Table 2.

Main approaches toward reduction of aminoglycoside nephrotoxicitya

MechanismCompound
I. Decrease or prevention of drug accumulation by kidneys
 Intracellular complexation of aminoglycosides
  Polyanionic compoundsDextran sulfate (59)
Inositol hexasulfate (67)
  Acidic drugsPiperacillin (44)
Latamoxef-moxalactam (68)
Fosfomycin (33, 54)
Pyridoxal-5′-phosphate (114)
 Competition with or decrease in aminoglycoside binding to brush border membrane
  Raising the urine pHBicarbonate (19, 29)
  CompetitorsCa2+ (diet supplementation [51] or vitamin D-induced hypercalcemia [21])
Lysine (81)
Aminoglycosides (as their own competitors) (39)
 Increase in exocytosisFleroxacin (9)
II. Prevention or decrease of lysosomal phospholipase inhibition
 Derivatives with lesser intrinsic bindingb
  N substitutionAmikacin (75), isepamicin (133), arbekacin,c 1- N - and 6′- N -peptidic and aminoacid derivative of kanamycin A and netilmicin (72)
  Other substitution6"-substituted kanamycin B (88)
  Fluorinated derivativesc 5, 3"′ or 3′ fluoro derivatives of tobramycin, dibekacin, arbekacin, or kanamycinc
  Disaccharidic aminoglycosidesAstromicin (fortimicin) (73)
Dactimicin (2- N "-formidoyl-astromicin) (53,73)
 Coadministration of agent preventing intralysosomal phospholipidosis
  Intralysosomal sequestration of aminoglycosidesPolyaspartic acid (55, 62)
  Increase of membrane negative chargeDaptomycin (41)
  OtherTorbafylline (32)
III. Protection against necrosis and other gross cellular alterations
 AntioxidantsDeferroxamine (11)
Methimazole (24)
Sairei-to (94)
Vitamin E + selenium, vitamin C (1, 57)
Lower copper feeding (58)
 Antioxidant and multifactorial factorsLipoic acid (107)
IV. Protection against vascular and glomerular effects
 Suppression of renin-angiotensin activationDeoxycortisone and saline drinking (45)
 Protection against Ca2+ influxCa2+ channel blockers (80)
 Undefined mechanismPlatelet activation antagonists (104)
V. Increase in kidney regeneration capabilities
 Unspecific mitogenic effectUlinastatin (92)
 Growth factorsFibroblast growth factor 2 (78)
Heparin-binding epidermal growth factor (106)
  • a References refer to publications dealing with the proposed mechanism; see text for further details on the extent and characterization of the protection.

  • b See reference 83 for structures.

  • c Mechanism is assumed on the basis of the substitution made (see reference 83 for a discussion and references to original papers), but it has not actually examined.