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Study of the effect of small dose of steroid to ephedrine--theophylline combination in chronic obstructive pulmonary disease.
For reversible expiratory obstruction, steroid preparations in addition to routine bronchodilators are commonly advised by doctors. Many patients, after discovering their beneficial effect in preventing acute paroxysms medicate themselves intermittently with steroids in small doses. As reported by us earlier,[4] the standard ephedrine-theophylline preparations without steroids have many side effects. The newer beta adrenergic bronchodilators have fewer side effects, but are not superior to the older combinations.[3], [5] Recent literature suggests that oral theophylline builds as effective blood levels as parenteral theophylline. These factors may explain the popularity of combination preparations with smaller dosages of theophylline, ephedrine and prednisolone. Somner and associates[9] have shown that, as maintenance, intermittent steroids in lower dose may control asthmatic patients satisfactorily as regards acute attacks axed lung function status. There is little objective data comparing the various combinations with added prednisolone. This paper reports successive double blind trials on various such combinations.
The study consisted of three series on 75, 30 and 50 adult patients (above 12 years) suffering from chronic and/or paroxysmal dyspnoea. The following standard criteria (detailed earlier[4]) were used for inclusion of patients in the study: (i) At least two weekly bronchospastic exacerbations for one year or longer. (ii) Low (< 75%) FEV1/FVC% value with at least 10% reversibility after isoprenaline aerosol on initial pulmonary function assessment. (iii) Absence of severe attacks, chronic productive cough, frequent use of antibiotics, serious general disease or cardiac failure. In addition, those who required high (over 10 mg daily) prednisolone for maintenance were excluded. All routine bronchodilator drugs were stopped 12 hours before the initial functional assessment but during the trial isoprenaline/orciprenaline or parenteral aminophylline for relief of acute dyspnoea, were allowed as additional treatment. [Table - 1] shows drug combinations used in the three series, which were administered in a random double blind crossover fashion. The design in Series A was incomplete as we compared the effect of adding steroids to a `Low' and a standard `High' combination. In the `High' preparation (Series A) we omitted phenobarbitone as there was some evidence that the addition of the latter gave a slower peak effect.[1] Drug schedule distribution [Table - 2] In each case the tablets were given 4 times daily for 3 weeks each for series A, and 2 weeks each for series B and C. (the period was shorter as in the data for third week in Series A, we found no further change). In series C, placebo was given four times a day for one week between the two schedules to account for any hangover effect of steroids. For series B and C, all patients received both drugs but in series A, those receiving "Low + S" crossed over to either "High" or "Low" for the remaining three weeks in a random order. Our sequence ensured that there was atleast one common link between the series for intercomparisons. For series A, the preparations were identical so also for series B and C. The weekly clinical assessment was done by a doctor who also scrutinised the record cards maintained by patients for the following parameters: (i) Clinical progress in relation to initial status. (ii) Frequency of bronchospastic attacks per week. (iii) Additional weekly treatment (scored as oral tablet given once as `1' and parenteral aminophylline as '2'). (iv) Side effects. A weekly lung function (FVC, FEV1, PEF) was measured by standard methods and corrected to BTPS (body temperature pressure saturated). Extensive statistical analyses by various methods were done to ascertain differences in pre-drug and post-drug status for various drug combinations accounting for effects of period in drug administration and subject variations over 2-3 weeks. As standard errors listed in [Table - 5], [Table - 6] and [Table - 9] are significant, we ultimately chose for changes in lung function non-parametric tests. For a comparison of clinical parameters between various schedules, proportional analyses were done. For series A, analyses were also done as paired comparisons for Low/Low + S or Low + S/High schedules and also to detect any residual effect of steroids being given in the first 3 weeks, (as these combinations were given in a random order).
Series A Clinical history There were 40 males and 35 females (M: F = 8:7). Several subjects had a history of 5-20 years. Initially, 36 (48%) had 2 to 5 paroxysmal attacks per week. In 25 subjects there was a history of significant sputum production during exacerbations. Regularity In 10 subjects no follow-up was obtained on either drugs (with a slightly greater frequency on 'Low' schedule). In 65 subjects default due to non-co-operation was greater on 'Low + S' schedule. Clinical deterioration occurred in 5 cases (1 each on 'High' and 'Low' and 3 on 'Low + S' schedule). Side effects There were no significant differences for either of the three schedules. However, 3 patients on 'Low + S' had severe side effects requiring stoppage of drugs. Of the total 353 man-weeks, in 125 weeks 166 symptoms as toxicity were observed. The distribution over 3 weeks among 3 regimens was similar. For epigastric or retrosternal burning (on 'Low + S' : 33; Low : 27, High 11: p < 0.05), there were significant differences by "Chi" square test; others commonly complained of palpitations, bodyache, vomiting and tremors. Clinical response (i) [Table - 3] details the clinical response for the total period for each schedule. The change over a week from the initial status (as 'O') was categorised as significant improvement in chest symptoms (1 +), absence of chest symptoms and signs (2 +), no change (0), increase in frequency and intensity of symptoms (1-) and development of status asthmaticus or severe persistent attacks (2-)[4]. The propertions improved varied from 59 to 68 per cent and were similar for all schedules and weeks. As there was no evidence of tolerance or enhancement over 3 weeks on further analyses [ Table 3 ] lists total man weeks for each schedule together. (ii) Frequency of paroxysmal attacks was smaller with `High' schedule and greater with `Low' schedule (p < 0.1) [Table - 4] If analyses for `Low + S' schedule are split according to the sequence of other schedules, the former still shows an intermediate behaviour, but the differences are insignificant. Additional treatment An analysis between the weeks and schedules revealed no significant differences for the three schedules; the respective mean treatment scores for `High', `Low' and `Low + S' were 1.27, 1.37 and 1.68. Lung function The analyses were done for schedule Low/Low + S and Low + S/High [Table - 5] according to the sequence for other drugs. The mean pretreatment values for all three tests are similar. In comparison, all treatments showed only small differences. There were neither significant differences between various schedules nor was there any evidence of delayed effect of 6 mg of prednisolone daily. If the two Low + S sequences are combined or `High' and Low schedules are compared by Wilcoxon Signed Rank Test, the results reveal similar conclusions. The overall trend was for the `High' schedule to be slightly better. Series B Out of 30 patients, 9 were males. Clinical profile was similar for both schedules. In 15 (50%) there was a history of chronic or recurrent productive cough. Regularity Out of the total of 120 man-weeks, 18 weeks were missed in 7 subjects. In one, there was no follow up, while in 4 subjects the second drug was not given. One patient stopped the second drug (`Low+S') due to side effects. Side effects There were side effects in 6 patients each week on 'High+S' and in ° and 8 patients each week on `Low+S' schedules. The common side effects were abdominal pain, bodyaches, palpitations, giddiness, insomnia, and weakness of limbs. There were insignificant differences between the two schedules though on `High + S', the complaints were less. Clinical response (i) The clinical response was assessed as in series A. Of the 24 subjects followed up, 21 improved on `High+S' as compared to 16 on `Low+S' schedule; the difference was insignificant. (ii) Frequency of attacks: The pooled mean frequency for 'High+S' was 1.52 while for 'Low+S' it was 2.41. The difference was insignificant. (iii) The additional treatment score for `High+S' and 'Low+S' was 1.52 and 2.74 respectively. In 29 'High+S' and 22 `Low+S' man-weeks no treatment was taken. These differences are all insignificant. Thus though `High+S' combination gave a slightly superior response by overall analyses, the differences were insignificant. Pulmonary function changes [Table - 6] While differences between the initial and post-drug status are insignificant, for FVC alone for `Low+S', the second week value is significantly (p C 0.05) better than the first week. Inter-drug differences for all tests for either drug or between the weeks are insignificant. Series C Of the 50 subjects, 18 (36%) had a history upto 5 years while 14 had symptoms for 6-10 years. Twenty-nine patients (58%) had upto 5, weekly paroxysmal attacks. Regularity On `High' schedule in the first and second weeks, there were 42 and 38, subjects. Two patients deteriorated while on `High' schedule and one of these also had side effects. In addition, 5 defaulted (3 in the first and 2 in the second week) due to non-co-operation. On placebo, 39 subjects completed one week; of the 4 patients defaulted while on placebo, 2 deteriorated clinically but other two also had side effects on the prior drug (High). On 'High+S' schedule (of 40' and 38 subjects followed in 2 weeks respectively) 3 deteriorated (2 in the first week) and one also had side effects. Thus there was a greater overall default on `High' schedule, mainly due to side effects. Side effects Of total 43 patients on `High' and 42 on 'High+S' schedule, side effects occurred similarly (18 cases); however, the side effects leading to default were slightly commoner with the `High' schedule. Main side effects were nausea, insomnia, headache, tingling, vertigo and tremors. However, there were no significant differences between the two schedules. Clinical response [Table - 7] (a) Clinical status: Those who were put on placebo showed some improvement (60%) as compared to 65% on `High' and 72% on `High+S' schedules. This trend is insignificant for either of the two schedules and the placebo showed no bias towards either, of the preceding drug schedule. (b) Paroxysmal attacks: [Table - 8] shows total number of attacks as seen on placebo and the two schedules. The estimated pre-treatment frequency was 3.25 per week. With 'High+S' schedule, this was significantly lower (2.1) as compared to `High' (3.5) in the second week only (p < 0.01). (c) Additional treatment: The mean score was 0.54 (21/39) on placebo while it was 0.36 and 0.66 in the first and second weeks on `High' schedule. The respective figures for High+S' schedules were 0.33 and 0.31. The differences were insignificant (p < 0.1 in favour of High+S). Lung function These were analysed by Wilcoxon Signed Rank Test [Table - 9] as pre- and post drug trends taking into account the subject, period and drug effects. In the second week on `High+S' schedule, FVC showed a significant improvement (p < 0.002 on 34 pairs). The overall post-drug status also was maintained better on `High+S' schedule (p < 0.01 on 70 pairs). But the changes for FEV1 and PEF were insignificant.
Since the advent of beta adrenergic bronchodilators, the interest in comparative assessment of older bronchodilators has waned. It is widely believed that new drugs are superior.[6] However, our recent work shows that oral salbutamol is similar to ephedrine in a 3 week trial though the latter showed greater tolerance .[3] In a 12 week trial theophylline-ephedrine combination was atleast equal to salbutamol and gave a superior functional improvement.[5] The role of steroids in controlling resistant bronchospasm particularly in asthma is well known.[7] In order to avoid the inherent side effects with a prolonged steroid treatment several alternatives like steroid aerosols, intermittent ACTH administration, short courses, lower doses or alternate day regimes are suggested.[6],[7],[8],[10] When steroids are indicated, the doctors tend to prescribe therapeutic doses. So the role of small dose of steroid in giving benefit can be questionable. Rees and Williams" claimed in a study of 317 asthmatic patients that many (42%) were controlled on half to one tablet of prednisolone a day (2.5 to 5 mg). This range of dosage was less likely to give side effects. Our aim was to seek objective data regarding the value of prevalent clinical practice of using low doses of steroid in combination with low or standard dosage of ephedrine-theophylline combination over a few weeks. The study was done in three series as it was impossible to do such large numbers in a short period. We wanted to first compare a standard low steroid-low bronchodilator combination with standard high bronchodilator preparation. The latter was given with a low bronchodilator preparation with the former, in a crossover fashion. The next two series were meant to compare the effect of adding a low-steroid dose to a high or low bronchodilator preparations. The results reveal that side effects in series A were somewhat commoner on `Low+S' schedule indicating that low dose (6 mg daily) prednisolone does cause a measurable increase in gastric distress. The `high' schedule showed a somewhat better response in series A. This combination was devoid of prednisolone or phenobarbitone; it may be suggested that these agents do not add to the bronchodilator action. Extensive analyses on the series B and C indicated that High+S schedule gave a better clinical status, fewer attacks and lesser need for additional treatment and also perhaps less severe side effects. Thus, in presence of low dose ephedrine-theophylline combination, prednisolone may have some effect but both `High' schedules had a better efficacy, in maintaining the patients' status. The reason for a slight difference in the two combinations of `High' schedule in this study is that one was patterned after the dosage in "cortasmyl" brand (x2) and the other after "tedral" brand of commercial products. For functional changes, on all schedules, the changes observed were small and in an insignificant range. As we measured the functions in the morning, only long-term benefits due to these drugs are reflected. As in chronic obstructive pulmonary disease, little if any change in the long term course of the disease by any of bronchodilator drugs occurs, this is to be expected. It may be stressed that all our subjects had a significant reversibility of obstruction after isoprenaline aerosol (mean for 3 series: 25-36%) . While lung function may not reflect the improvement in symptoms and paroxysmal attacks, maintenance of better clinical status should reflect in a more elevated function (however small the difference). Also we thought that due to innate variations in lung function and clinical picture over an extended 4-6 weeks' period, all analyses had to take into account these factors. As it was impractical to study such combination in a single series in such a large group, we scrutinised the overall lung function changes in 3 series [Table - 10] The mean values are shown as total man-weeks over the period of observation on each combination. Though the differences were insignificant, the mean indicated that `High' preparations are somewhat better. The addition of steroid to `Low' preparation does not make it better than the high preparations but there may be some evidence of its effect in a `high' combination. In conclusion, our results indicate that a low dose combination may not be desirable. The addition of small dose of (6 mg) prednisolone may have some effect. The `high' preparations have some efficacy which is enhanced to a degree by an addition of 6 mg prednisolone.
We thank the Dean, and Research Society for allowing us to carry out this study. We are grateful to Dr. H. B. Kathuria of Roussel Laboratories and Dr. (Mrs.) U. S. Chaubal of Warner Hindustan for the supply of drugs and the support.
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