KIDROLASE Solution for injection Ref.[27896] Active ingredients: Asparaginase

General Pharmacology

L-asparaginase does not have any apparent effect on the principal body functions. In the pentobarbital anesthetized dog, L-asparaginase, at a dose of 5,000 U/kg I.V. produces no effect on the ECG, the cardiac rhythm, the blood pressure, the respiratory system or the autonomic nervous system.

In addition, 5 injections (2-1/2 days apart) of 12,000 U/kg I.V. failed to produce any significant changes in the thromboelastogram and thrombocyte count in the mouse.

Antitumour activity

The activity of L-asparaginase has been tested on various tumours, lymphosarcomas and leukemias of animals. One study carried out on 109 leukemias in the mouse revealed that X-rayinduced and spontaneous leukemias are especially responsive to L-asparaginase while those which are viral-induced or caused by chemical agents, are only slightly or not responsive at all.

In addition, experiments with 2 sensitive tumour systems, EARAD-1 leukemia and C₅₇B1/Rho leucosarcomatosis, have demonstrated that the effect of L-asparaginase varies with the number of grafted tumour cells.

Furthermore, in EARAD-1 leukemia, it has been shown that the antitumour activity of the enzyme depends on the dose injected, but that it is not influenced by the parenteral route used.

Immunosuppressive activity

In several in vivo and in vitro tests, L-asparaginase exerts a marked inhibitory effect on the manifestations of humoral immunity (antibody production) and of cellular immunity (blast transformation of lymphocytes). In certain other immunological reactions where the participation of both immunological systems is possible, the action of L-asparaginase varies; it does not prolong the survival time of a skin homograft in the mouse but seems to impede the rejection of a nonhistocompatible leukemia. It has a marked inhibiting effect in the rat on 2 pathologies which strongly resemble auto-immune diseases: adjuvant-induced arthritis and experimental allergic encephalomyelitis.

Antiviral activity

L-asparaginase has been shown to exert an antiviral effect on 3 DNA viruses: vaccina virus, myxoma virus and Herpes simplex. This effect seems to be associated with an action of the enzyme on a cellular reactions requiring L-asparagine and essential to the replication of the DNA molecule.

NON-CLINICAL TOXICOLOGY

Acute Toxicity

The acute toxicity of L-asparaginase in the mouse and in the rat when administered by the I.V. route is rather low, the LD₅₀ in both species being above 200,000 U/kg; in the cat and the dog, the LD₅₀ is in the range of 50,000 U/kg while in the rabbit, the LD₅₀ of the enzyme is about 800 U/kg. The greater toxicity of L-asparaginase in the rabbit is probably due to a greater dependency of this species on L-asparagine rather than to a toxic effect of the enzyme.

Subacute Toxicity

In the mouse, the subacute LD₅₀ of L-asparaginase administered by the I.V. route for 5 consecutive days is approximately 300,000 U/kg I.V. per day. At a daily dose of 25,000 U/kg I.V., the animals became emaciated, but this more or less normalized after treatment was stopped. Two subacute toxicity studies have been dose in the rat. In the first of these, daily dosages of 200, 800 and 3,000 U/kg I.P. were administered over a period of 14 weeks.

L-asparaginase did not cause any deaths among the animals; however, a mild periportal steatosis, which was not dose related, was observed in the liver, and a few animals showed changes in the epithelial cells in the testicles or a hypertrophy of the cortex of the thymus with proliferation of the large and medium thymocytes and a decrease in the number of small thymocytes. In the second study, daily doses of 0, 200, 1,000 and 5,000 U/kg I.P. were administered for a period of one month. The only difference observed among the test animals, when compared with the control group, was a curtailment of weight gain at the 2 higher dosages.

In the rabbit, the subacute LD₅₀=s calculated 7 and 20 days after the end of a 5-day treatment period with L-asparaginase were respectively 1,150 and 760 U/kg I.V. per day.

A dog injected with 10,000 U/kg I.V. per day for 9 consecutive days responded with anorexia, weight loss, salivation and vomiting. Blood was also observed in the stools and there was a temporary decrease in the red cells.

By contrast, 6 dogs were treated at doses of 0, 200, 800 or 3,000 U/kg I.V., 5 days a week for 13 weeks, and no changes in the hemogram or urinalysis were noted. Vomiting occurred a few hours after the injection in animals receiving the highest dosages. At autopsy, atrophy of the thymus was observed and in one dog treated at the highest dose, a slight fatty infiltration and diffusion of hepatocytes could be seen in the liver.

In the monkey, five injections of 800 or 1,200 U/kg I.V. were given weekly for 4 weeks. At the end of the first week of treatment, the animals treated at the lower dose showed a weight loss accompanied by decreases in the number of reticulocytes and in hematocrit and serumcholesterol levels. Transitory increases of BSP retention and SGOT levels were also observed. At the end of the treatment, thrombocyte levels were elevated and there was a fatty infiltration of the hepatic cells.

TERATOGENICITY

Investigations of teratogenic activity were conducted in the rabbit and the rat; in both species, Lasparaginase was administered I.V. during the gestation period (on the 8^th and 9^th day in the rabbit and from the 6^th to the 15^th day in the rat).

These studies show that: in the pregnant rabbit, L-asparaginase exerts significant embryotoxic and teratogenic activities at a daily dose of 50 U/kg I.V.; in the pregnant rat, a daily dose of 300 U/kg I.V. demonstrates a rather clear embryotoxic activity while a teratogenic effect is observed at a dose of 1,000 U/kg I.V. per day.