Sole Upfront Therapy with Beclomethasone and Budesonide for Upper Gastrointestinal Acute Graft-versus-Host Disease

Systemic glucocorticoids remain the standard treatment for gastrointestinal (GI) acute graft-versus-host disease (aGVHD) despite their toxicity and incomplete efficacy. Controlled trials have tested poorly absorbable steroids as adjuncts with systemic glucocorticoids, but only small case series have reported treatment with poorly absorbed beclomethasone dipropionate (BDP) and budesonide (BUD) alone. Our team has adopted the practice of administering BDP or BDP+BUD without systemic glucocorticoids as first-line therapy for isolated upper GI (UGI) aGVHD. We report results in 76 patients treated with BDP alone and in 81 patients treated with BDP+BUD, with allocation by physician choice. Almost all patients received peripheral blood stem cells (92%) from a fully HLA-matched related or unrelated donor (80%) after myeloablative conditioning (76%) for acute leukemia (49%), myelodysplastic syndrome (17%), non-Hodgkin lymphoma (14%), or another hematopoietic disorders (20%). After 28 days of treatment with BDP, 46% of the patients had a complete response (CR) and 10% had a partial response (PR); after 200 days, 61 (80%) patients were alive, 34% maintained a CR, and 3% maintained a PR, whereas 53% required additional immunosuppression (IS). After 28 days of treatment with BDP+BUD, 67% had a CR and 10% a PR; after 200 days, 74 (91%) patients were alive, 46% maintained a CR, and 2% maintained a PR, whereas 43% required additional IS. Among the entire cohort of 157 patients, 66 (42%) were treated successfully without systemic glucocorticoids. This study reports the efficacy of poorly absorbable steroids alone for patients with isolated UGI aGVHD. Prospective trials should test for the potential advantages of BDP and BUD use over systemic glucocorticoids.     

Treatment of nasal polyps with intranasal beclomethasone dipropionate aerosol

In a double-blind trial thirty-five patients with moderately-severe nasal polyposis were treated with intranasal beclomethasone dipropionate aerosol for 3 weeks. The dose given (400 γg/day) had only local effect on the symptoms. Judged by diary card scores the nasal symptoms were reduced to 52% of the pre-trial level for the whole group. Corrected for the placebo effect the percentage was 68. The reduction of symptoms was equally apportioned to the three symptoms, sneezing, nasal secretion and blockage. The treatment was tolerated well, and it is concluded that intranasal treatment with beclomethasone dipropionate aerosol offers most patients with nasal polyps a good response without any risk of systemic steroid side-effects.     

Intra-nasal beclomethasone dipropionate and intra-nasal sodium cromoglycate: a comparative trial

Ten patients with either seasonal allergic or perennial rhinitis were treated with intra-nasal beclomethasone dipropionate B.P. (Beconase) and nine comparable patients were treated with sodium cromoglycate B.P. (Rynacrom). The beclomethasone dipropionate was administered as 50 μg per puff into each nostril three times a day and the sodium cromoglycate as one capsule insufflated into each nostril four times a day. Treatments were allocated on a randomized basis and each patient received a course of treatment lasting 2 weeks during the summer of 1973 when the pollen counts were high. Utilizing patient daily symptom diary cards, physician's assessment and by examination of the nasal mucosa prior to and at the end of treatment, it was concluded that both intra-nasal beclomethasone dipropionate and intra-nasal sodium cromoglycate effect a reduction in the symptoms associated with rhinitis. No side effects of importance were noted, nor were there any adverse changes observed in the state of the nasal mucosa.     

The effect of beclomethasone dipropionate aerosol on allergen induced nasal stenosis

Nasal resistance to air flow has been used to evaluate the effect of beclomethasone dipropionate aerosol on allergen induced nasal stenosis. Sixteen patients with allergic-rhinitis due to pollen were investigated in a randomized double-blind cross-over study with beclomethasone dipropionate aerosol and placebo aerosol. Only patients reacting to challenge were chosen. The study was carried out in the pollen-free season. After I week on either active or placebo aerosol a basic resistance value was determined followed by allergen challenge. Nasal resistance was determined 15 min and 7 hr after challenge. The aerosols were changed and after another week the procedure was repeated. There was significant preference (P<0.01) for beclomethasone dipropionate aerosol.     

Corticosteroid-sensitive lymphocytes are normal in atopic asthma

Corticosteroids, well known to increase susceptibility to infection, are often administered to atopic patients. Atopy may be associated with lymphocyte abnormalities and increased susceptibility to infections caused by intracellular organisms. We sought to determine whether atopic and nonatopic subjects respond in a similar manner to corticosteroids administered both systemically and locally. We compared the response of peripheral blood leukocytes of 15 atopic asthmatics and 10 nonatopic control subjects to prednisone or beclomethasone dipropionate. We determined leukocyte number, total eosinophil count, T-cell number, complement receptor lymphocyte number, and concanavalin A (Con A)- and phytohemagglutinin (PHA)-induced lymphocyte proliferation before and 5 hr after administration of 20 mg of prednisone orally or 336 jig of beclomethasone dipropionate by aerosol inhalation. Baseline values of the groups differed. The atopic asthmatic group had higher total eosinophil count, lower percent lymphocyte count, and slightly lower Con A- and PHA (high concentration) -induced lymphocyte proliferation. T-cell and complement receptor lymphocyte number were equivalent in both groups. Prednisone caused a profound eosinopenia, monocytopenia, T lymphopenia, depression of mitogen-induced lymphocyte proliferation, and increase in leukocyte number and complement receptor lymphocyte percent. Beclomethasone dipropionate was associated with little or no change in these parameters. We conclude that atopic asthma is not associated with a defect in corticosteroid-sensitive leukocyte populations and that beclomethasone dipropionate aerosol, as opposed to prednisone, does not alter peripheral blood mononuclear cell populations.     

Adrenal function in children with bronchial asthma treated with beclomethasone dipropionate or budesonide

The effect of inhaled beclomethasone dipropionate and budesonide on the adrenal function was studied in 30 children (aged 7 to 15 years) with mild bronchial asthma. The trial was designed as a prospective double-blind parallel study of the effect of stepwise increase of either beclomethasone dipropionate or budesonide from 200 micrograms through 400 micrograms, to 800 micrograms daily in three consecutive periods of 4 weeks. At the end of each period, the adrenal stress response was evaluated by measurements of serum cortisol and androstenedione during a short adrenocorticotropic hormone test. The unstimulated diurnal production of glucocorticosteroids was assessed by measurements of free cortisol in 24-hour urine samples. Free cortisol in urine was found a valid measure of the total diurnal excretion of cortisol metabolites, since it exhibited a good correlation to the fractional cortisol metabolites measured by gas chromatography. The adrenal response to adrenocorticotropic hormone stimulation was unaffected by treatment or dose. The unstimulated diurnal production of glucocorticosteroids demonstrated a highly significant dose-related suppression in response to the inhaled steroids. No significant difference was found between the two topical steroids (probability value 5.3%), and yet the suppression was apparent in the group of children treated with beclomethasone dipropionate but not in the group of children treated with budesonide. Further studies are desirable in order to ascertain whether budesonide offers an improved ratio between beneficial anti-inflammatory effect and unwanted systemic activity.     

The superiority of combination beclomethasone and salbutamol over standard dosing of salbutamol in the treatment of chronic asthma

We studied the clinical effect of a combination aerosol containing salbutamol and beclomethasone dipropionate in comparison to doubling the standard dose of salbutamol from an inhaler. Fifty-seven patients completed the double-blind, crossover study. They were treated with either an aerosol of 100 micrograms beclomethasone dipropionate and 200 micrograms salbutamol or 400 micrograms salbutamol alone. Both regimens were administered four times a day for 4 weeks. The patients showed significant improvement in FEV1, PEFR, and symptom scores after treatment with beclomethasone dipropionate and salbutamol compared with pre-trial values and with treatment with double the dose of salbutamol. The patients demonstrated a clear preference for treatment with the combination of beclomethasone dipropionate and salbutamol. Regular treatment with beclomethasone dipropionate in addition to salbutamol as a combination inhaler provides much better control of asthma than merely increasing the dose of salbutamol in those patients poorly controlled on standard doses of inhaled bronchodilators.     

Oral beclomethasone dipropionate for the treatment of gastrointestinal acute graft-versus-host disease (GVHD).

Acute graft-versus-host disease (aGVHD) remains one of the most severe complications after allogeneic transplantation; in particular, the presence of gut involvement has been related to increased mortality and poorer response. The use of systemic steroids remains the standard for first-line treatment despite its severe secondary effects. Beclomethasone dipropionate (BDP) is a topically active corticosteroid with low absorption, thereby avoiding many of the deleterious side effects associated with systemic steroids. In the present study we analyzed the efficacy of BDP in a series of 26 patients who were diagnosed with grade 1 and 2 gastrointestinal aGVHD. Twenty patients (77%) responded to BDP treatment, 17 (65.5%) reached complete remission (CR), and 3 (11.5%) showed partial response. Among those patients who reached CR, 5 relapsed, although 1 of them reached second CR after a second course of BDP; therefore, 13 (50%) of the 26 patients did not require systemic steroids to treat gastrointestinal aGVHD. CR rates in those showing gastrointestinal symptoms were 68% for patients with persistent nausea, 50% for those with vomiting, and 54% for those with diarrhea (P=.2). No patient included in the study developed any symptom related to adrenal axis suppression. Thirteen patients (50%) developed >or=1 infectious episode during the first 100 days after transplantation. Transplant-related mortality was 0% at 100 days, and overall transplant-related mortality was 30%, with only 2 patients dying due to infectious complications. Therefore, our study shows that monotherapy with oral BDP is an effective initial therapeutic approach for mild to moderate intestinal GVHD, which avoids complications related to systemic steroids.     

Effects of inhaled beclomethasone dipropionate and alternate-day prednisone on pituitary-adrenal function in children with chronic asthma.

Two corticosteroid regimens, alternate-day prednisone and inhaled beclomethasone dipropionate, have been more acceptable than daily oral corticosteroids for treatment of chronic asthma. To compare the effect of these regimens on hypothalamic-pituitary-adrenal function, 20 children with asthma were evaluated while receiving 20 to 40 mg of prednisone on alternate mornings or 400 to 800 microgram per day of inhaled beclomethasone dipropionate in divided daily doses; seven children requiring only non-corticosteroid medication served as controls. Early-morning serum cortisol concentration, urinary free-cortisol excretion and the 11-desoxycortisol response to metyrapone were decreased to a similar degree among children receiving both corticosteroid regimens in comparison with the control patients and were lowest when alternate-day prednisone and inhaled beclomethasone dipropionate were given together. Thus, inhaled beclomethasone dipropionate appears similar to alternate-day prednisone in its effect on hypothalamic-pituitary-adrenal function when used alone; the effect is additive when the two are used together.     

The effect of oral and inhaled beclomethasone dipropionate on adrenal function

Beclomethasone dipropionate differs from other steroids previously tried by inhalation in bronchial asthma in having marked topical potency and relatively weak systemic glucocorticoid effects. Experiments in human volunteer subjects demonstrating the effect of this steroid on the hypothalamo-pituitary adrenal axis (HPA axis) are described. These are part of a larger investigation into the reasons for the selectivity of beclomethasone dipropionate in bronchial asthma. From the evidence so far obtained, it may be concluded that suppression of the HPA axis is unlikely to occur at doses up to 1.0 mg/per day by inhalation.     

A comparison of fluticasone propionate 200 μg/day with beclomethasone dipropionate 400 μg/day in adult asthma

A total of 261 patients with symptomatic, mild to moderate asthma were randomized to treatment in this 4-week, double-blind, parallel-group comparison of fluticasone propionate 200 μg/d with beclomethasone dipropionate 400 μg/d. Improvements from both treatments were seen in diary card data. Morning peak expiratory flow rate (PEFR) improved from 375 to 390 and 371 to 382 1/min with fluticasone propionate and beclomethasone dipropionate, respectively. Symptom scores, percentage of symptom-free days and nights, and use of rescue (β₂-agonist medication also improved, as did clinical lung function. With the exception of percentage of rescue-free days, which was greater for beclomethasone dipropionate, none of the differences between the groups were statistically significant. There was a significant difference between treatments in the number of rescue-free days over days 1–28; however, there was no difference between treatments in the number of rescue-free days over days 1-14, nor was there any difference in the number of inhalations of rescue medication used throughout the study. Very few adverse effects were reported. Although all mean plasma cortisol values were within the normal range, they were significantly different between treatments, rising from 402 to 429 nmol/1 with fluticasone propionate, and falling from 435 to 394 nmol/1 with beclomethasone dipropionate (P= 0.006). Mean stimulated cortisol levels 30 min after tetracosactin injection were also significantly greater with fluticasone propionate (P = 0.024). In conclusion, fluticasone propionate 200 μg/d is as effective as beclomethasone dipropionate 400 μg/d with less effect on plasma cortisol levels.     

An open cross-over trial comparing two doses of astemizole and beclomethasone dipropionate in the treatment of perennial rhinitis

An open cross-over trial comparing astemizole with intra-nasal aqueous beclomethasone dipropionate was carried out in forty-five perennial rhinitis patients attending a S.W. London general practice. Each drug was given for 12 weeks, separated by 4–8 weeks without medication. The principal outcome measure was a 7-day symptom diary completed by patients during weeks 4, 8 and 12. Patients were skin tested to seven common inhalant allergens. Half the patients beginning either regime failed to respond adequately within 2 weeks. Doubling the dose in these patients achieved satisfactory symptom control in an additional 67% on beclomethasone dipropionate and 45% on astemizole. Symptom diary scores showed beclomethasone dipropionate to be significantly more effective than astemizole in the treatment of skin test negative patients; but the two drugs were of equal benefit in the treatment of skin test positive patients. Sneezing and rhinorrhoea were the same on both drugs, but nasal blockage tended to be less severe on beclomethasone dipropionate. There was no significant difference between drugs in the frequency or duration of side effects. Beclomethasone dipropionate and astemizole are equally effective in the symptomatic treatment of atopic perennial rhinitis, but beclomethasone dipropionate may offer superior symptom relief in non-atopic perennial rhinitis.     

Double-blind crossover trial comparing beclomethasone dipropionate and sodium cromoglycate in perennial allergic rhinitis

A double-blind crossover trial comparing the clinical efficacy of intranasal beclomethasone dipropionate and intranasal sodium cromoglycate was carried out in fourteen patients with perennial rhinitis due to animal danders. Intranasal beclomethasone dipropionate was significantly more effective than intranasal sodium cromoglycate in relieving nasal obstruction, nasal discharge and sneezing. Eleven patients reported preference for beclomethasone dipropionate and three had no preference for either drug.     

A prospective study of respiratory infection in asthmatic patients treated with beclomethasone dipropionate and sodium cromoglycate

A prospective study of forty adult asthmatic patients attending two chest clinics in the City of Liverpool was undertaken. All patients had reversible airways obstruction and were under treatment with either beclomethasone dipropionate or sodium cromoglycate. Satisfactory symptomatic control was achieved in both groups of patients on a subjective basis, but there was a statistically significant (P <0.001) reduction in the number of admissions to hospital in the treatment year compared to the preceding 12 months in the beclomethasone aerosol group. No increased incidence of lower respiratory tract infections or non-specific sore throats was found in either group studied. No cases of clinical oral Candida infection occurred in the beclomethasone aerosol treated patients. It is concluded that beclomethasone dipropionate in aerosol form is not only a safe and effective method for symptomatic control of adult bronchial asthma but is also economically worthwhile as a means of reducing hospital admissions in this vulnerable group of patients.     

The influence of a new corticosteroid,budesonide, on anaphylactic bronchoconstriction and SRS-A release in the guinea pig

Groups of guinea pigs sensitized with ovaibumin were treated with budesonide and beclomethasone dipropionate, respectively, in an intraperitoneal dose of 50 mg/kg. 20 h later, the anaphylactic release of histamine and slow reacting substance of anaphylaxis (SRS-A) from chopped lung tissue was studied. Whereas the corticosteroids studied had no effect on the tissue content of histamine or on the amount of antigen-induced release of this autacoid, budesonide and beclomethasone dipropionate to a great extent inhibited the release of SRS-A. The anti-anaphylactic effect of budesonide and beclomethasone was also shown in sensitized guinea pigs pretreated with mepyramine, 2.5 mg/kg intraperitoneally, and challenged with nebulized ovalbumin. We suggest that the partial protection given by the corticosteroids budesonide and beclomethasone dipropionate is due to the inhibition of SRS-A release.Subsidiary of AB Astra, Sweden.     

Double-blind trial comparing two dosage schedules of beclomethasone dipropionate aerosol with a placebo in the treatment of perennial rhinitis for twelve months

A double-blind trial comparing two dosage schedules of beclomethasone dipropionate, 200 μg and 400 μg, with a placebo in the treatment of perennial rhinitis for 12 months has been undertaken in 108 patients. Both schedules of beclomethasone dipropionate were therapeutically effective but the improvement in both the nasal and conjunctival symptoms was more marked with the higher dosage. Clinical candidiasis was not observed on inspection of the nose in any of the patients before or during the trial and in only one patient was clinical candidiasis observed on inspection of the throat. Epistaxes occurred in twelve of forty patients allocated to beclomethasone dipropionate and four of twenty-three allocated to placebo who had not had them before the trial. Most of the episodes were minor but four patients, all on beclomethasone dipropionate, reduced the aerosol dosage because of epistaxes.     

Comparative effects of inhaled salbutamol, sodium cromoglycate, and beclomethasone dipropionate on allergen-induced early asthmatic responses, late asthmatic responses, and increased bronchial responsiveness to histamine

Single-dose salbutamol (200 micrograms), beclomethasone dipropionate (200 micrograms), and sodium cromoglycate (SCG) (10 mg) administered by inhalation 10 minutes before allergen challenge were examined with regard to inhibition of allergen-induced early (EAR) and late (LAR) asthmatic responses and allergen-induced increase in bronchial responsiveness to inhaled histamine. Ten atopic subjects with asthma participated in a blinded, crossover, placebo-controlled trial. The EAR was inhibited by salbutamol and SCG but not by beclomethasone dipropionate or placebo (p less than 0.01). The LAR (p less than 0.01) and the allergen-induced increased bronchial responsiveness to histamine 7 hours (p less than 0.01) and 30 hours (p less than 0.05 and p less than 0.01 for various comparisons) were inhibited by SCG and beclomethasone diproprionate but not by salbutamol or placebo. The allergen-induced LAR and associated increased responsiveness are now believed to be more important clinically than the EAR. The clinical relevance of these results is to stress the importance of the prophylactic nonbronchodilator drugs (SCG and steroids) and the potential inadequacy of bronchodilators used alone in the treatment of both perennial and seasonal allergic asthma.     

A three- to five-year follow-up of the use of the aerosol steroid, beclomethasone dipropionate, in childhood asthma

Nineteen asthmatic children treated with the aerosol steroid, beclomethasone dipropionate, were followed 3 to 5 yr. Good control was maintained in all but one child throughout, although 73% have needed 1 or 2 wk of supplementary oral steroids per year for exacerbations. Growth has been along the percentile on which the child entered the study. No serious side effects have been encountered among 41 children treated between 1 and 5 yr with beclomethasone dipropionate. Seventeen percent needed prolonged alternate-day oral steroids, although all but one child did eventually return to good control with beclomethasone dipropionate.     

Effect of anti-asthmatic drugs on the response to inhaled endotoxin.

BACKGROUND: Endotoxin is a pro-inflammatory agent contaminating the dust that has been associated with the risk to develop pulmonary diseases. There is no data on the protective efficacy of anti-asthmatic drugs on the response induced by inhaled endotoxin in human. METHODS: Twelve mildly asthmatic subjects were submitted weekly to bronchial challenge tests with 20 microg endotoxin. The response was evaluated by the changes in FEV1, blood cells count, neutrophils activation (measured with the luminol-enhanced chemiluminescence) and blood concentration in the acute phase proteins, C-reactive protein (CRP) and haptoglobin. In a double-blind randomized cross-over placebo-controlled design, a single dose each of 500 microg beclomethasone dipropionate, 200 microg salbutamol, and 50 microg salmeterol were administered 30 minutes before the endotoxin challenge test. RESULTS: The 20-microg endotoxin challenge test induced a significant decrease in FEV1 and luminol-enhanced chemiluminescence (P < .001 and <.05, respectively). There was an increase in the blood neutrophils count (P < .05), in CRP (P < .02) and in haptoglobin (P < .03) concentrations. Pretreatment with beclomethasone dipropionate did not have any significant effect on the response to inhaled endotoxin. Salbutamol and salmeterol completely prevent the FEV1 decline due to their potent bronchodilatation activity. Salmeterol and salbutamol did not have any significant effect on the blood inflammation induced by endotoxin inhalation. CONCLUSION: The bronchodilating properties of beta2-agonists prevent the lung function response to inhaled endotoxin. When given in a single dose, an inhaled corticosteroid does not have protective activity on the endotoxin-induced blood inflammation.