Clindamycin phosphate (Dalacin® P注, 以後CLDM-Pと略す) は米国アップジョン社で開発され, そのものは抗菌力は弱いが, 生体内でClindamycin (CLDM) に分解され, グラム陽性球菌及び嫌気性菌に対して強い抗菌力を持つと言われている1)。又, CLDMはStreptomyces lincolnensisの培養液から発見されたLincomycin (LCM) の7位のOHをClで置換した誘導体である (図1)。又, 抗菌スペクトラムはLCMと同じであるが, その抗菌力はLCMの4～8倍も強いと言われている2)。
今回, われわれはCLDM-Pの産婦人科領域感染症に対する有用性を評価する目的で, 骨盤死腔液, 子宮各組織への移行性について検討したので報告する。

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(2R)-4'-O-Tetrahydropyranyladriamycin·HCl (THP), a new anthracycline antitumor antibiotic, was administered to Sprague-Dawley rats intraperitoneally for 13 weeks. In rats receiving 0.4mg/kg/day, piloerection, emaciation, loose feces and thickening of the injection site were evident, and 7 males and 2 females died after week 12. Inferior body weight gain was observed in both sexes starting week 4-6. The food consumption also decreased. Hematological examination revealed lower counts of total leucocyte and lymphocyte. At termination there were lower spleen, thymus and testes weights, thickening of the walls of the intestine and stomach, gastric ulceration, presence of ascitic fluid, and congestion and thickening at the injection site. Decreases in the lymphocyte populations of the thymus, spleen and lymph nodes were observed microscopically. A decrease in the number of hematopoietic cells in the bone marrow and a degeneration of the germinal epithelium in the testes were also seen, as were gastrointestinal disturbances. These treatment-related effcets were mainly confined to rats receiving 0.4mg/kg/day and to a lesser extent, to rats receiving 0.1mg/kg/day. The effects on rats receiving 0.025mg/kg/day were only at the microscopic level. No rats receiving 0.006mg/kg/day were toxicologically affected.

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(2R)-4'-O-Tetrahydropyranyladriamycin (THP) is a derivative of doxorubicin (adriamycin, ADM), a new antitumor antibiotic. THP has a stronger antitumor activity on L-1210 and other tumors implanted in mice but a lower cardiotoxicity than other anthracycline antibiotics1, 2).
The objective of this study was to examine toxic effects of THP in Beagle dogs with the intravenous administrations repeated for 13 weeks at daily dosages of 0.01, 0.02, 0.04 and 0.08mg/kg.
In addition, after completion of 13 weeks dosing, the animals received 0.02 and 0.04mg/kg of THP were subjected to recovery study for 5 weeks to monitor recovery from the toxic effects.

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In the previous paper1) on the subacute toxicity and recovery study of (2R)-4'-O-tetrahydropyranyladriamycin (THP), a new antitumor antibiotic in Beagle dogs, it has been suggested that the maximum non-toxic dose is less than 0.01mg/kg/day to males, because this compound has caused some damages on the testes even at the lowest dose of 0.01mg/kg/day.
Therefore, the objective of this study is furthermore to examine 13-week subacute toxicity of THP in male Beagle dogs at low doses of 0.0001, 0.001 and 0.01mg/kg/day to determine the level of nontoxic dose.

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(2R)-4'-O-Tetrahydropyranyladriamycin·HCl (THP), a new anthracycline antitumor antibiotic, was administered to Sprague-Dawley rats (each group 20 rats) intraperitoneally at dosages of 0.001, 0.008, 0.06 and 0.3mg/kg/day for 53 weeks. Piloerection, loose feces or perianal staining and thin or emaciated build were observed from week 12 in rats receiving 0.06 or 0.3mg/kg/day. All rats receiving 0.3mg/kg/day and 3 males and 1 female receiving 0.06mg/kg/day died or were prematurely sacrificed in the period from weeks 13 to 44. The overall food consumption and body weight gain of both sexes receiving 0.06 or 0.3mg/kg/day were lower than those of the controls. Hematological examination showed low leucocyte counts, disturbance in neutrophil and lymphocyte number and low erythrocytic characteristics in animals receiving 0.06 or 0.3mg/kg/day. At necropsy, macroscopic changes were found at the injection site, throughout the gastrointestinal tract and in the male reproductive system in rats receiving 0.06 or 0.3mg/kg/day. Microscopic examination revealed decrease in the small lymphocyte population in the hematopoietic and lymphoid system in rats receiving 0.008 to 0.3mg/kg/day. Degeneration of the germinal epithelium of the subcapsular tubules of the testes, gastric ulceration, epithelial adnexal atrophy of the skin and chronic cellulitis and necrosis at the injection sites were also observed. No rats receiving 0.001mg/kg/day were affected in these respects.

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Vol. 38 (1985) No. 7 p. 1785-1791
修正箇所：その他

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(2R)-4'-O-Tetrahydropyranyladriamycin (THP) is a derivative of doxorubicin (adriamycin, ADM), an anthracycline antibiotic1-4)
We have already reported the acute toxicity5) and subacute toxicity of THP in male and female Beagle dogs6, 7). The results suggest that THP causes some damages on the testes and haemopoietic tissues in Beagle dogs. The maximum non-toxic dose is presumed to be 0.001mg/kg to male and 0.01mg/kg to female Beagle dogs when administered intravenously (i.v.) for 13 weeks.
The objective of this study is to examine the chronic toxicity of THP in Beagle dogs with the intravenous administrations repeated for 53 weeks at daily dosages of 0.0007, 0.0025, 0.01 and 0.04mg/kg.

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(2R)-4'-O-Tetrahydropyranyladriamycinは梅沢らが発見したAnthracycline系の新抗癌抗生物質で, マウス移植L1210に対してDoxorubicin (Adriamycin, ADM) と同等か, あるいは, それより強い制癌作用を有し1), 一方, 心毒性はAclarubicinと同等か, それより弱いこと2) が報告されている。
今回,(2R)-4'-O-Tetrahydropyranyladriamycin (THP) が生殖細胞の形成, 妊娠の成立及び次世代の発生にどのような影響を及ぼすかを検討するために, ラットにおける妊娠前及び妊娠初期投与試験を実施し, 二三の知見を得たので報告する。

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Anthracycline系の新抗癌抗生物質である (2R)-4'-O-Tetrahydropyranyladriamycin (THP) のラットにおける妊娠前及び妊娠初期投与試験では, 最高投与群のラットで妊娠末期体重の増加抑制及び死亡・吸収胎仔 (胚) 率の増加が観察された1)。
従つて, 今回はTHPが胎仔あるいは新生仔の発育にどのような影響を及ぼすかを検討するために, ラット及びウサギにおける胎仔器官形成期投与試験を実施し, 二三の知見を得たので報告する。

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Anthracycline系の新抗癌抗生物質である (2R)-4'-O-Tetrahydropyranyladriamycin (THP) のラットにおける妊娠前及び妊娠初期投与試験1), ラット及びウサギにおける胎仔器官形成期投与試験2)についてはすでに報告した。
今回は本剤をラットの周産期及び授乳期に投与し, 新生仔の生後発育に及ぼす影響を検討し, 二三の知見を得たので報告する。

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(2R)-4'-O-TetrahydropyranyladriamycinはDoxorubicinから誘導された新しいAnthracycline系抗腫瘍性抗生物質である。この薬剤はマウスの実験腫瘍に対し高い抗腫瘍性を示し1), ハムスターにおいて他のAnthracycline系抗腫瘍剤より低い心毒性を示すことが知られている2)。又, そのマウス, ラット, イヌにおける毒性はすでに報告されている3～9)。本報においてこの新抗腫瘍剤の一般薬理作用を報告する。

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Daunorubicin, Doxorubicin等のAnthracycline系抗生物質は, 癌化学療法における有用な薬剤の一つである。特にDoxorubicin (Adriamycin, ADM) は, 広い抗癌スペクトラムを持ち, 各種の固型癌, 白血病及びリンパ肉腫等に有効であるが, その副作用として脱毛, 消化器障害, 造血器障害及び心毒性が報告されている。ADM の心毒性は総投与量が500～550mg/m²以上になると特異的な遅発性の心筋障害, 心不全 (ADM心筋症) を生じ, 臨床上問題となつている1)。最近では, 抗腫瘍性効果が高く, より心毒性の少ないAnthracycline 系抗生物質の開発が行われている2～4)。
(2R)-4'-O-Tetrahydropyranyladriamycin・HCl (THP) は, ADMの4位にTetrahydropyranyl基をエーテル結合を介して導入することにより得られた新しい誘導体であり, Fig. 1に示す化学構造を持つ薬剤である。この薬剤のゴールデンハムスターを用いた心筋微細構造に与える影響については, すでにDANTCHEVらにより報告されている5)。
今回・ゴールデンハムスターを用い, THPの心機能に及ぼす影響について, 心電図学的及び病理組織学的に ADMと比較検討したので報告する。

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(2R)-4'-O-Tetrahydropyranyladriamycin hydrochloride (THP), a new antitumor antibiotic, was administered to rabbits at a concentration from 0.02 to 0.5% by instillation, or by intracutaneous, subcutaneous or intramuscular injection to study its local irritative effect. The irritative effect of THP increased with concentration. At a concentration of 0.5%, THP was irritant to the eye, skin and muscle but at a concentration of 0.1% practically no effect was observed. The effect was equal to or lower than that of doxorubicin. An instillation of 0.5% THP caused reversible irritation effect on the eye. Slight conjunctival responses (redness and chemoisis) were observed. Rinsing reduced the irritative effect. Intracutaneous injection of 0.1ml of 0.5% THP caused well defined, moderate erythema, surface ulceration and dermal necrosis. Cutaneous muscle necrosis also occurred. At a concentration of 0.02%, dermal necrosis and inflammatory cell infiltration were observed. Erythema, as well as muscle necrosis and calcification with giant cell reaction and inflammatory cell infiltration were observed by an intramuscular injection at a concentration of 0.5%. Subcutaneous injection of 0.5% THP showed no irritative effect.

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(2R)-4'-O-Tetrahydropyranyladriamycin (以下THPと略す) は梅沢等1)により見い出された新しい抗腫瘍剤である。本薬剤はAnthracycline系抗生物質であるDoxorubicin (Adriamycin, 以下ADMと略す) の4, 位に酸素原子を介してTetrahydropyranyl基を化学的に導入することにより得られた新規な化合物である。
THPはマウスの可移植性腫瘍, 特にマウス骨髄性白血病L1210に対して高い抗腫瘍性を示すが1), 他のAnthracycline 系薬剤と同様に毒性試験において末梢白血球数の減少が認められた2)。
今回, THPをウサギに1回静脈内投与した場合に骨髄機能が受ける影響をADMを対照薬剤として調べたので報告する。

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(2R)-4'-O-Tetrahydropyranyladriamycin (以下THPと略す) は新しい抗腫瘍性抗生物質である1)。毒性試験結果2)から, 本薬剤が骨髄機能に対して影響を与えることが推定され, 前報においてTHPをウサギに1回静脈内投与した場合の骨髄機能変化を調べる単回投与試験結果について報告した3)。本報においては, THPをウサギ静脈内に反復投与した場合の骨髄機能変化について, Doxorubicin (Adriamycin, ADM) を対照薬剤として調べた結果を報告する。

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(2R)-4'-O-Tetrahydropyranyladriamycin (THPと略記) は, 梅沢ら1)により発見された新規なアントラサイクリン系抗腫瘍性抗生物質であり, Doxorubicin (Adriamycin, ADMと略記) の4, 位に酸素原子を介してテトラヒドロピラニル基を導入したADMの新規な誘導体である。
THPは各種実験腫瘍においてADMより優れた効果1, 2)を示し, 又, ハムスターにおいて心毒性が低いことが報告されている3)。
THPの生体内動態についてはすでにマウス4), ウサギ5), イヌ6)等における実験結果が報告されている。
今回著者等は, ¹⁴Cで標識したTHPを用い, ラットにおけるTHPの体内動態について検討したので報告する。

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前報1)において,(2R)-4'-O-Tetrahydropyranyladriamycin (THPと略記) の単回投与後のラットにおける体内動態について報告した。今回, 著者等はラットに¹⁴C-THP又はTHPを反復投与し, その体内動態及び蓄積性を検討した。又, 肝薬物代謝酵素の誘導についても検討を加えた。

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The pharmacokinetics and physiological disposition of a novel anthracyclines,(2R)-4'-O-tetrahydropyranyladriamycin (THP) were studied in dogs by an HPLC analysis. The THP administered intravenously (1.5mg/kg) disappeared rapidly from the plasma immediately after an injection of the drug. The plasma level of THP was lowered in a triphasic pattern up to 24 hours and was simulated by a three-compartment open model in which the half-lives of α-, β-and γ-phase were calculated to be 0.0116 hour, 0.152 hour and 7.02 hours, respectively. The blood cell level of THP was about 10 times as high as the plasma level during the observation. In the study of tissue distribution of THP 2 and 8 hours after the administration, the highest concentration of THP was found in the spleen and lung and these concentrations were diminished quickly. However, in the lymph nodes and bone marrow concentrations of THP increased with a lapse of time. THP and its metabolites were excreted in the bile by 2.7% of dose during 8 hours in the bile-cannulated dogs. Urinary recovery of THP and its metabolites was about 1.3% of the dose up to 72 hours. In these experiment, THP was metabolized to THP-OH and ADM, and to aglycones which were excreted in conjugated forms. The results obtained from a similar study on ADM were compared and discussed.

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