Sulphoxide reduction by rat intestinal flora and by Escherichia coli in vitro.

The caecal microflora from female rats show a greater ability to reduce the sulphoxide group of sulindac than either the liver or kidneys. Studies on sulphoxide reduction by Escherichia coli showed that NADH, NADPH and dithiothreitol (DTT), but not acetaldehyde could act as cofactors. The cytosolic fraction was responsible for about 90%, 80% and 60% of the total reducing activity with sulindac, diphenyl sulphoxide and sulphinpyrazone, respectively.

Sulphoxide reduction by rat and rabbit tissues in vitro.

The reduction of sulindac, sulphinpyrazone and diphenyl sulphoxide to their thioether analogues has been studied in vitro using rat and rabbit tissues. Sulindac reduction was about 10-fold higher in homogenates of rat kidney and liver than in other tissues although the tissue differences decreased when dithiothreitol was used as a co-factor. The greatest sulindac reducing activity in rat liver was in the cytosolic fraction whereas reoxidation of the thioether back to the sulphoxide was largely in the microsomal fraction.

Comparison of the metabolism of 7-ethoxycoumarin and coumarin in precision-cut rat liver and lung slices.

The metabolism of 7-ethoxycoumarin and [3-(14)C]coumarin was compared in precision-cut rat liver and lung slices. The lung slices were prepared using an agarose gel instilling technique enabling the production of tissue cylinders followed by lung slices employing a Krumdieck tissue slicer. Both 50 microM 7-ethoxycoumarin and 50 microM [3-(14)C]coumarin were metabolized by rat liver and lung slices.

The pharmacokinetics of nicotinamide in humans and rodents.

Nicotinamide, a derivative of the B vitamin niacin, is currently under trial for the prevention of insulin-dependent diabetes mellitus after success in the NOD mouse. However, the dose, route of administration, and formulation of nicotinamide given to humans is quite different from those used successfully in animals, and the aim of this study was to investigate the plasma pharmacokinetics of oral nicotinamide in humans in two doses and in two different formulations (standard and the long-acting Enduramide). There were no significant differences in the kinetics of the low dose of standard nicotinamide (2.

Toxicity of 3-methylindole, 1-nitronaphthalene and paraquat in precision-cut rat lung slices.

The toxicity of 3-methylindole, 1-nitronaphthalene and paraquat has been studied in precision-cut rat lung slice cultures. Lung slices were prepared from male Sprague-Dawley rats using an agarose gel instilling technique with a Krumdieck tissue slicer and cultured for 24 h in a dynamic organ culture system. Treatment of rat lung slices with 3-methylindole, 1-nitronaphthalene or paraquat produced concentration dependent decreases in lung slice protein synthesis and potassium content.

The teratogenic metabolites of vitamin A in women following supplements and liver.

Ten healthy female volunteers were given 5 doses of retinol as the palmitate; 50 and 150 mg retinol as an oral supplement, 50 and 150 mg as fried calf liver (50 and 150 g) and 3, 9 or 30 mg by intra-muscular injection. Plasma concentrations of retinyl palmitate were higher after 50 mg retinol given as an oral supplement compared with 50 mg as liver; there was no significant difference between the 150 mg doses. Plasma concentrations of retinol showed only small increases.

Intense sweeteners, food intake, and the weight of a body of evidence.

A review of published data shows that although intense sweeteners have been shown to increase hunger ratings in some studies in humans, this has not been a consistent and reproducible observation. Any slight effect on perceived hunger has not been translated into an increase in food ingestion or effects on blood concentrations of insulin or glucose. Studies on the covert substitution of caloric sweeteners by intense sweeteners have shown either a decrease or no change in body weight.

An analysis of the risk of exceeding the acceptable or tolerable daily intake.

The acceptable or tolerable daily intake (ADI or TDI) for food additives and contaminants is usually derived from chronic animal toxicity studies. The basis for the ADI or TDI is the determination of the no-observed effect level (NOEL) for the most sensitive toxicological effect in the most sensitive laboratory species. This "safe intake" for animals is then divided by a safety or uncertainty factor to allow for possible differences between the test species and humans and for possible differences within the human population.

Quercetin, an in vitro inhibitor of CYP3A, does not contribute to the interaction between nifedipine and grapefruit juice.

Quercetin, a flavonoid present in various fruits, is a potent in vitro inhibitor of CYP3A. Its role in the reported interaction between grapefruit juice and nifedipine has been determined in vivo in humans. Eight healthy volunteers were given in random order 10 mg nifedipine orally, either alone or with 200 ml double strength grapefruit juice, or with 400 mg quercetin.

The influence of dose and ethnic origins on the pharmacokinetics of nifedipine.

The pharmacokinetics of nifedipine capsules was investigated in healthy young Caucasian and South Asian subjects. Both the area under the plasma concentration-time curve (AUC) and terminal half-life of nifedipine were significantly higher in South Asians compared with Caucasian subjects after single oral doses of 10 and 20 mg. The AUC and half-life values of the nitropyridine metabolite were also higher in South Asians than in Caucasian subjects.

Induction of cytochrome P-450-dependent enzyme activities in cultured rat liver slices.

Precision-cut liver slices were prepared from male Sprague-Dawley rats with a Krumdieck tissue slicer and cultured in RPMI 1640 medium for up to 72 hr. After 48 hr, cytochrome P-450 content in the slices declined to 36% of levels present in freshly cut rat liver slices. The addition of either beta-naphthoflavone (BNF) or Aroclor 1254 (ARO) partially prevented the loss of cytochrome P-450.

A data-derived safety (uncertainty) factor for the intense sweetener, saccharin.

An increased incidence of bladder cancer is found when male rats are fed high dietary concentrations of sodium saccharin (3% or more) from birth. This toxicity has been used as the basis for the development of a data-derived safety factor. Such an effect would attract an extra factor (10-fold) for nature of toxicity and in the absence of other data would result in a high overall safety factor.

Data-derived safety factors for the evaluation of food additives and environmental contaminants.

A safety factor of 100-fold is commonly applied to animal data to derive the acceptable daily intake (ADI) of food additives; other factors have been used in some cases and higher values are used more frequently for determining the tolerable daily intake (TDI) of environmental chemicals. The 100-fold factor is considered to represent the product of a 10-fold factor to allow for species differences between the test animal and humans and a 10-fold factor to allow for inter-individual differences. A scheme is proposed whereby data relevant to the safety assessment of a compound, e.

The detection and isolation of protease activity associated with purified preparations of human chorionic gonadotropin.

The highly purified human CG (hCG) CR series is widely used as a reference material in immunological and biological assays. However these hormone preparations, specifically hCG (CR127), exhibit Arg-specific peptidase activity with synthetic peptide substrates. The putative serine protease-like activity associated with hCG (CR127) was almost completely inhibited by diisopropylfluorophosphate, soybean trypsin inhibitor, N-tosyl-L-phenylalanine chloromethyl ketone and to a lesser extent by N-alpha-p-tosyl-L-lysine chloromethyl ketone and was isolated after hydrophobic interaction and affinity chromatography with soybean trypsin inhibitor, which indicated the presence of exogenous protease contaminants rather than intrinsic peptidase activity.

The asparagine-linked oligosaccharides at individual glycosylation sites in human thyrotrophin.

The asparagine-linked carbohydrate structures at each of the three glycosylation sites of human thyrotrophin were investigated by 400 MHz 1H-NMR spectroscopy. Highly purified, biologically active human thyrotrophin (hTSH) was dissociated into its subunits hTSH alpha (glycosylated at Asn 52 and Asn 78) and hTSH beta (glycosylated at Asn 23). The alpha-subunit was further treated with trypsin which gave two glycopeptides that were subsequently separated by reverse-phase HPLC and identified by amino acid sequence analysis.

The influence of posture on the pharmacokinetics of orally administered nifedipine.

1. Nifedipine (20 mg as capsules) and soluble paracetamol (1 g) were co-administered to eight healthy young volunteers on three separate occasions, following which in random order they stood, lay on their left side or lay on their right side for 4 h. 2.

Blood pressure changes and sympathetic function in rats given cyclohexylamine by intravenous infusion.

Intravenous infusion of cyclohexylamine (30-120 mg/kg) caused a dose-dependent increase in blood pressure in urethane-anesthetized rats. The increase in blood pressure was inversely related to the duration of the infusion. The blood pressure returned to baseline values (+/- 5 mm Hg) within 60 min of the end of the infusion after doses of 30 and 60 mg/kg were administered over 20 and 40 min.

The metabolism of cyclamate to cyclohexylamine and its cardiovascular consequences in human volunteers.

A group of 194 diabetic patients were given calcium cyclamate (1 g/day as cyclamic acid equivalents) for a period of 7 days. Blood and urine samples were collected to determine the formation of cyclohexylamine, which is an indirectly acting sympathomimetic amine. Blood pressure and heart rate were recorded before and after treatment.

The effect of respiratory manoeuvres and pharmacological agents on the pharmacokinetics of nedocromil sodium after inhalation.

1. Eight healthy subjects inhaled nedocromil sodium from a metered-dose inhaler using a standardised inspiratory technique. Blood samples were taken for up to 270 min after inhalation for radioimmunoassay of plasma nedocromil sodium concentrations.

Inhaled histamine increases the rate of absorption of sodium cromoglycate from the lung.

Since many factors may alter lung epithelial permeability (LEP) to water soluble molecules, the effect of histamine on the absorption and clearance of inhaled sodium cromoglycate was examined in seven mildly asthmatic patients with hyperresponsive airways and eight normal subjects. The subjects underwent histamine challenge to determine the provocative concentration of histamine required to reduce the forced expiratory volume in one second (FEV1) by 20% (PC20) from baseline. On two further visits they inhaled either saline placebo or histamine and 5 min later inhaled an aerosol containing sodium cromoglycate.

An antipodean perception of the mode of action of glycoprotein hormones.

Continuance of vertebrate species and maintenance of metabolism have an absolute requirement for the glycoprotein hormones of the anterior pituitary gland. It is now firmly accepted that the N-glycans of these and the related placental hormone, chorionic gonadotropin, have essential if undefined roles in their mechanism of action. However, recent investigations by Weisshaar and his colleagues on the oligosaccharides of human luteinizing hormone and chorionic gonadotropin, do not support the generally accepted view of carbohydrates in hormone-receptor interactions and a further concept is proposed that invokes negative charges and changes in structured water.

The influence of levodopa on gastric emptying in healthy elderly volunteers.

Paracetamol absorption and 99Tc-DTPA measurements have been used to determine the influence of levodopa on gastric emptying in 8 healthy elderly volunteers. In the absence of levodopa 7 subjects showed a rapid gastric emptying pattern by gamma-camera and a single major peak in the plasma concentration-time curve of paracetamol. One subject showed two rapid phases of gastric emptying separated by a period of negligible emptying and had 2 separate peaks in the paracetamol plasma concentration-time curve.

Oral amino acids and gastric emptying: an investigation of the mechanism of levodopa-induced gastric stasis.

To investigate possible mechanisms of levodopa-induced gastric stasis, we have studied the effect of other amino acids on gastric emptying. The large neutral amino acid tryptophan delays gastric emptying in the dog at molar concentrations below those required to stimulate duodenal osmoreceptors. In healthy volunteers, we have shown that neither tryptophan nor the small neutral amino acid glycine delayed gastric emptying when given in concentrations similar to those of levodopa which produce gastric stasis.

Gastric emptying in healthy volunteers after multiple doses of levodopa.

1. Oral levodopa frequently produces an episodic delay in gastric emptying which leads to multiple peak concentrations of the drug in plasma. We have studied the effects of multiple dosing of levodopa on gastric emptying and levodopa absorption in eight healthy young volunteers in a randomised two-way cross-over study.