The pathological changes brought about by the i.p. administration of a new dosage format, cisplatin microcrystals suspended in oil (CDDP-Oil), was examined in mice. CDDP-Oil decreased the absolute weight and the relative weight (organ weight/body weight) of the kidney, liver and spleen in the mice receiving the dosage form. However, the severity of the reduction of the organ weight in the CDDP-Oil administration groups was not different from that in the cisplatin aqueous solution (CDDP-Sol) administration groups. Histologically, severe degeneration and atrophy were recognized in the kidney, large intestine, small intestine, thymus, spleen, bone marrow and lymph nodes in the CDDP-Oil administration groups as well as CDDP-Sol administration groups. However, there were no additional changes in the macroscopic and microscopic findings in the CDDP-Oil groups. From these results, we concluded that this dosage form did not change the toxicity of cisplatin in terms of pathological effects.
A new dosage formulation (PEP-CH) composed of activated carbon particles adsorbing peplomycin, was examined for its macroscopic and microscopic pathological effects of subcutaneous adminstration in mice. Both formulations of PEP-CH and peplomycin aqueous solution (PEP-SOL) decreased the organ weights and the relative organ weights (organ weight/body weight) of the kidney and the spleen. These two formulations caused histological damages of the renal tubules and atrophy in the spleen and the thymus. Macroscopic and microscopic examination found no pathological changes in the lung exept for the slight congestion. There were no differences between these two formulations in the autopsy findings.
A new dosage formulation (MTX-CH) comprising methotrexate (MTX) adsorbed onto a suspension of activated carbon particles was developed for the treatment of lymph node metastases. In vitro studies showed that activated carbon particles adsorbed a great amount of MTX. Subcutaneous Injection of MTX-CH Into the left hind foot pad of rats distributed a greater amount of MTX selectively to the regional lymph nodes (the left popliteal node and the para-aortic nodes) for a longer period of time than similar administration of MTX aqueous solution with a smaller amount of MTX distributed to the rest of the whole body.
The therapeutic effects of the new anti-angiogenesis factor TNP-470 were examined against carcinomatous peritonitis in mice. In the first experiment using carcinomatous peritonitis caused by i.p. inoculation of 106 M5076 tumor cells, TNP-470 solution was injected i.p. in a bolus of 50 mg/kg body weight into two groups of 10 mice either 1 or 8 days after the i.p. inoculation. The administration of TNP-470 on day 1 extended the survival time of the mice compared with 10 control mice receiving no treatment, whereas TNP-470 given on day 8 did not affect the survival time. In the next experiment on the M5076 tumor, TNP-470 solutions at 100 or 300 mg/kg were injected i.p. in a bolus into two groups of 20 mice 1 day after the inoculation 106 tumor cells, respectively. The administration of TNP-470 at 100 mg/kg also had an inhibitory effect. However, TNP-470 at 300 mg/kg caused toxic death in half of the mice. Next, we examined the effects of TNP-470 on another type of carcinomatous peritonitis model, which was caused by i.p inoculation of 106 B16 melanoma cells. In this experiment, TNP-470 solutions in a bolus of 150 mg/kg were injected i.p. into six groups of 10 mice each on day 1 only (group 1), on days 1 and 4 (group 2), on days 1, 4 and 7 (group 3), on day 8 only (group 4), on days 8 and 11 (group 5), or on days 8, 11 and 14 (group 6), respectively. The survival time was prolonged only in those groups receiving TNP-470 on days 1 and 4 (group 2), and days 1, 4 and 7 (group 3) as compared with a control group of untreated mice. In both M5076 tumor and B16 melanoma experiments, the early administration of TNP-470 was more effective at extending the survival times of mice receiving these drugs. However, there were significant differences in the relative sensitivities to TNP-470 between these two models.
A new dosage format, cisplatin microcrystals suspended in oil (CDDP-oil), was developed for the treatment of peritoneal carcinomatoses. We studied the acute toxicity of CDDP-oil injected intraperitoneally in mice. The 50% lethal dose was 30.3 mg/kg (27.1-33.7 mg/kg at the 95% confidence level), which was 1.79 times that of a cisplatin aqueous solution (CDDP-sol) of 16.9 mg/kg (16.1-17.8 mg/kg at the 95% confidence level). There were no significant differences in the duration of the toxic effects and the toxic symptoms between these two dosage forms. However, the severity of weight loss in the group given CDDP-oil was less than the group given CDDP-sol.
For the treatment of peritoneal carcinomatoses, we have developed a new dosage format, which comprises cisplatin microcrystals suspended in oil (CDDP-Oil). The acute toxicity of intraperitoneal CDDP-Oil was studied in mice. The LD50 value was 30.3 mg/kg in terms of cisplatin, which was 1.79 times that of a cisplatin aqueous solution (CDDP-Sol) of 16.9 mg/kg. There were no differences of the toxic symptoms between these two dosage forms, and any addisional side effects of cisplatin were not seen by the change of dosage form. However, the severity of body weight loss in the mice given CDDP-Oil was less than the mice given CDDP-Sol. We concluded that acute toxicity of cisplatin was redused by the change of dosage form.
