Aliment. Pharmacol. Therap. (1990) 4, 643-649
The effect of intravenous doxofylline or aminophylline on gastric secretion in duodenal ulcer patients
M. LAZZARONI, E. GROSS1 & G. BIANCHI P O R R O Gastrointestinal Unit, L. Sacco Hospital, Milan, ltaly Accepted for publication 7 June 1990
SUMMARY
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 Yo ( P < 0.01) and mean pepsin output by 129% ( P < 0.01). Intravenous doxofylline did not stimulate a significant increase of either acid or pepsin output (200 mg : acid output 4 %, pepsin output 10 Yo; 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.
+ +
+
+
Correspondence to : Professor G. Bianchi Porro, Gastrointestinal Unit, Ospedale L. Sacco, Via Grassi 74, 20157 Milano, Italy. 643
644
M. L A Z Z A R O N I , E. GROSS1 & G. BIANCHI P O R R O
Figure 1. Structural formula of doxofylline (molecular weight = 266.26).
INTRODUCTION Doxofylline is a new methyl-xantine derivative (Figure I), with potent antibronchospastic activity both in animals and in man.'r3 Doxofylline is used intravenously for the treatment of acute bronchospasm in single doses ranging from 200 to 400 mg,3 and orally for the treatment of chronic asthma at an average daily dose of 800 mg. In chronic treatment, doxofylline was shown to be associated with fewer gastrointestinal side-effects compared with theophylline. Unlike theophylline, doxofylline is a poor antagonist of adenosine receptors with an affinity with A1 and A2 sub-types of approximately M . Animal ~ studies have shown that this poor adenosine antagonism is associated with a negligible stimulation of gastric secretion by d~xofylline.~ The object of the experiments reported in this paper was to compare the effects of intravenous aminophylline with those of intravenous doxofylline on gastric secretion in patients with a history of duodenal ulceration. PATIENTS A N D M E T H O D S Twelve patients (7 males and 5 females), mean age 41.5 years (range 25-63 years), with endoscopically-proven healed duodenal ulcerations were admitted to two different studies after giving their informed consent and after having obtained the permission of The Ethics Committee. The patients were not allowed to take an anticholinergic or any other antisecretory drug for at least 5 days before the start of the secretory studies. They abstained from ingesting dietary methylxanthines (tea, coffee or chocolate) in the 24 h preceding each secretory test. After an overnight fast, a double-lumen nasogastric tube (Salem sump, 16 French, Sherwood Medical, Belgium) was inserted and positioned in the most dependent part of the stomach. Gastric juice was aspirated by intermittent suction, with a negative pressure of 30 mmHg. After I-h collection of basal gastric secretion, an intravenous infusion of the test drug was started and continued at a steady rate for 60 min, with continued gastric aspiration. At the end of the infusion, gastric juice was collected for a further hour. In the first series of cross-over experiments six patients received, under doubleblind conditions in a randomized order, either 240 mg aminophylline or 200 mg doxofylline, intravenously. In the second series of experiments, under identical
DOXOFYLLINE A N D G A S T R I C S E C R E T I O N
645
conditions, six patients were randomized to receive either 240 mg aminophylline or 400 mg doxofylline, intravenously. Each patient was studied twice, with a washout between experiments of at least 72 h. The volume of gastric secretion was recorded every 15 min, and acidity measured by titration of 5-ml samples with 0.1 M NaOH by means of an automatic titrator (Autoburette, Radiometer, Copenhagen). Acid output is expressed as mmol HCl/l5 min. Pepsin concentration was measured in gastric juice samples that were stored at 4 OC, using a modified haemoglobin substrate method.6 Pepsin output is expressed as mg protein/l5 min. The serum gastrin concentration was measured at base-line, and at 15-min intervals during and after the infusion of test drugs. The serum gastrin concentration was measured by radio-immunoassay (Beckton, Dickinson, Orangenburg, New York; normal values up to 100 pg/ml). The serum concentrations of the drugs were measured at 15-min intervals during the infusion, using standardized highpressure liquid chromatography. In the second study, the gastric juice concentration of the drugs was also obtained at 45 and 60 min after the start of the infusion.
+
S T A T I S T I C A L ANALYSIS The results are expressed as mean & S.E.M. One-way analysis of the variance was used to compare the base-line measurements of gastric secretion. Two-sided Student's t-test for paired data was used to compare gastric secretion during and after infusion of the test drugs. Values of P < 0.05 were considered significant. RESULTS
Firsf Study Figure 2 demonstrates gastric secretion before, during and after infusion of either 240 mg aminophylline or 200 mg doxofylline. Compared with before infusion, 240 mg aminophylline i.v. significantly increased the volume of gastric secretion during ( 42 %) and after ( 92 %) infusion. Similarly, acid and pepsin outputs were significantly increased both during ( 8 1Yo, and 49 %, respectively) and after infusion ( 189 % and 113%). Compared with before infusion, 200 mg doxofylline i.v. did not significantly increase the volume of gastric secretion during infusion ( 2 %), but only after infusion ( 26 %). However, acid and pepsin outputs were not significantly affected either during ( - 15 %, - 2 %, respectively) or after in10%). fusion ( 4 %,
+
+ +
+
+
+
+
+
+
Second 'study Figure 3 demonstrates secretory results before, during and after infusion of either 240 mg aminophylline or 200 mg doxofylline. Compared with before infusion, 240 mg aminophylline i.v. significantly increased the volume of gastric secretion during ( 42 %) and after ( 63 %) infusion. Similarly, acid and pepsin outputs were
+
+
M. LAZZARONI, E. GROSS1 & G. BIANCHI P O R R O
646
Basal
First hour
Second hour
First hour
Second hour
-
-I:
_am = w
a
+I
?+?c
:: 9 L
10
.-
T
f l
GF
-E 0 Bosal
I
T
Basal
First hour
Second hour
Figure 2. Volume of gastric output, gastric acid output, and pepsin output, before, during the 1-h infusion and 1 h after of either 200 mg doxofylline or 240 mg aminophylline i.v. in 6 healthy subjects. 0 ZOO mg doxofylline; 240 mg aminophylline; “ P < 0.05: * P < 0.01.
+
+
significantly increased both during ( 100Yo and 92 %, respectively) and after 144%). Compared with before infusion, 400 mg doxoinfusion (+237% and fylline significantly increased the volume of gastric secretion during the first hour after infusion ( 25 YO), but not during infusion ( 10%).Acid and pepsin outputs were not significantly affected either during ( +13%, IS%, respectively) or after infusion (+25 %, 27%).
+
+
+
+
+
Serum gastrin in both studies The serum gastrin concentrations were unchanged during and after infusion of either aminophylline or doxofylline.
Serum and gastric juice concentration of drugs Table 1 reports the mean serum concentrations of either doxofylline or aminophylline during the one hour infusion. Doubling the dose of doxofylline was
DOXOFYLLINE A N D GASTRIC SECRETION
647
2or 10
0
Bas0
First hour
Second hour
I
I ,w
cz=In +I o c
Figure 3. Volume of gastric output, gastric acid output, and pepsin output before, during the 1-h infusion and 1 h after of either 400 mg doxofylline or 240 mg aminophyllin i.v. in 6 healthy subjects. 400 mg d o x o f y h e ; 240 mg aminophylline ; P < 0.05 : *'P < 0.01.
loo
:L .. -F 0 Basal
Flrst hour
Second hour
Table 1. Serum concentration of doxofylline or aminophylline during the infusion (mg/L; mean fS.E.M.) Time (min)
Doxofylline us. Aminophylline (200 mg) (240 mg)
15 30 45 60
1.57f0.16 1.82 f0.15 2.52 f O . 1 8 2.42 f0.19
3.87f0.27 6.12 f0.44 7.73 k0.33 9.13 f0.60
Gastric juice concentration 45 60
Doxofylline us. Aminophylline (400 mg) (240 mg) 2.9 f0.39 3.8 f0.65 5.5 f 0 . 6 1 5.4 f0.65
2.6 f0.10 4.3 f0.36 6.2f0.81 7.2 f0.57
5.9 0.5 5.3 f0.5
5.5 & 0.4 5.7 f0.4
associated with a similar increase in the plasma doxofylline concentration. The gastric juice concentrations of either doxofylline or aminophylline at 45 and 60 min were similar.
648
M. L A Z Z A R O N I , E. GROSS1 & G. BIANCHI P O R R O
Adverse events The only adverse event recorded was 'slight sleepiness ' observed in 3 patients dosed with doxofylline (1patient with the 200 mg dose and two patients with the 400 mg dose).
DISCUSSION Gastric distress is one of the most frequent side-effects observed in patients treated with theophylline, even in the presence of serum concentrations that are within the therapeutic range.7 The increase of gastric acid and pepsin secretion produced by aminophylline is likely to be important, particularly in patients with an abnormal gastroduodenal mucosa.' Krasnov & Grossman in 1949,9 described stimulation of human gastric secretion of aminophylline, but in the last decade only two studies have been carried out on this topic. Foster et a2." studied nine patients with chronic obstructive pulmonary disease, reporting that aminophylline at a dose of 6 mg/kg i.v. increased basal acid output by over 200%. These patients had a normal basal gastric acid secretion. In another study Johannesson et a/." reported that theophylline, but not enprofylline (another novel methy-xanthine derivative with poor adenosine antagonism), infused intravenously at a dose of 5 mg/kg significantly increased gastric acid secretion. In the present study, carried out on duodenal ulcer patients, we have demonstrated that aminophylline (at an average dose of 3.7 mg/kg) is a potent stimulant of both gastric acid and pepsin secretion. This stimulatory effect appears to be long-lasting (increasing secretion was observed in the hour after cessation of the intravenous infusion of aminophylline) and associated with serum concentrations of aminophylline below 10 ,ug/ml, which is traditionally considered to be the lower limit of the therapeutic dose-range. Administration of doxofylline at therapeutic doses did not affect gastric acid secretion, at a time when serum and gastric juice concentrations were similar to those observed during aminophylline infusion in the same patients. The results of these experiments are relevant to the current understanding of the action of methyl-xanthine derivatives on gastric secretion. The original hypothesis suggested that the acid-stimulating effects of theophylline and caffeine were due to the inhibition of gastric phosphodiesterase, with a consequent increase in cellular cyclic AMP. This hypothesis has recently been questioned, as the concentrations required for the inhibition of phosphodiesterase activityI2 are higher than those in clinical practice. An alternative theory suggests that secretagogue activity might be due to the potent ability of theophylline to antagonize the action of adenosine, through competition at receptor level. Because doxofylline, like enprofylline, is a poor adenosine antagonist, it is possible that the observed difference between these drugs and aminophylline is due to a different action at adenosine receptors. To support this theory, GerberT3and co-workers found that
DOXOFYLLINE A N D GASTRIC SECRETION
649
adenosine inhibits acid secretion both in vivo and in vifro, thus suggesting the presence of inhibitory adenosine receptors on parietal cells. Scarpignato ef al.” have confirmed these findings, showing that activation of A1 receptors inhibits acid secretion in the rat. Recently Ota et all5 have suggested the presence of adenosine A2 receptors on rabbit parietal cells which may also modify gastric acid secretion. The type of experiment reported in this paper (acute intravenous administration) does not have a direct relationship to clinical practice, where gastric sideeffects of theophylline are generally encountered during chronic oral treatment. Nevertheless, the results of the present study support the hypothesis that the lower incidence of gastric symptoms associated with doxofylline therapy in clinical trials may be linked to its lower gastric secretagogue activity. The results of the present study suggest that patients with peptic ulceration requiring a bronchodilator may benefit from the use of a methyl-xanthine derivative with low adenosine antagonism, like doxofylline, when does not stimulate gastric acid and pepsin secretion. REFERENCES
acid and pepsin secretion: dose-response studies. Scand J Gastroenterol 1971; 6:
1 Franzoni, J S, Cirillo R, Biffignandi P. Doxofylline exerts a prophylactic effect against
453-7. 9 Krasnov S, Grossman MJ. Stimulation of
branchoconstriction and pleurisy induced by PAF Eur J Pharmacol 189; 165: 269-77. 2 Grossi E, Biffignandi, P, Franzone JS. Doxofylline: clinical profile and review of the literature Eur Rev Med Pharmacol 1988; 10:
gastric secretion in man by theophylline ethylendiamine Proc SOC Exp Biol Med
415-30. 3 Dolcetti A, Osella D, De filippis G. el al. Comparison of intravenously administered
doxofylline and placebo for the treatment of severe acute airways obstruction J Int Med Res 1988; 16: 264-9. 4 Cirillo R, Barone D, Franzone J S. Doxofylline, an anti-asthmatic drug lacking affinity for adenosine receptors. Arch Int Pharmacodyn Therap 1988; 295 : 221-37. 5 Franzone JS, Cirillo R Barone D. Doxofylline and Theophylline are xanthines with partly different mechanisms of actions in animals. Drugs Exp Clin Res 1988; 14: 479-89. 6 Berstad A. A modified hemoglobinic substrate method for the estimation of pepsin in gastric juice. Scand J Gastroenterol 1870; 5 : 343-8. 7 Greening A D, Baille E, Gribbon H R, Pride
N B. Sustained release aminophylline in patients with air-flow obstruction. Thorax 1981; 36: 303-7. 8 Debas H T, Cohen M M, Holubitsky I B,
Harrison R C. Caffeine-stimulated gastric
1949; 71 : 335-6. 10 Foster L J, Trudeau W L, Boldman A L. Bronchodilator effects on gastric acid secretion JAMA 1979; 241 : 2613-5. 11 Johannesson N, Andersson K E, Joelsson B, Persson C G A. Relaxation of lower esophageal sphincter and stimulation of gastric secretion and diuresis by anti-asthmatic xanthines. Arch Rev Respir Dis 1985; 131: 26-31. 12 Fredholm B B. Review article on the mechanism of action of theophylline and caffeine. Acta Med Scand 1985; 217: 149-153. 13 Gerber J G, Fadul S, Payne N A, Nies A S. Adenosine: a modulator of gastric acid secretion in vivo. J Pharmac Exp Therap 1984; 231: 109-13. 14 Scarpignato C, Tramacere R, Zappia L, Del Soldato P. Inhibition of gastric acid secretion by adenosine receptor stimulation in the rat. Pharmacology 1987; 34: 264-8. 15 Ota S, Hisaishi H, f e m a o A, Mutoh H, Kurachi T, Shimada S, h e y K J, Sugimoto T. The effect of adenosine and adenosine analogues on aminopyrine uptake of rabbit parietal cells. Gastroenterology 1988; 94: 337. (Abstract.)
The effect of intravenous doxofylline or aminophylline on gastric secretion in duodenal ulcer patients
M. LAZZARONI, E. GROSS1 & G. BIANCHI P O R R O Gastrointestinal Unit, L. Sacco Hospital, Milan, ltaly Accepted for publication 7 June 1990
SUMMARY
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 Yo ( P < 0.01) and mean pepsin output by 129% ( P < 0.01). Intravenous doxofylline did not stimulate a significant increase of either acid or pepsin output (200 mg : acid output 4 %, pepsin output 10 Yo; 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.
+ +
+
+
Correspondence to : Professor G. Bianchi Porro, Gastrointestinal Unit, Ospedale L. Sacco, Via Grassi 74, 20157 Milano, Italy. 643
644
M. L A Z Z A R O N I , E. GROSS1 & G. BIANCHI P O R R O
Figure 1. Structural formula of doxofylline (molecular weight = 266.26).
INTRODUCTION Doxofylline is a new methyl-xantine derivative (Figure I), with potent antibronchospastic activity both in animals and in man.'r3 Doxofylline is used intravenously for the treatment of acute bronchospasm in single doses ranging from 200 to 400 mg,3 and orally for the treatment of chronic asthma at an average daily dose of 800 mg. In chronic treatment, doxofylline was shown to be associated with fewer gastrointestinal side-effects compared with theophylline. Unlike theophylline, doxofylline is a poor antagonist of adenosine receptors with an affinity with A1 and A2 sub-types of approximately M . Animal ~ studies have shown that this poor adenosine antagonism is associated with a negligible stimulation of gastric secretion by d~xofylline.~ The object of the experiments reported in this paper was to compare the effects of intravenous aminophylline with those of intravenous doxofylline on gastric secretion in patients with a history of duodenal ulceration. PATIENTS A N D M E T H O D S Twelve patients (7 males and 5 females), mean age 41.5 years (range 25-63 years), with endoscopically-proven healed duodenal ulcerations were admitted to two different studies after giving their informed consent and after having obtained the permission of The Ethics Committee. The patients were not allowed to take an anticholinergic or any other antisecretory drug for at least 5 days before the start of the secretory studies. They abstained from ingesting dietary methylxanthines (tea, coffee or chocolate) in the 24 h preceding each secretory test. After an overnight fast, a double-lumen nasogastric tube (Salem sump, 16 French, Sherwood Medical, Belgium) was inserted and positioned in the most dependent part of the stomach. Gastric juice was aspirated by intermittent suction, with a negative pressure of 30 mmHg. After I-h collection of basal gastric secretion, an intravenous infusion of the test drug was started and continued at a steady rate for 60 min, with continued gastric aspiration. At the end of the infusion, gastric juice was collected for a further hour. In the first series of cross-over experiments six patients received, under doubleblind conditions in a randomized order, either 240 mg aminophylline or 200 mg doxofylline, intravenously. In the second series of experiments, under identical
DOXOFYLLINE A N D G A S T R I C S E C R E T I O N
645
conditions, six patients were randomized to receive either 240 mg aminophylline or 400 mg doxofylline, intravenously. Each patient was studied twice, with a washout between experiments of at least 72 h. The volume of gastric secretion was recorded every 15 min, and acidity measured by titration of 5-ml samples with 0.1 M NaOH by means of an automatic titrator (Autoburette, Radiometer, Copenhagen). Acid output is expressed as mmol HCl/l5 min. Pepsin concentration was measured in gastric juice samples that were stored at 4 OC, using a modified haemoglobin substrate method.6 Pepsin output is expressed as mg protein/l5 min. The serum gastrin concentration was measured at base-line, and at 15-min intervals during and after the infusion of test drugs. The serum gastrin concentration was measured by radio-immunoassay (Beckton, Dickinson, Orangenburg, New York; normal values up to 100 pg/ml). The serum concentrations of the drugs were measured at 15-min intervals during the infusion, using standardized highpressure liquid chromatography. In the second study, the gastric juice concentration of the drugs was also obtained at 45 and 60 min after the start of the infusion.
+
S T A T I S T I C A L ANALYSIS The results are expressed as mean & S.E.M. One-way analysis of the variance was used to compare the base-line measurements of gastric secretion. Two-sided Student's t-test for paired data was used to compare gastric secretion during and after infusion of the test drugs. Values of P < 0.05 were considered significant. RESULTS
Firsf Study Figure 2 demonstrates gastric secretion before, during and after infusion of either 240 mg aminophylline or 200 mg doxofylline. Compared with before infusion, 240 mg aminophylline i.v. significantly increased the volume of gastric secretion during ( 42 %) and after ( 92 %) infusion. Similarly, acid and pepsin outputs were significantly increased both during ( 8 1Yo, and 49 %, respectively) and after infusion ( 189 % and 113%). Compared with before infusion, 200 mg doxofylline i.v. did not significantly increase the volume of gastric secretion during infusion ( 2 %), but only after infusion ( 26 %). However, acid and pepsin outputs were not significantly affected either during ( - 15 %, - 2 %, respectively) or after in10%). fusion ( 4 %,
+
+ +
+
+
+
+
+
+
Second 'study Figure 3 demonstrates secretory results before, during and after infusion of either 240 mg aminophylline or 200 mg doxofylline. Compared with before infusion, 240 mg aminophylline i.v. significantly increased the volume of gastric secretion during ( 42 %) and after ( 63 %) infusion. Similarly, acid and pepsin outputs were
+
+
M. LAZZARONI, E. GROSS1 & G. BIANCHI P O R R O
646
Basal
First hour
Second hour
First hour
Second hour
-
-I:
_am = w
a
+I
?+?c
:: 9 L
10
.-
T
f l
GF
-E 0 Bosal
I
T
Basal
First hour
Second hour
Figure 2. Volume of gastric output, gastric acid output, and pepsin output, before, during the 1-h infusion and 1 h after of either 200 mg doxofylline or 240 mg aminophylline i.v. in 6 healthy subjects. 0 ZOO mg doxofylline; 240 mg aminophylline; “ P < 0.05: * P < 0.01.
+
+
significantly increased both during ( 100Yo and 92 %, respectively) and after 144%). Compared with before infusion, 400 mg doxoinfusion (+237% and fylline significantly increased the volume of gastric secretion during the first hour after infusion ( 25 YO), but not during infusion ( 10%).Acid and pepsin outputs were not significantly affected either during ( +13%, IS%, respectively) or after infusion (+25 %, 27%).
+
+
+
+
+
Serum gastrin in both studies The serum gastrin concentrations were unchanged during and after infusion of either aminophylline or doxofylline.
Serum and gastric juice concentration of drugs Table 1 reports the mean serum concentrations of either doxofylline or aminophylline during the one hour infusion. Doubling the dose of doxofylline was
DOXOFYLLINE A N D GASTRIC SECRETION
647
2or 10
0
Bas0
First hour
Second hour
I
I ,w
cz=In +I o c
Figure 3. Volume of gastric output, gastric acid output, and pepsin output before, during the 1-h infusion and 1 h after of either 400 mg doxofylline or 240 mg aminophyllin i.v. in 6 healthy subjects. 400 mg d o x o f y h e ; 240 mg aminophylline ; P < 0.05 : *'P < 0.01.
loo
:L .. -F 0 Basal
Flrst hour
Second hour
Table 1. Serum concentration of doxofylline or aminophylline during the infusion (mg/L; mean fS.E.M.) Time (min)
Doxofylline us. Aminophylline (200 mg) (240 mg)
15 30 45 60
1.57f0.16 1.82 f0.15 2.52 f O . 1 8 2.42 f0.19
3.87f0.27 6.12 f0.44 7.73 k0.33 9.13 f0.60
Gastric juice concentration 45 60
Doxofylline us. Aminophylline (400 mg) (240 mg) 2.9 f0.39 3.8 f0.65 5.5 f 0 . 6 1 5.4 f0.65
2.6 f0.10 4.3 f0.36 6.2f0.81 7.2 f0.57
5.9 0.5 5.3 f0.5
5.5 & 0.4 5.7 f0.4
associated with a similar increase in the plasma doxofylline concentration. The gastric juice concentrations of either doxofylline or aminophylline at 45 and 60 min were similar.
648
M. L A Z Z A R O N I , E. GROSS1 & G. BIANCHI P O R R O
Adverse events The only adverse event recorded was 'slight sleepiness ' observed in 3 patients dosed with doxofylline (1patient with the 200 mg dose and two patients with the 400 mg dose).
DISCUSSION Gastric distress is one of the most frequent side-effects observed in patients treated with theophylline, even in the presence of serum concentrations that are within the therapeutic range.7 The increase of gastric acid and pepsin secretion produced by aminophylline is likely to be important, particularly in patients with an abnormal gastroduodenal mucosa.' Krasnov & Grossman in 1949,9 described stimulation of human gastric secretion of aminophylline, but in the last decade only two studies have been carried out on this topic. Foster et a2." studied nine patients with chronic obstructive pulmonary disease, reporting that aminophylline at a dose of 6 mg/kg i.v. increased basal acid output by over 200%. These patients had a normal basal gastric acid secretion. In another study Johannesson et a/." reported that theophylline, but not enprofylline (another novel methy-xanthine derivative with poor adenosine antagonism), infused intravenously at a dose of 5 mg/kg significantly increased gastric acid secretion. In the present study, carried out on duodenal ulcer patients, we have demonstrated that aminophylline (at an average dose of 3.7 mg/kg) is a potent stimulant of both gastric acid and pepsin secretion. This stimulatory effect appears to be long-lasting (increasing secretion was observed in the hour after cessation of the intravenous infusion of aminophylline) and associated with serum concentrations of aminophylline below 10 ,ug/ml, which is traditionally considered to be the lower limit of the therapeutic dose-range. Administration of doxofylline at therapeutic doses did not affect gastric acid secretion, at a time when serum and gastric juice concentrations were similar to those observed during aminophylline infusion in the same patients. The results of these experiments are relevant to the current understanding of the action of methyl-xanthine derivatives on gastric secretion. The original hypothesis suggested that the acid-stimulating effects of theophylline and caffeine were due to the inhibition of gastric phosphodiesterase, with a consequent increase in cellular cyclic AMP. This hypothesis has recently been questioned, as the concentrations required for the inhibition of phosphodiesterase activityI2 are higher than those in clinical practice. An alternative theory suggests that secretagogue activity might be due to the potent ability of theophylline to antagonize the action of adenosine, through competition at receptor level. Because doxofylline, like enprofylline, is a poor adenosine antagonist, it is possible that the observed difference between these drugs and aminophylline is due to a different action at adenosine receptors. To support this theory, GerberT3and co-workers found that
DOXOFYLLINE A N D GASTRIC SECRETION
649
adenosine inhibits acid secretion both in vivo and in vifro, thus suggesting the presence of inhibitory adenosine receptors on parietal cells. Scarpignato ef al.” have confirmed these findings, showing that activation of A1 receptors inhibits acid secretion in the rat. Recently Ota et all5 have suggested the presence of adenosine A2 receptors on rabbit parietal cells which may also modify gastric acid secretion. The type of experiment reported in this paper (acute intravenous administration) does not have a direct relationship to clinical practice, where gastric sideeffects of theophylline are generally encountered during chronic oral treatment. Nevertheless, the results of the present study support the hypothesis that the lower incidence of gastric symptoms associated with doxofylline therapy in clinical trials may be linked to its lower gastric secretagogue activity. The results of the present study suggest that patients with peptic ulceration requiring a bronchodilator may benefit from the use of a methyl-xanthine derivative with low adenosine antagonism, like doxofylline, when does not stimulate gastric acid and pepsin secretion. REFERENCES
acid and pepsin secretion: dose-response studies. Scand J Gastroenterol 1971; 6:
1 Franzoni, J S, Cirillo R, Biffignandi P. Doxofylline exerts a prophylactic effect against
453-7. 9 Krasnov S, Grossman MJ. Stimulation of
branchoconstriction and pleurisy induced by PAF Eur J Pharmacol 189; 165: 269-77. 2 Grossi E, Biffignandi, P, Franzone JS. Doxofylline: clinical profile and review of the literature Eur Rev Med Pharmacol 1988; 10:
gastric secretion in man by theophylline ethylendiamine Proc SOC Exp Biol Med
415-30. 3 Dolcetti A, Osella D, De filippis G. el al. Comparison of intravenously administered
doxofylline and placebo for the treatment of severe acute airways obstruction J Int Med Res 1988; 16: 264-9. 4 Cirillo R, Barone D, Franzone J S. Doxofylline, an anti-asthmatic drug lacking affinity for adenosine receptors. Arch Int Pharmacodyn Therap 1988; 295 : 221-37. 5 Franzone JS, Cirillo R Barone D. Doxofylline and Theophylline are xanthines with partly different mechanisms of actions in animals. Drugs Exp Clin Res 1988; 14: 479-89. 6 Berstad A. A modified hemoglobinic substrate method for the estimation of pepsin in gastric juice. Scand J Gastroenterol 1870; 5 : 343-8. 7 Greening A D, Baille E, Gribbon H R, Pride
N B. Sustained release aminophylline in patients with air-flow obstruction. Thorax 1981; 36: 303-7. 8 Debas H T, Cohen M M, Holubitsky I B,
Harrison R C. Caffeine-stimulated gastric
1949; 71 : 335-6. 10 Foster L J, Trudeau W L, Boldman A L. Bronchodilator effects on gastric acid secretion JAMA 1979; 241 : 2613-5. 11 Johannesson N, Andersson K E, Joelsson B, Persson C G A. Relaxation of lower esophageal sphincter and stimulation of gastric secretion and diuresis by anti-asthmatic xanthines. Arch Rev Respir Dis 1985; 131: 26-31. 12 Fredholm B B. Review article on the mechanism of action of theophylline and caffeine. Acta Med Scand 1985; 217: 149-153. 13 Gerber J G, Fadul S, Payne N A, Nies A S. Adenosine: a modulator of gastric acid secretion in vivo. J Pharmac Exp Therap 1984; 231: 109-13. 14 Scarpignato C, Tramacere R, Zappia L, Del Soldato P. Inhibition of gastric acid secretion by adenosine receptor stimulation in the rat. Pharmacology 1987; 34: 264-8. 15 Ota S, Hisaishi H, f e m a o A, Mutoh H, Kurachi T, Shimada S, h e y K J, Sugimoto T. The effect of adenosine and adenosine analogues on aminopyrine uptake of rabbit parietal cells. Gastroenterology 1988; 94: 337. (Abstract.)
