TOXICITY OF CYTISINE
Tabex was experimentally studied for its toxicological action on different
kinds of experimental animals. The acute LD50 toxicity, the
subchronic (30 days) and the chronic (80-180 days) toxicity were
determined. The acute toxicity was determined on line H albino mice
(intravenously, subcutaneously and orally); rats (intraperitoneally,
subcutaneously and orally); dogs (subcutaneously and orally).
Table 1 Acute LD50 toxicity in mice, rats and dogs with different nodes of administration
| Mice | ||
| Intravenously |  |
2.3 (1.3-3.6) |
 |
3.1 (1.8-5.2) | |
| Subcutaneously | |
13 (11-15.3) |
| Orally | |
13 (8.5-19.9) |
| 29 (22.37) | ||
| Rats | ||
| Intraperitoneally | 9 (8.9-10.3) | |
| Subcutaneously | 11 (7.7-15.6) | |
| Orally | 38 (17-83.6) | |
| Dogs | ||
| LD0 | 4 mg/kg | |
| LD0 | 25 mg/kg | |
The mice and the rats were divided in groups of six animals and the
dogs in groups of 2 animals for each dose used. The behaviour of the
animals and the lethality were observed daily for 7 days after the drug
was applied. All the results obtained were statistically processed
according to Litchfield-Wilcoxon's method. During the experiments the
animals received standard food and water ad libitum (Angelova, O.).
During the observation the following toxic symptoms were found:
accelerated respiration, clonic and toxic convulsions, motility
disturbances in the hind legs, lower muscle tonus. The absorption index in
rats was 4.2. In dogs, injected subcutaneously with 4 mg/kg, the changes
occurred one hour after the treatment. The animals began vomiting, clonic
and tonic convulsions of body and limbs muscles appeared. The movement was
slow and phlegmatic. When stimulated by force, they became aggressive. On
the following day the animals restored their normal behavior. No lethality
was noted. After oral administration of doses of 15-25 mg/kg, the dogs
showed no external symptoms of toxicity.
The results of the acute toxicity studies showed that cytisine was much
less toxic than intravenously applied nicotine, but it was more toxic
after intraperitoneal and oral administration
Table 2 Comparison between acute toxicity of cytisine and nicotine
| Mode of administration | |||||
| i.v. | i.p. | p.o. | |||
| Nicotine | LD50 mmoles/kg | 1.92 | 59.0 | 1.425 | |
| 1.75 - 2.12 | 53.6 - 65.0 | 1.370 - 1.486 | |||
| LD50 mg/kg | 0.3 | 9.5 | 230 | ||
| (6) | (7) | (9) | |||
| Time of death | 32.0 +/- 0.8 | 2.42 +/- 0.1 | 2.86 +/- 0.1 | ||
| sec (28) | min (38) | min (45) | |||
| Equipotential molar ration | 1 | 1 | 1 | ||
| Cytisine | LD50 mmoles/kg | 9.10 | 49.5 | 535 | |
| 7.9 - 10.5 | 46.6 - 57.5 | 411-696 | |||
| LD50 mg/kg | 1.73 | 9.4 | 101 | ||
| (6) | (6) | (7) | |||
| Time of death | 37.2 +/- 3.1 | 5.32 +/- 0.4 | 12.7 +/- 0.6 | ||
| sec (36) | min (28) | min (46) | |||
| Equipotential molar ration | 4.75 | 0.84 | 0.37 | ||
SUBACUTE TOXICITY
The experiments for subacute toxicity were carried out on line H albino
mice and Wistar rats of both sexes equally, treated orally with aqueous
solution of Tabex with the following terms and doses: mice - for 45 days
with a dose of 3.3 mg/kg and rats - for 30 days with a dose of 7.6 mg/kg.
The chronic toxicity was studied on Wistar rats and on dogs treated orally
with aqueous solution for the rats and substance in the feed - for dogs,
at the following terms and doses:
Rats - for 90 days with doses: 1.36, 0.45,
0.90 mg/kg;
Rats - for 180 days with doses: 0.45, 0.90 mg/kg
Dogs - for 180 days with doses: 0.45 mg/kg
The control groups of animals were treated with equivalent amounts of
water. All the animals received standard feed and water ad libitum. The
behavior and lethality of the animals were observed daily. The following
clinical-laboratory and pathoanatomical examinations were carried out:
Hematological:
Hb, RBC, WBC, platelets, leukocyte formula, prothrombin index
Biochemical:
serum bilirubin, blood sugar, blood urea
Urine:
albumin and sediment
Pathoanatomical:
examination of internal organs
The data obtained were statistically processed according to
Student-Fisher's method.
No changes in the behavior of the experimental animals were observed
during the experiment carried out. No changes were likewise noted in the
clinical-laboratory indices studied. The pathoanatomical examinations
showed a different degree of dystrophic changes in the liver of the mice
treated with 3.3 mg/kg and in the dogs treated with 0.45 mg/kg.
The following enzyme indices were examined: transaminases - SGOT and SGPT,
and alkaline phosphatase in chronic experiment on white Wistar rats and
dogs treated orally with the following doses and terms:
Rats - for 90 days with a dose of 1.35 mg/kg
Rats - for 180 days with doses of 0.45 and 0.90 mg/kg
Dogs - for 180 days with a dose of 0.45 mg/kg
A statistically significant increase of SGOT was found in the group
treated with 1.35 mg/kg for 90 days. The SGOT level was twice higher than
that of the control group. The results obtained showed hyperenzynemia of
SGOT and coincided with the data of Veress and Rengei about the influence
of nicotine on the level of this enzyme.
On the basis of the toxicological studies we can make the following
conclusions:
- According to Hodge and Sterner's
classification for oral administration to rats, Tabex belongs to the
group of strongly toxic drugs with a good absorption index.
- When given orally to rats for 30 and 90
days, Tabex shows no toxic changes in the hemopoiesis and internal
organs of the experimental animals.
- When applied orally to mice for 45 days and to rats and dogs for 180 days, Tabex does not cause any toxic changes in the hemopoiesis and in the internal organs, except different degrees of dystrophic changes in the liver.