Meglumine Eicosapentaenoic acid (MeEPA) a new soluble omega-3 fatty acid formulation: in vitro bladder cancer cytotoxicity tests in combination with epirubicin and mitomycin.

OBJECTIVE: To determine if Meglumine-Eicosapentaenoic Acid (MeEPA) acts synergistically with epirubicin and mitomycin to enhance cytotoxicity towards bladder cancer cell lines in vitro. MATERIALS AND METHODS: Bladder cancer cells were exposed to MeEPA in combination with epirubicin or mitomycin. Residual viable cell biomass was estimated with the methyl-thiazoldiphenyl tetrazolium (MTT) assay following drug exposure. Drug interaction was analysed using median effect analysis to determine levels of synergism. RESULTS: Most combinations of MeEPA with both epirubicin and mitomycin showed a high-level of synergism. At high doses, drug precipitation adversely affected MTT assay analysis suggesting antagonism of action. However, the predominant pattern was of synergism for most dose combinations tested. CONCLUSION: Bladder cancer treated by endoscopic resection alone is subject to high recurrence rates. Post-operative intravesical instillation of epirubicin and mitomycin can halve recurrence rates, but there is no evidence that disease progression to invasive bladder cancer is altered. Thus, optimisation of current treatment strategies is required. The anti-tumour activity of fatty acids is well established and MeEPA is a new, soluble formulation with the potential to enhance intravesical drug efficacy.

Comparison of the mutagenic and clastogenic activity of amsacrine and other DNA-intercalating drugs in cultured V79 Chinese hamster cells.

The acridine derivative amsacrine (m-AMSA) is used clinically for the treatment of acute leukemias. The mutagenic activity of this drug has been evaluated at the 6-thioguanine (6-TG) and ouabain resistance loci in cultured Chinese hamster fibroblasts (V79-171b cell line). m-AMSA was found to have weak but significant mutagenic activity at the 6-TG but not at the ouabain resistance locus, after either 1- or 45-hr exposures at concentrations causing up to 90% cell kill. Two other intercalating agents with antitumor activity, Adriamycin and actinomycin D, provided essentially identical results. All three drugs were potent inducers of micronuclei in V79-171b cells, indicating high clastogenic activity. For these intercalating agents, the yield of 6-TG-resistant mutants was approximately 100-fold lower than that for ethyl methanesulfonate after exposures causing equivalent toxicity or equivalent chromosome breakage. The acridine half-mustard ICR-191 resembled ethyl methanesulfonate rather than the other intercalating agents in providing a high yield of 6-TG-resistant mutants relative to its clastogenic activity. The tumor-inactive intercalator 9-aminoacridine demonstrated only low clastogenic activity with a lack of significant mutagenic activity at toxic concentrations. These results suggest that, for m-AMSA, Adriamycin, and actinomycin D, both cell killing and mutagenesis could be direct consequences of chromosome breakage, while 9-aminoacridine may kill cells by a different mechanism. In view of its mutagenic and clastogenic activity at clinically achievable exposures and the similarity of its genotoxic properties to Adriamycin, m-AMSA should be considered a potential carcinogen.

The euthanasia debate.

Debates about the moral dilemmas of euthanasia date back to ancient times. Many of the historical arguments used for and against the practice remain valid today. Indeed, any form of discussion on the subject often provokes emotive responses, both from members of the medical profession and the general public. For this reason alone, the issue will continue to be debated at all levels of society. There are, however, other factors that ensure euthanasia will remain a subject of major controversy within medical, legal and governmental bodies. Firstly, the act of euthanasia itself is illegal, yet in its passive form occurs on a daily basis in many of our hospitals (1). Secondly, medical advances have made it possible to artificially prolong the life of an increasing number of patients far beyond what was possible only a few years ago. Furthermore, we must all contend with the reality that financial constraints are an important consideration in modern health care provision. Finally, there is an ethical difficulty in interpreting the concept of a patient's right, or autonomy, versus the rights and duty of a doctor. Before attempting to answer the questions posed by these issues, it is important to have some accurate definitions of both euthanasia and of the concept of morality. According to the House of Lords Select Committee on Medical Ethics, the precise definition of euthanasia is "a deliberate intervention undertaken with the express intention of ending a life, to relieve intractable suffering" (2). The term can be further divided into voluntary and involuntary euthanasia. The former is said to occur if a competent patient makes an informed request for a life terminating event and the latter can be used if a patient does not give informed and specific consent for such treatment. It is the occurrence of involuntary euthanasia which forms one of the main arguments against legalisation. This is discussed in greater detail below. Euthanasia is frequently separated into active and passive forms. A number of authors consider these terms to be misleading and unhelpful. They are, however, used in the literature and in discussion and consequently should be understood. Active euthanasia takes place if deliberate steps are taken to end a patient's life; this would include administration of potassium containing compounds to induce cardiac arrest, a practice that is illegal in this country. Passive euthanasia is the withholding of treatments necessary for the continuance of life. Whether the administration of increasingly necessary, albeit toxic doses of opioid analgesia is regarded as active or passive euthanasia is a matter of moral interpretation, but in order to pacify doctors' consciences, it is usually regarded as a passive measure. Many people, therefore, regard it as an acceptable facet of good professional practice.

Hospital and after: experience of patients and carers in rural and remote north Queensland, Australia.

INTRODUCTION: This article reports a study of patients and carers discharged from the Townsville General Hospital into rural and remote communities in north Queensland, Australia. The findings indicate the importance of focusing on the experiences of patients and carers in attempting to understand the impact of discharge procedures. The four stories and their implications exist within a particular healthcare context that impacts disproportionately on rural patients and their carers. Economic rationalism has shaped contemporary healthcare policy in Australia, creating a system that is encouraged to conform to market principles. The costs borne by individuals, groups and communities have been increasingly privatised. Later admission and earlier discharge from hospital is now the norm. Concern about the impact of this policy context on the lives of rural and remote patients and carers prompted the study, which aimed to: (1) examine, from the patient and carer perspective, the social, economic, cultural and emotional cost of hospitalisation away from home communities; (2) identify the needs of rural and remote patients and their carers before, during and after hospitalisation a long way from home; and (3) make recommendations for improved policies and practices concerning the continuum of care: from admission planning, through hospitalisation, discharge-planning, and post-discharge support, in the context of rural and remote location. METHODS: The experiences presented highlight the depth of the challenges faced by patients and their carers who live in rural and remote communities. Both quantitative and qualitative methodologies were used to obtain insight into the complexity of patients and carers' lives. The four vignettes presented in this paper are taken from in-depth, qualitative interviews with 12 patients and 12 carers. RESULTS: The four stories described reveal the high financial and emotional costs, for patients and carers, of negotiating a healthcare system a long way from home. Challenges faced included inadequate admission planning, excessive accommodation and transport costs, and lack of post-discharge support services in home communities, as well as business failure, marital and family strain. There was an over-reliance on carers who lacked medical caring expertise, had other major commitments (family and work) and who may have had a tenuous and uncertain relationship with the patient. CONCLUSIONS: Recognition of these complex circumstances, exacerbated by rural location, during the discharge planning process should mean that attention to ensuring patients and their carers are linked to adequate support services in their communities is of the highest priority. The communication and dissemination of information to patients and carers is also vital. Information on hospital admission, travel benefits, accommodation options, care requirements post-discharge are particular recommendations. To summarise, the experiences highlighted in this study suggest that patients and carers in rural and remote communities have not benefited from adequate discharge planning, and are struggling to cope in a policy context that encourages later admission, earlier discharge and over reliance on family and friends as carers.

In-vitro head and neck response to impact.

Two unembalmed and one embalmed human cadaveric head-neck systems were instrumented and subjected to central forehead impact of ballistically suspended 3.07-kg aluminum shell at velocities ranging from 50 to 345 cm/s. Occipital skull accelerations and disk pressures were measured by transducers, while the deformation of the system was determined by framing camera data. The results were found to be in accord with those from corresponding tests in artificial head-neck replica. Initial and terminal X-ray examination of the structure revealed no evidence of either skull or vertebral fractures.

Is sexual intercourse a significant cause of haematuria?

OBJECTIVES: To determine whether recent sexual intercourse might be a cause of microscopic haematuria in patients referred to a urological unit following dipstick detection of urinary haemoglobin. SUBJECTS AND METHODS: Forty-eight volunteers (24 men and 24 women) consented to have heterosexual intercourse with their regular partner, and to provide samples of urine for testing before and from the first void on the morning after intercourse. After appropriate instruction, volunteers tested their own urine for the presence of blood using standard dipsticks. Any volunteer with haematuria either before or after intercourse was offered a standard haematuria assessment. The results were analysed using the chi-squared test. RESULTS: None of the volunteers tested positively for haematuria immediately before sexual intercourse; six of the 24 women (25%), but no men, became positive after intercourse (P < 0.01). Only one of the six women accepted the offer of a haematuria evaluation and no pathology was identified. CONCLUSION: These results suggest that up to a quarter of women develop microscopic haematuria as a direct result of sexual intercourse. A history of recent sexual intercourse should therefore be considered when assessing the clinical significance of microscopic haematuria in women.

Intravesical pH: a potentially important variable affecting efficacy and the further development of anthracycline chemotherapy for superficial bladder cancer.

OBJECTIVE: To assess, using epirubicin-sensitive and multidrug resistant (MDR) derivatives of human bladder cancer cell lines in vitro, the probable effect of intravesical pH changes, with and without the MDR antagonist verapamil, on the uptake, intracellular distribution and cytotoxicity of epirubicin during intravesical chemotherapy. MATERIALS AND METHODS: Incubations for cytotoxicity testing were carried out in buffered medium containing epirubicin, at pH values of 6.0-8.5, with verapamil where appropriate. The cytotoxicity of epirubicin, with and without verapamil, was determined using the tetrazolium cytotoxicity assay. Intracellular epirubicin fluorescence was assessed using flow cytometry and confocal microscopy. Flow cytometric total intracellular epirubicin fluorescence was measured at pH 6.0, 6.4, 6.8, 7.2, and 7.6, and confocal microscopy was carried out at pH 6.0 and 8.0. The MDR-reversing agent verapamil was added at 100 micro g/mL to some incubations. RESULTS: Epirubicin cytotoxicity in resistant cell lines appears considerably enhanced by adding verapamil and further improved, especially in MDR cells, by alkalinization of the drug solution to pH 8.0. Flow cytometry results showed striking and consistent differences in epirubicin handling with pH. Sensitive cells can be induced to absorb considerably more drug at alkaline pH, whilst resistant cells show no such behaviour. Nuclear drug fluorescence was greater in sensitive cells at alkaline pH, but cytoplasmic drug fluorescence in the resistant cells was little changed by pH. Adding verapamil to resistant cells restored the sensitive phenotype of drug handling. CONCLUSION: Buffering epirubicin to an alkaline pH before intravesical application should increase its intrinsic cytotoxicity. The potential for synergy at certain drug combinations will be enhanced by applying these findings. MDR reversal and fatty acid augmentation of drug uptake are discussed as examples.

Intravesical meglumine gamma-linolenic acid in superficial bladder cancer: an efficacy study.

OBJECTIVES: Gamma-linolenic acid (GLA) is known to be cytotoxic to malignant cells. We assessed the efficacy of the novel intravesical formulation, meglumine gamma-linolenic acid (MeGLA), in a phase II trial, in patients with recurrent, superficial bladder cancer. PATIENTS AND METHODS: Thirty patients with recurrent, superficial transitional cell carcinoma (TCC) were recruited. The tumour pattern was recorded at flexible cystoscopy. Patients received a single intravesical instillation of 50ml of either 50mg (1mg/ml) (15 patients), or 125mg (2.5mg/ml) (15 patients) of MeGLA in water, retained for one hour. At subsequent cystoscopy, the tumour patterns were recorded, prior to undertaking routine cystodiathermy. Biopsies were obtained for histological assessment. Responses were divided into complete, partial or none. RESULTS: All 30 patients retained the drug for 1 hour without significant local or systemic side effects. There were 4 (13%) complete responses, 9 (30%) partial responses, and 17 (57%) non-responders. Histology showed no evidence of damage to surrounding urothelium. CONCLUSIONS: Our data confirms the safety and tolerability of MeGLA, which is consistent with findings from a previous phase I trial. A response rate of 43% also indicates that MeGLA has a significant cytotoxic effect against TCC and the results are similar to those obtained using standard, single-dose, intravesical regimens.