Salbutamol in the 1980s
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Salbutamol (albuterol) is a β2-selective adrenoceptor agonist which accounts for its pronounced bronchodilatory, cardiac, uterine and metabolic effects.
During the intervening years since salbutamol was first reviewed in the Journal (1971), it has become extensively used in the treatment of reversible obstructive airways disease. Numerous studies in this disease (including severe acute, childhood and exercise-induced asthma) have confirmed the bronchodilatory efficacy of salbutamol, and it has been shown to be at least as effective as most of the currently available bronchodilators, if not more effective.
The onset of maximum effect of salbutamol is dependent on the formulation used and the route by which it is administered. In most patients inhaled salbutamol is a first-line therapy, since it offers rapid bronchodilation, usually relieving bronchospasm within minutes. Although oral salbutamol has often proved to be less efficacious than the inhaled formulation, it still affords clinically significant bronchodilation, and it is particularly useful in those patients unable to coordinate the use of inhalers. Parenteral formulations of salbutamol are generally reserved for the treatment of severe attacks of bronchospasm and they are one of the treatments of choice in these life-threatening situations.
Studies of the concomitant use of salbutamol and other agents such as anticholinergics, methylxanthines and beclomethasone dipropionate have usually shown a complementary response in the majority of patients, as might be expected from the different mechanisms of action of these groups of drugs.
Salbutamol is generally well tolerated and any side effects observed are a predictable extension of its pharmacology. Since the frequency of side effects is dose related, and therefore dependent on the route of administration, it is not surprising that they are much more common following intravenous and oral rather than inhalation therapy. Tremor, tachycardia and hypokalaemia are the most frequently reported adverse effects.
After nearly 20 years of use, salbutamol is well established as a ‘first-choice’ treatment in reversible obstructive airways disease. Indeed, throughout this time many new bronchodilatory agents have been studied but none have proved more effective. Clinical evaluation of salbutamol in the treatment of premature labour, hyperkalaemia and cardiac failure awaits further studies, although to date some encouraging results have been reported.
Salbutamol is a β2-selective adrenoceptor agonist which has demonstrated considerable bronchodilatory effects. In studies in healthy volunteers, inhaled salbutamol caused a rapid and significant bronchodilation by reducing bronchomotor tone in both the large and small airways, as reflected by increases in sGaw, FEV1, FEF25–75, FEF50, FEV3, FEF75–88 and FEF75, and effectively inhibited histamine-induced bronchospasm. As would be expected, the bronchodilatory effects of salbutamol are greatly diminished following coadministration of non-selective β-blockers such as propranolol, betaxolol and tertatolol. The selective β-blocker atenolol had no such effect. Lower doses of inhaled salbutamol are required to bring about maximum bronchodilation in normal volunteers than in asthmatic patients. Although salbutamol has effective antitussive properties, its clinical application in this area requires further investigation.
In common with other β2-adrenoceptor agonists, salbutamol demonstrated vasodilatory and inotropic effects in healthy volunteers, and in patients with reversible obstructive airways disease or cardiovascular disease, particularly after intravenous administration. However, the clinical efficacy of salbutamol in the treatment of heart failure remains to be established.
Intravenous salbutamol causes a marked reduction in uterine tonicity in women suffering from primary dysmenorrhoea, and this was associated with pain relief in pregnancy. Furthermore, salbutamol by intravenous infusion reduced uteroplacental blood flow by 18 to 50%.
Salbutamol exerts a number of metabolic effects. Intravenous and nebulised salbutamol decrease serum potassium concentrations, although the effect is generally mild and transient. However, intravenous salbutamol has been used to treat hyperkalaemia in renal failure patients. Salbutamol possesses lipolytic activity which is manifested as significant increases in non-esterified fatty acid and high density lipid-cholesterol. Oral and intravenous salbutamol cause increases in blood glucose and insulin, by stimulating glycogenolysis in the liver and having a direct stimulatory effect on β2-receptors in insulin secretory pancreas cells. Studies in animals and humans indicate that maternally administered salbutamol exerts some effects on fetal metabolism, but the only change reported to date which could be of clinical significance is an increase in growth hormone levels.
Salbutamol possesses antidepressant properties, although the mechanism by which it exerts this activity is unclear. Other reported CNS effects in animals include anorexia, induced by mechanisms involving β-adrenergic sites in the brain of rats, and increased vasopressin levels in the cerebrospinal fluid of dogs.
Salbutamol has demonstrated some antiallergic activity. In vitro, salbutamol produces dose-related inhibition of histamine release from lung fragments. However, it has little or no effect on allergen-induced histamine release from leucocytes obtained from allergic patients and only weak activity at inhibiting anti-IgE-induced histamine release from human skin slices. Inhaled and oral salbutamol are potent inhibitors of mast cell mediator release; in addition, both effectively inhibit inhaled allergen-induced bronchoconstriction.
As with other β2-adrenoceptor agonists, salbutamol stimulates mucus secretion and mucociliary transport. Nebulised solutions of salbutamol increase mucociliary rates by up to 36% in obstructive airways disease patients and 16% in healthy volunteers.
The mechanism of action of salbutamol is thought to be mediated via the stimulation of the production of cyclic adenosine-3′ 5′-monophosphate (cAMP) by activation of the enzyme adenyl cyclase. Cyclic AMP is then capable of triggering a sequence of intracellular events that ultimately leads to the physiological effects associated with salbutamol therapy.
Despite its widespread use, pharmacokinetic information on salbutamol is limited, particularly with respect to newer formulations, and further studies are needed to fully define its pharmacokinetic profile in humans. The major portion of an inhaled dose of salbutamol is swallowed and handled orally; the small fraction that is delivered to the lung (approximately 10%) rapidly appears in the circulation as free drug. Salbutamol is well absorbed following oral administration, with peak plasma concentrations occurring between 1 and 4 hours later. However, due to extensive presystemic metabolism in the gut wall its systemic bioavailability is only 50%. After multiple oral doses of salbutamol 4mg 4 times daily, steady-state plasma concentrations are attained by the third day of administration. Additionally, salbutamol 2mg 4 times a day was found to be bioequivalent to a controlled release formulation given at a dosage of 4mg twice daily over a 5-day period
In animal studies it has been shown that salbutamol is rapidly cleared from all tissues. In addition, the drug undergoes placental transfer from maternal to fetal plasma, and slightly penetrates the blood-brain barrier. The apparent volume of distribution of salbutamol in humans is 156L, indicating extensive extravascular uptake. The plasma protein binding of salbutamol over the concentration range 0.05 to 2.0 mg/L is 7 to 64%. The blood/plasma concentration ratio of salbutamol is about 1.
Salbutamol and its metabolite(s) are rapidly excreted in the urine and faeces, with about 80% of a dose being recovered in urine within 24 hours, irrespective of the route of administration.
Unchanged salbutamol accounts for approximately 30% of the excreted dose following oral and inhaled administration, and about 65% after intravenous administration. Unchanged salbutamol appears to undergo active tubular secretion. Salbutamol is almost exclusively metabolised by conjugation to a 4′-O-sulphate ester in the gastrointestinal tract and liver. The metabolite possesses little or no β-adrenergic activity. The elimination half-life of salbutamol is 2.7 to 5.5 hours after oral and inhaled administration, and 2.4 to 4.2 hours after intravenous administration. The pharmacokinetic profile of salbutamol was generally very similar in patients receiving the drug for prevention of preterm labour, although renal clearance was significantly lower.
Many short and several long term studies have confirmed the therapeutic efficacy and good tolerability of salbutamol in reversible obstructive airways disease irrespective of the formulation or route of administration. Single and multiple doses of salbutamol were significantly superior to placebo in terms of improving respiratory function and, overall, inhaled salbutamol (usually 200 or 400µg) would seem to be the formulation of choice for the majority of patients with reversible obstructive airways disease. Inhalation produces peak bronchodilation within 10 minutes and the improvement in lung function has been reported to last for up to 6 hours. A similar bronchodilatory effect is obtained with nebulised salbutamol (usually 2.5mg); indeed, no significant difference was observed between inhaled and nebulised salbutamol, although a greater incidence of dose-related adverse effects occurred with the nebulised formulation. Peak bronchodilation after oral salbutamol (most frequently 4mg) usually occurred at about 2 hours, and lasted for up to 8 hours. After parenteral administration of salbutamol, rapid and effective bronchodilation occurred within 15 minutes and lasted for up to 3 hours, but this route of administration is often associated with cardiovascular-related side effects and is reserved for treating life-threatening attacks of severe acute asthma. A large number of short term studies comparing the efficacy of salbutamol and alternative bronchodilators in patients with reversible obstructive airways disease have been reported. Salbutamol was more effective than isoprenaline and isoetharine, and in general there were no major clinical differences compared with bitolterol, broxaterol, clenbuterol, fenoterol, orciprenaline (metaproterenol), procaterol, terbutaline and tulobuterol. Although some of these agents had longer durations of action than salbutamol, this was often offset by the rapid onset of bronchodilation and fewer adverse effects associated with the latter drug. In single-dose trials comparing salbutamol and anticholinergic drugs in reversible obstructive airwaysa disease, salbutamol was superior to atropine methonitrate and oxitropium, equivalent to atropine and ipratropium bromide, but, as might be expected, inferior to ipratropium bromide administered in combination with the β2-adrenoceptor agonist fenoterol. There have been few well-designed clinical trials comparing salbutamol with methylxanthine therapy in the long term management of reversible obstructive airways disease. In those studies that have been reported, usual oral doses of salbutamol (4mg 3 times daily) appeared to be as effective as oral aminophylline, choline theophyllinate and a combination of theophylline and hydroxyzine.
Studies evaluating the efficacy of salbutamol in combination with anticholinergic drugs or other agents such as theophylline or beclomethasone dipropionate have generally recorded superior improvements with combination therapy compared with the individual components alone, but such differences were not always statistically or clinically significant. Further well-designed studies are needed to confirm the apparent improvement in efficacy associated with combination therapy and to determine the most appropriate dosages for obtaining the greatest benefit.
Clinical studies in patients with severe acute asthma have confirmed that both nebulised and parenteral salbutamol are efficacious and relatively safe. Indeed, comparative studies in patients with severe acute asthma have shown that salbutamol is more effective than adrenaline (epinephrine) or aminophylline and equally as effective as terbutaline and ipratropium bromide.
Salbutamol has been successfully used in the treatment of childhood asthma and in short and long term studies it improved respiratory function to a significantly greater extent than placebo. Other comparative studies demonstrated that salbutamol was superior to isoprenaline, and at least as effective as terbutaline and fenoterol. Combination therapy with salbutamol and theophylline or ipratropium bromide was generally synergistic in childhood asthma.
Salbutamol administered by inhalation is a very effective agent in the prophylaxis of exertional asthma. In terms of protection against exercise-induced asthma, inhaled salbutamol was superior to sodium cromoglycate, theophylline, orciprenaline and ipratropium bromide, and it was at least as effective as terbutaline and fenoterol.
Clinical evaluation of salbutamol in the treatment of premature labour has tended to be of a preliminary nature, generally in uncontrolled trials. Firm conclusions regarding its relative efficacy await further research, although some encouraging results have been reported.
Salbutamol is a well-tolerated treatment for the majority of patients suffering from reversible obstructive airways disease. The most common adverse effects are dose related, and therefore dependent upon formulation and route of administration, and are characteristic of the sympathomimetic agents. Usual inhaled doses of salbutamol do not appear to produce significant adverse reactions. The principal adverse effects of the drug are mild skeletal muscle tremor and cardiovascular-related effects, including tachycardia, palpitations and peripheral oedema. Reported metabolic adverse effects include significant increases in plasma glucose and insulin, and dose-related decreases in plasma potassium concentrations, especially following intravenous therapy. The decrease in potassiuin concentrations is usually transient and supplemental potassium therapy is rarely required. The weight of evidence suggests that absolute clinical tolerance to the bronchodilatory effects of salbutamol does not develop, although some attenuation of bron-chodilatory response has been documented.
Dosage and Administration
Salbutamol is available in a wide range of formulations for the management of the various forms of reversible airways disease (in infants, children and adults) and threatened premature labour. The recommended dosage instructions are summarised in table VIII in section 6.
KeywordsSalbutamol Forced Vital Capacity Terbutaline Fenoterol Ipratropium Bromide
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- Abraham WM, Perruchoud AP, Stevenson JS. Beat frequency and antigen-induced changes in tracheal mucus velocity in allergic sheep. 3rd Congress of the European Society of Pneumology, Basel, September 16–22, 1984Google Scholar
- Agüero R, Dal-Re R. Comparative trial of tulobuterol, a new beta2-agonist, and salbutamol in adult asthmatic patients. Clinical Trials Journal 25: 109–120, 1988Google Scholar
- AHFS Drug Information 87. Albuterol. In McEvoy G (Ed.) Sympathomimetic (adrenergic) agents, pp. 567–569, American Society of Hospital Pharmacists, Bethesda, 1987Google Scholar
- Akam RM, Howarth PH. Differential effect of oral and inhaled salbutamol on mast cell-mediated bronchoconstriction in asthma. Abstract. 3rd Congress of the European Society of Pneumology, Basel, September 16–22, 1984Google Scholar
- Anandajeya C, Sirakumaran S. Single dose benefits by dry powder and aerosol inhalation of salbutamol in asthmatics. Abstract. 3rd Congress of the European Society of Pneumology, Basel, 16–22 September, 1984Google Scholar
- Arossa W, Spinaci S, Testi R. Salbutamol plus beclomethasone dipropionate versus theophylline for the prevention of methacholine-induced bronchospasm in patients with chronic bronchitis. International Journal of Clinical Pharmacology, Therapy and Toxicology 23: 565–568, 1985Google Scholar
- Arulkumaran S, Kitchener HC, Balasingham S, Rauff M, Ratnam SS. Myocardial strain associated with intravenous salbutamol therapy for preterm labour: case report. Singapore Journal of Obstetrics and Gynaecology 17: 54–58, 1986Google Scholar
- Berg I-M, Berg T, Ringqvist I. Salbutamol in the treatment of asthmatic children: a comparison of oral and inhalation therapy alone and in combination. European Journal of Respiratory Diseases 63: 305–309, 1981Google Scholar
- Berg I, Engstrom I, Graff-Lonnevig V, Hildebrand G, Hattevig G, et al. A multicentre comparison of a new inhalation device, the Diskhaler®, with Rotahaler® in the treatment of childhood asthma. European Respiratory Journal 1 (Suppl. 1): 156S, 1988Google Scholar
- Bianchi G. Treatment of asthma syndromes in pediatric patients using a combination of a β2-stimulant drug and a histamine antagonist. International Journal of Clinical Pharmacology, Therapy and Toxicology 23: 56–58, 1985Google Scholar
- Blasi A, Pezza A. Comparison of broxaterol, a new selective bronchodilator agent, with salbutamol. Current Therapeutic Research 37: 485–492, 1985Google Scholar
- Blom-Bülow B, Boe J, Bulow K, Hagelqvist I. A comparison of oral beta2-agonists clenbuterol and salbutamol in obstructive lung disease: a double blind crossover study. Current Therapeutic Research 37: 51–57, 1985Google Scholar
- Boe J. Domiciliary nebulised beta-agonists. European Journal of Respiratory Diseases 65 (Suppl. 136): 193–203, 1984Google Scholar
- Bonn D, Kalloghlian A, Jenkins J, Edmonds J, Barker G. Intravenous salbutamol in the treatment of status asthmaticus in children. Critical Care Medicine 12: 892–896, 1984Google Scholar
- Britton M. A multicentre comparison of 8mg salbutamol controlled release (SCR) tablets b.d. versus theophylline slow release tablets (300mg) b.d. in control of reversible airways obstruction. European Respiratory Journal 1 (Suppl. 2): 147S, 1988Google Scholar
- Bundgaard A. Exercise-induced asthma. European Journal of Respiratory Diseases 68 (Suppl. 143): 51–56, 1986Google Scholar
- Busse WW, Smith A, Bush RK. The use of a single daily theophylline dose and metered-dose albuterol in asthma treatment. Journal of Allergy and Immunology 78: 577–582, 1986Google Scholar
- Busse W, Smith A, Bush R, Maynard D. Treatment of asthma with subcutaneous albuterol. Journal of Allergy and Clinical Immunology 73 (Suppl.): 4, 1984Google Scholar
- Caccia S, Fong MH. Kinetics and distribution of the β-adrenergic agonist salbutamol in rat brain. Journal of Pharmacy and Pharmacology 36: 200–202, 1983Google Scholar
- Callaghan B, Ryan W, Hagstad H, Tegner K, Kotaniemi J. A multicentre study of a new controlled-release formulation of salbutamol (salbutamol CR) compared with a titrated dose of slow-release theophylline (Theo-Dur) in the treatment of chronic obstructive airways disease. Bulletin European De Physio-pathologie Respiratoire 22 (Suppl. 8): 111S, 1986Google Scholar
- Casali L, Rossi A, Manazza P, Colombo ML, Zoia MC. A comparison of the bronchodilator effects of broxaterol and salbutamol. International Journal of Clinical Pharmacology, Therapy and Toxicology 26: 93–97, 1988Google Scholar
- Chang B, Sly MR, Eby D, Middleton HB. Delivery of albuterol aerosol by inhal-aid to young children. Journal of Allergy and Clinical Immunology 75 (Suppl.): 159, 1985Google Scholar
- Chazan R, Droszcz W, Bobilewicz D, Maruchin JE. Changes in plasma high density lipoproteins (HDL) after salbutamol. International Journal of Clinical Pharmacology, Therapy and Toxicology 23: 427–429, 1985Google Scholar
- Chung KF, Morgan B, Keyes SJ, Snashall PD. Histamine dose-response relationships in normal and asthmatic patients. Review of Respiratory Diseases 126: 849–854, 1982Google Scholar
- Church MK, Holgate ST, Pao GJ-K. Histamine release from mechanically and enzymically dispersed human lung mast cells: inhibition by salbutamol and cromoglycate. British Journal of Pharmacology 79 (Suppl.): 374P, 1983Google Scholar
- Church MK, Howarth PH, Durham SR, Lee TH, Kay AB, et al. Influence of salbutamol and sodium cromoglycate on mast cell mediator release in vivo. Abstract no. 361. Journal of Allergy and Clinical Immunology 75: 195, 1985Google Scholar
- Church MK, Young KD. The characteristics of inhibition of histamine release from human lung fragments by sodium cromoglycate, salbutamol and chlorpromazine. British Journal of Pharmacology 78: 677–679, 1983Google Scholar
- Cochrane GM. The role of bronchodilators in severe acute asthma. In Clark & Cochrane (Eds) Bronchodilator therapy, p. 167, ADIS Press, Auckland, 1984Google Scholar
- Cogo R, Zavanella A, Gini M. Treatment of intrinsic or extrinsic asthma and chronic obstructive pulmonary disease: an extempore combination of bronchodilator (salbutamol) with antihistamine (oxatomide). Clinical Trials Journal 21: 384–392, 1984Google Scholar
- Creemers B. A multicentre comparative study of salbutamol controlled release (Volmax)® and sustained-release theophylline (Theo-dur)® in the control of nocturnal asthma. European Respiratory Journal 1 (Suppl. 2): 333S, 1988Google Scholar
- Cundell DR, Davies RJ. NCA release from human blood lymphocytes: effects of salbutamol and sodium cromolyn on this release. Abstract no. 20. Journal of Allergy and Clinical Immunology 75 (Suppl.): 109, 1985Google Scholar
- Dahl R. A multicentre trial of salbutamol controlled release tablets (Volmax)® and standard salbutamol tablets (Ventolin)® in the management of asthma and chronic bronchitis. European Respiratory Journal 1 (Suppl. 2): 306S, 1988Google Scholar
- Dal Negro RW, Pomari C, Zoccatelli O, Turco P. Airways flow limitation: acute responsiveness to combined salbutamol + be-clomethasone dipropionate. Current Therapeutic Research 35: 561–565, 1984Google Scholar
- Delbarre B, Casset-Senon D, Baertschi AJ, Delbarre G. Involvement of vasopressin secretion in antidepressant activity of a beta adrenergic agonist, salbutamol. Neuroendocrinology 4(2): 67–72, 1982Google Scholar
- Dellenbach P, Gulkaraty JP, Munch F, Ragon A, Schlewer G, et al. Passage transplacentaire d’un anesthésique et d’un betamimétique: intérêt des isotopes stables et de la spectrométrie de masse. In Pontonnier & Cross (Eds) Pharmacologie perinatale (colloque in Serm), pp. 55–77, Paris, 1977Google Scholar
- Desranges M-F, Moutquin J-M, Péloquin A. Effects of maternal oral salbutamol therapy on neonatal endocrine status at birth. Obstetrics and Gynecology 69(4): 582–584, 1987Google Scholar
- Dolvich MB, Ruffin RE, Roberts R, et al. Optimal delivery of aerosols from metered dose inhalers. Chest 80 (Suppl.): 911–915, 1981Google Scholar
- Earley B, Leonard BE. The effect of salbutamol on the activity of olfactory bulbectomized rat in the ‘open-field’ apparatus. British Journal of Pharmacology 80: 670, 1983Google Scholar
- Filuk RB, Easton PA, Anthonisen NR. Responses to large doses of salbutamol and theophylline in patients with chronic obstructive pulmonary disease. American Review of Respiratory Diseases 132: 871–874, 1985Google Scholar
- Fontana G, Mugnai M, Cresci F, Panuccio P. Histamine-induced bronchial response after administration of placebo, salbutamol and a combination of a beta-2-adrenergic drug (fenoterol) with an anticholinergic agent (ipratropium bromide) in asymptomatic asthma patients. Respiration 50 (Suppl. 2): 201–205, 1986PubMedGoogle Scholar
- Gaddie J, Skinner C, Palmer KNV. Intravenous indoramin and aerosol salbutamol in bronchial asthma. British Journal of Clinical Pharmacology 12: 855–875, 1981Google Scholar
- Gardey-Levassort C, Richard MO, Hauguel S, Thiroux G, Olive G. [3H]-Salbutamol placental transfer in pregnant rats on the 19th day of gestation. Development Pharmacology and Therapeutics 4: 151–157, 1982Google Scholar
- Ghiringhelli G, Schiavi M. Controlled trial to evaluate the therapeutic properties of an extempore combination of a bronchodilator (salbutamol) and an anti-histamine agent (oxatomide) in the treatment of intrinsic asthma. Current Therapeutic Research 36: 1158–1164, 1984Google Scholar
- Ghiringhelli P. Bronchospasm: prevention and treatment. International Journal of Clinical Pharmacology, Therapy and Toxicology 23: 52–55, 1985Google Scholar
- Godfrey S. Bronchodilators in exercise-induced asthma. In Clark & Cochrane (Eds) Bronchodilator therapy, pp. 112–130, ADIS Press, Auckland, 1984Google Scholar
- Gough PM. Preterm labour. Obstetric Care 24: 2237–2245, 1982Google Scholar
- Grimwood K, Fergusson DM, Dawson KP. Combination of salbutamol inhalation powder and tablets in asthma. Archives of Diseases in Childhood 58: 283–285, 1983Google Scholar
- Hauguel S, Gilbert M, Cedard L. Maternal and fetal metabolic effects of various salbutamol treatments in the pregnant rat. Development Pharmacology and Therapeutics 4 (Suppl.): 150–156, 1982bGoogle Scholar
- Haukkama M, Gummerus M. Decrease of serum oestriol during intravenous hexoprenaline or salbutamol treatment. British Journal of Obstetrics and Gynaecology 89: 917–920, 1982Google Scholar
- Hoernke JA, Kemp JP, Meltzer EO, Welch MJ, Orgel HA. Subcutaneous albuterol and terbutaline: a single-dose, crossover comparison in acute asthma. Journal of Allergy and Clinical Immunology 75 (Suppl.): 300, 1985Google Scholar
- Holt J, Bolle R. The use of fenoterol powder for the treatment of children with asthma. European Journal of Respiratory Disease 64 (Suppl. 130): 28–30, 1983Google Scholar
- Howarth PH, Durham SR, Lee TH, Kay AB, Church MK, et al. Influence of albuterol, cromolyn sodium and ipratropium bromide on the airway and circulating mediator responses to allergen bronchial provocation in asthma. American Review of Respiratory Diseases 132: 986–992, 1985Google Scholar
- Hutchings MJ, Pauli JD, Morgan DJ. Determination of salbutamol in plasma by high performance liquid chromatography with fluorescence detection. Journal of Chromatography — Biomedical Applications 227: 423–426, 1983Google Scholar
- Huupponen R, Pihlajamäki K. Effect of the blood glucose level on the metabolic response of intravenous salbutamol. International Journal of Clinical Pharmacology, Therapy and Toxicology 24: 374–376, 1986Google Scholar
- Jenne JW, Valcarenghi G, Druz WS, Starkey PW, Yu C. Comparison of tremor responses to orally administered albuterol and terbutaline. American Review of Respiratory Diseases 134: 708–713, 1986Google Scholar
- Johson AJ, Nunn AJ, Somner AR, Stableforth DE, Stewart CJ. Circumstances of death from asthma. British Medical Journal 288: 1870, 1984Google Scholar
- Keaney NP, Churton S, Stretton TB. Failure to demonstrate tolerance to inhaled salbutamol in volunteers. Abstract no. 828. World Conference on Clinical Pharmacology and Therapeutics, London, August 3–9, 1980Google Scholar
- Kemp JP, Orgel HA, Meltzer EO, Welch MJ. Comparison of subcutaneous albuterol, terbutaline, and epinephrine in acute asthma. Journal of Allergy and Clinical Immunology 75 (Suppl.): 232(S), 1985Google Scholar
- Kotaniemi J, Callaghan B, Hagstad H, Tegner K. Salbutamol controlled release tablets (Volmax)® and individually titrated slow release theophylline (Theo-Dur)® in the management of chronic obstructive airways disease. European Respiratory Journal 1 (Suppl. 2): 196S, 1988Google Scholar
- Lahdensuo A, Sovijäroi A, Muittari A. Inhaled powder and aerosol salbutamol in metacholine-induced bronchial obstruction. European Journal of Respiratory Disease 64 (Suppl. 128): 515–517, 1983Google Scholar
- Laitinen LA, Poppius H. A controlled trial of oral slow-release aminophylline and oral salbutamol in adult asthmatics. Current Therapeutic Research 31: 727–732, 1982Google Scholar
- Lalos O, Joelsson I. Effect of salbutamol on the non-pregnant human uterus in vivo. Acta Obstetricia et Gynecologica Scan-dinavica 60: 349–352, 1981Google Scholar
- Lehtonen A, Viikari J, Sallinen V-P, Elo J. Effect of beta2-adrenergic stimulation on serum lipids. International Journal of Clinical Pharmacology, Therapy and Toxicology 20: 530–531, 1982Google Scholar
- Light RW, Campbell SC, Degraff AC, Repsher L, Siegel SC. A multicenter 90 day study comparing the safety and efficacy of albuterol and isoproterenol nebulizer solutions. Abstracts of the 50th Annual Scientific Assembly. Chest 86: 328, 1984Google Scholar
- Lin C, Magat J, Calesnick B, et al. Absorption, excretion and urinary metabolic pattern of 3H-albuterol aerosol in man. Xenobiotica 6: 507–515, 1972Google Scholar
- Lipworth B, Clarke R, Parker C, Charter M, Palmer J, et al. The pharmacokinetics of controlled release tablets (SCR) in asthmatic patients. European Respiratory Journal 1 (Suppl. 2): 333S, 1988Google Scholar
- Löwhagen O, Larsson S, Lindholm N, Svedmyr N. Tolerance to beta2-agonists after treatment with large doses of salbutamol? Abstract no. 171. European Journal of Respiratory Diseases 63 (Suppl. 125): 82, 1982Google Scholar
- Luneli NO, Joelsson I, Lewander R, Nylund L, Sarby B, et al. Utero-placental blood flow and the effect of β2-adrenoceptor stimulating drugs. Acta Obstetricia and Gynecologica Scan-dinavica 108 (Suppl.): 25–28, 1982Google Scholar
- Maesen FPV, Smeets JJ. Comparison of the effects of a combination inhaler containing salbutamol and atropine methonitrate. Journal for Drug Therapy and Research 10: 1000–1004, 1985Google Scholar
- Maesen FPV, Smeets JJ. Comparison between salbutamol controlled release tablets and slow release theophylline tablets in the management of chronic obstructive airways disease. Bulletin European De Physiopathologie Respiratoire 22 (Suppl. 8): 29S, 1986bGoogle Scholar
- Mangiaracina A, Mancuso G, Salice P, Brunelli L. Treatment of bronchospastic conditions in children using a combination of a bronchodilating agent and an antihistamine. Current Therapeutic Research 37: 493–499, 1985Google Scholar
- Marshall SG, Pierson WE, Bierman CW, Shapiro GG, Furukawa CT, et al. Albuterol vs cromolyn therapy in the prevention of exercise induced bronchospasm. Journal of Allergy and Clinical Immunology 75 (Suppl.): 173 (274), 1985Google Scholar
- Martin P, Soubrie P, Simon P. Shuffle-box deficits induced by inescapable shocks in rats: reversal by the beta-adrenoceptor stimulants clenbutarol and salbutamol. Pharmacology Biochemistry and Behaviour 24: 177–181, 1986Google Scholar
- Massi-Benedetti M, Santeusanio F, Filipponi P, Nicoletti I, Santori P, et al. Effect of salbutamol infusion on insulin and glucagon secretion in normal man. Biochemistry 10: 12, 1982Google Scholar
- McFadden ER, Mills R. Prevention of exercise-induced bronchospasm with aerosolized albuterol. Current Therapeutic Research 39: 112–118, 1986Google Scholar
- Mclntyre E, Fitzgibbon B, Otto H, Minson R, Alpers J, et al. Inhaled verapamil in histamine-induced bronchoconstriction. Journal of Allergy and Clinical Immunology 71: 375–381, 1983Google Scholar
- Milner AD. Bronchodilators in childhood asthma. In Clark et al. (Eds) Bronchodilator therapy, pp. 93–111, ADIS Press, Auckland, 1984Google Scholar
- Milroy R, Carter R, Carlyle DL, Boyd G. Salbutamol controlled release: a clinical and pharmacokinetic study in asthmatic patients. European Respiratory Journal 1 (Suppl. 2): 334S, 1988Google Scholar
- Moore-Gillon J. Volmax® (salbutamol CR 8mg) in the management of nocturnal asthma: a placebo controlled study. European Respiratory Journal 1 (Suppl. 2): 306S, 1988Google Scholar
- Nielsen NH, Weeke B, Ostlerer L, Wilkinson P, Kay A, et al. Salbutamol controlled release (Volmax)® — A comparison with standard salbutamol tablets (ST) in the treatment of chronic obstructive airways disease (COAD). European Respiratory Journal 1 (Suppl. 2): 306S, 1988Google Scholar
- Oosterhuis B, Braat MCP, van Boxtel CJ. Analysis of β-sympathicomimetics in man with high performance liquid chromatography using mode sequencing and electrochemical detection. European Journal of Respiratory Diseases 65 (Suppl.): 153–156, 1984Google Scholar
- Pedersen B, Dahl R, Fauschbu P, Hyldebrandt N, Lorentzen K. A comparison of a new osmotic pressure mediated oral formulation of salbutamol controlled release tablets (Volmax®; SCR) and standard salbutamol tablets (SST) in the treatment of mild asthma in adults. European Respiratory Journal 1 (Suppl. 2): 333S, 1988Google Scholar
- Peel ET, Anderson G, Scriven W, Cheong B. A comparison of terbutaline durules with salbutamol tablets in asthma. Acta Therapeutica 9: 85–91, 1983Google Scholar
- Perri G. Giovannini M, Spada E. Salbutamol plus beclomethasone dipropionate (Ventolin Flogo) vs fenoterol (Dosberotec) in chronic obstructive lung disease therapeutic strategy: a 4 week clinical trial. International Journal of Clinical Pharmacology, Therapy and Toxicology 23: 274–278, 1985Google Scholar
- Pihlajamäki K, Huupponen R. Insulin and glucose responses to salbutamol after carbohydrate loading. British Journal of Clinical Pharmacology 14: 614P, 1982Google Scholar
- Pomari C, Turco P, Trevisan F, Zoccatelli D, Dal Negro RW. Multiparametrical approach to fog-challenge-induced bronchial hyperreactivity in asthmatics — protective effects of salbutamol plus beclomethasone dipropionate. International Journal of Clinical Pharmacology, Therapy and Toxicology 22: 515–518, 1984Google Scholar
- Pover GM, Langdon CG, Jones SR, Fidler C. Evaluation of a breath operated powder inhaler. Journal of Medical Research 16: 201–203, 1988Google Scholar
- Powell ML, Weisberger M, Dowdy Y, Gural R, Symchowicz S, et al. Comparative steady state bioavariability of conventional and controlled-release formulations of albuterol. Biopharmaceutics and Drug Disposition 8: 461–468, 1987Google Scholar
- Rolf Smith S, Kendall MJ. Metabolic responses to beta2 stimulants. Journal of the Royal College of Physicians of London 18: 190–194, 1984Google Scholar
- Rolf Smith S, Ryder C, Kendall MJ, Holder R. Cardiovascular and biochemical responses to nebulised salbutamol in normal subjects. British Journal of Clinical Pharmacology 18: 641–644, 1984Google Scholar
- Rossi F, Accorsi T, Spezia D, Visca U. Evaluation of antibronchospastic action of a combination of a β2-stimulant (salbutamol) and a new anti-allergic drug (oxatomide). Clinical Trials Journal 21: 451–458, 1984Google Scholar
- Saux JC, Girault J, Bouquet S, Fourtillan JB, Courtois Ph. Étude comparative des distribution Tissalaines de deux β-mimetiques le clenbutérol et le salbutamol chez le chien. Journal of Pharmacologie (Paris) 17: 692–698, 1986Google Scholar
- Senderovitch M, Levin S, Seggev J, Schey G. The effectiveness of intravenous salbutamol and aminophylline alone and combined in acute severe asthma. Journal of Allergy and Clinical Immunology 73 (Suppl.): 131 (S92), 1984Google Scholar
- Sheinman BD, Cundell D, Gomez F, Smart W, Davies RJ. Effects of inhaled salbutamol (S) and sodium cromoglycate (SCG) on mediator release in immediate asthma. Abstract. 3rd Congress of the European Society of Pneumology, Basel, September 16–22, 1984Google Scholar
- Shenfield GM, Brogden RN, Ward A. Pharmacology of bronchodilators. In Clark et al. (Eds) Bronchodilator therapy, pp. 17–46, ADIS Press, Auckland, 1984Google Scholar
- Slater RM, McLaren ID. Effect of salbutamol and suxamethonium on the plasma potassium concentration. British Journal of Anaesthetics 59: 602–605, 1987Google Scholar
- Soininen K, Allonen H, Posti J, Kleimola T. Pharmacokinetics of salbutamol. 2nd World Conference on Clinical Pharmacology and Therapeutics, Washington. Abstract 79, 1983Google Scholar
- Sorbini CA, Grassi V, Tantucci C, Corea L, Bentivoglio M, et al. Ventilatory effects of selective β1-(prenalterol) or β2-(salbutamol) adrenoceptor agonism in man. International Journal of Clinical Pharmacology, Therapy and Toxicology 22: 570–575, 1984Google Scholar
- Sovijärvi ARA, Lahdensuo A, Muittari A. Bronchodilating effect of salbutamol inhalation powder and salbutamol aerosol after metacholine-induced bronchoconstriction. Current Therapeutic Research 32: 566–573, 1982Google Scholar
- Spada EL, Donner CF, Fracchia C, Ioli F, Patessio A, et al. A comparative evaluation of salbutamol, disodium cromoglycate and ipratropium bromide in preventing exercise-induced asthma (EIA). Respiration 46 (Suppl. 1): 56, 1984Google Scholar
- Storms WW, Hudson LD, DeGraff AC, Mendelson LM, Greenstein S. Albuterol nebulizer solution for the treatment of asthma. Annals of Allergy 55: 779–782, 1986Google Scholar
- Stornello M, Di Rao G, Lachello M, Bosco V, Pantano S, et al. Effects of salbutamol, indomethacin and atenolol on insulin secretion. Drugs 25 (Suppl. 2): 255–256, 1983Google Scholar
- Sturani C, Schiavina M, Tosi I, Gunella G. Comparison of inhaled fenoterol and salbutamol in the prevention of exercise-induced asthma. European Journal of Respiratory Diseases 64 (Suppl. 128): 526–528, 1983Google Scholar
- Svedmyr N, Löfdahl C-G, Svedmyr K. The effect of powder aerosol compared to pressurized aerosol. European Journal of Respiratory Diseases 63 (Suppl. 119): 81–88, 1982Google Scholar
- Svendsen UG, Hyldebrant N, Hindberg W, Lorentzen KA, Hoick F. A multicentre comparison of Diskhaler® inhaler with the Rotahaler® inhaler for administration of salbutamol. European Respiratory Journal 1 (Suppl. 2): 355S, 1988Google Scholar
- Sykes RS, Reese ME, Meyer MC. Pharmacokinetic properties of a new sustained-release albuterol preparation, Volmax. Journal of Allergy and Clinical Immunology 79: 152, 1987Google Scholar
- Tattersfíeld AE. Bronchodilators in the prevention of asthma. In Clark et al. (Eds) Bronchodilator therapy, pp. 76–92, ADIS Press, Auckland, 1984Google Scholar
- Taylor DB, Buick B, Kinney C, Lowry RC, McDevitt DG. The efficacy of orally administered theophylline, inhaled salbutamol, and a combination of the two as chronic therapy in the management of chronic bronchitis with reversible air-flow obstruction. American Review of Respiratory Disease 131: 747–751, 1985PubMedGoogle Scholar
- Tinkelman DG, Kemp J, Webb R, Mingo T. Comparison of aerosols bitolterol mesylate and albuterol. Abstract no. 150. Journal of Allergy and Clinical Immunology 71: 126, 1983Google Scholar
- Tinkelman DG. Comparison of oral, controlled-release albuterol (CRA) and theophylline (T) in the treatment of chronic asthma. European Respiratory Journal 1 (Suppl. 2): 334S, 1988Google Scholar
- Trabacco M. Evaluation of therapeutic efficacy of an extempore combination of salbutamol and oxatomide in infantile allergic asthma. Clinical Trials Journal 21: 476–482, 1984Google Scholar
- Tsanakas JN, Bannister OH, Baxter P. Tachyphylaxis does not occur after long-term administration of salbutamol controlled release (Volmax® SCR). European Respiratory Journal 1 (Suppl. 2): 202S, 1988Google Scholar
- Tsanakas JN, Baxter P. A comparison of salbutamol controlled release (SCR) and slow release theophylline (SRT) in exercise induced asthma. European Respiratory Journal 1 (Suppl. 2): 356S, 1988Google Scholar
- Turpeinen M, Kuokkanen J, Backman A. Adrenaline and nebulised salbutamol in acute asthma. Archives of Disease in Childhood 57: 666–668, 1984Google Scholar
- Viskum K, Dahl R, Korsgaard J, Svedsen U. A comparison of controlled release salbutamol tablets (Volmax)® and sustained release terbutaline tablets (Bricanyl SA)®. European Respiratory Journal 1 (Suppl. 2): 305S, 1988Google Scholar
- Wager J, Fredholm B, Lunell NO, Persson B. Metabolic and circulatory effects of intravenous and oral salbutamol in late pregnancy in diabetic and non diabetic women. Acta Obstetricia et Gynecologica Scandinavica 108: 41–46, 1982Google Scholar
- Webber BA, Collins JV, Branthwaite MA. Severe acute asthma: a comparison of three methods of inhaling salbutamol. British Journal of Diseases of Chest 76: 69–74, 1982Google Scholar
- Weiler P. A comparison of a new osmotic pressure mediated oral formulation of salbutamol controlled release tablets (Volmax®: SCR) and standard salbutamol tablets (SST) in the treatment of childhood asthma — a multicentre trial. European Respiratory Journal 1 (Suppl. 2): 357S, 1988Google Scholar
- Wolfe JD, Yamate M, Biederman AA, Chu TJ. Comparison of the acute cardiopulmonary effects of oral albuterol, metaproterenol and terbutaline in asthmatics. Journal of the American Medical Association 253: 2069–2072, 1985Google Scholar
- Zeitlin S. A comparison of salbutamol controlled release tablets (Volmax®; SCR) with slow release theophylline at individually titrated doses, in the treatment of childhood asthma — a multicentre study. European Respiratory Journal 1 (Suppl. 2): 202S, 1988Google Scholar