الفهرس 
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Abstract
The present study was performed to investigate some pharmacodynamic effects of tilmicosin. The present study was divided into two types of experiments which were in vitro and in vivo experiments. The in vitro experiments were applied to investigate the effect of tilmicosin on isolated smooth, cardiovascular muscles and neuromuscular preparations. Smooth muscle preparations such as gastrointestinal (guinea pig’s ileum, rabbit’s duodenum, rat’s colon and rat’s fundic strip), rat’s uterus and guinea pig’s tracheal chain. Cardiovascular muscle preparations such as guinea pig’s auricles, rabbit’s heart and rabbit’s aortic strip. Neuromuscular preparations such as frog’s gastrocnemius muscle sciatic nerve, frog’s rectus abdominis muscle and rat’s phrenic nerve hemi diaphragm.
The in vivo experiments were applied to investigate the effect of tilmicosin on blood pressure in anaesthetized dogs, electrocardiograph parameters in conscious rabbits, analgesic activity of tilmicosin in mice and antipyretic effect of tilmicosin in rats.
Tilmicosin in concentrations of 0.0625 to 0.5 µg/ml bath had no effect while 1 to 10 µg/ml bath caused slight stimulation in the force of contraction of guinea pig’s ileum. Higher concentrations 20 µg/ml bath caused moderate stimulation in the force and rate of contractions. Tilmicosin in concentrations of 40 to 80 µg/ml bath produced marked stimulation in the force and rate of contractions. Maximum stimulation was achieved by addition of 160 µg of tilmicosin / ml bath.
Concentrations of tilmicosin from 0.0625 to 1 µg /ml bath had no effect on the duodenal motility of rabbits. Concentrations from 5 to 20 µg/ml bath caused slight stimulation in the force of contraction. Concentrations 40 and 80 µg tilmicosin /ml bath induced moderate stimulation in the force of contraction of isolated rabbit’s duodenum. Concentrations 160 and 320 µg tilmicosin /ml bath induced marked stimulation in the force of contraction of isolated rabbit’s duodenum. Maximum stimulation was achieved by a concentration of 640 µg tilmicosin /ml bath.
Tilmicosin in concentrations from 0.0625 to 0.25 µg/ml bath had no effect on the rat’s colon motility. Concentrations from 0.5 to 10 µg/ml bath tilmicosin caused slight stimulation in the force of contraction. Concentrations from 20 to 80 µg/ml bath tilmicosin caused marked stimulation in the force and rate of contraction. Maximum stimulation was achieved by concentration of 160 µg/ml bath tilmicosin. The stimulant effect of tilmicosin on the isolated intestinal smooth muscle preparations might be attributed to its direct effect. Tilmicosin in concentrations from 0.0625 to 0.5 µg/ml bath had no effect on the motility of rat’s fundic strip. The tilmicosin in concentrations from 1 to 10 µg/ml bath caused slight inhibition of the motility of rat’s fundic strip. The tilmicosin in concentrations from 20, 40 and 80 µg/ml bath caused moderate inhibition of the motility of rat’s fundic strip. Marked inhibition of the motility of rat’s fundic strip produced with concentrations 160 and 320 µg tilmicosin/ml bath . Complete relaxation was produced by the concentration of 640 µg/ml bath, histamine was not able to produce its stimulant effect on the rat’s fundic strip, so tilmicosin might appeared to have an antihistaminic like effect.
Tilmicosin in concentrations from 0.0625 to 1 µg/ml bath had no effect in different stages of sex cycle (non estrus, estrus, early pregnant, and late pregnant). Tilmicosin in concentration of 5 µg/ml bath had no effect on the isolated uterus in stages of non estrus, estrus and early stage of pregnancy while it induced a slight inhibition in the force of contraction at late stage of pregnancy. Tilmicosin in concentration 10 µg/ml bath have no effect in estrus and non estrus stages but induced slight inhibition in the force of contractions of the myometrium in the early and late pregnancy stages. Tilmicosin in concentration of 20 µg/ml bath have slight inhibition in force of myometrial contraction in non estrus stage while produced slight inhibition in force and frequency of contraction of myometrium in estrus, early and late pregnancy stages. Tilmicosin in concentration of 40 µg/ml produced moderate inhibition in frequency in non estrus stage, while induced slight inhibition in force and frequency of myometrial contraction in early pregnancy stage, while produced moderate inhibition in force and frequency of myometrial contraction at late pregnant stage. The concentrations of 80 µg/ml bath tilmicosin induced marked inhibition in the force and frequency of contractions of the myometrium in non estrus, early and late pregnancy stages while produced moderate inhibition in force and frequency of myometrial contraction in estrus stage. Tilmicosin in concentration of 160 µg/ml bath induced marked inhibition in force and frequency in all stages of myometrial contraction. Complete inhibition were achieved for all previous stages at concentration of 320 µg/ml bath tilmicosin.
The site of action of tilmicosin on the isolated uterus might appear to be myogenic in nature due to its direct effect on the myometrium.
All tested concentrations of tilmicosin didn’t induce any response on isolated guinea pig’s tracheal chain and rabbit’s aortic strip. The tilmicosin blocked the stimulant effects of histamine and nor adrenaline on isolated tracheal chain and aortic strip respectively and this might be referred to its direct effect on these tissues.
On isolated guinea pig’s auricles, tilmicosin in concentrations smaller than 0.5 µg/ml bath had no effect on isolated guinea pig’s auricles. Concentrations from 10 to 80 µg/ml bath induced slight negative inotropic effect while concentrations from 160 to 640 µg/ml bath evoked marked negative inotropic effect on the isolated auricles. This study proved that, the negative inotropic effect of tilmicosin might be referred to its direct myogenic effect on this tissue.
On the isolated rabbit’s heart, the concentrations of tilmicosin lower than 10 µg/ml canula induced no effects. The concentrations from 20 to 80 µg/ml canula caused slight negative inotropic effect. The concentration from 160 to 320 µg/ml canula evoked marked negative inotropic effect and 640 µg/ml canula caused very marked negative inotropic effect. The negative inotropic effect of tilmicosin was not referred to either ß1 adrenergic blocking effect or cholinergic stimulant effect but might be due to its direct myogenic effect.
Tilmicosin in concentrations lower than 1 µg/ml bath had no effect. Concentrations of 5 and 40 µg/ml bath caused slight neuromuscular blockade. Concentrations of 80 and 320 µg/ml bath induced marked inhibition in the force of muscular twitches of frog’s gastrocnemius muscle which was less potent than that induced by procaine hydrochloride 2 %. The effect might be attributed to the local anesthetic activity of tilmicosin on the sciatic nerve as well as its calcium antagonistic effect.
On the isolated frog’s rectus abdominis muscle, Concentrations of tilmicosin from 0.0625 to 0.125 µg/ml bath had no effect. Concentrations of 0.25 µg tilmicosin/ml bath caused slight decrease in the contracture in the presence of acetylcholine in concentration of 5 µg/ml bath. Concentration of 0.5 µg tilmicosin/ml bath caused moderate decrease of the contracture. Concentration of 1 µg tilmicosin/ml bath caused marked decrease of the contracture and maximum blockade was produced in the presence of 5 µg/ml bath of tilmicosin.
On isolated rat’s phrenic nerve hemidiaphragm, tilmicosin at concentrations from 0.0625 to 5 µg/ml bath had no effect, while concentrations of 10 µg/ml bath caused mild inhibition in the force of contraction. The concentrations from 20 to 40 µg/ml bath produced moderate inhibition in the force. The concentrations of 80 µg/ml bath produced marked inhibition in the force. Maximum neuromuscular blockade was achieved by 160 µg/ml bath. Tilmicosin did not impair the stimulatory effect of acetylcholine and neostigmine on this preparation. Therefore the neuromuscular blocking effect of tilmicosin seemed to be attributed to two mechanisms; the blockade after indirect stimulation which was due to local anesthetic effect of tilmicosin which was responsible for blocking of conduction through sciatic and phrenic nerve.
The blocking activity of tilmicosin after direct stimulation might be attributed to the calcium ions antagonistic effect of the tilmicosin.
Intravenous injection of tilmicosin at doses of 1 and 2 mg/kg b.wt. had a hypotensive effect on the blood pressure of an anaethetized dogs over a period of half hour after each dose. This result similar to these obtained in vitro study in the isolated rabbit’s aorta.
Single intramuscular injection of 111.2 and 222.4 mg/kg b.wt. of tilmicosin induced prolongation in QT interval a long period of 8 hours after injection in conscious rabbits.
Intramuscular injection of tilmicosin in a dose of 28 and 56 mg/kg body weight induced an analgesic effect along the four hours of the experiment which was indicated by the longer reaction time in treated than control group.
Intramuscular injection of tilmicosin in a dose of 20 mg/kg bwt.ody weight had an antipyretic effect after 2.5 hours. While tilmicosin in dose of 40 mg/kg b.wt. had an antipyretic effect after 1.5 hours of tilmicosin administration. The tilmicosin in dose of 80 mg/kg b.wt. had significant antipyretic effect after 0.5 hours of administration. This effect seemed to be mediated centrally through an action on heat regulating center in such manner to increase heat loss by peripheral vasodilatation of skin blood vessels, as well as the direct vascular relaxant effect of tilmicosin.