Nasally inhaled pulsating aerosols: lung, sinus and nose deposition.

OBJECTIVES: Topical delivery of drugs to the sinuses is challenging and requires also particular administration manoeuvres from the patient. This study was conducted to investigate 1) the delivery efficiency of a pulsating aerosol (Vibrent prototype device) to the sinuses and the nose, 2) the aerosol fraction that will deposit in the lungs and 3) potential differences regarding sinus and nasal deposition ratio when comparing aerosol administration during two different administration routes. METHODS: An open label deposition study in healthy volunteers was conducted using 99mTc-DTPA radiolabeled pulsating aerosols in comparison to nasal pump sprays. Deposition and retention of pulsating aerosols was assessed by gamma camera imaging during spontaneous nasal breathing and during closed soft palate administration. RESULTS: Aerosol administration during nasal breathing vs. application with closed soft plate results in significant lung, nasal and sinus deposition. No significant differences were observed for nasal clearance. In comparison, drug delivery using nasal pump sprays resulted in non-significant sinus, 100 % nasal and non-significant lung deposition. The clearance kinetics after nasal pump spray delivery was significantly accelerated. DISCUSSION: The standard application mode of pulsation aerosols with closed soft palate results in negligible lung deposition and therefore limits drug delivery to the nasal cavity only, minimizing unwanted side effects. Administration during spontaneous nasal breathing shows only 10% lung deposition, which is tolerable during drug administration. Relevant paranasal sinus deposition is noted during both application modes and clearance kinetics remains essentially unchanged. In contrast, nasal pump sprays do not show sinus drug delivery and nasal drug residence time is shortened. CONCLUSION: Pulsating aerosols offer advantageous topical nasal and sinus drug delivery options.

Particle clearance from the airways of subjects with bronchial hyperresponsiveness and with chronic obstructive pulmonary disease.

The aim of this study was to determine particle clearance and retention from non-alveolated airways of 14 healthy subjects (HS), 10 subjects with asymptomatic bronchial hyperresponsiveness (BHR), and 23 patients with chronic obstructive pulmonary disease (COPD). Monodisperse iron oxide particles of 1.6 micro m geometric and 3.5 micro m aerodynamic diameter labeled with (99m)Tc were delivered to the airways by inspiration of small aerosol boli into shallow volumetric lung depths. In each subject the penetration front depth of the aerosol boli was adjusted to 55% of the Fowler dead space of the airways. Particle deposition was enhanced by about 7 seconds of breath-holding after bolus inhalation. Retention of the particles in the airways during the 48 hours after their administration was assessed by measuring the decline in lung activity with a sensitive gamma counter. Particle deposition was not significantly different among study groups. Twenty-four hour particle retention in the airways was not different among study groups. Sixty-one percent of the particles were retained at 24 hours in HS, 58% in BHR, and 64% in COPD. However, subjects with BHR showed accelerated mucociliary clearance compared to healthy subjects, whereas clearance was retarded in COPD patients. This long-term particle retention in the airways has to be taken into account in aerosol toxicology risk assessment and aerosol therapy dose evaluation.

[Pulmonary nocardiosis with trimethoprime/sulphamethoxazole-resistant Nocardia paucivorans in a patient with no signs of immunosuppression]. / Pulmonale Nokardiose mit Trimethoprim/Sulfamethoxazol resistenter Nocardia paucivorans bei einem Patienten ohne Hinweise auf Immunsuppression.

This is so far the first published case report of a Nocardia paucivorans infection in an immunocompetent patient. A 54-year-old farmer was hospitalised with a history of coughing and fever for a period of five months. There was no indicator of either primary of secondary immunodeficiency in the prior medical history. A chest X-ray showed pneumonic infiltrates in the right middle und lower lobes, which progressed despite of antibiotic therapy with macrolides. A transbronchial biopsy revealed unspecific granulomatous inflammation of soft tissues. N. paucivorans - grew in cultures of sputum, bronchoalveolar lavage, and transbronchial biopsy. Oral antibiotic therapy was started with trimethoprime-sulphamethoxazole (TMP/SMX) and amoxicillin plus clavulanic acid. Susceptibility testing revealed high level resistance to TMP/SMX, which was consequently replaced by ciprofloxacin. Six months later, infiltrates had completely resolved and the patient did not report any residual clinical symptoms. The present case showed once again that nocardiosis is not limited to patients with immunodeficiencies. However, conservative combination therapy with oral antibiotics seems to be sufficiently effective for nocardiosis in the immunocompetent patient. For cases of suspected nocardiosis, a step-wise, risk-based diagnostic and therapeutic procedure is proposed.

Anticoagulative effects of the inhaled low molecular weight heparin certoparin in healthy subjects.

Inhalation of heparin results in local antiinflammatory and antifibrotic effects and an inhibition of blood coagulation. A number of experimental and clinical studies demonstrated that inhalant administration of heparin or low molecular weight heparin (LMWH) is a feasible and save tool for anticoagulative treatment. However, heparin and LMWH differ in respect to their molecular weight, pulmonary absorption, and principle of their anticoagulative pattern. In our study we investigated the anticoagulative effect of different doses of the LMWH certoparin after inhalation (3000 IU-9000 IU) and subcutaneous injection (3000 IU) in healthy individuals in a cross-over design. Inhalations were performed using a new device allowing inhalations with optimized and standardized breathing patterns. The anticoagulative effect was determined by measurement of the anti-factor-Xa (anti-FXa) activity. Lung function parameters were measured before and after drug inhalation. Analysis of the anti-FXa activity as a function of the time after administration revealed values of the area under the curve (AUC) of 5.70+/-1.58 U.hour/ml and 8.43+/-1.31 U.hour/ml (mean+/-SD) with interindividual coefficients of variation of 28% and 13% after injection of 3000 IU and inhalation of 9000 IU, respectively. The AUC after inhalation of 9000 IU was significantly higher (P=0.0007) compared with subcutaneous injection of 3000 IU. In consequence, in order to obtain plasma anti-FXa activities of above 0.2 U/ml, which is considered sufficient for prophylaxis of venous thrombosis, 9000 IU LMWH have to be inhaled. Compared with the subcutaneous administration, the action of certoparin is longer after inhalation than after injection. Apparently, the drug is released rapidly according to a two-compartment kinetics, and its anticoagulant activity lasts over a long time without a marked plasma peak after administration. In detail, an elevation of plasma anti-FXa activity is achieved for 12 hours to 24 hours without a distinct peak shortly after inhalation. Inhalation of LMWH does not result in any changes in lung function or other side effects. The administration of LMWH by inhalation bears the following: the non-invasive route of drug application, the low interindividual variability of the anticoagulative effect, and a long-time pharmacological effect. These properties suggest that controlled inhalation of heparin is an attractive alternative to subcutaneous administration.

[Comparison of unspecific bronchial provocation during controlled and spontaneous inhalation]. / Vergleich der unspezifischen bronchialen Provokation mit Methacholin unter kontrollierter und freier Inhalation.

Using controlled breathing patterns during inhalation of drugs is characterized by a high dose reproducibility which may be of advantage for bronchial provocation testing. In this study 30 healthy subjects with an anamnesis of atopy underwent in a randomized cross-over design bronchial provocation testing with methacholine either with the Viasys-Jäger-APS system or with controlled inhalations (AKITA-System) (controlled inhalation volume and flow). Measured was the frequency of positive test results. Positive test results were defined by a 20 % decline of FEV (1) or a 100 % increase of specific airway resistance (sRaw). There were no significant differences in the prevalence of positive test results obtained with both techniques: APS-FEV (1) : 8, AKITA-FEV (1) : 9; APS-sRaw: 18, AKITA-sRaw: 17. More subjects showed a 100 % increase of sRaw as compared to a 20 % decrease of FEV (1), which may be interesting in order to understand differences in the diagnostic information given by both parameters. However, there were some discrepancies: only in 25 of 30 cases (sRaw: 21 of 30 cases) the results (positive or negative) agreed between both techniques. Although the two techniques for bronchial provocation test showed some discrepancies, these data suggest that controlled inhalations may be an alternative to the APS-system.

[Six-minute-walking-test with and without oxygen in patients with COPD: comparison of walking distance and oxygen saturation in varying forms of application]. / Sechs-Minuten-Gehtest mit und ohne Sauerstoff bei Patienten mit COPD: Vergleich von Gehstrecke und Sauerstoffsättigung bei unterschiedlichen Applikationsformen.

BACKGROUND: Patients afflicted with COPD and respiratory Failure often experience a decrease of oxygen saturation (SaO (2)) under physical strain. The aim of our study was to find out which changes occur in walking distance and SaO (2) under the application of Oxygen (O (2)) 2 l/min continous flow, under demand (D) and under normal air (RL) when performing the Six-Minute-Walking-Test (6MWT) and further, in which way do the 10 patients of the shortest walking distance group (group I) differ from the eo patients with the longest walking distance (group II) concerning the starter 6 MWT (under CF). METHOD AND PATIENTS: 27 patients undertook a 6MWT three days in a row with CF, D and (RL), 6 minutes before (phase I), during (phase II) and after (phase III) the 6MWT oxygen was applied in CF (day I), D (day II) and RL (day III), the mean oxygen saturation in each phase was measured and the change (DeltaSaO (2)) during and after the 6MWT was calculated. Additionally we measured the DeltaSaO (2) between start and middle, as well as between middle and end of each phase. In close proximity to the tests FEV (1) and pO (2) was determined. RESULTS: In the total of all test persons there was no significant difference in the walking distance tetween the 3 forms of application. There was, however, a highly significant decrease of the oxygen saturation. The decrease in the two forms of oxygen application did not differ significantly. The decrease of SaO (2) under strain and the consecutive rise under rest occurred within the first 3 minutes of each phase. Patients of group II were often able to increase their walking distance under RL, whereas patients of group I decreased their walking distance further. In group II FEV (1) abs. was significantly higher, but FEV (1) % debit and pO (2) did not differ significantly between both groups. CONCLUSIONS: Patients with a long walking distance showed a marked learning effect even under RL, they presented a higher FEV (1), but not an increased pO (2). The phase of resaturation after the end of strain is short. Oxygen application through a demand valve with a flow rate of 2 l/min is not inferior to a continuous flow. In more than half of all patients the SaO (2) fell below 90 % under both forms of oxygen application, in conclusion the flow rate should be increased in these cases.

Autofluorescence bronchoscopy with white light bronchoscopy compared with white light bronchoscopy alone for the detection of precancerous lesions: a European randomised controlled multicentre trial.

BACKGROUND: The potential of autofluorescence bronchoscopy (AFB) to detect precancerous lesions in the central airways and its role in lung cancer screening is uncertain. A study was undertaken to evaluate the prevalence of moderate/severe dysplasia (dysplasia II-III) and carcinoma in situ (CIS) using a newly developed AFB system in comparison with conventional white light bronchoscopy (WLB) alone. METHODS: In a prospective randomised multicentre trial, smokers > or = 40 years of age (> or = 20 pack-years) were stratified into four different risk groups and investigated with either WLB+AFB (arm A) or WLB alone (arm B). RESULTS: 1173 patients (916 men) of mean age 58.7 years were included. Overall (arms A and B), preinvasive lesions (dysplasia II-III and CIS) were detected in 3.9% of the patients. The prevalence of patients with preinvasive lesions in the WLB arm was 2.7% compared with 5.1% in the WLB+AFB arm (p = 0.037). For patients with dysplasia II-III, WLB+AFB increased the detection rate by a factor of 2.1 (p = 0.03), while for CIS the factor was only 1.24 (p = 0.75). The biopsy based sensitivity of WLB alone and WLB+AFB for detecting dysplasia II-III and CIS was 57.9% compared with 82.3% (1.42-fold increase). The corresponding specificity was 62.1% compared with 58.4% (0.94-fold decrease). CONCLUSIONS: This first randomised study of AFB showed that the combination of WLB+AFB was significantly superior to WLB alone in detecting preneoplastic lesions. Our findings do not support the general use of AFB as a screening tool for lung cancer, but suggest that it may be of use in certain groups. The precise indications await further study.

[The ovarian hyperstimulation syndrome -- a rare differential diagnosis of a unilateral pleural effusion]. / Das ovarielle Hyperstimulationssyndrom -- eine seltene Differenzialdiagnose des einseitigen Pleuraergusses.

This case presentation describes a 29 year-old female who developed a severe ovarian hyperstimulation syndrome (OHSS) with ascites and a right-sided pleural effusion following in-vitro-fertilisation. A total of 4,2 l of pleural fluid was removed during 3 thoracocenteses. The symptoms as well as the fluid production ceased after 2 weeks. The OHSS is altogether a rare, but potentially life-threatening complication of in-vitro-fertilisation. Due to the well-characterized clinical setting in which the syndrome appears, there are only few differential diagnoses to consider. OHSS is likely to originate from altered capillary permeability, but its pathogenesis is not yet fully understood. Clinical symptoms usually resolve within 2 weeks of supportive therapy. In case of persistency, however, especially pulmonary embolism and infectious causes of pleural fluid production have to be excluded.

[Endobronchial lipoma: successful therapy by bronchoscopical laser resection vs. surgery]. / Endobronchiales Lipom: erfolgreiche Therapie mittels bronchoskopischer Laserresektion versus Chirurgie.

BACKGROUND: Endobronchial lipoma is a very rare benign lung tumor. Therapeutic alternatives are the interventional bronchoscopic laser resection or surgical treatment. METHODS: From 1996 to 2002 we diagnosed 16 patients with endobronchial lipoma in our institution. We examined the clinical data of the patients and their influence on the individual patient treatment. RESULTS: 14 (88 %) out of the 16 patients (60 +/- 14 y.) were male. Clinical symptoms were cough (81 %), dyspnea (75 %), pulmonary infiltration (63 %) and fever (31 %). In the right lung 11 lipomas (69 %) were located, in the left lung 5 lipomas (31 %). The distribution to main bronchus, upper lobe, middle lobe and lower lobe bronchus were 2 (12.5 %), 6 (37.5 %), 2 (12.5 %) und 6 (37.5 %). 14 (88 %) lipomas were found in the central airways, 2 were located in the periphery of the lung. All lipomas in the central airways were successfully treated by bronchoscopic laser therapy with a mean of 1.1 +/- 0.3 laser sessions. One patient died of concomitant bronchial carcinoma before therapy. Surgical treatment was only necessary in a very peripherally located huge lipoma and a lipoma with extensive parenchym destruction. CONCLUSIONS: Bronchoscopic laser resection should be considered as first line therapy in cases of endobronchial lipoma. It is safe, successful, rapid and less expensive compared to surgical resection. Surgery should only be indicated in patients with lipomas with very peripherally localisation or parenchym destruction, extrabronchial growth, suspected malignancy or technical problems at bronchoscopic resection.

Characterization of a population of small macrophages in induced sputum of patients with chronic obstructive pulmonary disease and healthy volunteers.

The inflammatory process in chronic obstructive pulmonary disease (COPD) is active mainly in the airways, but little is known about the properties of the inflammatory cells in this compartment. We have studied leucocytes in induced sputum of COPD patients compared to controls in order to uncover what types of macrophages might be involved in the disease. Sputum induction was performed by inhalation of nebulized sodium chloride solution. Leucocytes were isolated and stained with specific monoclonal antibodies for analysis in flow cytometry. Flow cytometry analysis revealed that a major portion of CD14+ macrophages in COPD has lower forward scatter, i.e. they are small macrophages. While in control donors these small macrophages accounted for 6.9% of all macrophages, the percentage of these cells in COPD was 45.7%. CD14 and HLA-DR expression was high on these small sputum macrophages while the large sputum macrophages expressed only low levels of these surface molecules, both in control donors and COPD patients. Small sputum macrophages of both control donors and COPD patients showed higher levels of constitutive tumour necrosis factor (TNF) compared to the large macrophages. TNF was inducible by lipopolysaccharide (LPS) preferentially in the small sputum macrophages in the control donors but there was no further induction in COPD patients. These data show that the small sputum macrophages are a major macrophage population in COPD and that these cells exhibit features of highly active inflammatory cells and may therefore be instrumental in airway inflammation in COPD.

[Powder inhalation systems]. / Pulverinhalationssysteme.

Inhalation of bronchodilators and corticosteroids is the mainstay treatment for patients with obstructive lung diseases. Many dry powder inhaler devices and drug combinations are now available, and competing promotional claims can confuse both prescribers and patients. The appropriate dose of a given drug may be different for a pressurized metered dose inhaler (pMDI) and a dry powder inhaler (DPI). DPIs create aerosols by drawing air through an aliquot of dry powder. The powder contains either micronized (< 5 micro m in diameter) drug particles bound into loose aggregates, or micronized drug particles that are loosely bound to large (> 30 micro m in diameter) lactose or glucose particles. Usually, the drug particles are bound to carrier particles and are stripped form the carrier particles by the energy provided by the patientacute;s inhalation. The release of respirable particles of the drug requires inspiration at relatively high flow rates (30 - 120 L/min). Other important factors influencing aerosol generation and lung deposition are device design (resistance to airflow) and environmental conditions (humidity, temperature). Preferably, patients should employ only one type of aerosol-generating device for inhalation therapy. The technique of use varies among devices, and repeated instruction is highly advisable, to ensure that the patient uses the device appropriately. At present, DPIs are recommended for prophylactic and maintenance therapy in patients with asthma and chronic obstructive pulmonary disease, but not for patients with acute severe bronchoconstriction or children less than 5 years of age.

Influence of inflammatory mechanisms on the redox balance in interstitial lung diseases.

This study investigated the hypothesis that inflammatory, regulatory and antioxidant systems control the redox balance in interstitial lung diseases. Spontaneous mRNA expression of inflammatory cytokines and redox-active enzymes was examined in bronchoalveolar lavage (BAL) cells from patients with idiopathic pulmonary fibrosis (IPF) and sarcoidosis (SARC) using RT-PCR analysis. Pulmonary oxidative stress was characterized by carbonyl-levels in the soluble BAL-fluid protein. Protein carbonyls were normal in SARC, but 2.4-fold increased in IPF. Here, the protein carbonyls correlated inversely with glutathione peroxidase mRNA. The message for IL-8 increased 14-fold in IPF and was accompanied by a marked influx of PMN, while these parameters were not altered in SARC. Levels of IL-10 transcripts increased in both diseases, but stronger in SARC (33-fold) than in IPF (22-fold), contributing to a high IL-10/IL-8 mRNA ratio in SARC (0.86) in comparison to IPF (0.07) and controls (0.04). In SARC but not in IPF, IFN-gamma mRNA was expressed at high levels and correlated inversely with the carbonyl levels. In both diseases, IL-1beta, TNF-alpha, and IL-6 mRNA transcripts remained at baseline level. In summary, a low IL-10/IL-8 mRNA ratio was paralleled with significant oxidative stress in IPF, while a high IL-10/IL-8 ratio and enhanced IFN-gamma expression went along with a physiological redox-balance in SARC.

[Inhaled antibiotic therapy in bronchiectasis?]. / Antimikrobielle Aerosoltherapie bei Bronchiektasen?

Antimicrobial therapy is an important aspect of disease management for patients with bronchiectasis. Delivery of an inhaled antibiotic is an appealing alternative to oral or intravenous administration because the antibiotic is delivered in high concentrations directly to the site of infection, eliminating the need for high systemic concentrations and reducing the risk of systemic toxicity. In recent controlled studies these potential benefits have been assessed in patients with bronchiectasis who became colonized by P. aeruginosa and the results support the use of nebulized antibiotics. In up to one-third of patients P. aeruginosa was eradicated from their sputum by inhaled antibiotic therapy and up to 62 % of patients showed improved medical condition. The further development of new aerosol devices supported by clinical testing will allow effective management of patients with bronchiectasis by an inhalation therapy that minimizes time constraints and drug loss which may improve health status and quality of life.

[Pulmonary infiltrates with blood eosinophilia in a 62-year-old patient]. / Pulmonale Infiltrate mit Bluteosinophilie bei einer 62-jährigen Patientin.

A 62-year-old woman was admitted because of chronic cough and bilateral infiltrates on chest roentgenogram. Additional history revealed that the patient had been taken diclofenac emulgel during the previous 10 years for arthrosis. Diagnostic bronchoscopy showed eosinophilic alveolitis. After ruling out infectious, parasitic or systemic diseases drug-induced eosinophilic pneumonia was diagnosed due to topical diclofenac therapy and subsequent percutaneous drug absorption. No previous case of eosinophilic pneumonia to topical diclofenac was discovered in our review of the literature. The diclofenac therapy was discontinued. Oral corticosteroid therapy cleared bilateral infiltrates on CT scan within seven days. Drug reactions are the most common cause of pulmonary infiltrates with blood eosinophilia and/or eosinophilic alveolitis and should be considered as a differential diagnosis.