John Welsh

Low-density lipoprotein metabolism in mice with soft tissue tumours

This study examines the potential value of low-density lipoprotein (LDL) as a vehicle for directing cytotoxic drugs to tumour cells in mouse model systems. Control and MAC 13 tumour-bearing NMRI mice were injected with tracer doses of 125I-labelled native and cyclohexanedione-modified 131I-labelled LDL. 18 h later the animals were killed and the radioactivities assimilated by various tissues were measured relative to plasma activity at the time of death. These values were used to calculate specific tissue receptor-mediated LDL uptake. All tissues expressed receptors but the liver and adrenal gland were particularly active. In tumour-inoculated animals, the neoplastic lesions were second only to liver in their net assimilation of LDL. CFLP mice bearing virus-induced parotid adenomata gave results similar to those obtained in NMRI animals. In order to improve the selectivity of LDL assimilation we attempted to downregulate LDL receptors in the liver and adrenal gland by administration of the bile acid sodium taurocholate or by subcutaneous injection of hydrocortisone sodium succinate. These manoeuvres together reduced uptake of the lipoprotein into both organs without affecting tumour activity.

A randomised multicentre single blind comparison of a cannabinoid anti-emetic (Levonantradol) with chlorpromazine in patients receiving their first cytotoxic chemotherapy☆

One hundred and eight patients selected to receive combinations of highly emetic cytotoxic chemotherapy for malignant disease were included in a study of anti-emetic therapy. The patients were randomly allocated to receive levonantradol (0.5, 0.75 or 1 mg) or chlorpromazine (25 mg) prior to receiving their first course of cytotoxic therapy. The appropriate anti-emetic was administered 2 hr prior to the start of chemotherapy, 2 hr after chemotherapy and subsequently at 4-hourly intervals for a further 8 hr. The extent of anorexia, nausea and vomiting along with other side-effects were assessed at regular intervals by physicians and nursing staff during the 24 hr following chemotherapy. In addition, a self-assessment questionnaire was completed by the patients. Levonantradol (0.5 mg) was superior to chlorpromazine (25 mg) as an anti-emetic. Both were reasonably well tolerated, although at this dose of levonantradol 22% of patients experienced dysphoric reactions. At higher doses of levonantradol the proportion of patients experiencing these reactions rose to 50%, but without a concomitant increase in antiemetic activity. Neither drug achieved satisfactory control of vomiting in patients receiving combinations containing cis-platinum. We conclude that levonantradol (0.5 mg) is a more effective anti-emetic than chlorpromazine (25 mg) in patients receiving cytotoxic chemotherapy. However, its use cannot be recommended due to its high incidence of unacceptable central nervous system side-effects.

The treatment of advanced bladder cancer with methotrexate and cis-platinum—a pharmacokinetic study

As part of a phase III study in advanced bladder cancer, 5 patients received methotrexate (MTX) 50 mg/m2 as a single agent every 2 weeks, and with every alternate dose of MTX (i.e. every 4 weeks) cis-platinum (CDDP) 50 mg/m2 was given simultaneously, together with saline hydration and diuresis. The clearance of MTX was measured in a total of 12 courses by serial serum sampling for up to 72 hr following injection. In 4 patients (with a mean pretreatment creatinine clearance of 97 ml/min) there was no significant difference between the clearance of MTX when given alone [mean t1/2 (beta) 3.2 hr] and when given 2 weeks later with concurrent CDDP [mean t1/2 (beta) 2.9 hr]. In 1 patient with a pretreatment creatinine clearance of 52 ml/min the clearance of MTX when given alone (without hydration) was significantly delayed compared with the clearance of MTX when given 2 weeks later concurrently with CDDP and saline hydration [t1/2 (beta) 19 and 4.5 hr respectively]. Of the 5 patients so far treated with MTX-CDDP, 2 have had a partial objective response and 3 have had stable disease (including 2 with a marked subjective response). These data indicate that in patients with satisfactory renal function, low-dose MTX and CDDP may be given concurrently without risk of enhanced drug toxicity.

Letter to editor: an observational study of red cell transfusion in specialist palliative care.

Dear Sir – We wish to report our findings of an observational study of red cell transfusion practice in specialist palliative care. This was conducted in two specialist palliative care inpatient units in the United Kingdom. The combined catchment population was one million and, in the period analysed, there were 944 admissions. One hundred transfusion episodes occurred and 73 individual patients received transfusions. Fifty-four (73.9%) patients received a single transfusion with the remaining 19 (26.1%) receiving multiple transfusions. Thirty-five (47.9%) patients were male and the mean age was 66.5 years (range 37–102 years, SD 13.56). Seventytwo (98.6%) patients had a malignant diagnosis. Prostate cancer was the most common primary tumour and occurred in 19 (26.3%) patients. There was a high proportion of patients with gastrointestinal cancer and lung cancer; 13 (17.8%) and 11 (15.1%) respectively. The most common site of metastases was bone, present in 32 (44%) patients. Low haemoglobin (Hb) level was documented as a trigger, either solely or in conjunction with other reasons, in 73 (73%) transfusions. Anaemia was deemed the only reason for transfusion in 26 (26%) cases. Haematinics (B12, folate, ferritin or combination) were checked in nine (9%) transfusions. The mean pre-transfusion Hb was 7.9 g/dL (range 4.3–11.4, SD 0.95) and mean post-transfusion Hb was 10.0 g/dL (range 7.2–13.0, SD 1.29). The mean number of units transfused was 2.2 (range 2–4 units). A response to transfusion was recorded in 38 (38%) transfusion episodes with 31 (31%) having a positive response. The transfusion decision was not documented as being discussed with either patients and/or relatives in the majority of cases (78%). The mean number of days between the last transfusion and death was 47 days (range 2–293 days, SD 57.1). Ten (13.7%) patients died within seven days of transfusion.

Physicians' knowledge of transdermal fentanyl:

Background: Different opioids for use in the control of moderate to severe cancer pain have become widely available. More recently, sophisticated formulations such as transdermal patches have been developed. One example, transdermal fentanyl (TF), has characteristic pharmacokinetics and along with the other opioids, equivalency conversions are often made when changing from or to other opioids. Aim of study: To explore the knowledge of general practitioners (GPs), hospital consultants and oncologists about the pharmacology and use of TF in the management of moderate/severe cancer pain. Method: During 2001 and 2002 a questionnaire survey was carried out. A randomized selection of GPs, hospital consultants and oncologists (n-1167) from the UK and Ireland were sent a questionnaire and 576 (49%) were returned and evaluated. Results: The results show doctors who had previously prescribed TF are more confident and knowledgeable about the indications and pharmacology of TF than doctors who had never prescribed TF. Overall knowledge and confidence in using TF was poor.

The analysis and animal pharmacokinetics of 1,2,4, triglycidyl urazol using a high-pressure liquid chromatographic technique

SummaryThis article details a procedure for the analysis of TGU by a simple high-pressure liquid chromatographic (HPLC) method. Linearity is maintained over the range from zero to at least 30 μg 1,2,4, triglycidyl urazol (TGU). The sensitivity of the assay is 250 ng/ml. A second peak, as yet unidentified, was setected on the chromatogram and probably represents a metabolite of TGU. The pharmacokinetic profile of TGU in Porton mice shows a first-order elimination process t1/2β of 5 min. The apparent volume of distribution is 0.75 ml and the clearance 0.10 ml/min with a elimination rate constant of 0.14 min.

Oral levonantradol in the control of cancer chemotherapy-induced emesis

SummaryA dose-ranging study with oral levonantradol was performed in 20 cancer patients. The optimum oral dose which attenuated vomiting accompanying chemotherapy was 1 mg 4-hourly. Side-effects comprised dizziness, confusion, euphoria, drowsiness, and difficulty in concentrating. There was no cardiovascular toxicity. Overall toxicity appeared to be dose-related and was mild and acceptable.

Book Review: A guide to symptom relief in advanced disease

Boston families are, with one exception, Caucasian and 70% Roman Catholic. The first part of the book places the study in the context of a meticulous review of previous research. It describes the experiences of children and their families when a parent dies, with finely observed details of changes in daily life. Worden seeks to identify the major factors influencing the course and outcome of a child’s adjustment to the loss, emphasizing the importance of the surviving parent or carers response to the death, and the ongoing ability to meet their children’s needs. Part two compares different experiences of childhood loss, including sibling death and the loss of a parent to divorce. Part three examines the implications of the research findings for intervention models, and suggests various activities that can be used to help bereaved children. It is the weakest section. The activities have all been written about elsewhere, and in greater detail, and feel at odds with the research context of the rest of the volume. There is, in addition, an important debate to be had about Worden’s preferred philosophy of intervention, early screening to identify those at risk and early intervention, rather than the provision of universal services. This places an unwarranted confidence in current screening instruments and, whilst Worden himself assets that the best bereavement outcomes occur in families where the surviving parent copes actively rather than passively, he fails to realize that many will require information and support in order to achieve such behaviours. The book is clearly written, with powerful quotations from children themselves, summaries at the end of each chapter and a helpful biography. It’s most important contribution is the detailed confirmation that children seek to maintain a connection to the deceased. Their task is not to achieve a crude separation, but to discover a sense of who this now dead parent is, and will be, in their lives.

Training abroad : a worthwhile experience

Address for correspondence: Dr Kathleen L Sherry, Senior Registrar in Palliative Medicine, Marie Curie Centre, Hunters Hill, Belmont Road, Springburn, Glasgow G21 3AY, UK. The palliative medicine curriculum in the UK’ provides a recommended core level of knowledge for future specialists in palliative medicine and affords the opportunity to spend time working in palliative care programmes abroad. We recently had the opportunity to set up a placement for a senior registrar in palliative medicine to spend time in a palliative care unit (PCU) in North America. Our objectives were that the trainee should have clinical responsibilities rather than acting as an observer and should be able to experience similarities and differences in clinical practice in the two specialist PCUs, observe the organization of palliative care services in a different country and be exposed to ongoing research. Four weeks were spent mainly in the Acute Palliative Care Unit, Grey Nuns Hospital in Edmonton, Alberta. This is a hospital-based 14-bed tertiary referral unit where patients are admitted for assessment and symptom control. There was also exposure to the Regional Palliative Care Program in the community, in neighbouring hospitals and in continuing care hospices. It is always easier to focus on differences than on similarities when making comparisons, but it was clearly apparent that the philosophy underlying the approach to patients and families and the focus on multidisciplinary care was essentially similar to that in the UK. However, a number of striking differences in clinical practice were apparent and are worth discussing: