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| Keftab for menEMETINE MODULATES P-GLYCOPROTEIN FUNCTION AND UPREGULATES IT'S M-RNA EXPRESSION IN CACO-2 CELLS Mller, M. 1, Weiss, J.2, Wink, M.1 1 Institut fr Pharmazie und Molekulare Biotechnologie, Universitt Heidelberg, INF 364, D-69120 Heidelberg, Germany 2 Abteilung Innere Medizin VI, Klinische Pharmakologie und Pharmakoepidemiologie, Universitt Heidelberg, INF 410, D-69120 Heidelberg, Germany Emetine, the main alkaloid of Psychotria ipecacuanha, Rubiaceae, inhibits protein biosynthesis in human cell lines and leads to cell death by induction of apoptosis. Caco-2 cells human colon carcinoma cells ; were treated with various concentrations of emetine seven days after seeding and analysed with a tetrazolium MTT ; as well with the Neutral Red colorimetric assay to assess viability. Emetine did not show any cytotoxic effect at concentrations up to 100 M after 48 h of incubation or rather the IC50 was above 100 M. Additionally no apoptosis induction was detected after 72 h incubation via FACScan analysis of the DNA content. In contrast Jukrat T-cells have been shown to undergo apoptosis with an IC50 of 0.5 M emetine after 48 h. One reason for this considerable difference might be the expression of multidrug resistance proteins MDR ; in Caco-2 cells. Here we show, using a flow cytometry assay with rhodamine123, that emetine interferes with the efflux function of ABC transporters like MDR1. Additionally, the level of mdr1 mRNA in Caco-2 cells was increased in a concentration dependent manner which could be shown via rt-pcr. Data were confirmed by quantitative real-time pcr. In conclusion, emetine, which is a strong toxin for most cells, shows moderate toxicity in Caco-2 cells. We assume that it activates MDR1 and functions as a MDR1 substrate.
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Table 2 Number and mean length and age data used to determine the von Bertalanffy parameters for the population grouped by sex. Length cm ; mean SE ; 30.75 0.37 ; 32.28 0.55 ; 31.51 0.41 ; Age years ; mean SE ; 7.62 0.56 ; 4.92 0.54 ; 7.62 0.56.
| The notion that insomnia is a disease that should be treated with medicine is deeply ingrained in Western society. Drugs that have a calming or relaxing effect are called ataractics, sedatives, or tranquilizers, and those that are intended to induce sleep are called hypnotics or soporifics. The search for a safe and effective hypnotic probably began before recorded time. But, until early in the present century, the pharmacopeia offered only alcohol, opiates, bromides, chloral hydrate, and a few other agents--all of them unpredictable, and most of them potentially toxic and habit-forming. In 1903 the first barbiturate was synthesized. Hypnotics and sedatives of that class dominated the treatment of insomnia and anxiety neuroses from then until mid-century, when the first phenothiazines and benzodiazepines became available. Although the first dose of a barbiturate can generally put the most desperate insomniac to sleep, these drugs have many disadvantages. Because all barbiturates are habit-forming, physical dependence develops quickly. Withdrawal of a regular nighttime dose of a barbiturate after even a few days often results in rebound insomnia and cinnarizine, for example, amoxycillin.
Niels Eijkelkamp, MSc University Medical Center Utrecht, The Netherlands Niels Eijkelkamp received his MSc with honor in 2003 from the university of Utrecht Netherlands ; . During the finalization of his MSc, he did basic research i n th.
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And seek licenses for its intellectual property, her work serves as a relevant example of the potential successes that may result from the Cancer and Tobacco Related Disease Grants. Johns Hopkins Institutions Moving scientific discoveries forward is recognized as necessary and imperative in order to improve patient care and maximize findings from university-based studies funded primarily with public dollars. This is an infrastructure task that is well supported and part of the everyday work of every school at the Johns Hopkins Institutions. As a condition of the CRFP cancer research grant, the JHI has followed a Plan to Expedite Research Discoveries to the marketplace since 2000. Tracking these activities is the responsibility of Dr. Ted Poehler, Vice Provost for Research, Johns Hopkins University. The JHI have produced the following intellectual property results with funding under the CRFP from fiscal year 2001 to fiscal year 2005. Publications Forty-nine 49 ; researchers supported by the CRFP at the JHI have published one hundred and twenty 120 ; scientific articles in peer-reviewed scientific journals See Appendix D ; . Scientific publications are the primary mode of releasing new findings and applications. These publications are a sampling of investigator output most relevant to the CRF and are not intended to be comprehensive. Inventions and Discoveries To date, seven inventions initiated under the CRFP have been disclosed and moved toward development into products useful to consumers. This process is time consuming and requires significant amounts of investment until the point of cash return on a license or a product. The process from discovery to commercialization may take years and millions of dollars, depending on the discovery. Drug development tends to take the longest and is the most costly. Thus, there is considerable collaboration between the University's research offices and investigators to assure that prospects are assessed well, patents obtained, licenses sold, and other steps in the process of commercialization are taken. Table 5 below describes briefly these seven inventions and the status of each discovery.
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Centre, the research group is able to perform large, single centre clinical trials, and to participate in multi-centre clinical trials. Particular focus is put on the individual treatment response determinants. The difference in patient characteristics between a responder and a non-responder is a perfect "model" for studying progression and response ; determinants including environmental as well as patient factors. General population and cohorts are studied to detect which parameters lead to initiation of progressive renal function loss. The PREVEND cohort of 8600 subjects from the general population is a good example. This population is enriched for the presence of an increased urinary albumin excretion. The natural course is followed to study possible causes of morbidity and mortality in relation with microalbuminuria. Besides, pharmacological interventions are performed. A well-established research set-up is available for physiological studies allowing integrated assessment of renal hemodynamics and circulation physiology in healthy volunteers and specific patient populations diabetes, transplant recipients ; . This set-up enables to explore the effects of specific interventions as pharmacological probes, the role of genetic background, and gene-environment interaction as determinants of specific renal risk profiles in these populations. Various animal rat ; models of proteinuria and progressive renal disease are being studied, in order to unravel the mechanisms of therapy resistance and to optimize antiproteinuric and renoprotective treatments. To this purpose we use the following models: adriamycin nephrosis, 5 6 nephrectomy, proteinuria overload model, chronic renal transplant dysfunction, the MWF rat spontaneous proteinuria ; , a model with combined cardiac infarction ; and renal dysfunction ablation ; , as well as genetic models of hypertension and renal damage, such as the Ren2TGR. In addition, a normal rat model is used for determination of individual vascular sensitivity to damage. Measurement of in vivo renal function is combined with a diversity of ex-vivo in-vitro techniques, including: vessel perfusion, vascular rings micro macro ; , tissue receptor determination and receptor blockade, tissue protein determination and localisation, expression of relevant genes, etc. Monitoring these parameters in relation to patho ; physiology is used to unravel the mechanisms that determine progressive renal function loss. B.1.2.6 Anticipated results To establish an independent role of proteinuria in progressive renal function loss and that this is an independent target for therapy Therapeutic strategies that optimize current antiproteinuric ; renoprotective therapy in each patient, by both environmental and patient modifications, to be done both in patients with renal disease and in patients with chronic transplant failure To establish an independent role of microalbuminuria as an independent target for therapy to stop cardiovascular and renal morbidity and mortality. To establish the role of renal hemodynamics as a primary and secondary trigger for renal function loss To establish the role of renal hemodynamics as a target for intervention in prevention of progressive renal function loss and propulsid.
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