Dose response relation to oral theophylline in severe chronic obstructive airways disease.

OBJECTIVE--To evaluate measurement of the trapped gas volume as a measure of respiratory function in patients with chronic obstructive airways disease and their response to treatment with theophylline. DESIGN--Patients able to produce consistent results on testing of respiratory function spent two weeks having dosage of theophylline adjusted to give individual pharmacokinetic data. This was followed by random assignment to four consecutive two month treatment periods--placebo and low, medium, and high dose, as assessed by serum concentrations of theophylline. Respiratory function and exercise performance was assessed at the end of each two month period. SETTING--Chest unit in district hospital. PATIENTS--Thirty eight patients with chronic bronchitis and moderate to severe chronic obstruction to airflow were recruited; 33 aged 53-73 years completed the study. INTERVENTIONS--Dosage of oral theophylline increased during two week optimisation period to 800 mg daily unless toxicity was predicted, when 400 mg was given. Targets for the steady state serum theophylline concentrations were 5-10 mg/l in the low dose period, 10-15 mg/l in the medium dose, and 15-20 mg/l in the high dose period. ENDPOINTS--Respiratory function as measured by forced expiratory volume in one second, forced vital capacity, peak expiratory flow rate, slow vital capacity, and static lung volumes using helium dilution and body plethysmography from which trapped gas volume was derived. Exercise performance assessed by six minute walking test and diary cards using visual analogue scale. MEASUREMENTS AND MAIN RESULTS--The forced expiratory volume in one second, forced vital capacity, and peak expiratory flow rate changed only slightly (about 13%) over the range of doses. There was a linear dose dependent fall of trapped gas volume from 1.84 l (SE 0.157) to 1.42 l (0.152), 1.05 l (0.128), and 0.67 l (0.102) during the placebo and low, medium, and high dose treatment periods. Mean walking distance increased by up to 55.6 m (20%). There was a modest improvement in dyspnoea as the dose of theophylline was increased. Side effects were mostly minor but they became more frequent as the dose was increased. CONCLUSION--The fall in trapped gas volume may reflect an improvement in peripheral ventilation (associated with treatment with theophylline) which is less apparent in the more common tests of lung function used in patients with chronic obstructive airways disease.     

Carbon monoxide and exercise tolerance in chronic bronchitis and emphysema.

The effects of carbon monoxide on exercise tolerance as assessed by the distance walked in 12 minutes were studied in 15 patients with severe chronic bronchitis and emphysema (mean forced expiratory volume in one second 0.56 1, mean forced vital capacity 1.54 1). Each subject walked breathing air and oxygen before and after exposure to sufficient carbon monoxide to raise their venous carboxyhaemoglobin concentration by 9%. There was a significant reduction in the walking distance when the patients breathed air after exposure to carbon monoxide (p less than 0.01), and the significant increase in walking distance seen after exercise when breathing oxygen at 2 1/minute via nasal cannulae was abolished if carbon monoxide has previously been administered. Thus concentrations of carboxyhaemoglobin frequently found in bronchitic patients who smoke may reduce their tolerance of everyday exercise, possibly by interfering with the transport of oxygen to exercising muscles.     

Portable oxygen and exercise tolerance in patients with chronic hypoxic cor pulmonale.

Breathing 30% oxygen during exercise alleviated arterial hypoxaemia and reduced minute ventilation in patients with severe chronic bronchitis. A similar level of oxygen (2 or 4 litres of oxygen/minute) from nasal prongs also increased their exercise tolerance, as assessed by the distance that they could walk on the level in 12 minutes. Nevertheless, a single-blind controlled study showed that the effort of carrying their portable supply of liquid oxygen, in the Union Carbide Oxygen Walker, abolished this gain in exercise tolerance. The improvement in walking distance was restored when oxygen on exercise was provided by wheeling the oxygen walker on a light-weight shopping trolley.     

Effect of beta-adrenergic blockade on hyperventilation and exercise tolerance in emphysema

Ventilation, heart rate, and arterial blood gas tensions were measured at rest and during incremental exercise in 10 patients with emphysema after intravenous placebo or 7 mg metoprolol. Metoprolol reduced heart rate by 14% (P less than 0.001) and ventilation by 11% (P less than 0.01), but there was no significant difference in arterial O2 or CO2 tension (Pao2 and PaCO2, respectively). Metoprolol increased the time to exhaustion on a cycle ergometer (P less than 0.05) but did not improve the 12-min walking distance. A double-blind randomized crossover comparison of 4 wk treatment with atenolol (100 mg/day), metoprolol (100 mg/day), or matched placebo was performed in 12 patients with emphysema. Both beta-adrenoceptor antagonists reduced resting heart rate by 33% (P less than 0.001) and resting minute ventilation by 11% (P less than 0.025). There was no change in resting or exercise Pao2 or Paco2. During steady-state exercise on a cycle ergometer, atenolol and metoprolol reduced ventilation by 14 and 4%, respectively. This was accompanied by 11 and 5% reductions in O2 consumption (P less than 0.05) and 13 and 6% falls in CO2 production (P less than 0.05). There were no significant changes in tests of exercise tolerance, but forced expiratory volume in 1 s and forced vital capacity were reduced during beta 1-adrenergic blockade. beta 1-Blocking drugs reduce hyperventilation in emphysema by reducing pulmonary gas exchange without a change in arterial blood gas tensions. Increased airflow obstruction prevents this reduction being of therapeutic value.     

Combined treatment with sustained-release theophylline and beta2-adrenoceptor-stimulating agents in chronic childhood asthma.

The effect of adding theophylline to treatment with a beta2-adrenoceptor stimulant was studied in 18 asthmatic children in a double-blind cross-over trial. Most patients were taking cromolyn sodium (cromoglycic acid) or beclomethasone aerosol, or both. A sustained-release preparation of theophylline was administered in individually titrated doses, producing a mean plasma theophylline concentration of about 8 micrograms/ml. Statistically significant improvements were found during the theophylline treatment in symptom score, consumption of beta2 stimulants in aerosol form, and morning peak expiratory flow rate and forced expiratory volume in one second. There was also a reduced need for emergency-room treatment during the theophylline period. Reported side effects were few and mild and were similar during the theophylline and placebo periods. Of the 17 patients who completed the trial, 14 preferred theophylline and three expressed no preference between theophylline and placebo. Adding submaximal doses of sustained-release theophylline to treatment with a beta2 stimulant gave further relief of asthmatic symptoms without appreciable side effects, suggesting that the drug combination has a favourable therapeutic index.     

Association between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis. Canadian Erythropoietin Study Group.

OBJECTIVE--To determine whether recombinant human erythropoietin improves the quality of life and exercise capacity of anaemic patients receiving haemodialysis. DESIGN--A double blind, randomised, placebo controlled study. SETTING--Eight Canadian university haemodialysis centres. PATIENTS--118 Patients receiving haemodialysis aged 18-75 with haemoglobin concentrations less than 90 g/l, no causes of anaemia other than erythropoietin deficiency, and no other serious diseases. INTERVENTIONS--Patients were randomised to three groups to receive placebo (n = 40), erythropoietin to achieve a haemoglobin concentration of 95-110 g/l (n = 40), or erythropoietin to achieve a haemoglobin concentration of 115-130 g/l (n = 38). Erythropoietin was given intravenously thrice weekly, initially at 100 units/kg/dose. The dose was subsequently adjusted to achieve the target haemoglobin concentration. All patients with a serum ferritin concentration less than 250 micrograms/l received oral or intravenous iron for one month before the study and as necessary throughout the trial. MAIN OUTCOME MEASURES--Scores obtained with kidney disease questionnaire, sickness impact profile, and time trade off technique; and results of six minute walk test and modified Naughton stress test. RESULTS--The mean (SD) haemoglobin concentration at six months was 74 (12) g/l in patients given placebo, 102 (10) g/l in those in the low erythropoietin group, and 117 (17) g/l in those in the high erythropoietin group. Compared with the placebo group, patients treated with erythropoietin had a significant improvement in their scores for fatigue, physical symptoms, relationships, and depression on the kidney disease questionnaire and in the global and physical scores on the sickness impact profile. The distance walked in the stress test increased in the group treated with erythropoietin, but there was no improvement in the six minute walk test, psychosocial scores on the sickness impact profile, or time trade off scores. There was no significant difference in the improvement in quality of life or exercise capacity between the two groups taking erythropoietin. Patients taking erythropoietin had a significantly increased diastolic blood pressure despite an increase in either the dose or number of antihypertensive drugs used. Eleven of 78 patients treated with erythropoietin had their sites of access clotted compared with only one of 40 patients given placebo. CONCLUSIONS--Patients receiving erythropoietin were appreciably less fatigued, complained of less severe physical symptoms, and had moderate improvements in exercise tolerance and depression compared with patients not receiving erythropoietin. At the doses used in this trial there was a higher incidence of hypertension and clotting of the vascular access in patients treated with erythropoietin.     

Use of Benzoctamine as Sedative in Patients with Respiratory Failure

Benzoctamine (Tacitin) was given by mouth as night sedation to patients admitted to hospital with respiratory failure. Fourteen patients had chronic obstructive bronchitis and six had acute severe asthma. One patient with asthma needed intravenous sedation with benzoctamine. No adverse effects were observed, and there was no significant change of forced expiratory volume in one second (FEV₁), forced vital capacity (FVC), or Pco₂ in any patient after benzoctamine. Nevertheless, further clinical experience of the drug is required before its use can be safely recommended in respiratory failure.     

Intermittent claudication. The effect of physical training on walking tolerance and venous lactate concentration

Twenty-one patients with intermittent claudication underwent a physical exercise program lasting 8 weeks. The patients were classified on the basis of maximal walking tolerance (MWT) and diagnosis at the initial examination. Seven of the patients had a MWT less than 1,000 m and no symptoms of chronic obstructive airways disease (COAD) or angina (group A), seven had a MWT less than 1,000 m plus angina and/or COAD (group B) and seven had an unlimited (greater than 1,250 m) MWT (group C). At the completion of the training program all three groups showed a significant improvement in walking distance to pain and stress test capacity. During the post-training walking tolerance test, the venous lactate concentrations in group A were lower after 2 min and 4 min of exercise, and at exhaustion (P less than 0.05). Group A patients showed a significant correlation between an increase in MWT after training and a decrease in maximum lactate concentration measured during walking. Although the patients in group B had a significant increase in MWT, blood lactate concentrations in this group were not always decreased by physical training. Group C lactate concentrations were lower after 8 min, 15 min, and 30 min of walking (P less than 0.05). It is concluded that a physical training program increases walking tolerance in different categories of claudicants, and possible mechanisms for the improvement are discussed.     

Effect of chronic caffeine administration on theophylline concentrations required to produce seizures in rats

Caffeine as well as the antiasthmatic drug theophylline can cause seizures when administered to humans or animals in excessive doses. Studies on rats have shown rapid development of functional tolerance to caffeine-induced seizures whereas repeated pretreatment with theophylline had no significant effect on the theophylline concentrations required to produce seizures. The purpose of this investigation was to determine whether chronic exposure to caffeine can affect susceptibility to the convulsant effect of theophylline. Rats received caffeine, 40 mg/kg, or solvent twice a day for 7 days as an intravenous injection. On the eighth day, theophylline was infused intravenously until the onset of maximal seizures. At this pharmacologic end point, rats pretreated with caffeine had significantly higher theophylline concentrations in the brain and cerebrospinal fluid than did control (solvent-pretreated) animals. Although the concentration differences were relatively small (approximately 11%), they demonstrate in principle the development of caffeine-induced tolerance to the neurotoxic effect of theophylline. Additional experiments showed that the caffeine effect on theophylline neurotoxicity is not acutely mediated by paraxanthine, a major metabolite of caffeine.     

Comparison of aerosol ipratropium bromide and salbutamol in chronic bronchitis and asthma.

The effects of inhaling 200 mu g of salbutamol were compared with those of inhaling 40 mu g of ipratropium bromide singly and in combination with salbutamol in eight patients with bronchitis and eight asthmatic patients in a double-blind controlled trial. Changes in airways resistance were assessed by measuring the forced expiratory volume in 1 second and specific airways conductance. Both drugs were significantly better in relieving airways obstruction than placebo. Salbutamol was significantly more effective than ipratropium bromide in patients with asthma, but in the patients with bronchitis there was no significant difference between salbutamol and ipratropium bromide. The combination of the two drugs produced a slightly greater and longer response than either drug alone but this was not significant.     

Topical Fat Reduction

The fat on women's thighs is more difficult to mobilize due to increased α-2 adrenergic receptor activity induced by estrogen. Lipolysis can be initiated through adipocyte receptor stimulation (β adrenergic) or inhibition (adenosine or α-2 adrenergic) or by inhibition of phosphodiesterase. Since many women desire regional thigh fat loss, a series of clinical trials were initiated using one thigh as a double-blinded control. Trial #1: Five overweight women had injections of isoproterenol at intervals around the thigh three times a week for 4 weeks with diet and walking. Trial #2: Five overweight woman had ointment containing forskolin, yohimbine and aminophylline applied to the thigh five times a week for 4 weeks after hypertonic warm soaks with a diet and walking. Trial #3: Eighteen overweight women were divided into three groups of six and trial #2 was repeated with each agent alone vs. placebo using forskolin, yohimbine or aminophylline in separate ointments. Trial #4: Thirty overweight women had 10% aminophylline ointment applied to the thigh five times a week for 6 weeks with diet and walking. Chemistry panel, theophylline level and patch testing wereperformed. Trial#5: Twelve women had trial #4 repeated with 2% aminophylline cream without a diet or walking. Trial #6: Trial #5 was repeated with 0.5% aminophylline cream. All trials except yohimbine ointment gave significantly more girth loss from the treated thigh (p < 0.05 to p < 0.001). Chemistry panel showed no toxicity. Theophylline was undetectable and patch testing was negative. We conclude that topical fat reduction for women's thighs can be achieved without diet or exercise.     

Controlled trial of supervised exercise training in chronic bronchitis.

In a controlled trial of exercise retraining in patients with severe chronic bronchitis, 33 subjects were followed for a mean period of 10.3 months. The exercise programme was supervised once a week, and daily training comprised a 12-minute walk and simple stair climbing exercises. The subjects in the exercise group showed a highly significant improvement in their walking distance, attaining a maximum increase of 24% after eight to 12 months. There was also considerable subjective improvement. The control group did not improve. No significant changes in cardiorespiratory function or muscle strength were seen. Simple exercise rehabilitation is of benefit to patients with disabling obstructive lung disease.     

Long acting β2 agonists for stable chronic obstructive pulmonary disease with poor reversibility: a systematic review of randomised controlled trials

Background

The long acting β2-agonists, salmeterol and formoterol, have been recommended, by some, as first line treatment of stable chronic obstructive pulmonary disease (COPD). We reviewed evidence of efficacy and safety when compared with placebo or anticholinergic agents in patients with poorly reversible COPD.

Methods

After searching MEDLINE, EMBASE, HealthSTAR, BIOSIS Previews, PASCAL, ToxFile, SciSearch, the Cochrane Library, and PubMed, as well as Web sites, selected journals, reference lists, and contacting drug manufacturers, two reviewers independently screened reports of randomised controlled trials of parallel or crossover design lasting four weeks or longer and including patients with a forced expiratory volume in one second (FEV1) ≤ 75% of predicted, a ratio of FEV1 to forced vital capacity (FVC) ≤ 88% of predicted, and < 15% improvement from baseline FEV1 after a dose of a β2 agonist. We included trials comparing salmeterol or formoterol with placebo or with ipratropium bromide and reporting one of these outcomes: lung function; exercise capacity; quality of life scores; dyspnea; exacerbations; rescue inhaler use; incidence of tachycardia, hypokalemia, or dry mouth. Two reviewers assessed the quality of included reports using the Jadad scale and allocation concealment, and abstracted data.

Results

Twelve trials satisfied our inclusion criteria; eight were high quality (Jadad score >2) and four were low quality (≤ 2). The adequacy of allocation concealment was unclear in all of them. We did not perform a meta-analysis due to differences in trial design and how outcomes were reported. Two trials comparing salmeterol with ipratropium did not detect differences; one trial comparing formoterol and ipratropium described greater improvement with formoterol in morning PEFR (15.3 versus 7.1 l/min, p = 0.040). Of twelve trials comparing long acting β2 agonists with placebo, six reported no improvement in exercise capacity, eleven reported improvements in FEV1 lung function (one reported no improvement), six reported less rescue inhaler usage (one reported no difference) and five reported improved dyspnea scores (two reported no improvement). Differences in quality of life were detected in one salmeterol trial ; however, two salmeterol, and one formoterol trial reported no differences. Adverse effects of interest were not reported.

Conclusion

In terms of clinical outcomes and safety, we could not find convincing evidence that salmeterol and formoterol have demonstrated advantages to ipratropium, a less expensive drug, for patients with stable COPD and poor reversibility. Compared to placebo, we found evidence of reduced rescue inhaler usage and improved spirometric outcomes without a significant impact on quality of life or exercise capacity.     

Prevalence and diagnosis of chronic respiratory symptoms in adults.

OBJECTIVE--To investigate the prevalence and diagnosis of chronic respiratory disease in adults. DESIGN--Screening questionnaire was sent to all patients aged 40-70 on the register of a group general practice; those responding positively were sent a detailed questionnaire and invited for assessment of respiratory function by forced expiratory volume in one second, forced vital capacity, peak flow rate, and reversibility studies with a beta adrenergic inhaler. SETTING--Group general practice in south west London. RESULTS--Of 2387 patients aged 40-70, 1444 completed a screening questionnaire. Of the 509 patients who reported cough, phlegm, wheeze, or shortness of breath, 324 responded to a detailed questionnaire, 256 of whom had simple respiratory function assessed. Chronic bronchitis affected 106 (17%) men and 58 (7%) women, and wheeze occurring at least once a week affected 60 (9%) men and 20 (3%) women. Only a half to a third of patients had received a diagnostic label of chronic bronchitis or asthma for their symptoms. There was considerable clinical and physiological similarity (including reversibility of the airways) between patients labelled as having asthma and having chronic bronchitis. A label of asthma was used more often for patients of social classes I and II. CONCLUSIONS--Comparison with prevalence surveys carried out in the 1950s showed that respiratory symptoms are as common now as then, but the risk of disabling chronic bronchitis has fallen, more among men than women, probably because of their reduced smoking. Changes in diagnostic fashion, together with increased detection, may have contributed to the upward trend in reported morbidity from asthma over the past 30 years.     

Effects of orally administered OP-1206 alpha-CD with loxoprofen-Na on walking dysfunction in the rat neuropathic intermittent claudication model

An orally active prostaglandin E1 analogue, OP-1206 alpha-CD improves walking dysfunction in the rat spinal stenosis model. Loxoprofen-Na, a non-steroidal anti-inflammatory drug, is used to relieve chronic pain in patients with lumbar spinal canal stenosis. To determine whether the OP-1206 alpha-CD in combination with loxoprofen-Na could induce a greater therapeutical effect on walking dysfunction and spinal cord blood flow (SCBF) than OP-1206 alpha-CD treatment alone after chronic spinal stenosis in the rat. Spinal stenosis was induced by placing two pieces of silicon rubber strips in the lumbar (L4 and L6) epidural space of rats. After surgery, walking function was measured using a treadmill apparatus and SCBF was measured using a laser-Doppler flow meter. Drugs were administered orally twice a day for 11 days from the day 3 post-surgery. OP-1206 alpha-CD elicited a significant improvement of walking dysfunction on days 7 and 14 post-surgery and significantly increased spinal cord blood flow on day 15, whereas walking dysfunction and SCBF of rats treated with loxoprofen-Na alone remained unchanged. Combined treatment of OP-1206 alpha-CD with loxoprofen-Na did not provide additive therapeutical effect. These results suggest that a significant improvement seen after OP-1206 alpha-CD treatment is primarily mediated by improvement of the local spinal cord blood flow. This effect is not ameliorated or potentiated by a combined treatment with loxoprofen-Na.     

Evaluation of the forced expiration technique as an adjunct to postural drainage in treatment of cystic fibrosis.

Sixteen patients with cystic fibrosis were treated with conventional physiotherapy aided by an assistant. The results were compared with those produced by physiotherapy using the forced expiration technique cleared more sputum in less time than conventional physiotherapy. A sputum in less time than conventional physiotherapy. A second study showed that an assistant did not further improve the results obtained by the patient performing the forced expiration technique himself. These findings mean that patients with cystic fibrosis who have had to rely on the help of others for their home treatment may now perform more effective treatment without help. The forced expiration technique might also be helpful for patients with chronic bronchitis, asthma, or bronchiectasis.     

Oral mucolytic drugs for exacerbations of chronic obstructive pulmonary disease: systematic review

ObjectiveTo assess the effects of oral mucolytics in adults with stable chronic bronchitis and chronic obstructive pulmonary disease.DesignSystematic review of randomised controlled trials that compared at least two months of regular oral mucolytic drugs with placebo.StudiesTwenty three randomised controlled trials in outpatients in Europe and United States.ResultsCompared with placebo, the number of exacerbations was significantly reduced in subjects taking oral mucolytics (weighted mean difference −0.07 per month, 95% confidence interval −0.08 to −0.05, P<0.0001). Based on the annualised rate of exacerbations in the control subjects of 2.7 a year, this is a 29% reduction. The number needed to treat for one subject to have no exacerbation in the study period would be 6. Days of illness also fell (weighted mean difference −0.56, −0.77 to −0.35, P<0.0001). The number of subjects who had no exacerbations in the study period was greater in the mucolytic group (odds ratio 2.22, 95% confidence interval 1.93 to 2.54, P<0.0001). There was no difference in lung function or in adverse events reported between treatments.ConclusionsIn chronic bronchitis and chronic obstructive pulmonary disease, treatment with mucolytics is associated with a reduction in acute exacerbations and days of illness. As these drugs have to be taken long term, they could be most useful in patients who have repeated, prolonged, or severe exacerbations of chronic obstructive pulmonary disease.

What is already know on this topic

Mucolytic drugs have properties that may be beneficial in chronic obstructive pulmonary diseaseThese drugs are not prescribed in the United Kingdom and Australasia, although they are widely used in many other countriesDrugs that reduce exacerbations may reduce the morbidity and healthcare costs associated with progressively severe disease

What this study adds

Regular use of mucolytic drugs for at least two months significantly reduces exacerbations and days of illness compared with placebo in patients with chronic bronchitis and chronic obstructive pulmonary diseaseExacerbations that do occur may not be as severe, and the benefit may be greater in those with more severe diseaseReductions are modest and treatment may not be cost effective     

Effects of oral and inhaled salbutamol and oral pirbuterol on right and left ventricular function in chronic bronchitis.

In many patients with chronic bronchitis and emphysema right and left ventricular ejection fractions (RVEF and LVEF) are reduced. A study was conducted using multiple gated equilibrium radionuclide ventriculography to compare the effects of oral salbutamol 4 mg and pirbuterol 15 mg on cardiac function in 12 patients with chronic bronchitis (forced expiratory volume in one second 0.86 (SEM 0.12) 1; arterial oxygen pressure 8.2 (SEM 0.5) kPa (61.7 (SEM 3.8) mm Hg)). Different doses of nebulised salbutamol (500 microgram and 5 mg) were also compared in nine of the patients. Both oral salbutamol and oral pirbuterol produced significant increases in RVEF and LVEF at 60 and 90 minutes after drug ingestion (p less than 0.01 in each case). There were no significant differences between salbutamol and pirbuterol in their effects on RVEF and LVEF. Inhaled salbutamol at doses commonly prescribed had no significant effect on RVEF and LVEF after 20 and 60 minutes. Salbutamol and pirbuterol given by mouth have similar actions on RVEF and LVEF. Further studies are necessary to assess the effects of long term B2 agonists in this group of patients.     

Dyspnoea,disability, and distance walked: comparison of estimates of exercise performance in respiratory disease.

Forty-four patients with airway obstruction and 18 with pulmonary infiltration were studied in an attempt to correlate exercise tolerance, as assessed by a simple walking test, with basic respiratory function values and differing subjective assessments of exercise performance. The distance walked in 12 minutes was significantly correlated with the response to a structured questionnaire and with the patients'' assessment of performance using an oxygen-cost diagram. The distance walked did not agree well with simple subjective estimates obtained in the clinical history. It was better correlated with forced vital capacity than with forced expiratory volume in one second in both groups of patients, and was well correlated with carbon monoxide transfer factor in those with pulmonary infiltration. The scatter of results, however, was such that exercise performance could not usefully be predicted from the respiratory function values or from subjective assessments. Simple exercise tests are an essential part of assessing disability and response to treatment in patients with respiratory impairment.