Prevalence of obstructive lung diseases and respiratory symptoms in southern Sweden.

The prevalence of obstructive lung diseases is increasing in Scandinavia and worldwide. The reasons for this are not known. The prevalence varies between countries but also between different areas within the same country. In northern Europe a north-south gradient and also an east-west gradient have been proposed. To our knowledge this is the first comprehensive epidemiological study concerning obstructive lung diseases and respiratory symptoms in the southern part of Sweden. The prevalence of bronchial asthma, chronic bronchitis/emphysema, respiratory symptoms, smoking habits and medication in a random sample of 12,071 adults aged 20-59 years was assessed in a postal survey with a slightly modified questionnaire previously used in central and northern Sweden (the OLIN Studies). The questionnaire was based on the British Medical Research Council (BMRC) questionnaire. We also compared the prevalence figures of asthma found in the postal survey with those reported in the medical records in a part of the study area. After two reminders, the response rate was 70.1% (n = 8469); 33.8% of the responders were smokers. Among younger (20-39 year age group) individuals, smoking was most common in women, whereas in those aged 40-59 years, smoking was more common in men. In all, 469 subjects (5.5%) stated that they had asthma, 41.6% of whom reported a family history of asthma compared to 15.9% of the study sample not reporting asthma. Of all subjects reporting asthma, 60.1% (n = 282) answered that they used asthma drugs. Inhaled steroids were used by 20.7%. Chronic bronchitis and/or emphysema was reported by 4.6% (n = 392), 28.6% of whom reported a family history of chronic bronchitis or emphysema compared to 6.8% of the study sample not reporting chronic bronchitis. The most common respiratory symptom in the study population was 'phlegm when coughing' reported by 15.1% (n = 1279). Our data show a prevalence of self-reported asthma of 5.5% compared with 7% reported by Lunbäck et al. in northern Sweden, which indicates a north-south gradient.

Systemic effects of two nasally administered glucocorticosteroids.

Two topical corticosteroids, budesonide (BUD) and beclomethasone dipropionate (BDP), both administered as suspensions in water, were investigated in healthy volunteers regarding influence on cortisol in plasma and urine (U-cortisol) after nasal application. In the first study, single doses of 200, 400, and 800 micrograms of BDP and BUD were given at 10:00 pm. In the second study, 100, 200, and 400 micrograms were given mornings and evenings for 4 days. In the single-dose study, none of the drugs or doses showed any significant influence on cortisol in plasma. However, U-cortisol decreased significantly after BUD 400 and 800 micrograms. In the multidose study, U-cortisol values were significantly reduced after all doses of BUD and the highest dose of BDP. The compounds tested showed different ability to cause measurable systemic effects after nasal application. The clinical implication is that the prescriber, when choosing a compound, should take the application site into consideration and should also be encouraged to find the lowest effective dose.

Dosimeter gel and MR imaging for verification of calculated dose distributions in clinical radiation therapy.

A dosimeter gel, based on an agarose gel infused with a ferrous sulphate solution and evaluated in a magnetic resonance scanner, was used for complete verification of calculated dose distributions. Two standard treatment procedures, treatment of cancer in the urinary bladder and treatment of breast cancer after modified radical mastectomy, were examined using pixel-by-pixel and dose volume histogram comparison. The dose distributions calculated with the dose planning system was in very good agreement with the measured ones. However, in the case of the more complicated breast cancer treatment, some discrepancies were found, mainly at the beam abutment region. This may be explained by field displacements errors and by a small limitation of the dose planning utilising small electron beams in this region. The dosimeter gel system have proven to be a useful tool for dosimetry in clinical radiation therapy applications.

Centrifuge man-rating of a conceptual internal abdominal bladder restraint in an extended coverage anti-G suit.

An extended coverage anti-G suit, has been demonstrated to improve +Gz tolerance substantially. In some pilots/subjects, however, the abdominal bladder of the anti-G suit may expand excessively upward and inward causing discomfort and pain. This man-rating was performed to evaluate the effects on +Gz protection of an internal abdominal bladder restraint in the Swedish Tactical Flight Combat Suit (TFCS) used in conjunction with pressure breathing during G (PBG). The tests were executed in the Armstrong Laboratory Centrifuge at Brooks AFB with four Swedish test fighter pilots. The centrifuge profiles included gradual onset runs (GOR, relaxed) and rapid onset runs (ROR, with straining), as well as simulated aerial combat maneuver (SACM) runs up to +9 Gz until subjects experienced light loss or fatigue or surpassed 228 s. All subjects withstood 60 s at +9 Gz during GOR and ROR runs with and without abdominal bladder restraint. No difference There was no difference in SACM duration times. In three of four subjects, abdominal pain or discomfort experienced without abdominal bladder restraint disappeared with the addition of a bladder restraint. Ratings of perceived exertion (after 5 peaks at +9 Gz in the SACM), subjective +Gz tolerance, overall comfort, fatigue, and heat stress demonstrated no relevant differences with and without abdominal bladder restraint. Therefore, to enhance comfort, it seems possible to modify the TFCS by adding an abdominal bladder internal restraint without compromising its operational +Gz protection.

Airway and lung elastic fibre is not reduced in asthma nor in asthmatics following corticosteroid treatment.

By morphometric investigation of the relative content of elastic and collagen fibres, we have tested the hypothesis that loss of elastic fibres in the conducting airways and lung parenchyma may reduce tissue elastic recoil, resulting in increased airway maximal closure and apparent increased responsiveness. The study groups comprised: Group A (n = 11) with relatively mild atopic asthma using inhaled bronchodilators prn (i.e. short-term corticosteroids users); Group B (n = 9) with more severe asthma requiring inhaled bronchodilators regularly, and daily inhaled glucocorticosteroids (i.e. longterm corticosteroid users); Group C (n = 12) normal healthy workers. Bronchial biopsy samples were taken from three sites from the left lung. Group A biopsy samples were taken before and after a 4 wk treatment period with inhaled corticosteroids (200 micrograms b.i.d.) and the relative elastic and collagen fibre content of a subepithelial zone was determined from electron micrographs. In a parallel study, the relative proportion of elastic fibre in post mortem lung tissue samples (inner aspect of the bronchial wall, alveolar wall, and points of attachment of surrounding alveoli to intrapulmonary bronchi) from subjects suffering a fatal asthma attack (n = 11), and non-asthmatic suffering sudden death (n = 9), were determined using Miller's elastic and eosin counterstain for light microscopy. In bronchial biopsies of normal subjects, 4.6 (SEM 1.1)% of subepithelial connective tissue was elastic fibre, similar to mild asthmatic subjects, 1.9 (SEM 0.48)%. Neither short-term (4 weeks) inhaled corticosteroid (200 micrograms b.i.d.) nor long-term (< 6 months) treatment with variable doses of inhaled steroids (100-1000 micrograms b.i.d.) significantly altered the elastic or collagen content of the tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of treatment on airway inflammation and thickening of basement membrane reticular collagen in asthma. A quantitative light and electron microscopic study.

We have obtained airway mucosal biopsies by fiberoptic bronchoscopy for light and electron microscopic analysis of three distinct airway levels of the left lung in three subject groups. Group A: 11 subjects with mild atopic asthma (mean age, 29 yr; %FEV1, 89 to 116%; mean PC20 histamine, 2.42 mg/ml), each biopsied twice, one prior to 4 wk of treatment with either inhaled terbutaline (250 micrograms, two puffs four times daily; n = 5) or inhaled budesonide (200 micrograms, one puff twice daily; n = 6) followed by a second biopsy to allow determination of the effects of treatment. Group B: 10 subjects with severe asthma receiving long-term (average, 3.7 yr) corticosteroid treatment were biopsied once only (mean age, 28 yr; %FEV1, 86 to 129%; mean PC20 histamine, 1.85 mg/ml). Group C: 12 normal healthy control subjects (mean age, 35 yr; %FEV1, 92 to 135%; PC20 histamine greater than 16 mg/ml) biopsied once. By light microscopy of plastic-embedded sections, Group A asthmatics had an increased cellular infiltrate when compared with either the healthy control group or the Group B asthmatics (p less than 0.05). Both asthma groups had a thickening of basement membrane reticular collagen compared with the healthy control group (p less than 0.01). Compared with the control group, there was an increase in the percentage of the total cells that were mast cells (p less than 0.01) and eosinophils (p less than 0.05) in Group A and of eosinophils (p less than 0.01) and histiocytes (p less than 0.01) in Group B. The results of cell counts by electron microscopy largely supported these findings, and, in addition, they demonstrated an increased frequency of foci of free eosinophil granules and decreased numbers of neutrophils (p less than 0.01). By light microscopy, budesonide reduced the percentage of mast cells and eosinophils (p less than 0.05). But for the percentage of lymphocytes, which increased (p less than 0.05), terbutaline was without effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Single-dose inhaled budesonide in subjects with chronic asthma.

In 30 stable asthmatics, a comparison was made between the changes in pulmonary function (FEV1, FVC, PEF, MEF75, MEF50 and MEF25) hourly for 9 h after a single dose of inhaled budesonide 1,600 micrograms, and placebo. All subjects used inhaled steroids daily; this medication was, however, withheld 8 days prior to the study. For all parameters of pulmonary function, a significant difference in favour of budesonide was demonstrated. The effect tended to decrease after 9 h, and had abated within 24 h. FEV1 age, sex, smoking habits, or results of an inhaled beta 2-agonist reversibility test could not be demonstrated as predictors of those subjects to react with the most pronounced responses to budesonide. In conclusion, our results demonstrate an effect 3 h after administration of an inhaled glucocorticosteroid in adult outpatients with chronic asthma. These results parallel previous findings in highly selected asthmatics and after systemic administration of glucocorticosteroids. Single-dose administration and subsequent monitoring for 8-9 h may therefore prove valuable in evaluating new prophylactic agents for the treatment of asthma.

A pharmacokinetic study of prednimustine as compared with prednisolone plus chlorambucil in cancer patients.

The pharmacokinetic characteristics of prednisolone and of chlorambucil and its beta-oxidized metabolite, phenylacetic mustard (PAM) were studied in plasma after the oral administration of 200 mg prednimustine (Sterecyt) and a regimen consisting of 20 mg prednisolone plus 20 mg chlorambucil, respectively. A total of 12 cancer patients completed this trial. The drugs were given in a cross-over study as single doses, and serial plasma samples were collected for 32 h. Chlorambucil and PAM were assayed by a gas chromatographic/mass spectrometry method and prednisolone, by radioimmunoassay. The median relative availability of the prednisolone and chlorambucil moiety in prednimustine was 19% and 16%, respectively. Prednisolone, as well as chlorambucil and PAM, appeared later and at a significantly lower concentration in plasma after treatment with prednimustine as compared with the mixture of chlorambucil and prednisolone. We also found that the elimination phase of chlorambucil and PAM in plasma is prolonged after the administration of prednimustine as compared with chlorambucil per se. In contrast, the elimination of the prednisolone moiety of prednimustine and that following the administration of a plain prednisolone tablet did not seem to differ. The modified plasma profile of the alkylating components following prednimustine administration may be important for the clinical efficacy of prednimustine.

The assessment of the systemic effects of inhaled glucocorticosteroids. The effects of inhaled budesonide vs oral prednisolone on calcium metabolism.

In a randomized, double-blind crossover study, the effects of 0.8, 1.6 and 3.2 mg/day inhaled budesonide and 5, 10 and 20 mg/day oral prednisolone on mineral metabolism were compared. Twelve healthy subjects (4 m, 8 f) were treated for 1 week at each dosage level, the graduated dosages being given in ascending order. Budesonide and prednisolone were given twice daily and once daily, respectively, which reflects the schedules common in clinical practice. Serum calcium and the regulatory hormones of calcium metabolism (parathyroid hormone, vitamin D metabolites and calcitonin) were not changed either by prednisolone or budesonide. Prednisolone significantly increased 24 h and 08.00 h fasting urinary calcium excretion and decreased renal calcium reabsorption, while budesonide had little or no effect on urinary calcium loss and increased renal reabsorption at the highest dose level. Both drugs significantly increased renal phosphate reabsorption and serum phosphate levels, but prednisolone caused greater increases than budesonide. In conclusion, during short-term treatment with the dosages used, inhaled budesonide had less effect on calcium and phosphate metabolism than oral prednisolone, and so it may have a lesser action on the skeleton of the type contributing to osteoporosis during long-term treatment.

Assessment of systemic effects of inhaled glucocorticosteroids: comparison of the effects of inhaled budesonide and oral prednisolone on adrenal function and markers of bone turnover.

The effects of inhaled budesonide (BUD) and oral prednisolone (PRED) on markers of bone turnover and adrenal function were compared in a randomized, double-blind, double-dummy, crossover study. Twelve healthy subjects were treated for one week with 0.8, 1.6 and 3.2 mg/day BUD and 5, 10 and 20 mg/day PRED, the three doses being given in ascending order. Plasma cortisol and adrenal cortical androgens showed a significantly decreasing trend with the increasing doses of both drugs, although PRED caused a significantly greater decrease than BUD. Osteoblast function, reflected by serum osteocalcin and alkaline phosphatase was significantly reduced by PRED, but BUD had a significantly different effect as it affected only osteocalcin. Urinary hydroxyproline/creatinine, a marker of bone resorption, was not changed by either drug. The average potency ratio for equivalent systemic effects was PRED:BUD 3.9:1. During short-term treatment at equivalent anti-asthmatic doses, BUD has significantly less effect on adrenal function and bone turnover than PRED, and it may carry less risk of bone complications during long-term treatment.

Inflammatory cells and eosinophilic activity in asthmatics investigated by bronchoalveolar lavage. The effects of antiasthmatic treatment with budesonide or terbutaline.

We investigated the constituents of bronchoalveolar lavage (BAL) regarding cell profiles and released eosinophilic cationic protein (ECP) in 11 patients treated occasionally with inhaled bronchodilators (Group A) and 11 patients treated regularly with inhaled corticosteroids (Group B). A normal, healthy control group of 12 subjects was also recruited. Compared with Group A, Group B had a reduced recovery percentage of infused volume (p less than 0.05) and total cell number (p less than 0.01). Compared with the control group, there was a significant increase in the percentage of eosinophils (p less than 0.05) in both groups of asthmatics. In Group A there was also a significant increase in mast cells (p less than 0.05), serum-ECP (p less than 0.05), and BAL-ECP (p less than 0.001). No correlations between any of the cell variables and the level of airway responsiveness measured as PC20 histamine were found in any group. Group A patients were investigated twice--before and after 4 wk of randomly allocated treatment with either a regular beta-2-receptor agonist (terbutaline 250 micrograms, two puffs four times a day) or a regularly inhaled corticosteroid (budesonide 200 micrograms twice a day). The BAL differential cell counts were similar and not significantly affected by either treatment. However, BAL-ECP levels were decreased by budesonide treatment (p less than 0.05). ECP levels in serum and BAL were significantly correlated (p less than 0.05 to 0.001). The eosinophilic cell involvement in asthma is further emphasized by this study but the increase in numbers of eosinophils seems less important than their activity, here measured as release of one degranulation product, ECP. To suppress disease activity, repeated long-term treatment is important, but clear preference for either treatment cannot be given on the basis of our present results.

A study of the mechanism of the antiasthmatic action of inhaled budesonide.

Inhaled antiasthmatic steroids have been assumed and yet never proved to exert their antiasthmatic effect by topical action in the airways. We tested the hypothesis that the efficacy of inhaled budesonide (BUD) might be due instead to its systemic activity after absorption. We compared inhaled and oral BUD with doses selected to ensure higher peak plasma levels and a greater area under the plasma concentration curve with the oral treatment. After pretreatment with beclomethasone to maximize asthma control, 47 adults with asthma were randomized to receive 0.4 mg of inhaled BUD per day (n = 16) or 1.4 mg of oral BUD per day (n = 15), or placebo (n = 16) in double-blind fashion and then followed weekly until asthma relapsed or for 8 weeks if no relapse occurred. "Relapse" was defined as a drop in the mean peak expiratory flow rate greater than 2 SEM below the mean during the baseline week before switching to the test drugs. The time to relapse was the primary outcome variable. Time to relapse was longer with inhaled than with oral BUD (medians, 22 versus 7.9 days; p = 0.003) or placebo (medians, 22 versus 9 days; p = 0.004). Oral BUD and placebo did not differ (p = 0.41). The morning serum cortisol levels remained normal during all three treatments. Thus, at conventional dosage the antiasthmatic effect of inhaled BUD may be fully explained by a local intrapulmonary action.

Assessment of the systemic effects of inhaled glucocorticosteroids: the influence of blood sampling technique and frequency on plasma cortisol and leucocytes.

Twelve healthy males (mean age 27.6 y, range 23-35 y) took part in a randomized, double-blind, cross-over study of the effect of blood sampling technique (separate isolated venepunctures vs use of an IV cannula) and frequency (overnight vs morning) on plasma cortisol and white blood cell count after inhalation of a single dose of budesonide 3.2 mg or placebo, in order to establish the more sensitive method for future use. Sampling technique and frequency affected neither leucocytes nor plasma or urinary cortisol. Budesonide suppressed both plasma and urine free cortisol and delayed the nocturnal rise due to the circadian rhythm, thus reducing the AUC of plasma cortisol vs time. Lymphocytes, eosinophils and monocytes were decreased and neutrophils and total white blood cells were increased by the high dose of budesonide used. Lymphocytes and neutrophils showed significant changes earlier than eosinophils and cortisol and may be the variables of choice under certain conditions. Frequent sampling gave more complete information about the systemic effect of the drug than single morning samples.

Impairment of estramustine phosphate absorption by concurrent intake of milk and food.

The effect of milk and food on the pharmacokinetics of estramustine phosphate was investigated in six patients with prostatic cancer. In a randomized three-way cross-over study, the patients were given single doses of the drug together with low calcium water, low calcium food and milk. The evaluation was based upon the plasma concentration of two metabolites, estromustine and estrone, as parent drug could not be detected in plasma. The tmax and lag time of estromustine were significantly increased by milk and food intake and Cmax and AUC were significantly decreased. In comparison with water, the AUC of estromustine was 41% when the drug was taken with milk and 67% after simultaneous intake of standardized food. Corresponding figures for the peak values were 32 and 57%, respectively. The effect of milk and food intake on the pharmacokinetics of estrone was similar. Studies in vitro demonstrated that the dissolution of estramustine phosphate disodium was markedly impaired in the presence of calcium. It was concluded that the rate and extent of absorption of estramustine phosphate were decreased when the drug was taken with milk or food due to the formation of a poorly absorbable calcium complex. To obtain high and reproducible absorption of Estracyt, the drug should not be taken together with milk, milk products or other calcium-rich food or drugs.

Bioequivalent doses of budesonide and prednisone in moderate and severe asthma.

We determined the relative antiasthmatic and systemic glucocorticoid potencies of inhaled budesonide (BUD) versus morning-dose oral prednisone (PRED) in 34 adult patients with asthma over a dose range extending from conventional to high and potentially toxic levels, 3.2 mg of BUD or 40 mg of PRED per day. Changes in symptom frequency and severity, FEV1, and peak expiratory flow rate were measured during a double-blind, double-dummy controlled, crossover protocol. The drugs proved equally effective, provided a sufficient dosage was administered. The dose required to eliminate recurrently disabling asthma relapses in these patients was about 2.0 mg of BUD per day or greater than 40 mg of PRED per day. On the average, BUD doses greater than or equal to 1.84 mg/day/70 kg adult (26.3 micrograms/kg/day) exhibited systemic effects on the 8 AM serum cortisol level and blood eosinophil count equivalent to greater than or equal to 15 mg of PRED per day. The latter doses are known to be associated with steroid-induced complications, such as osteoporosis. However, the level of systemic glucocorticoid activity produced by any particular dose of BUD in these patients was consistently much lower than that produced by the dose of PRED needed to achieve an equivalent level of antiasthmatic response. Thus, the use of high-dose inhaled BUD appears clinically reasonable and ethically acceptable in patients with severe asthma in whom the alternative is their continuing dependency on PRED.

Distribution and metabolism of estramustine in HeLa cells and the human prostatic tumour cell line 1013L.

The metabolism of estramustine [estradiol-3-N-bis(2-chloroethyl) carbamate] was investigated in the human prostatic tumour cell line 1013L and the human cervix tumour cell line HeLa S3. Uptake studies revealed that estramustine (EM), and its 17-ketoanalogue estromustine (EoM), differed in their nuclear binding pattern in 1013L cells but not in HeLa cells. Most of the nuclear radioactivity from both EM and EoM was found in the fraction containing the majority of the phospholipids. HPLC studies on EM-treated 1013L cells showed the presence of the oxidized metabolite EoM, in the medium, an enrichment of estradiol and estrone in whole cells and EM and EoM bound to the nuclear protein matrix. Similar studies on the HeLa cell line showed a completely different pattern, no metabolites other than EoM were found in the cell medium and whole cells but several very lipophilic metabolites were found bound to the nuclear protein matrix. On investigation of other tumour cell lines these metabolites were found to be unique to HeLa cells. The results extend our knowledge concerning EM and demonstrate that the cell line 1013L is a relevant model system for studying drugs active against human prostatic tumours.

A double-blind dose-response study of budesonide by inhalation in patients with bronchial asthma.

Budesonide by inhalation and placebo were tested in 18 patients with moderate chronic bronchial asthma. Three dose levels of budesonide were used (25, 100 and 400 micrograms q.i.d.) and the patients were to take two puffs q.i.d. in all periods. The active treatment was investigated using double-blind cross-over technique, and placebo at the end of the trial. The duration of each treatment period was 2 weeks. The study showed a high drop-out frequency while on placebo and that the PEF values were influenced in a dose-dependent way by budesonide. In spite of the double-blindness the patients had a tendency towards overuse of the trial aerosol on the lowest dose, but they used significantly less than prescribed during the period with the highest dose. No side effects were reported.

Plasma concentrations of estradiol and testosterone in single-drug polyestradiol phosphate therapy for prostatic cancer.

To evaluate the appropriate dosage of polyestradiol phosphate (PEP, Estradurin) as single-drug therapy, patients with metastatic prostatic carcinoma were given 80, 160 or 240 mg PEP every 4 weeks for at least 6 months. Injection of PEP was followed by rising plasma concentrations of estradiol in the first 2 weeks and slight fall in the next 2 weeks. Testosterone levels fell rapidly in the first 7 days and rose slightly in the following 3 weeks. Steady-state levels were reached after 2 months at the two lowest doses and after 4 months at the highest dose. Steady-state estradiol values increased in linear proportion to the dose. The steady-state concentrations of testosterone were about 45, 25 and 15% of the pretreatment values in the respective groups. At least 160 mg PEP at 4-week intervals is appropriate when the drug is used alone.

Use of spacers to facilitate inhaled corticosteroid treatment of asthma.

Budesonide, a topically active corticosteroid, was administered in doses of 400 and 1,600 micrograms/day to 35 asthmatic adults, using a standard inhalation device or a tube or cone spacer. The spacers reduced oropharyngeal candidiasis by an amount equivalent to a 90% reduction in drug dose (p = less than 0.005) and doubled the drug's overall antiasthmatic potency (delta FEV1, p = 0.05) without significantly increasing its overall effect on blood eosinophils (p = 0.14) or the A.M. serum cortisol (p = 0.12). Steroid-induced neutrophilia increased by an amount approximating that produced by an extra half tablet of prednisone per day (p = 0.002). Both the airways and systemic effects of the spacers were greater in patients who had small airways dysfunction present prior to the study. The data suggest an increase in intrapulmonary drug deposition during spacer treatment without a material shift in regional delivery within the lung. Spacers should be particularly useful for patients whose response to inhaled steroid is compromised by by dose-limiting oropharyngeal complications. They can also reduce drug costs. They should be used selectively in children until their effect on regional intrapulmonary drug deposition has been more clearly defined.