Stewart W. Clarke

Terbutaline sulphate Turbuhaler: effect of inhaled flow rate on drug deposition and efficacy

The deposition and efficacy of 0.5 mg terhutaline sulphate from Turbuhaler (Astra Pharmaceuticals). a multi-dose powder inhaler, have been measured simultaneously in 10 asthmatic subjects at two inhaled flow rates (fast, mean 57 l/min and slow, mean 28 l/min). At the fast flow rate, a mean (SEM) 16.8 (2.6)% of the dose was deposited in the lungs, compared with 9.1 (1.5)% of the dose at the slow flow rate (P < 0.01). At either flow rate, the majority of the dose was deposited in the oropharynx, and this quantity was significantly higher with slow inhalation (P < 0.01). There was a trend towards a reduced bronchodilator response at the lower flow rate, but this did not reach statistical significance. It is concluded that Turbuhaler works optimally at a fast inhaled flow rate, but functions adequately at a lower flow rate which some patients may find easier to attain.

Simple instructions for using pressurized aerosol bronchodilators

Although the manufacturers of pressurized aerosol bonchodilators issue instructions for using the inhalers, little or no experimental verification exists. Bronchodilatation has been measured after controlled inhalations of 500 μg terbutaline sulphate given in a systematic series of investigations to 8 patients with reversible airways obstruction at 2 different inhalation flow rates (25 1/min and 80 1/min), 3 different lung volumes (20%, 50% and 80% vital capacity) and followed by 2 different breath-holding pauses (4 and 10 seconds). The results indicate that patients may release the aerosol at any time during the course of a slow deep inhalation which should be followed by 10 seconds of breath-holding. This will ensure an optimal bronchodilator response.

The nasal distribution of metered does inhalers

The intranasal distribution of aerosol from a metered dose inhaler has been assessed using a radiotracer technique. Inhalers were prepared by adding 99Tcm-labelled Teflon particles (simulating the drug particles) to chlorofluorocarbon propellants, and scans of the head (and chest) taken with a gamma camera. Ten healthy subjects (age range 19-29 years) each performed two radioaerosol studies with the inhaler held in two different ways: either in a single position (vial pointing upwards) or in two positions (vial pointing upwards and then tilted by 30 degrees in the sagittal plane). The vast majority of the dose (82.5 +/- 2.8 (mean +/- SEM) per cent and 80.7 +/- 3.1 per cent respectively for one-position and two-position studies) was deposited on a single localized area in the anterior one-third of the nose, the initial distribution pattern being identical for each study. No significant radioaerosol was detected in the lungs. Only 18.0 +/- 4.7 per cent and 15.4 +/- 4.1 per cent of the dose had been removed by mucociliary action after 30 minutes, and it is probable that the remainder had not penetrated initially beyond the vestibule. Since the deposition pattern was highly localized and more than half the dose probably failed to reach the turbinates it is possible that the overall effect of nasal MDIs is suboptimal for the treatment of generalized nasal disorders.

Lung deposition of 5 mg Intal from a pressurised metered dose inhaler assessed by radiotracer technique

Deposition from a pressurised metered dose inhaler (MDI) delivering 5 mg sodium cromoglycate (Intal 5, Fisons plc), has been measured by a Tc99m-labelling technique Ten healthy volunteers inhaled (i) from a standard MDI at 30 l/min, (11) from a 10 cm spacer tube (Aerotube) at 30 l/min, and (111) from the Aerotube at 100 l/min A mean (SE) 8.8(11) % of the dose was deposited in the lungs from the standard MDI, but this amount was not significantly changed either for slow inhalation (11.3(1.9) %) or fast inhalation (7.1(1.3) %) through the spacer Lung deposition was lower than that observed previously for other cantsters delivering smaller amounts of drug per metered dose Oropharyngeal deposition fell from a mean 79% with standard MDI to a mean 29% with the spacer (P < 0.05). It is concluded that a 10 cm tube spacer does not significantly enhance lung deposition of 5 mg Intal in subjects with good inhaler technique, but may reduce the incidence of orophdryngeal irritation, cough and unpleasant taste.

The effects of changes in metered volume and propellant vapour pressure on the deposition of pressurized inhalation aerosols

The effects of changes in metered volume and propellant vapour pressure on the deposition of a pressurized inhalation aerosol have been studied in 10 patients with obstructive airway disease. Particles of Teflon (mass median aerodynamic diameter 3.2. μm), labelled with 99Tcm, were incorporated into canisters formulated with two different metered volume sizes (25 and 50 μ1) and with two different propellant vapour pressures (374 and 502 kPa). Increasing the metered volume had no effect on the quantity of aerosol deposited in the lungs, but produced a significantly (P < 0.05) more central pattern of deposition within the bronchial tree. An increase in vapour pressvre resulted in a significant (P < 0.05) increase in whole lung deposition and a significant (P < 0.05) reduction in extrathoracic deposition. It is concluded that changes in formulation alter the deposition pattern of metered dose aerosols, and might consequently bring about changes in clinical efficacy.

Effect of oral N-acetylcysteine on mucus clearance.

Oral N-acetylcysteine has been advocated as a mucolytic agent for use in chronic bronchitis. We have investigated the effects of regular use of this drug at a dose of 200 mg thrice daily for 4 weeks in nine patients with chronic bronchitis on lung function, lung mucociliary clearance and sputum viscosity in a controlled, double-blind, crossover study. No significant differences were found in lung function, mucociliary clearance curves or sputum viscosity following treatment with N-acetylcysteine compared to control or placebo measurements.

Cough syncope: a complication of adult whooping cough.

Abstract A case of adult whooping cough is described, with the unusual complication of cough syncope. The pathophysiology of cough syncope is discussed.

Necrotizing sarcoid granulomatosis.

We report a patient with necrotizing sarcoid granulomatosis (NSG) and point out that while the latter may have certain histological and radiological features distinct from sarcoidosis, sophisticated immunological tests show that the two disorders have essentially similar underlying immune mechanisms. We also stress that although the clinical course of NSG has been repeatedly described as benign and responsive to steroid therapy, the young patient may initially be critically ill with symptoms suggestive of an infective process rather than a granulomatous cause.

Effect of terbutaline administered from metered dose inhaler (2 mg) and subcutaneously (0.25 mg) on tracheobronchial clearance in mild asthma

Tracheobronchial mucus clearance was measured in nine mild asthmatics, using an objective radioaerosol technique, on 3 separate days at intervals of 1 week. Immediately after radioaerosol inhalation, drug or placebo was administered via subcutaneous injection (SC) plus metered dose inhaler (MDI)--2 puffs. Three randomized treatments were used: saline placebo SC plus 2 mg terbutaline by MDI (1 mg per puff); 0.25 mg terbutaline SC plus placebo (propellants and surfactant only) by MDI; and double placebo. Changes in lung mucociliary clearance showed an inverse relationship to baseline clearance of both proximal and distal ciliated airways following inhaled terbutaline, whereas terbutaline SC related inversely only to baseline clearance of the distal ciliated airways. This may reflect the surface concentrations of drug, established by each route.

Sarcoidosis and thyrotoxicosis.

Mrs V B, aged 31. Housewife Presented in January 1973 with headaches and typical erythema nodosum on her legs. She had recently lost 6.5 kg in weight, felt nervous and had developed a tremor. Six months earlier she had been involved, though not injured, in the Eltham train disaster. Clinical examination confirmed erythema nodosum (EN) and her chest X-ray showed bilateral hilar lymphadenopathy (BHL). She had the features of thyrotoxicosis, without eye signs and with only minimal thyroid enlargement. Investigations confirmed the diagnosis of thyrotoxicosis; protein-bound iodine (PBI) 14.7 ,ug/100 ml; effective thyroxine ratio (ETR) 1.48 (0.86-1.06). Supporting the diagnosis of sarcoidosis were a negative Mantoux, a negative throat swab and a normal antistreptolysin titre. Pulmonary function tests showed small lungs (vital capacity 67% predicted) but no defect in gas transfer. Ophthalmic examination negative. Himoglobin 11.7 g/100 ml, ESR 40 mm in the first hour (Westergren), serum calcium 9.0 mg/ 100 ml. Liver function tests and serum proteins normal. Antibody studies negative, including those to thyroid, smooth muscle, parietal cells and nuclei (ANF). Treatment with carbimazole 40 mg daily controlled her thyrotoxicosis rapidly and she regained and even exceeded her original weight (55 kg). She was then maintained on 15 mg daily. Salicylates reduced the discomfort from her erythema nodosum, which gradually disappeared over the next three months, by which time she was feeling very well.