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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL
Pharmacology Laboratory, GPRD Discovery, Abbott Japan Co., Ltd., Fukui, Japan
Received January 28, 2003; accepted April 15, 2003.
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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,
1991;
Harasawa and Miwa, 1993).
Mosapride was also reported to stimulate upper gastrointestinal motility in
vivo and in vitro (Mine et al.,
1997). On the other hand, cisapride hydrate (cisapride) was
reported to stimulate motor activity not only in the stomach but also in the
colon in conscious dogs (Yoshida et al.,
1991). Although cisapride was only prescribed for the treatment of
reflux oesophagitis or heartburn in the United States, cisapride was thought
to be useful in improving patients with constipation as well as functional
dyspepsia, gastroparesis, and gastric stasis
(McCallum et al., 1988).
Recently, it became problematic to use cisapride for the treatment of patients
with gastrointestinal disorders because of its side effects, namely, heart
rhythm disturbances, including QT prolongation, syncope, and serious
ventricular arrhythmias such as torsades de pointes
(Barbey et al., 2000). Under
this situation, new gastroprointestinal prokinetic agents are required for the
remedy of functional bowel disorders such as functional constipation. A novel
5-HT4 receptor agent, tegaserod, was recently accepted in the
United States as an agent for the female irritable bowel syndrome patients
complaining of constipation. However, there are little useful data showing the
stimulatory action of clinically available gastroprokinetics on colonic
motility. Therefore, we investigated the effects of itopride on colonic motility and in vitro and in vivo transit in comparison with cisapride and mosapride, to determine the possibility of using itopride as a remedy for functional bowel disorders as well as functional dyspepsia.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Contractile Activity in Isolated Guinea Pig Colon. Guinea pigs were
stunned by a blow on the head and exsanguinated. Segments (8 cm) of proximal
colon in the distance of 5 cm from the ileo-cecal junction and distal colon in
the distance of 5 cm from the anus were dissected, and the luminal contents
were washed out. The preparations were horizontally mounted in a 50-ml organ
bath containing Krebs' solution (composition 118 mM NaCl, 4.7 mM KCl, 1.2 mM
KH2PO4, 1.2 mM MgSO4, 2.6 mM
CaCl2, 25.0 mM NaHCO3, and 11.1 mM glucose) bubbled with
a mixture of 95% O2 and 5% CO2. Spontaneous contractions
were evoked according to a modified method of Bülbring and Lin
(1958).
The oral and aboral ends of the colonic segment were fastened over to the respective tubes in the organ bath. The oral end was connected to a syringe pump (STC-525; TERUMO, Tokyo, Japan). The intraluminal pressure was measured at the aboral side by connecting to a pressure transducer (TP-400T; Nihon Kohden Co., Tokyo, Japan) and recorded in the computer system. The intraluminal pressure was applied to the colon by infusing Krebs' solution into the colon with the use of the syringe pump at the speed of 2 ml/min. When long-lasting peristalsis was triggered as the visible contractions composed of peristaltic and segmental contractions, intraluminal pressure was considered to reach the threshold pressure and then the infusion was stopped to maintain the threshold pressure. The mean threshold pressure was about 3 cm H2O. Macroscopically, high- and low-amplitude contractions could be seen representing peristaltic and segmental motility, respectively. After this regular peristalsis was confirmed in the preparations, a single concentration of test drug was applied to the serosal side of the segment. For quantitative analysis, the contractions whose amplitudes were greater than 50 or were 10 to 50% of the highest contractions observed for the 15 min before application of the drugs were defined as peristaltic contractions or segmental contractions, respectively. The number of each contraction was counted using computer software (Eight Star; Star Medical, Tokyo, Japan), and the increase in frequency was expressed as the percentage of change of the frequency over the 15-min period after application of the drug compared with that in the preapplication period.
Contractile Activity in Conscious Dogs. Dogs were deprived of food 18 h before surgery with free access to water. Under general anesthesia with a mixture of nitrous oxide, oxygen, and enflurane (Ethrane; Abbott Laboratories, Chicago, IL), eight strain gauge force transducers (13 mm width x 8 mm depth, F-12IS; Star Medical) were implanted into the serosal side of the gastric body, gastric antrum, duodenum, upper and middle jejunum, ileum, and ascending and descending colon, in a direction that made it possible to measure circular muscle contractions. The sites of the implantation of the gastric body, gastric antrum, duodenum, upper and middle jejunum, ileum, and ascending and descending colon were 5 cm distal to the cardia, 5 cm proximal to the pylorus, 7 cm distal to the pylorus, 50 cm distal to the pylorus, in the middle of small intestine, 15 cm proximal to the cecum, 10 cm distal to the cecum, and nearest to the anus, respectively. The free end of the transducer was brought out through a skin incision between the scapulae and protected with a jacket. A silicon tube (2.0- mm o.d.; Kaneka Medix Corporation, Osaka, Japan) was inserted into the external jugular vein and sutured onto the adjacent skin as a route for the intravenous injection of the test drugs. The animals were allowed to recover for at least 10 days after this surgery before the commencement of the experiments.
The free end of the strain gauge force transducer was connected to an amplifier (FA-01; Star Medical) and contractile activity was recorded on a pen-writing recorder (WR-3701; GRAPHTEC, Tokyo, Japan) and simultaneously stored in a computer for quantitative analysis. The test drugs or solvent was given intravenously via the indwelling silicon tube after postprandial gastrointestinal motility became stable (more than 2 h after feeding). Drug was administered only once per day. Data for each contractile motor activity were stored continuously and then analyzed by means of a gastrointestinal motility measuring system (FA-01, FS-08M, and FB-01; Star Medical). The motor index was calculated by integrating the area under the contractile wave over every 30-min period and expressed as the percentage of change from the preadministration period.
Colonic Luminal Transit in Guinea Pigs and Rats. Colonic luminal
transit in guinea pigs and rats was examined with a slight modification of the
reported method (Ueda et al.,
1969). Each animal was anesthetized with pentobarbital sodium at
50 mg/kg i.p. and the cecum was exposed by laparotomy. A polyethylene tube
(1.2 mm o.d.; Natsume Seisakusho Co., Ltd., Tokyo, Japan) was inserted from
the small incision in the cecum to the beginning of the colon. The other end
of the tube came out through the back. The animals were allowed to adapt to
individual cages for more than 3 days.
Animals were deprived of food overnight before experiment. Test drugs were given orally. A marker [barium sulfate, 60% (w/v), 0.5 ml/animal] was administered through the colonic cannula 30 min later for the guinea pigs but immediately for the rats. The guinea pigs and rats were euthanized by cervical dislocation at 30 and 60 min, respectively, after administration of the marker. The colon was removed, and the length from the colo-cecal junction to the front traveling edge of the barium sulfate was measured. Colonic luminal transit was expressed as the percentage of distance traversed to the total length of the colon.
Gastric Emptying in Rats. A solution of 0.05% (w/v) phenol red in aqueous carboxymethyl cellulose [4.5% (w/v)] was used as a test meal. After an 18 h fast, test drug was administered orally and then the test meal was given 30 min later. Each rat was sacrificed at 15 min after the test meal administration, and the stomach was removed immediately.
The removed stomach containing residual phenol red solution was incised in 20 ml of distilled water and shaken for 10 min. The pieces of stomach were rinsed and discarded, and then the recovered phenol red solution was made up to a total volume of 40 ml with distilled water. The recovered phenol red solution was centrifuged at 3000 rpm for 10 min, and 3 ml of the supernatant was added to 2 ml of 1 M NaOH to develop the color. The absorbance at 558-nm wavelength of the solution was measured with a spectrophotometer (U-2000; Hitachi, Tokyo, Japan).
The gastric emptying (G.E.) for each rat was calculated according to the following formula: G.E. (%) = {1 – (amount of residual phenol red recovered 15 min after test meal administration)/(average amount of phenol red present in the stomach immediately after test meal administration)}x 100.
Drugs. Itopride, cisapride, and mosapride were synthesized by Abbott Japan Co., Ltd. Barium sulfate and phenol red were purchased from Wako Pure Chemicals (Osaka, Japan). Carboxymethyl cellulose was from Nakalai Tesque, Inc. (Kyoto, Japan).
Itopride was dissolved in saline or distilled water. Cisapride and mosapride were dissolved in a solution containing 1% lactic acid.
Statistical Analyses. All results are presented as means ± S.E.M. Statistical analysis of the in vivo data were performed with Williams' multiple range test. For the in vitro experiments, Student's t test was used to test the significance of any differences. Probability values less than 0.05 were considered statistically significant.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Effects on Gastrointestinal Motility in Conscious Dogs.
Figure 3 shows the stimulatory
effects of itopride (10 mg/kg i.v.), cisapride (0.3 mg/kg i.v.), and mosapride
(3 mg/kg i.v.) on the postprandial gastrointestinal motor activity in
conscious dogs. As shown in Figs.
3A and
4A, itopride dose dependently
stimulated gastrointestinal motility from the stomach through the colon,
although the stimulatory effect on the small intestine was weaker than for
other regions. Itopride enhanced contractile activities in the gastric antrum,
duodenum, and upper jejunum significantly at 3 mg/kg
(Fig. 4A). In the middle
jejunum, ileum, ascending colon, and descending colon, itopride stimulated
contractile activities significantly at 10 mg/kg
(Fig. 4A). Cisapride enhanced
antral, ileal, and colonic motility significantly at 0.03, 0.1, and 0.3 mg/kg,
respectively (Figs. 3B and
4B). On the other hand,
mosapride did not enhance colonic motility up to 3 mg/kg, although it
significantly stimulated antral and ileal motility at 1 and 3 mg/kg,
respectively (Figs. 3C and
4C). In addition, itopride
produced giant migrating contractions, which were high-amplitude, rapidly
migrating contractions that pro-pelled colonic contents to the rectum
(Sarna et al., 1984;
Karaus and Sarna, 1987),
followed by defecation in some dogs at 10 mg/kg, but this was not seen with
cisapride nor mosapride. Throughout this experiment, no behavioral changes
were observed.
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Colonic Transit in Guinea Pigs and Rats, and Gastric Emptying in Rats. Itopride accelerated colonic transit dose dependently in both guinea pigs and rats and significant acceleration was observed at 10 mg/kg p.o. in both animals (Figs. 5A and 6A). However, cisapride did not affect colonic transit significantly up to 10 mg/kg in guinea pigs and rats (Figs. 5B and 6B) nor did mosapride in guinea pigs (Fig. 5C). Moreover, mosapride slightly delayed colonic transit in rats, the delay being statistically significant at a dose of 1 mg/kg and above (Fig. 6C).
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In rats, itopride, cisapride, and mosapride all enhanced gastric emptying dose dependently (Fig. 7), with statistically significant effects being observed at doses of 10, 1, and 1 mg/kg, respectively. Therefore, itopride exerted stimulatory effects on gastric emptying and colonic transit at the same dose, whereas cisapride and mosapride were found not to accelerate colonic transit at 10 mg/kg p.o., a dose that was 10 times higher than that required to accelerate gastric emptying.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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,
1994). It is well established
that the M3 receptor exists on the smooth muscle layer throughout
the whole gut and that acetylcholine released from the enteric nerve endings
stimulates the contraction of smooth muscle through the M3
receptor. Therefore, we predicted that itopride might have a colonic
prokinetic action, but there was limited data with respect to the effects of
itopride on colonic motility. In this study, we evaluated the effects in vitro
and in vivo, in comparison with the benzamide derivatives cisapride and
mosapride, which both have a gastroprokinetic action with a 5-HT4
receptor agonist effect.
The in vitro study exhibited that cisapride and mosapride increased
segmental motility but inhibited the peristaltic motility in the isolated
guinea pig colon. Buchheit and Buhl
(1991,
1993) and Buchheit et al.
(1992) reported that benzamides
induced the inhibition of circular muscle contraction and an increase in
longitudinal muscle activity via 5-HT4 receptor activation.
Peristalsis is known to consist of the circular muscle contraction at oral
side and the relaxation at aboral side in the intestine. Although longitudinal
muscle contraction during the preparatory phase of peristalsis precedes
circular muscle contraction, the main propulsive drive in the peristaltic
reflex comes from the aborally directed contraction of the circular muscle
during the emptying phase (Kosterlitz et
al., 1956). Therefore, the peristalsis requires not only
coordination between contraction and relaxation in circular muscle but also
coordination between circular muscle and longitudinal muscle. Cisapride and
mosapride might collapse the coordinated peristalsis composed of peristaltic
and segmental motility due to their relaxant effects on the smooth muscles.
This could be responsible for their failure to have a stimulatory action on
colonic transit in guinea pigs and rats. Cisapride and mosapride both
decreased peristaltic motility in the isolated guinea pig colon, but mosapride
increased segmental motility in a concentration-dependent manner. Enhancement
of segmental motility not accompanied by peristaltic motility may interfere
with colonic transit in vivo. Stimulatory effect of mosapride on the segmental
motility seems stronger than that of cisapride and this explains that
mosapride did not accelerate colonic transit. In guinea pigs, cisapride tended
to accelerate colonic transit despite the in vitro inhibitory effect on the
peristaltic motility. The stimulatory effect of cisapride on the colonic
transit may be ascribed to the enhancement of gastric emptying and intestinal
motility. On the other hand, itopride enhanced both the peristaltic and
segmental motility in the isolated guinea pig colon. It is true that
stimulatory effects on the isolated gastrointestinal motility do not always
produce the propulsion of the luminal contents, but it was confirmed that the
stimulatory effects of itopride successfully increased colonic transit in
guinea pigs and rats.
In vivo studies using dogs and rats indicate gastrointestinal region
selectivity of the prokinetic action of each agent. As a result, cisapride and
mosapride selectively stimulated upper gastrointestinal motility, compared
with itopride. In conscious dogs, cisapride significantly stimulated antral
motility and the effective dose for antral motility was 10 times less than
that for colonic motility. Furthermore, mosapride failed to stimulate colonic
contractions. Our findings of the selectivity of cisapride and mosapride for
the stomach are consistent with the study by Mine at al.
(1997). Gastrointestinal
region selectivity for cisapride and mosapride was also demonstrated in rats.
Cisapride and mosapride had no stimulatory effect on the colonic transit at
the dose that was effective to enhance the gastric emptying. On the contrary,
itopride had stimulatory effects on all sites of the canine gastrointestinal
tract from the stomach through the colon. The effective dose of itopride
stimulating the canine colon was not more than 3 times greater than that
stimulating antral motility. In addition, itopride enhanced gastric emptying
and colonic transit at the same dose, 10 mg/kg, in rats.
Although stimulation of gastrointestinal motility by itopride is ascribed
to activation of the cholinergic drive based on D2 receptor
blocking and anti-AChE activity (Iwanaga et al.,
1990,
1994), the stimulatory action
on colonic motility seems mainly due to anti-AChE activity. Because
gastrointestinal smooth muscle is directly stimulated by ACh through the
activation of the M3 receptor irrespective of the gastrointestinal
site and animal species, it is apparent that itopride can stimulate colonic
contractions as well as antral contractions in all species. On the other hand,
benzamides, such as cisapride and mosapride, stimulate gastrointestinal
motility via activation of the 5-HT4 receptor (Yoshida et al.,
1991,
1993;
Mine et al., 1997). The
5-HT4 receptor is located on smooth muscle and the excitatory
neurons, which mediate relaxation and contractions, respectively. With regard
to stomach and colon, Sakurai-Yamashita et al.
(1999a,b)
reported that there are some differences in the 5-HT4 receptor
density between smooth muscle and the excitatory neurons. It can be
interpreted by the difference of 5-HT4 receptor localization
between stomach and colon that cisapride and mosapride both stimulated gastric
motility at lower doses than colonic motility. Moreover, the different effects
of cisapride and mosapride on colonic motility might be explained by a
distinct receptor binding affinity. Although mosapride exhibits no affinity
for the D2, adrenaline 
1, adrenaline
2, 5-HT1, and 5-HT2 receptors except
for the strong affinity for the 5-HT4 receptor, cisapride possesses
affinity for the D2, 5-HT2, 1, and
muscarinic receptors as well as the 5-HT4 receptor
(Yoshida et al., 1989;
Karasawa et al., 1990;
Briejer et al., 1995).
Recently, a 5-HT4 receptor partial agonist, tegaserod, was reported
to stimulate colonic motility in dogs
(Appel et al., 1996;
Nguyen et al., 1997) and
accelerate propulsion in isolated guinea pig colon
(Jin et al., 1999). It still
remains unclear but the difference of the effects on the colon among
tegaserod, cisapride, and mosapride might be related to the heterogeneity of
5-HT4 receptors between the stomach and the colon reported by
Gerald et al. (1995).
Differently from these benzamides, itopride had little affinity for
5-HT4 receptors in guinea pigs striatal membranes (pIC50
< 4) (Kakiuchi et al.,
1997), and it seems unlikely that itopride stimulates colonic
motility through the activation of 5-HT4 receptor.
Stimulation of gastrointestinal motility by itopride is ascribed to the
activation of the cholinergic drive based on D2 receptor blocking
and anti-AChE activity, but the stimulatory action on colonic motility seems
mainly due to anti-AChE activity. D2 receptor agonists domperidone
and metoclopramide are also accepted as gastroprokinetic agents. Domperidone
is a selective D2 receptor antagonist and metoclopramide possesses
5-HT4 receptor agonistic activity as well as D2 receptor
antagonistic activity. Although domperidone was reported to enhance the
gastric motor activity but not to stimulate small intestinal and colonic motor
activity in conscious dogs (Miyashita et
al., 1991).
A potent anti-AChE inhibitor, neostigmine is well known to improve
postoperative ileus, and it is worth while to notice that such old drug is
recently prescribed in patients with acute colonic pseudo-obstruction.
However, the use of neostigmine is limited because of its side effects.
Basically, neostigmine dose dependently and significantly enhanced the antral
and colinc motor activity in dogs at 30 and 100 µg/kg i.v. but tended to
increase blood pressure and to suppress respiration
(Kishibayashi et al., 1994).
Also, dogs often collapsed when neostigmine was intravenously administered at
1000 µg/kg (Iwanaga et al.,
1990). Itopride did not cause any adverse effects such as
salivation, snivel, vomiting, and diarrhea based on anti-AChE action
throughout our experiments. The inhibitory action of itopride on AChE was 100
times stronger than that on butyrylcholinesterase, whereas the inhibitory
action of neostigmine on AChE was 10 times stronger than that on
butyrylcholinesterase (Iwanaga et al.,
1994). The selectivity on AChE seems a cause of the differences of
safety window. Several studies on proarrhythmic potential of itopride
demonstrate that itopride is devoid of QT prolongation at least at the present
dose levels (Kakiuchi et al.,
1997). Furthermore, itopride was reported not to penetrate into
the blood-brain barrier (Yamada et al.,
1994).
In conclusion, it is anticipated that itopride could be of value as a safe and feasible alternative to other existing prokinetic agents for the treatment of functional bowel disorders such as functional constipation and constipation-dominant irritable bowel syndrome, without an excessive increase in dose.
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Footnotes |
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ABBREVIATIONS: 5-HT, 5-hydroxytryptamine; AChE, acetylcholinesterase.
Address correspondence to: Dr. Tadashi Tsubouchi, Research and Development Headquarters, Abbott Japan, Co., Ltd., 37-1-1, Inokuchi, Katsuyamacity, Fukui 911-8555, Japan. E-mail: tadashi.tsubouchi{at}abbott.com
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