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We compared in vitro drug delivery characteristics of two budesonide/formoterol dry powder inhalers, the Bufomix Easyhaler®and the budesonide/formoterol Turbuhaler®, at different patient air flow rates, and to test dose delivery from the Easyhaler in stressed conditions exposed to moisture, dropping, vibration and freezing/thawing. A total of 36 inhalers from two batches of both products (160/4.5 µg strength) were used when comparing the effect of flow rate; six inhalers for each of the three flow rates for uniformity of delivered dose (DD), fine particle dose (FPD), mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD). Consistency of DD, FPD, MMAD and GSD were determined for each inhaler at three different flow rates: 10th, 50th and 90th percentile air flows. Dosing properties as a function of inhaler life were tested. The effects of moisture, dropping, vibration and freezing/thawing on DD and FPD were tested with two to four inhalers per test using all three strengths of Easyhaler: 80/4.5, 160/4.5 and 320/9 µg. The Easyhaler, 160/4.5 µg, showed statistically significantly better dose consistency (expressed as percentage of labelled dose) at all three inhalation flows compared with the Turbuhaler, 160/4.5 µg, (p< 0.001 for three flow rates). Exposure to moisture, dropping, vibration and freezing/thawing did not affect DD or FDP. These results were similar to all three tested Easyhaler strengths. In vitro performance of the Easyhaler indicates reliable dosing. Dose consistency was superior compared with the Turbuhaler at all tested flow rates. Environmental moisture, dropping, vibration and freezing/thawing did not affect the performance. Orion Corporation Orion Pharma.

In a double-blind, randomized study, 136 children, 5–10-y-old, with newly detected persistent asthma received budesonide (BUD) 400 µg twice daily for 1 mo and thereafter 200 µg twice daily for 5 mo. Thereafter, 50 children were treated with BUD 100 µg twice daily, whereas 44 children used BUD as needed for 1 y; an additional 42 children received disodium cromoglycate (DSCG). Asthma exacerbations were treated with BUD for 2 wk in a dose of 400 µg twice daily in all groups. In this secondary analysis, bone mineral density (BMD) of the lumbar vertebrae was measured before and after the 18-mo treatment. Compared with DSCG, regular BUD treatment resulted in a significantly smaller increase in BMD (0.023 versus 0.034 g/cm2; p = 0.023) and height (7.75 versus 8.80 cm; p = 0.001). Periodic treatment did not affect BMD. No intergroup differences were observed when BMD data were adjusted for changes in height. Daily BUD treatment in prepubertal children may slow down the increment in BMD and standing height. This was not observed in children receiving BUD periodically after the initial regular BUD treatment. The correlation between height and BMD suggests that following children's height might afford an estimation of inhaled corticosteroid effects on bone.

In a double-blind, randomized study, 136 children, 5–10-y-old, with newly detected persistent asthma received budesonide (BUD) 400 g twice daily for 1 mo and thereafter 200 g twice daily for 5 mo. Thereafter, 50 children were treated with BUD 100 g twice daily, whereas 44 children used BUD as needed for 1 y; an additional 42 children received disodium cromoglycate (DSCG). Asthma exacerbations were treated with BUD for 2 wk in a dose of 400 g twice daily in all groups. In this secondary analysis, bone mineral density (BMD) of the lumbar vertebrae was measured before and after the 18-mo treatment. Compared with DSCG, regular BUD treatment resulted in a significantly smaller increase in BMD (0.023 versus0.034 g/cm2; p0.023) and height (7.75 versus8.80 cm; p0.001). Periodic treatment did not affect BMD. No intergroup differences were observed when BMD data were adjusted for changes in height. Daily BUD treatment in prepubertal children may slow down the increment in BMD and standing height. This was not observed in children receiving BUD periodically after the initial regular BUD treatment. The correlation between height and BMD suggests that following children's height might afford an estimation of inhaled corticosteroid effects on bone.

In adults, asthma treatment with high doses of inhaled corticosteroids has resulted in dermal thinning. The aim of this study was to investigate the skin thickness in children with asthma during budesonide treatment. In a double-blind study, 113 children, 5–10 y old, with persistent asthma received budesonide 400 μg twice daily for 1 mo and thereafter 200 μg twice daily for 5 mo. Thereafter, 56 children received 100 μg twice daily for 1 y, whereas 57 other children used budesonide periodically for exacerbations. An additional 54 children were treated with disodium cromoglycate (DSCG) for 18 mo. Skin thickness was measured on each forearm before and after treatment for 6, 12, and 18 mo using a 20-MHz high-resolution ultrasonic device. The initial 6-mo budesonide treatment resulted in a greater reduction in mean skin thickness in the forearms compared with DSCG (right: −35.9 versus−5.9 μm; p0.004; left: −30.6 versus−7.3 μm; p0.03). At month 18, the inter-group differences were no longer significant. Budesonide inhalations in daily doses of 400–800 μg in prepubertal children with newly detected asthma may cause minor dermal thinning. The changes were reversible during low dose or periodic treatment with budesonide.

This review evaluates dose-response and comparative studies with inhaled corticosteroids (ICS) in asthma. A dose-response relationship for lung function variables has been demonstrated for some ICS, but not for all. Measurements of anti-inflammatory properties, e.g. bronchial challenge with adenosine 6-monophosphate, may provide better possibilities to detect dose-response relationships and differences between ICS. Studies with the same ICS delivered by different inhalers with different lung deposition characteristics show that efficacy is strongly related to the amount of drug deposited in the airways. Comparative studies with different ICS using different inhalers have often used doses resulting in effects at the top of the dose-response curve. However, a lack of statistically significant difference between treatments does not mean therapeutic equivalence. Comparative clinical studies should be performed with dose-response curves of both products and the relative dose ratio should be estimated. The minimum criterion is to use one dose of one product and fit the result of that treatment to a dose-response curve of the other. Down titration represents an alternative, clinically reliable study design. Clinically relevant differences between doses and treatments should be defined prior to the study; a proper power calculation has to be performed; and comparisons should be made on the dose scale rather than the effect scale.

The dry-powder inhaler (DPI) Turbuhaler® has been on the market for nearly two decades. Products containing terbutaline, formoterol, budesonide, and the combination budesonide/formoterol are widely used by patients with asthma and COPD. Most patients and physicians find Turbuhaler® easy to use, and local side effects are rare. This is thought to arise from the lack of additives or only small amounts in the formulation, in addition to minimal deposition of the drug in the oropharynx and on the vocal cords during inspiration.

ABSTRACTObjective:To evaluate efficacy and costeffectiveness of budesonide/formoterol (Symbicort*) maintenance (one dose once or twice daily) plus additional doses as needed (Symbicort Maintenance And Reliever Therapy, SMART) compared with a higher fixed dose of budesonide/ formoterol with formoterol as needed in patients with persistent asthma. *Symbicort is a registered trade name of the AstraZeneca group of companiesStudy design and methods:6‐month, open, randomised study of 465 patients either not well controlled on an inhaled corticosteroid (ICS), or well controlled on a combination of ICS and a long-acting β2‐agonist (LABA). Treatments: budesonide/formoterol 160/4.5 µg, one inhalation, once or twice daily maintenance plus additional doses as-needed (1 × SMART or 2 × SMART), or budesonide/formoterol 160/4.5 µg two inhalations twice daily plus formoterol 4.5 µg as needed (2 × 2 FIX + F). Children 6–11 years old used an 80/4.5 µg dose strength. Primary variables of efficacy were the changes in the Asthma Control Questionnaire (ACQ5) and morning peak expiratory flow (PEF).Results:Mean age of patients 40 years (range 6–82 years); 53% female. No differences between the groups were found in ACQ5scores or asthma exacerbation rates. Morning PEF was higher in the 2 × 2 FIX + F group vs. the 1 × SMART and 2 × SMART groups (differences 13 L/min and 9 L/min, respectively; p< 0.002). The 1 × SMART group showed a significant decrease in asthma controlled days compared with the two other groups. No difference was seen between the 2 × SMART group and the 2 × 2 FIX + F group. Treatment costs were significantly lower in the SMART groups compared with the 2 × 2 FIX + F group.Conclusion:Compared with the 2 × 2 FIX + F treatment the use of budesonide/formoterol was 30–40% lower in the SMART groups while maintaining equal ACQ5scores. Daily asthma control improved equally with 2 × SMART compared to 2 × 2 FIX + F with a reduction in asthma medication cost. The one dose once daily maintenance treatment (1 × SMART) resulted in a low level of treatment failure (exacerbations) but led to more days with symptoms. Therefore, a daily dose of two inhalations seems to be the lowest appropriate dose in patients with moderate persistent asthma.

SUMMARYThe role of systemic corticosteroids in the treatment of exacerbations of chronic obstructive pulmonary disease (COPD) is well established. However, despite being frequently prescribed for the treatment of COPD, the clinical utility of inhaled corticosteroids (ICS) is less clearly defined.While individual clinical and epidemiological studies have yielded conflicting results, meta-analysis of available data suggests that ICS may reduce the frequency and severity of exacerbations, the number of hospitalisations and the mortality rate, as well as yielding improvements in lung function and health-related quality of life (HRQL) in some subgroups of COPD patients. More recently, clinical trials evaluating the effect of combination therapy with ICS and long-acting β2-agonists (LABA) have shown significant effects on the prevention of exacerbations and HRQL. Emerging data are expected to clarify the role of ICS in the management of patients with COPD of different severities as well as the place of treatment with ICS/LABA combinations in the management of this chronic and disabling disorder.

To evaluate the efficacy of oral prednisolone, followed by inhaled budesonide, in patients with newly diagnosed (< 3 months) stage I and stage II pulmonary sarcoidosis.

The presence of ozone is to a large extent due to the emissions of hydrocarbons and nitrogen oxides over large areas. During periodic peak concentrations of ozone in the range of 0.1-0.2 ppm in the polluted air of big cities, people may suffer reactions such as eye discomfort, headache, chest discomfort, shortness of breath, and cough. Bronchoconstriction, with an increased airway resis tance resulting in reductions in lung function parameters, arises at concentra tions of ozone > 0.2 ppm. Asthmatics seem to be more sensitive than healthy individuals, but long-term effects in humans are to a large extent unknown since they are very difficult to evaluate.

It is of great importance to investigate the role of air pollutants in causing and aggravating lung diseases. The levels of concentration of some of these com bustion products have shown a decreasing emission curve, but the emissions of nitrogen dioxide (NO2) are still increasing. Most of the NO2emissions origi nate from road traffic. The installation of catalytic converters may well change this. It is established that low concentrations of NO2affect the respiratory system; this is especially obvious in asthmatics. Regarding long-term effects, it is believed that high levels of NO2may cause an increased frequency of respi ratory illness, but it is not possible to confirm this suspicion completely.

One hundred five consecutive patients with mild or moderate asthma not earlier treated with inhaled corticosteroids and with a need of an inhaled bronchodilator of three or more doses a week, and/or asthma symptoms during day or night, and/or peak expiratory flow (PEF) or FEV1less than 75% of predicted normal values were given an inhaled corticosteroid for 2 years (budesonide delivered via an inspiratory flow-driven multidose dry powder inhaler [Turbuhaler]). According to duration of symptoms, they were divided into six groups; from a duration less than 6 months up to a duration more than 10 years. PEF and FEV1were measured before and after treatment for 3 months, 1 year, and 2 years. In the groups of patients with a duration of symptoms less than 2 years, mean FEV1and PEF were significantly higher at all time points as compared with the baseline and as compared with the groups of patients with a longer duration of asthma symptoms. The maximum effects were usually seen after 1 year's treatment with maintained control during the second year. A significant negative correlation was found between duration of symptoms and maximum increases in PEF (r=-0.34;p=0.0006) and FEV1(r=-0.32;p=0.0012), a correlation remaining also after correcting for baseline airway function. No correlation was found between the age of the patients or earlier regular use of ß2-agonists and improvements in airway function. The results give some evidence that early treatment of asthma with an inhaled steroid may prevent patients from developing chronic airway obstruction. They also support current asthma treatment guidelines advocating early introduction of inhaled anti-inflammatory drugs.

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.

Patients attending the emergency room with acute asthma, participating in a study comparing salbutamol (albuterol in the United States) via a dry powder inhaler (Turbuhaler®) with pressurized metered-dose inhaler (pMDI), were included in this 1-week follow-up study with the aim of assessing whether inhaled budesonide via Turbuhaler may be an alternative to prednisolone tablets after an acute asthma attack. Eighty-one patients with a mean age of 38 years and forced expiratory volume in 1 sec (FEV1) of 64% predicted normal value after treatment with salbutamol were randomized in this double-blind, double-dummy, parallel-group study. The doses given were budesonide 1600 μg b.i.d. or prednisolone in daily doses from 40 mg (day 1) decreased to 5 mg (day 7). FEV1 was recorded before and after the 7-day treatments and peak expiratory flow (PEF) morning and evening, clinical symptoms (visual analogue scale 0-100), and doses of rescue medication (terbutalineTurbuhaler 0.25 mg/dose) were recorded daily. The mean increase in FEV, from baseline to day 7 was 1 7.3% in the budesonide Turbuhaler group and 1 7.6% in the prednisolone group. Mean values of morning PEF increased from day 1 to day 7 by 67 L/min in the budesonide Turbuhaler group and by 57 L/min in the prednisolone group (not significant). There were no statistically significant differences between the groups in clinical symptoms and in the number of doses of rescue medication. Because of disease deterioration, five patients in the Turbuhaler group and three in the prednisolone group needed additional symptomatic as well as corticosteroid treatment. Inhaled budesonide in high doses may be a substitute for oral therapy as follow-up treatment after an acute asthma attack.

Polymyalgia rheumatica developed in a 71-year-old patient within 2 years of the onset of acute sarcoidosis with biopsy-verified involvement of the thyroid, and concomitant autoimmune thyroiditis with hyperthyroid symptoms. Three years after the onset of muscle symptoms a non-metastasizing breast carcinoma was discovered and treated surgically. Neither the long interval between the onset of polymyalgia rheumatica and the discovery of the breast tumour, nor the good response of muscle symptoms to a one-year maintenance treatment with corticosteroids, was consistent with a paraneoplastic mechanism of the polymyalgia rheumatica syndrome. It was therefore hypothesized that the various disorders suffered by this patient might be related to a partly age-dependent depression of T-lymphocyte function, leading to an altered immunological reactivity to which the various clinical manifestations could be attributed. Such a hypothesis is supported by recent reports showing that in old people and in ageing experimental animals, a decrease in T-lymphocyte function and in the number of circulating T-cells occurs concomitantly with an increase in the incidence of a variety of neoplasms and autoimmune disorders.

We measured the concentration of tumor-associated trypsin inhibitor (TATI) in plasma and pleural fluid of 84 patients with pleural effusions of various causes. We observed elevated (>30 μg/L) TATI levels in pleural fluid in 45 percent of patients with pleural effusion associated with malignant disease and in 15 percent of patients with benign disease. Similar results were obtained for TATI in plasma. The concentration of TATI in pleural fluid closely parallelled that in plasma. In patients with renal insufficiency and in patients with biliary obstruction, the TATI levels were elevated both in plasma and pleural fluid. A positive correlation was seen between the concentration of TATI and the activity of alkaline phosphatase in plasma. The results show that simultaneous determination of TATI in plasma and pleural fluid improves the diagnosis of cancer only marginally. Our results also support the hypothesis that elevated TATI levels may reflect an acute phase reaction caused by inflammatory disease or tissue destruction associated with cancer not only in inflammatory conditions, but also in malignant disease where the tumor itself is not producing TATI.

A study has been made of the relationship between platelet counts and immunologically active arthritis. Arthritis was induced by infra-articular injections of human fibrinogen into rabbits that had previously been immunized. Transient thrombocytosis was noted in some animals after the first intra-articular injection. A second injection gave rise to a persisting elevation of the platelet levels. The local synovial process seems to represent an Arthus type of reaction. In all probability, thrombocytosis is a compensatory phenomenon secondary to the initial consumption of platelets in the damaged tissues. The resemblance between rheumatoid arthritis in man, and that noted in this experimental model, is discussed.

Platelet counts have been recorded in respect of 41 amyloidosis patients. Persistently-elevated platelet counts were observable in 22 patients; 19 of them had amyloidosis secondary to rheumatoid arthritis (RA). In patients with amyloidosis secondary to RA, a positive correlation was noted between platelet counts and high Waler-Rose titres. No significant correlations were observable either between platelet counts and haemoglobin or leukocyte values, or between platelet counts and serum protein fractions, nephrotic syndrome or renal insufficiency. As far as is known, the amyloid deposit does not represent any immunological activity. The conclusion is drawn that in amyloidosis, elevated platelet counts are attributable to the underlying disease and its activity.Dr Olof Selroos, M.D. IV Medicinska kliniken Unionsgatan 38 00170 Helsingfors 17 Finland

The platelet level has been studied in 115 hospitalized patients with severe rheumatoid arthritis; an elevated platelet count was found in one-third of them. As a general rule, a relationship was apparent between thrombocytosis and the activity of the disease. A positive correlation was found between elevated platelet count and anaemia, sideropenia, leucocytosis and the rheumatoid factor. Thrombocytosis was also found in one-half of the patients with secondary amyloidosis. The passible cause of the thrombocytosis is discussed, and it is pointed out that the counting of platelets provides a useful additional method for follow-up examinations in rheumatoid arthritis.

A patient with polymyalgia rheumatica (PMR) is reported in whom, at the time of diagnosis, the number of lymphocytes in peripheral blood and bone marrow was normal. Lymphocytic infiltration typical of PMR was detected in renal and muscle biopsy specimens, and a liver fine-needle aspirate contained an abnormal lymphocytic infiltration, probably leukaemic. The number of lymphocytes gradually increased in bone marrow and peripheral blood until, almost 5 years after PMR had been diagnosed, a typical picture of chronic lymphatic leukaemia (CLL) was observable. The significance of the reported combination is discussed. The possibility is pointed out that a CLL in progress must be suspected when persistent lymphocytosis occurs in a patient with typical PMR, even if initially the response to treatment with corticosteroids suggests that PMR is the sole disorder.

Rabbit platelets bave been counted during the development of amyloidosis induced by twice-weekly injections of sodium caseinate. A rapid increase in platelet numbers was noted after commencement of the injection regimen. During injection periods of from 11 to 15 weeks, the platelet count remained at a higher level than that in the control animals. These results are in agreement with the clinical observations, which indicate that thrombocytosis in amyloidosis patients occurs in situations of prolonged antigenic stimulation concomitant with an intact immune system, as is observable in amyloidosis secondary to chronic infections and active rheumatoid arthritis, and which is independent of the amyloid deposit itself.