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Biomedical subjects

J H Toogood

Publications and source records attributed to J H Toogood.

At least 19 recordsLinked to original sources
PubMed1991

Effects of dose and dosing schedule of inhaled budesonide on bone turnover.

To assess whether the use of larger than usual doses of inhaled steroid to treat severe asthma may adversely affect bone turnover and whether such an effect may be mitigated by altering the dose schedule, we investigated the effects of budesonide (BUD) on serum osteocalcin and the urinary output of hydroxyproline and calcium. Healthy adults were administered 1.2 or 2.4 mg of BUD per day (N = 40) or placebo (N = 8) in a crossover, double-blind comparison of morning versus diurnal dosing schedules for 1 month each. Both BUD doses reduced the 24-hour urinary free-cortisol output (p less than 0.001) and serum osteocalcin (p less than 0.001). The larger dose reduced the morning serum cortisol levels (p = 0.002). Neither dose increased the 8 AM urinary calcium or hydroxyproline output. Osteocalcin and plasma cortisol levels were higher on morning than on diurnal dosing (p = 0.01). The 24-hour urinary free-cortisol output was the same with either schedule (p = 0.96). Additional study is required to assess the clinical importance of the inhibitory effect of BUD on bone formation, as evidenced by the reduction in osteocalcin levels. Of concern is the possibility of serious bone complications resulting from the long-term use of inhaled steroid, particularly in growing children or patients in whom other risk factors for osteoporosis are present. The clinical advantage, if any, of morning dosing remains questionable.

Administration, Inhalation↗
PubMed1991

Differential effects of inhaled budesonide and oral prednisolone on serum osteocalcin.

Inhaled glucocorticosteroids have been developed for the treatment of asthma in an attempt to minimize the suppression of endogenous adrenal function that complicates oral or injected steroid usage, but it is unclear whether this strategy leads to reduced systemic complications in other areas, such as the skeleton. In this study we evaluated serum osteocalcin levels as a marker of skeletal metabolism in healthy volunteers treated with oral and inhaled steroids alone and in response to an oral calcitriol stimulation test. Forty subjects, aged 33 +/- 9 (mean +/- SD) yr were randomized to receive either high or low dose oral prednisolone (40 vs. 10 mg/day) or inhaled budesonide (3.2 vs. 0.8 mg/day). Each dose of budesonide is known to have a greater antiasthmatic potency than the dose of prednisolone with which it was compared. In addition 10 control subjects received placebos containing no active steroid drugs. During the second week of treatment, half of the subjects in each of the 4 steroid-treated groups and all subjects in the control group received oral calcitriol (2.0 micrograms/day). There was a marked dose-dependent reduction in serum cortisol levels, but this reduction was significantly less pronounced during budesonide treatment, such that low dose budesonide was without effect. During the first week of steroid therapy there were significant dose-dependent reductions in serum osteocalcin (P = 0.003), but this reduction was not significantly different between budesonide and prednisolone treatments. In response to calcitriol, serum osteocalcin increased by 35% in the control group (P = 0.06). Osteocalcin levels increased by 56% and 50% in the low dose budesonide and prednisolone groups and by 106% in the high dose budesonide group, but did not change in the high dose prednisolone group. The osteocalcin response to calcitriol was significantly higher in the budesonide groups (P = 0.03, by analysis of variance). High dose prednisolone caused increases in serum 1,25-dihydroxyvitamin D3 (P less than 0.02), urinary calcium excretion (P = 0.07), and urinary hydroxyproline (P less than 0.01). None of these changes was seen during budesonide therapy. There are as yet no data for these variables after long term use of inhaled budesonide in asthmatic patients, but our acute studies suggest that this potent topical glucocorticoid may have considerably less impact on the skeleton than oral prednisolone, even if used at doses high enough to suppress endogenous adrenal function.

Administration, Inhalation↗
PubMed1990

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.

Administration, Inhalation↗
PubMed1990

Complications of topical steroid therapy for asthma.

The oropharyngeal complications of IS therapy are seldom a serious problem. They may be avoided or ameliorated by inhaling the drug via a spacer and/or reducing the dosing frequency. Severe esophageal candidiasis or atrophic glossitis are rare and generally require discontinuation of IS therapy. Reflex cough or bronchospasm triggered by the inhaled drug occur fairly commonly, but are easily corrected by appropriate treatment. The systemic complications of IS therapy are inconsequential in most patients treated with conventional low doses. Higher doses are more effective but also more active systemically. Despite this, the ratio of systemic-to-antiasthmatic activities may be more favorable with high dose IS than with oral prednisone when the two treatments are compared at equivalent levels of asthma response. The potential risk of adverse systemic effects accruing from the long-term use of intermediate or high doses of IS needs to be rigorously studied.

Administration, Inhalation↗
PubMed1989

High-dose inhaled steroid therapy for asthma.

Only a small minority of patients with asthma have symptoms severe enough to require high-dose inhaled steroid therapy. Because they need more aggressive treatment, this group is disproportionately represented in tertiary care referral centers. Therapeutic effects are dose dependent, and the daily dose of steroid required to normalize pulmonary function far exceeds that for symptom relief. Studies show that, if titrated to minimum dose levels of each the combination of inhaled and oral steroids provides a better balance between antiasthmatic and systemic glucocorticoid activity compared with oral steroid alone. Also, rapidly metabolized inhaled steroids such as budesonide may be associated with a lower risk for the osteoporotic complications seen with long-term oral steroid use. However, high dose of inhaled steroids may lead to adrenocortical suppression and hence estrogen deficiency in postmenopausal women. Morning dosing may mitigate this effect. Oropharyngeal thrush may be prevented by lowering the dose frequency or using a spacer. During prolonged inhaled steroid therapy, patient compliance has proved an important determinant of outcome.

Administration, Inhalation↗
PubMed1989

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.

Administration, Inhalation↗
PubMed1988

Effect of high-dose inhaled budesonide on calcium and phosphate metabolism and the risk of osteoporosis.

We investigated the effects of the antiasthmatic inhaled steroid budesonide at low and high dosage (0.6 and 2.4 mg/day) on calcium and phosphate metabolism (Ca, P) in 10 normal adults. Their endogenous production of cortisol dropped with budesonide treatment (p less than or equal to 0.0005), as did androgen production (p less than or equal to 0.003). This was associated with an increase in the renal tubular maximal reabsorption of Ca (p = 0.003) and P (p = 0.03), a decrease in the urinary output of Ca in the fasting morning state (p = 0.03), and an increase in serum P (p = 0.02). However, there was no change in the 24-h urinary excretion of Ca (p = 0.76) or P (p = 0.08) or the serum Ca level (p = 0.19). Similarly, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, parathyroid hormone, and urinary cAMP levels were not affected, indicating that absorption of Ca from the gut was not compromised. Thus, in contrast to the expected effects of oral steroid treatment, inhaled budesonide had no discernible short-term adverse effect on Ca or P metabolism under the conditions of this study, despite purposely using a dosage high enough to partially inhibit adrenocortical function. These data tend to support a broadening of the therapeutic role of budesonide, and possibly other inhaled steroid drugs, to include higher doses and more severe asthmatics. However, additional clinical and metabolic studies are needed to fully clarify the effects of high-dose inhaled steroid therapy on bone.

Absorption↗
PubMed1987

Beta-blocker therapy and the risk of anaphylaxis.

Beta-blocker therapy is associated with an increase in the severity and, possibly, the incidence of acute anaphylaxis. The population at risk consists of people with allergic conditions who are given a beta-blocker for an unrelated condition. Anaphylaxis under these conditions may be severe, protracted and resistant to conventional treatment because of the beta-adrenergic blockade. Severe or fatal attacks have been triggered by insect stings, the ingestion of allergenic foods or drugs, and injections of radiocontrast media, antisera or immunotherapy antigens. These occurrences are probably infrequent, but their incidence is unknown. At least two fatal cases have recently occurred in Canada. Clinical allergists, internists and family practitioners in particular should be aware of the need for aggressive and prolonged support in patients who experience anaphylaxis while receiving beta-blocker therapy and should report all such occurrences to the federal registry of adverse drug reactions. Allergy skin testing or immunotherapy is inadvisable in patients who take a beta-blocker orally or in the form of ophthalmic eyedrops. The list of relative contraindications to beta-blocker use should be extended to include susceptibility to recurrent anaphylaxis, whether it is idiopathic or due to an identifiable cause.

Adrenergic beta-Antagonists↗
PubMed1984

Personal observations on the use of inhaled corticosteroid drugs for chronic asthma.

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.

Aerosols↗
PubMed1982

The addition of an aerosol anticholinergic to an oral beta agonist plus theophylline in asthma and bronchitis. A double-blind single dose study.

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.

Administration, Oral↗