Prednisolone disposition in steroid-dependent asthmatics

A 40-mg intravenous dose of prednisolone was given as prednisolone phosphate to seven severe steroid-dependent asthmatics and to 13 healthy volunteers to determine if the large prednisone requirements of these patients were a function of the disease, cellular response, or rapid clearance of prednisolone. Plasma concentrations of prednisolone, prednisone, and cortisol were determined by high-performance liquid chromatography over an 8-hr test period. Circulating eosinophil concentrations were monitored concurrently. The apparent half-lifes of prednisolone in the asthmatics and normals were 3.33 ± 0.71 and 3.25 ± 0.58 hr (mean ± SD). The apparent plasma clearances of prednisolone were 201 ± 54 and 198 ± 38 ml/min11.73 m² and the apparent volumes of distribution were 50.8 ± 11.7 and 53.5 ± 13.5 L/1.73 m² for the asthmatic and normal groups, respectively. When the concentration-dependent binding of prednisolone to plasma protein was examined, no differences in the apparent clearances of unbound drug were found between the two groups. The eosinopenic response to prednisolone was similar in the steroid-dependent asthmatics and healthy normal volunteers. These studies indicate that binding, distribution, and clearance of prednisolone are not responsible for the large prednisone requirement of some steroid-dependent asthmatics. Differences in steroid-receptor sensitivity or in severity or pathophysiology of the disease state more likely account for the need for large prednisone dosages in these patients.     

A double-blind comparison of ketotifen and disodium cromoglycate in atopic adult asthmatics

The therapeutic effects of inhaled disodium cromoglycate (DSCG) and orally administered ketotifen were compared in thirty atopic asthmatics aged 15-34 years during a 22-week double-blind parallel group study. Ketotifen is a cycloheptathio-phene with experimental antihistaminic, anti-allergic and anti-anaphylactic effects equal or superior to those of DSCG. During the first 6 weeks of treatment, mean airflow meter readings increased and bronchodilator use diminished in those receiving DSCG, but no improvement was seen in those given ketotifen. In the next 10 weeks. concomitant therapy was reduced in both groups, but this reduction was greater in the group receiving DSCG. No serious adverse effects occurred. Asthma worsened after abrupt discontinuation of DSCG but not ketotifen. Although a small number of patients may have benefited from ketotifen. its effect on asthma was not comparable with that of inhaled disodium cromoglycate.     

Use of methotrexate in the treatment of steroid-dependent adolescent asthmatics

Five children 10 to 16 years of age with steroid-dependent asthma were treated with methotrexate. All were able to reduce their doses of prednisone and all had improvement in their clinical status. No significant side effects were noted in patients treated 1 to 3 years. This open study suggests that methotrexate should be considered in the treatment of older children with severe asthma and morbidity from their steroid therapy.     

Preventive effect of ketotifen, a new antiallergic agent, on histamine-induced bronchoconstriction in asthmatics

The preventive effect of ketotifen, a new drug with anti-histaminic and antiallergic properties, on histamine-induced bronchoconstriction was studied by open assessment in twenty-four adult patients with extrinsic asthma. A single oral dose of 1 mg ketotifen reduced the post-histamine mean drop in peak expiratory flow from 33 to 16% of the basal values (P<0.001). After a 4 weeks' regimen of 1 mg ketotifen twice daily the post-drug histamine-induced fall in PEF was further significantly reduced (P<0.001). Tests performed after 8 and 12 weeks of treatment showed no additional decrease in bronchial reactivity to histamine. Tests performed 1 week after cessation of treatment showed return of bronchial reactivity to the pretreatment level. The results suggest that a single dose of ketotifen has a marked preventive effect on histamine-induced bronchoconstriction and that this effect is enhanced during continued treatment.     

A controlled study on the preventive effect of ketotifen, an antiallergic agent, on methacholine-induced bronchoconstriction in asthmatics

We studied the preventive effect of ketotifen, an oral drug with antianaphylactic and antihistaminic properties on methacholine-induced bronchoconstriction in controlled cross-over experiments in twenty-six adult patients with extrinsic asthma. Both a single dose of 1 mg ketotifen and 4 weeks treatment of ketotifen, 1 mg twice daily, failed to reduce the methacholine-induced drop in peak expiratory flow. The spirometric findings remained unchanged during ketotifen treatment. There was no difference between treatments with ketotifen and placebo with regard to the patients assessment of the severity of asthma or airway sensitivity to tobacco smoke, fumes or dusts, or exercise. The results suggest that treatment during 4 weeks with ketotifen does not reduce unspecific broncial hyperreactivity in patients with extrinsic asthma.     

Hypogammaglobulinemia in steroid-dependent asthmatics correlates with the daily dose of oral prednisolone

BACKGROUND: Steroid-induced adverse effects including suppression of humoral immunity should be considered in steroid-dependent severe asthma. Only a few studies have determined the exact steroid dose that could potentially suppress humoral immunity in asthmatics. METHODS: Randomly selected 100 adult asthmatics treated with inhaled beclomethasone dipropionate (BDP) were classified into three groups based on the dose of steroid to determine the serum IgG, IgA and IgM levels by radioimmunoassay. Relationships between serum immunoglobulin levels and the daily dose and duration of oral prednisolone (PSL) therapy were examined. RESULTS: None of the patients on inhaled corticosteroid alone had hypogammaglobulinemia. Patients on oral PSL at a dose >12.5 mg/day for at least 1 year had low serum IgG. There was no significant correlation between the duration of oral PSL therapy and serum IgG. CONCLUSIONS: Oral PSL can potentially suppress humoral immunity in severe asthma. In asthmatics, hypogammaglobulinemia could develop in those on a daily dose of PSL >12.5 mg, but is independent of the duration of such treatment. No suppression of humoral immunity was noted on inhaled corticosteroid therapy alone, either at low or high dose.     

The incidence of corticosteroid side effects in chronic steroid-dependent asthmatics on TAO (troleandomycin) and methylprednisolone

The purpose of this study was to determine the effect of troleandomycin (TAO)-methylprednisolone (MP) regimens on the incidence of corticosteroid-induced side effects. Retrospective analysis was performed on the charts of 29 adult chronic steroid-dependent asthmatics on regimens of TAO-MP. These 29 met our criteria of a minimum of 1 year on TAO-MP and at least 6 to 12 months on daily or alternate-day corticosteroids before TAO-MP was instituted. Charts were reviewed for nine known corticosteroid (CS) side effects, all previously identified side effects were excluded. Charts were also reviewed for TAO dose, MP dose, and dose/duration on CS therapy before TAO-MP regimen began. Patients on TAO at an average dose of 250 mg/d were able to wean to an average MP dose of 10.8 mg every other day from an average MP equivalent dose of 16.8 mg every other day before TAO. In spite of lower MP doses on TAO we found that 35% showed an increase in CS-induced side effects, some (three) had more than one side effect. Three patients developed cataracts (10%), two become hypertensive (6.8%), one developed diabetes (3%), one had a psychotic episode (3%), and one patient developed TB (3%) and had a spinal compression fracture. Sixty percent of these patients were on 8 mg or less of MP on an alternate-day basis. We found that in this group of 29 chronic steroid-dependent asthmatics the incidence of corticosteroid-related side effects was increased on TAO-MP regimens despite a reduction in corticosteroid dose.     

The effect of ketotifen on aspirin-induced asthmatic reactions

The effectiveness of prophylactic treatment with ketotifen was assessed in ten asthmatic patients with aspirin idiosyncrasy in a randomized double blind trial. Increased airways obstruction following challenge with aspirin was significantly reduced when patients were pre-treated with ketotifen.     

The effect of ketotifen on bronchial hyperreactivity in childhood asthma

Eighteen children with perennial bronchial asthma with an average age of 9.6 yr were studied with respect to the protective effect of ketotifen on bronchial hyperreactivity. All children included demonstrated bronchial reversibility after inhalation of salbutamol, and the methacholine challenge produced a decrease of the forced expiratory volume during the first second of at least 20% in the concentration interval of 0.25 mg/ml to 4.0 mg/ml. The study was double-blind with patients divided into two parallel groups treated for 12 wk with ketotifen or placebo. Methacholine provocation tests were performed every fourth week during this period. No differences between the challenges before and during the treatment period were found in either group, nor were any differences found between the ketotifen and placebo groups. Long-term treatment with ketotifen does not appear to alter the bronchial hyperreactivity in children with bronchial asthma.     

Pranlukast allows reduction of inhaled steroid dose without deterioration in lung function in adult asthmatics]

We undertook a community based case-control study to measure the effect of pranlukast on the reduction of inhaled steroid in adult asthmatics. Forty-one adults completed a run-in period of 4 weeks on 800 microgram of beclomethasone dipropionate (BDP) documenting twice daily peak expiratory flow (PEF) and symptom score and therapeutic score on a standard diary. Forced expiratory volume in one second (FEV1.0), V50, V25 was measured once during the run-in period. Patients were then randomized to receive either pranlukast with 400 microgram of BDP or 400 microgram alone for 8 weeks. There was no difference in the symptom score and therapeutic between the two groups at any time point. However, morning and evening % PEF run-in expressed as a % of the PEF average during the run-in period was significantly lower at 8 weeks in the groups without pranlukast. There were subjects in the group without pranlukast (35.3%) compared to those with (20.8%) who had a 10% or more reduction in % PEF from the run-in period. The patients with an FEV1.0 < 80% predicted who were randomized to the control group were more likely (5 of 7) to have a fall in % PEF run-in and those randomized to received pranlukast were less likely to have a fall in % PEF run-in though this was not significant (2 of 6). In this study, pranlukast has demonstrated steroid sparing effect. Severe asthmatics (FEV1.0 < 80%) who deteriorate after reduction of inhaled steroid may benefit most from pranlukast. Larger studies are now required to explore this important effect.     

A multicenter trial of the prophylactic effect of ketotifen, theophylline, and placebo in atopic asthma

Three hundred seventy-four patients with asthma were entered into a year-long, double-blind, double-placebo controlled study comparing the prophylactic effect of ketotifen (229 patients), theophylline (73 patients), and placebo (72 patients). The ketotifen group was larger to allow the accumulation of additional long-term safety data. The primary measure of therapeutic effect was a decrease in concomitant medication without a significant increase in symptomatology or a decrement in pulmonary functions. A patient daily diary was used to document symptoms (cough, shortness of breath, and wheeze) and concomitant medications taken during the 2-week baseline and the subsequent 12 monthly periods. After 2 months of study-drug therapy, the ketotifen patients had a greater decrease in both concomitant medication and symptomatology than either of the other groups. This delay in the onset of therapeutic activity has been observed in other studies and is characteristic of this compound. The principal side effect observed with ketotifen is initial sedation, which was found to be self-limiting and of little concern to the patient after the first month.     

The effect of salt chamber treatment on bronchial hyperresponsiveness in asthmatics

BACKGROUND: Randomized controlled trials are needed to evaluate the effects of complementary treatments in asthma. This study assessed the effect of salt chamber treatment as an add-on therapy to low to moderate inhaled steroid therapy in asthma patients with bronchial hyperresponsiveness (BHR). METHODS: After a 2-week baseline period, 32 asthma patients who exhibited BHR in the histamine inhalation challenge were randomized: 17 to 2-week active treatment, during which salt was fed to the room by a salt generator, and 15 to placebo. The salt chamber treatment lasted 40 min and was administered five times a week. RESULTS: Median provocative dose causing a decrease of 15% in Fev(1) (PD(15)FEV(1)) [corrected] increased significantly in the active group (P = 0.047) but not in the placebo group. The difference in changes between the active and placebo groups was significant (P = 0.02). Nine patients (56%) in the active group and two patients (17%) in the placebo group exhibited at least one doubling dose decrease in BHR (P = 0.040). Six patients (38%) in the active group and none in the placebo group became non-hyperresponsive (P = 0.017). Neither the peak expiratory flow (PEF) values measured just before and after the treatment, nor FEV(1) values measured before the histamine challenges, changed. The reduction in BHR was not caused by changes in the baseline lung function. CONCLUSIONS: Salt chamber treatment reduced bronchial hyperresponsiveness as an add-on therapy in asthmatics with a low to moderate dose of inhaled steroids. The possibility that salt chamber treatment could serve as a complementary therapy to conventional medication cannot be excluded.     

Fatal varicella in steroid-dependent asthma

Disseminated varicella infection is a potentially life-threatening complication of chronic high-dose corticosteroid (CS) or immunosuppressive therapy. A review of the literature indicates that, with one possible exception, this complication has not occurred in a CS-dependent subject with asthma. We present in this article the clinical features and autopsy findings of a steroid-dependent subject with asthma who died of acute, disseminated varicella. A 16-year-old poorly compliant, steroid-dependent subject with asthma received two courses of high-dose intravenous methylprednisolone during a 3-week period, followed by a tapering schedule of oral prednisone. During this time, she was exposed to chickenpox. She subsequently developed a classic varicella rash, sever back pain, rapidly progressive hepatic failure, pneumonitis, and encephalopathy. Death ensued 3 days after the onset of the rash. Evidence of disseminated varicella infection was confirmed at autopsy. This case illustrates that a small number of subjects with severe asthma receiving high-dose CS need to be considered as a separate, high-risk group for developing disseminated varicella. We recommend that the immune status of these patients to varicella-zoster virus be assessed by a serum titer. If these patients are nonimmune, they would be candidates for varicella-zoster immune globulin on exposure, and for acyclovir therapy should varicella dissemination occur.     

Long-term corticosteroid effect on lymphocyte and polymorphonuclear cell function in asthmatics

The effect of long-term alternate-day steroid administration on lymphocyte and polymorphonuclear cell (PMN) functions was studied in 10 steroid-dependent adult asthmatic patients. The duration of alternate-day prednisone usage ranged from 3 to 12 yr with an average of 6.7 ± 3.6 yr. Maintenance steroid dosage at the time of study ranged from 20 to 50 mg on alternate days, averaging 31 ± 8 mg. Prednisone caused marked lymphopenia, suppression of phytohemagglutin (PHA) lymphocyte transformation and PMN adherence 4 hr after ingestion. By 24 hr these measurements returned to normal or higher. These effects appeared at all doses between 20 and 50 mg of prednisone. In contrast, there was no statistically significant suppression of the total leukocyte count, total and active erythrocyte (E) rosette-forming lymphocytes, serum immunoglobulin concentrations, polymorphonuclear cell (PMN) phagocytosis, or delayed skin reactivity. We conclude that the acute effects of prednisone on lymphocyte and PMN function are transient and return to normal levels by 24 hr. The continued administration of beclomethasone dipropionate by inhalation did not interfere with the recovery of the transient leukocyte abnormalities induced by oral prednisone.     

A pitfall in the cytodiagnosis of sputum of asthmatics

The sputum of an asthmatic often contains large, well-circumscribed clusters of benign columnar epithelial cells which can be misinterpreted as papillary fragments of an adenocarcinoma. Their presence is a manifestation of the excessive shedding of the mucosa of the lower respiratory tract accompanying an attack of bronchial asthma. These clusters are illustrated and compared with clusters of adenocarcinoma cells. To discriminate between the two types of cluster may be difficult and it is therefore important for the cytologist to know when a sputum is from an asthmatic.     

The impact of central sparing on the word-length effect in hemianopia

Studies suggest that a word-length effect of up to 160?ms/letter distinguishes hemianopic dyslexia from pure alexia. However, partial preservation of central vision is common in right hemianopia, but its effects on single-word reading are unknown. Eighteen healthy subjects read single words with a gaze-contingent right hemianopia simulation that varied the degree of central sparing. Mean reading onset time declined with small degrees of central sparing, but the word-length effect did not decrease until sparing exceeded 3.15°. We next evaluated the effects of font size. Effects of central sparing were constant when expressed in number of letters, with a decline in word-length effect beginning as sparing approached 4 letters. We conclude that the effects of central sparing on mean reading onset time and the word-length effect are distinct. We provide diagnostic word-length criteria for discriminating between pure alexia and hemianopic dyslexia with various degrees of central sparing.     

Prednisolone disposition in steroid-dependent asthmatic children

The pharmacokinetics of a 40-mg intravenous dose of prednisolone were determined in 10 steroid-dependent asthmatic children with highly variable prednisone requirements (5 mg every other day to 40 mg a day). Concentrations of prednisolone and cortisol in plasma over a 24-hr test period were measured by high-performance liquid chromatography. Eosinophil concentrations and the concentration-dependent protein binding of prednisolone were also determined. The mean (±SD) apparent half-life of prednisolone in these children was 2.5 ± 0.5 hr. The mean total volume of distribution was 52.8 ± 14.5 L/1.73 m² and mean plasma clearance was 246 ± 62 ml/min/1.73 m². These pharmacokinetic parameters, as well as the protein binding and eosinopenic response, were similar to values from healthy and steroid-dependent asthmatic adults. The data were also similar in both responsive and relatively resistant patients. The pharmacokinetics and protein binding of prednisolone are not responsible for the highly variable prednisone requirement and clinical response of these children to prednisone therapy.