Toxicological studies on a new macrolide antibiotic, midecamycin acetate (miokamycin). Part III-1. Chronic toxicity in rats

Miokamycin (MOM) is a derivative of midecamycin, a macrolide antibiotic isolated from a culture broth of Streptomyces mycarofaciens. The objective of this study was to determine the chronic toxicity of MOM in male and female rats (Wistar, SPF, 5-week-old) after repeated oral administration of MOM, non-crystalline solid, for 26 weeks at daily dosages of 62.5, 125, 250, 500 and 1,000 mg/kg. The lowest dosage level of 62.5 mg/kg/day was only applied for female rats. In conclusion, the maximum non-toxic dosage level of MOM, non-crystalline solid, is presumed to be 250 mg/kg in male and female rats with p.o. administered once daily for 26 weeks.     

Antitumor effect of a combination of 6-methylthioinosine and amphotericin B on mouse leukemia L1210

Antileukemic activity of 5 kinds of sulfur-containing purine ribonucleosides were examined in the presence and absence of amphotericin B against L1210 in mice. Among these compounds, 6-methylthioinosine was potentiated by amphotericin B. 6-Methylthioinosine in combination with amphotericin B produced a 75% increase in the lifespans, which was greater than the increase in lifespans by 6-methylthioinosine (38%) or amphotericin B alone (2%).Antitumor effects of other sulfur-containing ribonucleosides, such as 6-thiocyanatoguanine, 6-thiocyanatopurine, 6-thiocyanatoinosine, and 6-methylthiopurine, were not augmented by amphotericin B.     

An Ultrastructural Change in Developing Rat Cerebral Cortex: A Morphometrical Study

Abstract: Five age groups, each composed of four animals from each of the following ages, were used to assess age-related ultrastructural changes with development in the neuropil of the III layer of the frontal cortex (area 6) in rats; 1, 2, 3, 5 and 12 weeks old. Random samplings within the neuropil were taken to produce 25 electron micrographs in each rat (totaling 500). The profiles of axon terminals, dendrites and mitochondria in each element in the neuropil of each micrograph were traced. The percentage of their areas for the area of neuropil (relative volume fraction) was examined using the image analyzer system. The size and number of synaptic terminals were counted. The relative volume fractions of both the axon terminals and mitochondria in the terminals for the neuropil were found to have increased in the mature rats. On the other hand, the relative volume fraction of dendrites for the neuropil had been unchanged and the size of the terminals had gradually decreased. The number of terminals had progressively increased with development.     

Toxicological studies on a new macrolide antibiotic, midecamycin acetate (miocamycin). Part IV-2. Toxicity of metabolites of miocamycin: acute toxicity of Mb1 in rats

Acute toxicity studies on miocamycin (MOM), non-crystalline solid, and its metabolite Mb1 were performed in mice in the previous studies. In the present studies, we evaluated acute toxicity of Mb1 in male and female rats after single oral administration at the maximum physically applicable dose of 5,000 mg/kg. Observations were continued for 1 week after treatment. It is concluded that LD0 values of Mb1 were estimated more than 5,000 mg/kg.     

Effect of fosfomycin-calcium on reproductive performance of rat and rabbit: teratogenicity test (author's transl)]

The teratogenicity study of fosfomycin-Ca (FOM-Ca) was undertaken in Wistar strain rats and JW strain rabbits. Rats were treated orally at dose levels of 140,700 and 1,400 mg/kg/day from 7th to 17th day of gestation, and rabbits were treated orally at dose levels of 80, 140 and 420 mg/kg/day from 6th to 18th day of gestation. In the case of rats, two-thirds of pregnant mothers in each group were sacrificed on 20th day of gestation and then their fetuses were examined for external, visceral and skeletal observation. The remaining mothers were allowed to deliver naturally, and then their offsprings were examined for postnatal development. In the case of rabbits, all pregnant mothers were sacrificed on 29th day of gestation and their fetuses were examined. No effect of FOM-Ca treatment to rat and rabbit mothers was found except soft stool was seen with maximum dose in rats. Dead or resorbed rate of fetuses increased, external anomalies (short tail, abdominal hernia) were found and skeletal anomalies slight increased with maximum dose in rats. However, there was no significant difference from the control or background data. While, no effect of FOM-Ca treatment was observed in rabbits and rat offsprings. Consequently, it can be concluded that FOM-Ca has no teratogenicity effects on rats and rabbits.     

Laboratory study of collagen wound dressing (CAS). Part II. An immunological study (I) immunogenicity in rabbits and mice

In order to determine whether collagen wound dressing (CAS) has any immunogenicity, we carried out various immunological tests with Japanese albino rabbits and BALB/c mice. CAS extract produced no antibodies while atelocollagen, the source material of CAS, has less antigenicity than acid soluble collagen, a tropocollagen. Moreover, the antigenicity of CAS was much lower than that of lyophilized porcine skin which is much used in clinical practice. It is assumed that CAS would be immunologically safe as a wound dressing.     

Evaluation of weekly low-dose CPT-11 combined with 5-FU/l-LV therapy for advanced and recurrent colorectal cancer--preliminary study

In Japan, cancer chemotherapy for advanced and recurrent colorectal cancer has not been adequately developed in comparison with the USA and Europe. However, the number of patients with advanced colorectal cancer has increased dramatically in this decade. Therefore, effective and feasible regimens against colorectal cancer are urgently needed. We designed a new regimen to evaluate the efficacy and feasibility of weekly low dose CPT-11 combined with 5-FU/l-LV therapy based on an RPMI regimen against advanced and recurrent colorectal cancer. Twenty patients were enrolled in this study. Weekly administration (CPT-11; 60 mg/m(2) div for 1st-line chemotherapy, 40 mg/m(2) div for 2nd-or 3rd-line chemotherapy, l-LV; 200 mg/m(2) div, 5-FU; 500 mg/m(2) iv, 3 consecutive weeks, 1-week break) was performed on an ambulatory basis. The treatment cycles were repeated every 4 weeks until disease progression and/or severe toxic events occurred. The overall response rate was 31.6% with 5.3% complete response and 26.3% partial response in addition to 42.1% with no changes beyond 3 months. These results suggested that the clinical benefit was shown in 73.7% of patients. Furthermore, median TTF (time to failure) of this regimen was 6.5 months and MST was 20.4 months, respectively. On the other hand, adverse events were restricted to grade 3 with 30.0% neutorocytopenia and 5.0% thrombocytopenia. Therefore, weekly low-dose CPT-11 combined with 5-FU/l-LV therapy seems to be extremely useful, with excellent anti-tumor effect and tolerable adverse reactions, for the treatment of advanced and recurrent colorectal cancer on an ambulatory basis.