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Biomedical subjects

P N Dekhuijzen

Publications and source records attributed to P N Dekhuijzen.

At least 19 recordsLinked to original sources
PubMed2003

[Inhalation corticosteroids for COPD: possible less mortality].

General practitioners find it difficult to accurately distinguish asthma from COPD. However, this differential diagnosis is important, as the treatment of the two entities is different. Asthma is by definition steroid responsive, whereas several long-term trials have demonstrated that in COPD, the lung function is not affected by steroid treatment. Yet it is questionable whether lung function is a good parameter for evaluating treatment effects, as there are indications that steroids affect the quality of life and the number of exacerbations. Moreover, an observational study has shown that inhaled steroids might affect mortality. Observational studies do not normally provide conclusive evidence, due to the possible inclusion of many confounding factors (such as confounding by indication). Nevertheless, this observational study indicates that it might be possible to treat COPD with steroids. A large prospective randomised trial that is currently in progress will need to confirm whether or not this is the case.

Administration, Inhalation↗
PubMed2003

[Treatment of moderate persistent asthma: inhalation corticosteroids in combination with long acting beta 2-adrenergic agonists (bronchodilators) then with leukotriene receptor antagonists (anti-inflammatory agents); the 'step-3-dilemma'].

Apart from avoiding airway-irritating agents, the most important issue in the treatment of asthma is the suppression of airway inflammation by pharmaceutical treatment. Inhaled corticosteroids are the cornerstone of the medical treatment of asthma. Recent guidelines recommend the lowest possible effective dose for asthma management. In treatment steps 2 and 3, additive therapy of low to moderately high doses of inhalation corticosteroids in combination with add-on therapy with long-acting beta 2-adrenergic agonists (LABA) and leukotriene receptor antagonists (LTRA) has proved to be effective. LABA are inhaled agents with potent bronchodilator properties, whereas LTRA are taken orally and possess mainly systemic anti-inflammatory properties.

Administration, Inhalation↗
PubMed2003

[Inhaled corticosteroids for COPD].

Over 60% of patients with COPD are treated with inhaled corticosteroids (ICS), even though their use is still subject to debate. The inflammatory process in the lungs of patients with COPD is dominated by macrophages, CD8+ T-lymphocytes, neutrophilic granulocytes and mast cells, as well as an increased production and/or concentration of IL-8, TNF-alpha and leucotrine B4. This inflammatory process is less sensitive to the effect of corticosteroids than that in asthma. Placebo-controlled clinical studies show a beneficial effect of ICS on the number and severity of exacerbations, symptoms and quality of life, but not on the accelerated decline in lung function. Exacerbations occurred in a subgroup of patients in whom ICS were discontinued. A trial treatment with ICS should be considered in all COPD patients who have previously exhibited signs of asthma or allergy, or who have marked bronchial hyperresponsiveness, considerable reversibility, and recurrent exacerbations. In patients with moderate and severe COPD, a one-year trial with ICS should be considered, with exacerbations and symptoms as primary efficacy parameters and lung function decline as a secondary parameter. The combined use of ICS and long-acting beta-2 agonists may be considered in view of an additional effect on these parameters compared to administering the individual components.

Administration, Inhalation↗
PubMed2001

The effect of hypoxia on shortening contractions in rat diaphragm muscle.

Hypoxia is known to reduce isometric contractile properties of isolated rat diaphragm bundles. Its effect on isotonic contractile properties (i.e. force-velocity relationship and power output) has not been studied. We hypothesized that hypoxia reduces velocity of shortening and consequently power output of the unfatigued muscle, and shortens endurance time during isotonic contractions. Force-velocity relationship, power output, and fatigue resistance of rat diaphragm muscle bundles were measured during hypoxia (PO2: 6.6 +/- 0.2 kPa) and compared with hyperoxia (PO2: 91.8 +/- 0.7 kPa). Force was clamped from 1 to 100% of maximal tetanic force (Po). Fatigue during isotonic contractions was induced by repeated stimulation every 2 s at a clamp level of 33% of Po. Hypoxia did not affect isometric force generation compared with hyperoxia, nor contraction or relaxation time. In contrast, maximum shortening velocity decreased significantly (hypoxia: 4.2 +/- 0.3, hyperoxia: 6.0 +/- 0.2 Lo/s, P < 0.05). The force-velocity curve shifted downwards (P < 0.05). Hypoxia lowered power output at each load compared with hyperoxia (P < 0.05). The isotonic endurance time was shorter during hypoxia compared with hyperoxia (80 +/- 2 vs. 130 +/- 3 s, P < 0.05). These data show that hypoxia depresses isotonic contractile properties and power output, and reduces endurance time during repeated isotonic contractions.

Animals↗
PubMed2001

Free radicals in hypoxic rat diaphragm contractility: no role for xanthine oxidase.

Recent evidence indicates that hypoxia enhances the generation of oxidants. Little is known about the role of free radicals in contractility of the rat diaphragm during hypoxia. We hypothesized that antioxidants improve contractility of the hypoxic rat diaphragm and that xanthine oxidase (XO) is an important source of free radicals in the hypoxic diaphragm. The effects of N-acetylcysteine (NAC; 18 mM), Tiron (10 mM), and the XO inhibitor allopurinol (250 microM) were studied on isometric and isotonic force generation during hypoxia (PO(2) approximately 7 kPa). NAC and Tiron decreased maximal force generation, slowed the shortening velocity, and decreased the power output. Fatigue rate was decreased in the presence of either NAC or Tiron. Allopurinol did not alter the contractility or fatigability of the diaphragm. During hyperoxia (PO(2) approximately 85 kPa), neither NAC nor allopurinol affected the contractility or fatigability of the diaphragm. Thus free radicals play a significant role in diaphragm contractility during hypoxia. Whether antioxidants exert a beneficial or harmful effect on muscle performance depends on the contraction pattern of the muscle. Free radicals generated by XO do not play a role in diaphragm contractility during either hypoxia or hyperoxia.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗
PubMed2001

Nitric oxide affects sarcoplasmic calcium release in skeletal myotubes.

In the present study, we used real-time confocal microscopy to examine the effects of two nitric oxide (NO) donors on acetylcholine (ACh; 10 microM)- and caffeine (10 mM)-induced intracellular calcium concentration ([Ca2+]i) responses in C2C12 mouse skeletal myotubes. We hypothesized that NO reduces [Ca2+]i in activated skeletal myotubes through oxidation of thiols associated with the sarcoplasmic reticulum Ca2+-release channel. Exposure to diethylamine NONOate (DEA-NO) reversibly increased resting [Ca2+]i level and resulted in a dose-dependent reduction in the amplitude of ACh-induced [Ca2+]i responses (25 +/- 7% reduction with 10 microM DEA-NO and 78 +/- 14% reduction with 100 microM DEA-NO). These effects of DEA-NO were partly reversible after subsequent exposure to dithiothreitol (10 mM). Preexposure to DEA-NO (1, 10, and 50 microM) also reduced the amplitude of the caffeine-induced [Ca2+]i response. Similar data were obtained by using the chemically distinct NO donor S-nitroso-N-acetyl-penicillamine (100 microM). These results indicate that NO reduces sarcoplasmic reticulum Ca2+ release in skeletal myotubes, probably by a modification of hyperreactive thiols present on the ryanodine receptor channel.

Animals↗
PubMed2001

Nitric oxide impairs Ca2+ activation and slows cross-bridge cycling kinetics in skeletal muscle.

The effects of the nitric oxide (NO) donor spermine NONOate (Sp-NO, 1.0 mM) on cross-bridge recruitment and cross-bridge cycling kinetics were studied in permeabilized rabbit psoas muscle fibers. Fibers were activated at various Ca2+ concentrations (pCa, negative logarithm of Ca2+ concentration), and the pCa at which force was maximal (pCa 4.0) and approximately 50% of maximal (pCa50 5.6) were determined. Fiber stiffness was determined using 1-kHz sinusoidal length perturbations, and the fraction of cross bridges in the force-generating state was estimated by the ratio of stiffness during maximal (pCa 4.0) and submaximal (pCa 5.6) Ca2+ activation to stiffness during rigor (at pCa 4.0). Cross-bridge cycling kinetics were evaluated by measuring the rate constant for force redevelopment after quick release (by 15% of optimal fiber length, L(o)) and restretch of the fiber to L(o). Exposing fibers to Sp-NO for 10 min reduced force and the fraction of cross bridges in the force-generating state at maximal and submaximal (pCa50) Ca2+ activation. However, the effects of Sp-NO were more pronounced during submaximal Ca2+ activation. Sp-NO also reduced the rate constant for force redevelopment but only during submaximal Ca2+ activation. We conclude that Sp-NO reduces Ca2+ sensitivity by decreasing the number of cross bridges in the strongly bound state and also impairs cross-bridge cycling kinetics during submaximal activation.

Algorithms↗
PubMed2001

"Haemoxygenase-1 induction and exhaled markers of oxidative stress in lung diseases", summary of the ERS Research Seminar in Budapest, Hungary, September, 1999.

In recent years, there has been increasing interest in noninvasive monitoring of airway inflammation and oxidative stress. Several volatile and nonvolatile substances can be measured in exhaled breath and have been suggested as potential biomarkers of these events. Exhaled gases, including carbon monoxide (CO), alkanes (ethane, pentane), and substances measured in breath condensate, such as hydrogen peroxide (H2O2) and isoprostanes were all suggested as potential markers of oxidative stress in the lung. A European Respiratory Society (ERS) International Research Seminar entitled "Haemoxygenase-1 induction and exhaled markers of oxidative stress in lung diseases" was organized by the Airway Regulation and Provocation Group of the Clinical Allergy and Immunology Assembly in Budapest, Hungary in September, 1999 to integrate the latest knowledge on these issues and accelerate further improvement in this area. During this 2-day event several issues were raised about: the use and standardization of measurements in exhaled breath; problems of measuring expired H2O2 and other mediators in breath condensate; role and regulation of haemoxygenase (HO)-1 in the lung; and conditions and factors influencing exhaled CO. This report is a summary of the main presentations at the seminar, together with the current areas of research in this rapidly expanding field.

Antioxidants↗
PubMed2001

The Bronchitis Randomized On NAC Cost-Utility Study (BRONCUS): hypothesis and design. BRONCUS-trial Committee.

Chronic obstructive pulmonary disease (COPD) is an irreversible disorder characterized by airflow obstruction and a progressive decline in forced expiratory volume in one second (FEV1). At present, no treatment except quitting smoking appears to affect the progression of the disease. Oxidative stress has been implicated in its pathogenesis. The Bronchitis Randomized on NAC Cost-Utility Study (BRONCUS) is a phase III, randomized, double-blind, placebo-controlled, parallel group, multicentre study designed to assess the effectiveness of the antioxidant agent N-acetylcysteine (NAC) in altering the decline in FEV1, exacerbation rate, and quality of life in patients with moderate to severe COPD. In addition, cost-utility of the treatment will be estimated. Patients will be followed for 3 yrs and evaluated every 3 months. The necessary sample size to demonstrate an effect on the decline in FEV1 of 20 mL x yr(-1) was estimated to be 478 patients. Five hundred and twenty-three patients with moderate to severe COPD were recruited from 10 European countries from June 1, 1997-December 31, 1999. They were 63+/-8 yrs old and consisted of 243 (46%) current smokers and 280 (54%) exsmokers. Patients had on the average 4.9+/-1.6 exacerbations during the last 2 yrs. Postbronchodilator FEVI averaged 57+/-9% and the reversibility after 400 microg of Salbutamol averaged 4+/-4% predicted. The final results of the trial will be available in about 2 yrs. The study will provide objective data on the effects of N-acetylcysteine on outcome variables in chronic obstructive pulmonary disease.

Acetylcysteine↗
PubMed2000

Restoration by vacuum inflation of original alveolar dimensions in small human lung specimens.

Resection of lung specimens results in deflated and distorted lung structures. If no major airway is present (as in the case of small lung specimens from biopsies), lung dimensions cannot be restored by inflation under 25 cmH20. This impedes morphological analysis of the tissue. This report describes a simple and easy procedure to restore alveolar dimensions in deflated small lung specimens. Small human lung samples were inflated using moderate vacuum conditions which are provided by a common water stream-driven vacuum device. Restoration of alveolar dimensions and morphology was evaluated for paraffin-embedded as well as frozen tissue, using morphometric and immunohistological analysis. Vacuum inflation results in restoration of original lung dimensions as judged by light and scanning electron microscopy, and by analysis of the mean linear intercept, and the average length, width, perimeter and surface area. It also results in markedly improved cutting characteristics, allowing reliable sectioning of 2 microm cryosections and achieving high resolution images in immunofluorescence. Vacuum inflation is a simple and easy procedure to restore lung architecture of small human lung specimens/biopsies with a concomitant improvement of cutting characteristics. It allows for correct histological analysis of small specimens which cannot be inflated otherwise.

Adult↗
PubMed2000

Effects of emphysema and training on glutathione oxidation in the hamster diaphragm.

Loading of skeletal muscles is associated with increased generation of oxidants, which in turn may impair muscle contractility. We investigated whether the load on the hamster diaphragm imposed by pulmonary emphysema induces oxidative stress, as indicated by glutathione oxidation, and whether the degree of glutathione oxidation is correlated with contractility of the diaphragm. In addition, the effect of 12 wk of treadmill exercise training on contractility and glutathione content in the normal (NH) and emphysematous hamster (EH) diaphragm was investigated. Training started 6 mo after elastase instillation. After the training period, glutathione content and in vitro contractility of the diaphragm were determined. Twitch force and maximal tetanic force were significantly reduced (by approximately 30 and approximately 15%, respectively) in EH compared with NH. In sedentary hamsters, the GSSG-to-GSH ratio was significantly elevated in the EH compared with the NH diaphragm. A significant inverse correlation was found between GSSG-to-GSH ratio and twitch force in the diaphragm (P < 0. 01). Training improved maximal tetanic force and reduced fatigability of the EH diaphragm but did not alter its glutathione content. In conclusion, 1) emphysema induces oxidative stress in the diaphragm, 2) training improves the contractile properties of the EH diaphragm, and 3) this improvement is not accompanied by changes in glutathione redox status.

Animals↗
PubMed1999

Effects of anabolic steroids on diaphragm impairment induced by methylprednisolone in emphysematous hamsters.

This study was designed to investigate whether the administration of the anabolic steroid nandrolone decanoate is able to antagonize the loss in diaphragm function induced by long-term administration of a low-dose of methylprednisolone in emphysematous hamsters. Normal and emphysematous male hamsters were randomized to receive either saline or methylprednisolone 0.2 mg x kg(-1) x day(-1) for 9 months, with or without nandrolone decanoate 1 mg x kg(-1) x week(-1) i.m. during the final 3 months. Diaphragm contractile properties and myosin heavy chain composition were determined. Compared to control hamsters, the force generating capacity of isolated diaphragm strips decreased by approximately 12% in the emphysema group and by approximately 22% in the emphysema plus methylprednisolone group. Addition of nandrolone decanoate to the emphysema plus methylprednisolone hamsters significantly improved force generation. The atrophy of type IIa and IIx diaphragm fibres in the emphysema plus methylprednisolone group was completely reversed to the level of control hamsters by the addition of nandrolone decanoate. In conclusion, nandrolone decanoate in part reversed the loss in diaphragm force-generating capacity in emphysematous hamsters treated with methylprednisolone, and reversed type IIa and IIx fibre atrophy completely.

Anabolic Agents↗
PubMed1999

Long term effects of inhaled corticosteroids in chronic obstructive pulmonary disease: a meta-analysis.

BACKGROUND: The role of inhaled corticosteroids in the long term management of chronic obstructive pulmonary disease (COPD) is still unclear. A meta-analysis of the original data sets of the randomised controlled trials published thus far was therefore performed. The main question was: "Are inhaled corticosteroids able to slow down the decline in lung function (FEV1) in COPD?" METHODS: A Medline search of papers published between 1983 and 1996 was performed and three studies were selected, two of which were published in full and one in abstract form. Patients with "asthmatic features" were excluded from the original data. Ninety five of the original 140 patients treated with inhaled corticosteroids (81 with 1500 micrograms beclomethasone daily, six with 1600 micrograms budesonide daily, and eight with 800 micrograms beclomethasone daily) and 88 patients treated with placebo (of the initial 144 patients) were included in the analysis. The effect on FEV1 was assessed by a multiple repeated measurement technique in which points of time in the study and treatment effects (inhaled corticosteroids compared with placebo) were investigated. RESULTS: No baseline differences were observed (mean age 61 years, mean FEV1 45% predicted). The estimated two year difference in prebronchodilator FEV1 was +0.034 l/year (95% confidence interval (CI) 0.005 to 0.063) in the inhaled corticosteroid group compared with placebo. The postbronchodilator FEV1 showed a difference of +0.039 l/year (95% CI -0.006 to 0.084). No beneficial effect was observed on the exacerbation rate. Worsening of the disease was the reason for drop out in four patients in the treatment group compared with nine in the placebo group. In the treatment group six of the 95 subjects dropped out because of an adverse effect which may have been related to the treatment compared with two of the 88 patients in the placebo group. CONCLUSIONS: This meta-analysis in patients with clearly defined moderately severe COPD showed a beneficial course of FEV1 during two years of treatment with relatively high daily dosages of inhaled corticosteroids.

Administration, Inhalation↗
PubMed1999

beta2-adrenoceptor agonists reduce the decline of rat diaphragm twitch force during severe hypoxia.

The aim of the present study was to investigate the in vitro effects of the short-acting beta2-adrenoceptor agonist salbutamol and the long-acting beta2-adrenoceptor agonist salmeterol on hypoxia-induced rat diaphragm force reduction. In vitro diaphragm twitch force (Pt) and maximal tetanic force (Po) of isolated diaphragm muscle strips were measured for 90 min during hyperoxia (tissue bath PO2 83.8 +/- 0.9 kPa and PCO2 3.9 +/- 0.1 kPa) or severe hypoxia (PO2 7.1 +/- 0.3 kPa and PCO2 3.9 +/- 0.1 kPa) in the presence and absence of 1 microM salbutamol or 1 microM salmeterol. During hyperoxia, salbutamol and salmeterol did not significantly alter the time-related decreases in Pt and Po (to approximately 50% of initial values). Salbutamol had no effects on Po or the Pt-to-Po ratio. Salmeterol treatment significantly reduced Po and increased the Pt-to-Po ratio during hyperoxia (P < 0.05 compared with control value). Hypoxia resulted in a severe decrease in Pt (to approximately 30% of initial value) and Po after 90 min. Both salbutamol and salmeterol significantly reduced the decline in Pt during hypoxia (P < 0.05). The reduction in Po was not prevented. Salbutamol increased Pt rapidly but transiently. Salmeterol had a delayed onset of effect and a longer duration of action. Addition of 1 microM propranolol (a nonselective beta-adrenoceptor antagonist) did not alter Pt, Po, or the Pt-to-Po ratio during hypoxia but completely blocked the inotropic effects of salbutamol and salmeterol, indicating that these effects are dependent on beta2-adrenoceptor agonist-related processes.

Adrenergic beta-Agonists↗
PubMed1999

Xanthine oxidase is involved in exercise-induced oxidative stress in chronic obstructive pulmonary disease.

In the present study, we hypothesized that exhaustive exercise in patients with chronic obstructive pulmonary disease (COPD) results in glutathione oxidation and lipid peroxidation and that xanthine oxidase (XO) contributes to free radical generation during exercise. COPD patients performed incremental cycle ergometry until exhaustion with (n = 8) or without (n = 8) prior treatment with allopurinol, an XO inhibitor. Reduced (GSH) and oxidized glutathione (GSSG) and lipid peroxides [malondialdehyde (MDA)] were measured in arterial blood. In nontreated COPD patients, maximal exercise (approximately 75 W) resulted in a significant increase in the GSSG-to-GSH ratio (4. 6 +/- 0.9% at rest vs. 9.3 +/- 1.7% after exercise). In nontreated patients, MDA increased from 0.68 +/- 0.08 nmol/ml at rest up to 1. 32 +/- 0.13 nmol/ml 60 min after cessation of exercise. In contrast, in patients treated with allopurinol, GSSG-to-GSH ratio did not increase in response to exercise (5.0 +/- 1.2% preexercise vs. 4.6 +/- 1.1% after exercise). Plasma lipid peroxide formation was also inhibited by allopurinol pretreatment (0.72 +/- 0.15 nmol/ml preexercise vs. 0.64 +/- 0.09 nmol/ml 60 min after exercise). We conclude that strenuous exercise in COPD patients results in blood glutathione oxidation and lipid peroxidation. This can be inhibited by treatment with allopurinol, indicating that XO is an important source for free radical generation during exercise in COPD.

Adenosine Triphosphate↗