Distribution of the recombinant coagulation factor 125I-rFVIIa in rats.

Recombinant human factor VIIa (rFVIIa; NovoSeven) is a two-chain activated clotting factor that is used in the treatment of haemophilia. The distribution of radioactivity in male and pregnant and non-pregnant female rats has been examined by whole-body autoradiography (WBA) after single intravenous doses of 125I-radiolabelled rFVIIa at a dosage level of ca. 0.

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.

Relationship between pharmacokinetics and pharmacodynamics of tinzaparin (logiparin), a low molecular weight heparin, in dogs.

1. Pharmacodynamic models relating the plasma concentrations (C) of radioactive heparin material to anticoagulant effect (E) have been investigated after single i.v.

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.

Introduction to (pre)screening methods.

In summation I start this session with the opinion that in vitro methods cannot be considered as adequate replacements for entire animals at the level of regulatory testing. But, when used to identify mechanisms of action, they can be extremely useful as secondary stage supporting studies. They are of doubtful value for general purpose, broad spectrum screening of single chemical entities or for priority selection of unrelated chemicals.

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.

Identification of metabolites of halofantrine, a new candidate anti-malarial drug, by gas chromatography-mass spectrometry.

Two previously unknown metabolites of halofantrine, a candidate anti-malarial drug, have been isolated by thin-layer chromatography from the plasma of dogs administered a single oral dose of 60 mg/kg. Their identifies were investigated after trimethylsilylation by gas chromatography-mass spectrometry under electron-impact and negative-ion chemical ionization conditions. The structural assignment was further confirmed by using a combination of elemental composition analysis of all the isotope peaks at low mass resolution and isotope pattern matching.

Age-related changes in thyroid structure and function in Sprague-Dawley rats.

Investigation of thyroid glands from 500 male and 500 female Sprague-Dawley rats, at time points of 8, 17, 30, 56, and 108 weeks of toxicity studies conducted at the Huntingdon Research Centre between 1981 and 1984, revealed age-related structural and functional changes that have previously not been well documented. The number of ultimobranchial cysts decreased with age, while area(s) of C-cell hyperplasia appeared with age. Beginning at 56 weeks, some of the thyroid follicles were hyperdistended with colloid, had irregular lumens, and were lined by flattened epithelium.

Assessment of the genotoxic potential of Caramel Colour I in four short-term tests.

A battery of three short-term tests in vitro and one in vivo was used to determine the genotoxicity of Caramel Colour I. The results of the bacterial mutation assay, using five strains of Salmonella typhimurium, and the mouse micronucleus assay in vivo showed no evidence of genotoxic activity. Results from both the cytogenetics assay in vitro, using CHO cells, and the mouse lymphoma assay indicated that there was some genotoxic activity associated with Caramel Colour I but only in the absence of S-9 and at very high dose levels.

Absence of mutagenic activity in Salmonella and of clastogenic activity in CHO cells of Caramel Colours I, II, III and IV.

A total of 15 caramel colours were examined for genotoxic activity using the Salmonella typhimurium plate incorporation assay (Ames test). Five bacterial strains, TA1535, TA1537, TA1538, TA98 and TA100 were used in all the plate incorporation tests. Caramel colours can be divided into four classes, classification depending on the preparative method used.

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.

Pharmacokinetics of benzydamine after intravenous, oral, and topical doses to human subjects.

The pharmacokinetics of the anti-inflammatory drug benzydamine were determined after intravenous infusion of 5 mg to six healthy male subjects. Benzydamine was characterized as a drug of relatively low systemic clearance (ca. 160 ml min-1) but high volume of distribution (ca.

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.

The formation of methaemoglobin by 4-aminopropiophenone (PAPP) and 4-(N-hydroxy) aminopropiophenone.

Oral dosing of rats with the cyanide antidote 4-aminopropiophenone (PAPP), brought about peak methaemoglobin levels at 15-40 min, but peak levels were attained at at 15-25 min after intravenous dosing. After both oral and intravenous administration at equimolar doses, 4-(N-hydroxy)aminopropiophenone (PHAPP), the putative methaemoglobin-producing metabolite of PAPP, produced higher peak levels of methaemoglobin than PAPP. Plasma from rats injected with PAPP was capable of forming methaemoglobin when added to naive rat erythrocytes.

Pharmacokinetics of pyridostigmine in dogs.

The pharmacokinetics of the cholinesterase inhibitor pyridostigmine has been studied in six male Beagle dogs after iv infusion and after oral doses as an immediate-release syrup and as an extended-release tablet, all at a level of approximately 0.6 mg/kg. Pyridostigmine was characterized as a drug of relatively long terminal half-life (8.

Mast cell tumours in CD-1 mice.

A survey of the occurrence of mast cell tumours in CD-1 mice (Caesarian derived) recorded nine tumours in 24352 mice used for carcinogenicity studies over a period of six years (1984-1989). All except one appeared as multi centric tumours. Three of the mice had deposits only in the bone marrow, one of those cases was associated with intestinal adenocarcinoma and harderian gland adenoma.

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.