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We established a versatile method for the measurement of indocyanine green maximal removal rate (ICG Rmax) to detect hepatic functional mass in conscious rats using a repeated blood sampling procedure. On investigation of the optimal technical conditions, the appropriate intravenous administered doses of ICG were 2.5, 5, 10 or 20 mg/kg, and the best blood collection times for calculating plasma half-life at these doses were immediately before, and 4, 7 and 10 min after ICG injection. The interval among the respective ICG injections was more than 4 hr. In hepatectomized rats, the ICG Rmax value was reduced to about 50% and 20% of sham-operated rats in mean 2/3 and 4/5 liver resections, respectively, suggesting that it would almost extrapolate to hepatic surviving reserves under these experimental conditions. In rats treated subcutaneously with carbon tetrachloride (CCl4, 0.1 and 0.25 ml/kg) thrice weekly during a 17-week period (120 days), a decrease in ICG Rmax value did not correlate with increases in serum alanine transaminase (ALT), alkaline phosphatase (ALP) and total bilirubin values throughout the experimental periods. However, the reduced ICG Rmax well correlated with decreases in serum albumin and cholinesterase (CHE) values from day 50. Histological examinations in the liver revealed that nodules of hepatocytes were separated by thick fibrous bands, defining the typical aspect of cirrhosis on day 30 to 90. These results suggest that the measurement of ICG Rmax is a valuable tool for the estimation of hepatic functional integrity in rats.

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OBJECTIVE: To establish a versatile and reliable procedure for the determination of indocyanine green maximal removal rate (ICG Rmax) to measure hepatic functional mass in dogs within 9 hours (9-hour method). DESIGN: Relation between 9-hour and standard 3-day methods was examined. ANIMALS: 101 healthy dogs. PROCEDURE: On investigation of the optimal technical conditions allowing completion of all procedures in a day, the appropriate IV administered doses of ICG were 0.125, 0.5, and 2.0 mg/kg of body weight, and the best blood sample collection times for obtaining plasma half-life at these 3 doses were before and 3, 6, and 9 minutes after ICG administration. RESULTS: Comparison of the 9-hour with 3-day method yielded a correlation coefficient (r) of 0.84, indicating close (P < 0.01) correlation. In the 9-hour method, mean +/- SD of ICG Rmax in healthy dogs was 0.24 +/- 0.09 mg/kg/min in male (n = 62) and was 0.23 +/- 0.06 mg/kg/min in female (n = 21) Beagles, and was 0.21 +/- 0.10 mg/kg/min in male (n = 11) and 0.20 +/- 0.07 mg/kg/min in female (n = 7) mixed-breed dogs. In Beagles treated orally with carbon tetrachloride (0.1 ml/kg in gelatine capsules) thrice weekly during a 10-week period, plasma alanine transaminase activity plateaued at a high value (> 2,000 IU/L) on day 5, and remained at this value until the end of the study. The ICG Rmax changed accordingly: day 5, 0.17; day 10, 0.11; day 40, 0.05; and day 60, 0.06 mg/kg/min. CONCLUSION: The 9-hour method for determination of ICG Rmax correlates favorably with the 3-day method. CLINICAL RELEVANCE: This procedure may be practically applied in veterinary clinics in terms of prediction of hepatic functional mass, and for diagnosis of hepatotoxicosis induced by certain compounds.

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Single oral dose toxicity of nefiracetam (N-(2,6-dimethylphenyl)-2-(2-oxo- 1-pyrrolidinyl) acetamide, DM-9384, CAS 77191-36-7), a new cognition-enhancing agent, was examined in ddY mice, SD rats and beagle dogs. The LD50 values of nefiracetam were 2005 mg/kg for male mice and 1940 mg/kg for female mice, 1182 mg/kg for male rats and 1408 mg/kg for female rats and more than 500 mg/kg for beagle dogs. Common toxic signs in all species were a decrease in locomotor activity, lying on the side or back and loss of righting reflex, considered to be caused by depression of the central nervous system. Pathologically, no remarkable change associated with nefiracetam administration was observed in any species. In addition, toxicities of the decomposition product (D-2) and by-products (Bis, 3-Me and 4-Me) of nefiracetam were examined by oral administration, and of the metabolites (M-3 and M-11) by intravenous injection in male ddY mice. LD50 values of the 3-Me and 4-Me forms were 1399 and 1534 mg/kg, respectively. Clinical signs in mice treated with these by-products were similar to those caused by nefiracetam. The other compounds induced no toxic signs or death up to the highest dose (2000 mg/kg) used.

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A 52-week toxicity study by oral gavage administration was performed in Sprague-Dawley rats with nefiracetam (N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide, DM-9384, CAS 77191-36-7), a new cognition-enhancing agent, as a part of a safety evaluation program. Dosages of 0 (control), 10, 30, 100 and 300 mg/kg/d were selected for this study. Treatment-related findings were confined to the 300 mg/kg/d level and, to a lesser extent, the 100 and 30 mg/kg/d levels, with the investigations indicating the kidney as the main target organ for toxicity. The microscopic pathology examination of this organ showed papillary epithelial hyperplasia and/or collecting duct epithelial hyperplasia, with cortical scarring and occasional mineralisation in the papilla. Histopathological changes in the liver, centrilobullar hepatocyte enlargement (accompanied by fine vacuolation) and foci/areas of eosinophilic hepatocytes were considered to reflect the induction of drug-metabolising enzymes in the liver. Other tissues showing treatment-related findings included the salivary glands, urinary bladder, spleen, pancreas and adrenals. Additionally, other notable findings included (in the high dosage males only) a decline in body weight (from week 34), lower erythrocytic characteristics and slightly higher plasma urea nitrogen and alkaline phosphatase values. The results in this study, therefore, indicated that the non-toxic effect level was 10 mg/kg/d of nefiracetam.

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A 52-week toxicity study by oral administration (capsule) was performed in beagle dogs with nefiracetam (N-(2,6-dimethylphenyl)-2-(2- oxo-1-pyrrolidinyl) acetamide, DM-9384, CAS 77191-36-7), a new cognition-enhancing agent, as a part of a safety evaluation program. Dosages of 0 (control), 10, 30 and 90 mg/kg/d were selected for this study. Treatment-related findings were confined to the 90 mg/kg/d level and indicated the kidney and the testis as the main target organs for toxicity. Signs of systemic toxicity, as indicated by the laboratory investigations, were not apparent until the second half of the study and included the principal findings of higher urea nitrogen, and creatinine, with higher urinary volumes and corresponding lower specific gravity, osmolarity and protein values. The microscopic pathology examination showed various changes at the renal papilla, collecting ducts, and medullary and cortical scarring. This examination also revealed decreased spermatogenesis in the testes, with associated decreased numbers/absence of spermatozoa in the epididymides. At the 30 mg/kg/d level, the minor microscopic pathology changes seen in the kidneys of one male animal were considered to be of equivocal toxicological importance. There were no treatment-related findings at the low dosage level (10 mg/kg/d) and, therefore, this level was considered as the non-toxic effect level of nefiracetam.

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The nephrotoxicity of (-)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1- piperazinyl)-7-oxo-7H-pyrido [1,2,3-de][1,4]benzoxazine-6-carboxylic acid hemihydrate (levofloxacin, DR-3355, CAS 100986-85-4), a new quinolone antibacterial agent, was evaluated in male New Zealand White (NZW) rabbits after oral administration of 30 or 120 mg/kg for 10 days. Although reduced body weight gain was observed in the 120 mg/kg, DR-3355 induced no change in function and morphology of the kidneys at both doses.

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Rats developed anemia during treatment with high doses of malotilate, a hepatotropic agent. A repeated dose of 1,000 mg/kg caused a 20-30% decrease in the number of red blood cells and in hematocrit and hemoglobin values within the first week. In response to the anemia, the reticulocyte count increased, and target cells, acanthocytes and Howell-Jolly bodies appeared in the peripheral blood. In the spleen, hemosiderin deposition was enhanced. The life span of 51Cr-labelled erythrocytes was shortened from 15 to 2 days in the high-dose group, whereas plasma iron disappearance and hemoglobin synthesis were significantly potentiated. Hemorrheological examinations revealed an increase in blood viscosity. Hemolytic resistance to mechanical stimuli was reduced, but that to osmotic stimuli was enhanced. At the same time as the onset of the anemia, serum and red cell membrane cholesterol and phospholipid began to increase on day 4 or 6. Incorporation of cholesterol into red cell membranes in vitro was significantly potentiated when serum obtained from rats after a single administration of 1,000 mg/kg was added to the culture. These results suggest that malotilate causes an increase in the surface area of the erythrocytes by accelerating the incorporation of cholesterol into their membranes, and such erythrocytes might be rheologically impaired and captured more easily by the spleen.

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The relation between the neutralization of herpesvirus of turkeys HVT) and the antibodies to early appearing membrane antigen (EMA), late appearing membrane antigen (LMA) and intracellular antigen (IA) induced by the virus was examined by blocking of direct immunofluorescence using 38 sera from chickens infected with HVT. Our results provide evidence that anti-LMA is significant in the neutralization of the infectivity (P less than 0.001) since the neutralizing capacity of the serum was related to its blocking index (BI) and not to its anti-EMA titre (BI). Furthermore, the anti-IA titres (BI) of the sera were also related to their neutralizing activity to a lesser extent (P less than 0.025). However, no relationships among any two of the titres of EMA, LMA and IA were observed. The implication of these results of the relationship of LMA to infectious virus particles is discussed.

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The synthesis of membrane antigen (MA) and intracellular antigen (IA) in arginine-deficient cultures infected with herpesvirus of turkeys (HVT) and their antigenic relationships were examined. By the indirect immunofluorescence test, two kinds of MA were detected using anti-HVT chicken serum [early appearing MA (EMA) and late appearing MA (LMA)], but few IA positive cells were detected. Absorption of the serum by MA positive cells resulted in reduction of reactivity to MA but not to IA. Differential absorption of the serum by EMA positive cells and LMA positive cells considerably reduced their reactivities to homologous cells but not to heterologous cells which were used in the absorptions. Both absorbed sera had similar IA reactivity when compared with the reactivity of un-absorbed serum, but the serum absorbed by LMA positive cells decreased its neutralising titre. These results provide evidence that (1) MA and IA are antigenically different from each other; (2) EMA is different from LMA; and (3) antibody against LMA is closely related to antibody for neutralisation of HVT.

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The mechanism of immunity conferred by herpesvirus of turkeys (HVT) was investigated using Marek's disease virus (MDV)-infected chicken kidney cell (CKC) cultures as target cells. Peripheral blood lymphocytes (PBL) from normal or HVT-vaccinated chickens killed MDV-infected target cells in the presence of anti-MDV or anti-HVT serum, whereas normal lymphocytes and HVT-sensitised lymphocytes themselves had no specific cytotoxic effect. Cell-mediated cytotoxicity of PBL from HVT-vaccinated chicken was exhibited specifically against HVT-infected CKC, and that of PBL from chickens inoculated with MDV was exhibited against MDV-infected CKC. From these results, it was concluded that antibody-dependent cellular cytotoxicity to MDV-infected cells may contribute to resistance to Marek's disease induced by HVT vaccination.