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The influence of a new prostaglandin E2 analogue (FCE 20700) on gastric acid and pepsin secretion in the dog.
Prostaglmdins Leukomenes and Medicine C 1987 Loneman Grow UK Ltd
(1987)
26,
I I-20
THE INFLUENCE OF A NEW PROSTAGLANDIN E2 ANALOGUE (FCE 20700) ONGASTRIC ACID AND PEPSIN SECRETION IN THE DOG. 1 C. Arrigoni and ‘R. Ceserani. Laboratory of G. Soldani, G. MengOZZi, yharmacology.Veterinary Medical Clinic. University of Pisa. Italy: Biological Research and Development. Farmitalia-CarloErba, Milan, Italy (Reprint requests to GS). ABSTRACT The effects of FCE 20700, a new prostaglandin E2 analogue,ongastric acid and pepsin secretion stimulated by different secretagogueswere studied in dogs. Intravenous FCE 20700 produced a significant inhibition of total acid output (TAO) induced by pentagastrin or histamine in gastric fistula (GF) dogs. This effect was short-lasting and mainly due to a reduction in the volume of gastric juice with little acid concentration change. TAO and pepsin output stimulated by 2-deoxy-D-glucosewere simililarly inhibited by intravenous FCE 20700. In dogs chronically fitted with both GF and Heidenhain pouch (HP), intragastric FCE 20700 significantly inhibited TAO stimulated by pentagastrin or histamine from HP, while acid secretion from GF wasnot significantly affected. It is concluded that FCE 20700 possesses aweak antisecretory activity in dogs. Consequently the antiulcer effects of this prostaglandin derivative seem to be largely independent from its influence on gastric acid and pepsin secretion. INTRODUCTION Prostaglandins,particularly those of the E series, have been identified in the gastric mucosa (1, 2) and inhibit basal and stimulated gastric acid secretion in experimental animals both in vivo (3, 4, 5, 6) and in vitro (7, 8). Moreover, at non antisecretory doses, prostaglandins prevent gastric mucosal damage produced by noxious agnets, a property that has been named cytoprotection (9). However the lack of oral activity, the short duration of action and a
11
variety of side effects have prevented the clinical use of natural prostaglandins as therapeutic agents for peptic ulcer disease.Several prostaglandin analogue have been consequently synthesized with improved pharmacological profile (10, 11, 12, 13). Recently it has
been
reported
that a new prostaglandin E2 analogue, ll-deoxy-13,14-didehydro-16(S)methyl PGE2 methylester (FCE 20700) possesses cytoprotective and antisecretory activities in the rat (14, 15). The present study was carried out to characterize the influence of the prostaglandin E2 analogue, FCE 20700, on gastric acid and pepsin secretion in conscious dogs. MATERIALS AND METHODS Six female mongrel dogs (lo-18 kg b.w.) were preparedwith agastric fistula (GF) on the corpus of the stomach and four female mongrel dogs (14-21 kg b.w.) were prepared with both a GF on the corpus of the vagally innervated main stomach and a vagally denervated Heidenhain pouch (HP) of the fundus. Four weeks were allowed for surgery before experiments were begun. The dogs were deprived of food but not ofwater for 18 h before each experiment. At least 48 h elapsed between each test. In a first series of experiments performed in dogs with GF, gastric secretion was stimulated by continuous intravenous (i.v.) infusion of pentagastrin (lmcg/kg/h) or histamine (40mcg/kg/h) or by an i.v. bolus of 2 deoxy-D-glucose (2DG; 200 mg/kg). In these experiments FCE 20700 (0.3 - 0.6 - 1.2 and 0.6 - 1.2 - 2.4mcg/kg) was administered by i.v. bolus during the secretory plateau induced by pentagastrin or hjstamine and by continuous i.v. infusion (2mcg/kg/h over 30 min) before the injection of 2DG. In a second series of experiments in dogs with both GF and HP, gastric acid secretion was stimulated by pentagastrin (lmcg/kg/h)or histamine (40mcg/kg/h). FCE 20700 (2.5 - 5.0 mcg/kg ina volume of 5 ml of vehicle) or the same volume of vehicle was given intragastrically (i.g.) 1 h after starting secretagogue infusion and the GF closed for 30 min. Gastric juice collected from GF and HP by gravity drainage was measured andanaliquot titrated to pH 7 with NaOH C.OlN by electrometric titration (TTS 822, Radiometer, Copenhagen, Denmark). Total acid output (TAO)was calculated in mEq H+/15 min. Pepsin concentration was determined by the method of Berstad (16) and the output calculated bymultiplying
the ml of gastric
juice of each sample by the pepsin concentration. Drugs, statistics. The following drugs were used: FCE 20700 (Farmitalia Carlo Erba, Milan, Italy), pentagastrin (Peptavlon, ICI, Alderley Edge, UK), 2-deoxy-D-glucose (2DG) and histamine dihydrochloride (Calbiochem, La Jolla, CA, USA). Doses of histamine refer to the salt. All drugswere dissolved in 0.9% NaCl, except for FCE 20700. FCE 20700 was dissolved
12
in absolute ethanol
at
the concentration of 10
mg/ml,
stored at -2O'C
and diluted before the use to the desired concentration by suspension in 0.5% hydroxy-methylcellulose (Methocel A 4C Premium, Dow Chemical Europe, Horgen, Switzerland) + 0.1% Tween 80 (Carlo Erba, Milan, Italy). Statistical analysis of data was performed by 3-way ANOVA (2 fixed factors: treatments and times and 1 random factor: dogs). When the interactions "times x treatments" was significant, a Dunnett's test at each time was performed in order to compare each treatment group versus control group. RESULTS Effects of i.v. FCE 20700 on stimulated secretion in GF dogs. As reported in Fig. 1, FCE 20700, administered i.v. 1 h after heginning the infusion of pentagastrin, inhibited acid secretion. Threshold dose was 0.3 mcg/kg, while maximal inhibitory effects were obtained at the dose of 1.2 mcg/kg; at this dose the reduction of volume and TAOlasted for about 90 min (Fig. 1). Acid concentration was significantly inhibited by FCE 20700 (1.2 mcg/kg) 15 min after its injection (84.5 t 26.5 mEq/L versus 147.9 t 4.8 mEq/L; P < 0.05), although the lowering in gastric acidity was due in part to biliary reflux into the stomach.
Fig. 1 -
Inhibition,
by intravenous
by pentagostrin * = P < 0.05
On
histamine-stimulated
FCE 20700,
(1 mcg/kg/h)
of acid secretion
in the dog with gastric
stimulated fistula
(No=4).
** = P < 0.01 secretion,
i.v.
FCE 20700 significantly
inhibited volume and TAO (Fig. 2), while reduction in acid concentration was not significant (131.4 + 8.8 mEq/L versus 145.8 + 3.3 mEq/L; n.s.). Maximal inhibition in TAO was obtained with the dose of 1.2 mcg/kg, the duration of inhibition being more transient than in the case of pentagastrin-stimulated secretion (Fig. 2).
13
FcE20700
WhOCd
0.6 mcg/kp ---
_--_
mEq tot HCI
7000_
histamine
F’X 20700
FCE 207M
1.2 mq/kg --
2.4 mse/b -
40 mcg/kg/h
4 FCE 20700 6000. 5000 _
B
15
30
45
60 75 minute3
histamine
ml
90
105
120
135
150
40 mcg/kg/h
40_
4
4 FCE 20700
35 _ 30 _ 25 _ 20. 15. 10.
0 9
Fig. 2 -
15
30
45
6kinu75_
Inhibition, by intravenous by histamine
(40
* = P < 0.05
90
FCE 20700.
mcg/kg/h)
105
120
135
1 150
of acid secretion
stimulated
in the dog with gastric fistula
(No=4).
+* = P < 0.01
infusion (2 mcg/kg/h over acid and pepsin output were 30 min) to GF dogs stimulated with 2DG, 3). In this case the volume was significantly inhibited (Fig.
When FCE 20700
was
administered
by
continuous
significantly reduced (22.5 + 3.6 ml versus 33.5 + 2.2 ml at the 45 min; P< 0.05), while acidity (119.3 + 7.8 mEq/L versus 128.4 ) 11.5 mEq/L; n.s.) and pepsin concentration (0.26 + 0.04 mg/ml versus 0.24 + 0.07 mg/ml; n.s.) were not significantly modified. Effects of i.g. FCE 20700 on
stimulated
secretion
in
GF
and
HP dogs.
As reported in Fig. 4, FCE 20700 administered i.g. to dogs chronically fitted with both GF and HP, inhibited acid secretion stimulated by pentagastrin. However the reduction in volume and in TAO was significant for both the doses tested only in the case of HP, as the
14
volume and TAO from GF were not significantly modified (Fig. 4). By contrast acid concentration from both GF (66.2 + 12.5 mEq/L vs. 94.4 + 19.8 mEq/L) and HP (90.7 + 8.1 mEq/L vs. 123.5 5 5.2 mEq/L) was not affected by FCE 20700. After histamine stimulation, volume and TAO from HP were dose-dependently inhibited by FCE 20700 (Fig. 5). Acid
FcE2o700 maumcd
zmcp/lcg/h --
-_--
A
5000_
4500. 40GQ.
FCE 20700 m
2 DG __a--..
‘\
I< /’
3!wo_
‘\.
xxm. 2500-
B
lo_ 9_
FCE 20700 -2
DG
8.
,’
--..
f j-
\
-
-
y--Y \
15
30
45
\
“‘...___y~
-
is,, , , , E
Fig. 3 -
‘-._
:
6.
jj
-.
I’
7. 5. 4,
:---._
60
minutas
75
90
(
(
105 120
Inhibition. by introvenous FCE 20700, of acid (A) ond pepsin (B) secretion stimuloted by 2-deoxy-D-glucose (2 DG, 200 mg/kg i.v.) in the dog with gastric fistula (No = 4).
concentration from HP was significantly reduced by FCE 20700 2.5 mcg/kg (126.3 + 5.9 mEq/L vs. 147.9 + 9.8 mEq/L), while the dose of 5 mcg/kg did not induce a significant inhibition (144.9 + 4.2 mEq/L vs 147.9 + 9.8 mEq/L). Volume and acidity from GF were not significantly reduced, while TAO was inhibited by both the doses of FCE 20700 (Fig. 6).
15
5 mc9/kp -
2.5 WI/$ --
____
600, mEq tot I-ICI
FCE 207W
FCE 20700
uethawl
1 mcg/kg/h
pentagastrin
+ FCE 20700
700 _ /
I “.
4
‘\
600 _ 500 _ 400. 300 . 200 100 O_
B
15
30
45
60
75
90
105
120
135
150
minutes
7
ml
pentagastrin
1 mcg/kg/h 4
+ FCE 20700 6
B
Fig.
4 -
15
30
45
tinu;i
90
105
120
135
150
Inhibition, by intragastric FCE 20700, of acid secretion stimulated by pentagastrin (1 mcg/kg/h) in the dog with Heidenhein pouch (No=4) ** = P < 0.01 * = P < 0.05
16
M#local ___-
,200
mEq tot HCI
4
FCE207w =fJ=ah4 --
FCE20700 Smw/b -
histamine 40 mcg/kg/h t FCE 20700 _______.
4
1000. 800. 600. 400. 200. O_ minutea
9 ml 8
Fig. 5 -
histamine 40 mcg/kg/h 4 FCE 20700
4
Inhibition, by intragastric FCE 20700, of acid secretion stimulated by histamine (40 mcg/kg/h) in the dog with Heidenhain pouch (No=4). ** = P < 0.01 * = P < 0.05
17
Fig. 6 - Inhibition. by introgastric by histamine
FCE 20700,
(40 mcg/kg/h)
of acid secretion
in the dog with gastric
stimulated
fistula (No=4)
** = P < 0.01
DISCUSSION
The present study indicates that FCE 20700 possesses a weak and short lasting antisecretory activity in the dog. The main effect of FCE 20700 was indeed to lower the volume of gastric juice with little acid concentration change. This effect was generally independent from the type of stimulant, as FCE 20700 inhibited acid secretion induced by agents acting directly on parietal cells (histamine or pentagastrin) or by vagally mediated pathways (2DG). However FCE 20700 showed greatest activity in inhibiting acid secretion stimulated by 2DG, in agreement with the results obtained with natural prostaglandin E in the dog by Nezamis et al. (4). FCE 20700 was active by both i.v.land i.g. route, although the i.g. route was from 6 to 8 times less effective than i.v. one. The difference in activity between the different routes of administration has been also observed with other prostaglandin derivatives in experimental animals and in humans (17; 18; 8). The finding that i.g. FCE 20700 was more active on HP than GF suggests that FCE 20700 is well absorbed by the stomach or that HP is more sensitive than GF to this antisecretory drug. Furthermore the present results showing that FCE 20700 decreases pepsin output, without an effect on pepsin concentration, confirms previous experiments with natural or synthetic prostaglandins (4; 19; 8). As far as side-effects are concerned, it has been reported that FCE 20700 induces diarrhoea in rats at very high doses compared to
18
cytoprotective ones and does not affect C.N.S., endocrine andplatelet system (20). In the present study, when FCE 20700 was administered at very high doses, we observed, in some instance, vomiting and biliary reflux into the stomach of the dog. However, it is worth mentioning that in one dog vomiting was also produced by the administration of the vehicle. In conclusion, the present results confirm also in dogs the weak antisecretory activity of FCE 20700 observed in rats (15) and indicate that antiulcer effects of this prostaglandin derivative are largely independent from its influence on gastric acid and pepsin secretion. REFERENCES 1.
Coceani F, Pace-Asciak C, Volta F, Wolfe LS. Effect of nerve stimulation on prostaglandin formation and release from the rat stomach. Am. J. Physiol. 213:1056, 1967.
2. Bennet A, Murray JC, Willie JG. Occurrence of prostaglandin E
in
the human stomach and a study of its effects on human isolates gastric muscle. Br. J. Pharmacol. Chemother. 32:339, 1968. 3. Ramwell PW, Shaw JE. Prostaglandin inhibition of gastric secretion. J. Physiol. 281:34P, 1968. 4. Nezamis JE, Robert A, Stewe DF. Inhibition by prostaglandin E
1
of
gastric secretion in the dog. J. Physiol. 281:369, 1971. 5. Wilson ED, Levine RA. The effect of prostaglandin E gastric acid secretion and gastric mucosal blood f&w.
on canine Am. J. Dig.
Dis. 17:527, 1972. 6. Main IHM, Whittle BJR. The effect of E and A prostaglandins on gastric mucosal blood flow and acid secretion in the rat. Br. J. Pharmacol. 49:428, 1973. 7. Sol1 AH. Specific inhi$ition by prostaglandin E and I2 of C aminopyrine accumulati$n and cyclic histamine stimulated adenosine monophosphate generation by isolated parietal cells. J. Clin. Invest. 65:1222, 1980. 8. Bauer RF. Misoprostol: preclinical pharmacology. Dig. Dis. Sci. 30 (Nov. Suppl.):118S, 1985. 9. Robert A. Cytoprotection by prostaglandin. Gastroenterology 77: 761, 1979.
19
10. Dajani EZ, Callison DA, Berstermann RE. Effects of E prostaglandins on canine gastric potential difference. Dig. Dis. Sci. 23:436,1978. 11. Scarpignato C, Spina G, Signorini GC, Bertaccini G. Action of MDL 646, a new synthetic prostaglandin, on gastric acid secretion of some experimental animals. Res. Commun. Chem. Pathol. Pharmacol. 39:211, 1983. 12. Ohno T, Yamaguchi Y, Yajima T, Nakamura K. The antiulcerogenic and cytoprotective effects of trimoprostil (R-21-6937) in experimental animals. Folia Pharmacol. Jpn. 82:131, 1983. 13. Bianchi RG, Casler JJ, Dajani EZ. Gastric antisecretory and antiulcer activity of SC 29333: a synthetic E-prostaglandin analogue. Pharmacologist 23:121, 1981. 14. Ceserani R, Arrigoni C, Mizzotti B, Tremolada L, Ferrari M, Buttinoni A. FCE 20700, a cytoprotective PGE2 derivative, does not interfere with the antiinflammatory activity of indomethacin. Int. J. Tiss. Reac. 5:349, 1983. 15. Arrigoni C, Mizzotti B, Toti D, Faustini F, Ceserani R. Cytoprotective and antisecretory effects of ll-deoxy-13,14-didehydro-16(S)-methyl PGE2 methylester (FCE 20700). Prost. Leukotr.Med. 15:79, 1984. 16. Berstad A. A modified hemoglobin substrate method for the estimation of pepsin in gastric juice. Stand. J. Gastroenterol. 5:343. 1970. 17. Dajani EZ, Callison DA. Gastric antisecretory actions of 15(S),15methyl prostaglandin E2 methyl ester and natural prostaglandin E2 in rhesus monkeys. Prostaglandins 11:799, 1976. 18. Reele SB, Bohan D. Oral antisecreotry activity of prostaglandin E in man. Dig. Dis. Sci. 29: 390, 1984.
2
19. Robert A. Prostaglandins and the gastrointestinal tract. p. 1407 in Physiology of gastrointestinal tract.(LR Johnson ed), Raven Press, New York, 1981. 20. Ceserani R, Arrigoni C, Mizzotti B, Soldani G, Costa G. Pharmacological activity of a new antiulcer: FCE 20700 (ll-deoxy13,14-didehydro-16(S)-methyl PGE2 methylester). 4th Congress of the Hungarian Pharmacological Society with International Participation, August 27-29, 1985, Abstract book, p. 19.
20
(1987)
26,
I I-20
THE INFLUENCE OF A NEW PROSTAGLANDIN E2 ANALOGUE (FCE 20700) ONGASTRIC ACID AND PEPSIN SECRETION IN THE DOG. 1 C. Arrigoni and ‘R. Ceserani. Laboratory of G. Soldani, G. MengOZZi, yharmacology.Veterinary Medical Clinic. University of Pisa. Italy: Biological Research and Development. Farmitalia-CarloErba, Milan, Italy (Reprint requests to GS). ABSTRACT The effects of FCE 20700, a new prostaglandin E2 analogue,ongastric acid and pepsin secretion stimulated by different secretagogueswere studied in dogs. Intravenous FCE 20700 produced a significant inhibition of total acid output (TAO) induced by pentagastrin or histamine in gastric fistula (GF) dogs. This effect was short-lasting and mainly due to a reduction in the volume of gastric juice with little acid concentration change. TAO and pepsin output stimulated by 2-deoxy-D-glucosewere simililarly inhibited by intravenous FCE 20700. In dogs chronically fitted with both GF and Heidenhain pouch (HP), intragastric FCE 20700 significantly inhibited TAO stimulated by pentagastrin or histamine from HP, while acid secretion from GF wasnot significantly affected. It is concluded that FCE 20700 possesses aweak antisecretory activity in dogs. Consequently the antiulcer effects of this prostaglandin derivative seem to be largely independent from its influence on gastric acid and pepsin secretion. INTRODUCTION Prostaglandins,particularly those of the E series, have been identified in the gastric mucosa (1, 2) and inhibit basal and stimulated gastric acid secretion in experimental animals both in vivo (3, 4, 5, 6) and in vitro (7, 8). Moreover, at non antisecretory doses, prostaglandins prevent gastric mucosal damage produced by noxious agnets, a property that has been named cytoprotection (9). However the lack of oral activity, the short duration of action and a
11
variety of side effects have prevented the clinical use of natural prostaglandins as therapeutic agents for peptic ulcer disease.Several prostaglandin analogue have been consequently synthesized with improved pharmacological profile (10, 11, 12, 13). Recently it has
been
reported
that a new prostaglandin E2 analogue, ll-deoxy-13,14-didehydro-16(S)methyl PGE2 methylester (FCE 20700) possesses cytoprotective and antisecretory activities in the rat (14, 15). The present study was carried out to characterize the influence of the prostaglandin E2 analogue, FCE 20700, on gastric acid and pepsin secretion in conscious dogs. MATERIALS AND METHODS Six female mongrel dogs (lo-18 kg b.w.) were preparedwith agastric fistula (GF) on the corpus of the stomach and four female mongrel dogs (14-21 kg b.w.) were prepared with both a GF on the corpus of the vagally innervated main stomach and a vagally denervated Heidenhain pouch (HP) of the fundus. Four weeks were allowed for surgery before experiments were begun. The dogs were deprived of food but not ofwater for 18 h before each experiment. At least 48 h elapsed between each test. In a first series of experiments performed in dogs with GF, gastric secretion was stimulated by continuous intravenous (i.v.) infusion of pentagastrin (lmcg/kg/h) or histamine (40mcg/kg/h) or by an i.v. bolus of 2 deoxy-D-glucose (2DG; 200 mg/kg). In these experiments FCE 20700 (0.3 - 0.6 - 1.2 and 0.6 - 1.2 - 2.4mcg/kg) was administered by i.v. bolus during the secretory plateau induced by pentagastrin or hjstamine and by continuous i.v. infusion (2mcg/kg/h over 30 min) before the injection of 2DG. In a second series of experiments in dogs with both GF and HP, gastric acid secretion was stimulated by pentagastrin (lmcg/kg/h)or histamine (40mcg/kg/h). FCE 20700 (2.5 - 5.0 mcg/kg ina volume of 5 ml of vehicle) or the same volume of vehicle was given intragastrically (i.g.) 1 h after starting secretagogue infusion and the GF closed for 30 min. Gastric juice collected from GF and HP by gravity drainage was measured andanaliquot titrated to pH 7 with NaOH C.OlN by electrometric titration (TTS 822, Radiometer, Copenhagen, Denmark). Total acid output (TAO)was calculated in mEq H+/15 min. Pepsin concentration was determined by the method of Berstad (16) and the output calculated bymultiplying
the ml of gastric
juice of each sample by the pepsin concentration. Drugs, statistics. The following drugs were used: FCE 20700 (Farmitalia Carlo Erba, Milan, Italy), pentagastrin (Peptavlon, ICI, Alderley Edge, UK), 2-deoxy-D-glucose (2DG) and histamine dihydrochloride (Calbiochem, La Jolla, CA, USA). Doses of histamine refer to the salt. All drugswere dissolved in 0.9% NaCl, except for FCE 20700. FCE 20700 was dissolved
12
in absolute ethanol
at
the concentration of 10
mg/ml,
stored at -2O'C
and diluted before the use to the desired concentration by suspension in 0.5% hydroxy-methylcellulose (Methocel A 4C Premium, Dow Chemical Europe, Horgen, Switzerland) + 0.1% Tween 80 (Carlo Erba, Milan, Italy). Statistical analysis of data was performed by 3-way ANOVA (2 fixed factors: treatments and times and 1 random factor: dogs). When the interactions "times x treatments" was significant, a Dunnett's test at each time was performed in order to compare each treatment group versus control group. RESULTS Effects of i.v. FCE 20700 on stimulated secretion in GF dogs. As reported in Fig. 1, FCE 20700, administered i.v. 1 h after heginning the infusion of pentagastrin, inhibited acid secretion. Threshold dose was 0.3 mcg/kg, while maximal inhibitory effects were obtained at the dose of 1.2 mcg/kg; at this dose the reduction of volume and TAOlasted for about 90 min (Fig. 1). Acid concentration was significantly inhibited by FCE 20700 (1.2 mcg/kg) 15 min after its injection (84.5 t 26.5 mEq/L versus 147.9 t 4.8 mEq/L; P < 0.05), although the lowering in gastric acidity was due in part to biliary reflux into the stomach.
Fig. 1 -
Inhibition,
by intravenous
by pentagostrin * = P < 0.05
On
histamine-stimulated
FCE 20700,
(1 mcg/kg/h)
of acid secretion
in the dog with gastric
stimulated fistula
(No=4).
** = P < 0.01 secretion,
i.v.
FCE 20700 significantly
inhibited volume and TAO (Fig. 2), while reduction in acid concentration was not significant (131.4 + 8.8 mEq/L versus 145.8 + 3.3 mEq/L; n.s.). Maximal inhibition in TAO was obtained with the dose of 1.2 mcg/kg, the duration of inhibition being more transient than in the case of pentagastrin-stimulated secretion (Fig. 2).
13
FcE20700
WhOCd
0.6 mcg/kp ---
_--_
mEq tot HCI
7000_
histamine
F’X 20700
FCE 207M
1.2 mq/kg --
2.4 mse/b -
40 mcg/kg/h
4 FCE 20700 6000. 5000 _
B
15
30
45
60 75 minute3
histamine
ml
90
105
120
135
150
40 mcg/kg/h
40_
4
4 FCE 20700
35 _ 30 _ 25 _ 20. 15. 10.
0 9
Fig. 2 -
15
30
45
6kinu75_
Inhibition, by intravenous by histamine
(40
* = P < 0.05
90
FCE 20700.
mcg/kg/h)
105
120
135
1 150
of acid secretion
stimulated
in the dog with gastric fistula
(No=4).
+* = P < 0.01
infusion (2 mcg/kg/h over acid and pepsin output were 30 min) to GF dogs stimulated with 2DG, 3). In this case the volume was significantly inhibited (Fig.
When FCE 20700
was
administered
by
continuous
significantly reduced (22.5 + 3.6 ml versus 33.5 + 2.2 ml at the 45 min; P< 0.05), while acidity (119.3 + 7.8 mEq/L versus 128.4 ) 11.5 mEq/L; n.s.) and pepsin concentration (0.26 + 0.04 mg/ml versus 0.24 + 0.07 mg/ml; n.s.) were not significantly modified. Effects of i.g. FCE 20700 on
stimulated
secretion
in
GF
and
HP dogs.
As reported in Fig. 4, FCE 20700 administered i.g. to dogs chronically fitted with both GF and HP, inhibited acid secretion stimulated by pentagastrin. However the reduction in volume and in TAO was significant for both the doses tested only in the case of HP, as the
14
volume and TAO from GF were not significantly modified (Fig. 4). By contrast acid concentration from both GF (66.2 + 12.5 mEq/L vs. 94.4 + 19.8 mEq/L) and HP (90.7 + 8.1 mEq/L vs. 123.5 5 5.2 mEq/L) was not affected by FCE 20700. After histamine stimulation, volume and TAO from HP were dose-dependently inhibited by FCE 20700 (Fig. 5). Acid
FcE2o700 maumcd
zmcp/lcg/h --
-_--
A
5000_
4500. 40GQ.
FCE 20700 m
2 DG __a--..
‘\
I< /’
3!wo_
‘\.
xxm. 2500-
B
lo_ 9_
FCE 20700 -2
DG
8.
,’
--..
f j-
\
-
-
y--Y \
15
30
45
\
“‘...___y~
-
is,, , , , E
Fig. 3 -
‘-._
:
6.
jj
-.
I’
7. 5. 4,
:---._
60
minutas
75
90
(
(
105 120
Inhibition. by introvenous FCE 20700, of acid (A) ond pepsin (B) secretion stimuloted by 2-deoxy-D-glucose (2 DG, 200 mg/kg i.v.) in the dog with gastric fistula (No = 4).
concentration from HP was significantly reduced by FCE 20700 2.5 mcg/kg (126.3 + 5.9 mEq/L vs. 147.9 + 9.8 mEq/L), while the dose of 5 mcg/kg did not induce a significant inhibition (144.9 + 4.2 mEq/L vs 147.9 + 9.8 mEq/L). Volume and acidity from GF were not significantly reduced, while TAO was inhibited by both the doses of FCE 20700 (Fig. 6).
15
5 mc9/kp -
2.5 WI/$ --
____
600, mEq tot I-ICI
FCE 207W
FCE 20700
uethawl
1 mcg/kg/h
pentagastrin
+ FCE 20700
700 _ /
I “.
4
‘\
600 _ 500 _ 400. 300 . 200 100 O_
B
15
30
45
60
75
90
105
120
135
150
minutes
7
ml
pentagastrin
1 mcg/kg/h 4
+ FCE 20700 6
B
Fig.
4 -
15
30
45
tinu;i
90
105
120
135
150
Inhibition, by intragastric FCE 20700, of acid secretion stimulated by pentagastrin (1 mcg/kg/h) in the dog with Heidenhein pouch (No=4) ** = P < 0.01 * = P < 0.05
16
M#local ___-
,200
mEq tot HCI
4
FCE207w =fJ=ah4 --
FCE20700 Smw/b -
histamine 40 mcg/kg/h t FCE 20700 _______.
4
1000. 800. 600. 400. 200. O_ minutea
9 ml 8
Fig. 5 -
histamine 40 mcg/kg/h 4 FCE 20700
4
Inhibition, by intragastric FCE 20700, of acid secretion stimulated by histamine (40 mcg/kg/h) in the dog with Heidenhain pouch (No=4). ** = P < 0.01 * = P < 0.05
17
Fig. 6 - Inhibition. by introgastric by histamine
FCE 20700,
(40 mcg/kg/h)
of acid secretion
in the dog with gastric
stimulated
fistula (No=4)
** = P < 0.01
DISCUSSION
The present study indicates that FCE 20700 possesses a weak and short lasting antisecretory activity in the dog. The main effect of FCE 20700 was indeed to lower the volume of gastric juice with little acid concentration change. This effect was generally independent from the type of stimulant, as FCE 20700 inhibited acid secretion induced by agents acting directly on parietal cells (histamine or pentagastrin) or by vagally mediated pathways (2DG). However FCE 20700 showed greatest activity in inhibiting acid secretion stimulated by 2DG, in agreement with the results obtained with natural prostaglandin E in the dog by Nezamis et al. (4). FCE 20700 was active by both i.v.land i.g. route, although the i.g. route was from 6 to 8 times less effective than i.v. one. The difference in activity between the different routes of administration has been also observed with other prostaglandin derivatives in experimental animals and in humans (17; 18; 8). The finding that i.g. FCE 20700 was more active on HP than GF suggests that FCE 20700 is well absorbed by the stomach or that HP is more sensitive than GF to this antisecretory drug. Furthermore the present results showing that FCE 20700 decreases pepsin output, without an effect on pepsin concentration, confirms previous experiments with natural or synthetic prostaglandins (4; 19; 8). As far as side-effects are concerned, it has been reported that FCE 20700 induces diarrhoea in rats at very high doses compared to
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cytoprotective ones and does not affect C.N.S., endocrine andplatelet system (20). In the present study, when FCE 20700 was administered at very high doses, we observed, in some instance, vomiting and biliary reflux into the stomach of the dog. However, it is worth mentioning that in one dog vomiting was also produced by the administration of the vehicle. In conclusion, the present results confirm also in dogs the weak antisecretory activity of FCE 20700 observed in rats (15) and indicate that antiulcer effects of this prostaglandin derivative are largely independent from its influence on gastric acid and pepsin secretion. REFERENCES 1.
Coceani F, Pace-Asciak C, Volta F, Wolfe LS. Effect of nerve stimulation on prostaglandin formation and release from the rat stomach. Am. J. Physiol. 213:1056, 1967.
2. Bennet A, Murray JC, Willie JG. Occurrence of prostaglandin E
in
the human stomach and a study of its effects on human isolates gastric muscle. Br. J. Pharmacol. Chemother. 32:339, 1968. 3. Ramwell PW, Shaw JE. Prostaglandin inhibition of gastric secretion. J. Physiol. 281:34P, 1968. 4. Nezamis JE, Robert A, Stewe DF. Inhibition by prostaglandin E
1
of
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Dis. 17:527, 1972. 6. Main IHM, Whittle BJR. The effect of E and A prostaglandins on gastric mucosal blood flow and acid secretion in the rat. Br. J. Pharmacol. 49:428, 1973. 7. Sol1 AH. Specific inhi$ition by prostaglandin E and I2 of C aminopyrine accumulati$n and cyclic histamine stimulated adenosine monophosphate generation by isolated parietal cells. J. Clin. Invest. 65:1222, 1980. 8. Bauer RF. Misoprostol: preclinical pharmacology. Dig. Dis. Sci. 30 (Nov. Suppl.):118S, 1985. 9. Robert A. Cytoprotection by prostaglandin. Gastroenterology 77: 761, 1979.
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10. Dajani EZ, Callison DA, Berstermann RE. Effects of E prostaglandins on canine gastric potential difference. Dig. Dis. Sci. 23:436,1978. 11. Scarpignato C, Spina G, Signorini GC, Bertaccini G. Action of MDL 646, a new synthetic prostaglandin, on gastric acid secretion of some experimental animals. Res. Commun. Chem. Pathol. Pharmacol. 39:211, 1983. 12. Ohno T, Yamaguchi Y, Yajima T, Nakamura K. The antiulcerogenic and cytoprotective effects of trimoprostil (R-21-6937) in experimental animals. Folia Pharmacol. Jpn. 82:131, 1983. 13. Bianchi RG, Casler JJ, Dajani EZ. Gastric antisecretory and antiulcer activity of SC 29333: a synthetic E-prostaglandin analogue. Pharmacologist 23:121, 1981. 14. Ceserani R, Arrigoni C, Mizzotti B, Tremolada L, Ferrari M, Buttinoni A. FCE 20700, a cytoprotective PGE2 derivative, does not interfere with the antiinflammatory activity of indomethacin. Int. J. Tiss. Reac. 5:349, 1983. 15. Arrigoni C, Mizzotti B, Toti D, Faustini F, Ceserani R. Cytoprotective and antisecretory effects of ll-deoxy-13,14-didehydro-16(S)-methyl PGE2 methylester (FCE 20700). Prost. Leukotr.Med. 15:79, 1984. 16. Berstad A. A modified hemoglobin substrate method for the estimation of pepsin in gastric juice. Stand. J. Gastroenterol. 5:343. 1970. 17. Dajani EZ, Callison DA. Gastric antisecretory actions of 15(S),15methyl prostaglandin E2 methyl ester and natural prostaglandin E2 in rhesus monkeys. Prostaglandins 11:799, 1976. 18. Reele SB, Bohan D. Oral antisecreotry activity of prostaglandin E in man. Dig. Dis. Sci. 29: 390, 1984.
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19. Robert A. Prostaglandins and the gastrointestinal tract. p. 1407 in Physiology of gastrointestinal tract.(LR Johnson ed), Raven Press, New York, 1981. 20. Ceserani R, Arrigoni C, Mizzotti B, Soldani G, Costa G. Pharmacological activity of a new antiulcer: FCE 20700 (ll-deoxy13,14-didehydro-16(S)-methyl PGE2 methylester). 4th Congress of the Hungarian Pharmacological Society with International Participation, August 27-29, 1985, Abstract book, p. 19.
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