Cimadronate (YM175) is a novel bisphosphonate with potent inhibitory activity on bone resorption under development for the treatment of tumor-induced hypercalcemia, metastatic bone disease and osteoporosis. We conducted intravenous reproductive toxicity and teratology studies (Segment I, II and III) of this compound in rats and teratology study in rabbits. The test compound was dissolved in physiological saline, which was also given as the vehicle control. Rats were administered at a dosage of 0.06, 0.16 and 0.62 mg/kg/day in the male Segment I study. Dose levels in the other studies in rats including the female Segment I were 0.16, 0.31 and 0.62 mg/kg/day. In the Segment I study, no treatment-related abnormalities were observed in reproductive parameters or fetuses. In the Segment II study, slightly retarded fetal ossification was noted at 0.31 mg/kg/day or more, but the incidence of malformation did not increase. In the Segment III study, death of the dams and abnormal tooth growth of offspring were observed at 0.16 mg/kg/day or more. Further Segment III study showed that the no toxic effect level was 0.003 mg/kg/day. In the rabbit teratology study, dose levels were 0.01, 0.025 or 0.05 mg/kg/day. No toxic effects on pregnant females or their litters were observed at up to 0.05 mg/kg/day.

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Cimadronate (YM175) is a novel bisphosphonate with potent inhibitory activity on bone resorption under development for the treatment of tumor-induced hypercalcemia, metastatic bone disease and osteoporosis. We conducted toxicity studies of cimadronate intravenously, single dose, 30-day repeated dose and 26-week weekly dose in F344 rats. In the single dose study, cimadronate was administered to rats and the animals were observed for 14 days. Major toxic symptoms were decreased motility and piloerection and LD₅₀ values were 23 mg/kg for males and 21 mg/kg for females. In the 30-day study, the animals received cimadronate at doses of 0, 0.16, 0.31, 0.62 or 1.25 mg/kg/day. At 0.16 mg/kg/day or more, an increased amount of primary spongiosa was observed in the femur. At 0.62 mg/kg/day or more, renal and testicular/epididymal toxicity were observed. After a 30-day recovery period, the finding in the kidney disappeared, but the findings remained in the bone, testis and epididymis. In the 26-week weekly close study, animals received cimadronate at doses of 0, 0.31, 0.62 and 1.25 mg/kg/week. At 0.31 mg/kg/week or more, an increased amount of primary spongiosa was seen in the femur. Renal and testicular/epididymal toxicity, however, were not observed.

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Cimadronate (YM175) is a novel bisphosphonate with potent inhibitory activity on bone resorption under development for the treatment of tumor-induced hypercalcemia, metastatic bone disease and osteoporosis. We conducted intravenous single and repeated dose toxicity studies of cimadronate in beagle dogs. In the single dose study, animals received a single dose of 0.3, 1, 3 or 10 mg/kg of cimadronate and the animals were observed for at least 14 days. At 10 mg/kg, both the male and female dog showed toxic signs such as vomiting, decreased locomotor activities and hypothermia and were killed in extremis within a week after dosing. In the 30-day study, animals received cimadronate at a dosage of 0 (vehicle), 0.03, 0.1, 0.3 or 1 mg/kg/day. At 0.03 mg/kg/day or more, histological findings indicated an increased amount of primary spongiosa in the rib and ilium. At 1 mg/kg/day, degenerative nephropathy, aggregation of spermatozoa and glandular hypoplasia of the prostate gland were observed. On day 16 of dosing one male animal died of acute renal failure. In the 26-week study, animals received cimadronate once weekly at a dosage of 0 (vehicle), 0.31, 0.62, or 1.25 mg/kg. Histopathological examination showed an increased amount of primary spongiosa in the rib at all dosage levels. In addition, similar findings were observed in the lumbar vertebrae at 1.25 mg/kg/week. Histopathological changes in the kidney and male reproductive organs were not observed.

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We used 13-week repeated oral administration of lactitol as part of a study to clarify the mechanism by which lactitol induces the proliferation of adreno-medullary chromaffin cells. There was a marked increase in urinary calcium (Ca) excretion even though the lactitol administration had no effect on the blood Ca level. A tendency for an increase in adrenal venous blood epinephrine (EPI) and norepinephrine (NE) concentrations was seen. Organ weight measurement of adrenal glands revealed a tendency for an increase in absolute weight and a significant increase in relative weight. Morphometric analysis of adrenomedulary chromaffin cells showed a tendency for an increased total cell volume and a decreased numerical density ; but, there was no conspicuous change in the total cell number. Determinations of the anti-bromodeoxyuridine (BrdU) and anti-proliferative cell nuclear antigen (PCNA) antibody-positive cell counts showed a tendency for an increased proliferation rate for adrenomedullary chromaffin cells. Electron microscopy showed a slight increase in the number of Golgi apparatuses in these cells. Because the marked increase in urinary Ca excretion was concomitant with morphological changes that suggested the hyperfunction of chromaffin cells in the adrenal medulla and a tendency for an increased cell proliferation rate, we assume that persistent hyperfunction of the adrenomedullary chromaffin cells, which was mediated by enhanced Ca absorption from the intestinal tract, may have induced proliferative lesion.

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The single-dose intravenous toxicities of iodixanol, a new nonionic isoosmolar contrast medium, were investigated in mice, rats and monkeys. The LD₅₀ values were estimated to be 17.9 gI/kg for male mice and 16.2 gI/kg for female mice, 18.8 gI/kg for male rats and 22.0 gI/kg for female rats, and more than 10.0 gI/kg for monkeys. There was no marked sex difference in mice or rats, nor any significant difference observed between these two rodent species. Decrease in spontaneous locomotor activity, ptosis, respiratory depression and abdominal posture were observed in many mice and rats. These signs disappeared mostly by 8 days after dosing in surviving animals. Death occurred between immediately and 4 days after dosing in mice, and between immediately and 14 days after dosing in rats. Transient depression of body weight gain was observed in the surviving mice and rats by 7 days after dosing. Histological examinations revealed congestion or hemorrhage in the renal medulla, vacuolation or necrosis of the renal proximal tubular epithelium in mice and rats that died and vacuolation of the renal proximal tubular epithelium in surviving rats. There were no significant treatment-related changes in the laboratory and pathological examinations in monkeys.

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Groups of 10 male and 10 female Crl : CD (SD) BR rats were given iodixanol, a radiographic contrast medium, by intravenous injection at dosage levels of 30, 100 or 300 mgI/kg/day for four weeks to evaluate its toxicity. An extra 5 rats of each sex were given 300 mgI/kg/day for 4 weeks and then retained for 4 weeks without treatment to assess recovery. No clinical signs indicative of a toxic effect of iodixanol were noted. No effects of treatment with iodixanol on bodyweight gains, food consumption, laboratory investigations, ophthalmoscopic examinations, organ weights, bone marrow smears or macroscopic pathology were noted. Treatment related changes were noted microscopically in the kidneys only. Minimal cytoplasmic vacuolation in the proximal tubules was noted in a proportion of rats given 100 mgI/kg/day and all rats given 300 mgI/kg/day at the end of the treatment period. This effect was noted not to be fully reversible during four weeks off dose although recovery did occur in some rats.

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Groups of 3 male and 3 female wild-caught cynomolgus monkeys were given iodixanol, a radiographic contrast medium, by intravenous injection at dosage levels of 100, 300 or 1, 000 mgI/kg/day for four weeks to evaluate its toxicity. An extra 2 animals of each sex were given 1, 000 mgI/kg/day for 4 weeks and then retained for 4 weeks without treatment to assess recovery. There were no deaths during the treatment period. Bruising at the injection sites was noted clinically and macroscopically was caused in part by the injection procedure itself and in part by the viscosity of the test formulation and the size of the dose. This finding is therefore, of no toxicological significance. No effects of treatment with iodixanol on body weights, food consumption, laboratory investigations, ophthalmoscopic examinations, organ weights or bone myelograms were noted. Cytoplasmic vacuolation of the kidney proximal tubules was noted with incidence and severity increasing with dosage level among animals given 100, 300 or 1, 000 mgI/kg/day. This effect was noted not to be fully reversible at 1, 000 mgI/kg/day after 4 weeks off-dose although reduced severity was noted and recovery was apparent in some animals.

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The reproductive toxicity of iodixanol, a non-ionic isotonic contrast medium, was investigated in rats and rabbits. Iodixanol was administered intravenously to male rats at doses of 0.3, 1.0 or 2.0 gI/kg/day for 80 days or more until successful copulation. Female rats were treated with iodixanol at the same dose levels for at least 14 days prior to and in the early stage of pregnancy. No remarkable adverse effects on fertility were noted at any dose level. Increased water consumption and swollen paws/face were observed among male rats receiving > 1.0 gI/kg/day. In addition, decreased food consumption was observed in males of the 2.0 gI/kg/day group. In female rats, no remarkable adverse effects were noted at any dose level. Iodixanol elicited no evidence of teratogenicity when administered during the fetal organogenesis period to pregnant rats arid rabbits at doses of 0.3, 1.0 or 2.0 gI/kg/day. No remarkable changes were observed in rat or rabbit fetuses, nor in dams of any dose group. In a perinatal and postnatal dosing study in rats using doses of 0.3, 1.0 or 2.0 gI/kg/day, iodixanol did not adversely affect the reproductive performance of the treated parent animals and pre- and postnatal development of their offspring.

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Antigenic potential of iodixanol, a new non-ionic contrast agent, was evaluated by systemic anaphylaxis (SA) test and homologous passive cutaneous anaphylaxis (Homo-PCA) test using guinea pigs and IgE mediated heterologous PCA (Hetero-PCA) test using rats passively sensitized with mouse sera. SA test was conducted in guinea pigs sensitized with iodixanol at dose levels of 32 or 320 mgI/kg emulsified with Freund's complete adjuvant, followed by challenge with iodixanol (320 mgI/kg). Four- or 24-hr Homo-PCA test was performed with sera from the sensitized animals. Neither positive SA nor Homo-PCA reaction was observed. Hetero-PCA test was performed with the sera from the mice which were sensitized with iodixanol (32 or 320 mgI/kg) with aluminum hydroxide gel. No positive Hetero-PCA reaction was detected in the sera, followed by challenge with iodixanol (320 mgI/kg). Thus, it is concluded that iodixanol possesses no antigenic potential under the present experimental conditions.

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A new non-ionic isotonic contrast medium, iodixanol (a diastereomeric mixture of 5, 5-[(2-hydroxytrimethylene) bis (acetyliminol)] bis [N, N'- bis (2, 3-dihydroxypropyl)-2, 4, 6-triiodo-1, 3-benzene-dicarboxamide]) was studied for mutagenicity by using the Ames method, in vitro cytogenetics and micronucleus test. Iodixanol had no mutagenic effect on S. typhimurium (TA1535, TA1537, TA1538, TA98 and TA100) or E. coli (WP2uvrA) in the reverse mutation assay with or without metabolic activations. In the cytogenetic study, iodixanol had no effect on the Chinese hamster cells with or without metabolic activations. Intravenous injections of iodixanol for two times at a dose of 800, 1, 600 or 3, 200 mgI/kg in the mouse micronucleus test did not increase the incidence of micronucleated polychromatic erythrocytes. These results show that iodixanol has no mutagenic potential.

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The general pharmacological study of iodixanol, a non-ionic isotonic contrast medium, was conducted. 1) Iodixanol administered intravenously over a dose range of 320 to 3, 200 mgI/kg had little or no effect on the general behavior, spontaneous locomotor activity, hexobarbital sleeping time, pain response, electroshock- or pentylenetetrazol-induced convulsion (mouse), EEG or body temperature (rabbit), gastrointestinal propulsion (mouse) or skeletal muscle contraction (rabbit). Iodixanol had no specific interaction with acetylcholine, histamine, serotonin, nicotin, BaCl₂ (ileum), methacholine (trachea), isoprenaline (atrium) or oxytocin (pregnant uterus), nor had any effect on spontaneous contractility (atrium and uterus), or transmural electrostimulation-induced contractility (vas deferens) at concentrations of ≤ 3.2 × 10^-3 gI/ml in vitro. Iodixanol had no effect on the cardiovascular system of dog, except that it increased femoral blood flow and respiratory rate at doses of ≤ 1, 000 mgI/kg. Iodixanol at 3, 200 mgI/kg i.v. reduced urine output with a decrease in Na⁺ and Cl^- excretion, whereas at 320 mgI/kg i.v., it slightly increased urine output (rat). 2) Injections of iodixanol into the cerebroventricular (0.96, 9.6 mgI/mouse and 3.2, 32 mgI/rat), left ventricular (1, 920, 6, 400 mgI/dog) or coronary artery (640, 1, 920 mgI/dog) had no conspicuous effect on the central nervous system or the cardiovascular system, respectively. There was no marked difference among iodixanol, iohexol and iopamidol in this respect. Vascular pain during injection into the femoral artery (300 -320 mgI/guinea pig) appeared to be less intense with iodixanol, compared with the other contrast media iohexol and iopamidol. These results suggest that intravenous injection of iodixanol is relatively free from pharmacological activity, and effects of iodixanol on the central nervous system (intra-cerebroventricular injection) and cardiovascular system (intra-left ventricular and -coronary injections) are comparable to those of iohexol and iopamidol. Furthermore, intra-femoral injection of iodixanol has less of a tendency to produce vascular pain than those of iohexol and iopamidol.

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