Henrik Riska

Delivery Devices for Inhaled Asthma Medication

This review deals with results of comparative clinical studies where 2 or more delivery devices have been used, the lung deposition of the drug has been measured or is known and the clinical efficacy has been documented. With optimal inhalation technique the lung deposition of inhalation devices is approximately as follows: pressurised metered dose inhalers (pMDIs) 10 to 15% [salbutamol (albuterol) around 20%]; pMDI + spacer 20 to 30%; Rotahaler®, Diskhaler® and Inhalator Ingelheim® around 10%; Easyhaler® 20 to 25%; and Turbuhaler® 20 to 35% of the metered dose depending on the substance. These differences in deposition figures have been reflected in the results of most single-dose crossover studies with bronchodilator substances. A pMDI is clinically more effective than Rotahaler® and Diskhaler®. Turbuhaler® is more effective than a pMDI. In single-dose studies where expected differences based on deposition values have been undetected, all responses have probably been on the top of the dose-response curves. Studies with a cumulative-dose design have not usually reflected known differences in deposition values between bronchodilator devices. This discrepancy between single-dose crossover studies and cumulative-dose studies seems to be the result of different doses and amounts of drug administered at different time points (especially the first dose) in the cumulative-dose studies. Studies with repeated doses over weeks and months do not reflect differences in deposition values between bronchodilator devices, since short-acting bronchodilators, irrespective of the delivery system, do not affect the level of airway function in the morning. There are only 2 studies comparing the efficacy of a long-acting bronchodilator given via 2 different devices. Anti-inflammatory medication is impossible to evaluate without using long screening periods, when the lowest required maintenance dosage of the inhaled corticosteroid has to be individually defined. Comparative studies are meaningless without knowing that patients are neither under- nor over-treated when entering the study. Thereafter, comparisons can be made in studies with a duration of several months. Very few studies fulfil these criteria. However, the results of these types of studies do reflect differences in deposition values between delivery devices. Studies reported so far show that the budesonide Turbuhaler® is clinically approximately twice as effective as a budesonide pMDI or a beclomethasone pMDI with spacer. The results of short-term studies seem to indicate that fluticasone is twice as effective as beclomethasone, irrespective of pMDI or Diskhaler® delivery system. So far no well-designed double-blind studies have been performed comparing the budesonide Turbuhaler® with fluticasone via pMDI or Diskhaler®. No deposition data are available for fluticasone (in pMDI, Diskhaler® or Diskus®/Accuhaler®), or for the most recent device introductions such as the Diskus®/Accuhaler® with any substance. The Easyhaler® (available with salbutamol or beclomethasone) has good deposition values, but has not been compared clinically with Turbuhaler®, Diskhaler® or Diskus®/Accuhaler®. Even when used properly, delivery devices may deposit very different amounts of drug into the lungs. Also, pMDIs may have different deposition properties. Recent studies with bronchodilators and corticosteroids have shown that there is a good correlation between the amount of drug deposited in the lungs and the level of clinical efficacy.

Transformation of Membranous Glomerulonephritis into Crescentic Glomerulonephritis with Glomerular Basement Membrane Antibodies

This case report describes a patient who initially had a pleuritis and arthalgias. During the follow-up he developed first a membranous glomerulonephritis with nephrotic syndrome and subsequently a crescentic, rapidly progressive glomerulonephritis with glomerular basement membrane antibodies (anti-GBM). An analysis of the serum samples obtained during the follow-up revealed no infections at the onset of renal failure. However, anti-GBM could be demonstrated in the serum samples obtained 2 months before the deterioration of the renal function. The anti-GBM did not react with alveolar BM and the patient had no signs of pulmonary hemorrhage. The etiology and the sequence of the pathological events of rapidly progressive glomerulonephritis is discussed in the light of these observations.

Pleural fluid beta-2-microglobulin and angiotensin-converting enzyme concentrations in rheumatoid arthritis and tuberculosis

Concentrations of beta 2-microglobulin (B2M) and angiotensin-converting enzyme (ACE) were measured in pleural fluid (Pf) and serum (S) of 364 patients with pleural effusions. Eleven patients had rheumatoid arthritis (RA), 36 verified tuberculosis (TB), 15 suspected TB, 120 cancer, 21 empyema, 34 pneumonia, 33 various defined diseases, 67 effusions of unknown aetiology and 27 congestive heart failure. The median concentrations of Pf-B2M and Pf-ACE were significantly higher in patients with RA than in patients with any other disease (p < 0.005). Tuberculous effusions contained higher Pf-ACE concentrations than any other type of non-rheumatoid effusion (p < 0.05). With sensitivities of 91%, the specificity of Pf-B2M and Pf-ACE for the diagnosis of RA was 86% and 55%, respectively. Local cellular immune events probably account for the abundance of B2M and ACE in rheumatoid and tuberculous pleural effusions. Pf-B2M and Pf-ACE determinations may aid in the differentiation of rheumatoid and tuberculous pleurisy from other types of pleural disease.

Studies of cytokine levels in bronchoalveolar fluid lavage from patients with interstitial lung diseases

Cytokine levels in bronchoalveolar lavage fluid from patients with eosinophilic pneumonia (n=7), allergic alveolitis (n=11), (cryptogenic) fibrosing alveolitis (n=8), sarcoidosis (n=10) were determined, as well as levels in control samples from healthy non‐smoking volunteers (n=11). Fibronectin levels were increased in all the patient categories, the highest absolute levels of fibronectin (100‐fold increase) being found in eosinophilic pneumonia and allergic alveolitis. TGF‐β (transforming growth factor‐β) was significantly elevated in allergic alveolitis only. There was a significant difference between allergic alveolitis on the one hand and both sarcoidosis and fibrosing alveolitis on the other. Tumour necrosis factor‐α (TNF‐α) was significantly increased in eosinophilic pneumonia and allergic alveolitis; allergic alveolitis and fibrosing alveolitis differed significantly in this respect. Platelet‐derived growth factor‐BB (PDGF‐BB) levels were significantly elevated in allergic alveolitis and fibrosing alveolitis. It was found that the level of PDGF‐BB was significantly decreased in the case of sarcoidosis, with no overlapping with allergic alveolitis or fibrosing alveolitis. Interferon‐γ (IFN‐γ) was decreased in all patient categories. A significant difference in extent of the decrease was found between allergic alveolitis and sarcoidosis. The interstitial lung diseases thus differed in the pattern of cytokines expressed, indicating that these cytokines could well be a part of the pathogenic process, and also that the measurement of cytokine levels could be diagnostically useful.

Preventive effects of inhaled formoterol and salbutamol on histamine-induced bronchoconstriction : a placebo-controlled study

The preventive effects of inhaled formoterol (a new beta 2-agonist) and salbutamol aerosols on histamine-induced bronchoconstriction were studied in 12 patients with mild or moderate asthma in a placebo-controlled, double-blind study. Three hours after the administration of 12 micrograms formoterol, 200 micrograms salbutamol (doses with equal bronchodilator effects) or placebo via aerosol, histamine challenge was undertaken, using a dosimetric jet nebulizer with controlled tidal breathing. The noncumulative dose of histamine diphosphate aerosol provoking a 15% fall in FEV1 (PD15) was calculated. The PD15 after inhalation of 12 micrograms formoterol was significantly higher than that after 200 micrograms salbutamol (median values 640 and 310 micrograms, respectively; p < 0.01). For both treatments, the PD15 was significantly higher than that after placebo (median 185 micrograms). The results indicate that the preventive effect against histamine-induced bronchoconstriction at 3 h after drug is significantly better with formoterol than with salbutamol when using inhaled doses with an equal acute bronchodilator effect.

Plasmapheresis for idiopathic thrombocytopenic purpura unresponsive to intravenous immunoglobulin.

To the Editor Several alternative treatments, including immunosuppressive drugs, intravenous immunoglobulin (IVIg) and plasmapheresis are available for patients with idiopathic thrombocytopenic purpura (ITP), unresponsive to corticosteroids and splenectomy. We report a patient with severe acute ITP, whose thrombocytopenia was not affected by corticosteroids or IVlg, but reversed after plasmapheresis treatment followed by splenectomy. A 26-yr-old woman previously in good health presented with a respiratory tract infection, a 2-d history of cutaneous and mucosal bleeding and a platelet count of 1 x 109/l. Her haemoglobin value was 113 g/l and her leukocyte count 4.9 x 109/1 with a normal differential. A sternal marrow aspirate contained an elevated number of megakaryocytes. Anti-platelet antibodies were detected both in the serum (indirect Coombs technique) and on the platelets (direct Coombs technique). The titre of anti-nuclear antibodies was 1/10 and anti-DNA ranged from 17 to 23 mg/l (reference value < 5 mg/l). Incipient systemic lupus erythematosus was considered possible, but the patient fulfilled only 2 of the American Rheumatism Associations criteria revised in 1982. A test for anticardiolipin antibodies was negative. The concentration of C3 fell from 0.61 to 0.30 g/l (0.55-1.20 g/l) and that of C4 from 0.14 to 0.04 g/l (0.20-0.50 g/l). No anti-viral antibodies were detected. Therapy with prednisone (120 mg/d) was started immediately, but the severe thrombocytopenia persisted and bleeding continued. On the 3rd d after she had been admitted, a 5-d course of IVIg (Sandoglobulin@ 0.4 g/kg/d) was initiated, but no effect on the platelet count was seen (Figure 1). Another 5-d course of IVIg 2 wk later also proved unsuccessful. On d 25, 27 and 29 after admission, the patient underwent plasmapheresis in an attempt to reduce the concentration of anti-platelet antibodies. Plasmapheresis was performed with a Travenol CPS-10 plasmafilter (using a Gambro AK-10 blood unit and a right femoral vein catheter). The substitution fluid consisted of 20% albumin solution (Finnish Red Cross Blood Service, Helsinki) and Ringers lactate in a ratio of 1/5. During the 3 d a total of 9000 ml of plasma was exchanged. Each plasmapheresis resulted in an increase in the 120 n Prednisone (mg/day)

Proteomic changes of alveolar lining fluid in illnesses associated with exposure to inhaled non-infectious microbial particles.

Background Hyperresponsiveness to inhaled non-infectious microbial particles (NIMPs) has been associated with illnesses in the airways. Hypersensitivity pneumonitis (HP) is considered to be the prototype for these NIMPs-related diseases; however, there is no consensus on the definitions or diagnostic criteria for HP and the spectrum of related illnesses. Methods and Findings In order to identify the possible diagnostic markers for illnesses associated with NIMPs in alveolar lining fluid, we performed a proteomic analysis using a two-dimensional difference gel electrophoresis on bronchoalveolar lavage (BAL) fluid from patients with exposure to NIMPs in the context of damp building-related illness (DBRI) or conditions on the borderline to acute HP, designated here as agricultural type of microbial exposure (AME). Samples from patients with HP and sarcoidosis (SARC) were included for reference. Results were compared to results of healthy subjects (CTR). Western blot was used for validation of potential marker proteins from BAL fluid and plasma. Protein expression patterns suggest a close similarity between AME and HP, while DBRI was similar to CTR. However, in DBRI the levels of the inflammation associated molecules galectin-3 and alpha-1-antitrypsin were increased. A novel finding emerging from this study was the increases of semenogelin levels in BAL fluid from patients with AME, HP and SARC. Histone 4 levels were increased in AME, HP and SARC. Elevated plasma levels of histone 2B were detected in HP and SARC, suggesting it to be a potential blood indicator for inflammatory diseases of the lungs. Conclusions In this study, the proteomic changes in bronchoalveolar lavage of DBRI patients were distinct from other NIMP exposure associated lung diseases, while changes in AME overlapped those observed for HP patient samples. Some of the proteins identified in this study, semenogelin and histone 4, could function as diagnostic markers for differential diagnosis between DBRI and HP-like conditions.