The environmental impact of aeronautical activities : legal aspects

Note:The development of resistance of malignant tumors to the chemotherapeutic agents used in the treatment of neoplastic disease is a major factor responsible for treatment failure. Rat mammary adenocarcinoma cells (MatB) which model the human disease in their pattern of growth were studied to elucidate mechanisms of drug resistance. Cell lines that have acquired drug resistance in vitro as a result of continuous exposure to increasing concentrations of drug have been utilized to this effect. Two separate cell lines were selected for resistance to either a "natural product" (AdrR) or an alkylating (MlnR) antineoplastic drug. Each line displayed phenotypic changes that were stereotypic for the selecting agent. Adriamycin selected cells maintained the multidrug resistant phenotype in vitro and in vivo. […]Le développement de la résistance des tumeurs aux médicaments anti-cancéreux est l'une des causes majeures des échecs thérapeutiques en clinique. Afin d'étudier les mécanismes de la résistance, des cellules isolées d'adénocarcinome mammaire de rat (MatB) ont été utilisées comme modelé expérimental. En traitant ces cellules avec des concentrations croissantes d'agents anti-cancéreux, deux lignées cellulaires résistantes ont été sélectionnées: l'une a l'adriamycine (antibiotique naturel) et l'autre au melphalan (agent alkylant). Les cellules résistantes a l'adriamycine possèdent les caractéristiques classiques du phénotype de "résistance multiple". Les cellules résistantes au melphalan (MlnR) présentent essentiellement une surexpression des glutathione-S-transferases (GST). Cette dernière classe d'enzymes joue un rôle très important dans les mécanismes de défense (cellulaires) contre les agents cytotoxiques et cancérigènes. […

Glutathione <i>S</i>-transferase in chemotherapy resistance and in carcinogenesis

Cytosolic glutathione S-transferases are composed of two monomeric subunits. These monomers are the products of different gene families designated alpha, mu, and pi. Dimerization yields either homodimeric or heterodimeric holoenzymes within the same family. The members of this complex group of proteins have been linked to the detoxification of environmental chemicals and carcinogens, and have been shown to be overexpressed in normal and tumor cells following exposure to cytotoxic drugs. They also are overexpressed in carcinogen-induced rat liver preneoplastic nodules in rat liver. In all of these cases, the changes in exprssion of glutathione S-transferases are paralleled by increased resistance to cytotoxic chemicals. The degree of resistance is related to the substrate specificity of the isozyme. The relationship of the glutathione S-transferase genes to drug resistance has been directly demonstrated by gene transfer studies, where cDNAs encoding the various subunits of glutathione S-transferase have been transfected into a variety of cell types. This review discusses the results of numerous studies that associate resistance to alkylating agents with overexpression of protective detoxifying glutathione S-transferase enzymes.Key words: glutathione S-transferase, chemotherapy, carcinogenesis, alkylating agents, DNA damage. </jats:p

Canadian Experience with Fingolimod: Adherence to Treatment and Monitoring

AbstractBackground: The Canadian GILENYA® Go ProgramTM provides education and support to people with relapsing-remitting multiple sclerosis during fingolimod treatment. Methods: Data were collected and analyzed from the time of the first individual enrolled in March 2011 to March 31, 2014. Individuals were excluded if they withdrew from the program prior to receiving the first dose, or had not completed the first dose observation (FDO) at the time of data cut-off. Reports of adverse effects were validated with a database of adverse events reported to Novartis Pharmaceuticals Canada Inc. Results: A total of 2,399 individuals had completed FDO at the end of the three-year observation period. Mean age was 41.2 years; 75.2% were female. The most recent prior therapies reported were interferon-β agents (50.2%), glatiramer acetate (31.1%), natalizumab (14.2%), no prior therapy (3.3%), and other agent (1.1%). Reasons for switching to fingolimod were lack of efficacy (34.9%), side effects (34.6%), and dissatisfaction with injections/infusion (30.4%). Continuation rates with fingolimod at 12, 24 and 30 months were 80.7%, 76.6% and 76.0%, respectively. The discontinuation rate due to reported lack of efficacy during the three-year period was 1.3%. There was 94.4% adherence to the scheduled ophthalmic examination. Conclusions: The GILENYA® Go ProgramTM captures data for virtually all fingolimod-treated patients in Canada, enabling the evaluation of fingolimod use in routine practice. Ongoing patient support and reminders to take the medication, in conjunction with physicians’ and/or patients’ perception of the efficacy and tolerability of fingolimod, resulted in a high rate of continuation during longer-term therapy.</jats:p

Diagnosis and management of secondary-progressive multiple sclerosis: time for change

Identifying the transition of relapsing-remitting multiple sclerosis (MS) to the secondary-progressive MS form remains a clinical challenge due to the gradual nature of the transition, superimposed relapses, the heterogeneous course of disease among patients and the absence of validated biomarkers and diagnostic tools. The uncertainty associated with the transition makes clinical care challenging for both patients and physicians. The emergence of new disease-modifying treatments for progressive MS and the increasing emphasis of nonpharmacological strategies mark a new era in the treatment of progressive MS. This article summarizes challenges in diagnosis and management, discusses novel treatment strategies and highlights the importance of establishing a clear diagnosis and instituting an interdisciplinary management plan in the care of patients with progressive MS. </jats:p

Rate of discontinuation at the 6-, 12- and 24-month time points.

*indicates significant difference vs. fingolimod at P < 0.001; BRACE: Betaseron, Rebif, Avonex, Copaxone, and Extavia.</p