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Signature: Med Sci Monit, 2002; 8(4): CR297-304 WWW.MEDSCI MONIT.COM
PMID: 11951074 Clinical Research

CR
Received: 2001.11.05
Efficacy and safety of doxofylline compared
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Accepted: 2002.01.10
Published: 2002.04.12
to theophylline in chronic reversible asthma
– a double-blind randomized placebo-controlled

SE
Authors’ Contribution:
multicentre clinical trial
A Study Design
B Data Collection
C Statistical Analysis Marc F. Goldstein1 abde, Paul Chervinsky2 abde
D Data Interpretation

U
1
E Manuscript Preparation The Asthma Center, Philadelphia, PA, USA
2
F Literature Search New England Clinical Studies, North Dartmouth, MA, USA
G Funds Collection

LY L
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Summary
Background:
N A
Experimental studies have shown that doxofylline is endowed with a remarkable bronchodila-
tor activity with less extra-respiratory effects than theophylline. This trial was designed to
compare the efficacy and safety of doxofylline, theophylline, and placebo in patients with
O N
chronic reversible bronchial asthma.
Material/Methods: Three hundred forty-six patients were randomly assigned to a 12-week oral treatment with
SO

either doxofylline 400 mg t.i.d. (high dose), doxofylline 200 mg t.i.d. (low dose), theophylline
250 mg t.i.d. (active control) or placebo. Pulmonary function tests (PFTs) were performed
biweekly. Patients kept records of peak flow meter (PFM) measurements, asthma attack rate
and beta-2-agonist use (albuterol).
Results: Changes in FEV1 2 hours after the administration of treatments versus baseline exhibited sta-
tistically significant differences between doxofylline 400 mg t.i.d. and placebo and between
R

theophylline and placebo. Similar differences were monitored on the other variables (FVC,
PFER, FEF25-75% . Asthma attack rate and use of albuterol decreased remarkably with doxo-
fylline 400 mg t.i.d. and theophylline. There were few statistically significant differences
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PE

between doxofylline 200 mg t.i.d. and placebo. Significantly more patients had to interrupt
treatment because of adverse events under theophylline than under doxofylline 400 mg t.i.d.
(p=0.001). With doxofylline 400 mg t.i.d., the number of patients treated to spare one drop-
out due to theophylline was 5.
Conclusion: This study provides evidence that doxofylline 400 mg t.i.d. is an effective treatment for reliev-
ing airway obstruction and displays a better safety profile with respect to theophylline 250 mg
t.i.d. with a favorable risk-to-benefit ratio.

key words: bronchial asthma • methylxanthines • theophylline • doxofylline

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Tables: 4
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Figures: 3
References: 27

Author’s address: Marc F Goldstein MD, The Asthma Center, Professional Arts Building, Suite 300, 205 North Broad Street,
Philadelphia, PA 19107-1578, USA, email: Gpike35@aol.com

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single-blind. double-blind.distribution prohibited.distribution prohibited.This copy is for personal use only . doxofylline. administration. doxofylline. 400 mg t.8. they had to have a forced expiratory volume in 1 second (FEV1) that was Doxofylline [7-(1. vals during the active-treatment period and the end of the placebo run-out period. The sisted of 346 adult patients with reversible obstructive patients used the diary cards to record date and time CR298 Electronic PDF security powered by ISL-science. the efficacy of doxo- fylline with daily doses ranging from 200 mg to 1200 Treatments mg was found to be superior to that of placebo and sim- ilar to that of theophylline or aminophylline at dosages After written informed consent had been given. the patients were given a diary card.com . schedule dur- In asthmatic patients with concomitant duodenal ulcer ing all three study phases. and the PFTs were repeated 2 hours later. double-blind trial was carried out in United States in 22 study centers according to the Good At each visit.i. Treatments with oral xan- treated with intravenous xanthines. sleep architecture [20]. All PFTs in the efficacy and safety of orally administered doxofylline in study were performed in triplicate. single-blind.i. peak expira- tion similarly to theophylline but with less adverse tory flow rate (PEFR) and forced expiration flow during events. Patients theophylline). were randomly assigned to receive placebo.distribution prohibited. or 250 mg U Although it has been recognized that doxofylline shares t. The primary efficacy variable. with less extra-respiratory effects than theophylline LY L [10–12].d. placebo run-in phase.d. nor did it interfere with All patients received placebo during the run-in and run- the influx of calcium into the cells [15]. PFTs were MATERIAL AND METHODS measured before the first dose of the day was taken and py is for personal use only . theophylline.3-dioxolan-2-ylmethyl] theophylline is within 50% to 80% of the predicted FEV1 for their age a novel bronchodilator xanthine drug which differs and height. ing women were likewise excluded. the use of doxofylline as a respiratory who still had an FEV1 that was 50% to 80% of the pre- stimulant in COPD patients with nocturnal hypoxaemia dicted value were given their first dose of double-blind was not accompanied by relevant alterations in their medication. the present study was designed to evaluate the the middle half of the FVC (FEF25%-75%). hepatic or metabolic diseases. N A unlike theophylline. The Study visits absence of clinically important arrhythmogenic effects of the drug was also documented by other authors Baseline pulmonary function tests (PFTs) were per- This copy is for personal use only .distribution prohibited. At the screening visit. which was identified in the protocol. variables were forced vital capacity (FVC). The study population con.d.14].i. Bronchodilator activities of doxofylline have been renal. Dini [17] proved by 24-hour ECG hours preceding any pulmonary function test. In contrast containing beverages or chocolate was excluded for 24 to theophylline.i.19]. a significantly less thines. 2002. providing at least 8 Study population hours had elapsed between the first PFT measurement and the last use of albuterol. experimental studies have shown that it is associated 1) a 1-week. three was recorded. Patients were excluded from participation in This copy is for personal use only . out phases. Cardiovascular tolerability of the agent Patients were permitted to use inhaled albuterol in case has been addressed in a number of studies carried out of exacerbation of asthma. active-treatment phase. In were also considered non-eligible. the better safety profile of the drug [1. Patients who had als involving patients with either bronchial asthma or taken drugs known to affect theophylline clearance chronic obstructive pulmonary disease (COPD) [4–7].i. All treatments were taken orally with imme- O N diate release formulations and on a t. doxofylline did not antagonize cal- cium channel blocker receptors.d. inhaled or systemic β2-adrenergic agonists and SO pronounced stimulation of gastric secretion was inhaled corticosteroids were withheld between 72 hours observed by Lazzaroni et al [16] following doxofylline and one week before the beginning of the study.9]. This randomized.i. 8(4): CR297-304 BACKGROUND airways disease. At each visit. As shown in a recent study (different from formed at the end of the placebo run-in phase. – compared to theophylline 250 mg t. It has been suggested that decreased affinities 2) a 12-week. and toward adenosine A1 and A2 receptors may account for This copy is for personal use only . Moreover. The consumption of caffeine- in patients with chronic respiratory diseases. The secondary efficacy PFT Since doxofylline was found to relieve airway obstruc.5. the study in case of serious concomitant cardiovascular. Pregnant or lactat- demonstrated in animal studies [1–3] and in clinical tri. albuterol. The study consisted of three phases: most of the characteristics of the methylxanthine drugs. patients currently used in clinical practice [4. Holter recording that intravenous doxofylline does not R exert significant cardiac chronotropic actions. PE [8.d. and the best of the a multicentre double-blind randomized placebo-con. SE most of the comparative studies. 3) a 1-week. trolled trial in patients with chronic reversible asthma using different dosages of the drug – 400 mg and 200 Patients returned for subsequent PFTs at 14-day inter- mg t. 2 hours after dose administration. a Clinical Practice guidelines. 200 mg t. was FEV1.13.d.18.distrib Clinical Research Med Sci Monit. and showed at least a 15% increase in FEV1 from theophylline by the presence of a dioxolane group 30 minutes after inhalation of two puffs (180 µg) of in position 7. peak flow meter (PFM) and albuterol inhalers. placebo run-out phase.

1% Mean age at asthma onset (yrs) 13.5±17. Two-way analysis of variance with covariates. at any time throughout the study for relief of acute asth. from the diaries during the placebo run-in phase.i. for a possible relationship between serum levels and Removal of subject from therapy or assessment was FEV1 response using the correlation analysis approach. black were drawn immediately before all PFTs after 5. R each group based on FEV1.distribution prohibited. Characteristic Doxo 200 mg t.05 with patient's willingness to discontinue treatment.i.d. descriptive ed.. The aerosol use. The statistical analysis compared the results of the PFTs obtained at baseline (immediately prior to the Baseline efficacy variables were similar and not statisti- start of double-blind treatment) with the results cally different in the study groups (Table 2).i. Active Table 1.05 [21]. mild. RESULTS This copy is for personal use only .9 16. study patients.d. reduc.4 64. group.d.i. 2) possibly related. ine non-parametric variables. 86 to theophylline 250 mg t.9 Precipitating factors 98. Hematology. Albuterol inhalers could be used ed by total number of days on study medication) and This copy is for personal use only .8% 97. date and time of each albuterol tion at each visit during double-blind treatment.i. Theo 250 mg t.1 16. 88 were assigned to doxofylline 400 mg istry and urinalysis were performed at the screening t. Placebo N 83 88 86 89 Sex (M/F) 44/39 44/44 38/48 44/45 Mean age (yr) 33. A two-way analysis of variance was used for analysis of all SE All clinical adverse events were recorded and graded as efficacy variables. after having considered: 1) 24% in the doxofylline 200 mg t. 200 mg t.0 Mean height (cm) 171.d. A 12-lead ECG tracing was performed at number of days on study medication).0 20. Serum doxofylline levels tion of the symptoms and the action taken (none. date and time obtained 2 hours after administration of study medica- of asthmatic episodes.5% 96. and (n=19). Doxo 400 mg t. Theo: theophylline. The recordings of PFM were performed derived variable was the percent change between these two assessments.d.4 Legend: Doxo: doxofylline.d. CR299 Electronic PDF security powered by ISL-science. 2002.d. Characteristics of the study patients. from patients in the doxofylline group were analyzed U tion of the dose or discontinuation of treatment). group.9% 37. and 89 to the placebo group.8 18.0 36. N A Study groups Drugs and laboratory analyses The mean age of the study population was 35. 3) definitely related or 4) statistics and the Wilcoxon model was utilized to exam- unknown. 2) level.i.6% 42. and 2) identified the mini. Their relationships with active treatments were classified as follows: 1) not relat.distribution prohibited. A majority of the subjects The study sample was estimated to be 50 subjects in received one or more concomitant medications.7% 96.i. hispanic (n=32) and mongolian (n=6).0 171.05 and an α error of 0.com .1 78. LY L serum theophylline levels exceeding 20 µg/mL or 3) ele- vated doxofylline concentrations (>2 standard devia.i.9 78.d.7 168. The percent of women was 51%. received oral treatment with corticosteroids.0 O N years.8 83. group and 18% in the placebo group This copy is for personal use only . Mean % of predicted FEV1 66.2 19. history of asthma and precipi- tating factors (Table 1). doxofylline 400 mg t. a β error of 0.d. moderate or severe.0 Mean years since onset 19. 16% in the a standard deviation of 7%. Baseline for the the screening visit and at the end of double-blind treat. PE 95%. albuterol use rate (total number of puffs divided by total ma symptoms. 83 to doxofylline visit and after 3 and 13 weeks.i. Of note. tions of means [SD]) in the presence of any drug-related adverse event.0 36. 8(4): CR297-304 Goldstein MF et al – Efficacy and safety of doxofylline compared to theophylline… each dose of study medication was taken. blood chem.4 Mean weight (kg) 79.5 66.This copy is for personal use only .. Races of the Blood samples for drug concentration measurements study population included caucasian (n=289).distribution prohibited.distribution prohibited.2 18.0% 41. Absolute changes were calculated for CR by the patient each morning before the first dose of the the asthmatic attack rate (total number of attacks divid- medication was taken. latter two variables was defined as the value obtained ments. 9. The four treatment groups were comparable at baseline with Statistical analysis respect to demographics.6% Hospitalizations for asthma 38.8 py is for personal use only .1 169. 9% in the theophylline mal difference of clinical significance with a power of 250 mg t.distrib Med Sci Monit.. determined by: 1) persistent drug-related adverse event Differences were considered significant at the p<0. Also recorded for each event were the dura. Data are expressed as mean ± standard error of means Pulmonary function tests (SEM). Of the SO 13 weeks of active treatment. PFM measurements and date and time of adverse events.2 64.6 36.

2002.i.40 3.d.i. Placebo 0 * * * This copy is for personal use only .08 2.d.5 * (p<0.5 * xc * Similar differences were monitored on the other vari. 0 2 4 6 8 10 12 * -0. Theo 250 mg t. compared to placebo were statistically signifi- 4. -0.05 PEFR increase over placebo was statistically significant Doxo 400 mg t. Peak flow meter measurements T-bars represent SEM. There were sustained increases in the average daily peak flow meter rate in both doxofylline 400 mg t.d. PEFR (L/sec) 6. PEFR and FEF25%-75%).59±0.20 1. The percent increases in mean FEV1 dur- This copy is for personal use only .88±0.85±0.i. The change in FEF25%-75% was double-blind treatment. 10 for the doxofylline 400 mg t.21 Albuterol use (puffs/day) 3.d.d. group and at week 4 and 8 through the end of the study for Figure 2B.i.24 FEF25–75% (L/sec) 2.05) at every visit.6 * * * Doxo 400 mg t. and theophylline 250 mg t.d. 8(4): CR297-304 Table 2. Baseline efficacy variables.05) at every visit. The differences nificant at week 2 and 12 (p<0.d.i. T-bars represent SEM. The differences between dox- ofylline 400 mg t.i.i.72±0.22 5.distribution prohibited. between theophylline and placebo were statistically sig- nificant at week 2 and 6 (p<0.40±0.07 FVC (L) 3. every visit except week 6 for the theophylline group.d.4 * 5 * Doxo 200 mg t. Figure 2A. Mean decrease of number of daily albuterol puffs during the theophylline group.55±0.i.d. Placebo O N active treatment. py is for personal use only .22 5. group and at cant (p<0. except week 0 and 8 for doxofylline double-blind treatment.87±0.38 3.05 Figure 1.) group -1.05). 2.20 1.distrib Clinical Research Med Sci Monit. 400 mg t. CR300 Electronic PDF security powered by ISL-science. treatments resulted in improvements in primary and secondary PFT variables that were sustained through- out the period of active treatment. and placebo were significant (p<0.distribution prohibited.i.01±0. while statistical significance with theophylline was not accomplished at week 0.11 1.This copy is for personal use only .29±0.d. and theophylline groups. Mean FVC increase * * * * over placebo was significant at every visit except week 0 * * * * and 4 for the doxofylline (400 mg t.05).d.i. The differences from doxofylline significantly different from placebo (p<0. *: p <0./day) 1. Mean percent increase in FEV1 two hours after the adminis.49±0. T- bars represent SEM.12 3.05). while the differences between theophylline and placebo were significant (p<0.(N=88) Theo 250 mg t. and placebo and between theophylline and place- bo for FEV1.59±0.i.93±0.11 This copy is for personal use only . Mean decrease of number of daily asthma attacks during (p<0. Placebo at week 10 and 12 in the doxofylline 400 mg t. 6 and 10.05 -0. tration of active treatments or placebo during the 12-week of Doxo 400 mg t.34 3.8 * Weeks of active treatment N A *: p <0. SE * 20 * * Weeks of active treatment * * 2 4 6 8 10 12 * * * 0 * Percent increase in FEV1 15 * * * Change in asthmatic attack rate U -0.07 2.(N=86) Placebo(N=89) FEV1 (L) 2.d.i. 8.i.d.18 1. Theo: theophylline.11 3. LY L * p <0.48 Doxo: doxofylline. Differences from placebo were significant for doxofylline 400 mg t. PE Albuterol use rate (puffs/day) ing double-blind therapy are displayed in Figure 1. The differences between doxofylline SO 400 mg t.i.06 2.d. Variable Doxo 200 mg t.i. Mean -2 Doxo 200 mg t.d.(N=83) Doxo 400 mg t.d.d.40±0. Theo 250 mg t.20 5.i. There were statisti- R Weeks of active treatment cally significant differences between doxofylline 400 mg 2 4 6 8 10 12 0 t. Theo 250 mg t.d.com .41±0.d.11 1. 400 mg t.05) at every evaluation during active treatment.05) at week 2 through 8.10 3.92±0.d.94±0.73±0.i.77±0.distribution prohibited.12 1. the differences from placebo were statistically significant at every visit except week 10.i.05) at week 2.i.28±0.i.d.i.07±0. For the theophylline group.distribution prohibited. * -1 ables (FVC. and placebo were statistically sig.31±0.36±0.d.i.37±0.d.09 Asthma attacks (no. -1 Doxo 200 mg t.2 (number of attack/day) 10 * -0.i.84±0.

d. 8 because of 10 adverse events plus a theophylline level above 20 µg/mL SO and 4 patients were withdrawn solely because their theo. also occurred more often with theo- fylline 200 mg. CR study.d. statistical significance over placebo (p<0.This copy is for personal use only . doxofylline 200 mg t.distribution prohibited.d.05) at towards a more frequent occurrence of nausea in the every visit with doxofylline 400 mg t.d. patients (Table 3). (49%) or placebo (44%). that were withdrawn from the study because of adverse events in the doxofylline 400 mg t. t. Of the 9 patients 250 mg t. were particularly effective in reducing the treat to spare one treatment interruption was 5. SE by statistically significant decreases in the use of The most common adverse event was headache.4% in the doxofylline 400 mg t. The number needed to 250 mg t. There was only one signifi- cant difference (week 2) between doxofylline 200 mg Adverse events were reported in 180 of the study t. group. PE Event Doxo 200 mg t. 50 Drop-Out patient percent from baseline LY L Safety This copy is for personal use only .d.i. which albuterol to relieve asthmatic symptoms in patients took place in about the same proportion of patients in receiving active treatments (Fig. 2002. 2B). Both doxofylline 400 mg t.4% in the theophylline 30 group. (N=86) Placebo (N=89) Headache 2 3 4 2 Nausea 1 3 1 Nervousness 1 3 1 Insomnia 1 1 2 Asthma 1 1 Anxiety 1 1 Dizziness 1 1 Palpitations 1 1 Dyspepsia 1 Chest pain 1 1 Thinking abnormal 1 1 Tremor 1 1 Overdose 1 Abdominal pain 1 py is for personal use only .d.d. nervousness. In the theophylline group. 15 were withdrawn because of adverse events. Statistical significant differences interrupted treatment due to adverse events (or to drug con- were reached either with theophylline and doxofylline centrations above the upper limit of normality) in the study groups.i. and theophylline fylline 400 mg t. theophylline group (33%) than with doxofylline 400 mg phylline group. 2A). More interestingly. They occurred more frequently with theophylline (63%) than with doxofylline 400 mg t. With doxo. Table 3. The decreases in asthma attack rate were accompanied (52%).distribution prohibited.i. CR301 Electronic PDF security powered by ISL-science. The differences all treatment groups (27–29%).d.6% in the doxofylline 200 mg t. 200 mg t.i.4% in 20 O N the placebo group (Fig. theophylline and placebo or doxofylline 400 mg groups. This copy is for personal use only . Dyspepsia.i. and placebo. 3. (N=83) Doxo 400 mg t.i.d.i.distrib Med Sci Monit. 3 had drug Figure 3. Proportion (±95% confidence interval) of subjects who serum levels >2 SD.05) was obtained only at week 2.d.i.com . 0 theophylline doxofylline doxofylline placebo phylline levels were above 20 µg/mL.i.distribution prohibited. 8(4): CR297-304 Goldstein MF et al – Efficacy and safety of doxofylline compared to theophylline… Asthmatic attacks and beta-2 agonist consumption and placebo. Number of subjects in each group with drug-relateda adverse events.d.i.distribution prohibited.i.i. asthma attack rate (Fig. (p =0.i. group and 3.d. (16%) or placebo (19%). There was a trend from placebo were statistically significant (p<0. the differences from placebo were statis.d. (N=88) Theo 250 mg t.d.i.d. group. Vasodilatation Gastritis No drug effect 1 Dyspnea 1 Lung function decreased 1 An adverse event was considered drug related if the investigator rated the relation to study medication as "possible".i.d. 40 Forty-three patients dropped-out because of occurrence N A of criteria for interruption: 31. 3). R This copy is for personal use only . 400 mg t. For the theo.d. insomnia and U tically significant at every visit but week 10. significantly more patients had to interrupt the treatment because of There was a decrease in the average asthma attack rate in all treatment groups at every evaluation during the adverse events (or drug concentrations above the upper limit of normality) under theophylline than under doxo.01). "definite" or "unknown".i.i. 11.

2 other.d.d.i. was effective in relieving airway obstruction of patients N 55 23 31 with chronic reversible asthma. (+17.8±5.6 11 (p<0.8 11.i. were 12. 9 and 13 weeks. Both treated with theophylline. the percentage of adverse events in the Elevations in serum theophylline levels exceeding the doxofylline 400 mg t.1% with theophylline.2±3. 8(4): CR297-304 Table 4. In patients receiving theophylline 250 mg similar to that of previous comparative studies of xan- t.2 dose.9%) with previous studies [22. Specifically.i.i. At of patients were withdrawn because of adverse events.7 brought about improvements in FEV1 after the first Serum level (µg/mL) 10. N 68 66 60 monary function parameters as compared to baseline Change in FEV1 (%) 11.8 16. 11. Percent increase in FEV1 and serum doxofylline levels during piratory diseases [4–7.i. Indeed. doxofylline 400 mg t. period (+13%). fylline in the management of patients with chronic res- CR302 Electronic PDF security powered by ISL-science.8% with doxofylline and N 69 59 53 +16. the percent changes in FEV1 at after Doxo 400 mg t.. group.i.6 19. Melillo et al [22] examined double-blind therapy. ved on FEV1 with doxofylline 400 mg t. gastro-intestinal adverse and theophylline 250 mg t. doxofylline was associated with marked increases U in the bronchodilator response after the first week of treatment (Figure 1). ly decreased during doxofylline treatment. or theophylline 300 mg slow-release b. Particu.d.i.2±2.d.8 11.2 17. the clinical effects of doxofylline in 139 patients with asthma treated in a double-blind randomized fashion week 5 week 9 week 13 with either doxofylline 400 mg b.7±3. their frequency was mg t. group exceeded slightly that of upper limit of normality were observed in 12 patients.d. 28-day treatment was +13.i.5±3. they were 4. elicited improvement in FEV1 after 12-week treatment phylline (7%) than with doxofylline 400 mg (5%).5 µg/mL.i.This copy is for personal use only .7 13. On vital frequencies of asthma exacerbation episodes and β2-ago- N A signs.d.26].9 µg/mL after 5.9 µg/mL and 3. of doxofylline. PE 10. whereas it remained unchanged or slight. respectively. doxo. the placebo. Since LY L subjective benefits do not always correlated closely to There were no clinical significant effects on laboratory PFT changes.d.d.2 3. doxofylline was better tolerated the tolerability of doxofylline in the management of than theophylline.0 µg/mL. but were not statistically different from each Serum level (µg/mL) 4.d.i.distribution prohibited. and theophylline 250 mg t. with theophylline than with doxofylline. spared by doxofylline 400 mg t. The variability of the bronchodilatory fylline 200 mg (1%) or placebo (none).7±4. (+14.22].i. significantly improved spirometric variables.d. the mean serum concentration of drug were thine medications in asthmatic patients [24.distribution prohibited.2 17.05). This copy is for personal use only .distribution prohibited.i.1 12. Doxofylline 400 mg was particu- phylline compared with either the doxofylline groups or larly efficacious in decreasing the asthma attack rate placebo. heart rate increased in average by 2–5 bpm with nist consumption appears to be particularly advanta- theophylline. Headache was the most commonly reported adverse larly.25].d. doxofylline. event in the overall study population. 2002.8±4. Furthermore.d. low dose doxofylline O N and tachycardia occurred more frequently with theo. phylline treatments significantly improved all pul- This copy is for personal use only .7 12. Inclusion of the 400 mg t.3 µg/mL and 11.i.i. oral treatment with doxofylline Theo 250 mg t. and/or the need for rescue albuterol inhalation. there was one adverse event patients with chronic reversible asthma in a double.i.d.i. Although the number of adverse events in the study R 3. While palpitations or tachycardia occurred similarly in both doxofylline and theophylline treatment Our results are consistent with those of previous studies groups. SE Change in FEV1 (%) 16. 13. 9 and 13 and the corresponding serum levels of xan. test results. ECG or physical examination. these events led to discontinuation more often that assessed the effects of orally administered doxo. the end of the same periods.distribution prohibited.d.5 In the present study.com . the ability of doxofylline to reduce the This copy is for personal use only .8 µg/mL for doxofylline 200 population was rather elevated.3 µg/mL.1 µg/mL and patients in the theophylline group and a higher number 12. significant improvement over placebo was obser. Both doxofylline and theo- Doxo 200 mg t. The results showed that.2 Serum level (µg/mL) 12. while their frequency in the doxofylline The comparative values of the changes in FEV1 at visits 200 mg group was comparable with that of the placebo 5. in our study was done specifically to allow us to com- pare the tolerability of the highest recommended dose DISCUSSION to that of the standard recommended dose of 400 mg b. responsiveness may partly account for the absence of SO statistically significance in the group given doxofylline Drug concentration measurements 200 mg t. even at The results of the study demonstrated the efficacy and this maximum dosage. Whereas theophylline Change in FEV1 (%) 16.i. dose of doxofylline thines are displayed in Table 4.7±4.4%) at the end of events were more common with theophylline than with the 12-week active treatment period.d. In accordance py is for personal use only .d.7 3. The mean serum concentrations of doxofylline 400 mg Adverse events occurred in a greater proportion of t.9 µg/mL.2±5. for every 5 patients blind randomized placebo-controlled clinical trial.d. Palpitations Even if not statistically significant.distrib Clinical Research Med Sci Monit. geous in patients with bronchial airway obstruction [23].

Doxofylline has 11. 14.i. Orange. Pozzar F. Res exhibited two characteristics that may expand its useful. CA. Philadelphia. 1990. FL. 18: 131-138 promising alternative to theophylline therapy in the 16. 14: 479-489 serum doxofylline levels and the occurrence of adverse 2. 7. 1993. Barone D: Doxofylline and theophylline are This copy is for personal use only . Dini FL: Alterazioni del ritmo cardiaco in pazien- List of principal study investigators: MA Anderson. REFERENCES CR fylline 200 mg t. 65: 21-34 ness in the clinical setting. 1997. Ther. Finally. Com Chem Path Pharmacol. North Dartmouth. or doxofylline 400 mg t. Arerugi. RJ Dockhorn. 1988. A single findings in obstructive pneumopathy following 2(7. Aliment Pharmacol Therap. Grossi E. LE Mansfield. However. AZ. 96: 772-778 LY L phylline levels had been drawn with dose adjustment. Eur J Pharmacol. Los Angeles.. Tinton Falls. 1989. Drug Explt Clin Res. Short-term effects in mechanically ventilated have led to less toxicity and fewer withdrawals from the patients with airflow obstruction and respiratory failure. Grasso S. our intent was N A to compare a single dosing schedule of theophylline 8. Salt Lake City. symptom relief and methylxanthines in its movement of cytosolic calcium. Vero Beavh. Monaldi Arch Chest Dis. Naunyn and associated with a reduction in the prevalence of Schmiedebergs Arch Pharmacol. evaluated Appendix by Holter monitoring. Minerva Cardioangiol.distribution prohibited. PE Pharmacodyn. Cogo R: Doxofylline. 8(4): CR297-304 Goldstein MF et al – Efficacy and safety of doxofylline compared to theophylline… It is well known that the concentration of theophylline CA. E Bronsky. 1980. Franzone JS: Doxofylline. does not induce cardiostimulants effects. Chest. D Auerbach. TX. 281: 1336-1338 CA Maccia. Poggi R. PA. 40: 31-39 Jacksonville. B ic airways obstruction with doxofylline compared with slow-release Prenner. FL. Ronchi E et al: Oral doxophylline in patients this might have led to less theophylline toxicity and a with chronic obstructive pulmonary disease. it seems to offer a React. doxofylline and theophylline. in the blood is directly related to bronchodilator NE. 20. 10.d. Cirillo R. With either doxo. 1989.distribution prohibited. J Pinnas. RG Townley. Jodice F et al: Treatment of reversible chron- FJ Picone. is in relation to locomotor activity. Lazzaroni M. in the treat. 356: 48-55 asthma attacks. Dini FL. NY. Philadelphia. 440 ment of chronic reversible asthma. an antiasthmatic profile that suggests that this drug might be of particu. No evidence of an association between xanthines with partly different mechanisms of action in animals. P Eptstein. Arch Int This copy is for personal use only . Balzano G. SP Galant. Magni M. San Diego. ti con broncopneumopatia cronica ostruttiva. 1997. P devoid of major cardiovascular adverse effects. W Sinclair. Cirillo R. Grossi E et al: The effects of doxofylline ver- py is for personal use only . it has a favorable tolerability 13. Banchi Porro G: The effect of intravenous doxofylline or aminophylline on gastric secrection in duodenal chronic management of patients with chronic reversible ulcer patients. Drug Metab Dispos. Opin. Adjusting doses may 6. 1988. Patients with levels greater venously administered doxofylline and placebo for the treatment of U than or equal to 20 mcg/ml with or without symptoms severe airways obstruction. Curr Med Res & Chervinsky. 9: 397-405 CR303 Electronic PDF security powered by ISL-science. 1995. Franzone JS. TX. Cherry Hill. Omaha. -theophyllin- methyl)1. J Hallett. Reboani MC. PA. Barone D.d. 1994. 1982. Altman DG: Statistics and ethics in medical research. 1989. the data from this double-blind placebo. Cirillo R. Bucca C. 22. Cortellini G et al: Methylxanthine drug therapy CONCLUSIONS in chronic heart failure associated with hypoxaemia: double-blind placebo controlled clinical trial of doxofylline versus theophylline and bamifylline. an adenosine non- blocking xanthine. Villani F. ma: time for reappraisal? Eur Respir J. III. MA. 7: 579-591 phylline. Checchini M. multicentre trial. Idaira K et al: Effects of theophylline and doxo- SE fylline on airway responsiveness in beagles. theophylline: a double-blind. 15. Int J Clin Pharm Res. El Paso. Dallas. 165: 269-277 test results. T Edwards/J Grossman. 46: 7-15 There are several limitations to this study especially as 4. response. neither doxofylline nor theo.distribution prohibited. Cravanzola C. theophylline treatment group. If more frequent theo. KS.i. 35: 107-111 smaller number of dropouts. 50: 98-103 CA.distrib Med Sci Monit. – therefore precluding dose adjustments. drug lacking affinity for adenosine receptors. Imai T. 1997. Cirillo R. Cipri A. TX. Grossi E. Franzone JS. Sacco C. Dolcetti A. 17. NJ. 16: 264-269 were dropped from the study. 4: dosing schedule of theophylline was used without 101-103 attempts made at dose adjustment based on theo. study (Table 4). De Sarro A. 295: 221-237 lar benefit in selected groups of asthmatic patients. Braghiroli A. Rolla G. Second. 45: 185-190 O N 9. 2001. 16: 258-268 Prairie Village.com . GN Gross. Dini FL: Chronotropic and arrhythmogenic effects of two methylx- anthine bronchodilators. 1991. Melillo G. GS Rachelefsky. Cranford. 1989. Int J Tiss potentially less adverse events. R Grubbe. Austin. Osella D. Dini FL. Int J Clin Pharm Res. Palm Bay.distribution prohibited. UT. Biffignandi P: Doxofylline exerts a prophy- events was noted. J Int Med Res. Scaglione M et al: Studio clinico controllato doxofillina versus aminofillina nel trattamento delle sindromi da with two different single dosing schedules of doxofylline insufficienza acuta cardiorespiratoria. 17: 437- as effective as theophylline 250 mg t. Franzone JS: Doxofylline. 1997. GW 19. Int J Clin Pharm Res. Cirillo R. randomized. Stockton CA. Bernasconi M et al: Doxofylline and respi- ratory mechanics. 13: 305-316 SO In conclusion. 2002. Reboani MC: Doxofylline differs from able bronchodilatory response. De Filippis G et al: Comparison of intra- phylline level and/or toxicity. it produces improve- 12.This copy is for personal use only . M Goldstein. 3. 1992. First. 21. Albany. 5. 3-dioxolane (doxofylline). NJ. Sugeta A. sus theophylline on sleep architecture in COPD patients. Fonzo D et al: Acute clinical-pharmacological concerns the theophylline treatment group.d. 1991. Pasini G. a new xanthine bronchodilator Bensch. 4: 643-649 asthma. 1988. NJ. FL. 49: 978-984 18. De Maria P.i. Since doxofylline was associated with remark. Curr Ther Res. lactic effects against bronchocostriction and pleurisy induced by phylline had any apparent effect on other laboratory PAF. How large a sample? Br Med J. Pauwels RA: Theophylline in the management of asth- especially those with gastrointestinal intolerance to theo. serum doxofylline levels were found stable throughout the 1.i. Tucson. Brandolese R. Zappala M et al: Convulsant effects of some ments in airflow obstruction similarly to theophylline R xanthine derivatives in genetically epilepsy-prone rats. Grosa G et al: Doxofylline in rat brain controlled study showed that doxofylline 400 mg t. 1989.d. Int J Clin Pharmacol This copy is for personal use only . Minerva Cardioangiol. Barnes PJ. Franzone JS. but may easily produce toxic levels in both asthmatic and COPD patients [27].

Biffignandi P. Chapman KR. Enpofylline and theophylline compared. Passato. 1989. Ljungholm K. Clin Pharmacokinetic. In: Postma DS. 1994. Rees PJ: Bronchodilators in the therapy of chronic obstructive pul. CR304 Electronic PDF security powered by ISL-science. Chest. Siafakas NM (eds). PE py is for personal use only . chronic obstructive pulmonary disease.distribution prohibited. Dini FL: Metilxantine e sistema cuore-polmoni. 1998.G. 8(4): CR297-304 23. Grossi E. N A O N SO R This copy is for personal use only . 7: 135-149 27. Kallen A: Long-term xanthine thera- This copy is for personal use only .distribution prohibited.This copy is for personal use only . presente e phylline: rationale and current status. Edizioni Medico-Scientifiche. 1993: pp 23-30 17: 377-384 25. 10: 1-16 Monograph. Franzone JS: La doxofilina: profilo del far- monary disease.distribution prohibited. International Enprofylline Study Group.distribution prohibited. 2002. futuro. Bierman CW. The European Respiratory 1988. 106: 1407- 1413 SE U LY L This copy is for personal use only . Eur Rev Med & Pharmacol Sci. Management of maco e rassegna degli studi clinici.distrib Clinical Research Med Sci Monit. py of asthma. 26. Torino.com . C. Williams PV: Therapeutic monitoring of theo- 24.

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