[Toxicity study of cefmatilen hydrochloride hydrate (S-1090) (5)--Six-month repeated oral dose toxicity study and supplement study in rats].
Cefmatilen hydrochloride hydrate (S-1090) was orally administered to rats at dose levels of 100, 300 and 1000 mg potency/kg once daily for 6 months. All the S-1090 treated groups showed soft feces, reddish-brown feces (due to chelated products of S-1090 or its decomposition products with Fe3+ in the diet), abdominal distention, increased food and water consumption, lower urine pH, and a decrease of white blood cells counts (except for males of the 100 mg potency/kg group). One male in the 300 mg potency/kg group showed mucous feces and marked decrease in body weight, and diet in the middle stage of the administration period. In necropsy of the survivors of all treated groups, marked cecal enlargement was noted. No remarkable changes were observed in the other examination items. From the early stage of the withdrawal period, animals in the 1000 mg potency/kg group showed again soft or mucous feces and a marked decrease in body weight. Of these animals, one male died and another male was sacrificed in a moribund state at about 2 weeks of the withdrawal period. Enterocolitis was observed in these cases. Almost all animals recovered within 3 weeks of withdrawal. A supplemental study of the 6-month toxicity study was conducted to examine the mechanisms of enterocolitis and the changes observable in the 100 or 300 mg potency/kg groups after drug withdrawal. As a reference, cefdinir (CFDN), an oral cephem antibiotic the same as S-1090, was added in the 1000 mg potency/kg group. No deaths occurred in any groups. Decreased intestinal flora were noted in all the groups treated with S-1090 or CFDN at the end of the dosing period. At 2 weeks of the withdrawal period, C. difficile and its D-1 toxin in the cecal contents were highly detected in the S-1090 300 and 1000 mg potency/kg groups and CFDN group. Inflammatory changes in the cecum and colon were observed in these groups. At 4 weeks of the withdrawal period, intestinal flora in the S-1090 groups almost returned to the condition before dosing, but those in the CFDN group were retained highly. Cecal D-1 toxin in the CFDN group was positive and higher than in the S-1090 groups. It was thus considered that the critical condition with enterocolitis resulted from C. difficile, which proliferated more rapidly than the other bacteria and D-1 toxin produced by this bacteria in the withdrawal period. Above changes were commonly observed in the CFDN group. The NOAEL of S-1090 was assessed to be 100 mg potency/kg/day which induced no enteritis.
Sameshima
H
H
Shin Nippon Biomedical Laboratories, Ltd., 2438 Miyanoura, Yoshida, Kagoshima 891-1394, Japan.
Omori
M
M
Nishimura
Y
Y
Chihaya
Y
Y
Itoh
F
F
Mizushima
Y
Y
Yabuuchi
K
K
Ohno
K
K
Furukawa
H
H
Yoshida
I
I
Ueno
M
M
Yahara
I
I
Kato
I
I
D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity; D001773:Blood Cells / Q000187:drug effects; D001774:Blood Chemical Analysis; D001835:Body Weight / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology; D000077525:Cefdinir; D002511:Cephalosporins / Q000633:toxicity*; D016360:Clostridioides difficile / Q000187:drug effects; D004326:Drinking / Q000187:drug effects; D004334:Drug Administration Schedule; D004435:Eating / Q000187:drug effects; D004755:Enterobacteriaceae / Q000187:drug effects; D005260:Female; D006309:Hearing / Q000187:drug effects; D007422:Intestines / Q000382:microbiology; D008099:Liver / Q000737:chemistry; D008297:Male; D009780:Occult Blood; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D013291:Streptococcus / Q000187:drug effects; D016482:Urinalysis
D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D000077525:Cefdinir; C419864:cefmatilen