The pharmacokinetics and metabolism of sucralose in the rabbit.

The excretion and metabolism of (14)C-sucralose has been investigated in non-pregnant and pregnant rabbits after administration of single 10mg/kg oral doses. Means of 22% and 55% of the dose were excreted in urine and faeces, respectively, by non-pregnant animals during 5 days. Excretion was similar in pregnant animals with means of 22% and 65% of the dose in urine and faeces, respectively, during the same time.

The pharmacokinetics and metabolism of sucralose in the mouse.

The excretion and metabolism of (14)C-sucralose has been investigated in mice following intravenous and oral administration. A 20mg/kg intravenous dose was rapidly excreted mainly in the urine (80% in 5 days). After 100, 1500 and 3000mg/kg oral doses of (14)C-sucralose, means of 23%, 15% and 16% of the dose, respectively, were excreted in the urine during 5 days.

The pharmacokinetics and metabolism of sucralose in the dog.

The pharmacokinetics and metabolism of sucralose were investigated in dogs following intravenous or oral administration. Oral doses of (14)C-sucralose were rapidly absorbed, although there was some variation in the extent of absorption (range 18-48% of the dose). After intravenous or oral administration, radioactivity excreted in the urine was associated mainly with unchanged sucralose.

[Four-week intravenous toxicity study of montirelin hydrate (NS-3) in dogs followed by 4-week recovery test].

A repeated dose toxicity study of montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, was conducted in beagle dogs. The dogs were given the drug intravenously for 4 weeks at doses of 0 (control), 0.0002, 0.

Induction of rodent hepatic drug-metabolizing enzyme activities by the novel anticonvulsant remacemide hydrochloride.

Remacemide hydrochloride [FPL 12924AA; 2-amino-N-(1-methyl-1,2-diphenylethyl) acetamide hydrochloride] is being evaluated as a novel neuroprotective treatment for epilepsy and stroke. Preliminary safety evaluation studies in the rat have shown that repeated doses of the compound produce histological and biochemical changes consistent with hepatic enzyme induction. To examine this further, the levels and activities of the major drug metabolizing cytochrome P450 (CYP) subfamilies (CPY1, CYP2, and CYP3) were monitored in microsomal samples from male Sprague-Dawley rats dosed by gavage with FPL 12924AA (250 mg base.

beta-Cyclodextrin: 52-week toxicity studies in the rat and dog.

A 52-wk toxicity study by dietary administration was performed in Sprague-Dawley rats and in pure-bred beagle dogs with beta-cyclodextrin, a starch derivative that acts as a molecular inclusion agent. Doses of 0 (control), 12,500, 25,000 and 50,000 ppm were selected for the rat study, and 0 (control), 6200, 12,500 and 50,000 ppm were selected for the dog study. The liver and kidney were identified at the histopathological examination as target organs for toxicity in the rat at doses of 50,000 and 25,000 ppm, with the hepatic changes associated with increased plasma liver enzyme and reduced plasma triglyceride concentrations.

Genotoxicity testing of pidotimod in vitro and in vivo.

The mutagenic potential of pidotimod ((R)-3-[(S)-(5-oxo-2- pyrrolidinyl)carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) was assessed in a series of five assays designed to measure gene mutation, chromosomal damage and primary DNA damage. All tests were carried out in accordance with appropriate EEC and OECD Guidelines. No indications of mutagenic potential were observed in any of the assays.

Fifty-two-week oral toxicity study of the new cognition-enhancing agent nefiracetam in dogs.

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.

Fifty-two-week oral toxicity study of the new cognition-enhancing agent nefiracetam in rats.

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.

Metabolic fate of 14C-camostat mesylate in man, rat and dog after intravenous administration.

1. The metabolic fate of N,N-dimethylcarbamoylmethyl 4-(4-guanidino[14C]benzoyloxy)phenylacetate methanesulphonate (14C-camostat mesylate) was investigated after i.v.

Identifying environmental factors harmful to reproduction.

Reproduction is essential for the continuation of the species and for life itself. In biological terms, living and reproducing are essentially one and the same. There is, therefore, no sharp division between identifying factors harmful to reproduction and identifying factors harmful to life or vice versa.

Toxicity of the novel anti-peptic ulcer agent catena-(S)-[mu-[Na- (3-aminopropionyl)histidinato(2-)-N1,N2,Q:N tau]-zinc in male cynomolgus monkeys.

A preliminary dose-range finding study and a 13-week toxicity study were performed in male cynomolgus monkeys with catena-(S)-[mu-[N a-(3-aminopropionyl) histidinato (2-)-N1,N2,O:N tau]-zinc] (Z-103, CAS 107667-60-7), a novel anti-peptic ulcer agent, as part of a safety evaluation program. In the preliminary ascending dose study emesis was observed in animals treated at 625 mg/kg and transient reductions in food intake with associated body weight loss in a male treated at 625 or 312.5 mg/kg.

Survey on spontaneous systemic amyloidosis in aging mice.

The incidence of systemic amyloidosis in CD-1 mice (Charles River, caesarian derived) obtained from long term studies over more than a 15-year period is reported. The survey included samples of visceral organs, peripheral and central nervous tissues, bone and bone marrow. The total incidence in all mice of this survey did not show any clear evidence of a difference between males and females.

Metabolism of the anti-psoriatic agent 5-methoxypsoralen in humans: comparison with rat and dog.

1. Single oral doses of 14C-5-methoxypsoralen (5-MOP) to human subjects (50 mg), rats (1 mg/kg) and dogs (1 mg/kg) were fairly well absorbed but subjected to extensive first-pass metabolism, at least in rat and human. Means of 62, 51 and 40% dose in urine and 31, 38 and 48% dose in faeces, were excreted by humans (during 5 days), rats (3 days) and dogs (1 day), respectively.

Survey on spontaneous peripheral neuropathy in aging mice.

The incidence of peripheral neuropathy in CD-1 mice (caesarean-derived) obtained from long term studies over a 10 year period is reported. The survey included peripheral nerve samples of 15,223 males and 15,075 females. The incidence of peripheral neuropathy is 8% in untreated males and 12% in untreated females aged 80 to 104 weeks.

Evaluation of the efficacy of Broilact in preventing infection of broiler chicks with Salmonella enteritidis PT4.

A study was conducted to evaluate treatment of day-old broiler chicks with Broilact, a live-culture preparation, for preventing intestinal colonization by a non-host-specific Salmonella (S. enteritidis PT4, with high resistance to nalidixic acid). Newly hatched broiler chicks were sprayed with Broilact at a commercial hatchery and delivered on the same day to Huntingdon Research Centre.

Percutaneous absorption of co-administered N-methyl-2-[14C]pyrrolidinone and 2-[14C]pyrrolidinone in the rat.

The percutaneous absorption has been investigated in rats of a mixture (3:2, w/w) of N-methyl-2-pyrrolidinone (NMP) and 2-pyrrolidinone (2-P), a combination intended for use as a vehicle in the formulation of an antimycotic drug to enhance skin penetration on dermal application, following co-administration of the two 14C-radiolabelled compounds by the dermal and oral routes. Radioactivity was excreted predominantly in the urine after either route of administration, and comparison of the respective excretion profiles indicated that about three-quarters of the applied dose was absorbed through the skin. Plasma concentrations of each parent compound, as determined by radio-HPLC, reached peak values at 2 hr after oral dosing, and remained relatively uniform during 1-6 hr after application to the skin, suggesting constant percutaneous absorption during this period.

Dystrophic mineralisation in cerebrum of aging mice.

The incidence of cerebral dystrophic mineralisation in CD-1 mice (Charles River bred, cesarean-derived) obtained from long term studies over a 10 year period is reported. The survey included brain samples from 15869 males and 15729 females. The incidence of cerebral dystrophic mineralisation is 0.

Studies of the pharmacokinetics and metabolism of 4-amino-propiophenone (PAPP) in rats, dogs and cynomolgus monkeys.

The pharmacokinetics and metabolism of 4-aminopropiophenone (PAPP), a cyanide antidote, have been studied in rats, dogs and cynomolgus monkeys using 14C-PAPP. Radiolabelled material was rapidly excreted in all three species, mainly in urine. In rats, PAPP was metabolized by N-acetylation, while in dogs, ring and aliphatic hydroxylation occurred.

Pharmacokinetics of the anti-inflammatory drug ximoprofen in healthy young and elderly subjects: comparison with elderly rheumatic patients.

The pharmacokinetics of ximoprofen were studied in young and elderly subjects after single and repeated doses up to 30 mg. In healthy elderly subjects (30 mg dose), a mean peak plasma drug concentration of 1.78 micrograms ml-1 +/- 0.

Dose-proportional pharmacokinetics of cefepime in rats.

Cefepime (BMY-28142) is a new parenteral cephalosporin antibiotic with excellent activity against a broad-spectrum of clinically important pathogens resistant to other new cephalosporins. A single bolus dose of 10, 20 or 40 mg/kg cefepime was given i.v.