Ceftriaxone is a broad spectrum cephalosporin resistant to various types of
beta-lactamases with potent activity against gram-positive and gram-negative
bacteria including Enterobacteriaceae, Haemophilus influenzae, Streptococcus
pneumoniae and other nonenterococcal streptococci, Methicillin-resistant
staphylococci, Enterococci, Pseudomonas aeruginosa and Bacteroides fragilis
were typically resistant (Neu et al., 1981).
The drug acts through inhibition of transpeptidase enzymes responsible for the
final step in bacterial cell wall synthesis (Waxam and Strominger,
1982) and has broad stability against beta-hydrolysis (Neu,
1985). In human medicine, ceftriaxone is widely used because of its prolonged
terminal half-life (5.4-8.2 h) that allows its prescription on a single administration
per day basis (Patel et al., 1982; Meyers
et al., 1983; Ti et al., 1984; Zhou
et al., 1985; Bourget et al., 1993).
So, expanded informations concerning the pharmacodynamic effects of ceftriaxone
will be of benefits to physicians and their patients. The present study was
aimed to study pharmacodynamic aspects of ceftriaxone on isolated gastrointestinal
MATERIALS AND METHODS
Drug: Ceftriaxone is a sterile, semisynthetic, broad-spectrum 3rd generation cephalosporin antibiotic for intravenous or intramuscular administration. Ceftriaxone is a white to yellowish-orange crystalline powder which is readily soluble in water, sparingly soluble in methanol and very slightly soluble in ethanol. The pH of a 1% aqueous solution is approximately 6.7. It was produced by Smithkline Beecham for Novartis Pharma Company (Egypt) and has the commercial name Ceftriaxone®.
Perfusion fluids for pharmacological experiments: The isolated guinea
pigs ileum, rabbits duodenum and rats colon was suspended
in the organ bath containing warm oxygenated tyrods solution at 37°C.
While rats fundic strip was suspended in the organ bath containing warm oxygenated
Krebs ringer solution at 37°C. The above mentioned physiological salt
solutions were prepared as indicated by staff members of the University
of Edinburgh, Department of Pharmacology (1970).
||Nicotine sulphate (Hopkin and Williams Company, England)
||Atropine sulphate (Memphis Company, Cairo, Egypt)
||Adrenaline (Cid, Giza, Egypt)
Glass jar bath: A glass water bath of about 750 mL capacity fitted into
a metal stand in which a movable electric heater was located to maintain the
temperature as requied. An inner glass tube (organ bath) of 40 mL capacity passed
through the bottom of the stand and was connected by a T-shaped glass tube.
Harvard universal oscillographe and transducers: Two channels curvilinear
oscillograph (Harvard UK) with an isotonic transducer (Harvard App. Ltd.) which
was employed for recording the effect of ceftriaxone on isolated tissues. The
method explained by Valeri et al. (1990) was
used for studying the effect of ceftriaxone on the isolated ileum of guinea
pigs. The method described by the staff members of Pharmacology Department,
University of Edinburg UK, 1968 was used for studying the effect of ceftriaxone
on isolated rabbits duodenum and rats colon. The effect of ceftriaxone
on isolated rats fundic strip was investigated according to the method
described by Milenov and Kalfin (1996).
RESULTS AND DISCUSSION
The effect of ceftriaxone on isolated guinea pigs ileum, rabbits
duodenum, rats colon and rats fundic strip were shown in Table
1. The maximum stimulant effect of ceftriaxone on isolated guinea pigs
ileum, rabbits duodenum, rats colon and rats fundic strip
were shown in Fig. 1a-d. The site of action
of ceftriaxone on isolated guinea pigs ileum, rabbits duodenum,
rats colon and rats fundic strip were shown in Fig.
2a-d. The stimulant effect of ceftriaxone on the isolated
intestinal smooth muscle preparations might be attributed to its direct effect.
Ceftriaxone in concentration of 1024 μg mL-1 bath has a serotonin
like effect on rats fundic strip.
The present investigation showed that ceftriaxone in vitro stimulated
the contractility of guinea pigs ileum, rats colon and rabbits
duodenum. The stimulatory effect of ceftriaxone was proportional to the graded
tested concentrations. Presence of atropine sulphate as muscarinic cholinergic
receptor blocker and large dose of nicotine sulphate as ganglionic (Nicotinic
receptor) blocker did not inhibit the stimulatory effect of ceftriaxone. In
addition, the adrenaline as adrenoceptor agonist produced its inhibitory effect
in presence of ceftriaxone. These results proved that ceftriaxone might directly
stimulates the intestinal smooth muscles of rabbits duodenum, guinea pigs
ileum and rats colon. These obtained results were similar to those obtained
by Takai et al. (1980) who found that cefeperazone
in vivo enhanced the ileal motility in guinea pigs at 62.5 and 125 mg
kg-1, respectively and in vitro enhanced slightly the motility
of isolated rabbits gastrointestinal tract at 0.001 g mL-1.
Also, these results were similar with those obtained by Yamaki
et al. (1984) who stated that the spontaneous motility of smooth
muscle was temporarily increased with 800 mg kg-1 cefminox when administered
intravenously and in upper doses. In contrast, Hasegawa
et al. (1979) stated that cefadroxil had no effects on the isolated
smooth muscle organs in mice. In addition, Honda et al.
(1980) stated that ceftizoxime sodium neither affected the spontaneous motility
of isolated rabbitss and guinea pigs ileum at concentration equal
to 10-2 g mL-1 nor interacted with acetylcholine or histamine
on the isolated guinea-pigs preparation.
||Effect of Ceftriaxone (Ceft.) on isolated gastrointestinal
muscles: a) 1024 μg mL-1 bath Ceftriaxone (Ceft.) on isolated
guinea pigs ileum; b) 1024 μg mL-1 bath Ceftriaxone
(Ceft.) on isolated rabbits duodenum; c) 512 μg mL-1
bath Ceftriaxone (Ceft.) on isolated rats colon and d) 1024 μg
mL-1 bath Ceftriaxone (Ceft.) on isolated rats fundic strip
|| The effect of ceftriaxone on isolated guinea pigs ileum,
rabbits duodenum, rats colon and rats fundic strip
||Site of action of Ceftriaxone (Ceft.) on isolated gastrointestinal
muscles: a) 5 μg mL-1 bath nicotine sulphate (LDN.) followed
by 256 μg mL-1 bath Ceftriaxone (Ceft.) on isolated guinea
pigs ileum; b) 1 μg mL-1 bath atropine sulphate (Atr.)
followed by 256 μg mL-1 bath Ceftriaxone (Ceft.) on isolated
rabbits duodenum; c) 256 μg mL-1 bath Ceftriaxone
(Ceft.) followed by 0.5 μg mL-1 bath Adrenaline (Adr.) on
isolated rats colon and d) Cyproheptadine 5x10-6 mmol (Cypro.)
followed by 1024 μg mL-1 bath Ceftriaxone (Ceft.) on isolated
rats fundic strip
Takai et al. (1982) found that the spontaneous
movement and tone of isolated ileum, colon and acetylcholine-, histamin-, nicotine-
or barium chloride-induced contraction of ileum were not affected following
cefbuperazone application. Further more, Goto et al.
(1990) recorded that cefprozil did not affect the isolated smooth muscles
of rats uterus, guinea pigs ileum or rabbits duodenum and
did not influence ganglionic transmission in cats. Goto
et al. (1992) stated also that cefetriaxone had no effect on the
intestinal smooth muscle and did not show any antagonism against some smooth
muscle contracting drugs. El-Sayed et al. (1997)
proved that cefamandole at concentrations of 512 and 1024 micrograms mL-1
bath caused complete relaxation in isolated guinea pigs ileum and rabbits
duodenum, respectively. Ceran et al. (2006) found
that maximum contractile responses to carbachol and histamine were significantly
reduced in response to the ceftriaxone sodium. Ceftriaxone stimulated contractility
of the rats fudnic strip. This stimulatory effect was dose dependant.
Ceftriaxone in a high concentration produce a serotonin like effect on rats
fundic strip (a sensetive preparation for detection of serotonin). These results
might be attributed to the ability of ceftriaxone to release serotonin from
its stores. The seotonin stimulating effect of ceftriaxone overcomed its direct
effect on the smooth muscle of rats fudnic strip. The obtained results
came in harmony with those obtained by Jankovic et al.
(1996) recorded that cefotaxime, ceftriaxone and ceftazidime cefamandole
had stimulatory effect on the rats fundic strips. On the other hand, Honda
et al. (1980) who stated that ceftizoxime sodium after intravenous
dose of 320-1000 mg kg-1 dose-dependently suppressed spontaneous
contraction of the pyloric part in morphine-urethane-anesthetized dogs. Hasegawa
et al. (1979) recorded that cefadroxil had no effects on the motility
of the stomach in rabbits.
These findings indicated that ceftriaxone had stimulatory effect on isolated gastrointestinal smooth muscles.