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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 17/01/2001

2 Isepamicin and nephrotoxicity
Lets do a Medline Search … isepamicin isepamicin and nephrotox* amikacin amikacin and nephrotox* 245 gentamicin gentamicin and nephrotox* 908 isepamicin nephtotoxicity 17/01/2001

3 The birth of isepamicin…1
Diaminocyclitol derivatives. Wright, John J.; Daniels, Peter John L. (Scherico Ltd., Switz.). Ger. Offen. (1975), pp. CODEN: GWXXBX DE Patent written in German. Application: DE Priority: US 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 17/01/2001

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), 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 17/01/2001

5 isepamicin nephtotoxicity
Why isepamicin ? (1) OH OH O HO H N OH 2 HO HO O OH NH O 2 O 2HN NH 2 kanamycin A isepamicin nephtotoxicity 17/01/2001

6 isepamicin nephtotoxicity
Why isepamicin ? (2) 3’ OH OH O HO H N OH 2 HO HO O OH NH O 2 O 2” 2HN NH 2 6’ 3 resistance to kanamycin A isepamicin nephtotoxicity 17/01/2001

7 isepamicin nephtotoxicity
Why isepamicin ? (3) 2” 3 3’ O HO NH 2 H N OH HN HOHC 6’ amikacin A isepamicin nephtotoxicity 17/01/2001

8 isepamicin nephtotoxicity
Why isepamicin ? (4) OH O H C 3 HN H N HO O CH 2 2 OH CH 3 O NH H N O NH 2 2 2 gentamicin C1a isepamicin nephtotoxicity 17/01/2001

9 isepamicin nephtotoxicity
Why isepamicin ? (5) garosamine = gentamicin c = netillmicin = sisomicin 2’, 3’, 4’ hydroxy = kanamycin A = amikacin OH OH O H C 3 HN OH HO HO O CH 2 OH CH 3 O NH 2 H N O NH 2 2 gentamicin B isepamicin nephtotoxicity 17/01/2001

10 isepamicin nephtotoxicity
Why isepamicin ? (5) 3’ OH OH O H C 3 HN OH HO HO O CH 2 OH CH 3 O NH H N O NH 2 2” 2 2 6’ 3 resistance to gentamicin B isepamicin nephtotoxicity 17/01/2001

11 isepamicin nephtotoxicity
Why isepamicin ? (6) O CH 2 HO NH OH HN H 3 C HOHC 6’ 3’ making an ”amikacin-like” gentamicin B... isepamicin nephtotoxicity 17/01/2001

12 The nearly (but not entirely) twins...
HO NH 2 H N OH HN HOHC O CH 2 HO NH OH HN H 3 C HOHC Quizz ... which is amikacin, which is isepamicin… ??? isepamicin nephtotoxicity 17/01/2001

13 Aminoglycoside nephrotoxicity
Incidence: 0-50% - patient factors - drug factors gentamicin netilmicin amikacin isepamicin - schedule of administration - concomitant drugs isepamicin nephtotoxicity 17/01/2001

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 17/01/2001

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 17/01/2001

16 isepamicin nephtotoxicity
Protection against aminoglycoside nephrotoxicity (see more in AAC 43:1008, 1999) 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 once-a-day schedule polyaspartic acid desferrioxamine and oxydant scavengers growth factors corticoids, saline isepamicin nephtotoxicity 17/01/2001

17 isepamicin nephtotoxicity
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 amikacin isepamicin netilmicin ?? ? ? isepamicin nephtotoxicity 17/01/2001

18 Lower uptake, lesser phospholipidosis ...
C = saline G = gentamicin N = netilmicin A = amikacin I = isepamicin SD rats 10 mg/kg 10 days isepamicin nephtotoxicity 17/01/2001

19 isepamicin nephtotoxicity
Aminoglycoside-phospholipid interactions leading to inhibition of lysosomal phospholipase activity isepamicin nephtotoxicity 17/01/2001

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 Sep;62(2): 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 Nov 17;44(10): isepamicin nephtotoxicity 17/01/2001

21 isepamicin nephtotoxicity
Isepamicin interacts less with phospolipids N NMR Studies (interactions of amines with phospholipids) O H 2 N NH OH 3 C HO HN CH R AG alone AG + PI 3 isepa 3” 6’ 5 3 amika 3” 5 6’ 1 6’ kana A 3 3” 1 3 3” kana B 6’ 2’ isepamicin nephtotoxicity 17/01/2001

22 isepamicin nephtotoxicity
Isepamicin interacts less with phospolipids ... deuteriumNMR Studies (segregation of PI in membrane plane) DPPC d control DPPCd62:PI 1:1 control + Kanamycin B + Kanamycin A + Amikacin + Isepamicin isepamicin nephtotoxicity 17/01/2001

23 isepamicin nephtotoxicity
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 strong Calculated interaction (KJ / mol) - 23.4 - 35.7 - 46.8 - 48.5 isepamicin nephtotoxicity 17/01/2001

24 Isepamicin inhibits less the lysosomal phospholipases A1
100 200 300 400 Drug concentration (µM) 20 40 60 80 lysophosphatidylcholine Release of (% control) Gentamicin Isepamicin IC50 = 220 µM 100 µM IC50 for amikacin = 205 µM isepamicin nephtotoxicity 17/01/2001

25 The Japanese trip of isepamicin…
everything you’d like to know, the japanese way, on microbiology, pharmacology, toxicology, etc... Jpn J Antibiot Dec;39(12) Jpn J Antibiot Jan;40(1) isepamicin nephtotoxicity 17/01/2001

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 Oct 15;247(2): 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 Mar 29;79(2): isepamicin nephtotoxicity 17/01/2001

27 Experimental (belgian) studies on isepamicin toxicity …3...
reviewed in Mingeot-Leclercq and Tulkens, 1999, AAC 43: isepamicin nephtotoxicity 17/01/2001

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 17/01/2001

29 isepamicin nephtotoxicity
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 17/01/2001

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), 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), Sturm-W Isepamicin versus amikacin in the treatment of urinary tract infection. J-Chemother Jun; 7 Suppl 2: isepamicin nephtotoxicity 17/01/2001

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 Jun; 7 Suppl 2: 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 Jun; 7 Suppl 2: Colardyn-F The efficacy and safety of isepamicin and ceftazidime compared with amikacin and ceftazidime in acute lower respiratory tract infection. J-Chemother Jun; 7 Suppl 2: isepamicin nephtotoxicity 17/01/2001

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 Jul; 44(1): isepamicin nephtotoxicity 17/01/2001

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 17/01/2001

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 Mar;44(3): isepamicin nephtotoxicity 17/01/2001

35 Evidence of apoptosis in proximal tubular cells
Laurent et al., AAC, 1983 Gentamicin 10 mg/kg 10 days; HE staining isepamicin nephtotoxicity 17/01/2001

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 17/01/2001

37 Evidence of apoptosis in proximal tubular cells: TUNEL staining
El Mouedden et al., 2000 gentamicin 10 mg/kg, 10 days isepamicin nephtotoxicity 17/01/2001

38 Aminoglycoside-induced apoptosis occurs at low doses ...
* 250 200 150 TUNEL (+) nuclei (no. / sq mm) 100 * 50 El Mouedden et al., 2000 10 20 Gentamicin daily dosage (mg/kg) isepamicin nephtotoxicity 17/01/2001

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 b 80 60 40 c d d a 20 El Mouedden et al., 2000 ct gm nt is am isepamicin nephtotoxicity 17/01/2001

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 20 40 60 gentamicin accumulation (µg/mg prot.) Fibroblasts El Mouedden, 2000 isepamicin nephtotoxicity 17/01/2001

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 17/01/2001

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 17/01/2001


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