence survival as potential new therapeutic targets. In our study, expression of the tyrosine kinase c-erbB-2 (HER2/neu) receptor in tumor tissues of 107 consecutive newly diagnosed patients with primary SCLC was quantified using a monoclonal antibody directed against the c-terminal domain of c-erbB-2. A clear-cut positive expression of c-erbB-2 was observed in 13% of patients. Surprisingly, c-erbB-2 was an independent prognostic factor (RR = 2.16; p = 0.014) when a proportional-hazard model was adjusted to stage (limited vs. extensive disease) and performance status (WHO I-IV), the most relevant clinical parameters. Similarly, a significant association between c-erbB-2 and survival was obtained if a larger number of clinical parameters were included into the analysis, namely response to chemotherapy, TNM stage, lactate dehydrogenase (LDH), neuron-specific enolase (NSE), gender and age (p = 0.033). Interestingly, c-erbB-2 expression was more relevant for patients with advanced tumors. In the subgroup of patients with bad performance status (WHO II-IV), median survival of patients with undetectable c-erbB-2 expression was 274 days compared with only 23 days for patients with clear-cut positive c-erbB-2 immunohistochemistry (p = 0.0031; log-rank test). Similar results were obtained for patients with extensive disease (p = 0.028) and high TNM stages (T>2 or N>1 or M1; p < 0.068, all comparisons). In contrast, c-erbB-2 expression was not associated with survival in patients with limited disease (p = 0.97), low TNM stages (p > 0.56, all comparisons) and good performance status (p = 0.97). In conclusion, c-erbB-2 is expressed in more than 10% of SCLC. Expression of c-erbB-2 is an independent prognostic factor of survival. The effect of c-erbB-2 expression seems to become more important in advanced stages of the disease. Since c-erbB-2 is a therapeutical target in other types of cancer, further studies to identify the role of c-erbB-2 in SCLC are clearly warranted.

Age Factors↗

PubMed2001

[Pathogenesis of bronchial asthma--unveiling new therapeutic prospects].

BACKGROUND: Bronchial asthma is a chronic inflammatory disease of the lower respiratory tract. It is characterized by nonspecific bronchial hyperresponsiveness, which may lead to variable, reversible airflow obstruction in affected patients. Despite therapeutic improvements, the worldwide prevalence and morbidity of asthma have risen during the past decades. An improved understanding of underlying pathological features and mechanisms of asthmatic inflammation is essential to achieve an enhanced asthma symptom control and may lead to prevention in the future. RESULTS: Besides the impact of genetic and environmental factors, scientific interest has especially been focused on the molecular and cellular biology of the asthmatic response. Mucosal inflammation in asthmatics is mainly orchestrated by T cells and derived cytokines. Immunoglobulin E and mast cells play a pivotal role in the initiation and pathogenesis of the early asthmatic reaction, while recruitment and activation of eosinophils seem to be crucial for the persistent asthma phenotype with chronic airflow obstruction. Additionally, smooth muscle cells, parasympathetic nerve fibers, bronchial epithelial cells and a vast amount of mediators may either promote or inhibit the inflammatory pathology of bronchial asthma. CONCLUSION: The recent insights from molecular biology have found their correlate in actual therapeutic guidelines, and have further led to the development of new innovative asthma drugs such as monoclonal antibodies against IgE or IL-5. Hopefully, future progress in revealing pathogenetic mechanisms of asthma may lead to further therapeutic improvement and eventually reverse the trend of rising asthma morbidity in western societies.

Anti-Asthmatic Agents↗

PubMed2001

Sputum levels of metalloproteinase-9 and tissue inhibitor of metalloproteinase-1, and their ratio correlate with airway obstruction in lung transplant recipients: relation to tumor necrosis factor-alpha and interleukin-10.

BACKGROUND: Chronic transplant rejection is characterized by progressive narrowing of small airways caused by matrix remodeling and fibrosis. Matrix-metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), are involved in the turnover of extracellular matrix. METHODS: To clarify the contribution of MMPs and TIMPs to airway inflammation in patients after lung transplantation (LTx), we used enzyme immunoassays to measure induced sputum concentrations of MMP-9, TIMP-1, and controlling cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 of 30 LTx patients and 15 control subjects. RESULTS: Sputum concentrations of MMP-9, TIMP-1, the MMP-9:TIMP-1 ratio, and TNF-alpha were higher in LTx patients than in control subjects (p < 0.04, all comparisons). The MMP-9, MMP-9:TIMP-1, and TNF-alpha levels were also significantly higher in LTx patients with chronic rejection compared with those with stable organ function (p < 0.03, all comparisons), whereas IL-10 levels were higher in the latter group (p = 0.05). In all LTx patients, MMP-9 and the MMP-9:TIMP-1 ratio were negatively correlated with forced expiratory volume in 1 second values (rho = -0.47, p = 0.01, and rho = -0.53, p = 0.003, respectively). We found that MMP-9 positively correlated with sputum neutrophils and TNF-alpha whereas MMP-9 and TIMP-1 did not correlate with IL-10. CONCLUSIONS: These data underline the possible contribution of proteases such as MMP-9 to chronic transplant rejection, and suggest that an imbalance of MMP-9 and TIMP-1 may be involved in the pathogenesis of airway obstruction after LTx. We found that MMP-mediated inflammation seems to be controlled by TNF-alpha whereas IL-10 might elicit anti-inflammatory effects through different pathways.

Adolescent↗

PubMed2001

Oral supplementation with whey proteins increases plasma glutathione levels of HIV-infected patients.

HIV infection is characterized by an enhanced oxidant burden and a systemic deficiency of the tripeptide glutathione (GSH), a major antioxidant. The semi-essential amino acid cysteine is the main source of the free sulfhydryl group of GSH and limits its synthesis. Therefore, different strategies to supplement cysteine supply have been suggested to increase glutathione levels in HIV-infected individuals. The aim of this study was to evaluate the effect of oral supplementation with two different cysteine-rich whey protein formulas on plasma GSH levels and parameters of oxidative stress and immune status in HIV-infected patients. In a prospective double blind clinical trial, 30 patients (25 male, 5 female; mean age (+/- SD) 42 +/- 9.8 years) with stable HIV infection (221 +/- 102 CD4 + lymphocytes L-1) were randomized to a supplemental diet with a daily dose of 45 g whey proteins of either Protectamin (Fresenius Kabi, Bad Hamburg, Germany) or Immunocal (Immunotec, Vandreuil, Canada) for two weeks. Plasma concentrations of total, reduced and oxidized GSH, superoxide anion (O2-) release by blood mononuclear cells, plasma levels of TNF-alpha and interleukins 2 and 12 were quantified with standard methods at baseline and after therapy. Pre-therapy, plasma GSH levels (Protectamin: 1.92 +/- 0.6 microM; Immunocal: 1.98 +/- 0.9 microM) were less than normal (2.64 +/- 0.7 microM, P = 0.03). Following two weeks of oral supplementation with whey proteins, plasma GSH levels increased in the Protectamin group by 44 +/- 56% (2.79 +/- 1.2 microM, P = 0.004) while the difference in the Immunocal group did not reach significance (+ 24.5 +/- 59%, 2.51 +/- 1.48 microM, P = 0.43). Spontaneous O2- release by blood mononuclear cells was stable (20.1 +/- 14.2 vs. 22.6 +/- 16.1 nmol h-1 10-6 cells, P = 0.52) whereas PMA-induced O2- release decreased in the Protectamin group (53.7 +/- 19 vs. 39.8 +/- 18 nmol h-1 10-6 cells, P = 0.04). Plasma concentrations of TNF-alpha and interleukins 2 and 12 (P > 0.08, all comparisons) as well as routine clinical parameters remained unchanged. Therapy was well tolerated. In glutathione-deficient patients with advanced HIV-infection, short-term oral supplementation with whey proteins increases plasma glutathione levels. A long-term clinical trial is clearly warranted to see if this "biochemical efficacy" of whey proteins translates into a more favourable course of the disease.

Administration, Oral↗

PubMed2001

Cigarette smoking, but not sensitization to Alternaria, is associated with severe asthma in urban patients.

Hereditary susceptibility and allergen exposure have been identified as general risk factors for asthma. However, risk factors for severe asthma still remain to be identified. To further assess and quantify risk factors associated with severe asthma in adult patients apart from clinical exacerbations, 306 randomly selected subjects (mean age 40+/-17 years, 46% males) presenting to an inner city pulmonary practice between 1995 and 1996 were retrospectively investigated. Of these, 117 patients were atopic, 112 had current asthma, and 22 asthmatics had severe asthma. Risk factors associated with atopy were family history of atopy and any domestic pet ownership (OR: 3.1, 95% CI: 1.64-6.1). Asthma was generally associated with atopy (OR: 4.2, CI: 2.4-7.4) and pet ownership (OR: 2.4, CI: 1.2-4.6). Severe asthma was strongly associated with current smoking (OR: 4.8, CI: 1.3-18.3), and lung function was negatively correlated with the amount of consumed cigarettes per day (r = -0.61, p = 0.04). However, no association with sensitization to Alternaria was found in severe asthma. Cigarette smoking is an independent risk factor associated with severe asthma in urban patients, whereas sensitization to Alternaria is of less importance in these patients.

Adult↗

PubMed2001

Induced sputum cell profiles in lung transplant recipients with or without chronic rejection: correlation with lung function.

BACKGROUND: Sputum induction is a non-invasive procedure for measuring inflammatory processes of the lower respiratory tract. The aim of this study was to establish sputum cell counts and differentials in patients after lung transplantation (LTx), with or without chronic transplant rejection. METHODS: Sputum induction was performed in 41 LTx patients (25 single LTx (sLTx), 16 double LTx (dLTx) and 15 healthy non-smoking volunteers. Sputum was processed according to standard protocols. Total cell count was calculated as mean (SE) cells x 10(6)/ml sputum and cell differential (%) was evaluated after staining. Cellular profiles were correlated with lung function. RESULTS: Total sputum cell counts were increased in sLTx (9 (1.9) cells x 10(6)/ml, p=0.01) and dLTx patients (7.2 (1.5) x 10(6)/ml, p=0.01) compared with healthy controls (2.6 (0.6) x 10(6)/ml). There was also a marked sputum neutrophilia in both patient groups (59 (6)% and 62 (6)%, respectively, p<0.001 v controls). Moreover, in both sLTx and dLTx patients with chronic transplant rejection there was an increased number of sputum neutrophils compared with patients with normal graft function (p<0.05 both comparisons), and neutrophils were inversely correlated with lung function (forced expiratory volume in one second (FEV(1)) % predicted): sLTx, r=-0.61, p=0.001; dLTx, r=-0.75, p=0.001, respectively). Sputum lymphocytes and eosinophils were similar in both groups. No relevant side effects occurred during sputum induction. CONCLUSIONS: Sputum induction is a safe and non-invasive tool for monitoring lower respiratory tract inflammation in LTx patients. Both sLTx and dLTx patients with chronic rejection had increased sputum neutrophils compared with patients with normal transplant function. These data support findings of other authors highlighting a possible role for neutrophils in the pathogenesis of chronic transplant rejection.

Adolescent↗