I.C. Shaw

Complete airway obstruction during awake fibreoptic intubation

Awake fibreoptic intubation is well established as the optimum method of securing the airway in patients in whom difficulty is anticipated. We report a patient undergoing awake fibreoptic intubation in whom the use of topical local anaesthetic precipitated acute loss of the airway so that urgent surgical intervention was required.

Depletion of protein‐bound furazolidone metabolites containing the 3‐amino‐2‐oxazolidinone side‐chain from liver, kidney and muscle tissues from pigs

Ten 3-month-old pigs were treated with feed containing 300 mg furazolidone per kg for a period of 7 days, followed by withdrawal periods of 0, 1, 2, 3 or 4 weeks (two per group). The treatment resulted in the formation of protein-bound metabolites containing an intact 3-amino-2-oxazolidinone (AOZ) side-chain that could be chemically released and then detected in liver, kidney and rump muscle tissues even 4 weeks after dosing. In tissues from animals killed at the end of the medication period, 993, 600 and 124 ng of AOZ were released from 1 g of liver, kidney and muscle respectively. In the tissues of the animals killed after a further 4 weeks the corresponding levels were 41, 7 and 10 ng/g respectively. It may be concluded that long withdrawal periods prior to slaughter for human consumption are required for pigs treated with furazolidone, because of the long residence time of protein-bound AOZ and the possibility that it might be released from its protein-bound form in the stomach and subsequently be transformed into a hydrazine.

Estrogenicity of pyrethroid insecticide metabolites

There is concern that insecticides are able to mimic the action of 17beta-estradiol by interaction with the human estrogen receptor. Pyrethroids are commonly used insecticides and several have been assessed for potential endocrine disrupting activity by various methods. It has been noted that some metabolites of pyrethroids, in particular, permethrin and cypermethrin, have chemical structures that are more likely to interact with the cellular estrogen receptor than the parent pyrethroid. For this study permethrin and cypermethrin metabolites 3-(4-hydroxy-3-phenoxy)benzyl alcohol, 3-(4-hydroxy-3-phenoxy)benzoic acid, and N-3-(phenoxybenzoyl)glycine were synthesised, and together with the commercially available 3-phenoxybenzyl alcohol, 3-phenoxybenzaldehyde, and 3-phenoxybenzoic acid, were studied in a recombinant yeast assay expressing human estrogen receptors (YES). Three metabolites, 3-phenoxybenzyl alcohol, 3-(4-hydroxy-3-phenoxy)benzyl alcohol, and 3-phenoxybenzaldehyde, showed estrogenic activity of approximately 10(5) less than that of 17beta-estradiol. No activity was observed in the yeast assay for 3-phenoxybenzoic acid, 3-(4-hydroxy-3-phenoxy)benzoic acid, and N-3-(phenoxybenzoyl)glycine. The results from this study show that pyrethroid metabolites are capable of interacting with the human estrogen receptor, and so might present a risk to human health and environmental well being. The impact would be expected to be small, but still add to the overall environmental xenoestrogen load.

Identifying small-molecule lead compounds: The screening approach to drug discovery

A number of new technologies that enable high-throughput, cost-effective screening of potential drug candidates have been developed in recent years. Such compounds may be derived from the large proprietary collections held by pharmaceutical companies, from new synthetic approaches such as combinatorial chemistry, or from natural sources. The latter remain a major source of new chemicals: many are already used in human treatment and many others are currently undergoing evaluation as the potential medicines of the future.

Preliminary results of proton magnetic resonance spectroscopy in motor neurone disease (amytrophic lateral sclerosis)

Possible changes in brain metabolites in motor neurone disease/amytrophic lateral sclerosis (MND/ALS) were investigated using 1H magnetic resonance spectroscopy (MRS). A series of normal, healthy volunteer controls and MND patients have been studied using a spin echo (SE) 135 ms sequence, acquiring spectra from the region of the motor cortex. A further limited series of studies have been made for similar groups of volunteers and MND patients using a STEAM 20 ms sequence (stimulated echo). Analysis of the SE 135 ms spectra indicates there are statistically significant differences in the ratios of N-acetyl-aspartate to creatine and N-acetyl-aspartate to choline between controls and MND patients. Furthermore, metabolites identified using the STEAM 20 ms may be of great importance in the investigations of free radical mediated mechanisms, which have been postulated as being important contributors to the disease process. Preliminary results indicate that 1H MRS may provide important data to help understand the disease processes in MND and it could form a useful method for monitoring the effects of future trial treatment regimens.

Dietary exposure to xenoestrogens in New Zealand

Continuing evidence of the feminising effects of xenoestrogens on a range of wildlife species increases the need to assess the human health risk of these estrogen mimics. We have estimated the exposure of New Zealand males, females and young men to a range of naturally occurring and synthetic xenoestrogens found in food. Only estrogenic compounds that act by interaction with the estrogen receptor have been included. Theoretical plasma estrogen activity levels were derived from estrogen exposure estimates and estrogenic potency data. Theoretical plasma levels were compared with published data for specific xenoestrogens. There was surprisingly close agreement. Xenoestrogenicity from dietary intake was almost equally attributed to naturally occurring and synthetic xenoestrogens. Relative contributions for a male, for example were isoflavones (genistein and daidzein) (36%) and bisphenol A (34%) with smaller contributions from alkyl phenols (18%) and the flavonoids (phloretin and kaempferol) (12%). It is suggested that dietary xenoestrogens might have a pharmacological effect on New Zealand males and postmenopausal women, but are unlikely to be significant for pre-menopausal women.

Decreased plasma half-life of cyclophosphamide during repeated high-dose administration.

SummaryCyclophosphamide was given as IV doses of 50 mg/kg/day on each of four successive days as treatment for ovarian and lung cancer. Blood samples were taken at regular intervals and analysed for cyclophosphamide by gas liquid chromatography.The plasma half-lives (t1/2) and volumes of distribution (VD) were calculated for each of the treatment days; t1/2 was found to decreased with subsequent doses whereas VD was not significantly changed.

Mechanisms of non-genotoxic carcinogenesis

Until recently, the mechanism of carcinogenesis has been regarded as a two-stage phenomenon involving damage to the genetic material, which initiates the process, followed by a cell-division stimulus, which promotes the development of the tumour. However, exposure to some chemicals has been shown to result in carcinogenesis without involvement of the initiation step. The mechanism of non-genotoxic carcinogenesis is not fully understood, but is believed to involve stimulation of cell division with a consequent increased probability of a mutation occurring spontaneously. In this article, Ian Shaw and Huw Jones review the theories of non-genotoxic carcinogenesis with reference to specific examples of known non-genotoxic carcinogens.

3′-O-Methyl-(+)-catechin glucuronide and 3′-O-methyl-(+)-catechin sulphate: new urinary metabolites of (+)-catechin in the rat and the marmoset

The major urinary metabolites of (+)-catechin (cyanidanol-3) in the rat were (+)-catechin glucuronide, 3′-O-methyl-(+)-catechin glucuronide and 3′-O-methyl-(+)-catechin sulphate. The latter conjugate was the major metabolite in marmoset urine.

The influence of intraperitoneal bupivacaine on pain following major laparoscopic gynaecological procedures.

We present the results of a randomised, double‐blind controlled trial to determine the effect of adding bupivacaine to intraperitoneal Hartmanns solution, used to reduce the incidence of postoperative adhesions, on postoperative pain and on analgesic consumption in patients presenting for major laparoscopic gynaecological procedures. Fifty‐six women were studied and postoperative analgesic requirements and visual analogue scores were used to assess the pain experienced by the treatment group when compared with the control group. There was no statistical difference in the pain scores between the two groups at any time during the study period (Students t‐test; p = 0.29–0.74) nor was there any difference in analgesic consumption (Mann–Whitney U‐test; p = 0.34–0.79).