Value of theophylline treatment in patients handicapped by chronic obstructive lung disease.

BACKGROUND: It is still not certain whether it is worth using theophylline in addition to inhaled bronchodilators and corticosteroids to treat obstructive airways disease. This trial was designed to test whether the addition of prescribed theophylline in doses sufficient for sustained optimal steady state plasma concentrations would produce any detectable additional advantage in spirometric or functional variables in these handicapped patients. METHODS: A randomised, double blind, placebo controlled, crossover study of added theophylline treatment was aimed at steady state plasma concentrations of 10 and 17 mg/l, the dose being calculated individually by Bayesian parameter estimation and maintained for six weeks along with the patient's previously prescribed bronchodilators and steroids. Of 20 patients sequentially recruited, 15 provided data that could be analysed. All had chronic obstructive lung disease with a mean forced expiratory volume in the first second (FEV1) up to about 30% of the predicted value and gave no history of being treated with theophylline. The protocol included spirometry, whole body plethysmography, and treadmill exercise. Measurements also included steady state plasma theophylline concentrations and trapped gas volume. Quality of life was assessed by an established questionnaire method covering breathlessness in everyday activities, fatigue, emotional function, and control over the disease. RESULTS: Both target plasma concentrations were achieved. Improvements in peak flow (PEF; mean 20%), trapped gas volumes (38%), two stage vital capacity (15%), distances walked (48%), breathlessness in everyday activities (32%), and fatigue (18%) were found at the higher plasma concentration only. FEV1, forced vital capacity (FVC), emotional function, and control did not change. CONCLUSION: Theophylline treatment with sustained steady state concentrations about 17 mg/l provides worthwhile objective and subjective further benefits for patients handicapped by chronic obstructive lung disease when it is added to bronchodilators and corticosteroids.

Salbutamol induced hypokalaemia: the effect of theophylline alone and in combination with adrenaline.

1. We have previously shown that salbutamol induced hypokalaemia, like adrenaline induced hypokalaemia, is the result of stimulation of a membrane bound beta 2-adrenoreceptor linked to Na+/K+ ATPase. We have also demonstrated that adrenaline induced hypokalaemia is potentiated by therapeutic concentrations of theophylline. 2. In a single-blind study of 14 normal volunteers, we infused salbutamol in doses used in clinical practice and examined the effects of the addition of theophylline alone or combined with (-)-adrenaline on plasma potassium levels, heart rate and blood pressure. The combinations studied were (i) salbutamol + vehicle control adrenaline infusion + placebo theophylline; (ii) salbutamol + vehicle control adrenaline infusion + theophylline; (iii) salbutamol + adrenaline + theophylline. 3. In a randomised, balanced placebo controlled design oral slow release theophylline or placebo was given for 9 days. Subjects were studied twice on the active limb (days 7 and 9) and once on the placebo limb (day 9) and the procedure was identical on each of the 3 study days except for the solutions administered. 4. Theophylline increased salbutamol induced hypokalaemia and in some individuals profound hypokalaemia (less than 2.5 mmol l-1) was observed with these relatively low doses of salbutamol and theophylline. Adrenaline did not further increase the magnitude of the fall in potassium observed. Combining theophylline with salbutamol increased the tachycardia resulting from the salbutamol infusion. Salbutamol infusion caused a fall in diastolic and rise in systolic blood pressure on all 3 study days and this was not altered by either theophylline or adrenaline alone or together.(ABSTRACT TRUNCATED AT 250 WORDS)

Respiratory function measurements in clinical pharmacological studies including an assessment of the area under the MEFV curve as a new parameter in chronic bronchitic patients.

We have assessed the value of the area under the MEFV curve (AUC) as an index of respiratory function in chronic bronchitis and compared it with PFR, FEV1, FVC, volume at 75% PFR (V75), V50, V25, F50 and F75. The reproducibility of these parameters was tested in 10 normal subjects and 10 patients with chronic bronchitis. The FVC was the most reproducible while the coefficient of variation for the AUC was the same as for the other MEFV curve indices. The sensitivity (percentage change on bronchodilatation after intravenous aminophylline) of the above measurements was also tested in a further nine patients with chronic bronchitis. The AUC was much more sensitive to bronchodilatation than any of the other measurements. Therefore although the AUC was less reproducible than simple spirometric indices, it was more sensitive to bronchodilatation by a greater factor. This probably outweighs its poor reproducibility and AUC would therefore seem to be a useful new index of bronchodilatation in chronic bronchitis.

Failure of chronic theophylline therapy to alter circulating catecholamines.

An increase in circulating adrenaline and noradrenaline has been reported following acute dosing with theophyllines. This effect on catecholamines has been proposed as a possible mechanism of action of theophyllines. In a double-blind placebo controlled trial we have studied the effects of 5 days oral theophylline therapy on circulating catecholamines and adrenaline clearance. There were no significant changes in circulating catecholamines or adrenaline clearance following theophylline. We also examined the effects of theophylline on the hypokalaemic and haemodynamic actions of adrenaline. Theophylline increased the hypokalaemia, tachycardia and rise in systolic blood pressure which occurs in response to intravenous infusion of doses of L-adrenaline (0.02-0.06 microgram kg-1 min-1). Our results suggest that chronic theophylline therapy does not significantly increase circulating catecholamines. Increased circulating catecholamine concentrations are thus not an explanation for the chronic actions of theophylline. We have demonstrated significant, potentially hazardous metabolic and haemodynamic interactions between theophylline and adrenaline.

The mechanism of salbutamol-induced hypokalaemia.

The following four intravenous treatments were administered in a balanced, randomized Latin square design to eight healthy volunteers: (-)-adrenaline (0.06 microgram kg-1 min-1 for 90 min) + vehicle control (+)-glucose infusion (60 min), salbutamol (120 ng kg-1 min-1 for 30 min) + vehicle control (+)-glucose infusion (90 min), (-)-adrenaline (0.06 microgram kg-1 min-1 for 90 min) + salbutamol (120 ng kg-1 min-1 for 30 min) and two vehicle control infusions of (+)-glucose. All active solutions were preceded by a 1 h control infusion and the control infusion was continued for 1 h following the active solutions. Both the active solutions, (-)-adrenaline and salbutamol were increased stepwise to the above doses. Heart rate and blood pressure were recorded at frequent intervals throughout and venous blood was taken for the estimation of potassium, insulin, glucose, catecholamine and salbutamol levels. Adrenaline levels similar to those seen in acute illness were achieved using this infusion protocol. Salbutamol levels rose throughout the period of the salbutamol infusions and steady-state was not achieved. Potassium levels were unchanged on the control + control study day and fell on all active treatments (0.45 mmol l-1 following (-)-adrenaline + control; 0.48 mmol l-1 following salbutamol + control; 0.93 mmol l-1 following (-)-adrenaline + salbutamol). Insulin levels rose insignificantly after salbutamol alone and fell slightly on all other treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic control of plasma magnesium in man.

Regulation of magnesium balance is poorly understood. However, hypomagnesaemia has been reported in patients in clinical situations where circulating catecholamines are raised including myocardial infarction, cardiac surgery and insulin-induced hypoglycaemia stress tests. The effects of L-adrenaline infusions, sufficient to achieve pathophysiological levels of adrenaline, and of therapeutic intravenous infusions of salbutamol, a beta 2-agonist, on plasma magnesium, plasma potassium, plasma glucose and plasma insulin levels were studied in a placebo-controlled design in eight normal subjects. Plasma magnesium levels fell significantly during the adrenaline infusion and also during the salbutamol infusion, though more slowly. In a 1 h period of observation after cessation of the infusions no recovery of plasma magnesium levels was seen. Significant falls in plasma potassium levels were also observed during both infusions with spontaneous recovery within 30 min after the infusions. No significant changes in plasma insulin levels occurred with either salbutamol or L-adrenaline compared with control. Plasma glucose levels rose significantly during the adrenaline infusion. The study suggests that both L-adrenaline and salbutamol cause shifts in plasma magnesium which are not mediated by insulin. We propose that intracellular shifts of magnesium occur as a result of beta-adrenergic stimulation.

The pharmacokinetics of high dose metoclopramide in patients with neoplastic disease.

High dose metoclopramide infusions (10 mg/kg) were administered to nineteen patients with bronchial carcinoma who were receiving intravenous cyclophosphamide as single agent chemotherapy. Considerable interindividual variability in metoclopramide disposition was observed. Mean clearance was 0.33 +/- 0.13 (s.d.) l h-1 kg-1, mean volume of distribution at steady state was 3.8 +/- 1.2 (s.d.) l/kg and mean elimination half-life was 8.3 +/- 4.4 (s.d.) h. These results were significantly different from mean values previously reported for young healthy volunteers given conventional doses (0.70 l h-1 kg-1, 2.2 l/kg and 2.6 h respectively). Significant correlations were found between serum urea, serum creatinine and metoclopramide clearance. The metoclopramide regimens were well tolerated and, with the exception of two patients, were completely effective in the prevention of nausea and vomiting. To achieve and maintain target serum metoclopramide concentrations of 1 microgram/ml, we now administer a loading infusion of 3.61 mg/kg over 30 min followed by a maintenance infusion of 0.36 mg kg-1 h-1 for 10 h. Cyclophosphamide is normally administered concurrently with the second infusion. For patients with evidence of mild renal impairment, the maintenance infusion rate of metoclopramide hydrochloride should be adjusted according to the predicted individual clearance value; CL (l h-1 kg-1) = 0.57 - [0.036 X urea (mmol/l)].

How many blows really make an FEV1, FVC, or PEFR?

We have collected peak expiratory flow rates, one-second forced expiratory volumes, and forced vital capacities in sets of 10 or 20 values at one-minute intervals from 30 normal, 49 asthmatic, and 26 bronchitic subjects. Analysis shows that the derivatives are compatible with a normal distribution of the values in the sets, so that the true value is best represented by the arithmetic mean of all valid attempts. One-third of all subjects showed skewness in one or more indices but these were equally divided between positive and negative directions. There is no sign of the dominant negative skewness that would result if the true value was indeed a maximum, which could be approached or equalled but never exceeded. There is no sign that repetition worsens performance. Seventy-two subjects showed no regression in any index and those of the remainder who deteriorated were balanced by equal numbers in all categories who improved. There is a significant tendency for both the highest and the lowest values to occur in the earlier part of any series. Probability theory suggests that this is a statistical phenomenon. The best estimate of the true value of these indices is probably the mean of as many observations as can be conveniently obtained and the data can be treated statistically as if they were a sample from a normally distributed population.

The influence of theophylline on maximal response to salbutamol in severe chronic obstructive pulmonary disease.

We have previously shown that inhaled salbutamol further increases the bronchodilator response after the maximum effect of theophylline has been obtained in patients with severe chronic bronchitis. We now report the results of adding maximally effective doses of theophylline to the maximum response obtainable from salbutamol in ten of these patients. We constructed dose response curves to ensure maximum possible effect from salbutamol. Response plateaus (in nine out of ten patients) were achieved with cumulative doses of between 200 micrograms and 3,000 micrograms salbutamol and there was a significant response (p less than 0.05) in every subject: the mean FVC response was 1.11 (ranging from 0.5 to 1.81) and the mean FEV1 response was 0.41 (ranging from 0.1 to 0.81). Theophylline, in their previously determined maximally effective doses, produced statistically significant (p less than 0.05) small further increases in both FVC (0.2 to 0.61) and FEV (0.1 to 0.61) in four patients only. The other six did not respond. In patients classified as chronic bronchitics there is clearly a wide variation in response to bronchodilators and a surprising degree of reversibility can be achieved. But because of this variation in response, conventional drug doses may be too small in some cases. Ideally, each bronchodilator should be prescribed after some form of individual dose response studies. Although this acute study shows little or no benefit in the height of the bronchodilator response the usefulness of this combination can only really be decided after similar studies including the duration of effect in long term administration.

Modelling theophylline response in individual patients with chronic bronchitis.

1 In six patients with chronic bronchitis, serial changes in both ventilatory function and plasma theophylline concentrations were measured simultaneously for 8 h following 500 mg aminophylline intravenously. 2 Using empirical mathematical models which can integrate this data, parameters were estimated which can express response as a linear function of steady state plasma theophylline levels. 3 Taking Forced Vital Capacity (FVC) as the target response, the mean (+/- s.d.) increase in FVC was 0.06 +/- 0.02 l/micrograms ml-1, starting with pretreatment values in the range 1-21. 4 This analytical approach could be used to determine whether or not a patient with chronic bronchitis could obtain a satisfactory response to theophylline at plasma levels normally encountered in clinical practice.