CHEMOTHERAPY188

SEPT.1992

PHARMACOLOGICALEFFECTSOF CEFCLIDINONGASTROINTESTINAL
TRACT,SECRETORYFUNCTIONANDRENAL FUNCTION
Masatoshi

Fujimoto, Kanemasa Katsu, Takeru Kaneko and Hiroshi Yamauchi
Tsukuba Research Laboratories, Eisai Co., Ltd.

Algate, D.R., Baines, M.W., Jobling, C.M. Kerwin,
Departmentof Pharmacology,

Huntingdon

N.D. and Munt, P.L.,

Research

Centre Limited,

An examination of some general pharmacological effects of cefclidin (CFCL) and (CEZ)
cefazolin had been made. A range of standard pharmacological tests were used toinvestigate effects on the gastrointerstinal tract, secretory function and renal function.
Local anaesthetic activity was also evaluated.
Some increase in the activity of gastrointestinal smooth muscle was observed following
both CFCL and CEZ but there was no evidence of an effect on gastrointestinal
conduction speed. Secretory function was not affected by CFCL, however, changes ingastric secretion, bile secretion and pancreatic output were observed after CEZ.
The highest does of CFCL caused an increase in urine volume and Nat, K+, and Cl
excretion in rats, Whilst an increase in Nat was seen after CEZ no notable change in urine
output was recorded. Glomerular filtration rates were not affected.
CFCL and CEZ were devoid of local anaesthetic activity.
Key words : cefclidin, generalfunction.
Introduction(CFCL)
is a newCefclidin

pharmacology,

parenteralce-phalosporin synthesized by Eisai Co. Ltd, Japan. It
has a broad antibacterial
spectrumand potent
activity

againstgram-negative

Pseudomonas aeruginosa.
resistance to hydrolysis
variousbacteria

including

CFCL also showed highby and low affinity fortypes of P-lactamases.

This paper describes the results of the pharmacological studies with CFCL in comparison withcefazolin(CEZ) . CFCL and CEZ were each evaluat-

ed at two dose levels using a battery of standard
laboratory
tests designed to inverstigate the effecton the gastrointestinal
renal function.

tract, secretory

Local anaesthetic

function

activity

andwere also

inverstigated.
Materials

and Methods

1. Materials
1) Animals
Male and female Swiss derived25 g) ,

male

Wistarrats(150

CD-1 mice(20

436 g) ,male

gastrointestinal,

secretory

and

renal

Dunkin-Hartley guinea-pigs (312 382 g), andmale and female beagle dogs (9.3
17 kg), werehoused appropriately in air-conditioned temperature and humidity controlled rooms. The lighting
schedule was 12:12 light/dark.
The animals were fed an appropriate laboratory
diet. Tap water was available ad libitum except
where otherwise indicated.
2) Test compounds
CFCL and CEZ were dissolved in physiologicalsaline solution at different concentrations.
The other test materials used were cefazolin (CEZ)(Fujisawa PharmaceuticalCo., Ltd.), medicinal
harcoal, lidocaine, inulin, p-aminohippuriccacid(P.A.H.)(Sigma
Chemical Co., Limited): heparin (Evans
Pharmaceuticals)
chloralose (BDH
Limited): sodium thiopentone, sodium pentobarbitone (RMB Animal Health): frusemide (Hoechst): urethane (Aldrich Chemical Company Limited) mannitol (F.S.A. Laboratory Supplies) andVOL.40

Cefclidinの 消 化 器 系 ・腎 機 能 へ の 影 響

S‑4

Table

1. Effects of intravenous
the volum of stomach

189

administrationof cefclidin
and cefazolin
on ionic
contents,
and gastric damage
in the pylorus-ligatedconcentrations,rat(a) Expressed as mEq/vol

Significanceof difference

fromvehicle-treatedcontrolgroupsSignificanceof difference

fromvehicle-treatedgroupsusing

Kruskal-Wallis

using analysis

analysisof varianceof mean*:controlgroupsanalysisof variancep < 0.05* *:p<0.01p<0.05

* *:

ranks

(b) Expressed as mEq/ml

SignificanceAll groupsof difference
consistedfromvehicle-treatedof 10 animals

using

*:

p<0.01

CHEMOTHERAPY

190

sodium chloride (Animalcare
Limited). The materials were dissolved in a medium compatible withthe test procedure.
2. Methods
1) Effects

on gastrointestinal

motilityin themouse
Groups of 10 male mice were used in this experiment.
The method used was similar to that described
Takemoriby

et al1).

The mice were fasted overnight prior to the test but
water was available ad libitum.
CFCL and CEZ (1,000 andformulated
in saline
into a tail vein.
Immediately

mg/kg)

were

intravenously

after dosing each mouse received

oral dose of 0.25
medicinal charcoal
Exactly

2,000

administeredml ofin water.

thirty minutesa

5% suspension

anof

after dosing with charcoal

the mice were sacrificed
and the entire gastrointerstinal
tract wasquicklyandcarefully
removed.

The distancethat the charcoal

travelledfrom the pyloric sphincter
caecum was measured and expressed
age of thetotal2) Effects

intestinal

length.

on gastro-intestinalTable

2. Groupmean

pre-treatment
cefclidinn=10meal had

towards theas a percent-motility
percentage

in thechanges

(±SD)

SEPT.

1992

anaesthetised dog
Four female beagle dog were used in this experiment.
Prior to the commencement of the experiment,
the dogs were deprived of food for a period of notless than 16 hours. Anaesthesia was induced by an
intravenous injection of sodium thiopentone andmaintained by intravenous er-chloralose (60-80
mg/kg initially, and supplemented as required).
Catheters were introduced into a femoral
artery and a cephalic vein to facilitate measurement of blood pressure and the administration of
the test drugs and anaesthetic respectively. The
femoral arterial cannula was connected to a saline/
heparin (250 U/ml) -filled pressure transducer coupled to a chart recorder.
The trachea was cannulated to facilitate
unimpeded respiration.
Two smallsaline-filledrubberballoons
attached to catheter tubing were inserted into thestomach and lower small intestine via incisions
made in the duodenum and upper ileum, respectively. The cannulae were coupled to appropriatepressure transducers and the contractions of thestomach and small intestine were recorded on thechart recorder throughout the experiment.
in bile and pancreaticor pre-dose values) following intravenous

secretions (from mean

administrationof vehicle orCefclidinの 消 化 器 系 ・腎機 能 へ の 影 響
VOL.40

S‑4

191

Table

3. Group

mean

percentage

mean pre-treatment
vehicle or cefazolin

n= 10,
Table

Significance*: <0.05

4. Effects

unlessotherwiseof intravenousof difference
**:
<0.01

from
***:

changes(±SD)
in bile and pancreatic secretions (fromor pre-dose values) following intravenous administration ofstatedadministration

vehicle-treated<0.001

groupof cefclidin,

cefazolinusing Kruskal-Wallisand frusemide

analysison urineof meanranks

outputin the rat

CHEMOTHERAPY

192

Once baseline levels had stabilised,vehicle, CFCL

and CEZ were administered intravenously(5 ml/kg) with a minimum dose interval of 30 minutes.
3) Effects
Groupson gastricsecretionof 10 male rats

were

used

experiment
which was performed
described by Shay et al2)
The animals
hours priorable before

were fasted

for

this

essentiallyasfor approximately

18

to pyloric-ligation.
Water was availpyloric-ligation
but not during theexperiment.
The rats were anaesthetisedwith ether and an
incision was made in the abdomen. The duodenum
wasligated

0.5 cm below

thepyloric

sphincter.

Before the incision was sutured, 4 ml of warm 0.9%
saline was injected into the abdominal cavity
tominimise any stress effect.
Immediately after recovery
the animals
vehicle,werefrom the anaesthetic

intravenously

dosed with either

CFCL or CEZ at a constantof 10 ml/kg.
Five hours

after

dosing,thedose volume

animalswereanaesthetisedwith ether and the stomach of each
rat was carefully
removed after clamping
theoesophagus.

The rat was then killed by cervicaldislocation.

The

gastric

contents

wereanalysed for H+, Na,+ K+ and Cl- content
following methods

thenusing theH+ pH meter titration
Na+Flame photometryK+ Flame photometry
Cl + Roche Cobas centrifugal analysis
Each stomach was opened along the greater
ture and examined

macroscopicallycurva-

for damage

inthe glandular portion any damage was subjectively
scored using the following scoring system
0 = normal

3 = haemorrhages
4 = small ulcers ( 1 mm)
5 = large ulcers ( 1 mm)secretion

Twelve male rats were used in this experiment.
Each animal was anaesthetisedwith urethane (125mg/100facilitateg, i. p.).

The

respiration.

trachea

1992

nulated to permit measurement of blood pressureusing a heparin/saline-filled(250 U/ml) polyethylene catheter connected to a suitable pressuretransducer and chart recorder. Heart rate wasderived electronically from the blood pressure signal. The jugular vein was cannulated to facilitate
intravenous administration of vehicle (10 ml/kg),
CFCL and CEZ.
With the aid of a dissection microscope, oneparotid duct in each animal was cannulated using
polyethylene tubing of the widest possible internal
diameter. Saliva produced was collected in calibrated micropipettes (10 #1).
Following a twenty-minute stabilisation period,
vehicle (0.9% saline, 10 ml/kg) was administeredintravenously. This was followed at approximately 20-minute intervals by CFCL and CEZ. The
volume of saline secreted over the 20 minutepost-dose collection period was recorded.
5) Effect on bile and pancreatic secretions
Groups of 10 male rats were used in this experiment.
Rats were anaesthetised with urethane (5 ml/kg
of a 25% vv/v solution, i.p.). The animals weremaintained at 37c on a heated table and thetrachea was intubated to allow unimpeded respiration. A carotid artery and a jugular vein werecannulated to permit measurement of blood pressure and the administration of test drug respectively. The carotid arterial cannula was connected toa heparin/saline-lled(250 U/ml) pressure transducer, coupled with a suitable chart recorder. The
heart rate was electonically derived from thepressure signal.
The bile duct was isolated at the point before
entry into the pancreas and was cannulated at thatpoint with polyethylene tubing of the widest
possible diameter. The fluid was collected into
calibrated
100 ylglass
micropipettes(intraMARKR) and the volume of bile secretion
produced per 15-minute period was measured. A
second polyethylene cannula was inserted into the

1 = slight hyperaemia
2 = marked hyperaemia

4) Effect on salivary

SEPT.

was cannulated

The carotid

arterytowas can-pancreatic
duct at the point of entry into theduodenum and the flowof pancreatic secretion
was measured
in 10/41 glass micropipettes(intraMARKR).
The basal flow rate from both cannulae wasCefclidinの 消 化 器 系 ・腎機 能 へ の 影 響
VOL.40measuredfora minimum

minutesamples)

prior

ment.

Vehiclesingledoseof bile

and

was
of

on
of

this

tiallyasadministered,followed

by

CEZ

rat.

flow

in eachsecretions

were

at

45

least

urine

and

electrolyte

5 maleand5 femalewhich

described

were

On thematelyTheameasuredatminutes

after

test

day

volumeof 15ml/kg

metabolism
24
each

water

analysedetexperimentation

removedandapproxi-

CFCL

or

CEZ

using

by

oral
was

placed

urine

was

hours

and

the

volume

1,

3,

4,

2,

during
Na+,

the

in an

first

of

5 and

Cl-ions

5. Effects

of intravenous
content

from

rat

a

dose

individual
over

urine
24

hours

after
Urine

period
and

the

was
proteinadministrationof urine

vehicle-treatedtheexcret-recorded.

5-hourK+and

Significanceof difference*:<0.05**:<0.01***:<0.001

volumeatcontent using the following methods
Na+-Flame photometry
K+-Flamephotometry
Cl+-Roche Cobas Centrifugal Anaylser using
the BDH chloride reagent
Protein content
Roche Cobas Centrifugal
Analyser using the modified method of Macartand Gerbaut (Clin, Chim. Acta.1984,Issue
141,77)
7)Effect on renal function
Three female and one male beagle dogs were usedin this experiment.
Anaesthesia was induced by an intravenous injection of sodium thipentone and maintained inanaesthersia by intravenoue a-chloralose (initially
40-50mg/kg).The trachea was cannulated to facilitate breathing.
An incision was made in the lower abdomen andboth ureters were cannulated close to their junctions
with the bladder.
Both femoral veins and the right cephalic vein
were cannulated for the administration of theinfusates and test articles respectively.
A femoral artery was cannulated and connected
to a heparin/saline-filled(250U/ml)pressure

was

each

collected

waselectrolyte

dose

gavage

The

at

and

a

thereafter,

cage.

Table

al 3).

wasadministration

for

used
essen-

vehicle,salinerat

articlewereperformed

beforeImmediately

0.9%

collected

Lipschitz
hours

intravenously

received

by

by
18

later

10.0ml/kg.

following

rats

was

fasted.

2 hours

administeredtest(3•~15treat-

orexperimentanimalsed

minutesofforApproximatelyof45

administration

dose.

Groups

the

then

CFCL

intervals

6)Effect

in

of
to

pancreatic

15-minute
each

193

S-4

of cefclidin,

cefazolin

and collected

for 5 hours

group

Kruskal-Wallis

using

after

and frusemide

on the protein

drug

administration

analysisof mean

ranks

and

CHEMOTHERAPY

194

transducer coupled to a suitable chart recorder.
Heart rate was derived electronically from theblood pressure signal.
Blood samples (5 ml)
were obtained as required via the blood pressure
cannula and placed into a heparin tube. The
samples were centrifuged and the plasma removed
and frozen.
Both femoral venous cannulae were connected toTable

6. Assessmentof the local

Significanceof difference

Fisher'

test

exact

*:

from

p< 0.05anaesthetic

vehicle-treated
**:p<

0.01

activity

group

1992

Sage Model 355 syringe pumps, and were set todeliver 0.9% sodium chloride at 0.25 ml/kg/minute and inulin/P.A.H./mannitol

solution at a rate of

0.4 ml/minutethroughout the experiment.
Sixty minutes following the commencement

Ofthe

infusionswereblood and urine sample

collectionscommenced.
Urine samples were collected over 20
minute periods and a blood sample was removedof cefclidin

using

SEPT.

and cefazolin

using

the guinea-pig

cornealreflexCefclidinの 消 化 器 系 ・腎 機 能 へ の 影 響
VoL.40midwayVehicle,S‑4througheach urine collection
period.
CFCL
and
CEZ
were
administeredintravenously

using

an

interdoseintervalof 60

minutes.
The

rates

of renal(Glomerular filtration
calculated as follows

clearance

for

both

inulinroute)and

P.A.H.

were

UV/
Clearance

=
P

where

U = concentration of either inulin or P.A.
H. in the urine (mg/1)
V = volume of urine passed (ml/min)
P = concentration of either inulin or P.A.
H. in the plasma (mg/1)
8) Local anaesthetic activityi) Corneal reflex

Groups of five male guinea-pigs were used inthis experiment which was performed essentiallyas described by Chance and Lobstein4).
One drop (100 /21) of CFCL or CEZ was applied tothe cornea of the left eye of each animal and an
equal volume of vehicle administered tothecontralateral eye. Control animals received vehicle(100 #1) in both eyes.
ii) Weal test
Five male guinea-pigs were used in theexperiment which was performed according to themethod of Bulbring and Wadja5).
On the day prior to the experiment both flanks ofeach animal was depilated by shaving.
Intradermal injections of 0.1 ml of saline or test
drug were made into the marked sites on the
depilated flanks of the guinea-pigs. Each dilution oftest preparation was tested in five guinea-pigs.
The pain response to six light pinpricks were
determined at the site of drug application at intervals of 5 minutes for 30 minutes.
Results
1) Effects on gastrointestinal motility in the mouse.
Neither CFCL nor CEZ (1,000 and 2,000 mg/kg) caused any noteworthy effect on intestinal
motility when compared with vehicle-treated mice.
2) Effects on gastrointestinal
motility in theanaesthetised dog.
Motility of the stomach and small intestine weremonitored in four anaesthetised female beagle

195

dogs following intravenous administration of vehicle (5 ml/kg
0.9% saline), CEZ (300, 1,000
mg/kg) and CFCL (300, 1,000 mg/kg).
Stomach and intestinal motility were assessed as
the mean amplitude of contractions over fiveminute periods and by rate of contraction (mm-1),
averaged over five-minute periods also.
Intravenous administration of vehicle (5 ml/kg)
did not exert any effect on either arterial bloodpressure or gastro-intestinal motility.
Administration of CFCL at 1,000 mg/kg decreased stomach motility by up to 85% in all fouranimals. However, CFCL administered at 300 mg/
kg induced an increase in size of contractions in one
animal. No consistent effects on the rate ofstomach contraction were observed following
administration of CFCL at either dose.
Unlike its actions on stomach motility, CFCL
administered at 1000 mg/kg, increased the strengthof the contractions of the small intestine up to
approximately 2000%, but did not affect rate ofcontractions in any of the animals at this dose.
The effects after CFCL administration at 300 mg/
kg were variable.
CEZ at doses of 300 and 1,000 mg/kg had apositive effect on both stomach and small intestine
contractions. The strength of stomach contractions
was increased by up to 267% following the 300
mg/kg dose and 4550% following 1,000 mg/kg
dose. CEZ had little effect on rate of contractions.
The onset of the increase in contractions occurred
within 5 minutes post-dose, although peak increase
was not attained, in some cases, until approximately 30 minutes post-dose.
Administration of CEZ (300 and 1000 mg/kg)
had a marked effect on small intestine activity.
Strength of contraction was increased by up to 1033
% (1000 mg/kg), and rate of contraction by up to600% (300mg/kg).
3) Effect on gastric secretion (Table 1)
CFCL and CEZ were examined for effects on gastric secretion and damage using the pylorusligated (Shay) rat model. The compounds were
examined at intravenous doses of 300 and 1000 mg/
kg.
Compound CFCL at 1000 mg/kg caused aweak to moderate, but statistically significant

CHEMOTHERAPY

196

decrease in gastric K+ and H+ output.
noteworthy effects were observed.
Compound

CEZ caused

No othera dose-related

decreasein volumeof gastricfluid, with concomitantobserved decreases in gastric ion secretion whichwere all statisticallysignificant

at

1000

effecton

gastric

concentration
however, was a decrease4) Effect on salivary excretion

in H.

The

only

noteworthy

mg/kg.
ion

SEPT.

1992

K+ andCl" ion excretion

were

all significantly

elevatedas was the total

proteincontentof thein the volume of urine excretedwereurine.
No changes
observed

following

intravenous

treatment

CEZ at doses of 300 or 1,000 mg/kg.
but statisticallysignificant
reduction
excretion

with

A smallin K+ ion

was observed.
was noted

of vehicle, CFCL (250,

Significant elevation in Na + excretionat a dose of 1,000 mg/kg.

500 mg/kg) or CEZ (500 mg/kg)
did not induce aflow of saliva from the parotid gland in any of the

The reference
standard
frusemide
significantly
increasedurine volume(2 mg/kg)
throughout

animalsatthe experimentsecretion
responseof saliva
salivary
to a secretogogue.

Intravenous

administationthese doses.

sion, neither
intravenously,

There

was no restingflow only occurs in
Therefore in conclu-

CFCL nor CEZ when administered
act as secretogogues
in the anaesth-and Na + and Cl- ion excretion

also significantly
increased.
ProteinK+ ion excretion were unaffected.
7) Effect on renal function
Both CFCL and CEZ increased

urine flows in theetised rat.

20 minutes following administration,5) Effect on bile and pancreatic secretions (Tables
2 and 3)
Bile secretion was unaffected by administrationof either vehicle or CFCL at doses of 250 and 500

in general however,that caused by vehicle administration.
The glomerular filtration
rates forin-

duced a marked increase in bile output in all of the
9 surviving animals,with a maximum
individ-8) Local anaesthetic
activityi) Corneal reflex (Table 6)

ual increase
Pancreaticconsider-concentrations

variation.

significant
Lidocaine

able

Administrationof CEZ at 500 mg/kg

of 224%.
secretions

inter-group

ObservationofTopicalwere subject

to

and

inter-animal

individual

data

indicatedthatadministrationof both vehicle and CFCL (250, 500
mg/kg) did not modify pancreatic
output.
The
effects following

administrationof CEZ were vari-able although there were indications
to suggestthat CEZ also elicited a reduction in pancreatic
output, althoughevidence

for the latter

finding is

not conclusive.
6) Effects
5)Intravenous

administration(Tables4 andof CFCL caused

noadministrationof 5

inulin anaffected by the dosesof CFCL and CEZ

and

10%

at

w/v produced noeffect on corneal reflex in the guinea-pig.
at concentrationsof 1 and 2% w/v

produced a good
dose-related
local anaesthetic
effect, which was statisticallysignificant at thehighest concentrationof 2% w/v.
ii) Weal test (Table 7)
Intradermal
administrationand 10% w/v)
activity.

on urine and electrolytes

but the effects

were not notably different from

P.A.H. were not consistentlyof either CFCL or CEZ.

mg/kg.

werecontent andof CFCL and CEZ (5had no significant

Lidocainecally significant

causedweal anaesthetic

a markedand statisti-

inhibition of the pinkrick
Discussion

In the anaesthetiseddog, administration

response.
of CFCLchanges in urine volume at a dose of 300 mg/kg
but a large and statisticallysignificant increase inincreased small intestine motility and reduced themuscle activity of the stomach.
The frequency ofurine volume

thewas observed

up to 5 hours post-dose

following treatment
urinary electrolyte

at 1000 mg/kg. No changes inexcretion or total protein con-tent of the urine

werevenousadministration

mg/kg.

At a dose

observed

following

intra-of CFCL at a dose of 300
of 1000 mg/kg,

however,Nat,

contractile

responses

following both CFCL and

CEZ however, was not affected
and it is unlikelythat the conduction speed of the gastro-intestinal
contents would be changed.
This observation is
supported by the results of the charcoal propulsion
in mice test

where the transit

time of a charcoal

Cefclidinの 消 化 器 系 ・腎 機 能 へ の 影 響
VOL.40S-4

meal was unaffected
Secretory function
by intravenous
salivery,administration

pancreaticunchanged.

by either treatment.
would seem to be unaffectedof

In contrast,

however,

volume and H+ concentrationkg, a marked increase in bileand a possiblelevels being

CEZ administra-tion resulted in a slight reduction

mg/kg

CFCL, gastric,

and bile secretionin overall

followingsecretion

decreasein pancreaticput.
Effects on the kidney were only observed
ing the higher doses of CFCL.

gastric
1000 mg/
after 500

In

out-

follow-rats CFCL 1000

mg/kg caused a significant increase in the urine
volume excreted which was paralleled by marked
increasesin Na+, K+ and Cl- output.

IncreasedNa

excretion was also seen following CEZ although anotable increase in urine output was not observed .
The small reductionin K excretion

may have gonesome way to compensate.
Slight increases

in urine

outputweresimilarly197

observed in the anaesthetised dog following CFCL
and CEZ but whether the change was treatmentrelated is equivocal since similar changes also occurred after vehicle. The glomerular filtration
rate was unaffected by either test compound.
CFCL and CEZ were both without local anaesthetic activity either topically or when administered intradermally.
References
1. Takemori, A.E., Kupferburg, H.J., Miller, J.W.,(1969), J. Pharm. exp. Ther., 169, 39-45.
2. Shay, H., Komarov, S.A., Fels, S.S., Meranze,D., Gruenstein, M., Siplet, H., (1945), Gastroenterology, 5, 43-61.
3. Lipschitz, E.L., Hadidian, A., Kerpcsar, A.,(1943), J.Pharm. exp. Ther., 79, 97.
4. Chance, M.R.A. and Lobstein, H., (1944), J.
Pharmacol., 82, 203.
5. Bulbring, E. and Wadja, I., (1945), J. Pharmacol., 85, 78-84.

CHEMOTHERAPY

198

Cefclidinの

一 般 薬 理 作 用:消SEPT.

化 器 系 ・腎 機 能 へ の 影 響

藤 本 昌俊,勝鎌 政,金 子 武 稔 山 内
エーザイ株式会社 筑波研究所*

Algate,D.R., Baines, M.W., Jobling,

Departmentof Pharmacology,

C.M. Kerwin,

Huntingdon

Cefclidin(CFCL)の

一 般 薬 理 試 験 の 一 環 と して,消て,cefazolin(CEZ)を比 較 薬 剤 と し て 検 討 し た。

CFCLは

麻 酔 犬 に お い て,300mg/kgで博

N.D. and Munt, P.L.,

Research

Centre Limited,

化 器 系 ・腎 機 能 な どに 対 す る 影 響 に つ いは 明 確 な 変 化 を 示 さ な か っ た が,1000mg/kgで胃の収

縮 抑 制 と小 腸 の 収 縮 冗 進 を示 した 。 しか し,収 縮 頻 度 に は 影 響 しな か っ た 。 ま た,マウスの消化 管 輸 送 能 は 変 化 し な か っ た 。 そ の 他,胃た。CEZは一方,尿mg/kgで

液 分 泌,膵 液 ・胆 汁 分 泌,唾

消 化 管 収 縮 を増 加 し,胃 液 お よ び 膵 液 分 泌 の 低 下.胆・
電 解 質 排 泄 に つ い て は,CFCLの300mg/kgで液分 泌に は影響 しなか っ汁 分 泌 の 増 加 が 認 め られ た 。

は ま っ た く影 響 しな か っ た が,1000

尿 量 ・電 解 質 排 泄 と もに 増 加 し た。 しか し,糸 球 体 ろ過 率 に は 有 意 な 変 化 が な か った。 そ の 他,CFCLは
以 上,CFCLは局 所 麻 酔 作 用 を示 さ な か っ た 。

消 化 器 系 に対 す る 影 響 は 極 め て 少 な く,ま た 尿 量 の 増 加 に 伴 う電 解 質 排 泄 の 増

加 も,高 用 量 で 認 め ら れ た作 用 で あ り,特 に 問 題 と な る変 化 で は な い と考 え る。

*〒300

‑26茨

城 県 つ くば 市 東 光 台5‑1‑31992