Oxatomide administration

The results obtained in the guinea-pig anaphylaxis test after oral oxatomide administration are presented in Fig. 1. A dose-dependent increase in the number of animals protected from the acute anaphylactic shock was observed and the histamine-induced paw oedema was similarly reduced by increasing doses of oxatomide. As previously found with cinnarizine, protection from anaphylactic shock was a more sensitive measure of the activity of oxatomide than was the reduction of paw oedema. In comparison with cinnarizine, however, oxatomide was considerably more potent. The calculated ED5o s, 2 h after oral administration, were 0. 16(0. 081 - 0. 31) mg/kg for protection from anaphylactic shock and 0. 30(0. 18 - 0. 50) mg/kg for inhibition of histamine oedema. 

Figure 1. Individual survival time and histamine oedema after oral oxatomide administration (t 2 hr) in the guinea pig anaphylaxis test...

The Compound 48/80 Lethality Test. Control data and the protection obtained after oxatomide administration have fully been... 

De Parades V, Roulot D, NeyroUes N, Rautureau J, Coste T. Hepatite cytolotique an cours de 1 administration d oxatomide. [Acute cytolytic hepatitis during administration of oxatomide.] Gastroenterol Clin Biol 1994 18(3) 294. 

Oxatomide has a relatively long duration of action. When challenged 6 h after oral administration of the compound, the guinea-pigs were protected from lethal anaphylaxis at about the same dose as found in the standard procedure. The calculated ED5Q for the 6 h-interval was 0. 14(0. 075 - 0. 28) mg g. Inhibition of the paw oedema induced by exogenous histamine in the same animals required a dose of 0. 56(0. 27 - 1.14) mg g. 

Oral administration of oxatomide to sensitized guinea-pigs prevented the anaphylactic symptoms following ovalbumin challenge and at the same time the characteristic changes in peribronchiolar mast cells, including those of the nucleus and of the mitochondria (18). 

The individual intensities of PCA and histamine-induced reactions in rats after oral administration of oxatomide are presented in Fig. 2. A progressive dose-dependent inhibitory effect of oxatomide was obtained on both PCA and histamine reactions. 

Acute Toxicity of Oxatomide in Rats. Upon intravenous injection the LD5Q of oxatomide in mafe Wistar rats was 34. 4 (26. 3 - 45. 0) mg g and in female Wistar rats 28. 2(21.6 - 36. mg/kg. Upon oral administration the LD50 in male rats was higher than 2, 560 mg/kg in female rats there was no linear... 

In preliminary experiments oxatomide was administered at a relatively high dose of 10 mg/kg. This dose had no effect on gross behaviour of the animals, but virtually totally abolished the skin responses both to ACF (1 100) and to histamine (0. 5/ig), 4 h after its oral administration. 

The time course of the effectiveness of different oxatomide doses in reducing the reactions is presented in Fig. 3. The reactions in solvent-treated dogs (dose 0) remained stable throughout the 24 h-test period, whereas increasing doses of oxatomide, from 0. 16 up to 10. 0 mg/kg had an increasingly pronounced and lasting inhibitory effect. In Table VIII the results are summarized for oxatomide, R 35 918 and R 37 281 (compounds 8, 23 and 25). It appears that, 4 h after administration, there is no significant difference between the three compounds. 

In our experiments 30 adult Beagle dogs of either sex were used. Four hours after the oral administration of oxatomide or solvent 5 ml blood was sampled. This was followed by intravenous injection of Cremophor EL (BASF) 25 %, in a volume of 0. 1 ml/kg and further blood samples were collected 5, 15 and 30 min after the Cremophor injection. During this period behavioural changes were recorded. 

Figure 3. Individual oedema indices for Ascaris coeloma fluid (ACF 1 100) and histamine reactions at various times after oral administration of oxatomide in the...

The median normal histamine concentration in the 30 control plasmas was 5. 0(4. 8 - 6. 1) ng/ml (confidence limits according to Owen, 44). Four hours after oral administration of oxatomide the median of the treated groups stayed within the control limits, except for the group treated with 10 mg g, in which the median plasma histamine concentration was 3. 0 ng/ml. 

The results are presented in Fig. 4. The clearance of injected histamine from the circulating blood was very rapid in the control session and oral administration of a high dose of oxatomide did not change the elimination curve. 

Figure 4. Histamine levels in the circulating blood of three dogs after iv injection of 0.1 mg/kg histamine in the control experiment (O) and 4 hr after the oral administration of 10 mg/kg oxatomide (0)...

---