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The effects of fluidity and vesicle size on the antitumor activity and myelosuppressive activity of liposomes loaded with daunorubicin, an anthracycline antitumor drug, were investigated in Yoshida sarcoma-bearing rats. Liposomes composed of egg phosphatidylcholine (EPC) or hydrogenated egg phosphatidylcholine (HEPC), cholesterol and dicetyl phosphate in a molar ratio of 5:4:1 were injected intravenously into rats 5 d after subcutaneous inoculation of Yoshida sarcoma. At non-effect dosage in free drug, HEPC-liposomes with a diameter of 58 or 142 nm showed the greatest inhibitory effect against Yoshida sarcoma among liposomes tested, whereas larger ones (272 nm) had weaker effect. Small EPC-liposomes (57 nm) had no effect. Larger HEPC-liposomes (especially 142 nm) greatly decreased the number of peripheral white blood cell compared with free drug at the same dose, indicating relatively strong myelosuppressive toxicity. However, small EPC- and HEPC-liposomes with a diameter of 57 and 58 nm, respectively, showed toxic effects comparable to that of free drug. Examination of the dose-dependency of therapeutic effects and toxicity indicated encapsulation of daunorubicin in the small HEPC-liposomes to enhance the therapeutic index about 3 times that of free drug. These findings indicate the possibility of using small HEPC-liposome as a drug carrier for targeting solid tumors.

The purpose of this study concerns a novel method for preclinical assessment of rectal irritation caused by suppositories introduced into the rectum. Rectal irritation was assessed by the balloon method in fasting conscious rats. This method is based on measuring rectal contractions due to possible irritation caused by the presence of drugs and adjuvants in the suppository. In control experiments (vehicle only), significant rectal contractions were not observed in a range of pH 1.5-11.0 and osmotic pressure 70-2000 mOsm kg-1 H2O, respectively. On the other hand, strong contractions were observed after rectal administration of an aqueous solution of 50% glycerin, 100 mM sodium caprate or 25 mM sodium cholate. The intensity of contraction after rectal administration of sodium caprate or sodium cholate was dependent on the concentration in the dosing solution. In addition, the effect of sodium caprate and sodium cholate on rat rectal mucosa was investigated by optical light microscopy. Although slight or moderate alteration such as the presence of mucinous substance in lumen and congestion, oedema and haemorrhage of the rectal membrane 20 min after rectal administration, there was no major damage to the rectal mucosa. There was a correlation between the median score for mucinous substance in lumen and mean intensity of rectal contraction. For comparative purposes, defecating sensations, pain, itch, burning sensations, and awareness of the presence of a foreign body after administration of suppositories containing 0, 1, 2 and 4% sodium caprate were examined in eight healthy volunteers. The defecating sensation in the human subjects correlated with the intensity of rectal contraction in rats. The results suggest that rectal contraction in conscious rats could be a useful index for prediction of a defecating sensation in man.

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