WO1988004925A1 - Protection contre la nephrotoxicite induite par un aminoglycoside - Google Patents

Protection contre la nephrotoxicite induite par un aminoglycoside Download PDF

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Publication number
WO1988004925A1
WO1988004925A1 PCT/US1987/003468 US8703468W WO8804925A1 WO 1988004925 A1 WO1988004925 A1 WO 1988004925A1 US 8703468 W US8703468 W US 8703468W WO 8804925 A1 WO8804925 A1 WO 8804925A1
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drug composition
gentamicin
compound
aminoglycoside
radical scavenger
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PCT/US1987/003468
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English (en)
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Patrick D. Walker
Sudhir V. Shah
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The Administrators Of The Tulane Educational Fund
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Priority to JP88501216A priority Critical patent/JPH01502268A/ja
Publication of WO1988004925A1 publication Critical patent/WO1988004925A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes

Definitions

  • the present invention is directed to the in vivo use of compounds that prevent the generation of, effectively scavenge, or detoxify a reactive oxygen metabolite that mediates a toxic effect of an aminoglycoside.
  • the compounds of the invention include agents which prevent the generation of, effectively scavenge, or detoxify free radicals such as the hydroxyl radical, or their metabolic precursors such as hydrogen peroxide and superoxide radical.
  • compounds that are hydroxyl radical scavengers can provide protection against the nephrotoxicity of aminoglycosides.
  • compounds which are iron chelators can reduce aminoglycoside- induced renal damage.
  • aminoglycoside antibiotics e.g., streptomycin, gentamicin, kanamycin, tobramycin, etc.
  • aminoglycosides all contain amino sugars in glycosidic linkage to a hexose (aminocyclitol) nucleus.
  • the hexose is either streptidine (in streptomycin) or 2-deoxystreptamine.
  • Aminoglycoside families are distinguished on the basis of the amino sugars attached to the hexose (Goodman and Gilman, eds., 1980, The Pharmacological Basis of Therapeutics, 6th Ed., Ch. 51, pp. 1162-1199).
  • the rapid bactericidal action of the aminoglycoside antibiotics occurs by inhibition of protein synthesis in susceptible microorganisms.
  • Some susceptible microorganisms include Escherichia spp., Haemophilus spp., Listeria spp., Pseudomonas spp., Nocardia spp., Yersinia spp., Klebsiella spp., Enterobacter spp., Salmonella spp., Staphyloccocus spp., Streptococcus spp., Mycobacteria spp., Shigella spp., and Serratia spp., to name but a few. Protein synthesis inhibition appears to occur by a direct action on the 30S ribosomal subunit, causing interference with translation, initiation, and misreading of the genetic code (Goodman and Gilman, supra).
  • aminoglycosides are cationic at physiological pH, with the degree of cationicity being a function of both the number of amino groups present and their positions within the molecule.
  • the polarity of the aminoglycosides is primarily responsible for the pharmacokinetic properties shared by the members of the group. For instance, these drugs are not adequately absorbed after oral administration, they do not easily penetrate the cerebrospinal fluid, and they are rapidly excreted by the kidney. Also, since they are highly polar, there is little passive diffusion, and they must be actively transported adross the cell membrane (Goodman and Gilman, supra). The cationicity also appears to play a critical role in aminoglycoside toxicity.
  • ototoxicity which can involve both auditory and vestibular functions of the eighth cranial nerve
  • nephrotoxicity which is manifest as acute tubular necrosis
  • acute toxicity which can follow intrapleural and intraperitoneal administration and is manifest as a neuromuscular blockade culminating in respiratory distress.
  • Nephrotoxicity is a major complication of the use of antibiotic aminoglycosides (reviewed in Humes, H.D. and Weinberg, J.M., supra), accounting for 10 to 15% of all cases of acute renal failure. It is initially manifested as enzymuria.
  • Renal K + and Mg ++ wasting may also occur, leadi.ng to overt hypokalemia and hypomagnesemia.
  • Polyuria as a result of vasopressin-resistant urinary concentrating defect also develops early in the course of aminoglycoside nephrotoxicity.
  • the acute renal failure occurs typically after 5-7 days of treatment and is manifested clinically by progressive increases in blood urea nitrogen and plasma creatinine levels. The most evident histopathological change under light microscopy is proximal tubule necrosis.
  • Tubule ultrastructure shows evidence of prominent cytosegresomes that contain concentric laminated dense membranes, designated as myeloid bodies.
  • gentamicin for renal toxicity is apparently related to its preferential accumulation in the renal proximal convoluted tubules (50 to 100 times greater than serum) .
  • the cause for the observed fall in the glomerular filtration rate is unclear, since histological damage is limited to the proximal tubule cells.
  • gentamicin's effect on biological membranes is presumably critical in the pathogenetic sequence, the exact mechanisms of its nephrotoxicity are unknown.
  • aminoglycoside cationicity is presumed to play an important role in its nephrotoxicity.
  • acidic phospholipids are the major membrane binding site of the drugs.
  • the affinity of aminoglycosides for membrane acid phospholipids may potentially influence multiple plasma membrane and subcellular membrane processes, because membrane acid phospholipids contribute to membrane structure and permeability, and play an important role in the function of membrane bound enzymes and in hormone-membrane receptor interactions.
  • Some of the observed in vitro effects of aminoglycosides on cellular and subcellular membranes include (Humes and Weinberg, supra): (a) inhibition of the activity of sodium-potassium ATPase, (b) inhibition of the activity of lysosomal phospholipases A and C from renal cortex and of extralysosomal phosphatidylinositol-specific phospholipase C, (c) inhibition of sodium-dependent glucose uptake in isolated renal brush border membranes, (d) inhibition of the ability of anti-diuretic hormone to stimulate adenyl cyclase and thus increase water permeability in isolated toad urinary bladder, (e) stabilization of lysosomes at low aminoglycoside concentrations, and increase in lysosomal lability at high aminoglycoside concentrations, and (f) mitochondrial swelling and alterations in mitochondrial respiratory function.
  • lipid peroxidation is linked causally to the pathogenesis of aminoglycoside nephrotoxicity was tested by determining whether administration of diphenyl-phenylenediamine (DPPD) would inhibit lipid peroxidation and thus ameliorate gentamicin-induced renal failure (Ramsammy, L.S., et al., 1986, J. Pharm. Exp. Ther. 238:83).
  • DPPD diphenyl-phenylenediamine
  • Gentamicin increased the lipid peroxidation product, malondialdehyde in rat renal cortex.
  • concurrent treatment with DPPD inhibited the lipid peroxidation, it did not prevent either the functional or the histological renal damage caused by gentamicin treatment.
  • Polyamino acids such as polyasparagine and polyaspartic acid have been shown to inhibit gentamicin binding to renal brush border membrane vesicles in vitro and to inhibit gentamicin and amikacin nephrotoxicity in rats (Williams, P.D., et al., 1986, J. Pharm. Exp. Therap. 237:919). Side effects of aminoglycoside antibiotics, renal toxicity, and 8th nerve toxicity can be reduced by administering 2 , 5-di-O-acetyl-D- gluco-saccharo-1,4: 6,3-dilactone (U.S. Patent No.
  • Glutathione peroxidase a selenium-dependent enzyme
  • Glutathione peroxidase is effective at low concentrations of hydrogen peroxide and can also act upon lipid hydroperoxides, thus countering the toxicity of a wide range of peroxides (Lawrence, R.A. and Burk, F.R., 1976, Biochem. Biophys. Res. Commun. 71:952-958).
  • a selenium-independent glutathione peroxidase activity which can detoxify organic peroxides but not metabolize hydrogen peroxide has been identified (Lawrence, R.A. and Burk, R.F., 1978, J. Nutr. 108:211-215).
  • GSH reduced glutathione
  • superoxide and hydrogen peroxide may not only be directly cytotoxic, but, in addition, may interact (with iron as catalyst) by the Haber Weiss reaction to generate the hydroxyl radical (Hoe, S., et al., 1982, Chem.-Biol. Interactions 41:7501; Aust, CD., et al., 1985, J. Free Radicals Biology & Medicine 1:3-25): Fe 3 + O 2 - -- ⁇ Fe 2+ + O 2 ⁇
  • the present invention is directed to the in vivo use of compounds, termed hereinafter "protective agents", which prevent the generation of, effectively scavenge, or detoxify a reactive oxygen metabolite (ROM) that mediates a toxic effect of an aminoglycoside.
  • the protective agents of the invention include but are not limited to free radical scavengers, iron chelators, and enzymes which metabolize reactive oxygen metabolites, converting them to less toxic states and/or preventing the production of other toxic species.
  • the protective agents also include oxidizable compounds which effectively detoxify the ROMs, exerting a protective effect by undergoing oxidation in lieu of important cellular components.
  • Another group of protective agents includes any compounds (e.g.
  • biosynthetic precursors which increase the effective in vivo concentrations of endogenous protective agents.
  • the invention is based, in part, on the discovery that the nephrotoxic effects of aminoglycosides in vivo are mediated by ROMs.
  • the protective agents can be used therapeutically, in accordance with the present invention, before, during, or after aminoglycoside administration to prevent or reduce aminoglycoside-induced nephrotoxicity.
  • hydroxyl radical scavengers or iron-chelators can be used to protect against renal damage.
  • enzymes such as catalase and/or superoxide dismutase can be used to convert the reactive metabolites H 2 O 2 and O 2 - to less harmful products and to prevent the generation of other toxic metabolites.
  • the iron-chelator deferoxamine, the hydroxyl radical scavenger dimethylthiourea, or glutathione biosynthetic precursors can be administered to protect against antibiotic aminoglycoside- induced nephrotoxicity.
  • Protective agent A compound that prevents the generation of, effectively scavenges, or detoxifies an aminoglycoside- induced reactive oxygen metabolite which mediates a toxic effect.
  • OC Oxidizable compound.
  • a protective agent which detoxifies a reactive oxygen metabolite by undergoing oxidation by the reactive oxygen metabolite, in lieu of and preventing the detrimental oxidation of other cellular components.
  • BUN blood urea nitrogen.
  • DMSO dimethyl sulfoxide
  • ROM reactive oxygen metabolite
  • Figure 1A depicts the protective effect of hydroxyl radical scavengers dimethylthiourea (DMTU) and dimethyl sulfoxide (DMSO) on gentamicin (GENT)-induced acute renal failure, as measured by blood urea nitrogen (mg/dl).
  • DMTU dimethylthiourea
  • DMSO dimethyl sulfoxide
  • GENT gentamicin-induced acute renal failure, as measured by blood urea nitrogen (mg/dl).
  • Saline represents a control group of saline-treated rats.
  • N equals the number of animals in each group.
  • Figure 1B depicts the protective effect of hydroxyl radical scavengers dimethylthiourea (DMTU) and dimethyl sulfoxide (DMSO) on gentamicin (GENT)-induced acute renal failure, as measured by plasma creatinine levels (mg/dl).
  • DMTU dimethylthiourea
  • DMSO dimethyl sulfoxide
  • Saline represents a control group of saline-treated rats. N equals the number of animals in each group.
  • Figure 2A depicts the protective effect of the hydroxyl radical scavenger sodium benzoate (BENZOATE) and the iron chelator deferoxamine (DFO) on gentamicin (GENT)-induced acute renal failure, as measured by blood urea nitrogen (mg/dl).
  • BENZOATE hydroxyl radical scavenger sodium benzoate
  • DFO iron chelator deferoxamine
  • Saline represents a control group of saline-treated rats. N equals the number of animals in each group.
  • Figure 2B depicts the protective effect of the hydroxyl radical scavenger sodium benzoate (BENZOATE) and the iron chelator deferoxamine (DFO) on gentamicin (GENT) -induced acute renal failure, as measured by plasma creatinine levels (mg/dl).
  • BENZOATE hydroxyl radical scavenger sodium benzoate
  • DFO iron chelator deferoxamine
  • Saline represents a control group of saline-treated rats. N equals the number of animals in each group.
  • Figure 3 depicts the protective effect of the iron chelator 2,3-3ihydroxybenzoic acid (DHB) on gentamicin (GENT)- induced acute renal failure, as measured by blood urea nitrogen (mg/dl).
  • DLB iron chelator 2,3-3ihydroxybenzoic acid
  • GENT gentamicin- induced acute renal failure
  • Figure 4A is a light microscopic section of kidneys from rats receiving gentamicin alone, showing severe tubular epithelial necrosis with sloughing of the lining epithelium and luminal debris. Magnification is X 200.
  • Figure 4B is a light microscopic section of kidneys from rats receiving gentamicin plus deferoxamine showing essentially no pathologic abnormalities. Magnification is X 200.
  • the present invention relates to the use of compounds in vivo that prevent the generation of, effectively scavenge, or detoxify a reactive oxygen metabolite (ROM) that mediates a toxic effect of an aminoglycoside.
  • ROM reactive oxygen metabolite
  • the invention is based, in part, on the discovery that the nephrotoxic effects of aminoglycosides in vivo are mediated by ROMs.
  • the compounds of the invention act by preventing the production of, by removing, or by preventing the detrimental reaction with cellular components of hydroxyl radicals, superoxide radicals, hydrogen peroxide, and other ROMS . These compounds shall be termed hereinafter "protective agents”.
  • the protective agents of the present invention are compounds that can be used in vivo to prevent toxic side effects such as renal damage caused by aminoglycosides.
  • the protective agents exert their effect by preventing the generation of, by effectively scavenging, or by detoxifying ROMs, and include but are not limited to free radical and other ROM scavengers, iron chelating agents, and compounds (e.g. biosynthetic precursors) which increase the effective in vivo concentrations of endogenous protective agents.
  • the scavengers of ROMs which may be used in the practice of the present invention include but are not limited to scavengers of hydroxyl radicals, superoxide radicals, hydrogen peroxide, and singlet oxygen.
  • the hydroxyl radical scavengers of the present ivnention include but are not limited to dimethylthiourea, dimethyl sulfoxide, and sodium benzoate.
  • the protective agents also include but are not limited to enzymes (e.g. superoxide dismutase, catalase, and glutathione peroxidase) which convert ROMs to less toxic states or metabolize ROMs (e.g. O 2 - and H 2 O 2 ) thus preventing the further generation of other ROMs.
  • Another category of protective agents includes nonenzymatic, oxidizable compounds (termed hereinafter OCs) which effectively detoxify the ROMs, by undergoing oxidation in lieu of important cellular components.
  • Such OCs include but are not limited to thiols, e.g. glutathione. Because thiols are easily oxidized, they may be preferentially oxidized by the reactive oxygen metabolites, thereby protecting the tissues from oxidative damage. Molecules which are metabolic precursors of OCs can be administered in order to increase effective endogenous OC concentrations in vivo.
  • biosynthetic precursors of reduced glutathione can be used which include but are not limited to gamma-glutamylcysteine, gamma-glutamylcysteine disulfide, and gamma-glutamylcystine (Anderson, M.E. and Meister, E., 1983, Proc.
  • the iron chelators of the present invention include compounds that bind iron which is necessary for the generation of toxic free radicals or their precursors, thus preventing such generation.
  • Metabolic precursors of free radicals which the protective agents of the present invention can convert to less harmful products include but are not limited to hydrogen peroxide and superoxide radical, which, if not converted by protective agents, can react to produce hydroxyl radicals.
  • the ROM scavengers, iron chelators, and enzymes of the invention are molecules that can effect their protective function in vivo at the appropriate site of ROM generation or accumulation, without significant toxic effects.
  • the protective agents for use in the present invention include but are not limited to the scavengers, OCs, metabolic precursors, iron chelators, and enzymes of Table I, infra.
  • AET aminoethylisothiuronium adenine triphosphate
  • GED bis(2-guanidinoethyl) disulfide
  • PAPP gallic acid derivatives sodium gallate propyl gallate p-aminoacetophenone p-aminopropiophenone
  • the protective agents of the present invention can be used to protect against the toxic side effects of any aminoglycoside whose toxic effect is mediated by a reactive oxygen metabolite.
  • the protective agents may be administered prior to, concurrently with, or after the administration of aminoglycosides, in order to prevent or reduce toxicity.
  • the protective agents can be administered by any of a variety of routes, including but not limited to intraperitoneal, intravenous, subcutaneous, oral, intranasal, intramuscular, etc.
  • the protective agents can be delivered in various formulations. They can be incorporated into or on liposomes, modified by conjugation to polymers or carrier molecules, etc. Such formulations can be used to enhance the desired localization, delivery, or cellular penetration. For example, superoxide dismutase or catalase can be encapsulated in liposomes to enhance their intracellular delivery.
  • the protective agents can be included in the therapeutic regimen to prevent undesired side effects.
  • Such therapeutic uses of aminoglycosides include but are not limited to the use of antibiotic aminoglycosides in the treatment of bacterial infections.
  • Protective agents can be used to reduce toxicity when aminoglycosides are employed to treat septicemia, to prevent the in vivo formation of certain bacterial metabolic products, or to prevent the in vivo bacterial degradation of certain compounds, etc.
  • free radical scavengers, iron chelators, superoxide dismutase, or catalase can be administered both concurrently and after the administration of antibiotic aminoglycosides.
  • Aminoglycosides whose detrimental side effects may be avoided or reduced in accordance with the present invention include but are not limited to those listed in Table II, infra.
  • the protective agents of the present invention can be used before, during, or after administration of aminoglycosides to protect against renal damage resulting from reactive oxygen metabolite production.
  • Toxic effects on the kidney caused by aminoglycoside administration, that can be reduced or prevented by the protective agents include, for example, acute tubular necrosis and renal failure (see Section 6., infra).
  • protective agents such as dimethylthiourea, sodium benzoate, dimethyl sulfoxide, deferoxamine, or 2,3-dihydroxybenzoic acid can be used to reduce the renal damage induced by the nephrotoxic compounds tobramycin or gentamicin.
  • the iron-chelator deferoxamine can be formulated with gentamicin and a pharmaceutical carrier, and administered intramuscularly for the prevention of gentamicin-induced nephrotoxicity.
  • glutathione biosynthetic precursors can be used to increase the renal concentration of the endogenous OC glutathione.
  • Rats Male male Sprague-Dawley rats weighing 200-250 g and . having free access to water and standard rat chow (1.00%calcium, 0.21% magnesium, 0.40% sodium, 1.10% potassium) were used in these experiments. The rats received daily subcutaneous injections of either 1 ml of sterile, isotonic saline or gentamicin (100 mg/Kg/day) for 8 consecutive days
  • Kidney Intl. 25: 778-7808 twice a day intraperitoneally, and sodium benzoate, at a dosage of 150 mg/Kg IP twice a day.
  • the iron chelator deferoxamine B mesylate (Desferal, Ciba-Geigy Corp., Summit N.J.) was administered intravenously in doses of 20 mg/rat just prior to the first gentamicin injection.
  • deferoxamine was administered via an osmotic pump (type 2ML 2: ALZA Corp., Palo Alto, CA) that was implanted subcutaneously.
  • the drug was reconstituted in water at a concentration of 175 mg/ml, and the pumps (with a 2 ml capacity) delivered 20 mg deferoxamine per rat at a continuous rate of 5 ul/hr.
  • Previous studies have shown that constant plasma levels of the drug are maintained when the deferoxamine is administered by this route (Bowern, N., et al., 1984, J. Exp. Med. 160:1532-1543).
  • kidney homogenates from the non-gentamicin treated rats were assessed by measurement of gentamicin in kidney homogenates from the non-gentamicin treated rats, and a kidney homogenate from a non-gentamicin treated rat to which gentamicin was added in concentrations of 2, 5, 10, 15, and 20 ug/ml.
  • Mitochondria were sedimented by centrifugation at 600 x g for 10 minutes, followed by centrifugation of the resulting supernatant at 10,000 x g for 10 minutes.
  • the mitochondrial pellet was resuspended in 0.25 M sucrose and centrifuged at 10,000 x g for 10 minutes.
  • the final pellet was suspended in 0.25 M sucrose to give a protein concentration of about 10 mg protein/ml. Only mitochondria that had a respiratory control index (state 3/state 4 respiration) of greater than 2.5 were used for experiments. Hydrogen peroxide production was measured using the scopoletin method (Boveris, A., et al., 1973, Anal . Biochem. 80 : 145-158 ) .
  • mitochondrial protein 0.5 mg was added to the reaction mixture containing 150 mM KC1, 10 mM Tris-phosphate, 5 mM Tris-HCl, pH 7.4, and 0.1 ml of horseradish peroxidase (400 ug/ml) in a total volume of 3 ml. Scopoletin was added to a final concentration of 5 nM, and the 100% baseline fluorescence was set in a Farrand System 3
  • Spectrofluorometer (Farrand Optical Co., Valhalla, New York). The decrease in fluorescence (excitation wavelength 385 nm and emission wavelength 460 nm) was first recorded after the addition of substrate (10 mM sodium succinate, baseline values), and then after gentamicin (4 mM) was added to the same reaction mixture. The effect of DMTU (10 mM) and deferoxamine (1 mg/ml) added prior to the addition of gentamicin, on gentamicin-stimulated production of hydrogen peroxide was examined.
  • DMTU dimethylthiourea
  • deferoxamine mesylate has been shown to block the generation of hydroxyl radical (Hoe, S,, et al., 1982, Chem. -Biol. Interactions, 41:75-81).
  • DMTU administered intraperitoneally
  • concentrations sufficient to scavenge hydroxyl radical with a half-life of 34 hours in rats Fox, R.B., supra.
  • DMTU or deferoxamine might be related to some direct interference with the ability of renal cortical mitochondria to respond to gentamicin.
  • DMTU or deferoxamine had no significant effect on gentamicin-enhanced generation of hydrogen peroxide.
  • DMTU (Varani, J., et al., 1985, Lab. Invest. 53 (6) :656-663; Fox, R.B., 1984, J. Clin. Invest.
  • DHB iron chelator 2,3- dihydroxybenzoic acid
  • DMTU dimethylthiourea
  • DMSO dimethyl sulfoxide
  • Benzoate sodium benzoate
  • DFO deferoxamine
  • PAS-positive indicates a reaction with the periodic acid-Schiff reagent to produce an insoluble purple or magenta color visible under the light microscope.
  • the PAS-positive cytoplasmic bodies were also seen in all the animals; however, as shown in Table III, there was a marked reduction in the extent of tubular damage.
  • Light microscopic sections demonstrating the protective effect of deferoxamine on kidneys of gentamicin-treated rats are shown in Figures 4A and 4B.
  • hydroxyl radical scavengers DMTU, DMSO, and sodium benzoate and the iron chelators deferoxamine and 2,3-dihydroxybenzoic acid and 2,3- dihydroxybenzoic acid afford both functional and histological protection against gentamicin-induced acute renal failure in rats. While not bound to a particular theory, several mechanisms may explain the essential role of iron in mediation of renal damage.
  • the protective effect of deferoxamine may be caused by the prevention of hydroxyl radical formation from hydrogen peroxide in the iron-catalyzed Haber Weiss reaction (Hoe, S., et al., 1982, Chem. -Biol. Interactions 41:75-81; Aust, S.D., et al., 1985, J. Free Radicals Biology and Medicine 1:3-25):
  • iron could stem from its involvement in the formation of the perferryl ion, a reaction which requires iron, NADPH-cytochrome P-450 reductase, NADPH, and oxygen:
  • Fe 3+ O 2 -- i.s the free radical or precursor thereof which mediates renal toxicity.

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Abstract

Utilisation in vivo de composés qui éliminent, détoxifient ou empêchent la production d'un métabolite réactif d'oxygène servant de médiateur de l'effet toxique d'un aminoglycoside. Les composés de l'invention peuvent être utilisés pour prévenir ou limiter les lésions rénales induites par un aminoglycoside et comprennent (sans se limiter à ces composés) des entraîneurs de radicaux libres, des chélateurs de fer, des composés oxydables, des enzymes qui métabolisent des métabolites réactifs d'oxygène ou leurs précurseurs, et leurs précurseurs biosynthétiques.
PCT/US1987/003468 1986-12-29 1987-12-21 Protection contre la nephrotoxicite induite par un aminoglycoside WO1988004925A1 (fr)

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JP88501216A JPH01502268A (ja) 1986-12-29 1987-12-21 アミノグリコシド誘因腎臓毒に対する保護

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5079234A (en) * 1989-03-23 1992-01-07 Bristol-Myers Squibb Co. Inhibitors of aminoglycoside nephrotoxicity
EP0906121A1 (fr) * 1996-03-12 1999-04-07 University Of South Florida Effets vasoactifs et production de radicaux libres induite par des peptides beta-amyloides
US5929039A (en) * 1993-11-15 1999-07-27 Baker Medical Research Institute Method for treating cardiac dysfunction and pharmaceutical compositions useful therefor
US6933104B1 (en) 1999-04-23 2005-08-23 Shiva Biomedical, Llc Diagnosis and treatment of human kidney diseases
WO2006017650A2 (fr) * 2004-08-06 2006-02-16 Shiva Biomedical, Llc Procedes de traitement d'humains recevant une injection d'un agent de contraste
US7345018B2 (en) 2002-04-25 2008-03-18 Reception Aps Method of treating side effects induced by therapeutic agents

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US5079234A (en) * 1989-03-23 1992-01-07 Bristol-Myers Squibb Co. Inhibitors of aminoglycoside nephrotoxicity
US5929039A (en) * 1993-11-15 1999-07-27 Baker Medical Research Institute Method for treating cardiac dysfunction and pharmaceutical compositions useful therefor
EP0906121A1 (fr) * 1996-03-12 1999-04-07 University Of South Florida Effets vasoactifs et production de radicaux libres induite par des peptides beta-amyloides
EP0906121A4 (fr) * 1996-03-12 2003-04-23 Univ South Florida Effets vasoactifs et production de radicaux libres induite par des peptides beta-amyloides
US6998396B2 (en) 1999-04-23 2006-02-14 Shiva Biomedical, Llc Diagnosis and treatment of human kidney diseases
US6995152B2 (en) 1999-04-23 2006-02-07 Shiva Biomedical, Llc Diagnosis and treatment of human kidney diseases
US6933104B1 (en) 1999-04-23 2005-08-23 Shiva Biomedical, Llc Diagnosis and treatment of human kidney diseases
US7037643B2 (en) 1999-04-23 2006-05-02 Shiva Biomedicals, Llc Diagnosis and treatment of human kidney diseases
US7045282B2 (en) 1999-04-23 2006-05-16 Shiva Biomedical Llc Diagnosis and treatment of human kidney diseases
US7235542B2 (en) 1999-04-23 2007-06-26 Shiva Biomedical, Llc Diagnosis and treatment of human kidney diseases
US7345018B2 (en) 2002-04-25 2008-03-18 Reception Aps Method of treating side effects induced by therapeutic agents
WO2006017650A2 (fr) * 2004-08-06 2006-02-16 Shiva Biomedical, Llc Procedes de traitement d'humains recevant une injection d'un agent de contraste
WO2006017650A3 (fr) * 2004-08-06 2006-11-09 Shiva Biomedical Llc Procedes de traitement d'humains recevant une injection d'un agent de contraste

Also Published As

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JPH01502268A (ja) 1989-08-10
AU1100388A (en) 1988-07-27
EP0294462A4 (fr) 1990-01-23
EP0294462A1 (fr) 1988-12-14

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