Antitumoral efficacy and pharmacokinetic properties of pirarubicin upon hepatic intra-arterial injection in the rabbit V x 2 tumour model.

To improve the efficiency of hepatic intra-arterial (h.i.a.) chemotherapy, we selected pirarubicin (THP) because it shows good properties for h.i.a. chemotherapy, such as fast and efficient cellular uptake, and used it for h.i.a. chemotherapy in rabbits with V x 2 tumour implanted in the liver. The anti-tumour effect of THP upon h.i.a. administration was compared with that upon intravenous (i.v.) injection and also with the anti-tumour activity of epirubicin (EPI) upon h.i.a. injection using optimal and maximal tolerated doses of each drug. When tumour growth rates and morphometric examinations were evaluated, it was found that THP and EPI were effective against V x 2 tumour when injected via the h.i.a. route. The activity of THP was stronger than that of EPI. As regards h.i.a. injection-related complication, plasma transaminase levels were temporarily elevated. To demonstrate higher anti-tumour activity and other advantages of h.i.a. injection of THP, plasma and tumour drug concentrations were determined by high-performance liquid chromatography after THP or EPI was administered at an equal dose to the rabbit V x 2 model. Hepatic intra-arterial injection of THP accomplished a selective and higher uptake into the tumour and lower effusion into the plasma than i.v. injection of THP or h.i.a. injection of EPL. Our findings indicate that THP is the better candidate of the two drugs tested for the h.i.a. chemotherapy because of its greater anti-tumour activity and the lower systemic drug exposure achieved upon h.i.a. injection.

Antitumor activity and metabolism of a new anthracycline-containing fluorine (ME2303) in Lewis lung carcinoma-bearing mice.

(7-O-(2,6-Dideoxy-2-fluoro-alpha-L-talopyranosyl)adriamycinone-14- hemipimerate (ME2303) showed a more marked growth inhibition of Lewis lung carcinoma than adriamycin (ADM). When administered to s.c. Lewis lung carcinoma-bearing mice, ME2303 in the plasma and liver was rapidly metabolized and disappeared. However, ME2303 was incorporated into the tumor at higher concentrations and remained in the tumor for a longer period than in the plasma and liver. ME2303 was metabolized to 7-O-(2,6-dideoxy-2-fluoro-alpha-L-talopyranosyl)adriamycinone (M1), the product of esterolysis, and its reduced derivative at the C-13 position (M2). Larger amounts of these metabolites were found in the analyzed tissues than in plasma. The maximum concentration of M1 in the tumor was observed at 2 h posttreatment, while the maxima in the plasma and liver were observed at 15 min. On the other hand, i.v. injection of M1 into mice showed a weaker antitumor effect than ME2303 injection, though M1 levels in the plasma and tumor were almost the same as those after administration of ME2303 at the maximum tolerated doses. Some metabolites of ME2303 were found in the tumor after administration of ME2303, but not after administration of M1. ADM remained in the analyzed tissues for a long period and ADM concentrations in the tumor were much higher than in the plasma but less than in the liver. M1 reached a concentration higher than that of ADM in the tumor, opposite to the pattern observed in the liver. The conversion process from ME2303 to M1, the metabolites and their locations in the tumor may be important for the marked antitumor effect of ME2303 in vivo.

Therapeutic activity and tissue distribution of ME2303, a new anthracycline containing fluorine, and its metabolites in mice bearing hepatic metastases of Lewis lung carcinoma.

Doxorubicin (DXR) and ME2303, a new fluorine-containing (C'-2) anthracycline derivative, were studied for their tissue distributions--particularly in the plasma, liver and bone marrow--following administration at the maximum tolerated doses to normal mice and mice bearing hepatic metastases of Lewis lung carcinoma. ME2303 was rapidly metabolized and disappeared rapidly from the plasma, liver and bone marrow. Its metabolites--the product of esterolysis (M1) and its reduced derivative at the C-14 position (M2)--remained for a long period except in bone marrow. On the other hand DXR remained in the analyzed tissues for a long period; an especially large amount of DXR was found in the bone marrow even at 24 h after administration of the drug while, in the case of ME2303, by this time even its metabolites had disappeared. The concentrations of M1 and DXR in the liver at 2 h were about 50- and 300-fold higher than their plasma concentrations. The tissue distributions in the normal mice and hepatic-metastases-bearing mice showed no significant differences. Regarding the antitumor effects of ME2303, M1, M2 and DXR in the hepatic-metastases-bearing mice, ME2303 was the most effective compound, and M1 was also active; DXR showed only a marginal effect, and M2 showed no effect.

In vitro and in vivo antibacterial activities of MT-141, a new semisynthetic cephamycin, compared with those of five cephalosporins.

The in vitro and in vivo antibacterial activities of MT-141 were compared with those of cefoxitin, cefmetazole, moxalactam, cefotaxime, and cefoperazone. The MICs of MT-141 for 90% of bacterial isolates were lower than the reference drugs against clinical isolates of Campylobacter jejuni, Clostridium difficile, and Bacteroides fragilis, whereas against clinical isolates of other gram-positive, gram-negative, and anaerobic bacteria, the MICs of MT-141 were similar to or higher than those of the reference drugs. In contrast, the bactericidal activity of MT-141 after 6- and 24-h exposures was superior to all of the reference drugs against 9 to 10 of the 12 bacterial strains studied, including Escherichia coli, Klebsiella pneumoniae, Salmonella enteritidis, indol-positive Proteus species, Serratia marcescens, Yersinia enterocolitica, Pseudomonas cepacia, and Clostridium perfringens. In the treatment of systemic infections in mice, MT-141 was again superior against 9 of the 12 strains tested, showing a good correlation with the bactericidal activity. It was found that the 50% effective doses of the six cephalosporins studied correlated better with the MBCs than with the MICs. As the serum levels of MT-141 in mice after subcutaneous administration were similar to those of the reference drugs, it was concluded that the bactericidal activity of MT-141 was a dominant factor in its in vivo activity.

[Pharmacological studies on a new cephamycin, MT-141. (2) Its effect on preparations of neuromuscular junction, smooth muscle organs and gastro-intestinal system].

The results for pharmacological experiments of MT-141 were as follows; Twitch tension of gastrocnemius muscle evoked by the stimulation of sciatic nerve was slightly reduced with 400 mg/kg MT-141 i.v. and upper doses. As the change was very small, however, it seems that MT-141 has no neuromuscular junction blocking action. Although MT-141 did not show any effects on most of isolated smooth muscle organs, only isolated tracheal muscle was somewhat relaxed with 10(-3) g/ml MT-141. The spontaneous motility of smooth muscle in situ was temporarily increased with 800 mg/kg MT-141 i.v. and upper doses. Two hundred mg/kg MT-141 showed no effect on the value of blood sugar and functions of kidney and liver. Any hemolysis did not appear even in the highest dose of 200 mg/kg MT-141 used in this experiment. From the present results and previous report (Krebe, M. et al., Jap. J. Antibiotics, in press), it seems that MT-141 is promised to be a highly safe and useful antibiotic agent in clinical use.