[in Japanese]

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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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[in Japanese]

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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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The effect of a new antitumor antibiotic on the fertility was studied using SD rats.(2R)-4'-O-Tetrahydropyranyladriamycin (THP) was administered to each rat at 0.01, 0.03 or 0.1mg/kg daily.
Males were given the drug intravenously for 63 days prior to mating and during the mating period; females were given the drug intravenously from 14 days prior to mating until day 7 of pregnancy. All the pregnant rats were sacrificed on day 20 of pregnancy, followed by external, visceral and skeletal observations of their fetuses. Results were summarized as follows.
1. THP, at 0.1mg/kg, suppressed body weight gain in females during the late period of pregnancy but did not affect body weight gain in males.
2. THP, at 0.1mg/kg, increased the numbers of dead fetuses and of resorptions. It caused no external, visceral or skeletal anomalies at any dose levels.
3. The results suggest that, in rats, the maximum “no effect” dose of THP is 0.03mg/kg/day intravenously regarding fertility and fetal development.

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This paper describes the embryotoxicity and teratogenic effects of (2R)-4'-O-Tetrahydropyranyladriamycin (THP). The drug was administered intravenously to female rats at 0.01, 0.03, 0.1 or 0.3mg/kg daily from day 7 to day 17 of pregnancy and to female rabbits at 0.01, 0.05 or 0.1mg/kg daily from day 6 to day 18 of pregnancy. Results were summarized as follows.
1. Rats
THP, at the highest dose of 0.3mg/kg, decreased body weight gains of pregnant females. This dose caused a decrease in body weights of fetuses, tendencies to increase the rate of death of fetuses or of resorption, an increase in the number of lumbar vertebrae and a delayed ossification of forelimbs of fetuses. Other parameters were not affected by THP at any dose levels. At any dose levels, THP did not produce external, visceral or skeletal malformations in the offspring (F₁), nor did it affect the development, physiological functions, behavior, mating, fertility or pregnancy of the offspring. However, at the highest dose level, THP decreased the weight of testes of the offspring.
The results suggest that the maximum “no effect” dose level of THP to pregnant females and offspring is 0.1mg/kg/day intravenously.
2. Rabbits
The highest dose of THP, 0.1mg/kg, decreased the consumption of food and water by pregnant females, but at any dose levels, it did not affect their body weight gain. THP did not cause teratological effects such as external malformation or visceral and skeletal anomalies in the fetuses at any dose levels tested. The results suggest that the maximum “no effect” dose of THP is 0.05mg/kg/day intravenously to pregnant females and above 0.1mg/kg/day intravenously to fetuses.

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This paper describes effects of (2R)-4'-O-tetrahydropyranyladriamycin hydrochloride (THP) on perinatal and postnatal rats. The drug was administered intravenously to female rats at 0.01, 0.03 or 0.1mg/kg daily from day 17 of pregnancy to 21 days after delivery. Results were described below.
1. At any dose levels tested, THP did not affect the body weight gain, food and water consumption by pregnant rats, and length of gestation period or delivery rate. However, at the highest dose level, THP decreased spleen weight.
2. THP, at any dose levels, did not have toxic effect on development, physiological functions, behavior, mating, fertility or pregnancy of the first generation offspring (F1). At the highest dose of 0.1mg/kg, however, THP produced delayed ossification of sacrococcygeal vertebra in the second generation fetuses (F2).
3. The results suggest that the maximum “no effect” dose of THP to pregnant rats and offsprings is 0.03mg/kg/day intravenously.

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General pharmacology of (2R)-4'-O-tetrahydropyranyladriamycin hydrochloride (THP) was studied in experimental animals. Intravenous administration of THP showed no significant effect on the respiratory and cardiovascular systems, such as blood pressure, heart rate, ECG and respiration in anesthetized rabbits and dogs. But in rats and cats, THP produced a transient decrease in blood pressure resulted from vasodilation. The hypotension was not inhibited by antihistaminics. Contraction of isolated guinea-pig atria was stimulated by THP at high concentrations (10⁴g/ml). THP inhibited the spontaneous movement of isolated rabbit ileum and rat uterus (virgin and pregnant) at high concentrations (10⁴g/ml). In some isolated guinea-pig ileum preparations, THP partially (6-36%) antagonized the contraction inducing by acetylcholine, histamine, serotonin and barium chloride. Urine volume and urinary excretion of electrolytes were increased by intravenous injection of 5.0mg/kg THP. Vascular permeability was progressed when administered intracutaneously. Hemolytic effect was shown at high concentrations (10⁴g/ml) but no effect on the coagulation was found. No significant effect of THP was observed on the general behavior and central nervous system, autonomic nervous and peripheral nervous systems. Also, THP had no significant effect on gastrointestinal propulsion in mice, the mucous membranes of the stomach and duodenum of rats, or gastric acid and bile secretion in rats.

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Cardiovascular effects of (2R)-4'-O-tetrahydropylanyladriamycin·HCl (THP) and doxorubicin (adriamycin, ADM) were studied in hamsters. In experiments to observe acute effects, THP was administered intravenously at a dose of 12.5, 25.0 or 50.0mg/kg, and ADM at 1.56, 3.13 or 6.25mg/kg was given to different subjects. The THP caused slight ECG alterations at a dose of 12.5mg/kg. At a dose of 25.0mg/kg or 50.0mg/kg, THP caused moderate to remarkable alterations in ECG like a widening of PR and PRc interval, A-V block, ST segment depression and T wave flattening. The ADM caused moderate to remarkable alterations in ECG at a dose of 3.13mg/kg or 6.25mg/kg, including arrhythmia, bradycardia, A-V block, ST segment changes and T wave flattening. These changes caused by THP and ADM recovered within 5-10 minutes after injection. Alterations in the ultrastructure of the myocardium caused by THP at a dose of 50.0mg/kg included some cells with slight changes like swelling of mitochondria, focal intracellular edema, and enlargement of myofibrils. The ADM, at a dose of 3.13mg/kg, induced severer swelling of mitochondria than THP, dilatation of sarcoplasmic reticulum, intracellular edema, and disorganization of myofilaments. At a dose of 6.25mg/kg of ADM, these changes became more pronounced.
In experiments to observe subacute effects, hamsters were treated with THP or ADM by daily intraperitoneal injections for 15 consecutive days, and then allowed to be recovered for 15 days. Dose levels of THP or ADM were 0.125, 0.25, 0.5 and 1.0mg/kg. General toxicity, ECG, hematological and blood biochemical analysis, and electron microscopic examination were studied. In the ECG study, THP-treated hamsters showed a reversible elevation of R wave amplitude at a daily dose of 0.5mg/kg. Widening of PR and PRc interval, elevation of R and S wave amplitude, and reduction of T wave amplitude were observed at a daily dose of 1.0mg/kg of THP. Hamsters treated with ADM showed increase of heart rate, reduction of T wave amplitude, and shortening of PR and PRc interval at a daily dose of 0.5mg/kg. Severe changes were observed at a daily dose of 1.0mg/kg of ADM including an increase of heart rate, elevation of R wave amplitude, reduction of S and T wave amplitude, and shortening of QT interval. The electron microscopic examination revealed that THP-treated hamsters showed separation of intercalated discs, formation of myelin structure, and dilatation of T-tubules at a daily dose of 1.0mg/kg. Similar changes were caused by ADM at a daily dose of 0.25 to 1.0mg/kg. Hematorogical and blood biochemical examination showed no abnormal changes related to cardiovascular effects of THP or ADM.
In conclusion, both antibiotics caused similar effects on the cardiac function of hamsters. Effects of THP on the heart, however, were milder than ADM on the basis of same dose levels.

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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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New Zealand White rabbits were treated with (2R)-4'-O-tetrahydropyranyladriamycin-HCl (THP), a new antitumor antibiotic, by an intravenous bolus injection at a dose of 1, 2 or 4mg/kg. The peripheral leucocyte counts decreased markedly at doses of 2 and 4mg/kg 1 to 7 days after injection, and the lymphocytes and neutrophils were affected. The nucleated cell count decreased in the bone marrow. Especially 3 days after injection, remarkable reductions of erythroids and immatured myelocytes were observed, with a subsequent rise of the matured myelocytes ratio in bone marrow cell constituents. These changes resulted in a marked increase of M/E ratio. Doxorubicin also showed an inhibitory effect on the bone marrow function of rabbits but the effect was slightly lower than THP. These changes of the bone marrow cells reverted 7 days after injection and the recovery of the reduced peripheral leucocyte was also observed 14 days after injection. Therefore, it can be concluded that THP showed suppressive but reversible effects on the bone marrow function of rabbits.

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[in Japanese]

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Blood levels, tissue distribution and excretion of (2R)-4'-O-tetrahydropyranyladriamycin (THP) were studied in rats received ¹⁴C-THP or unlabeled THP at a dose of 5mg/kg, respectively.
The THP disappeared rapidly from the blood and transferred to tissues immediately after an administration. Pharmacokinetic analysis of the plasma level of THP by the simulation according to a three-compartment open model provided large values of apparent volume of distribution in the tissue compartment. The plasma half-lives of THP in α, β and γ-phases were 0.25 minute, 0.241 hour and 5.11 hours, respectively.
The THP was distributed to the lung and spleen at a level about 100 times as high as the plasma level after an intravenous administration. A high level of THP was also found in the lymph node and gland tissues. Concentrations of THP in many tissues decreased to 1μg/g or less 24 or 72 hours after an injection of the drug, while the drug remained at higher levels in the thymus, spleen and tumor for a long time. After an injection of THP into the carotid artery, its distribution to the brain was apparent, but the level was lower after an injection to the tail vein. The amount of the drug transferred to a fetus was less than 0.2% of the dose.
The major route for the excretion of THP after an intravenous administration was the fecal excretion via bile. Ratios of excretion of the radioactivity in the feces, urine and expired air were 80.3, 5.6 and 9.7% of the dose, respectively, 168 hours after an injection of ¹⁴C-THP. About 65% of the radioactivity was excreted in the bile up to 24 hours after injection but THP itself accounted for only 1/6 of the total radioactivity. About 80% of the excreted THP in the bile was in a conjugated form. Enterohepatic circulation of THP was observed mostly as metabolites or decomposed products of THP.

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The accumulation of (2R)-4'-O-tetrahydropyranyladriamycin (THP) was studied in rats received intravenous administration of ¹⁴C-THP at a dose of 0.5mg/kg/day for 14 consecutive days by determining blood and tissue levels and the excretion of the radioactivity. The radioactivity levels in plasma and blood cells after the multiple administration were higher than those after single administration. The half-life of the radioactivity after the multiple administration was longer in the blood cells but not in the plasma than the half-life after a single administration. Tissue levels of the radioactivity after the multiple injection were 2 to 4 times as high as the levels after a single injection except for the brain and testes in which a large accumulation of the radioactivity was observed. However, little accumulation of unlabeled THP was found in most tissues when determined by HPLC. The accumulation of radioactivity in tissues, therefore, was due to metabolites of THP.
The disposition of ¹⁴C-THP was also examined in rats which had previously received unlabeled THP (0.5mg/kg/day) for 13 days. The pretreatment did not affect the disposition of ¹⁴C-THP seriously, although the pretreatment raised tissue levels slightly and a rebound of plasma level of ¹⁴C-THP, and lowered the fecal excretion ratio.
No induction of hepatic drug metabolizing enzymes was observed in rats after repeated administrations of THP for consecutive 14 days.

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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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