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Isepamicin and nephrotoxicity

Isepamicin and nephrotoxicity. Paul M. Tulkens Unité de pharmacologie cellulaire et moléculaire Université catholique de Louvain Brussels, Belgium. Isepamicin and nephrotoxicity. Lets do a Medline Search … isepamicin 142 isepamicin and nephrotox* 12

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Isepamicin and nephrotoxicity

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  1. Isepamicin and nephrotoxicity Paul M. Tulkens Unité de pharmacologie cellulaire et moléculaire Université catholique de Louvain Brussels, Belgium isepamicin nephtotoxicity

  2. Isepamicin and nephrotoxicity Lets do a Medline Search … • isepamicin 142 • isepamicin and nephrotox* 12 • amikacin 4005 • amikacin and nephrotox* 245 • gentamicin 11525 • gentamicin and nephrotox* 908 isepamicin nephtotoxicity

  3. The birth of isepamicin…1 Diaminocyclitol derivatives.Wright, John J.; Daniels, Peter John L. (Scherico Ltd., Switz.). Ger. Offen. (1975), 65 pp. CODEN: GWXXBX DE 2502296 19750925 Patent written in German. Application: DE Priority: US 74-452571 19740319. Bactericides, 1-N-(S-4-amino-2-hydroxybutyryl) sisomicin, -gentamicin B,-verdamicin, and -gentamicin C1a, effective at 1-15 mg/kg doses, were prepd. by treatment of sisomicin, gentamicin, or verdamicin derivs. with N-(S-4-phthalimido- or -trifluoroacetamido-2-hydroxybutyryloxy) succinimide. 1-N-(S-3-amino-2-hydroxypropionyl)gentamicin C1 was similarly prepd. isepamicin nephtotoxicity

  4. The birth of isepamicin…2 Nagabhushan, T. L.; Cooper, A. B.; Tsai, H.; Daniels, P. J. L.; Miller, G. H. Schering Corp., Bloomfield, N. J., USA. J. Antibiot. (1978), 31(7), 681-7. The syntheses and biological properties of 1-N-(S-4-amino-2-hydroxybutyryl)gentamicin B and 1-N-(S-3-amino-2-hydroxypropionyl)gentamicin B. isepamicin nephtotoxicity

  5. Why isepamicin ? (1) OH OH O HO OH H N HO 2 O HO OH NH 2 O O NH 2HN 2 kanamycin A isepamicin nephtotoxicity

  6. Why isepamicin ? (2) 3’ OH OH O HO OH H N HO 2 O HO OH NH 2 O O NH 2” 2HN 2 6’ 3 resistance to kanamycin A isepamicin nephtotoxicity

  7. 3’ OH OH O HO OH H N HO 2 O HO OH NH 2 O O HN NH 2” 2 NH 6’ HOHC 2 3 Why isepamicin ? (3) amikacin A isepamicin nephtotoxicity

  8. Why isepamicin ? (4) OH O H C 3 HN H N O CH HO 2 2 OH CH 3 O NH O 2 H N NH 2 2 gentamicin C1a isepamicin nephtotoxicity

  9. garosamine 2’, 3’, 4’ hydroxy = gentamicin c = netillmicin = sisomicin Why isepamicin ? (5) = kanamycin A = amikacin OH OH O H C 3 OH HN HO O CH HO 2 OH CH 3 O NH 2 O H N NH 2 2 gentamicin B isepamicin nephtotoxicity

  10. Why isepamicin ? (5) 3’ OH OH O H C 3 OH HN HO O CH HO 2 OH CH 3 O NH 2 O H N NH 2 2 2” 6’ 3 resistance to gentamicin B isepamicin nephtotoxicity

  11. 3’ OH OH O H C 3 OH HN HO O CH HO 2 OH CH 3 O NH 2 O HN NH 2 6’ HOHC NH 2 3 Why isepamicin ? (6) making an ”amikacin-like” gentamicin B... isepamicin nephtotoxicity

  12. OH OH O HO OH H N HO 2 O HO OH NH OH 2 O O HN NH 2 OH O H C NH 3 OH HOHC 2 HN HO O CH HO 2 OH CH 3 O NH 2 O HN NH 2 HOHC NH 2 The nearly (but not entirely) twins... Quizz ... which is amikacin, which is isepamicin… ??? isepamicin nephtotoxicity

  13. Aminoglycoside nephrotoxicity Incidence: 0-50% - patient factors - drug factors gentamicin netilmicin amikacin isepamicin - schedule of administration - concomitant drugs isepamicin nephtotoxicity

  14. Proximal tubular cells of rats (10 mg/kg.day gentamicin for 7 days) Kosek et al [1974] Lab. Invest 30: 48-57 isepamicin nephtotoxicity

  15. Aminoglycoside nephrotoxicity sequence ... • AG uptake (adsorbtive pinocytosis) by proximal tubular cells • AG transport, accumulation to lysosomes, and development of a lysosomal phospholipidosis • Rupture (?) of lysosomes, cell necrosis, phospholipiduria • Tubular necrosis / tubular regeneration • Acute tubular necrosis • Non-oliguric renal failure isepamicin nephtotoxicity

  16. Protection against aminoglycoside nephrotoxicity(see more in AAC 43:1008, 1999) once-a-day schedule • reduce uptake (adsorbtive pinocytosis) • reduce phospholipidosis • stabilize lysosomes and / or prevent the damaging effects of lysosomal rupture • promote cellular regeneration and tissue repair • protect againts glomerular effects polyaspartic acid desferrioxamine and oxydant scavengers growth factors corticoids, saline isepamicin nephtotoxicity

  17. Can better aminoglycosides exist ? (see also more in AAC 43:1008, 1999) tobramycin amikacin isepamicin • reduce uptake (adsorbtive pinocytosis) • reduce phospholipidosis • stabilize lysosomes and / or prevent the damaging effects of lysosomal rupture • promote cellular regeneration and tissue repair • protect againts glomerular effects amikacinisepamicin netilmicin ?? ? ? isepamicin nephtotoxicity

  18. Lower uptake, lesser phospholipidosis ... C = saline G = gentamicin N = netilmicin A = amikacin I = isepamicin SD rats 10 mg/kg 10 days isepamicin nephtotoxicity

  19. Aminoglycoside-phospholipid interactions leading to inhibition of lysosomal phospholipase activity isepamicin nephtotoxicity

  20. Experimental (belgian) studies on isepamicin toxicity …1... Schanck A, Mingeot-Leclercq MP, Tulkens PM, Carrier D, Smith IC, Jarrell HC. Interactions of aminoglycoside antibiotics with phospholipids. A deuterium nuclear magnetic resonance study. Chem Phys Lipids. 1992 Sep;62(2):153-63. Mingeot-Leclercq MP, Tulkens PM, Brasseur R.Accessibility of aminoglycosides, isolated and in interaction with posphatidylinositol, to water. A conformational analysis using the concept of molecular hydrophobicity potential.Biochem Pharmacol. 1992 Nov 17;44(10):1967-75. isepamicin nephtotoxicity

  21. OH OH O H C 3 OH HN HO O HO OH CH NH 3 2 O O HN NH 2 R OH OH OH O H C 3 OH H N HO 2 O HO OH NH 2 O O HN NH 2 OH R OH OH O H C 3 OH H N HO 2 O HO OH NH 2 O O H N NH 2 2 OH OH OH O H C 3 OH H N H N 2 O HO 2 OH NH 2 O O H N NH 2 2 Isepamicin interacts less with phospolipids ... 15N NMR Studies (interactions of amines with phospholipids) AG + PI AG alone 3 isepa 6’ 3” 5 3 3” amika 6’ 5 6’ 1 3 kana A 3” 3 1 3” kana B 6’ 2’ isepamicin nephtotoxicity

  22. Isepamicin interacts less with phospolipids ... deuteriumNMR Studies (segregation of PI in membrane plane) DPPC d62 control DPPCd62:PI 1:1 control + Kanamycin B + Kanamycin A + Amikacin + Isepamicin isepamicin nephtotoxicity

  23. Aminoglycoside-phospholipid interactions: correlation between the theoretical and experimental studies Aminoglycoside isepamicin amikacin kanamycin A kanamycin B Interaction detected by equilibrium dialysis Kd (µM) 47 30 7 6 Interaction detected by 15N NMR weak medium medium strong Calculated interaction (KJ / mol) - 23.4 - 35.7 - 46.8 - 48.5 isepamicin nephtotoxicity

  24. Gentamicin 100 Isepamicin 80 60 Release of lysophosphatidylcholine (% control) IC50 = 220 µM IC50 = 100 µM 40 20 0 0 100 200 300 400 Drug concentration (µM) Isepamicin inhibits less the lysosomal phospholipases A1 IC50 for amikacin = 205 µM isepamicin nephtotoxicity

  25. The Japanese trip of isepamicin… • everything you’d like to know, the japanese way, on • microbiology, • pharmacology, • toxicology, • etc... • Jpn J Antibiot. 1986 Dec;39(12) • Jpn J Antibiot. 1987 Jan;40(1) isepamicin nephtotoxicity

  26. Experimental (belgian) studies on isepamicin toxicity …2... Van Bambeke F, Mingeot-Leclercq MP, Schanck A, Brasseur R, Tulkens PM. Alterations in membrane permeability induced by aminoglycoside antibiotics: studies on liposomes and cultured cells. Eur J Pharmacol. 1993 Oct 15;247(2):155-68. Van Bambeke F, Mingeot-Leclercq MP, Brasseur R, Tulkens PM, Schanck A. Aminoglycoside antibiotics prevent the formation of non-bilayer structures in negatively-charged membranes. Comparative studies using fusogenic (bis(beta-diethylaminoethylether)hexestrol) and aggregating (spermine) agents. Chem Phys Lipids. 1996 Mar 29;79(2):123-35. isepamicin nephtotoxicity

  27. Experimental (belgian) studies on isepamicin toxicity …3... reviewed in Mingeot-Leclercq and Tulkens, 1999, AAC 43:1003-1012 isepamicin nephtotoxicity

  28. Amikacin / Isepamicin animal and clinical studies at UCL • rat studies (0-100 mg/kg): • low cortical accumulation • low phospholipid accumulation • low incidence of necrosis/regeneration • human studies (young female subjects; 15 mg/kg) • minimal phospholipiduria • no sign of renal dysfunction isepamicin nephtotoxicity

  29. Conclusions of the modelling, in vitro, animal and human studies of isepamicin at UCL / ULB / Gembloux Isepamicin is systematically either similar or better than amikacin ... tip... • Accepted toxicity ranking * • gentamicin > tobramycin > amikacin • gentamicin > netilmicin • -----------* at equal level of risk factors isepamicin nephtotoxicity

  30. The European clinical scene… 1 ... Carbon, C. Overview of the efficacy of isepamicin in the adult core clinical trial program.J. Chemother. (Florence) (1995), 7(Suppl. 2), 79-85. Beaucaire, G. Evaluation of the efficacy and safety of isepamicin compared with amikacin in the treatment of nosocomial pneumonia and septicemia. J. Chemother. (Florence) (1995), 7(Suppl. 2), 165-73. Sturm-W Isepamicin versus amikacin in the treatment of urinary tract infection. J-Chemother. 1995 Jun; 7 Suppl 2: 149-54 isepamicin nephtotoxicity

  31. The European clinical scene… 2…. Vigano-A; Principi-N A randomised comparison of isepamicin and amikacin in the treatment of bacterial infections in paediatric patients. J-Chemother. 1995 Jun; 7 Suppl 2: 95-101 Covi-M; Velluti-G Comparison of the efficacy and safety of isepamicin and amikacin in the treatment of acute lower respiratory tract infections caused by gram-negative organisms. J-Chemother. 1995 Jun; 7 Suppl 2: 137-42 Colardyn-F The efficacy and safety of isepamicin and ceftazidime compared with amikacin and ceftazidime in acute lower respiratory tract infection. J-Chemother. 1995 Jun; 7 Suppl 2: 129-35 isepamicin nephtotoxicity

  32. The European clinical scene… 3…. Tod-M; Minozzi-C; Beaucaire-G; Ponsonnet-D; Cougnard-J; Petitjean-O Isepamicin in intensive care unit patients with nosocomial pneumonia: population pharmacokinetic-pharmacodynamic study. J-Antimicrob-Chemother. 1999 Jul; 44(1): 99-108 isepamicin nephtotoxicity

  33. Conclusions of the (limited) european clinical evaluation Isepamicin is systematically similar or better than amikacin ... • Accepted toxicity ranking: • gentamicin > tobramycin > amikacin • gentamicin > netilmicin • -----------* at equal level of risk factors tip... isepamicin nephtotoxicity

  34. Very recent experimental (Belgian) data ... El Mouedden M, Laurent G, Mingeot-Leclercq MP, Taper HS, Cumps J, Tulkens PM. Apoptosis in renal proximal tubules of rats treated with low doses of aminoglycosides. Antimicrob Agents Chemother. 2000 Mar;44(3):665-75. isepamicin nephtotoxicity

  35. Evidence of apoptosis in proximal tubular cells Laurent et al., AAC, 1983 Gentamicin 10 mg/kg 10 days; HE staining isepamicin nephtotoxicity

  36. Evidence of apoptosis in proximal tubular cells: histology HE staining methyl green-pyronin El Mouedden et al., 2000 gentamicin 10 mg/kg, 10 days isepamicin nephtotoxicity

  37. Evidence of apoptosis in proximal tubular cells: TUNEL staining El Mouedden et al., 2000 gentamicin 10 mg/kg, 10 days isepamicin nephtotoxicity

  38. Aminoglycoside-induced apoptosis occurs at low doses ... † * 250 200 150 TUNEL (+) nuclei (no. / sq mm) 100 * 50 El Mouedden et al., 2000 0 0 10 20 Gentamicin daily dosage (mg/kg) isepamicin nephtotoxicity

  39. AG-induced apoptosis severity varies among derivatives ... 150 b 100 b,d gm = gentamicin nt = netilmicin is = isepamicin am = amikacin a,d a,d 50 a TUNEL (+) nuclei DNA specific (no./sq mm) radioactivity 0 b 80 60 c 40 d d a 20 El Mouedden et al., 2000 0 ct gm nt is am isepamicin nephtotoxicity

  40. Aminoglycosides also induce apoptosis in cultured cells ... LLC-PK1 fibroblasts cells (R = 0.943) MDCK cell lines (R = 0.954) LLC-PK1 cell lines (R = 0.945) 30 Apoptosis (% of TUNEL (+) nuclei) 20 MDCK 10 0 0 20 40 60 gentamicin accumulation (µg/mg prot.) Fibroblasts El Mouedden, 2000 isepamicin nephtotoxicity

  41. Conclusions of the apoptosis studies (kidney and cultured cells) Isepamicin is systematically similar or better than amikacin ... • apoptosis ranking: • gentamicin > tobramycin > amikacin • gentamicin > netilmicin tip... isepamicin nephtotoxicity

  42. The isepamicin UCL / ULB / Gembloux team ... P. Maldague P. Lambricht K. Matsumoto M. El Mouedden M.P. Mingeot B.K. Kishore M. Dellale F. Van Bambeke B. Carlier R. Brasseur G. Laurent J.M. Ruysschaert ... isepamicin nephtotoxicity

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