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Aminoglycoside nephrotoxicity: from molecular pharmacology and pathology to some applications

Aminoglycoside nephrotoxicity: from molecular pharmacology and pathology to some applications. Paul M. Tulkens, MD, PhD Unité de Pharmacologie Cellulaire et Moléculaire Université Catholique de Louvain Brussels, Belgium. Aminoglycosides. highly bactericidal and wide spectrum

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Aminoglycoside nephrotoxicity: from molecular pharmacology and pathology to some applications

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  1. Aminoglycoside nephrotoxicity: from molecular pharmacology and pathology to some applications Paul M. Tulkens, MD, PhD Unité de Pharmacologie Cellulaire et Moléculaire Université Catholique de Louvain Brussels, Belgium

  2. Aminoglycosides... • highly bactericidal and wide spectrum • post-antibiotic effect • synergistic with beta-lactams • dose proportionate PKs • no metabolism and 95 % renal excretion • BUT… • neuro-muscular blockade (high doses) • nephrotoxicity • ototoxicity (irreversible)

  3. Aminoglycosides... • cytological and molecular mechanisms of nephrotoxicity • the “once-a-day” schedule • polyaspartic acid • recent data on apoptosis

  4. Evidence of apoptosis in proximal tubular cells Gentamicin 10 mg/kg 10 days; HE staining

  5. Evidence of apoptosis in proximal tubular cells: histology HE staining methyl green-pyronin gentamicin 10 mg/kg, 10 days

  6. Evidence of apoptosis in proximal tubular cells: TUNEL staining gentamicin 10 mg/kg, 10 days

  7. Apoptosis in proximal tubular cells:quantification and correlation between TUNEL and Brachet

  8. Apoptosis in proximal tubular cells:correlation with tubular/peritubular proliferation

  9. Apoptosis in cultured cells: EM chromatin condensation rat embryo fibroblats gentamicin 2 mM 4 days apoptotic body

  10. Apoptosis in cultured cells:DNA size analysis (agarose electrophoresis) control GM 2mM 4 days fibroboblats 1 2 MDCK cells 3 4 LLC-PK1 cells 5 6

  11. Gentamicin-induced apoptosis in cultured cells:Quantification by TUNEL

  12. Gentamicin-induced apoptosis in cultured cells:correlation with gentamicin accumulation

  13. Gentamicin-induced apoptosis in cultured cells:correlation with phospholipidosis

  14. Modulation of gentamicin-induced apoptosis in cultured cells • blocked by cycloheximide (fibroblasts and MDCK-cells) (LLC-PK1 cells show apoptosis with CH) • blocked by over-expression of BCl-2 protein in bcl-2 transfected cells (MDCK- and LLC-PK1 cells) • associated with increased caspase-3 activity (MDCK cells) • blocked by caspase-3 inhibitor ZVAD.fmk (MDCK-cells)

  15. Aminoglycosides... cytological and molecular mechanisms of nephrotoxicity G. Laurent B. Carlier R. Brasseur J.M. Ruysschaert Starting in the early 80’s ...

  16. Aminoglycosides... The once-a-day story... S. Ibrahim P. Maldague B. Carlier G. Laurent D. Beauchamp … and many others In the mid 80’s ...

  17. Aminoglycosides... The poly-aspartic acid saga... Z. Kallay B.K. Kishore J. Piret S. Ibrahim P. Maldague D. Beauchamp … and many others Early 90’s ...

  18. Aminoglycosides... The apoptosis finale ... P. Maldague (+ 1994) M. El Mouedden H. Taper M.P. Mingeot G. Laurent M. Dellale The 90’s ...

  19. Aminoglycosides... Where has that been published ? • So many papers, but start with two last reviews: • Mingeot-Leclercq, M.P. and Tulkens, P.M.: Aminoglycosides: nephrotoxicity. Antimicrob. Agents Chemother. 43: 1003-1012, 1999. • Mingeot-Leclercq, M.P., Glupczynski, Y. and Tulkens, P.M.: Aminoglycosides: activity and resistance. Antimicrob. Agents Chemother. 43: 727-737, 1999.

  20. Aminoglycosides... Where has that been published ? and then, make a Medline Search on the following names (a selection): • Laurent-G • Kishore-BK • Mingeot-Leclercq-MP • Carlier-MB • Beauchamp-D • Piret-J • Van-der-Auwera-P • …. • Lambricht-P • Wagner-R • Vanschepdael-A • Claes-JP • Vanderhaeghe-HJ • Langhendries-M • Porter-G • ...

  21. Aminoglycosides... Or, just come and visit us...

  22. Aminoglycosides... But, where is that ? Cellular and Molecular Pharmacology Unit Catholic University of Louvain, Belgium http://www.md.ucl.ac.be/facm

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