Iopamidol: new preclinical and clinical data.

Iopamidol was rapidly eliminated from the central nervous system of dogs (greater than 90% in 24 hours). In rabbits, renal excretion involved tubular mechanisms at low blood levels, and predominant glomerular filtration at higher levels. Injection of iopamidol into the right atriums of rabbits produced hemodynamic effects similar to those of other contrast media, but less severe. The effect of iopamidol on peripheral vascular resistance was significantly lower than that of metrizamide. Iopamidol was found useful in clinical neuroradiology and angiography.

B-19036, a potential new hepatobiliary contrast agent for MR proton imaging.

B-19036 is an octadentate chelate of the paramagnetic ion Gd3+ under investigation as a proton relaxation enhancer (PRE) in magnetic resonance (MR) proton imaging. Its relaxivity was determined at 0.5 T by pulse spectrometry in various biologic fluids and in liver tissue homogenate. The ligand selectivity versus gadolinium was assessed in comparison with that versus other ions of biologic interest. Acute toxicity was determined after intravenous (IV) and intracerebral administration to mice. Pharmacokinetic studies conducted in rats indicated that unlike Gd-DTPA, where excretion is exclusively renal, biliary route plays a significant role in the excretion of B-19036, suggesting its possible use for hepatobiliary imaging.

An experimental study on the neurotolerability of gadobenate dimeglumine in a rat model of focal brain ischemia.

RATIONALE AND OBJECTIVES: The neurologic safety of the new magnetic resonance imaging contrast agent gadobenate dimeglumine has been assessed in rats suffering from localized blood-brain barrier damage. METHODS: The adopted experimental model was the photochemically induced brain ischemia in the rat. Flash-evoked visual potentials were recorded simultaneously from the damaged area and from the corresponding contralateral position in conscious rats before and after the administration of the contrast medium. RESULTS: The intravenous administration of 0.9 mmol/kg of gadobenate dimeglumine did not induce any significant changes in the visual responses recorded from the ischemic side compared with the intact side. Rats treated with saline or with the reference compounds gadopentetate dimeglumine (Magnevist) and gadoteridol (ProHance) gave comparable results. CONCLUSIONS: The results are in favor of the use of gadobenate dimeglumine in patients suffering from a localized damage to blood-brain barrier.

Neurotolerability of nonionic X-ray contrast media. The role of chemotoxicity.

RATIONALE AND OBJECTIVES: Because small quantities of x-ray contrast agents can cross the blood-brain barrier, the authors evaluate the properties that contribute to neurotoxicity. METHODS: The acute toxicity of various monomer and dimer contrast media was assessed after intracerebroventricular (ICV) injection to mice and intracisternal (ICI) injection to rats. RESULTS: In mice, median lethal dose (LD50) values for monomer contrast media apart from iohexol were higher than those for dimer contrast media. In rats, iopentol and iopromide were more neurotoxic than all other contrast media. The signs of toxicity for all contrast media included convulsions, dyspnea, hypoactivity, and sedation. Hypertonic D-mannitol solution was tolerated as well as artificial cerebrospinal fluid. Neither the hydrophilicity of the molecules nor the physicochemical properties of their solutions explain the toxicities satisfactorily. CONCLUSIONS: Neurotoxicity of monomer or dimer contrast media depends more on chemical structure characteristics other than hydrophilicity than on the physicochemical characteristics of their solutions.

Neurotolerability of gadobenate dimeglumine. Evaluation of brain dopamine concentration in freely moving rats by microdialysis.

RATIONALE AND OBJECTIVES: Magnetic resonance imaging with contrast agents (CAs) is a procedure currently used for the diagnosis of neurologic pathologies. These pathologies are often characterized by blood-brain barrier disruptions, which determines a direct contact between CA and brain tissue. For this reason, an accurate assessment of neurotolerability is useful for the development of new CAs. The present study was designed to evaluate the neurotolerability of a new CA for MRI, gadobenate dimeglumine, employing a neurochemical method. The effect of gadobenate dimeglumine on the striatal levels of neurotransmitters was determined. In particular, the brain concentrations of dopamine and dopamine metabolites, 3,4-dihydroxyphenylacetic and homovanillic acid, were measured using microdialysis, after the direct application of gadobenate dimeglumine into the rat corpus striatum. Gadopentetate dimeglumine and gadoteridol were employed as reference compounds. METHODS: A microdialysis probe for brain extracellular fluid sampling and a stainless-steel cannula for CA application were chronically inserted into the right corpus striatum of rats. All CAs were administered at a dose of 5.4 nmol/rat. Dopamine and metabolite concentrations were analyzed using high-performance liquid chromatography. RESULTS: Gadobenate dimeglumine did not induce any significant changes in the extracellular levels of dopamine or dopamine metabolites up to 2 hours after administration. Gadoteridol produced similar results. Gadopentetate dimeglumine caused a moderate but not significant increase in dopamine levels throughout the duration of the experiments. CONCLUSIONS: Gadobenate dimeglumine directly administered into the corpus striatum of freely moving rats did not affect the dopaminergic system. This result demonstrates the safety of gadobenate dimeglumine under the experimental conditions used, thus confirming previous behavioral and electrophysiologic findings.

Neurotolerability of gadobenate dimeglumine in a rat model of focal brain ischemia: EEG evaluation.

RATIONALE AND OBJECTIVES: The neurologic pathologies for which contrast-enhanced MRI is indicated are often accompanied by a disruption of the blood-brain barrier (BBB), which allows the contrast agent to come into contact with the nervous tissue. Thus, assessment of the neurologic safety for a new contrast agent is of crucial importance. The objective of this study was to assess the neurotolerability of the new MRI contrast agent gadobenate dimeglumine using EEG in the presence of focal lesions of the BBB. METHODS: Lesions of the BBB were obtained inducing a photochemical ischemia in rats. Gadobenate dimeglumine was intravenously administered at 4.0 mmol/kg. An EEG was recorded during sleep/awake behavior and was analyzed for pathologic tracing and for changes in spectral content in terms of total power and frequency index. The presence of the BBB lesions was verified using high-performance liquid chromatography measurement of the gadobenate ion content in the brain. RESULTS: Gadobenate dimeglumine did not have any epileptogenic effect in ischemic rats. However, it caused a transitory shift of the EEG power spectrum toward the 0.5 to 9 Hz frequency bands of the lesioned hemisphere during quiet wake. In the lesioned cortex, higher levels of gadobenate ion were found until 3 hours after administration. CONCLUSIONS: In experimental conditions of focal brain ischemia associated with BBB lesions, gadobenate dimeglumine was well tolerated up to doses even 10 times higher than the maximum clinical dose (0.3 mmol/kg) intended for brain imaging procedures.

Toxicity in animals and safety in humans: the predictive value of animal studies.

Up to the beginning of the 1980s the surveys on adverse reactions to uro-angiographic, iodinated contrast media administered intravenously failed to recognize any significant correlation between the incidence of such reactions and the type and/or dose of administered compound. Consequently the role of pharmaco-toxicological characteristics of the different iodinated molecules was considered negligible in comparison with the individual risk factors causing for the systemic adverse reactions. More recent surveys have shown that the risk of severe adverse reactions is about six times lower with non-ionic than with ionic compounds. These clinical results confirm the findings of animal studies that showed a two- to three-fold greater safety margin for non-ionic compounds than ionic compounds. In view of these data, the predictive value of pre-clinical safety assessment of iodinated contrast agents is re-examined. The interspecies scaling approach is considered useful owing to the well-known and very simple pharmacokinetic behaviour of these compounds both in humans and in animals.

Cardiac effects of contrast media in MR angiography: evaluation in an experimental model of myocardial ischemia.

RATIONALE AND OBJECTIVES: The authors evaluated the cardiac tolerability of paramagnetic contrast agents for magnetic resonance (MR) angiography in an in vitro model of ischemic rat heart. MATERIALS AND METHODS: The left anterior descending coronary artery was temporarily occluded in a perfused rat heart model to induce cardiac ischemia and reperfusion. A dose of 0.4 mL of gadobenate dimeglumine, of gadopentetate dimeglumine, or of D-mannitol was injected directly into the aorta both during the ischemia and during the reperfusion period. The left ventricular pressure and heart rate were recorded. RESULTS: Myocardial ischemia resulted in decreased cardiac activity, with a reduction in left ventricular pressure and heart rate. A further decrease in cardiac activity was temporarily induced by injection of contrast medium during both the ischemic and early reperfusion phases. Less marked responses were induced by a hyperosmolal solution of mannitol. CONCLUSION: These results suggest that the transient cardiac effects induced by bolus injection of paramagnetic contrast medium may be regarded as the combined effects of the osmotoxicity of the contrast medium solution and the chemotoxicity of the contrast medium molecule.

Hepatic transport of the magnetic resonance imaging contrast agent gadobenate dimeglumine in the rat.

RATIONALE AND OBJECTIVES: Gadobenate dimeglumine is a new octadentate gadolinium (III) complex salified with meglumine. The compound is currently under evaluation as an intravenously administered paramagnetic contrast agent for magnetic resonance (MR) imaging. We investigated the mechanisms involved in the biliary excretion of gadobenate ion, the contrast-effective ion in gadobenate dimeglumine. METHODS: Biliary and urinary excretion of gadobenate ion injected intravenously to rats at 0.25 mmol/kg was studied following pretreatment with bromosulfophthalein (BSP) disodium salt, sodium taurocholate (TC), or oxyphenonium bromide (OP) and at various times after common bile duct ligation. Gadobenate ion was assayed by high-pressure liquid chromatography in bile and urine. Plasma bilirubin levels after duct ligation were measured by colorimetric assay. RESULTS: The 90-min excretion of gadobenate ion into bile accounted for 35.5 +/- 3.7% and excretion into urine for 45.7 +/- 3.5% of the injected dose (mean +/- SD). Pretreatment with BSP reduced recovery of the compound in bile to less than 1% and increased urinary excretion to 65.6 +/- 4.7%. Gadobenate dimeglumine had a substantial choleretic effect that was completely abolished by pretreatment with BSP. Pretreatment with TC and OP did not change the biliary or urinary excretion of gadobenate ion. Surgical cholestasis led to a massive increase in plasma bilirubin levels from 3.9 +/- 2.2 (day of surgery) to 129 +/- 37 mumol/L (4 days after common bile duct ligature) and decreased 6-hr cumulative biliary excretion of gadobenate ion from 45 +/- 16% to 5.3 +/- 4.2% of the injected dose. Urinary excretion increased correspondingly from 49 +/- 15% to 83 +/- 12%. CONCLUSION: The transport of gadobenate ion from plasma to bile occurs in the rat mainly through the BSP/bilirubin transport systems.

Iopiperidol: nonionic iodinated contrast medium with promising anticoagulant and antiplatelet properties.

RATIONALE AND OBJECTIVES: The purpose of this study was to determine the anticoagulant and antiplatelet characteristics of iopiperidol, a nonionic, triiodinated contrast agent. MATERIALS AND METHODS: Anticoagulant effects of iopiperidol were assessed both in vitro and in vivo after single or repeated intravenous administrations to rats. To this aim, results of prothrombin time, activated partial thromboplastin time, thrombin time, and fibrinogen tests were evaluated. To define better the mechanism of action of iopiperidol and of the contrast media used for comparison, in vitro tests to study the effects on thrombin activity and on thrombin generation were performed. In addition, the effect of iopiperidol was studied on adenosine diphosphate- and collagen-induced platelet aggregation both in vitro and in vivo after single or repeated intravenous administrations in the rat. RESULTS: In vitro, iopiperidol showed anticoagulant properties similar or superior to those of the ionic ioxaglate. Iopiperidol also inhibited collagen-induced platelet aggregation statistically significantly more than iodixanol and ioxaglate (P < .05). In vivo, no significant differences between iopiperidol and ioxaglate were observed after single or repeated administrations. CONCLUSION: The in vitro anticoagulant effect of iopiperidol is similar or even superior to that of ioxaglate; the in vivo effect is similar to that of reference nonionic contrast media.

Effects of iodinated contrast media on pulmonary airway resistance in anesthetized guinea pigs.

RATIONALE AND OBJECTIVES: Bronchospasm is occasionally observed following iodinated X-ray contrast medium administration. We performed an in vivo study in guinea pigs to investigate the effects of a number of iodinated contrast media on pulmonary airway resistance and the mechanisms underlying the potential bronchoconstrictor effect. METHODS: The contrast media studied were the pharmaceutical formulations of iomeprol (400 mg I/ml), iopamidol (370 mg I/ml), and iohexol (350 mg I/ml), which are nonionic, triiodinated contrast media; diatrizoate (370 mg I/ml), an ionic, triiodinated contrast medium; iotrolan (300 mg I/ml), a nonionic, hexaiodinated contrast medium; and iocarmate (280 mg I/ml) and ioxaglate (320 mg I/ml), which are both hexaiodinated and ionic contrast media. Each contrast medium was administered intravenously at 2 g I/kg. Changes in pulmonary airway resistance were evaluated by measuring intratracheal pressure at the moment of maximum insufflation, or maximal insufflation pressure (MIP), in anesthetized guinea pigs submitted to forced ventilation. RESULTS: All contrast media except ioxaglate caused mean increases of MIP of no more than 20%. By contrast, ioxaglate caused a marked bronchoconstrictor effect, increasing MIP by 242% +/- 46%. Of the drugs tested for antagonistic action on this increase in MIP, salbutamol inhibited almost completely the increase in MIP for the first 40 min posttreatment. Similarly, lysine acetylsalicylate and indomethacin consistently reduced MIP after contrast media administration to levels only 30% and 14% above those of baseline precontrast media, respectively. Promethazine had only a minor inhibitory effect, and the response to prednisolone varied. CONCLUSION: There was no apparent relationship between the size of the increase in airway resistance and the charge or molecular weight of the contrast agent molecule or the pharmaceutical formulation. The increase induced by ioxaglate must be attributed to inherent molecular toxicity mediated through a direct action on the production of bradykinin and/or the prostanoid products of the cyclooxygenase pathway, rather than through a direct action on the release of histamine.

Serious or fatal complications after inadvertent administration of ionic water-soluble contrast media in myelography.

The consequences of the inadvertent administration, by the intrathecal route, of ionic contrast media instead of iopamidol in seven subjects are reported. The ionic compounds were diatrizoate, iodamide and ioxitalamate. The outcome was fatal in three out of seven subjects, and it depended on the type and the dose of the administered contrast agent. The serious or fatal reactions observed are a tragic confirmation of the predictive power of neurotoxicity data obtained in animal studies with various iodinated water-soluble compounds. The margin of safety, represented by the ratio of LD50 i.ce. in mice to clinical dose in humans, both normalized to bodyweight, appears to reliably reflect the risk of toxic reactions after intrathecal administration of iodinated contrast agents.

Toxicological safety assessment of iomeprol, a new X-ray contrast agent.

The toxicology of pharmaceutical formulations of iomeprol, a new nonionic iodinated radiographic contrast agent, was studied in rodents (mice, rats and guinea-pigs) and non-rodents (rabbits and dogs). When injected intravascularly the acute toxicity of iomeprol, both in terms of median lethal dose and symptoms, was comparable to that of analogous triiodinated nonionic contrast media (CM). Intravenous daily dosing for 4 weeks showed that iomeprol was well tolerated at doses as high as the maximum dose anticipated for clinical use. Moreover, the compound did not possess reproductive, developmental, or genetic toxicity. Tissue tolerability was completely superimposable on those of reference CM such as iopamidol and iohexol. Finally, no antigenic potential was detected either in mice or guinea-pigs. These favourable toxicological characteristics bode well for iomeprol as an intravascular radiographic contrast agent.

Pharmacokinetics and tissue distribution of iomeprol in animals.

The pharmacokinetics of iomeprol, a new triiodinated nonionic radiographic contrast agent, has been studied in rats, rabbits and dogs. Following intravenous administration, iomeprol did not bind measurably to plasma proteins and was rapidly excreted in unchanged form, mostly through the kidneys. The compound was rapidly distributed to the plasma and thence to the extracellular spaces. Iomeprol did not accumulate in specific organs or tissues except for those involved in its elimination, i.e. the kidneys and the liver. However, 24 h after administration, less than 1% of the injected dose remained in the tissues. The overall profile was very similar to the published profiles of other radiographic contrast agents used in uroangiography.

Pharmacodynamic effects of iomeprol for injection in experimental animals.

Iomeprol for injection is a new nonionic triiodinated contrast medium for diagnostic radiology, which combines low osmolality with low viscosity. The effects of iomeprol for injection on the cardiovascular system, blood parameters, renal function and the central nervous system were studied after intravascular administration to several animal species of doses at least as high as the highest presumed clinical doses. The following observations were made with respect to the central circulatory system: moderate and short-lasting increases of left ventricular end-diastolic pressure and cardiac output, no significant effects on heart rate either in vitro or in vivo, some episodes of arrhythmia and ventricular fibrillations only at doses far higher than the highest presumed clinical ones, no significant increases in diastolic and systolic coronary flow. The following observations were made with respect to peripheral circulation: no significant changes on blood pressure, moderate and short-lasting increases in renal and pulmonary arterial flow, together with a decrease in peripheral vascular resistance, no crossing of the blood-brain barrier in healthy animals. Cardiovascular and haemodynamic changes were all significantly milder than those induced by ionic contrast media (CM) and were similar to effects caused by some other nonionic contrast media. When injected into the femoral artery of rats, iomeprol was shown to be less algogenic than iopamidol and iohexol. In comparison with the same reference CM, iomeprol affected to a lesser extent the filterability of red blood cells in vitro and showed a less marked effect on their deformability. When administered intravenously at very high dosages, iomeprol had no effect on the glomerular filtration rate, but increased both renal blood flow and diuresis. Proteinuria and enzymuria were also increased, albeit more transiently. The neurotolerance of iomeprol for injection after intravenous administration was higher than or at worst equal to that of iopamidol and iohexol. Iomeprol is therefore a promising new contrast agent particularly suitable for intravascular use in humans.

Preclinical safety assessment of iomeprol for injection as contrast medium for myelography.

A series of pharmaco-toxicological investigations were carried out in animals in order to assess the neurotolerance of iomeprol, a new nonionic iodinated contrast medium. After intrathecal administration iomeprol was completely eliminated from the cerebrospinal fluid, rapidly cleared from the plasma and excreted unchanged through the kidneys. When administrated intrathecally, iomeprol did not significantly alter the behavioural functions or the physiological activities of the brain. Unlike other contrast media, iomeprol was devoid of any epileptogenic activity. The acute neurotoxicity of iomeprol was comparable with that of iopamidol, but less than that of iohexol, iotrolan and iodixanol. Iomeprol was well tolerated in both rats and dogs following weekly intrathecal administrations for four weeks of doses up to three times higher than those foreseen for clinical use. High neurotolerance in animals and favourable physico-chemical characteristics make iomeprol particularly suitable as a contrast medium for both myelography and cerebral ventriculography.

The haemodynamic effects of iodinated water soluble radiographic contrast media: a review.

All classes of iodinated water-soluble radiographic contrast media (RCM) are vasoactive with the iso-osmolar dimers inducing the least changes in the vascular tone. The mechanisms responsible for RCM-induced changes in the vascular tone are not fully understood and could be multifactorial. A direct effect on the vascular smooth muscle cells causing alterations in the ion exchanges across the cell membrane is thought to be an important factor in RCM-induced vasodilatation. The release of the endogenous vasoactive mediators adenosine and endothelin may also play a crucial role in the haemodynamic effects of RCM particularly in the kidney. In addition, the effects of RCM on blood rheology can cause a reduction in the blood flow in the microcirculation. The purpose of this review is to discuss the pathophysiology of the haemodynamic effects of RCM and to offer some insight into the biology of the endothelium and vascular smooth muscle cells as well as the pharmacology of the important vasoactive mediators endothelin and adenosine.

[General toxicity study of gadobenate dimeglumine formulation (E7155) (1)--single dose intravenous and intracisternal toxicity study in rats].

Gadobenate dimeglumine formulation (E7155) was evaluated for its general toxicity potential following a single intravenous and intracisternal administration to rats. Dosage levels tested were 3.3, 4.5, 6.0 and 8.0 mmol/kg at the injection rate of 6 ml/min and 7.50, 8.89, 10.54 and 12.50 mmol/kg at 1 ml/min for the intravenous administration route, and 0.15, 0.21, 0.29 and 0.40 mmol/kg for the intracisternal administration route. Parameters measured during the 14-day observation period were mortality, clinical signs and macroscopic examination. After intravenous administration at the injection rate of 6 ml/min, twitches, respiratory blocking and prostration were observed at 6.0 mmol/kg, and dyspnoea and sedation at 3.3 and 4.5 mmol/kg. Deaths occurred within 1 min after administration at 6.0 mmol/kg and above. LD50 values were 7.97 mmol/kg in males and 6.22 mmol/kg in females. After intravenous administration at the injection rate of 1 ml/min, shallow breathing, twitches and sedation were observed at 7.50 mmol/kg and above and respiratory arrest at 8.89 mmol/kg. Deaths occurred within 1 min after administration at 8.89 mmol/kg and above. LD50 values were 9.0 mmol/kg in males and 9.7 mmol/kg in females. After intracisternal administration, symptoms consisted of sedation, staggering gait, dyspnoea, twitches and ataxia at 0.15 mmol/kg and above, prostration, paralysis of forelimbs, and/or hind limbs and chromodacryorrhea at 0.21 mmol/kg, and convulsions at 0.29 mmol/kg and above. Deaths occurred within 7 days after administration at 0.21 mmol/kg and within 5 min at 0.29 mmol/kg and above. LD50 values were 0.42 mmol/kg in males and 0.25 mmol/kg in females.

[General toxicity study of gadobenate dimeglumine formulation (E7155) (2)--Single dose intravenous toxicity study in dogs].

Gadobenate dimeglumine formulation (E7155) was given by single intravenous injection to 4-5 month-old beagle dogs at doses of 2 or 6 mmol/kg. Treatment was followed by a 14-day observation period in order to evaluate the test article's toxicity. The male and female dogs at 6 mmol/kg vomited and showed reddened gums and ears as clinical signs. One male dog at 6 mmol/kg was euthanized approximately 23 hr after administration due to its very poor clinical condition, which included an unwillingness to move, pale gums and weak pulse. Body weight was decreased at 6 mmol/kg, and also slightly at 2 mmol/kg. Decreased food consumption was noted both at 2 and 6 mmol/kg. Hematology for the euthanized male at 6 mmol/kg showed increases in the total white blood cell count, packed cell volume, hemoglobin and red cell count and a decrease in the platelet count. Biochemistry showed a dose-related increase in alkaline phosphatase, GPT and GOT at 2 and 6 mmol/kg. Males and females at 6 mmol/kg showed increases in bilirubin, calcium and urea, and a reduction in glucose. Females at 6 mmol/kg also showed a reduction in total protein. Urinalysis showed an increase in pH at 2 mmol/kg and above. For females at 6 mmol/kg, an increase in urine volume and a decrease in specific gravity and osmolality were noted. An increase in relative liver and kidney weights was recorded for males and females dosed at 6 mmol/kg. For the euthanized male at 6 mmol/kg, postmortem examination revealed a pale liver with rounded edges and an accentuated lobular pattern, and dark material on the gastro-intestinal mucosal surface. In macroscopic pathology, the male at 6 mmol/kg revealed single liver cell necrosis, minimal early hyperplasia in small biliary ductules, inflammatory cells in the sinusoidal and portal tracts, centrilobular inflammatory cells, diffuse vacuolation of the hepatocytes and sinusoidal dilatation in the liver, and cortical tubular vacuolation in the kidneys. In the female dog treated at 6 mmol/kg, hyperplasia in the small biliary ductules, inflammatory cells in the portal tracts, diffuse vacuolation of hepatocytes and sinusoidal dilatation were seen in the liver, and increases in the severity of cortical tubular basophilia, cortical tubular dilatation and cortical tubular casts were detected in the kidney. Based on these results, the lethal dose of E7155 was set at 6 mmol/kg. It is also concluded that a dose of 2 mmol/kg was tolerated in the beagle dog after a single injection followed by a 14-day observation period.

[General toxicity study of gadobenate dimeglumine formulation (E7155) (3)--4-week repeated dose intravenous toxicity study followed by 4-week recovery period in rats].

A 4-week repeated dose toxicity study of gadobenate dimeglumine formulation (E7155) was conducted in Sprague-Dawley rats to assess its non-clinical safety. E7155 was administered intravenously at doses of 0.3, 1.0 and 3.0 mmol/kg/day to male and female rats once a day during 4 weeks. The reversibility of toxicity was evaluated during a 4-week recovery period at 3.0 mmol/kg/day. At 0.3 mmol/kg/day and higher, vacuolation of the cortical epithelium was seen in the kidneys and an increase in the incidence of local damage at the injection sites. In the 1.0 and 3.0 mmol/kg/day male and female groups, scabbing/ulceration of the tail at the injection sites, macroscopic pale/thickened fundic mucosa in the stomachs, vacuolation of the urinary bladder, and mucosal mineralization with epithelial hyperplasia of the glandular stomach were found. In the 1.0 and 3.0 mmol/kg/day male group and 3.0 mmol/kg/day female group, increases of water consumption and urinary potassium excretion, increased kidney weight and enlargement of the kidneys were observed. In the 3.0 mmol/kg/day male and female group, hepatocyte necrosis with inflammatory cells in the liver and epithelial degranulation in the interlobular ducts of the salivary glands were found. In addition, in the 3.0 mmol/kg/day male group, increases in plasma sodium and decreases of urinary sodium and chloride excretion, and degenerative changes in the testes and epididymides were observed. After the 4-week recovery period, except for an increase in urinary potassium excretion, increased kidney weights and changes in the testes and epididymides, all of the above findings had complete or partial recovery. Vacuolation of renal tubular cells was common, expected, and known as an adaptive change of treatment with hypertonic solutions, and an increase in the incidence of local damage at the injection sites was due to irritation by repeated intravenous dosing with hypertonic solutions. Therefore, these changes were not toxic changes. In conclusion, the dose level of 0.3 mmol/kg/day should be regarded as the No Observed Adverse Effect Level (NOAEL) after repeated administration of E7155 in rats.