Metabolism and pharmacokinetics of ethyl N(alpha)-lauroyl-L-arginate hydrochloride in human volunteers.

The human metabolism and pharmacokinetics of ethyl N(alpha)-lauroyl-L-arginate hydrochloride (LAE), a new antimicrobial agent for use in foods have been investigated using both in vitro and in vivo techniques with (14)C-LAE and (13)C-LAE respectively. LAE was readily hydrolysed to the corresponding lauroyl arginine (LAS) on incubation with human plasma samples to the extent of about 50% during 4h. LAE was stable in simulated gastric fluid but in simulated intestinal fluid it was rapidly hydrolysed to LAS and arginine with more than 90% conversion to arginine after 1h. Oral doses of (13)C-LAE in propylene glycol were administered to human volunteers at dose levels of 1.5mg/kg (4 subjects) and 2.5mg/kg (2 subjects). LAE was only detected in two plasma samples in one individual at the higher dose level close to the limit of quantification (1 ng/ml). Maximum plasma concentrations of LAS generally occurred at 2h with mean peak levels of 18.2 ng/ml (1.5mg/kg dose) and 23.9 ng/ml (2.5mg/kg dose). Maximum concentrations of (13)C-arginine occurred earlier (0.5 to 1h) and at much higher levels than LAS with mean peak levels of 124 ng/ml (1.5mg/kg dose) and 240 ng/ml (2.5mg/kg dose). The results showed that in humans LAE was rapidly metabolized to the naturally occurring dietary components lauric acid and arginine.

Soluble soybean fiber: a 3-month dietary toxicity study in rats.

Soluble soybean fiber (SSF) is a food ingredient intended for human consumption. SSF was administered in the diet to Sprague-Dawley CD(R) rats at concentrations up to 40,000 ppm for three months. Unformed stool was detected during the early and middle part of the treatment period and was considered an exaggeration of a normal physiological response to the fibre content in the diets, to which the animals appeared to adapt. This finding has been reported with other water-soluble fibres and was not considered an adverse effect. Decreased weight gain and food intake during the first half of the treatment period are possible sequelae of increased intestinal throughput. Adaptation was indicated by subsequently improved weight gain and food consumption. Decreased serum cholesterol occurred in males receiving 30,000 or 40,000 ppm and this has been reported before in rats fed soluble fibre. Haemoconcentration (indicated by increased erythrocyte count, haematocrit and haemoglobin concentration) and decreased spleen weight are likely related to minor fluid imbalances during exposure to high concentrations of dietary fibre and occurred at all SSF concentrations. The spleen was microscopically normal. In conclusion, the no-observed-adverse-effect level (NOAEL) for SSF in this study was 40,000 ppm (equivalent to 2.43 g/kg bodyweight/day for males and 2.91 g/kg bodyweight for females).

Tri-isobutylphosphate: a prenatal toxicity study in rats.

To assess the prenatal toxicity to rats of the anti-foaming agent, tri-isobutylphosphate (CAS 126-71-6), a study was conducted in which daily dosages of 0, 100, 300 and 1000 mg/kg were administered to different treatment groups by gavage from day 6 to 15 of pregnancy. Dams were killed and foetuses examined on day 20 of pregnancy. Maternal effects during the dosing period included a dosage-related increase in the frequency, persistence and severity of post dosing salivation in all test groups and significantly increased water consumption at 1000 mg/kg. Bodyweight gain at 1000 and 300 mg/kg was lower than that of controls but the differences were not statistically significant. The lowest dosage of 100 mg/kg could be considered as the maternal 'lowest observed adverse effect level' (LOAEL) or 'no observed adverse effect level' (NOAEL) according to whether increased salivation is perceived to be a true toxic effect or simply a reaction to the taste of the test material. Neither litter values nor the prevalence of foetuses with abnormalities indicated any embryotoxic effects (including teratogenicity) at any dosage. The most notable feature of the results was the occurrence of a cluster of foetuses with the congenital abnormality referred to as 'hunched posture syndrome' or 'squat foetus syndrome'. However, the incidence of this finding was similar to that noted among background data for the same strain and, in the absence of any other embryotoxic findings, was considered likely to have arisen coincidentally.

Oncogenicity studies of the new serotonin (5-HT)3-receptor antagonist ramosetron in mice and rats.

Oncogenicity studies of ramosetron ((R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazol e hydrochloride, CAS 132907-72-3, YM060), a new compound having serotonin (5-HT)3 receptor antagonist activity, were carried out in male and female mice and rats. Six groups (two control and four treated) of B6C3F1 mice and F344 rats were given YM060, dissolved in distilled water, once daily by oral intubation at doses of 0, 1, 10, 30 and 100 mg/kg/d. Toxicokinetics indicated that sufficient exposure of the animals to the test material was achieved during the oncogenicity studies. Cmax and AUC of YM060 at 100 mg/kg/d were in the range of 3-5 micrograms/ml and 8 micrograms.h/ml in mice, 1-5 micrograms/ml and 7-16 micrograms.h/ml in rats, respectively. The administration of YM060 resulted in a slightly increased mortality rate among female rats treated with 30 or 100 mg/kg/d, particularly during the Weeks 38-87. Body weights of the high-dosed male and female rats during the Weeks 36 to 96 were significantly decreased when compared to controls. An approximately 30% suppression of body weight gain was recorded during Weeks 36-96 for both male and female rats, and 15% suppression of body weight gain was recorded during Weeks 0-104 for male mice. There was no evidence of a treatment-related effect on the incidence of any tumor or tumor type, and there were no non-neoplastic findings considered to be related to the administration of YM060. All microscopic changes seen in mice and rats were of the usual type commonly occurring in untreated aged B6C3F1 mice and F344 rats. In conclusion, there was no evidence of an oncogenic effect of YM060 in mice and rats.

Buflomedil: one-year oral safety evaluation in rats.

Buflomedil was given as a dietary mix to Sprague-Dawley Rats for one year at dosages of 0, 25, 75, and 400 mg/kg/day. Each group contained thirty rats of each sex, of which 10/sex/group were preassigned to a withdrawal period of 3 months following the 1-year drug administration period. There were no treatment-related deaths or clinical signs. Dosage-related decreases in body weight gain occurred during the 1-year treatment period. Food consumption was comparable to controls, except for a 10% decrease in high-dosage males during the first week of treatment. During the withdrawal period, body weight gain was higher than controls in all drug-treated groups. Hematocrit (PCV) and hemoglobin were slightly decreased during week 52 in high-dosage males; hematology values were comparable to controls during weeks 13 and 26 and at the end of the withdrawal period. There were no treatment-related changes in blood biochemistry. Urine pH was decreased in females at 75 mg/kg/day and in both sexes at 400 mg/kg/day. Discolored urine was observed in males at 75 mg/kg/day and in both sexes at 400 mg/kg/day. Urine pH and color were comparable to controls after the 3-month withdrawal period. There were slight decreases compared to controls in urine volume at all dosages in females during week 52; these changes were still evident in the mid- and high-dosage groups at the end of the withdrawal period. The only possibly treatment-related observation at necropsy was dirty tails at the end of the treatment period in the high-dosage group which may have been related to the discolored urine. Liver and kidney weights were slightly increased in males at 400 mg/kg/day at the end of the 1-year treatment period; these changes were not evident after the 3-month withdrawal period. There were no treatment-related histopathological changes. The changes observed were thought to result from either pharmacologic activity or physiological adaptation to compound administration or were marginal in severity. None were considered toxicologically significant. Therefore, the no-toxic-effect dosage was 400 mg/kg/day which is 40 times the maximum clinical dosage.