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Biomedical subjects

M F Wilks

Publications and source records attributed to M F Wilks.

At least 19 recordsLinked to original sources
PubMed2003

Prospects for treatment of paraquat-induced lung fibrosis with immunosuppressive drugs and the need for better prediction of outcome: a systematic review.

BACKGROUND: Acute paraquat self-poisoning is a significant problem in parts of Asia, the Pacific and the Caribbean. Ingestion of large amounts of paraquat results in rapid death, but smaller doses often cause a delayed lung fibrosis that is usually fatal. Anti-neutrophil ('immunosuppressive') treatment has been recommended to prevent lung fibrosis, but there is no consensus on efficacy. AIM: To review the evidence for the use of immunosuppression in paraquat poisoning, and to identify validated prognostic systems that would allow the use of data from historical control studies and the future identification of patients who might benefit from immunosuppression. DESIGN: Systematic review. METHODS: We searched PubMed, Embase and Cochrane databases for 'paraquat' together with 'poisoning' or 'overdose'. We cross-checked references and contacted experts, and searched on [www.google.com] and [www.yahoo.com] using 'paraquat', 'cyclophosphamide', 'methylprednisolone' and 'prognosis'. RESULTS: We found ten clinical studies of immunosuppression in paraquat poisoning. One was a randomized controlled trial (RCT). Seven used historical controls only; the other two were small (n = 1 and n = 4). Mortality in controls and patients varied markedly between studies. Three of the seven non-RCT controlled studies measured plasma paraquat; analysis using Proudfoot's or Hart's nomograms did not suggest that immunosuppression increased survival in these studies. Of 16 prognostic systems for paraquat poisoning, none has been independently validated in a large cohort. DISCUSSION: The authors of the RCT have performed valuable and difficult research, but their results are hypothesis-forming rather than conclusive; elsewhere, the use of historical controls is problematic. In the absence of a validated prognostic marker, a large RCT of immunosuppression using death as the primary outcome is required. This RCT should also prospectively test and validate the available prognostic methods, so that future patients can be selected for this and other therapies on admission.

Acute Disease↗
PubMed2001

Human in vivo studies of non-pharmaceutical products.

Two principal types of human in vivo studies with non-pharmaceuticals can be distinguished: (1) human metabolism studies are used for identification of target metabolites which can subsequently be used in biological monitoring studies. Furthermore, they allow extrapolation from excretion of metabolite(s) to exposure to the parent compound on the basis of an understanding of human pharmacokinetics. (2) Pharmacodynamic or effect studies are restricted to the study of acute and inherently reversible changes and are most likely to improve risk assessment in the following areas: neurobehavioural effects (e.g. alcohol, organic solvents), alterations in biochemical markers (e.g. cholinesterase inhibition following organophosphate exposure) and topical effects (e.g. skin irritancy). Ethical considerations are of prime importance and, as a minimum, any human study must comply with the principles of the Declaration of Helsinki. The protocol should include scientifically sound objectives, a justification of subject numbers, a formal risk-benefit analysis and provisions for appropriate ethical review. The welfare of the individual participating in the study must be paramount. Informed consent has to be obtained and subjects must be free to withdraw from the study at any time. Compensation should be given for the inconvenience of participating in the study, but never for undergoing risk. Provided these conditions are met, human volunteer studies can be a powerful tool in risk assessment and risk management of exposure to non-pharmaceutical products.

Ethics↗
PubMed2001

Pharmacokinetics and pharmacodynamics of NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) and mesotrione, inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD) following a single dose to healthy male volunteers.

AIMS: NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) and mesotrione (2-(4-methylsulphonyl-2-nitrobenzoyl)-1,3-cyclohexanedione) are inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD). NTBC has been successfully used as a treatment for hereditary tyrosinaemia type 1 (HT-1), while mesotrione has been developed as an herbicide. The pharmacokinetics of the two compounds were investigated in healthy male volunteers following single oral administration. The aim of the NTBC study was to assess the bioequivalence of two different formulations and to determine the extent of the induced tyrosinaemia. The mesotrione study was performed to determine the magnitude and duration of the effect on tyrosine catabolism. Additionally, the urinary excretion of unchanged mesotrione was measured to assess the importance of this route of clearance and to help develop a strategy for monitoring occupational exposure. METHODS: A total of 28 volunteers participated in two separate studies with the compounds. In the first study, the relative bioavailability of NTBC from liquid and capsule formulations was compared and the effect on plasma tyrosine concentrations measured. In the second study the pharmacokinetics of mesotrione were determined at three doses. Plasma tyrosine concentrations were monitored and the urinary excretion of mesotrione and tyrosine metabolites was measured. RESULTS: Both compounds were well tolerated at the dose levels studied. Peak plasma concentrations of NTBC were rapidly attained following a single oral dose of 1 mg x kg(-1) body weight of either formulation and the half-life in plasma was approximately 54 h. There were no statistical differences in mean (+/- s.d.) AUC(0,infinity) (capsule 602 +/- 154 vs solution 602 +/- 146 microg x ml(-1) h) or t1/2 (capsule 55 +/- 13 vs solution 54 +/- 8 h) and these parameters supported the bioequivalence of the two formulations. Mesotrione was also rapidly absorbed, with a significant proportion of the dose eliminated unchanged in urine. The plasma half-life was approximately 1 h and was independent of dose and AUC(0,infinity) and Cmax increased linearly with dose. Following administration of 1 mg NTBC x kg(-1) in either formulation, the concentrations of tyrosine in plasma increased to approximately 1100 nmol x ml(-1). Concentrations were still approximately 8 times those of background at 14 days after dosing, but had returned to background levels within 2 months of the second dose. Administration of mesotrione resulted in an increase in tyrosine concentrations which reached a maximum of approximately 300 nmol x ml(-1) following a dose of 4 mg x kg(-1) body weight. Concentrations returned to those of background within 2 days of dosing. Urinary excretion of tyrosine metabolites was increased during the 24 h immediately following a dose of 4 mg mesotrione x kg(-1), but returned to background levels during the following 24 h period. CONCLUSIONS: NTBC and mesotrione are both inhibitors of HPPD, although the magnitude and duration of their effect on tyrosine concentrations are very different. When normalized for dose, the extent of the induced tyrosinaemia after administration of NTBC and over the duration of these studies, was approximately 400 fold greater than that following administration of mesotrione. The persistent and significant effect on HPPD following administration of NTBC make it suitable for the treatment of patients with hereditary tyrosinaemia type 1 (HT-1), whilst the minimal and transient effects of mesotrione minimize the likelihood of a clinical effect in the event of systemic exposure occurring during occupational use.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed2001

Acute diquat poisoning with intracerebral bleeding.

A case of severe diquat poisoning complicated by the development of aggressive behaviour, oliguric renal failure, and intracerebral bleeding is described. The patient was successfully managed and made a complete recovery. In this paper special attention has been given to the major clinical differences between diquat and paraquat intoxication.

Acute Kidney Injury↗
PubMed2000

Pyrethroid-induced paresthesia--a central or local toxic effect?

BACKGROUND: Pyrethroid-induced paresthesia is frequently seen after dermal exposure to pyrethroids. Affected individuals experience a sensation of burning, tingling, itching, or numbness, most commonly in the face. This occurs 1-2 hours after the beginning of exposure and resolves spontaneously. MECHANISMS: Paresthesia occurs as a result of a direct effect on intracutaneous nerve endings at very low pyrethroid doses. It is related to potency of the pyrethroid with pyrethroids without an alpha-cyano group generally showing the weakest effect. CONCLUSION: Doses sufficient to cause paresthesia are far lower than those causing central or systemic toxicity. Paresthesia is therefore considered to be a localized nuisance effect. The best advice to affected individuals is to prevent paresthesia from occurring through appropriate hygiene measures and personal protection.

Administration, Topical↗
PubMed1995

Contact dermatitis due to a new fungicide used in the tulip bulb industry.

We describe an outbreak of contact dermatitis in a tulip bulb processing company. Shortly after the introduction of a new pesticide, the fungicide fluazinam, employees started to complain of dermatitis of the arms and the face. 8 employees were investigated and showed positive patch tests to fluazinam. The dermatitis disappeared quickly when they stopped work, but returned as soon they restarted. Subsequent investigations showed that the fungicide had not been used according to the manufacturer's recommendations. Fluazinam was shown to be a strong sensitizer under these circumstances.

Adult↗
PubMed1994

Effect of dosing vehicle on the dermal absorption of fluazifop-butyl and fomesafen in rats in vivo.

One important factor which may influence the extent and rate of percutaneous absorption is the dosing vehicle. The purpose of the experiments described was to compare the effect of dosing vehicles of different polarities on the absorption of two herbicides across rat skin in vivo. Rats were dosed dermally with either fluazifop-butyl (logP(oct) 4.5) or fomesafen sodium salt (logP(oct) -1.2) in propylene glycol (PG), octanol (OCT), or ethyl decanoate (ED), and the amount of radioactivity excreted in urine was determined. Absorption rates were estimated from the urinary excretion data and from blood kinetic data derived from intravenously dosed rats. For fluazifop-butyl the average rate of absorption (x10(-2) micrograms/hr-1 +/- SE) was not greatly influenced by the dosing vehicle (OCT, 2.94 +/- 0.08; ED, 3.66 +/- 0.10; PG, 3.95 +/- 0.32) despite relatively large differences in solubility (PG, 38 mg/ml; OCT, and ED, > 600 mg/ml). These results were consistent with the finding that there was at most only a twofold difference in the epidermal membrane:vehicle partition coefficients (km). In contrast, the absorption rate of fomesafen from PG (1.98 +/- 0.04) was approximately half that of ED (3.98 +/- 0.06) and OCT (4.49 +/- 0.08) for the first 30 hr after application and was in keeping with solubility data (PG, 638 mg/ml; OCT, 12 mg/ml; ED, < 10 mg/ml). At later time points the absorption of fomesafen from PG increased; this is discussed in relation to the penetration-enhancing properties of PG.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMed1994

An assessment of the dietary uptake of di-2-(ethylhexyl) adipate (DEHA) in a limited population study.

The plasticizer di-2-(ethylhexyl) adipate (DEHA), which may be present in food-contact films, can migrate into certain foodstuffs. Results from plasticizer migration studies into food have enabled an indirect estimate of the maximum daily dietary intake of DEHA. A previous study of the metabolism and pharmacokinetics of DEHA in humans identified the urinary metabolite 2-ethylhexanoic acid (EHA) as a useful marker metabolite for assessing DEHA intake. The present study was designed to investigate urinary EHA concentrations following a controlled dose of DEHA presented with food, and to assess the average daily intake of DEHA in a limited population survey. The urinary elimination profile of EHA, following a dose of DEHA in food, showed that in order to extrapolate DEHA intake from EHA measurements, a 24-hr urine sample was required. In the survey the elimination of EHA was determined in 24-hr urine samples in 112 individuals from five different geographical locations in the UK. No restrictions were placed on age or gender. Estimates of daily intake of DEHA show a skewed distribution with a median value of 2.7 mg. This is similar to an estimated maximum daily intake of 8.2 mg/day, derived using an indirect method by the UK Ministry of Agriculture, Fisheries and Food.

Adipates↗
PubMed1994

Vehicle effects on in vitro percutaneous absorption through rat and human skin.

We studied the effects of three vehicles (propylene glycol, octanol and ethyl decanoate) with differing polarity on the in vitro percutaneous absorption of three chemicals (fluazifop-butyl, dimethyl phthalate and fomesafen sodium salt) with a range of physico-chemical properties. Absorption rate measurements were made from high vehicle volume (200 microliters/cm2) and low vehicle volume (< 10 microliters/cm2) applications. For the lipophilic fluazifop-butyl absorption rate was highest from the more polar vehicle propylene glycol, but this effect was only significant under high-volume conditions. There was a variable vehicle effect on absorption of the intermediate chemical dimethyl phthalate. The largest vehicle effect was seen for the more hydrophilic fomesafen sodium salt where absorption was fastest from the least polar vehicle ethyl decanoate. These results support the hypothesis that the absorption process can in part be predicted from a knowledge of solute solubility. Vehicle effects were greater from high volume applications than from those more comparable to occupational exposure conditions.

Animals↗
PubMed1994

A physiologically based mathematical model of dermal absorption in man.

A sound understanding of the mechanisms determining percutaneous absorption is necessary for toxicological risk assessment of chemicals contacting the skin. As part of a programme investigating these mechanisms we have developed a physiologically based mathematical model. The structure of the model parallels the multi-layer structure of the skin, with separate surface, stratum corneum and viable tissue layers. It simulates the effects of partitioning and diffusive transport between the sub-layers, and metabolism in the viable epidermis. In addition the model describes removal processes on the surface of the skin, including the effects of washing and desquamation, and rubbing off onto clothing. This model is applied to data on the penetration of the herbicide fluazifop-butyl through human skin in vivo and in vitro. Part of this dataset is used to estimate unknown model parameter values and the remainder is used to provide a partial validation of the model. Only a small fraction of the applied dose was absorbed through the skin; most of it was removed by washing or onto clothing. The model provides a quantitative description of these loss processes on the skin surface.

Administration, Cutaneous↗
PubMed1994

Comparison of two methods for determining the toxicokinetics of fluazifop-butyl after intravenous dosing in rats.

1. We have described and compared the use of two blood sampling techniques to measure the kinetics of fluazifop-butyl, a selective herbicide. Following intravenous administration of radiolabelled compound, blood samples were collected from female rats either by tail vein puncture or from chronically implanted catheters inserted in tethered rats. Urine samples were also collected from tethered animals. 2. Both techniques indicate that fluazifop-butyl is rapidly eliminated from blood into urine (t(1/2)3-4.5 h) and the overall blood concentration profiles were comparable between the two methods. However, by using cannulated rats, kinetic data were obtained from individual animals, providing evidence of inter-animal variation and allowing compartmental and statistical analysis. 3. The tethered rat technique is relatively simple and reliable. Compared to tail vein bleeding, results obtained from cannulated animals are more informative, providing comprehensive data from a small number of rats. It is therefore the preferred method for our kinetic based research studies using compounds known to exhibit multicompartmental elimination kinetics.

Animals↗
PubMed1994

Human volunteer studies with non-pharmaceutical chemicals: metabolism and pharmacokinetic studies.

1. Human volunteer studies are an essential part of drug development but their use in the area of non-pharmaceutical chemicals has so far been very limited. Such studies can have considerable value in the assessment and improvement of the safe use of chemicals. 2. Once metabolic pathways and target metabolites have been identified in volunteers this information can be used in studies in the workplace or in the general population. Studies should be performed selectively only if there is both a toxic hazard and a significant exposure potential. In addition, they should only be carried out if the required information cannot be obtained in any other way. 3. Volunteer studies with non-pharmaceuticals have become increasingly acceptable in the light of established international guidelines, no-fault compensation, improvements in study design and technical developments which allow the use of very low dose levels. The final decision on whether to carry out a study must always rest with an independent ethical committee. 4. The practical aspects of the study should be specified in a detailed protocol conforming with the principles of good clinical practice. The safety of volunteers must be of paramount concern throughout. Depending on the nature of the chemical and the study, it may be advisable to carry out studies in a clinical facility where equipment is available for the treatment of any emergencies that might occur. 5. Numerous investigators have now shown that human volunteer studies are ethically acceptable, practicable and yield important information. The risk to volunteers is minimal and this approach can lead to an improved foundation for occupational hygiene standards, more accurate risk assessment and thus better protection of the workforce and the general population.

Animals↗
PubMed1993

Metabolism and pharmacokinetics of deuterium-labelled di-2-(ethylhexyl) adipate (DEHA) in humans.

The metabolism and pharmacokinetics of [2H10]di-2-(ethylhexyl) adipate (DEHA) labelled on the ethyl side-chains was determined in six male volunteers. The dose administered was 46 mg [2H10]DEHA given orally. No parent molecule was found in plasma; however, the metabolite [2H5]2-ethylhexanoic acid (EHA) was detected (mean rate of formation: 1.63 +/- 1.19/hr; mean rate of elimination: 0.42 +/- 0.1/hr). Further oxidative metabolism products were detected in urine; the dominant metabolite identified was EHA present as a conjugate and accounted for an average of 8.6% of the administered dose. [2H5]2-Ethyl-5-hydroxyhexanoic acid, [2H5]2-ethylhexanedioic acid, [2H5]2-ethyl-5-keto-hexanoic acid and [2H5]2-ethylhexanol together accounted for a further 3.5% of the dose. The fate of the remainder was not determined.

Adipates↗