Cochrane review summary for cancer nursing : drug therapy for cancer-related fatigue

Cancer-related fatigue (CRF) is one of themost debilitating symptoms in patients with cancer. It is prevalent at the time of diagnosis and during and after antineoplastic treatment and in patients with advanced disease. The multifactorial and complex nature of CRF makes it challenging for health professionals to identify a clear underlying mechanism and manage this symptom effectively. Often, the management plan for CRF (whether pharmacological or nonpharmacological) can be further complicated by the coexistence of other symptoms. This systematic review1 is therefore important in informing health professionals on the effectiveness of pharmacological management for CRF.

ASAP ECMO : antibiotic, sedative and analgesic pharmacokinetics during extracorporeal membrane oxygenation : a multi-centre study to optimise drug therapy during ECMO

BACKGROUND: Given the expanding scope of extracorporeal membrane oxygenation (ECMO) and its variable impact on drug pharmacokinetics as observed in neonatal studies, it is imperative that the effects of the device on the drugs commonly prescribed in the intensive care unit (ICU) are further investigated. Currently, there are no data to confirm the appropriateness of standard drug dosing in adult patients on ECMO. Ineffective drug regimens in these critically ill patients can seriously worsen patient outcomes. This study was designed to describe the pharmacokinetics of the commonly used antibiotic, analgesic and sedative drugs in adult patients receiving ECMO. METHODS: This is a multi-centre, open-label, descriptive pharmacokinetic (PK) study. Eligible patients will be adults treated with ECMO for severe cardiac and/or respiratory failure at five Intensive Care Units in Australia and New Zealand. Patients will receive the study drugs as part of their routine management. Blood samples will be taken from indwelling catheters to investigate plasma concentrations of several antibiotics (ceftriaxone, meropenem, vancomycin, ciprofloxacin, gentamicin, piperacillin-tazobactum, ticarcillin-clavulunate, linezolid, fluconazole, voriconazole, caspofungin, oseltamivir), sedatives and analgesics (midazolam, morphine, fentanyl, propofol, dexmedetomidine, thiopentone). The PK of each drug will be characterised to determine the variability of PK in these patients and to develop dosing guidelines for prescription during ECMO. DISCUSSION: The evidence-based dosing algorithms generated from this analysis can be evaluated in later clinical studies. This knowledge is vitally important for optimising pharmacotherapy in these most severely ill patients to maximise the opportunity for therapeutic success and minimise the risk of therapeutic failure

Age-related changes in hepatic function: An update on implications for drug therapy

The accumulation of deficits with increasing age results in a decline in the functional capacity of multiple organs and systems. These changes can have a significant influence on the pharmacokinetics and pharmacodynamics of prescribed drugs. Although alterations in body composition and worsening renal clearance are important considerations, for most drugs the liver has the greatest effect on metabolism. Age-related change in hepatic function thereby causes much of the variability in older people’s responses to medication. In this review, we propose that a decline in the ability of the liver to inactivate toxins may contribute to a proinflammatory state in which frailty can develop. Since inflammation also downregulates drug metabolism, medication prescribed to frail older people in accordance with disease-specific guidelines may undergo reduced systemic clearance, leading to adverse drug reactions, further functional decline and increasing polypharmacy, exacerbating rather than ameliorating frailty status. We also describe how increasing chronological age and frailty status impact liver size, blood flow and protein binding and enzymes of drug metabolism. This is used to contextualise our discussion of appropriate prescribing practices. For example, while the general axiom of ‘start low, go slow’ should underpin the initiation of medication (titrating to a defined therapeutic goal), it is important to consider whether drug clearance is flow or capacity-limited. By summarising the effect of age-related changes in hepatic function on medications commonly used in older people, we aim to provide a guide that will have high clinical utility for practising geriatricians.

Washout hole for bi-ventricular assist device (BVAD) centrifugal blood pump

The shortage of donor hearts for patients with end stage heart failure has accelerated the development of ventricular assist devices (VAD) that act as a replacement heart. Mechanical devices involving pulsatile, axial and centrifugal devices have been proposed. Recent clinical developments indicate that centrifugal devices are not only beneficial for bridge to transplantation applications, but may also aid myocardial recovery. The results of a recent study have shown that patients who received a VAD have extended lives and improved quality of life compared to recipients of drug therapy. Unfortunately 25% of these patients develop right heart failure syndrome, sepsis and multi-organ failure. It was reported that 17% of patients initially receiving an LVAD later required a right ventricular assist device (RVAD). Hence, current research focus is in the development of a bi-ventricular assist device (BVAD). Current BVAD technology is either too bulky or necessitates having to implant two pumps working independently. The latter requires two different controllers for each pump leading to the potential complication of uneven flow dynamics and the requirements for a large amount of body space. This paper illustrates the combination of the LVAD and RVAD as one complete device to augment the function of both the left and right cardiac chambers with double impellers. The proposed device has two impellers rotating in counter directions, hence eliminating the necessity of the body muscles and tubing/heart connection to restrain the pump. The device will also have two separate chambers with independent rotating impeller for the left and right chambers. A problem with centrifugal impellers is the fluid stagnation underneath the impeller. This leads to thrombosis and blood clots.This paper presents the design, construction and location of washout hole to prevent thrombus for a Bi-VAD centrifugal pump. Results using CFD will be used to illustrate the superiority of our design concept in terms of preventing thrombus formation and hemolysis.

In vivo confocal microscopy of the bulbar conjunctiva

Background: The aim of this work is to develop a more complete qualitative and quantitative understanding of the in vivo histology of the human bulbar conjunctiva. Methods: Laser scanning confocal microscopy (LSCM) was used to observe and measure morphological characteristics of the bulbar conjunctiva of 11 healthy human volunteer subjects. Results: The superficial epithelial layer of the bulbar conjunctiva is seen as a mass of small cell nuclei. Cell borders are sometimes visible. The light grey borders of basal epithelial cells are clearly visible, but nuclei can not be seen. The conjunctival stroma is comprised of a dense meshwork of white fibres, through which traverse blood vessels containing cellular elements. Orifices at the epithelial surface may represent goblet cells that have opened and expelled their contents. Goblet cells are also observed in the deeper epithelial layers, as well as conjunctival microcysts and mature forms of Langerhans cells. The bulbar conjunctiva has a mean thickness of 32.9 1.1 mm, and a superficial and basal epithelial cell density of 2212 782 and 2368 741 cells/ mm2, respectively. Overall goblet and mature Langerhans cell densities are 111 58 and 23 25 cells/mm2, respectively. Conclusions: LSCM is a powerful technique for studying the human bulbar conjunctiva in vivo and quantifying key aspects of cell morphology. The observations presented here may serve as a useful marker against which changes in conjunctival morphology due to disease, surgery, drug therapy or contact lens wear can be assessed.

Queensland Aborigines, multiple realities and the social sources of suffering: Psychiatry and moral regions of being (Part 1)

This two part paper considers the experience of a range of magico-religious experiences (such as visions and voices) and spirit beliefs in a rural Aboriginal town. The papers challenge the tendency of institutionalised psychiatry to medicalise the experiences and critiques the way in which its individualistic practice is intensified in the face of an incomprehensible Aboriginal „other‟ to become part of the power imbalance that characterises the relationship between Indigenous and white domains. The work reveals the internal differentiation and politics of the Aboriginal domain, as the meanings of these experiences and actions are contested and negotiated by the residents and in so doing they decentre the concerns of the white domain and attempt to control their relationship with it. Thus the plausibility structure that sustains these multiple realities reflects both accommodation and resistance to the material and historical conditions imposed and enacted by mainstream society on the residents, and to current socio- political realities. I conclude that the residents‟ narratives chart the grounds of moral adjudication as the experiences were rarely conceptualised by local people as signs of individual pathology but as reflections of social reality. Psychiatric drug therapy and the behaviourist assumptions underlying its practice posit atomised individuals as the appropriate site of intervention as against the multiple realities revealed by the phenomenology of the experiences. The papers thus call into question Australian mainstream „commonsense‟ that circulates about Aboriginal and Torres Strait Islander people which justifies representations of them as sickly outcasts in Australian society.

Notch and NOXA-related pathways in melanoma cells

Notch receptor-mediated intracellular events represent an ancient cell signaling system, and alterations in Notch expression are associated with various malignancies in which Notch may function as an oncogene or less commonly as a tumor suppressor. Notch signaling regulates cell fate decisions in the epidermis, including influencing stem cell dynamics and growth/differentiation control of cells in skin. Because of increasing evidence that the Notch signaling network is deregulated in human malignancies, Notch receptors have become attractive targets for selective killing of malignant cells. Compared with proliferating normal human melanocytes, melanoma cell lines are characterized by markedly enhanced levels of activated Notch-1 receptor. By using a small molecule gamma-secretase inhibitor (GSI) consisting of a tripeptide aldehyde, N-benzyloxycarbonyl-Leu-Leu-Nle-CHO, which can block processing and activation of all four different Notch receptors, we identified a specific apoptotic vulnerability in melanoma cells. GSI triggers apoptosis in melanoma cells, but only G2/M growth arrest in melanocytes without subsequent cell death. Moreover, GSI treatment induced a pro-apoptotic BH3-only protein, NOXA, in melanoma cells but not in normal melanocytes. The use of GSI to induce NOXA induction overcomes the apoptotic resistance of melanoma cells, which commonly express numerous cell survival proteins such as Mcl-1, Bcl-2, and survivin. Taken together, these results highlight the concept of synthetic lethality in which exposure to GSI, in combination with melanoma cells overexpressing activated Notch receptors, has lethal consequences, producing selective killing of melanoma cells, while sparing normal melanocytes. By identifying signaling pathways that contribute to the transformation of melanoma cells (e.g. Notch signaling), and anti-cancer agents that achieve tumor selectivity (e.g., GSI-induced NOXA), this experimental approach provides a useful framework for future therapeutic strategies in cutaneous oncology.

FGFR2 as a molecular target in endometrial cancer

Although molecularly targeted therapies have been effective in some cancer types, no targeted therapy is approved for use in endometrial cancer. The recent identification of activating mutations in fibroblast growth factor receptor 2 (FGFR2) in endometrial tumors has generated a new avenue for the development of targeted therapeutic agents. The majority of the mutations identified are identical to germline mutations in FGFR2 and FGFR3 that cause craniosynostosis and hypochondroplasia syndromes and result in both ligand-independent and ligand-dependent receptor activation. Mutations that predominantly occur in the endometrioid subtype of endometrial cancer, are mutually exclusive with KRAS mutation, but occur in the presence of PTEN abrogation. In vitro studies have shown that endometrial cancer cell lines with activating FGFR2 mutations are selectively sensitive to a pan-FGFR inhibitor, PD173074. Several agents with activity against FGFRs are currently in clinical trials. Investigation of these agents in endometrial cancer patients with activating FGFR2 mutations is warranted.

Malnutrition and chemotherapy-induced nausea and vomiting : implications for practice

PURPOSE/OBJECTIVES: To determine the prevalence of malnutrition and chemotherapy-induced nausea and vomiting (CINV) limiting dietary intake in a chemotherapy unit. DESIGN Cross sectional descriptive audit. SETTING: Chemotherapy ambulatory care unit in an Australian teaching hospital. SAMPLE 121 patients receiving chemotherapy for malignancies, ≥18yrs and able to provide verbal consent. METHODS: An Accredited Practicing Dietitian collected all data. Chi-square tests were used to determine the relationship of malnutrition with variables and demographic data. MAIN RESEARCH VARIABLES: Nutritional status, weight change, BMI, prior dietetic input, CINV and CINV that limited dietary intake. FINDINGS Thirty one (26%) participants were malnourished, 12 (10%) had intake-limiting CINV, 22 (20%) reported significant weight loss and 20 (18%) required improved nutrition symptom management. High nutrition risk diagnoses, CINV, BMI and weight loss were significantly associated with malnutrition. Thirteen (35%) participants with malnutrition, significant weight loss, intake-limiting CINV and/or critically requiring improved symptom management reported no dietetic input; the majority of whom were overweight or obese. CONCLUSIONS: This audit determined over one quarter of patients receiving chemotherapy in this ambulatory setting were malnourished and the majority of patients reporting intake-limiting CINV were malnourished. IMPLICATIONS FOR NURSING Patients with malnutrition and/or intake-limiting CINV and in need of improved nutrition symptom management may be overlooked, especially patients who are overweight or obese - an increasing proportion of the Australian population. Evidence-based practice guidelines recommend implementing validated nutrition screening tools, such as the Malnutrition Screening Tool, in patients undergoing chemotherapy to identify those at risk of malnutrition requiring dietitian referral.

An introduction to anticancer drugs

An introduction to anticancer drugs 24.1 Introduction 24.2 The rationale behind anticancer drug therapy 24.3 Drugs used in cancer 24.3.1 Alkylating agents 24.3.2 Cytotoxic antibiotics 24.3.3 Antimetabolites 24.3.4 Microtubule inhibitors 24.3.5 Monoclonal antibodies 24.3.6 Steroid hormones and their antagonists 24.3.7 Other treatments

Thyroxine and reserpine-induced changes in metabolic profiles of rat urine and the therapeutic effect of Liu Wei Di Huang Wan detected by UPLC-HDMS

The promise of metabonomics, a new "omics" technique, to validate Chinese medicines and the compatibility of Chinese formulas has been appreciated. The present study was undertaken to explore the excretion pattern of low molecular mass metabolites in the male Wistar-derived rat model of kidney yin deficiency induced with thyroxine and reserpine as well as the therapeutic effect of Liu Wei Di Huang Wan (LW) and its separated prescriptions, a classic traditional Chinese medicine formula for treating kidney yin deficiency in China. The study utilized ultra-performance liquid chromatography/electrospray ionization synapt high definition mass spectrometry (UPLC/ESI-SYNAPT-HDMS) in both negative and positive electrospray ionization (ESI). At the same time, blood biochemistry was examined to identify specific changes in the kidney yin deficiency. Distinct changes in the pattern of metabolites, as a result of daily administration of thyroxine and reserpine, were observed by UPLC-HDMS combined with a principal component analysis (PCA). The changes in metabolic profiling were restored to their baseline values after treatment with LW according to the PCA score plots. Altogether, the current metabonomic approach based on UPLC-HDMS and orthogonal projection to latent structures discriminate analysis (OPLS-DA) indicated 20 ions (14 in the negative mode, 8 in the positive mode, and 2 in both) as "differentiating metabolites".

Genotypes of the MTHFR C677T and MTRR A66G genes act independently to reduce migraine disability in response to vitamin supplementation

BACKGROUND: Migraine is a chronic disabling neurovascular condition that may in part be caused by endothelial and cerebrovascular disruption induced by hyperhomocysteinaemia. We have previously provided evidence indicating that reduction of homocysteine by vitamin supplementation can reduce the occurrence of migraine in women. The current study examined the genotypic effects of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) gene variants on the occurrence of migraine in response to vitamin supplementation. METHODS: This was a 6-month randomized, double-blinded placebo-controlled trial of daily vitamin B supplementation (B(6), B(9) and B(12)) on reduction of homocysteine and of the occurrence of migraine in 206 female patients diagnosed with migraine with aura. RESULTS: Vitamin supplementation significantly reduced homocysteine levels (P<0.001), severity of headache in migraine (P=0.017) and high migraine disability (P=0.022) in migraineurs compared with the placebo effect (P>0.1). When the vitamin-treated group was stratified by genotype, the C allele carriers of the MTHFR C677T variant showed a higher reduction in homocysteine levels (P<0.001), severity of pain in migraine (P=0.01) and percentage of high migraine disability (P=0.009) compared with those with the TT genotypes. Similarly, the A allele carriers of the MTRR A66G variants showed a higher level of reduction in homocysteine levels (P<0.001), severity of pain in migraine (P=0.002) and percentage of high migraine disability (P=0.006) compared with those with the GG genotypes. Genotypic analysis for both genes combined indicated that the treatment effect modification of the MTRR variant was independent of the MTHFR variant. CONCLUSION: This provided further evidence that vitamin supplementation is effective in reducing migraine and also that both MTHFR and MTRR gene variants are acting independently to influence treatment response in female migraineurs.

Comparative study on the protective effects of Yinchenhao Decoction against liver injury induced by alpha-naphthylisothiocyanate and carbon tetrachloride

OBJECTIVE: To optimize the animal model of liver injury that can properly represent the pathological characteristics of dampness-heat jaundice syndrome of traditional Chinese medicine. METHODS: The liver injury in the model rat was induced by alpha-naphthylisothiocyanate (ANIT) and carbon tetrachloride (CCl(4) ) respectively, and the effects of Yinchenhao Decoction (, YCHD), a proved effective Chinese medical formula for treating the dampness-heat jaundice syndrome in clinic, on the two liver injury models were evaluated by analyzing the serum level of alanine aminotransferase (ALT), asparate aminotransferase (AST), alkaline phosphatase (ALP), malondialchehyche (MDA), total bilirubin (T-BIL), superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) as well as the ratio of liver weight to body weight. The experimental data were analyzed by principal component analytical method of pattern recognition. RESULTS: The ratio of liver weight to body weight was significantly elevated in the ANIT and CCl(4) groups when compared with that in the normal control (P<0.01). The contents of ALT and T-BIL were significantly higher in the ANIT group than in the normal control (P<0.05,P<0.01), and the levels of AST, ALT and ALP were significantly elevated in CCl(4) group relative to those in the normal control P<0.01). In the YCHD group, the increase in AST, ALT and ALP levels was significantly reduced (P<0.05, P<0.01), but with no significant increase in serum T-BIL. In the CCl(4) intoxicated group, the MDA content was significantly increased and SOD, GSH-PX activities decreased significantly compared with those in the normal control group, respectively (P<0.01). The increase in MDA induced by CCl(4) was significantly reduced by YCHD P<0.05). CONCLUSION: YCHD showed significant effects on preventing liver injury progression induced by CCl(4), and the closest or most suitable animal model for damp-heat jaundice syndrome may be the one induced by CCl(4).

Chemotherapy induced reversible posterior leukoencephalopathy syndrome

The reversible posterior leukoencephalopathy syndrome (RPLES) is a condition characterised by reversible neurological and radiological findings that has been associated with use of immunosuppressive, chemotherapeutic and more recently novel targeted therapies. We describe the case of a 50-year-old woman with advanced non-small cell lung cancer who developed status epilepticus shortly after receiving cisplatin and gemcitabine chemotherapy. The clinical, radiological and EEG findings during and post event are presented and are in keeping with a diagnosis of RPLES. Early recognition of this rare syndrome, supportive management and withdrawal of the offending agent appear to result in a reversal of the manifestations described. © 2007 Elsevier Ireland Ltd. All rights reserved.