Drug and Alcohol Rehabilitation: Metformin Inhibits the Inflammatory Response Associated With Cellular Transformation and Cancer Stem Cell Growth.

Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth.

Filed under: Drug and Alcohol Rehabilitation

Proc Natl Acad Sci U S A. 2012 Dec 31;
Hirsch HA, Iliopoulos D, Struhl K

Metformin, the first-line drug for treating diabetes, inhibits cellular transformation and selectively kills cancer stem cells in breast cancer cell lines. In a Src-inducible model of cellular transformation, metformin inhibits the earliest known step in the process, activation of the inflammatory transcription factor NF-?B. Metformin strongly delays cellular transformation in a manner similar to that occurring upon a weaker inflammatory stimulus. Conversely, inhibition of transformation does not occur if metformin is added after the initial inflammatory stimulus. The antitransformation effect of metformin can be bypassed by overexpression of Lin28B or IL1?, downstream targets of NF-?B. Metformin preferentially inhibits nuclear translocation of NF-?B and phosphorylation of STAT3 in cancer stem cells compared with non-stem cancer cells in the same population. The ability of metformin to block tumor growth and prolong remission in xenografts in combination with doxorubicin is associated with decreased function of the inflammatory feedback loop. Lastly, metformin-based combinatorial therapy is effective in xenografts involving inflammatory prostate and melanoma cell lines, whereas it is ineffective in noninflammatory cell lines from these lineages. Taken together, our observations suggest that metformin inhibits a signal transduction pathway that results in an inflammatory response. As metformin alters energy metabolism in diabetics, we speculate that metformin may block a metabolic stress response that stimulates the inflammatory pathway associated with a wide variety of cancers.
HubMed – drug

Implementing a pharmacovigilance program to evaluate cutaneous adverse drug reactions in an antiretroviral access program.

Filed under: Drug and Alcohol Rehabilitation

J Infect Dev Ctries. 2012; 6(11): 806-8
Mudzviti T, Sibanda M, Gavi S, Maponga CC, Morse GD

Cutaneous adverse drug reactions (cADRs) can cause significant morbidity and distress in patients, especially in the HIV-infected population on antiretroviral therapy. Adverse drug reaction monitoring and ascertaining causality in resource-limited settings remain serious challenges. This study was conducted to evaluate causality and measure the incidence of cADRs in HIV-infected patients on highly active antiretroviral therapy. The study was also designed to test a three-step approach in the monitoring and evaluation of ADRs in resource-limited settings.A retrospective review of patient medical records was performed at the Parirenyatwa Family Care Centre, Harare, Zimbabwe. Cases of cADRs were reported to the Medicines Control Authority of Zimbabwe, the main drug regulating body in Zimbabwe, for assessment and causality classification.We reviewed 221 randomly selected patient records to determine whether any diagnoses of cADRs were made by clinicians. Causality assessment revealed that 13.1% of cADRs were due to an offending agent in the antiretroviral therapy versus an initial incidence of 17.6% which had been determined by the physicians.cADRs had an incidence of 13.1% within the population under study due to non nucleoside reverse transcriptase inhibitors (NNRTIs). Most reactions were caused by the NNRTIs which contributed 72.4 % of all cADRs. A panel of experts from the drug regulatory authority can be used as an implementation based mechanism in ascertaining causality objectively in settings where resources are constrained.
HubMed – drug

Oncogenic driver mutations in patients with non-small-cell lung cancer at various clinical stages.

Filed under: Drug and Alcohol Rehabilitation

Ann Oncol. 2012 Dec 30;
Zhou JX, Yang H, Deng Q, Gu X, He P, Lin Y, Zhao M, Jiang J, Chen H, Lin Y, Yin W, Mo L, He J

BackgroundOncogenic driver mutations are responsible for the initiation and maintenance of non-small-cell lung cancer (NSCLC). Elucidation of driver mutation occurrence in NSCLC has important clinical implications.Patients and methodsNSCLC at various clinical stages were studied for their oncogenic mutations and their association with patients’ disease-free survival (DFS).ResultsOf 488 patients with NSCLC, 28 had EML4-ALK fusions. Female, young age (<60 years old), and nonsmoker patients had significant greater mutation frequencies than male, old age (?60 years old), and smoker patients, respectively (P<0.05). Of 392 patients with NSCLC, 13 had PIK3CA mutations and 3 had MEK1 mutations. EML4-ALK, PIK3CA, and MEK1 mutations were mutually exclusive. EML4-ALK fusion was found to be of coexistence with EGFR and KRAS mutations in two cases. In stage IA NSCLC, EML4-ALK-positive patients had longer DFS than EML4-ALK-negative patients (P = 0.04). However, in stage IIIA NSCLC, EML4-ALK-positive patients had poorer DFS than EML4-ALK-negative patients (P < 0.01). Moreover, multivariate analysis indicated that in stage IIIA NSCLC EML4-ALK fusion was the only significant indicator for poor DFS (P < 0.001). Furthermore, tumors with EML4-ALK fusions had significantly higher levels of ERCC1, a molecule with a key role in platinum drug efficacy, than tumors without EML4-ALK fusions.ConclusionEML4-ALK, PIK3CA, and MEK1 mutations occurred in NSCLC with various distinct clinicopathological characteristics. EML4-ALK fusions could serve as a significant prognostic indicator for locally advanced NSCLC. HubMed – drug

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