Peter J. Ravenscroft

Effects of opioids and sedatives on survival in an Australian inpatient palliative care population

Abstract

Inhibition of purified rat liver glutathione S-transferase isozymes by diuretic drugs

Seven soluble rat liver glutathione S-transferase isozymes were isolated and the inhibition of these isozymes by selected diuretics was investigated using 1-chloro-2,4-dinitrobenzene as substrate. All isozymes were inhibited to some extent under the experimental conditions used, but there was significant isozyme dependent selectivity of inhibition. The greatest inhibitory effect (over 80%) was found when the phenoxyacetic acid diuretics and indacrynic acid were incubated with glutathione S-transferase 3-3, 3-4 and 4-4. The sulphamoylbenzoic acid diuretics, furosemide and bumetanide, were found to have a lesser effect on the isozymes studies. As glutathione S-transferase are thought to play an important protective role in the various tissues of animals and man, by catalysing the glutathione conjugation of electrophilic drugs and drug metabolites, their inhibition may be toxicologically important.

Inhibition of soluble glutathione S-transferase by diuretic drugs

Glutathione transferases are believed to play an important protective role in the various tissues of animals and man by catalysing the glutathione conjugation of electrophilic drugs and electrophilic drug metabolites. Many of these compounds have the potential to react with vital cellular macromolecules in the absence of this enzyme system. We have investigated the interaction of a number of high ceiling diuretics with the glutathione transferases contained in the cytosolic fraction of the rat liver. Of bumetanide, ethacrynic acid, furosemide, indacrynic acid and tienilic acid, only ethacrynic acid was conjugated with glutathione. Further experiments revealed that ethacrynic, indacrynic and tienilic acids are all potent inhibitors of glutathione S- aryltransferase . Glutathione S- alkyltransferase and glutathione S-epoxide transferase were also inhibited by the diuretics, but to a lesser extent than glutathione S- aryltransferase . The diuretics giving the greatest inhibition of these reactions were chemically related to ethacrynic acid. The concept where inhibition of glutathione-S-transferase by a drug may enhance its own toxicity is considered. This mechanism has also the potential of enhancing the toxicity of other concurrently administered drugs which normally require glutathione S-transferase for detoxication.

A quick, sensitive high-performance liquid chromatography assay for monoethylglycinexylidide and lignocaine in serum/plasma using solid-phase extraction.

Recent advances in the investigation of liver disease and transplantation have seen the introduction of lignocaine as a probe of liver function. For this purpose, an assay that is sensitive and rapid is required for the major metabolite of lignocaine, monoethylglycinexylidide (MEGX). We have developed an accurate, low-cost high-performance liquid chromatography (HPLC) method using Bond-Elut phenyl (1 cc) cartridges for sample preparation. The total preparation time for five samples is less than 10 min and the run time is approximately 10 min/sample. Each cartridge can be used at least four times. Simultaneous measurement of another metabolite of lignocaine, glycinexylidide (GX), can be achieved by adjustment of the mobile phase and flow rate. The chromatogram is monitored with an UV detector at 210 nm. The inter- and intra-assay coefficients of variation for MEGX (10-250 micrograms/L) and lignocaine (100-2,000 micrograms/L) are less than 9.5 and less than 2%, respectively, with recoveries for MEGX, trimethoprim (internal standard), and lignocaine all greater than 85%. This method offers a rapid, sensitive assay that is clinically useful in the new role for lignocaine/MEGX in dynamic liver function testing.

Pharmacokinetics and efficacy of rectal versus oral sustained-release morphine in cancer patients

SummarySustained-release morphine (MST) given by the rectal route was compared with oral MST in an open randomised cross-over trial in ten patients with cancer who received stable doses of MST. No significant difference was found in the areas under the curve of the concentration-time profiles (AUC) following oral or rectal administration for parent morphine. The AUCs determine for morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) after oral administration were approximately twice those obtained following rectal administration. The maximal concentration achieved was lower and the time to maximal concentration was longer following rectal administration for morphine, M6G and M3G. The relative mean arrival times following rectal administration were significantly longer for morphine and M3G but not for M6G. These findings suggest slower absorption but less first-pass metabolism of MST after rectal administration. No significant difference was noted between the oral and the rectal route in measurements on visual-analogue scales for pain or side effects. We recommend the rectal route as being suitable for MST administration when the oral route is no longer available. In changing from oral to rectal administration, the same dose and dose interval may be used, but dose adjustment may be needed.

Using National Health Policies to Improve Access to Palliative Care Medications in the Community

Access to affordable priority palliative care medicines needs to be informed by good clinical data from well-conducted clinical trials designed to address efficacy, cost-effectiveness, and safety. Availability of priority palliative care symptom control medicines improves the provision of palliation in the place of patients choice including the community. Within Australia, a National Medicines Policy and a Palliative Care Strategy endorsed by Federal and State and Territory health ministers have facilitated a process to improve the evidence for palliative clinical practice and, through this, improve community availability of key medications for people at the end of life. The initiative, coordinated by a working party under government auspices, has brought together medicine regulators, the pharmaceutical industry, government, policy makers, and clinicians. The brief was to improve availability of key palliative care medications within the current national drug regulatory and funding frameworks. The results to date include: a palliative care section within the Pharmaceutical Benefits Scheme generating the first ever patient-defined section; medicines not previously listed now available; commitment of AU

Sensitive high-performance liquid chromatographic assay with ultraviolet detection of methadone enantiomers in plasma

9.46 M for a national multisite collaborative clinical study network to improve the evidence for clinical interventions in the palliative care setting through systematic investigation with rigorous Phase III and IV studies to inform registration and subsidy applications; and establishing a national Communication Network of the Palliative Care Medications Working Group for the health workforce and community to improve the quality use where improved access has been achieved.

A reliable high-performance liquid chromatography assay for high-throughput routine cyclosporin A monitoring in whole blood.

Methadone is being prescribed increasingly as an analgesic in palliative medicine. R-Methadone has been shown to be responsible for most of the pharmacological activity of this drug. Despite that in most countries it is administered as the racemate. Few assay methods for the enantiomers are available; e en fewer can determine accurately the low concentrations of enantiomers required to undertake pharmacokinetic studies in patients taking the drug in analgesic doses. We present here an HPLC method used to determine concentrations of the specific enantiomers of methadone as low as 5.0 ng/ml with adequate precision and accuracy. The mean R/S ratio of the plasma concentrations was 0.80 +/- 0.05 (n = 3 samples) in one patient taking 25-27.5 mg daily and 1.21 +/- 0.12 (n = 6 samples) in another taking 10-20 mg daily. In the second patient, concentrations of the enantiomers ranged between 5.8 and 25.9 ng/ml. Tricyclic antidepressants did not interfere with the assay but dextropropoxyphene did. Its presence could be detected by dual wavelength monitoring.

Cancer patients’ attitudes towards euthanasia and physician-assisted suicide: The influence of question wording and patients’ own definitions on responses

We report here a reliable high-performance liquid chromatography-ultraviolet assay for routine assay of cyclosporin A (CsA) in whole blood using solid-phase extraction. This assay is linear, between 20 and 2,000 μg/L, with correlation coefficients >0.998 for five consecutive standard curves. All coefficients of variation (CV) were <8% at CsA concentrations of 45, 480, and 1,800 μg/L, with the exception of the between-day CV at 45 μg/L, which was <15%. The relative accuracy of the method is >94% at 45, 480, and 1,800 μg/L. The mean recoveries for CsA and cyclosporin D (internal standard) were 38.2 ± 4.8% (n = 45) and 40.1 ± 6.7% (n = 45), respectively. This method has proven to be reliable and robust in a high-throughput therapeutic drug monitoring laboratory.

Neuropathic pain: are we out of the woods yet?

Objectives: The aims of this study were to: (1) investigate patients’ views on euthanasia and physician-assisted suicide (PAS), and (2) examine the impact of question wording and patients’ own definitions on their responses. Design: Cross-sectional survey of consecutive patients with cancer. Setting: Newcastle (Australia) Mater Hospital Outpatients Clinic. Participants: Patients over 18 years of age, attending the clinic for follow-up consultation or treatment by a medical oncologist, radiation oncologist or haematologist. Main Outcome Measures: Face-to-face patient interviews were conducted examining attitudes to euthanasia and PAS. Results: 236 patients with cancer (24% participation rate; 87% consent rate) were interviewed. Though the majority of participants supported the idea of euthanasia, patient views varied significantly according to question wording and their own understanding of the definition of euthanasia. Conclusions: Researchers need to be circumspect about framing and interpreting questions about support of ‘euthanasia’, as the term can mean different things to different people, and response may depend upon the specifics of the question asked.