The effects of repeated oral administration of cefuroxime axetil, were assessed in Beagles. The test material, an ester, is hydrolysed following absorption from the intestine to yield the therapeutically active moiety, cefuroxime, together with acetic acid and acetaldehyde ; in this study cefuroxime and unhydrolysed cefuroxime axetil were detected in the blood. Cefuroxime axetil was administered twice daily during 27 weeks by gavage of aqueous, suspensions, total daily doses were equivalent to 100, 400 or 1600 mg cefuroxime/kg/day. Apart from three cases of intercurrent illness, unrelated to treatment, the dogs remained in good health. Effects observed in the 1600 mg/kg group included vomiting and slight suppression of body weight gain. Minor variations in haematological measurements included rather low haemoglobin levels, packed cell volumes and erythrocyte counts. Slightly smaller numbers of neutrophils were thought to reflect reduced demand on normal defensive mechanisms due to continued antibiotic treatment. Prolongation of prothrombin time and activated partial thromboplastin time is attributed to disturbance of the intestinal microbial flora and reduced synthesis of vitamin K, on which the dog is highly dependent. Cefuroxime does not have the N-methylthiotetrazole side chain thought to be responsible for inhibition by other cephalosporins of the vitamin K-dependent step in the synthesis of clotting factors. Variations in plasma chemistry included rather low levels of plasma protein. Electrophoresis showed this to be a generalized reduction; only gamma globulins were proportionally decreased and this finding, like the low neutrophil counts, is attributed to the protective action of the antibiotic. Minor metabolic adjustments to the compound are reflected in plasma levels of cholesterol and triglycerides. This spectrum of findings was seen only to a very limited extent in the 400 mg/kg group ; the 100 mg/kg group was, with very few exceptions, unaffected by the treatment. Macroscopic post mortem examination and microscopic examination of tissues revealed no treatment-related features indicative of toxicity. Cefuroxime axetil was thus shown to possess very little toxicity when administered repeatedly in large doses to Beagles. The lowest dose level in this study was ten times the proposed daily clinical dose in man.

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We examined the effects of mitomycin C and aminopterin on ovulation in vivo and, fertilization, subsequent cleavage and implantation in slc-ICR female mice using methods of fertilization and culture in vitro. Chemicals were injected into mice at the MI (meiosis I) stage or 3 hours before the MI stage in order to examine their toxicity. Mitomycin C did not affect ovulation, but decreased the rate of fertilization. A high dose of mitomycin C (4 mg/kg) inhibited fertilization and the development of ova to the 2-cell stage. Aminopterin affected neither ovulation nor fertilization. At either the MII (meiosis II) stage or 3 hours before the MII stage, high doses (4 and 2 mg/kg) of mitomycin C arrested cleavage and implantation. The cleavage was blocked frequently between the 3-4 cell stage and the 5-8 cell stage. Aminopterin affected neither cleavage nor implantation.

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The marmoset, a small non-human primate, has rarely been used in toxicological studies. A short-term toxicity study was performed on common marmosets (BW=330±32g). Fifteen male marmosets received oral administration of DAB at a dose level of 56 mg/kg/day and 4 control animals received corn oil alone for a period of 15 days. Hematological, biochemical, histopathological and bone marrow examinations were carried out on the 5th, 10th and 15th day of treatment. Body weight decreased continuously and two animals died on day 10. Decreases in RBC, Hb and Ht and increases in MCV and WBC were observed. Uric acid and glucose were increased and AlP and LAP were decreased. Aldolase, GOT and GPT were increased by day 10, and thereafter recovery of aldolase to the control level and decreases of GOT and GPT were observed. Relative organ weights of the liver, kidney, spleen and adrenal were increased. Histologically, C-cell hyperplasia of the thyroid and slight changes of the liver were noted. Marrow total cell counts were not changed, but the G/E ratio was reduced. Thus, macrocytic anemia, an increase of marrow erythroblasts due to anemia and changes of biochemical parameters indicating liver injury were observed in marmosets; these findings were similar to those in rats in the previous experiments.

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新規抗アレルギー薬MY-5116およびその主要活性代謝物MY-1250の抗原性の有無について, ウサギ, モルモットおよびマウスを用いて検討した。本試験においてはMY-5116, MY-1250およびMY-5116と蛋白との非可逆的結合物を免疫原あるいは誘発原として用いることにより, 薬物を生体内に投与したときに薬物が免疫原性および誘発原性を示すかどうかを検討し以下の結果を得た。1. MY-5116を免疫補助剤であるFCAとともにウサギおよびモルモットを頻回免疫しても, PCA反応およびPHA反応によりMY-1250に対する特異的なIgGクラスの抗体は検出されなかった。同様に, 本検体をAlumとともに免疫した C3H/He, BALB/c 近交系マウスにおいてもMY-5116に対するIgE抗体はみられなかった。さらに, MY-5116により免疫されたモルモットに対してMY-1250およびMY-5116-BSA結合物を惹起抗原として能動性全身アナフィラキシー反応, Schultz-Dale反応および皮膚反応を誘発したが, いずれの反応も陰性であった。以上の結果よリMY-5116が生体内に投与されてもMY-5116が免疫原性を獲得することはないものと推察される。2. MY-5116-OVA結合物をFCAとともにウサギ, モルモットを, またAlumとともに C3H/He, BALB/c 近交系マウスをそれぞれ免疫した。その結果, モルモット血清およびマウス血漿に対して惹起抗原としてMY-5116-BSA結合物を用いるとPCA反応は陽性を示したものの, MY-1250単独を用いた際には同反応は陰性であった。また, 感作されたモルモットにMY-1250単独を皮内注射しても遅延型皮膚反応は認められなかった。これらの結果から, MY-5116が誘発原性を発現することはないと推察される。3. Maximization test 法に準じて, MY-5116を皮内注射と貼布による免疫を行った後, MY-5116とMY-1250を貼布して遅延型接触皮膚アレルギー反応を誘発したが, 同反応は全例陰性であった。以上結果から, 本試験条件下ではMY-5116あるいはMY-1250には免疫原性および誘発原性のいずれも認められないことから, MY-5116には抗原性はきわめて少いと推察される。

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