Phase I study of the anthrapyrazole biantrazole: clinical results and pharmacology

Summary In a phase I study the anthrapyrazole biantrazole (Warner-Lambert Company) was given to 41 patients with tumour refractory to existing therapy. The drug was given i.v. weekly for 3 weeks, with a 3-week interval between courses. At the 1st week a full pharmacokinetic study was performed, and at weeks 2 and 3, blood samples were taken at 1 and 6 h following treatment to check for drug accumulation. Biantrazole pharmacokinetics were linear with respect to the AUC (r=0.924) over the full range of doses studied (4–36 mg/m²) but exhibited large inter-patient variations at each dose level. Elimination was triphasic, comprising two rapid early phases and a long terminal half-life (mean, 14.1±7.8 h). There was no evidence of drug accumulation over the 3-week treatment period. Approximately 12% of the parent drug was excreted unchanged in the urine together with two non-circulating, more water-soluble metabolites. Biantrazole was well tolerated but did cause moderate emesis at doses of >18 mg/m² and mild alopecia. The dose-limiting side effect was leucopenia, with no other major toxicity being observed. One patient developed biventricular failure that was not clearly related to biantrazole administration. On the present schedule, the recommended dose of biantrazole is 24 mg/m². No response were seen in this patient population. Authors: on behalf of the EORTC Early Clinical Trials Group and the CRC Phase I/II Trials Committee     

Melanoma differentiation associated gene-7 (mda-7)/IL-24: a 'magic bullet' for cancer therapy?

An ideal cancer gene therapy would selectively kill cancer cells without harming normal cells and induce multipronged 'bystander' antitumor effects, facilitating eradication of both primary and metastatic tumors. Melanoma differentiation associated gene-7 (mda-7)/interleukin-24 (IL-24) exhibits all of these attributes and more. It induces cancer-selective apoptosis, inhibits angiogenesis, stimulates an antitumor immune response, sensitizes cancer cells to radiation and other modalities of conventional therapies, and exhibits profound 'bystander' activity eliminating both primary and distant tumors in animal models. Moreover, a replication-incompetent adenovirus expressing mda-7/IL-24, Ad.mda-7 (INGN-241), has now undergone evaluation in a Phase I clinical trial for multiple solid tumors, including melanomas, and has demonstrated safety and significant objective clinical activity. Considering these exciting observations, mda-7/IL-24 is being hailed as a 'magic bullet' for cancer gene therapy. This review elaborates on the pleiotropic properties of mda-7/IL-24 and unravels novel aspects of the molecule mandating future studies and expanded clinical applications.     

AGI-1067: a multifunctional phenolic antioxidant,lipid modulator,anti-inflammatory and antiatherosclerotic agent

To explore the therapeutic efficacy and potential mechanisms of action of a new class of antiatherosclerotic drugs, AGI-1067 [mono[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenyl] ester] (butanedioc acid) was tested in several animal models of atherosclerosis. AGI-1067, a novel phenolic antioxidant, was well tolerated in a 1-year study in hypercholesterolemic cynomolgus monkeys. It lowered low-density lipoprotein cholesterol (LDLc) by 41 and 90% at oral doses of 50 and 150 mg/kg, respectively and increased high-density lipoprotein cholesterol (HDLc) by 107% at the higher dose. In contrast, another phenolic antioxidant, probucol, had a modest LDLc-lowering effect (15% at 250 mg/kg) while decreasing HDLc (37% at 150 mg/kg). Histopathology of the aortas and coronary arteries revealed no atherosclerosis in the AGI-1067 (150 mg/kg) group and minimal-to-moderate atherosclerosis in the vehicle and probucol (150 mg/kg) groups. AGI-1067 also inhibited atherosclerosis in LDL receptor-deficient (LDLr -/-) mice and apolipoprotein E-deficient (ApoE -/-) mice even in the absence of a lipid-lowering effect. In LDLr -/- mice, AGI-1067 reduced aortic atherosclerosis by 49%. In ApoE -/- mice, AGI-1067 reduced atherosclerosis by 25, 41, and 49% in the arch, thoracic, and abdominal regions of the aorta. AGI-1067 also reduced vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) mRNA levels in lungs of lipopolysaccharide-stimulated mice. At the cellular level, AGI-1067 inhibited tumor necrosis factor-alpha-inducible expression of VCAM-1, MCP-1, and E-selectin in human aortic endothelial cells (IC50 values = 6, 10, and 25 microM, respectively). These data show that AGI-1067 can inhibit atherosclerosis not only via its lipid-lowering effects but also by having direct anti-inflammatory effects on the vessel wall and suggest that it may be a novel therapeutic agent for coronary artery disease.     

Implementing reflection: insights from pre-registration mental health students

Reflection and reflective practice continues to be contentious issues in nursing. The focus of this article is the use of reflection by pre-registration mental health students. The broad aim of this preliminary study was to discover student mental health nurses' perceptions of reflection as a learning strategy during clinical placement. Using a constructivist grounded theory methodology [Charmaz, K., 2000. Grounded theory: Objectivist and Constructivist Methods. In: Denzin, N., Lincoln, Y. (Eds.), Handbook of Qualitative Research, second ed. Sage, Thousand Oaks, California], five students were interviewed individually in their clinical placements. Data analysis revealed three major categories: understanding the process of reflection, using reflection in clinical practice, and needing support and guidance. Findings indicated that students were primarily using reflection-on-action, but to varying extents. Overall, students felt that reflection facilitated their learning. Factors were discovered that both helped and hindered students' use of reflection. These included level of preparation to reflect, a limited culture of reflection and the level of support from preceptors, clinical staff, clinical placement co-ordinators, and lecturers. In conclusion, it appears that a collaborative approach between students, Health Service Providers and institutes of nursing is vital for the successful development and implementation of reflective learning strategies in clinical placement. Suggestions are made as to how a collaborative approach may be developed to enhance this process.     

Complex Tracheocarinal Reconstructions Using Extrathoracic Muscle Flaps as Airway Substitutes

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Reduced risk of peanut sensitization following exposure through breast-feeding and early peanut introduction

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mda-7/IL-24: exploiting cancer's Achilles' heel.

The mda-7/IL-24 cDNA was isolated almost a decade ago in a screen for genes differentially upregulated following growth arrest and terminal differentiation of a human melanoma cell line employed as an in vitro cell differentiation model. The underlying rationale for the screen was that oncogenesis arises from a cellular dedifferentiation process culminating in uncontrolled proliferation and acquisition of invasive and metastatic potential. Identification of genes upregulated during the process of reactivation of faulty or inoperational differentiation maintenance programs was postulated to have cancer gene therapeutic potential. In this context, it is heartening to note that mda-7/IL-24 has made a methodical and progressive journey, from an unidentified novel sequence with little homology to known genes at its time of isolation to currently having the status of a molecule belonging to the IL-10-related family of cytokines, with considerable cancer gene therapeutic potential. Extensive in vitro and in vivo human tumor xenograft studies have established its transformed cell apoptosis-inducing capacity in various model systems. It has recently taken an important step for a candidate cancer gene therapeutic molecule, in the ultimate goal of benchtop to clinic, by being currently utilized in human Phase I/II clinical trials. This review provides a current perspective of our understanding of mda-7/IL-24, including established and more recent information about the molecular properties, specificity of anti-tumor-cell apoptosis-inducing activity, and underlying mechanisms of this action relative to its cancer gene therapeutic potential.     

Psychosocial diagnoses occurring after patients present with fatigue

ObjectiveTo discover the frequency of psychosocial and other diagnoses occurring at the end of a visit when patients present to their FPs with concerns about fatigue.DesignCross-sectional study of patient-FP encounters for fatigue.SettingTen FP practices in southwestern Ontario.ParticipantsA total of 259 encounters involving 167 patients presenting to their FPs between March 1, 2006, and June 30, 2010, with concerns about fatigue.ResultsPsychosocial diagnoses were made 23.9% of the time. Among psychosocial diagnoses made, depressive disorder and anxiety disorder or anxiety state were diagnosed more often in women (P = .048). Slightly less than 30% of the time, the cause of patients’ fatigue remained undiagnosed at the end of the encounter. A diagnosis was made more often in men.ConclusionCauses of fatigue frequently remain undiagnosed; however, when there is a diagnosis, psychosocial diagnoses are common. Therefore, it would be appropriate for FPs to screen for psychosocial issues when their patients present with fatigue, unless some other diagnosis is evident. Depression and anxiety could be considered particularly among female patients with fatigue.