technicla paper of Doxofylline

Doxofylline:
A New Generation Xanthine Bronchodilator Devoid of Major Cardiovascular Adverse Effects

From Current Medical Research and Opinion
Frank Lloyd Dini, Unità Operativa di Cardiologia, Ospedale Villamarina, Piombino, Italy; and Roberto Cogo, Unità di Pneumologia Riabilitazione Respiratoria, Ospedale Zappatoni, Cassano d'Adda, Italy.
Doxofylline (7-(1,3-dioxalan-2-ylmethyl) theophylline) is a novel xanthine bronchodilator which differs from theophylline in that it contains a dioxalane group in position 7. Similarly to theophylline, its mechanism of action is related to the inhibition of phosphodiesterase activities, but in contrast it appears to have decreased affinities towards adenosine A1 and A2 receptors, which may account for its better safety profile. The bronchodilating activities of doxofylline have been demonstrated in clinical trials involving patients with either bronchial asthma or chronic obstructive pulmonary disease. In contrast to other bronchodilators, experimental and clinical studies have shown that the drug is devoid of direct stimulatory effects. This may be of importance because the arrhythmogenic actions of bronchodilators may have a negative impact on the survival of patients with respiratory diseases.

Methylxanthines are a group of structurally related compounds that are widely used in the treatment of patients with asthma, chronic obstructive pulmonary disease (COPD) and chronic cor pulmonale. Their effect is a generalised reduction of airway obstruction that decreases the overall resistance of the airways, improves blood gas exchange and reduces the dyspnoea. It has been recognised that these drugs may provide benefits above and beyond the usual bronchodilation. Unfortunately, therapy with xanthines is generally associated with a number of adverse events, affecting the cardiovascular system, the central nervous system and the gastrointestinal system. Serious ventricular arrhythmias, arrhythmia aggravation and cardiac arrest are of major concern in patients treated with methylxanthines intravenously.









Doxofylline

Current Medical Research and Opinion
Effect of Doxofylline on Cardiac Rhythm in Man
The effect of doxofylline on cardiac rhythm has been investigated in a number of studies.[44-48] In a series of 10 patients with COPD, no significant changes were noted in heart rate, compared with baseline values, during or after the infusion of doxofylline (400 mg i.v.) or placebo as assessed by 24-hour Holter monitoring. In contrast, mean heart rate rose significantly during and after the infusion period in those patients treated with i.v. aminophylline (240 mg i.v.). In a double-blind randomised cross-over study, 14 patients with COPD and a high incidence of ventricular (VPB) and supraventricular premature beats (SVPB), were submitted to i.v. administration of either doxofylline (200 mg in 60 min, bid) or aminophylline (240 mg in 60 min, bid). The results of the trial displayed a significant reduction in the occurrence of VPB/24 h during doxofylline administration, whereas no changes from baseline in the incidence of premature beats were observed during aminophylline (Figure 3).[ In another cross-over study performed in 10 patients with acute respiratory failure, heart rate increased more with theophylline (240 mg i.v.) than with doxofylline (600 mg i.v.), while the number of VPBs and SVPBs was significantly increased only with theophylline.















Doxofylline and respiratory mechanics. Short-term effects in mechanically ventilated patients with airflow obstruction and respiratory failure


R Poggi, R Brandolese, M Bernasconi, E Manzin and A Rossi Department of Anesthesia and Intensive Care, City Hospital, Padua, Italy.

To assess the short-term effects of a methylxanthine (doxofylline) on respiratory mechanics in mechanically ventilated patients with airway obstruction and respiratory failure, nine consecutive patients were examined within three days from the onset of mechanical ventilation. Flow, changes in pulmonary volume, and Paw were measured using a ventilator (Servo 900C). End-expiratory and end-inspiratory airway occlusion was performed to measure PEEPi, Cstrs, Rrsmax, and Rrsmin. Measurements were performed before and at 5, 15, and 30 minutes after an intravenous loading dose of doxofylline (5 to 6 mg/kg). We found that doxofylline determined, on the average, a marked decrease in respiratory resistance (Rrsmax and Rrsmin, -27.2 percent and -36.5 percent, respectively) without significant changes in Cstrs and Pmax. The PEEPi, reflecting pulmonary dynamic hyperinflation, was also significantly decreased by doxofylline (-41 percent, on the average). The Pmax was not reliable for evaluation of a single patient, since changes in the elastic pressure can offset changes in the resistive one. No patient experienced significant side effects due to doxofylline. We conclude that (1) the effects of therapy can be assessed noninvasively at bedside in critically ill patients; (2) doxofylline is a rapid and efficient bronchodilator in mechanically ventilated patients with ARF and airflow obstruction; and the decrease in the respiratory resistance and PEEPi, associated with an improved mechanical efficiency of the respiratory muscles at a lower pulmonary volume, can provide better conditions for the patient- ventilator interaction and for weaning.










Efficacy and safety of doxofylline compared to theophylline in chronic reversible asthma -- a double-blind randomized placebo-controlled multicentre clinical trial.
Goldstein MF, Chervinsky P.

Med Sci Monit. 2002 Aug;8(8):LE27-8
The Asthma Center, Philadelphia, PA 19107-1578, USA.
Experimental studies have shown that doxofylline is endowed with a remarkable bronchodilator 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 chronic reversible bronchial asthma. MATERIAL/METHODS: Three hundred forty-six patients were randomly assigned to a 12-week oral treatment with 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 statistically significant differences between doxofylline 400 mg t.i.d. and placebo and between theophylline and placebo. Similar differences were monitored on the other variables (FVC, PFER, FEF(25-75%). Asthma attack rate and use of albuterol decreased remarkably with doxofylline 400 mg t.i.d. and theophylline. There were few statistically significant differences 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. CONCLUSIONS: This study provides evidence that doxofylline 400 mg t.i.d. is an effective treatment for relieving airway obstruction and displays a better safety profile with respect to theophylline 250 mg t.i.d. with a favorable risk-to-benefit ratio.






Doxofylline:

A New Generation Xanthine Bronchodilator Devoid of Major Cardiovascular Adverse Effects

Source: Current Medical Research and Opinion, Volume 16, Number 4, 22 February 2001, pp. 258-268(11)

Doxofylline

It is a (7-(1,3-dioxalan-2-ylmethyl) theophylline) is a novel xanthine bronchodilator which differs from theophylline in that it contains a dioxalane group in position 7. Similarly to theophylline, its mechanism of action is related to the inhibition of phosphodiesterase activities, but in contrast it appears to have decreased affinities towards adenosine A1 and A2 receptors, which may account for its better safety profile. The bronchodilating activities of doxofylline have been demonstrated in clinical trials involving patients with either bronchial asthma or chronic obstructive pulmonary disease. In contrast to other bronchodilators, experimental and clinical studies have shown that the drug is devoid of direct stimulatory effects. This may be of importance because the arrhythmogenic actions of bronchodilators may have a negative impact on the survival of patients with respiratory diseases.








Effect of doxofylline on calcium-activated potassium channels in human peripher
B Zhou, SX Cai, F Zou, CQ Cai, HJ Zhao
To study the effects of doxofylline on calcium-activated potassium (K(Ca)) channels of human peripheral blood eosinophils in asthma. METHODS: Peripheral blood eosinophils from patients with asthma were isolated and divided equally into two groups, a control group and a doxofylline incubated group. The data were recorded using cell-attached configuration of patch-clamp technique and the kinetic changes of K (Ca) channels activated by 0.2 micromol/L platelet activating factor (PAF) were compared. RESULTS: As compared with the control group, the open probability of the K(Ca) channels decreased from 0.135 +/- 0.021 to 0.044 +/- 0.018, the open time from (5.75 +/- 0.40) ms to (2.39 +/- 0.13) ms, while the close time increased from (2.17 +/- 0.50) ms to (23.73 +/- 2.50) ms in the doxofylline incubated group. The differences were significant between the two groups (all P < 0.05). CONCLUSION: Doxofylline could decrease the open probability of the channels as a result of both the shortening of open period and the prolongation of close time.






DOXOFYLLINE

R. Cogo, A. Castronuovo Unità Operativa di Pneumologia Riabilitativa,
Ospedale Zappatoni,
Cassano d’Adda
Milano
(Italy)
The effects of oral doxofylline (400 mg BID) on bronchial airway mucosa were investigated in 14 patients with chronic obstructive bronchitis. The eligible patients had to have forced expiratory volume in 1 second > 60% of the predicted value and oxygen partial tension > 55 mm Hg. At the onset and the end of the study, bronchial biopsies were performed via a flexible fiberoptic bronchoscope. Chronic inflammation of the airways was graded according to absence of lesions = 0, involvement of 1-10% = 1, 10-50% = 2 and > 50% = 3. After three months of treatment, 57% of patients in the doxofylline group presented absence of lesions, while the remaining 43% exhibited advanced lesions. In the control group, absence of lesions was observed in 14%, while lesions of grade 1, 2 and 3 were visible in 14%, 29% and 43%, respectively. At histological examination, a significant difference in the degree of structural changes was observed in the doxofylline group between baseline and the end of the study (p < 0.03). In conclusion, doxofylline may induce favorable effects on inflammatory changes and altered cell proliferation of the airway mucosa in patients with chronic obstructive bronchitis.







Doxofylline:

The next generation methylxanthine
Indian J Pediatr. 2008 Mar; 75(3):251-4.

Sankar Jhuma, Lodha Rakesh, Kabra SK Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India

Methylxanthines are widely used in the treatment of asthma. Being one of the few drugs that can be administered orally, they are especially helpful in resource restricted settings. Theophylline, the commonly used methylxanthine drug is associated with a wide range of adverse effects accounting for the poor compliance and high drop-out rates. Moreover, a narrow therapeutic index warrants routine monitoring of its levels in the blood. Doxofylline, a new methylxanthine derivative, is shown to have similar efficacy with significantly less side effects in both animal studies as well as human adults. However, there is a paucity of studies in children with asthma. Retrospective data suggest that 11% patients experienced some side effects, but only 5% reported moderate side effects. Available evidence suggests that it improves spirometric parameters in children with asthma as compared to placebo. Extrapolating data from adult patients, it may be used in place of theophylline as an add on therapy in step 3 and step 4 in children with asthma. Dosage recommended for children >6 yrs of age is 6 mg/Kg/dose BID. Doxofylline produces stable serum concentrations; hence plasma monitoring is required only in patients with hepatic insufficiency and intolerance to xanthine drugs.





The effects of Doxofylline versus Theophylline on sleep architecture in COPD patients.

SACCO C, BRAGHIROLI A, GROSSI E, DONNER CF.
Monaldi Arch Chest Dis 1995; 50(2):98-103. Division of Pulmonary Disease, Clinica del Lavoro Foundation, Medical Center of Rehabilitation, Veruno (NO), Italy


Theophylline is known to alter sleep architecture because of its affinity to adenosine receptors. One of the consequences of disrupted sleep is impaired cognitive performance. A single-blind, randomized cross-over study of eight male chronic obstructive pulmonary disease (COPD) patients was undertaken to evaluate the effects of theophylline versus doxofylline on sleep architecture. The patients, who were all ex-smokers, had been treated with theophylline. Mean age was 53 +/- 12 yrs, forced expiratory volume in one second (FEV1) 50 +/- 22% predicted and forced vital capacity (FVC) 70 +/- 18% predicted. Following a wash-out period, four patients were given oral slow-release theophylline (T) (300 mg b.i.d.) for one week, followed by a cross-over to doxofylline (D) (400 mg t.i.d.) for a second week. The other four patients were given the drugs in the reverse order. All patients underwent polysomnography at baseline and at the end of each week of treatment. The number of arousals per hour was 5.5 +/- 2.9 at baseline, 9.4 +/- 5.2 during T treatment and 5.4 +/- 4.4 during D treatment. During T treatment, sleep efficiency was 60 +/- 19% vs 75 +/- 13% recorded at baseline trial and 68 +/- 25 recorded during D treatment. Sleep quality, during T treatment, was poorer than at baseline, with a greater increase in the percentage of wakefulness and more stage 2 sleep than at baseline. Slow wave sleep was reduced with both treatments, particularly D. Neither drug affected the arterial oxygen saturation (Sao2) or respiratory.





Development and validation of a sensitive LC-MS/MS method with electrospray ionization for quantitation of doxofylline in human serum: application to a clinical pharmacokinetic study.
Sreenivas N, Narasu ML, Shankar BP, Mullangi R.
Biomed Chromatogr. 2008 Feb 6
Centre for Biotechnology, IPGSR, JNTU, Kukatpally, Hyderabad‐500 072, India.
A highly sensitive and specific LC-MS/MS method has been developed and validated for the estimation of doxofylline (DFL) with 300 microL human serum using imipramine as the internal standard (IS). The API-3000 LC-MS/MS was operated under multiple reaction-monitoring mode using the electrospray ionization technique. The assay procedure involved direct precipitation of DFL and IS from human serum with acetonitrile. The resolution of peaks was achieved with formic acid (pH 2.5):acetonitrile (10:90, v/v) on an Amazon C(18) column. The total chromatographic run time was 3.0 min and the elution of DFL and IS occurred at approximately 1.46 and 2.15 min, respectively. The MS/MS ion transitions monitored were 267.5 --> 181.1 for DFL and 281.1 --> 86.2 for IS. The method was proved to be accurate and precise at linearity range of 1.00-5000 ng/mL with a correlation coefficient (r) of >/=0.999. The method was rugged with 1.00 ng/mL as lower limit of quantitation. The intra- and inter-day precision and accuracy values were found to be within the assay variability limits as per the FDA guidelines. The developed assay method was applied to a pharmacokinetic study in human volunteers following oral administration of DFL tablet.









Effect of doxofylline on calcium-activated potassium channels in human peripheral blood eosinophils in asthma

Zhou B, Cai SX, Zou F, Cai CQ, Zhao HJ.
Department of Respiratory Medicine, Nanfang Hospital, Nanfang Medical University, Guangzhou 510515, China.
Zhonghua Jie He He Hu Xi Za Zhi. 2005 Dec;28(12):817-9.


To study the effects of doxofylline on calcium-activated potassium (K(Ca)) channels of human peripheral blood eosinophils in asthma. METHODS: Peripheral blood eosinophils from patients with asthma were isolated and divided equally into two groups, a control group and a doxofylline incubated group. The data were recorded using cell-attached configuration of patch-clamp technique and the kinetic changes of K(Ca) channels activated by 0.2 micromol/L platelet activating factor (PAF) were compared. RESULTS: As compared with the control group, the open probability of the K(Ca) channels decreased from 0.135 +/- 0.021 to 0.044 +/- 0.018, the open time from (5.75 +/- 0.40) ms to (2.39 +/- 0.13) ms, while the close time increased from (2.17 +/- 0.50) ms to (23.73 +/- 2.50) ms in the doxofylline incubated group. The differences were significant between the two groups (all P < 0.05). CONCLUSION: Doxofylline could decrease the open probability of the channels as a result of both the shortening of open period and the prolongation of close time.











Cochrane Database Syst Rev. 2003;(2):CD002168.
Methyl-xanthines for exacerbations of chronic obstructive pulmonary disease.
Barr RG, Rowe BH, Camargo CA Jr.
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, 181 Longwood Ave, Boston, MA 02115, USA. gbarr@partners.org
International guidelines currently recommend the use of methyl-xanthines for exacerbations of chronic obstructive pulmonary disease (COPD) for patients who have incomplete responses to bronchodilators. However, available clinical trials are small and underpowered to evaluate the benefits and risks of methyl-xanthines in this acute setting. OBJECTIVES: To determine the benefit of methyl-xanthines compared to standard care for COPD exacerbations. SEARCH STRATEGY: Randomised controlled trials (RCTs) were identified from the Cochrane Airways Review Group COPD Register which is a compilation of systematic searches of CINAHL, EMBASE, MEDLINE and CENTRAL and hand searching of 20 respiratory journals. In addition, primary authors and content experts were contacted to identify eligible studies. Bibliographies from included studies, known reviews and texts were also searched. SELECTION CRITERIA: Only RCTs were eligible for inclusion. Studies were included if patients presented with acute COPD exacerbations and were treated with either methyl-xanthines (oral or intravenous) or placebo (with or without standard care) early in the acute treatment. Studies also needed to report either pulmonary function or admission results. Two reviewers independently selected potentially relevant articles and selected articles for inclusion. Methodological quality was independently assessed by two reviewers. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers if the authors were unable to verify the validity of information. Missing data were obtained from authors or calculated from other data presented in the paper. The data were analysed using the Cochrane Review Manager 4.0.4 Studies were pooled to yield weighted mean differences (WMD) or odds ratios (OR) and reported using 95% confidence intervals (95%CI). MAIN RESULTS: From 28 identified references, 4 RCTs met inclusion criteria (172 patients). Mean change in forced expiratory volume in one second (FEV1) at 2 hours was similar in methyl-xanthine and placebo groups (FEV1 WMD: -8 ml; 95% CI: -85 to 69 ml). The only study to report hospitalization rates showed a non-significant reduction with methyl-xanthines (OR: 0.3; 95% CI: 0.1 to 1.8) among 39 patients. Patients receiving methyl-xanthines had similar improvements in symptom scores, but reported more gastrointestinal side effects (OR: 5.3; 95% CI: 1.3 to 21.0) than patients receiving placebo. REVIEWER'S CONCLUSIONS: There is no evidence to support the routine use of methyl-xanthines for COPD exacerbations. Methyl-xanthines do not appreciably improve FEV1 during COPD exacerbations and cause adverse effects; evidence of their effect on admissions is limited.

Curr Med Res Opin. 2001;16(4):258-68.
Doxofylline

A new generation xanthine bronchodilator devoid of major cardiovascular adverse effects.

Dini FL, Cogo R.

Unità Operativa di Cardiologia, Ospedale Villamarina, Via Forlanini, 24, 57025 Piombino, Italy. frankld@tin.it

Doxofylline (7-(1,3-dioxalan-2-ylmethyl) theophylline) is a novel xanthine bronchodilator which differs from theophylline in that it contains a dioxalane group in position 7. Similarly to theophylline, its mechanism of action is related to the inhibition of phosphodiesterase activities, but in contrast it appears to have decreased affinities towards adenosine A1 and A2 receptors, which may account for its better safety profile. The bronchodilating activities of doxofylline have been demonstrated in clinical trials involving patients with either bronchial asthma or chronic obstructive pulmonary disease. In contrast to other bronchodilators, experimental and clinical studies have shown that the drug is devoid of direct stimulatory effects. This may be of importance because the arrhythmogenic actions of bronchodilators may have a negative impact on the survival of patients with respiratory diseases.






Controlled clinical study of doxophylline versus aminophylline in the treatment of acute cardiorespiratory insufficiency syndrome



Checchini M, Magni M, Scaglione M, Franzini C, Vaccarella A, Omboni E.

Unità Operativa di Cardiologia, INRCA Casatenovo, Lecco.

Twenty patients of both sexes, hospitalized because they were suffering from acute cardiorespiratory syndromes, have been studied in a clinical blind test on unbalanced groups of patients. This research aims to evaluate the therapeutic efficiency and intravenous tolerance of doxophylline. Patients were observed for 24 hours. Signs and symptoms were recorded on a semi-quantitative scale, and the clinical situation, haemogasanalysis, blood pressure, cardiac frequency, and other analytic controls were performed in order to verify the systemic tolerability. We can conclude, in agreement with the literature, that the group treated with doxophylline showed a better reduction in cardiac frequency, while maintaining the same effects on the respiratory apparatus.



Oral doxophylline in patients with chronic obstructive pulmonary disease.
Villani F, De Maria P, Ronchi E, Galimberti M.

Int J Clin Pharmacol Ther. 1997 Mar;35(3):107-11.
Links
Divisione di Fisiopatologia Respiratoria, "C", Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Doxophylline, or 2-(7'-theophyllinemethyl)1,3-dioxolane, is a theophylline derivative which has shown interesting bronchodilating activity, and it appears to determine few adverse effects. The aim of the present investigation was to evaluate clinical therapeutic effects of the drug in the treatment of 2 groups of patients suffering from moderate to severe chronic obstructive pulmonary disease differing in acute response to the inhaled beta 2-agonist salbutamol and to compare changes of lung function tests to serum concentration of doxophylline. We studied 67 patients with chronic obstructive pulmonary disease (median age 63 years, 9 females and 58 males) who were all clinically stable at the time of the study. Patients were separated into 2 groups on the basis of their reaction to inhalation of 200 micrograms of salbutamol: those with an increased FEV1 of more than 20% from baseline value (group 1), and those with no increase (group 2). Doxophylline was administered orally at the dose of 400 mg 3 times daily. Serum levels of doxophylline were determined by high-pressure liquid chromatography. Spirometry and blood gas analysis were performed before and 10 days after treatment. Four patients stopped drug assumption because of side effects (3 for dyspepsia and 1 for anxiety). In group 1 (34 patients), a significant increase in SVC, FVC, FEV1, FEF 25-75% and PEFR was observed. In group 1 (29 patients), only PEFR significantly increased. No modifications in blood gas analysis were observed. The mean serum level of doxophylline was 14 micrograms/ml in group 1 and 9 micrograms/ml in group 2: the difference was statistically significant. The relation between serum levels of doxophylline and FVC showed an increase in the parameter up to the concentration of 12-13 micrograms/ml, after which a plateau phase was observed. On the basis of our data, doxophylline appears to have an interesting bronchodilating effect in patients responsive to the inhaled beta 2-agonist salbutamol. The lower limit of the therapeutic range seems to be 12-13 micrograms/ml. The upper limit of the therapeutic range was not determined because it was not possible to obtain serum samples when side effects occurred.

Effects of theophylline and doxofylline on airway responsiveness in beagles
Arerugi. 1997 Jan; 46(1):7-15.

Sugeta A, Imai T, Idaira K, Horikoshi S, Okamoto M, Adachi M.

First Department of Internal Medicine, School of Medicine, Showa University.
We examined the effects of doxofylline, which is a new methylxanthine analog, on heart rate, respiratory rate, respiratory resistance and airway responsiveness in five beagles, and compared with those effects of theophylline. Airway responsiveness to inhaled methacholine was determined by modified Astograph (7Hz oscillation method). Theophylline (10 mg/kg, 20 mg/kg, 40 mg/kg) was orally administered one hour prior to the determination of airway responsiveness and doxofylline (20 mg/kg, 40 mg/kg, 80 mg/kg) was orally administered thirty minutes prior to determination of airway responsiveness at intervals of about one week. Heart rate increased significantly by all dose of theophylline in a dose-dependent manner and by 80 mg/kg of doxofylline. Respiratory rate increased significantly only by 40 mg/ kg of theophylline. Respiratory resistance decreased significantly after administration of 40 mg/kg of theophylline. Airway responsiveness decreased significantly by 40 mg/kg of theophylline and 40 mg/kg, 80 mg/kg of doxofylline in a dose-dependent manner. These results suggest that doxofylline decreased airway responsiveness at the dosage which dose not affect the heart rate and respiratory rate compared with theophylline.





The effects of doxofylline versus theophylline on sleep architecture in COPD patients.
Sacco C, Braghiroli A, Grossi E, Donner CF.

Monaldi Arch Chest Dis. 1995 Apr; 50(2):98-103.
Links


Division of Pulmonary Disease, Clinica del Lavoro Foundation, Medical Center of Rehabilitation, Veruno (NO), Italy.
Theophylline is known to alter sleep architecture because of its affinity to adenosine receptors. One of the consequences of disrupted sleep is impaired cognitive performance. A single-blind, randomized cross-over study of eight male chronic obstructive pulmonary disease (COPD) patients was undertaken to evaluate the effects of theophylline versus doxofylline on sleep architecture. The patients, who were all ex-smokers, had been treated with theophylline. Mean age was 53 +/- 12 yrs, forced expiratory volume in one second (FEV1) 50 +/- 22% predicted and forced vital capacity (FVC) 70 +/- 18% predicted. Following a wash-out period, four patients were given oral slow-release theophylline (T) (300 mg b.i.d.) for one week, followed by a cross-over to doxofylline (D) (400 mg t.i.d.) for a second week. The other four patients were given the drugs in the reverse order. All patients underwent polysomnography at baseline and at the end of each week of treatment. The number of arousals per hour was 5.5 +/- 2.9 at baseline, 9.4 +/- 5.2 during T treatment and 5.4 +/- 4.4 during D treatment. During T treatment, sleep efficiency was 60 +/- 19% vs 75 +/- 13% recorded at baseline trial and 68 +/- 25 recorded during D treatment. Sleep quality, during T treatment, was poorer than at baseline, with a greater increase in the percentage of wakefulness and more stage 2 sleep than at baseline. Slow wave sleep was reduced with both treatments, particularly D. Neither drug affected the arterial oxygen saturation (Sao2) or respiratory rate during sleep.

Methylxanthine drug therapy in chronic heart failure associated with hypoxaemia: double-blind placebo-controlled clinical trial of doxofylline versus theophylline and bamifylline.
Dini FL, Pasini G, Cortellini G, Cani E, Bettini R, Garagnani A, Gobbi G, Greco A, Onorato G, Pasini P, et al.

Int J Clin Pharmacol Res. 1993;13(6):305-16.
Links
Postgraduate Specialization School of Pharmacology, University of Pisa, Italy.
The effects of the methylxanthine drugs doxofylline, theophylline and bamifylline were investigated on the basis of clinical and gasometric parameters in hypoxic patients with chronic heart failure. A parallel, double-blind, randomized study was conducted in 48 in-patients with NYHA II-IV chronic heart failure with normo- or hypercapnic hypoxaemia. They were divided into three groups and then submitted to a 4-day run-in with placebo. Either doxofylline 800 mg b.i.d., theophylline slow-release 400 mg b.i.d. or bamifylline 1200 mg b.i.d. were administered orally in each group of 16 patients for 10 days. Exercise capacity was estimated through NYHA class modification. Gasometric determinations, including arterial oxygen tension (PaO2), carbon dioxide tension (PaCO2) and oxygen saturation (SaO2), were measured from arterial blood samples at the time of enrollment (T-4), at the onset of xanthine therapy (T0) and at the end of the trial (T9). After 10 days' treatment, the NYHA class was found to be diminished in 50% of the doxofylline group, 50% of the bamifylline group and 44% of the theophylline group. PaO2 showed a > 15% increase in 75% of the doxofylline group, 56% of the theophylline group and 43% of the bamifylline group (responders). In all three groups the responders presented a highly significant enhancement in PaO2 and SaO2 (p < 0.01 T0 vs T9). Doxofylline exhibited the highest percent increase in PaO2 and SaO2 with respect to T0. The effects on cardiac rhythm showed a progressive heart-rate reduction in the doxofylline group, whereas patients receiving theophylline presented an increase rate of beating. In conclusion, the use of methylxanthines in patients with chronic heart failure seems to be particularly effective especially when a significant ventilatory dysfunction is present. Doxofylline appears to be specially useful because of its ability not to interfere with cardiac rhythm.
Pharmacological studies in animals of beta-hydroxyethyltheophylline, the major metabolite of doxofylline in humans.
Franzone JS, Cirillo R, Reboani MC.
Istituto Biologico Chemioterapico ABC S.p.A., Research Laboratories, Torino, Italy.


Beta-HET (beta-Hydroxyethyltheophylline), the major metabolite of the antibronchospastic, antiasthmatic drug doxofylline was studied in several in vitro and in vivo trials to characterize its pharmaco-toxicological profile. When compared to the parent compound, beta-HET was found to be significantly less active. It was also discovered to be a very weak inhibitor of phosphodiesterase activity. Its affinity for A1- and A2-adenosine receptors was even lower than that of doxofylline, which was quite low. The oral toxicity of beta-HET was about three times lower than that of doxofylline. The pharmacological activity of doxofylline is due to the drug in its original form and not to its major metabolite.











Doxofylline differs from methylxanthines in its movement of cytosolic calcium.
Franzone JS, Cirillo R, Reboani MC.

Int J Tissue React. 1991;13(3):131-8.
Links

Research Laboratories, Istituto Biologico Chemioterapico ABC S.p.A., Turin, Italy.
This paper contributes to the pharmacological profile of doxofylline (Ansimar), a new xanthine derivative with high antibronchospastic activity and no extrapulmonary or cardiac side-effects, clearly demonstrating its inability to mobilize intracellular calcium stores, unlike other xanthines. In vitro, doxofylline does not cause rabbit ear artery contraction under Ca(++)-free conditions. In vivo, doxofylline does not induce a decrease in the calcium concentration of rabbit washed blood platelets. In the same trials theophylline showed opposite results. Furthermore, doxofylline does not antagonize receptors of Ca-antagonists, and does not interfere with the influx of calcium into the cell. Doxofylline also has a very low affinity for adenosine receptors inhibiting cAMP-phosphodiesterase as does theophylline. The absence of typical methylxanthine side-effects is undoubtedly due to doxofylline's low affinity for adenosine receptors, although this does not explain the absence of cardiovascular effects. The present study presents clear evidence that the inability of doxofylline to cause positive inotropism can be linked to its inability to induce calcium movement from intracellular stores.











The effect of intravenous doxofylline or aminophylline on gastric secretion in duodenal ulcer patients.
Lazzaroni M, Grossi E, Bianchi Porro G.


Aliment Pharmacol Ther. 1990 Dec;4(6):643-9.

Gastrointestinal Unit, L. Sacco Hospital, Milan, Italy.
The aim of this study was to compare the effects upon gastric secretion of therapeutic doses of aminophylline, with doxofylline, a new xanthine derivative proposed for the treatment of chronic asthma. Twelve patients with endoscopically-proven healed duodenal ulcer were studied twice under double-blind conditions in cross-over experiments. In a 1-hour infusion, six patients received either 240 mg aminophylline i.v. or 200 mg doxofylline i.v., and six received either 240 mg aminophylline i.v. or 400 mg doxofylline i.v. Compared with basal gastric secretion, for the hour after the infusion 240 mg aminophylline i.v. stimulated gastric acid output by a mean 213% (P less than 0.01) and mean pepsin output by 129% (P less than 0.01). Intravenous doxofylline did not stimulate a significant increase of either acid or pepsin output (200 mg: acid output +4%, pepsin output +10%; 400 mg: acid output +25%, pepsin output +27%). These findings suggest that doxofylline, unlike aminophylline, has a low secretagogue activity and it may be more suitable for asthmatic patients with peptic ulcer disease.





Oral and intravenous pharmacokinetic profiles of doxofylline in patients with chronic bronchitis.

Bologna E, Laganà A, Terracino D, Bolignari P, Biffignandi P.


J Int Med Res. 1990 Jul-Aug;18(4):282-8.
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Clinical Pharmacology Unit, San Giovanni Calibita Hospital, Rome, Italy.
Serum doxofylline concentrations were evaluated after solid-phase extraction by high-performance liquid chromatography following administration of 100 mg doxofylline given as a single intravenous dose over 10 min or 400 mg doxofylline given orally twice daily for 5 days in six and eight non-smoking, fasting, chronic bronchitic patients, respectively. Doxofylline possessed a very short distribution phase following intravenous administration, with a sustained elimination phase (half-life 1.83 +/- 0.37 h). After oral administration, the peak serum doxofylline concentration was 15.21 +/- 1.73 micrograms/ml and the mean elimination half-life was 7.01 +/- 0.80 h; there was a large inter-subject variability. No side-effects were experienced by the patients during the study.









Doxofylline and respiratory mechanics. Short-term effects in mechanically ventilated patients with airflow obstruction and respiratory failure.
Poggi R, Brandolese R, Bernasconi M, Manzin E, Rossi A.

Chest. 1989 Oct;96(4):772-8.

Department of Anesthesia and Intensive Care, City Hospital, Padua, Italy.
To assess the short-term effects of a methylxanthine (doxofylline) on respiratory mechanics in mechanically ventilated patients with airway obstruction and respiratory failure, nine consecutive patients were examined within three days from the onset of mechanical ventilation. Flow, changes in pulmonary volume, and Paw were measured using a ventilator (Servo 900C). End-expiratory and end-inspiratory airway occlusion was performed to measure PEEPi, Cstrs, Rrsmax, and Rrsmin. Measurements were performed before and at 5, 15, and 30 minutes after an intravenous loading dose of doxofylline (5 to 6 mg/kg). We found that doxofylline determined, on the average, a marked decrease in respiratory resistance (Rrsmax and Rrsmin, -27.2 percent and -36.5 percent, respectively) without significant changes in Cstrs and Pmax. The PEEPi, reflecting pulmonary dynamic hyperinflation, was also significantly decreased by doxofylline (-41 percent, on the average). The Pmax was not reliable for evaluation of a single patient, since changes in the elastic pressure can offset changes in the resistive one. No patient experienced significant side effects due to doxofylline. We conclude that (1) the effects of therapy can be assessed noninvasively at bedside in critically ill patients; (2) doxofylline is a rapid and efficient bronchodilator in mechanically ventilated patients with ARF and airflow obstruction; and (3) the decrease in the respiratory resistance and PEEPi, associated with an improved mechanical efficiency of the respiratory muscles at a lower pulmonary volume, can provide better conditions for the patient-ventilator interaction and for weaning.




Clinical evaluation of Doxofylline sachets in a pediatric population


Bagnato G, Fodale P, Bottari M.


Riv Eur Sci Med Farmacol. 1989 Aug;11(4):359-63.
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Therapeutic efficacy and tolerability of doxofylline 200 mg sachets, were evaluated, in a pediatric population in comparison with placebo. After double blind randomization, 11 patients aged from 6 to 12 years, were treated for 14 consecutive days. Doxofylline was administered at the daily dose of 12 mg/kg in two times. In the doxofylline group the authors observed a significative improvement of the evaluated spirometric paramethers (FEV1, FCV, FEF, FMF, PEF, MVV); in the placebo group there were only casual modifications. None of the patients treated complained of any side effect.






Doxofylline, an adenosine-nonblocking xanthine, does not induce cardiostimulant effects.
Cirillo R, Grossi E, Franzone JS.

Res Commun Chem Pathol Pharmacol. 1989 Jul;65(1):21-34.
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ABC Pharmaco-Toxicological Research Laboratories, Turin, Italy.
Doxofylline (ANSIMAR) is a new adenosine-nonblocking anti-asthmatic drug with potent bronchodilator activity that does not display the typical extrapulmonary side effects of theophylline--a potent adenosine antagonist. The cardiac activity of doxofilline and theophylline was investigated in guinea pig right and left atrial preparations and in anestetized cat. In spontaneously beating right atria doxofylline slightly increased the atrial rate only at 0.3 mM, while theophylline induced a concentration-dependent positive chronotropic effect starting at 0.03 mM. The contractile force of electrically stimulated left atria was affected by doxofylline starting at 0.3 mM. Theophylline induced the same effect already at 0.03 mM. In the anesthetized cat, doxofylline (1-30 mg/kg.i.v.) did not affect the diastolic blood pressure, but the heart rate increased slightly at a dose of 30 mg/kg i.v. On the contrary, theophylline induced a marked dose-dependent hypotensive and positive chronotropic effect. Doxofylline was 10 times less potent that theophylline is its ability to antagonize the cardiodepressant activity induced by adenosine in isolated guinea pig atria. The pharmacodynamic differences between doxofylline and theophylline may bring new insights to the understanding of the mechanisms underlying the positive chronotropic effects of xanthines, and the functional importance of endogenous adenosine. Additionally, the lack of cardiostimulant effects makes doxofylline highly suitable for the treatment of chronic obstructive lung disease particularly in combination with beta 2-adrenergic agonists.




Doxofylline exerts a prophylactic effect against bronchoconstriction and pleurisy induced by PAF.
Franzone JS, Cirillo R, Biffignandi P.

Eur J Pharmacol. 1989 Jun 20; 165(2-3):269-77

ABC S.p.A. Research Laboratories, Turin, Italy.
The effect of doxofylline, a new xanthine drug with a low incidence of side-effects in the central nervous, renal and gastroenteric system, on the actions of PAF-acether on bronchopulmonary functions was studied. Doxofylline inhibited: (1) PAF-induced bronchoconstriction in vitro, and the concomitant generation of TXA2-like activity in perfused guinea-pig lungs; (2) PAF-induced bronchoconstriction in vivo and the concomitant release of TXA2-like activity into the circulation; (3) PAF-acether-induced pleurisy and the liberation of type C4 leukotriene into the rat pleural cavity. The results suggest that doxofylline, like theophylline, is able to counteract the bronchoconstriction induced by PAF-acether and, in addition, displays anti-inflammatory properties. These pharmacological data support the notion that doxofylline exerts a prophylactic effect against the respiratory damage induced by mediators, such as PAF-acether, of lung bronchial hyperreactivity; its mechanism of action is unusual, it has slight antagonistic activity at A1- and A2-adenosine receptors.




Systemic cardiorespiratory effects induced by doxofylline

Bagnato GF, Allegra A, De Leo A, Giacobbe MS, Mileto A, Cinquegrani M, Leotta G, Buemi AL, Spina E, Scibilia M, et al.

Riv Eur Sci Med Farmacol. 1989 Feb;11(1):29-35.
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The authors evaluated the clinical effectiveness and tolerability of doxofylline, a new methyl-xanthinic derivative with peculiar pharmacodynamic properties. 13 patients affected with chronic obstructive lung disease (mean age +/- 54 years) were studied. Doxofylline (200 mg) and theophylline (240 mg) were randomly administered by intravenous route in 60'. Arterial haemogasanalysis, FEV1 and ECG data were obtained after the infusion. Doxofylline proved to possess an equal therapeutic efficacy in comparison to theophylline, with a better clinical tolerability. In conclusion, doxofylline is a new and effective drug for the treatment of bronchostructive disorders.







Treatment of reversible chronic airways obstruction with doxofylline compared with slow-release theophylline: a double-blind, randomized, multicentre trial.
Melillo G, Balzano G, Jodice F, De Felice A, Campisi V, Capone M, Di Filippo A, Foddai G, Franzone JS, Grossi E, et al.

Int J Clin Pharmacol Res. 1989;9(6):397-405.
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Cardarelli Hospital, Naples, Italy.
A multicentre, double-blind, randomized trial was carried out in 11 Italian Pneumologic Clinics to investigate the therapeutic efficacy and tolerability of doxofylline compared with slow-release theophylline in 139 patients (86 males, 53 females) aged 17-77 years suffering from reversible chronic airways obstruction. The two groups of 69 patients on doxofylline and 70 patients on theophylline did not differ in their baseline clinical and functional parameters. After one week of wash-out, the two drugs were administered orally at a dose of 400 mg twice daily of doxofylline and 300 mg twice daily of theophylline. The treatment and follow-up lasted 28 days. Inhaled salbutamol on demand was allowed in the wash-out week and throughout the trial. The average serum levels at day 14 and 28 were: doxofylline 7.5 and 8.5 micrograms/ml; theophylline 10.4 and 7.95 micrograms/ml respectively. Both drugs significantly increased spirometric parameters (p less than 0.001 for all tests) and significantly reduced salbutamol consumption (p less than 0.001 for both drugs). Doxofylline was better tolerated than theophylline considering either the number of unwanted side-effects: (doxofylline 12; theophylline 37) or number of drop-outs due to side-effects (doxofylline 5; theophylline 10). From these results doxofylline seemed to be a good alternative to theophylline in the treatment of reversible chronic airway obstruction in view of its better safety profile.





Doxofylline, an antiasthmatic drug lacking affinity for adenosine receptors.
Cirillo R, Barone D, Franzone JS.

Arch Int Pharmacodyn Ther. 1988 Sep-Oct;295:221-37

ABC Research Laboratories, Torino, Italy.
In the present study the interaction of doxofylline, a new antiasthmatic drug, with A1- and A2-adenosine receptors of the guinea-pig brain and rat striatum was investigated in comparison with known methylxanthine derivatives. Inhibition studies of N6-cyclohexyl-3H-adenosine (3H-CHA), 1,3-diethyl-8-3H-phenylxanthine (3H-DPX) binding and 3H-5'-N-ethylcarboxamidoadenosine (3H-NECA) binding showed how doxofylline did not bind to adenosine receptors in a pharmacological fashion, since doxofylline affinity for A1- and A2-adenosine receptors lies in a 10(-4) M range, a concentration which is too high to have any pharmacological meaning or predictability. However, saturation binding studies demonstrate that doxofylline behaves as a competitive inhibitor of the 3 radioligands used to label adenosine receptors. These data seem to corroborate the theory that antagonism to adenosine receptors is not necessarily associated with bronchodilator activity of methylxanthines, and explain the lack of the typically unwanted side effects induced by methylxanthine derivatives after doxofylline administration.




Comparison of intravenously administered doxofylline and placebo for the treatment of severe acute airways obstruction.
Dolcetti A, Osella D, De Filippis G, Carnuccio C, Grossi E.
VI Division of Pneumology, Hospital S. Luigi, Orbassano, Turin, Italy.
J Int Med Res. 1988 Jul-Aug; 16(4):264-9.


This double-blind, randomized, placebo-controlled study investigated the therapeutic effects of a single dose of doxofylline, a methylxanthine derivative, in 10 patients aged 26-79 years. All patients had acute exacerbation of chronic obstructive airways disease partially reversible with salbutamol inhaler. Doxofylline was administered intravenously at a dose of 200 mg over 15 min on two different occasions separated by at least 24 h. Doxofylline increased forced expiratory volume in the first second of expiration compared with baseline as follows: +20% after 2 h (P less than 0.01); +31% after 4 h (P less than 0.01); and +13% after 6 h (NS). Changes produced by placebo at these times were -4.4%, -14% and -5% (all NS). The average differences between the groups were significant at all observation times. At the end of the observation period eight out of 10 patients given doxofylline and one out of 10 patients given placebo had improved clinically according to the patients' own opinion. Clinical tolerability of doxofylline proved to be good since no signs of local or general side-effects were observed in any of the patients treated.




Doxofylline and theophylline are xanthines with partly different mechanisms of action in animals.
Franzone JS, Cirillo R, Barone D.
Drugs Exp Clin Res. 1988;14(7):479-89


Research Laboratories, Institute of Biological Chemotherapy, ABC S.p.A., Turin, Italy.
Doxofylline is a new antibronchospastic drug, recently introduced in therapy, with pharmacological properties like theophylline, a potent adenosine receptor antagonist. The authors have investigated the occurrence, after doxofylline administration, of the typical side-effects displayed by methylxanthines in general. The EC50 values of doxofylline in inhibiting the adenosine-induced relaxation of tracheal smooth muscle and the negative inotropic effect induced by adenosine on isolated guinea-pig atria were about 15 and 10 times greater respectively than those of aminophylline. Again, doxofylline increased diuresis only slightly (+15.8) with 20 mg/kg os, and did not increase sodium excretion; aminophylline, on the contrary, produced a dose-dependent increase in urine volume and natriuresis. In mice, aminophylline (6-24 mg/kg given intraperitoneally) dose-dependently increased locomotor activity, while doxofylline (6-24 mg/kg, i.p.) had no effect on behaviour. In anaesthetized guinea-pigs, doxofylline, in continuous intravenous infusion (0.5 ml/min) at 10 and 30 mg/ml, demonstrated fewer toxic effects than those induced by aminophylline: the effect on diastolic blood pressure, on threshold-dose for convulsions, on death-time and on lethal dose came later than with aminophylline. Finally, doxofylline did not affect gastric acid secretion, either in vitro or in vivo, unlike theophylline. The lack of side-effects with doxofylline indicates that this drug can be used safely and effectively in the treatment of obstructive lung disease.