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.

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.

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.

Topically active inhaled corticosteroid (IC) drugs are highly effective for chronic asthma. Formalized conceptions of "high, low or safe" dosages of these drugs may be less appropriate than one of "optimal dosage". It seems reasonable to formulate a specific goal of treatment, and then fit dosage to the individual needs and tolerances of the patient rather than to a conventionalized "safe" limit, based on averaged data from different and perhaps quite dissimilar subjects. The studies reviewed here illustrate some principles applicable to the effective use of IC drugs.

The influence of various dosing regimens on the response of asthmatic patients to aerosol steroid was investigated. Budesonide, a topically active corticosteroid like beclomethasone dipropionate, was given q.i.d. or b.i.d., in the morning or A.M./P.M., at doses of 400, 800, and 1600 micrograms/day. Each patient (n = 34) took every treatment combination for 2 wk. The antiasthmatic and systemic effects, measured by changes in peak expiratory flow rate (PEFR), blood eosinophils, and serum cortisol levels increased approximately linearly on log dose budesonide (p less than 0.0005). Systemic effects of the drug were nonsignificant at low dosage. At high dosage, morning dosing conserved hypothalamic-pituitary-adrenal function, but at the cost of a marginal reduction in efficacy (delta PEFR, p = 0.12). Having the dose frequency reduced the antiasthmatic potency of the drug, i.e., PEFR fell by an amount equivalent to approximately eightfold reduction in daily dosage (p = 0.002). This effect was not evident when asthma was in remission but became so with asthma in relapse. Overall, the q.i.d. A.M./P.M. regimen showed the best risk-benefit relationships. The data indicate (1) that reductions in dose frequency made with the hope of improving patient compliance and thus conserving the drug's long-term efficacy are likely to lead to the reverse effect, (2) that the clinician can conserve a better balance of risk vs benefit by titrating dosage in terms of puffs per dose rather than doses per day, and (3) that patients can increase the antiasthmatic efficacy of this aerosol steroid without any increase in drug costs (or apparent risk) by simply increasing dosing frequency. These therapeutic considerations probably apply to some or all of the other topically active steroids currently used to treat asthma.

In two groups of patients, 15 with asthma and 15 with chronic bronchitis, the bronchodilator effects of ipratropium bromide, of fenoterol plus theophylline, and of the combination of the three drugs, were compared using a double-blind, single-dose, placebo-controlled format. Ipratropium bromide caused rapid bronchodilatation which was not significantly different in asthmatic patients and patients with bronchitis (delta FEV1 = .29 L in one hour in asthmatic patients, .18 L in patients with bronchitis). In contrast, fenoterol plus theophylline induced a considerably greater effect in asthmatic patients (delta FEV1 = .41 L in one hour) than in those with bronchitis (delta FEV1 = .07 in one hour). The use of the three drugs in combination compared with ipratropium bromide alone, or fenoterol plus theophylline alone, resulted in a significant additional bronchodilatation in asthmatic patients. In the patients with bronchitis, the triple combination was clearly superior to fenoterol plus theophylline. A similar trend was present in comparing the triple combination to ipratropium bromide, but the difference did not reach statistical significance. There was no evidence of synergism when ipratropium bromide was combined with fenoterol plus theophylline in that the total bronchodilator effect was approximately additive. Asthmatic patients and the physician were able to distinguish the triple combination from placebo. No such ability was demonstrated with respect to those with bronchitis. All three drugs were well tolerated. Side effects were mostly mild, and none was related to the use of ipratropium.

Some patients with chronic asthma treated with beclomethasone aerosol (BA) derive significant symptom benefit, yet have persisting adrenal suppression due in part to their BA therapy. The daily dose of BA required is higher in patients with atopy. We therefore assessed the usefulness of ancillary treatment with cromolyn sodium (CS), a drug known to inhibit atopic asthma, to try to improve the balance of risk vs benefit in such patients. Thirty asthmatics, well controlled on high-dose BA (mean, 1,040 micrograms +/- 97 SE) but with morning cortisol levels averaging approximately 10 micrograms/dl, were allocated randomly to placebo or CS inhalant, used in addition to their regular BA and other asthma medications. After 4 wk, their BA dose was halved. Both groups were monitored for greater than 6 mo by daily symptom diaries and peak flows, and by spirograms and morning serum cortisol tests every 4 wk. Mean cortisol levels rose 27% after BA dose reduction (p less than 0.05) but asthma worsened. Risk-benefit assessments 20 wk after reducing the BA showed a general tendency for higher cortisol values to be coupled with worsening of the asthma symptoms and FEF25%-75%. The distributions of good, fair, and poor risk-benefit responses were the same in both CS and placebo-treated groups (p = 0.20). In other asthmatics who may have less associated bronchitis or small airways obstruction than these patients, CS might prove useful, but in these adult chronic asthmatics with this particular therapeutic problem, there was no discernible BA-sparing effect or other clinical advantage from adding CS to their established BA regimen.

Nicotine produced cholinergic excitatory and adrenergic and non-adrenergic inhibitory responses in isolated guinea-pig trachea. Responses were blocked by hexamethonium (10 micro M), lidocaine (85 micro M) or tetrodotoxin (0.01 micro M) demonstrating that nicotinic receptors in nervous tissue were being activated. In the presence of atropine (0.1 micro M), inhibitory responses to nicotine were partially blocked by specific, experimentally determined, beta-blocking concentrations of pindolol or sotalol or by pretreatment with 6-hydroxydopamine or reserpine but were completely blocked by the less specific beta-blocking drugs 1- and dl-propranolol. Parallel experiments on guinea pig ileum revealed a marked attenuation by dl-propranolol of the atropine sensitive, cholinergic excitatory response to applied nicotine. The non-beta-adrenoceptor blocking agent d-propranolol, produced qualitatively similar attenuation of all excitatory and inhibitory responses to nicotine on both preparations. The remarkable susceptibility of nicotine-induced, neurally mediated responses to low, beta-blocking concentrations of dl-propranolol and to low concentrations of both of its racemates suggests that the non-specific actions of these compounds may have much more significance than is customarily believed. Such studies on the interaction between nicotine and some beta-adrenoceptor blocking drugs are consistent with the hypothesis that non-beta-blocking so-called 'non-specific membrane depressant actions' of dl-propranolol may in concentrations previously considered 'sub-local anaesthetic', significantly depress physiological transmission induced by activation of nicotinic receptors.

Electrical (field) stimulation of the isolated guinea pig trachea with normal intrinsic tone produced a biphasic response which consisted of an initial (cholinergic) contraction followed by (adrenergic and nonadrenergic) relaxation. Treatment of the tissue with the prostaglandin synthetase inhibitor indomethacin (2.8–5.6 μM) removed intrinsic tone and increased the responsiveness of the tissue to stimulation of cholinergic nerves and to exogenous acetylcholine. Indomethacin-relaxed tracheae were subsequently used to study cholinergic neurotransmission because under these experimental conditions only the contractile component of the response to electrical stimulation was observed. The β adrenoceptor blocking agents dl-propranolol and sotalol and the adrenergic neuron blocking agent guanethidine produced further enhancement of the contraction to electrical stimulation at low frequency (1–10 Hz). Prostaglandin E1, l-noradrenaline, l-adrenaline, salbutamol, phenylephrine, and phentolamine selectively attenuated the contractions to electrical stimulation in concentrations which did not significantly alter the matched responses to exogenous acetylcholine. The selective depressant effect of l-noradrenaline, l-adrenaline, salbutamol, phenylephrine, and phentolamine but not prostaglandin E1 were blocked by dl-propranolol or sotalol. The present results demonstrate that responses to stimulation of cholinergic nerves were altered by (1) prostaglandins and inhibitors of their synthesis, (2) neurally released adrenergic transmitter, and (3) exogenously added β adrenoceptor agonists. The possibility that prostaglandins and adrenergic neurotransmitter may modulate cholinergic neurotransmission at both pre- and post-junctional sites is hypothesized. It is proposed that more attention should be paid to the role of cholinergic transmission and its modulation in the studies of airway smooth muscle.

In 34 steroid-dependent asthma patients who improved markedly during 2 mo of treatment when progressively larger doses of beclomethasone aerosol were added to their oral prednisone regimen, we subsequently reduced both steroids to ascertain the minimum dose of each needed to prevent recurrence of significant asthmatic disability. After 80 wk of follow-up, 15 patients had successfully terminated oral prednisone; 19 were better controlled with a combination of aerosol plus oral steroid than with either drug alone; all patients previously unable to convert to alternate-day prednisone did so successfully during the combined therapy. The minimum effective maintenance dosage varied greatly among these patients-the median values being 2.5 mg prednisone and 1,200 microgram beclomethasone per day. The latter ranged from 200 to 1,8000 microgram. Only 4 patients were satisfactorily controlled without prednisone on 400 microgram beclomethasone per day or less. Seven needed extra intranasal beclomethasone to help control the nasal polyps which worsened after prednisone withdrawal. Suppression of plasma cortisol levels, apparently attributable to the beclomethasone, persisted in most patients, but on the average this was no worse than before commencing this treatment and valuable clinical improvement accrued. There were no other important complications of the regimen. In most of these patients with severe chronic asthma, optimum control of the disease required combined aerosol-oral therapy and maintenance doses of beclomethasone higher than those usually recommended. In some patients, effective control of chronic asthma by beclomethasone treatment may require acceptance of some persisting suppression of adrenal function as a considered risk.