Chihiro Yoneyama

Safety and efficacy of intraperitoneal injection of etoposide in oil suspension in mice with peritoneal carcinomatosis.

We compared the safety and efficacy in mice with peritoneal carcinomatosis of two etoposide formulations: an aqueous solution (Etp-sol) and particles suspended in oil (the addition products of iodine and the ethyl esters of the fatty acids obtained from poppy-seed oil (Lipiodol) or sesame oil; Etp-oil). We also investigated tissue distribution of etoposide in rats treated with Etp-oil and Etp-sol. Etoposide was injected intraperitoneally at concentrations ranging from 52 to 392 mg/kg (increasing geometrically by a factor of 1.4). The 50% lethal dose (LD50), determined over a 2-week period of observation, was 135 mg/kg for Etp-oil and 108 mg/kg for Etp-sol. Autopsy findings included macroscopic intestinal bleeding, necrosis of the intestinal mucosa, and pulmonary congestion in mice from both treatment groups. In the efficacy trials. 106 P388 leukemia cells were transplanted into CDF1 male mice, and Etp-oil and Etp-sol were injected at doses of 20 mg/kg and 80 mg/kg. In the groups receiving the 20 mg/kg dose, 11 of 19 mice in the Etp-oil group survived to day 60 compared with 3 of 20 mice in the Etp-sol group. Toxicity-related deaths occurred in 1 of 20 mice treated with 80 mg/kg Etp-oil and in 8 of 20 mice treated with 80 mg/kg Etp-sol. No cancer-related deaths were associated with the 80 mg/kg dose in either treatment group. Our findings showed that the Etp-oil was associated with a lower toxicity and a higher efficacy than the Etp-sol. To evaluate tissue distribution, rats were injected intraperitoneally with 5 mg/kg body weight of Etp-sol or Etp-oil. The tissue distribution of etoposide was subsequently analyzed by high performance liquid chromatography. Compared with Etp-sol, Etp-oil delivered significantly greater amounts of etoposide and for a longer period to the omentum, taken as representative of the intraperitoneal tissue, and the etoposide concentration in blood plasma was increased more slowly and decreased more gradually.

Selective distribution of aclarubicin to regional lymph nodes with a new dosage form: aclarubicin adsorbed on activated carbon particles.

A new dosage form (ACR-CH) comprising aciarubicin adsorbed on activated carbon particles was designed to sustain release of aclarubicin. ACR-CH or aclarubicin aqueous solution (ACR-sol) was injected subcutaneously Into the fore foot-pads of rats. ACR-CH distributed a statistically significantly higher level of aclarubicin to the axillary lymph nodes (detectable up to 7 days after injection) than aclarubicin distributed in an ACR-sol (not detectable after 48 h). To other tissues, ACR-CH distributed statistically significantly low levels of aclarubicin, as compared with ACR-sol.

A new dosage form comprising a suspension of activated carbon particles adsorbing aclarubicin: toxicity in mice.

A new dosage form (ACR-CH), a suspension of small activated carbon particles adsorbing aclarubicin, was studied for its toxicity and histopathological effects on organs in mice. The 50% lethal subcutaneous dose of ACR-CH was 83.5 mg/kg, a value 2.42 times that (34.5 mg/kg) of the aclarubicin aqueous solution. The duration of the toxic effects of ACR-CH was prolonged compared with that of the aclarubicin aqueous solution. On autopsy there was no remarkable difference in macroscopic and microscopic examinations between the two dosage forms.

Acute toxicity of aclarubicin adsorbed on carbon particles injected subcutaneously in mice.

A new form (ACR-CH) of anticancer drug administration for treatment of breast cancer is prepared, the new dosage form of ACR-CH comprised 12.5 mg/ml of activated carbon, 5 mg/ml of polyvinylpyrrolidone and 5 mg/ml of aclarubicin (ACR) in saline. ACR-CH distributes less amount of ACR in blood and systemic organs than ACR aqueous solutionin (ACR-SOL) does. ACR-CH and ACR-SOL were studied on the acute toxicity. Some doses of ACR-CH and ACR-SOL were injected subcutaneously into the back of mice. Survival rate and general conditions were observed during 14 days after the injection. The mice were subjected to autopsy. The LD50 values of ACR-CH and ACR-SOL calculated following Litchfield-Wilcoxon method were 83.5 mg/kg and 43.5 mg/kg, respectively. Except for the recovery of body weight, there was no difference between the two dosage form in the intoxication symptomes and the autopsy findings. It was concluded that ACR-CH was adimistrated more safely than ACR-SOL.

Tissue distribution of intraperitoneally administrated aclarubicin adsorbed on activated carbon particles in rats.

The tissue distribution of aclarubicin(ACR)was studied and compared between the two dosage forms, namely the new dosage form (ACR-CH) and the aclarubicin aqueous solusion (ACR-sol). ACR-CH comprises 50 mg/ml of activated carbon (Mitsubisi #1500AA) and 5 mg/ml of aclarubicin in saline. Aclarubicin at 5 mg/kg was injected intrapritoneally in the form of ACR-CH or ACR-sol, and the tissues (the greater omentum, the liver, the spleen, the heart. the lung and the intracardial blood) were taken upto 7 days later. The organs and the blood was subjected to measuring aclarubicin level through the high pressure liquid chromatography(HPLC)method. The experiment showed that ACR-CH distributed higher level (2 to 10 times) of ACR concentration to the greater omentum for a long period, and lower level to the heart, the lung and intracardial blood than those of ACR-sol. These results leads to think that intraperitoneal ACR-CH distributes a large amount of ACR to the intraperitoneal tissues and small amount to the tissues of extraperitoneal organs.