Effect of beclomethasone dipropionate on bone mineral content assessed by X-ray densitometry in asthmatic children: a longitudinal evaluation

There is little information on bone turnover in asthmatic children taking long-term treatment with inhaled steroids (ICS). The aim of this longitudinal study was to determine the effects of inhaled beclomethasone dipropionate (BDP) on bone mineral density (BMD), in asthmatic children treated over a period of six months. BMD and growth were studied in two age- and sex-matched groups of asthmatic children. These comprised: 14 asthmatic children (Group 1) who had taken BDP in a dosage of 300-400 micrograms daily through a 145 ml spacer device for at least 6 months (mean age 9.1 yrs); and a control group of 16 age- and sex-matched asthmatic patients (Group 2) not treated with ICS (mean age 9.5 yrs). Mean duration of asthma was 5.7 yrs in Group 1 and 5.5 yrs in Group 2. Vertebral BMD (L2-L4) was measured by dual energy X-ray absorptiometry (DEXA) at the beginning (baseline) of the study and 6 months later. There were no significant differences in the baseline bone mass (mean +/- SEM) between the two groups (0.63 +/- 0.03 and 0.64 +/- 0.02 g.cm-2 in Group 1 and 2, respectively). During the observation period, bone density increased, by 4% (95% confidence interval (95% CI) 2-6) in the control group and by 2.3% (95% CI 0.4-4.2) in the group under BDP treatment, showing no significant influence of the treatment. No difference was found in height velocity evaluated before starting BDP and after 6 months of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Beclomethasone dipropionate use in chronic asthmatic patients. Effect on adrenal function after substitution for oral glucocorticosteroids

The clinical effectiveness of beclomethasone dipropionate (BDP) aerosol and adrenal function after withdrawal of oral corticosteroid therapy were evaluated in 32 severely steroid-dependent asthmatic patients. Twenty-four of 28 patients were able to discontinue oral glucocorticosteroid therapy, while four failed to do so. Ventilatory studies showed no substantial changes at the end of six months' BDP treatment. In 24 patients, adrenal insufficiency was present before BDP therapy was started. In 20 of those patients, the response of cosyntropin returned to normal two months after discontinuation of systemic steroid treatment and administration of BDP.     

Serum levels of tumor necrosis factor alpha and soluble tumor necrosis factor-receptor I in asthmatic patients and patients with chronic respiratory tract infection

In order to investigate the role of tumor necrosis factor alpha (TNF-alpha) in bronchial asthma or chronic respiratory infection, we measured serum levels of TNF-alpha and serum soluble tumor necrosis factor-receptor I (sTNF-RI) in asthmatic patients (n = 11) and patients (n = 10) with chronic respiratory infection by Pseudomonas aeruginosa. We also measured serum levels of eosinophil cationic protein (ECP) in the asthmatic patients. The serum levels of TNF-alpha in the asthmatic patients, patients with chronic respiratory tract infection and control group were 2.864 +/- 0.719 g/ml, 2.564-1.384 pg/ml and 0.681 +/- 0.453 pg/ml respectively. The levels of the former two groups were higher than those of the control group (p < 0.05). The serum levels of sTNF-RI in the asthmatic patients, the patients with chronic respiratory tract infection, and the control group was 758 +/- 268 pg/ml, 999 +/- 242 pg/ml and 909 +/- 268 pg/ml respectively. The levels of the former two groups did not differ significantly from those of the control group. There were significant correlations between TNF-alpha and sTNF-RI in the control group and in the patients with chronic respiratory tract infection, but there was no significant correlation in the asthmatic patients. In the asthmatic patients. TNF-alpha/s TNF-RI correlated with %best of PEF (r = 0.691, n = 9, p 0.0373). The serum levels of ECP correlated significantly with TNF-alpha, but not with sTNF-RI in the asthmatic patients. It is suggested that TNF-alpha plays a significant role in the pathogenesis of bronchial asthma and chronic respiratory tract infection as a factor causing inflammation and that the increase of TNF-alpha/sTNF-RI reflects the activation of eosinophil functions in an asthmatic attack.     

Investigation of treating steroids dependent asthmatic patients with kidney-tonifying herbs and high dose beclomethasone dipropionate aerosol

The steroids dependent asthmatic(SDA) patients need prolonged oral steroids administration. Because of the significant adverse effects with long-term use of steroids, especially the damage of the hypothalamus-pituitary-adrenocortical(HPA) axis, long-term steroids administration should be avoided or withdrawn gradually. Many modes of withdrawing the oral steroids have be used. But, the results were not satisfactory. So far, recently, investigations have revealed that high dose corticosteroids inhalation, such as beclomethasone dipropionate (BDP), could provide an effective alternative; they were delivered locally in the airway and had minimal systemic absorption as well as side effects. On the other hand, it has been shown that the Kidney-Tonifying herbs (KTH) exert protective effect on the adrenocortical cells of the SDA patients by suppressing the exogenous steroids and could regulate the disorders in different levels on HPA axis in the patients. In order to provide the more effective alternative therapy for the patients, 30 SDA patients replaced their oral steroids with KTH and high dose BDP (1500 micrograms/day) inhalation were investigated. The changes of clinical features, pulmonary function and the Synacthen Test were followed up. The results showed that about 70% of the patients replaced their oral steroids successfully with the new therapy, the clinical features were improved in 16% of the patients and the ineffective rate was only 6.6%; the results also revealed that, after replacement, the pulmonary function of the patients were improved (P < 0.05); the data of Synacthen Test indicated, after alternative therapy for 3-6 months, the damaged reserve power and secretive ability of adrenal cortex of the patients were also improved partially (P < 0.001).     

Chemical and pharmacological studies of Phyllanthus caroliniensis in mice

We studied retrospectively the effect of long-term treatment with an inhaled corticosteroid on bronchial hyperresponsiveness (BHR) and clinical asthma in moderate-severe asthmatic subjects. Fifty-eight patients who had used beclomethasone dipropionate (BDP) over one year, were enrolled in this study. BHR was measured before and after treatment with BDP by the methods recommended by Japanese Society of Allergology. Moreover we examined the clinical factors and the frequency of acute exacerbations. The results as follows: 1) The mean age was 48.8 years and the mean asthma history was 9.2 years. The mean dose and mean time of BDP administration was 801 micrograms/day and 28.1 months, respectively. 2) Patients during BDP treatment over one year showed about 6-fold mean improvements in BHR, but there were many patients who showed no improvements in BHR. 3) We retrospectively divided all the patients into two groups. Namely, the improved group (n = 25) showed more than 4 fold improvement in BHR and unchanged group (n = 33), less than 4-fold. But there were no significant differences in clinical characteristics and %FEV1 during treatment with BDP. 4) The unchanged group had more near fatal episodes in the past than the improved group. 5) There was significant decrease in acute exacerbation during treatment with BDP, but the unchanged group had more acute exacerbations than the improved group during treatment with BDP. These results indicates that there are many patients who had no improvement on BHR with long term BDP treatment and they have more acute exacerbations due to various stimuli. In conclusion, asthma is recognized chronic inflammatory disease and inhaled corticosteroid therapy has been recommended as the first line therapy. We must further study the clinical problems and underlying mechanisms concerning about treatment with an inhaled corticosteroid.     

Inhibitory effect of low molecular weight heparin on the bronchoconstriction in ovalbumin-sensitized guinea pigs after antigen exposure

To elucidate the effect of low molecular weight heparin (LMWH) on the bronchoconstriction, we examined the serial changes of the resistance of respiratory system (Rrs) in ovalbumin (OA)-sensitized guinea pigs after antigen exposure. After sensitization of guinea pigs with repeated OA inhalation, Rrs was measured at immediate asthmatic response (IAR) and late asthmatic response (LAR) with or without LMWH inhalation. Alteration in the number of inflammatory cells of the lung by LMWH inhalation was examined in the broncholaveolar lavage fluid (BALF) and in the histological sections of airway walls. Peak Rrs at 1 min up to 9 min, except 8 min, after antigen exposure significantly decreased by the pretreatment with LMWH inhalation as compared with saline inhalation. Peak Rrs at LAR (after 4 hours up to 24 hours, except 6 hours) also showed a significant decrease in the pretreatment with LMWH inhalation. Pretreatment of LMWH exhibited a decrease of eosinophil percentage in BALF (5.5 +/- 1.2% from 8.2 +/- 0.4% in saline inhalation) and a decrease of infiltrated eosinophil count in airway walls (71.0 +/- 7.3 from 155 +/- 15.8 in saline inhalation). These data show LMWH might play an important role as an inhibitory factor to bronchial asthma.     

Effect of a nitric oxide synthase inhibitor and a glucocorticosteroid on exhaled nitric oxide

Nitric oxide (NO) is produced by a variety of cells within the respiratory tract, including inflammatory epithelial cells. NO has been detected in the exhaled air of normal human subjects, and its concentration is raised in asthmatic patients. To study whether exhaled NO arises from the respiratory tract, we administered a NO synthase (NOS) inhibitor, NG-monomethyl-L-arginine (L-NMMA), by inhalation (490 mg) in a double-blind randomized manner in nine normal and six asthmatic subjects. Because exhaled NO may arise from an inducible isoform of NO synthase that may be inhibited by glucocorticosteroids, we also studied the effects of oral prednisolone (30 mg orally for 3 d) in seven normal and six asthmatic subjects in a separate double-blind crossover study with matched placebo. After nebulized L-NMMA, there was a significant fall in peak exhaled NO compared with saline control values, with a mean fall of 43.6 +/- 5.6% in normal subjects (p < 0.01) and of 39.7 +/- 6.5% (p < 0.01) in asthmatic subjects, which persisted for 4 h. There were no effects of L-NMMA inhalation on heart rate, blood pressure, or FEV1 in either normal or asthmatic patients. Administration of oral prednisolone (30 mg) resulted in a fall in exhaled NO concentrations in asthmatic subjects by 21.6 +/- 5.0% at 48 h (p < 0.01) but no significant change in normal subjects. These data suggest that NOS inhibitors may be safely given in normal and asthmatic patients and that the increased exhaled NO seen in asthmatic patients is likely to be caused by induction of inducible NOS.     

Anti-inflammatory effects of inhaled beclomethasone dipropionate in nonatopic asthmatics

The effects of inhaled beclomethasone dipropionate (BDP) on asthma symptoms and infiltration of the bronchial mucosa by inflammatory cells were investigated in an open study of 10 patients with mild-to-moderate nonatopic bronchial asthma. Asthma scores were recorded in an asthma diary. Peak expiratory flow (PEF), PEF diurnal variation (PEF%), forced expiratory volume in one second (FEV1%), methacholine airway hypersensitivity (minimum dose of methacholine) (Dmin) were measured. Biopsy of the bronchial mucosa was performed before and after 8 weeks of treatment with BDP (400 micrograms.day-1). The following inflammatory cells were immunostained: eosinophils with anti-EG2; mast cells with AA1; neutrophils with NP57; T-lymphocytes with anti-CD3, CD4, and CD8; and activated T-lymphocytes with anti-CD25. There was a significant improvement in the asthma symptom score, PEF%, FEV1%, and Dmin after BDP therapy and the number of EG2-, AA1-, CD3-, CD4-, and CD25-positive cells decreased significantly. We conclude that inhaled beclomethasone dipropionate inhibited inflammatory cell infiltration of airway tissue and that associated with this there was an improvement of symptoms in this open study of inhaled beclomethasone dipropionate in a group of nonatopic asthmatic subjects.     

Allergy and infection

The majority of infectious asthma in children is of viral etiology. The respiratory syncytial and parainfluenza viruses are the etiologic agents in most young children, whereas rhinovirus primarily initiates asthmatic episodes in older children. Short-term or alternate day maintenance corticosteroid therapy probably does not significantly increase the asthmatic child's susceptibility to infection.     

A case of toxic epidermal necrolysis with a low level of IgA in serum

A case of the toxic epidermal necrolysis in a 52-year-old woman treated for hypoxia of cerebral trunk during the severe attack of bronchial asthma and the bacterial infection of respiratory system was described. The pause of toxic epidermal necrolysis was treated with ceftriaxone and cefuroxime. The woman died on the 20th day of disease.     

The effect of a new tear substitute containing glycerol and hyaluronate on keratoconjunctivitis sicca

The present study of asthmatic children examined relationships among the frequencies of prior respiratory infections (i.e., those prior to the development of asthma) and recent (past year) respiratory infections, asthma severity, and the impacts of 12 common asthma triggers: air pollution, allergy problems, anger, cigarette smoke, excitement, high humidity, high or low environmental temperature, laughter, nighttime hours, physical activity, respiratory infection, and stress or worry. Data on these variables were obtained through a survey in which 325 families completed questionnaires; 121 families had asthmatic children who were 2-20 years of age. Pearson correlational analyses revealed many significant positive correlations: The frequencies of prior and recent infections were correlated. The frequency of prior infections was correlated with the impacts of all asthma triggers except allergy problems, but the frequency of recent infections was correlated only with the impacts of air pollution, cigarette smoke, respiratory infection, and nighttime hours as triggers of asthma attacks. Asthma severity was correlated with the frequencies of prior and recent respiratory infections and with the impact of respiratory infection as an asthma trigger.     

Oesophageal dysfunction in male patients with angina-like pain

The value of betamethasone valerate by inhalation in the prophylactic therapy of severe childhood asthma has been established. To determine whether the efficacy of this drug is due to a local or a systemic action a double-blind crossover study of 28 days' treatment with oral betamethasone valerate and 28 days' treatment with inhaled steroid was carried out in 10 asthmatic children. Daily doses used were 1 mg orally and 800 mug by inhalation. Nine patients had fewer symptoms, higher peak expiratory flow rates, and a lower bronchodilator requirement on inhaled than on oral therapy. Exercise-induced bronchoconstriction was diminished on inhaled therapy. Five children requested early termination of the oral therapy period because of unacceptable symptoms. Nine parents stated a preference for the period of inhaled therapy. It is concluded that betamethasone valerate is highly effective by inhalation but that a comparable oral dose has no appreciable clinical effect.     

Asthma and infection: risk or prevention?

Upper respiratory tract infections and wheezing illnesses occur frequently in early childhood. Most viral infections associated with wheeze in infancy are attributable to respiratory syncitial virus, whereas in older children rhinovirus, influenza and parainfluenza virus prevail. The detection rate of viruses has increased since PCR techniques have been used. A British study for example showed that in 80% of episodes in asthmatic children aged 9-11 years viruses could be detected in nasal aspirates which had been taken within 4 days of the wheezing attack. In most cases rhinovirus was identified. Two major hypotheses have been proposed to explain the association between respiratory tract infections and subsequent respiratory abnormalities. One hypothesis states that viral infections early in life damage the growing lung or alter host immune regulation. The second hypothesis holds that respiratory infections are more severe in infants and children with some underlying predisposition. These notions await further clarification. Early childhood bacterial and viral infections may, however, also be associated with a reduced risk of developing atopic sensitization or allergic conditions, as the results of several recent studies suggest.     

Analysis of perception in patients during an acute attack of bronchial asthma

An analysis of subjective sensations during an asthmatic attack in 51 asthma patients was performed. A difficult inspiration or inspiration and expiration was the most prevalent sensation, while isolated difficult expiration was only sparse finding. A tightness on the chest was often noticed as well. The probable explanation for these observation could be the breathing a high lung volume (hyperinflation), caused by closing small airway a mostly due to bronchoconstriction during the asthmatic attack. The authors suggest not to generally use the term "expiratory breathlessness" when describing the clinical picture of an asthmatic attack.     

Relaxin activates the L-arginine-nitric oxide pathway in vascular smooth muscle cells in culture

The effects of usual or low doses of inhaled corticosteroids on airway mucosal inflammation have not yet been examined. We therefore, compared the effects of inhaled beclomethasone dipropionate (BDP) 336 microg x day(-1) on asthma control outcomes and markers of airway inflammation. Twenty-four adult subjects with mild and moderate asthma were randomized to receive either BDP or placebo for four weeks; then subjects entered a single blind four week placebo run-in period. We found that the BDP group had significantly greater improvements in forced expiratory volume in one second (FEV1), morning peak flow, and rescue salbutamol use than the placebo-treated group. The improvement in FEV1 largely reversed one week after treatment was stopped. The decrease in the median percentage of eosinophils in induced sputum in the BDP group from 3.8% to 3.4% was not significant, but because eosinophils increased from 8.4% to 12.7% in the placebo group, there was a significant difference between treatment groups (p=0.03). There was no significant difference between groups during treatment in the levels of eosinophil cationic protein (ECP), tryptase mucin-like glycoprotein, or fibrinogen in induced sputum. The change in FEV1 in the BDP group did not correlate significantly with the change in eosinophil percentage or ECP levels. We concluded that four weeks of treatment with inhaled beclomethasone dipropionate 336 microg x day(-1) was associated with significant improvements in peak flow, forced expiratory volume in one second, and rescue salbutamol use in asthmatic subjects but was not associated with large reductions in markers of eosinophilic inflammation, bronchovascular permeability, or mucus hypersecretion.     

The effect on blood pressure of an acute fall in ionized calcium during hemodialysis. A randomized study in two patients

In school children with atopic asthma the beneficial effects of disodium cromoglycate (DSCG) and beclomethasone dipropionate (BDP) are well-established. In preschool children, wheezing is quite common, and in the majority of cases the symptoms are episodic and reported to be associated with viral infections rather than atopy. We compared the efficacy of regular treatment with DSCG and BDP for prevention of wheezing in preschool children. We were interested to establish whether regular treatment with inhaled anti-inflammatory drugs could lead to a decrease in bronchial responsiveness. In 15 patients (median age, 56 months; range, 43-66 months) bronchial responsiveness was assessed by measuring specific airway resistance (sRaw) during a histamine provocation test. The concentration of histamine eliciting a 100% increase in sRaw (PC100his) was determined. In a double-blind crossover study, patients inhaled either DSCG 10 mg three times a day or BDP 100 microg three times a day for 2 months. After a wash-out period, treatment was changed to BDP or DSCG, respectively. Daily peak flow measurements were carried out, and exacerbations were noted. PC100his was measured at the start and end of each treatment period. No significant decrease in bronchial responsiveness was seen (PC100his DSCG: before 1.3, after 1.66 mg/ml, Pvalue not significant; BDP: before 1.1 after 1.22 mg/ml, Pvalue not significant). Significantly higher morning peak flows were observed on BDP therapy (160 on BDP vs. 150 L/min on DSCG, P < 0.03). BDP treatment resulted in significantly fewer wheezing exacerbations (7 vs. 16, P < 0.005) compared with DSCG therapy. We conclude that in preschool children with episodic virally induced wheezing, BDP therapy was superior to DSCG aerosol treatments for the prevention of exacerbations of wheezing, although no significant effect on bronchial responsiveness was noted during either treatment protocol.     

Increased nitric oxide in exhaled air of asthmatic patients

Nitric oxide (NO) gas is produced by various cells within the lower respiratory tract, including inflammatory and epithelial cells, and is detectable in the exhaled air of normal human subjects. We have measured exhaled NO in patients with asthma, since several cell types that are activated in asthma can produce NO after induction. NO was measured reproducibly by a slow vital capacity manoeuvre and an adapted chemiluminescence analyser. NO was detectable in exhaled air of 67 control subjects (mean peak concentration 80.2 [SE 4.1] ppb) and was significantly reduced by inhalation of the specific NO synthase inhibitor NG-monomethyl-L-arginine. 61 non-steroid-treated asthmatic subjects had significantly higher peak expired NO concentrations than controls (283 [16] ppb, p < 0.001) but 52 asthmatic patients receiving inhaled corticosteroids had levels similar to controls (101 [7] ppb). High exhaled NO concentrations in asthmatic patients may reflect induction of NO synthase, which is known to be inhibited by steroids. Measurement of exhaled NO concentrations may be clinically useful in detection and management of cytokine-mediated inflammatory lung disorders.     

Comparison of bronchial reactivity to ultrasonically nebulized distilled water, exercise and methacholine challenge test in asthmatic children

We studied the responses to ultrasonically nebulized distilled water (UNDW) challenge, exercise challenge and methacholine challenge in asthmatic children. Fifty-four asthmatic and fourteen nonasthmatic control children participated in this study. The UNDW inhalation test was by the methodology described by Anderson. The average output of water was approximately 3.0 mL/min (SD = .1) and inhalation times were 30 seconds, one minute, two minutes and four minutes. Some subjects performed exercise challenge on a bicycle ergometer and methacholine challenge by an Astrograph technique. Twenty-three of 54 asthmatic patients (42.6%) and none of the controls showed a fall in FEV1 greater than 20% with UNDW challenge. The fall in FEV1 with UNDW correlated with that induced by exercise challenge (r = .89) and Log Dmin, which may reflect bronchial sensitivity (r = .70). Our method is not sensitive enough for detecting bronchial hyperresponsiveness in all asthmatic children. Bronchoconstriction induced by UNDW has a similar mechanism of action as exercise and methacholine.     

Investigation into the therapeutic efficacy of continuous isoproterenol inhalation in relation to respiratory infections in asthmatic children

In our Department, continuous isoproterenol inhalation therapy has been conducted on status asthmatics over the last 10 years. In the present study, we investigated whether there are any differences in the therapeutic efficacy of continuous inhalation of isoproterenol in the presence or absence of respiratory infections which may induce or aggravate asthma attacks. The treatment period was significantly longer in patients with pneumonia. Further prolongation of the treatment period was noted in patients with atelectasis. However, there were no apparent differences in therapeutic efficacy according to age or the severity of attacks. These findings suggest that continuous inhalation of isoproterenol is very effective for status asthmatics if respiratory infections are thoroughly controlled.     

Cultured gastric parietal cells from the guinea pig: adherence, cell growth and stimulus coupling of Ca2+ and cyclic AMP

The physical properties of aerosols are reviewed. The physiological basis of inhalation therapy is then briefly reviewed together with the aerosol devices currently available and the therapeutic uses of inhaled drugs, focusing on the treatment of parenchymal lung diseases and extra respiratory disorders. Finally, new perspectives for inhalation therapy are examined.