Dactimicin, a new, less toxic aminoglycoside antibiotic active against resistant bacteria

Dactimicin is a new member of the pseudodisaccharide group of antibiotics. It possesses an unusual N-formimidoyl group which differentiates it from astromicin. Dactimicin is active against wide variety of bacteria, including resistant strains with aminoglycoside-modifying enzymes. However, AAC(3)-I enzyme slowly acetylates dactimicin. Animal toxicity studies show that the ototoxicity and nephrotoxicity of dactimicin are lower than those of amikacin and gentamicin. No notable abnormal findings have been found in pharmacological and toxicological studies.     

Comparative nephrotoxicity and tissue accumulation of dactimicin, amikacin and gentamicin

Dactimicin (ST 900) is a new pseudo-disaccharide aminoglycoside antibiotic which has been shown to be active against systemic infections in mice. Few data have so far been reported on dactimicin tissue accumulation or its potential nephrotoxicity. In this study, nephrotoxicity and renal tissue concentrations of gentamicin, amikacin and dactimicin were compared in Wistar rats. Liver, heart and lung accumulation of these drugs were also evaluated. Groups of 5 rats were respectively injected with 100 mg/kg body weight of the different drugs daily for 7 days. Five control rats were also injected with saline. Twenty-four hours after the last injection, all rats were sacrificed and bled to death. Blood samples were taken for BUN and serum creatinine assay. Kidney, liver, heart and lung tissues, as well as blood, were removed and processed for microbiological assay of gentamicin, amikacin and dactimicin. The results of this study showed that dactimicin, as well as amikacin, did not induce any significant increase in BUN and serum creatinine, while gentamicin administration resulted in severe uraemia in all rats. Consequently a much higher accumulation of gentamicin than amikacin and dactimicin was achieved in serum and tissues.     

Prostaglandins and aminoglycoside nephrotoxicity

The role of prostaglandins in the development of aminoglycoside-induced acute renal failure was studied in CD-COBS rats (200 to 250 g). The animals were treated with gentamicin (80 mg/kg), acetylsalicylic acid (ASA, 100 or 200 mg/kg), or both drugs or saline for 5 or 10 days. Renal function was studied measuring creatinine clearance, blood urea nitrogen (BUN), and serum electrolytes, urine osmolality, and maximal urinary concentrating capacity after water deprivation and vasopressin administration. Gentamicin toxicity on the proximal tubule was evaluated by measuring urinary excretion of the lysosomal enzyme N-acetylglucosaminidase (NAG). Renal prostaglandin (PG) production was evaluated measuring the concentration of PGE2, PGD2, PGF2 alpha, 6-keto-PGF1 alpha, and thromboxane B2 (TXB2) in whole renal homogenate after a 15-min incubation at 37 degrees C using gas chromatography-mass spectrometry. Gentamicin alone reduced the glomerular filtration rate (GFR) 20 to 30% after 5 and 10 days of treatment. Combination with ASA potentiated the toxic effect of the aminoglycoside after 10 but not after 5 days of treatment. Similarly, gentamicin reduced the urinary concentrating capacity and addition of ASA worsened the effects. Gentamicin markedly increased NAG excretion but this effect was reduced by ASA, probably as a result of lysosomal stabilization. ASA alone inhibited the production of prostaglandins in renal tissue by 70 to 90% after single or multiple doses. The animals treated with gentamicin alone presented a significant, specific increase in PGE2 production after 10 days of treatment but this increase did not occur when the two compounds were given together. Since PGE2 has a vasodilatory effect in the kidney these results suggest that it may play a specific role in maintaining normal renal blood flow and GFR during the development of aminoglycoside nephrotoxicity. The inhibition of prostaglandin production by nonsteroid anti-inflammatory drugs prevents this compensatory mechanism and worsens the renal damage.     

Nephrotoxicity of piperacillin combined with furosemide in rats

Nephrotoxicity of piperacillin (PIPC) was evaluated in rats after combined administration with furosemide. After intravenous administration of PIPC (1600 mg/kg), the rats showed no change in urinalysis, biochemical analysis of plasma and histopathological analysis. The rats receiving furosemide (100 mg/kg) showed elevation of urinary NAG, BUN and creatinine concentrations, and showed slight degeneration of the renal proximal tubules. The rats receiving PIPC (1600 mg/kg) and furosemide (100 mg/kg) showed elevation of BUN and creatinine concentrations, and showed slight degeneration of the proximal tubules. These changes were comparable to those in rats receiving furosemide alone. The rats receiving cephaloridine (1600 mg/kg) showed elevation of urinary protein, BUN and creatinine concentrations, and showed moderate degeneration and necrosis of the proximal tubules. The nephrotoxicity was enhanced by combination with furosemide. In conclusion, no enhanced effect of nephrotoxicity was observed by combination of PIPC with furosemide.     

Developed resistance to mercuric chloride nephrotoxicity: failure to protect against other nephrotoxicants

Daily, oral treatment of rats for 14 days with 5 mg/kg of mercuric chloride (HgCl2) caused hypertrophy of the kidney, but no change in percent tissue water, or serum urea nitrogen (BUN) or creatinine concentrations. Upon histological examination, hypercellularity and increased basophilia of the outer medulla were observed. A single, subcutaneous injection of 20 mg/kg of potassium chromate (K2CrO4) increased kidney size and water content, as well as BUN and serum creatinine concentrations, and produced coagulative necrosis of the proximal convoluted tubules. Intraperitoneal injection of 125 mg/kg of hexachloro-1,3-butadiene (HCBD) increased kidney weight, percent water, BUN and serum creatinine, and produced necrosis of the proximal straight tubules in approximately half of the animals. 1 g/kg biphenyl, orally, produced only diffuse tubular swelling. Rats treated with 20 mg/kg K2CrO4, 125 mg/kg HCBD or 1 g/kg biphenyl following 14 days of treatment with 5 mg/kg HgCl2 generally displayed the symptoms of both types of treatment, and the severity of the K2CrO4, HCBD and biphenyl effects were substantially the same as in those without HgCl2 pretreatment. Developed resistance to HgCl2 nephrotoxicity, therefore, appears to have little effect on response of the kidney to other nephrotoxicants.     

In vitro response of rat and human kidney lysosomes to aminoglycosides

To study aminoglycoside nephrotoxicity, renal cortical lysosomes were prepared from rat kidneys and from healthy portions of five human kidneys removed for tumor. The renal cortex was homogenized in 1 mM EDTA with 0.3M sucrose, and the lysosomes were separated by differential centrifugation. Lysosomes were incubated in isotonic sucrose solution with various drug concentrations for 1 hr at 37°. They were resedimented adn the N-acetyl-β-glucosaminidase (NAG) activity was measured in the supernatant fraction and in the disrupted pellet. Incucation with four aminoglycosides at therapeutic plasma concentrations lowered the percentage of NAG released into the supernatant fraction in a dose-related fashion. Incubation with the polyamines spermine and spermidine also produced this effect, with spermine and gentamicin being additive. This apparent lysosomal stabilization at clinically achieved plasma concentrations was also observed after substituting isotonic glycine for sucrose in the incubation mixture. High concentrations of aminoglycoside consistent with those accumulated in the renal cortex of patients and rats produced a dose-dependent release of lysosomal NAG with a rank order of potency paralleling their clinically observed potential for producing nephrotoxicity. Rats were treated with 20 mg/kg gentamicin twice a day for 28 days producing kidneys resistant to aminoglycoside nephrotoxicity. Lysosomes prepared from these animals compared to saline-treated controls showed decreased response to gentamicin at 2 and 4μg/ml and to apermine. Human renal cortical lysososomes also exhibited aminoglycoside- and polyamine-induced changes in NAG release. We conclude taht the lysosome is a site of action for aminoglycoside nephrotoxicity. We propose that aminoglycoside stabilization of this lysosomal membrane may lead to eventual disruption of the proximal tubular lysosomal system and cell injury.     

Comparison of the effect of aminoglycosides on excretion of N-acetyl-beta-glucosaminidase

Urinary N-acetyl-beta-glucosaminidase (NAG) activity was determined in ten patients receiving 200 mg of astromicin and ten patients receiving 100 mg of dibekacin; each dose was administered twice a day for five days. There was a significant difference between the aminoglycosides in the rate at which NAG activity increased, suggesting that astromicin has a lower nephrotoxicity.     

Influence of iron,deferoxamine and ascorbic acid on gentamicin-induced nephrotoxicity in rats

1. Nephrotoxicity was induced in rats by injecting gentamicin intramuscularly (i.m.) at a dose of 80 mg/kg for 6 days. Treated animals demonstrated a typical pattern of nephrotoxicity characterized by increased serum creatinine and urea concentrations, and by necrosis of proxinal tubular epithelium.2. Pretreatment of rats with iron (Fe³⁺) at daily i.m. doses of 2, 4 and 8 mg/kg for 14 days, with gentamicin given during the last 6 days of treatment, significantly potentiated the gentamicin-induced increases in creatinine and urea concentrations and exacerbated renal histological damage.3. Gentamicin significantly increased serum Fe³⁺ concentration in rats treated with Fe³⁺ and gentamicin, compared to Fe³⁺-treated rats.4. The Fe³⁺ antidote deferoxamine (100 mg/kg, i.m.) given with gentamicin was ineffective in antagonizing the potentiating effect of Fe³⁺ on gentamicine-induced nephrotoxicity.5. Ascorbic acid (50 mg/kg, i.m. for 14 days) was ineffective in altering the nephrotoxicity of gentamincin (80 mg/kg) given during the last 6 days of treatment. At a dose of 100 mg/kg for 14 days, ascorbic acid significantly reduced gentamicin-induced increases in creatinine and urea levels, and ameliorated proximal tubular damage. However, at a dose of 200 mg/kg, ascorbic acid exacerbated gentamicin-induced increases in creatinine and urea levels and increased the severity of the histological damage.     

Cisplatin nephrotoxicity is mediated by gamma glutamyltranspeptidase, not via a C-S lyase governed biotransformation pathway

Cisplatin exhibits dose-limiting nephrotoxicity in rodents and man. This study investigates the mechanism of cisplatin nephrotoxicity in vivo and in an in vitro model system. Nephrotoxicity was induced in rats (6 mg/kg cisplatin i.p.) and mice (10 mg/kg cisplatin i.p.). Cisplatin administration significantly elevated blood urea nitrogen (BUN) and serum creatinine in male Sprague Dawley rats day 5 post-treatment (BUN Delta+28+/-5 micromol/ml; serum creatinine Delta+108+/-4 nmol/ml, P<0.05) and in male C57BL6 mice day 4 post-treatment (BUN Delta+21+/-4 micromol/ml; serum creatinine Delta+81+/-5 nmol/ml, P<0.05). Nephrotoxicity was confirmed by histological analysis that revealed significant damage to the proximal tubules of cisplatin- versus saline vehicle-treated animals. Inhibition of gamma glutamyltranspeptidase prevented cisplatin nephrotoxicity in Sprague Dawley rats (day 5 BUN Delta+1+/-2 micromol/ml; serum creatinine Delta+8+/-4 nmol/ml) and C57BL6 mice (day 4 BUN Delta+1+/-0.8 micromol/ml; serum creatinine Delta-1+/-2 nmol/ml), but not cellular toxicity in rat proximal tubular (RPT) or human proximal tubular (HPT) cultures. Inhibition of aminopeptidase N (AP-N) or renal dipeptidase (RDP) in male Sprague Dawley rats, or in RPT and HPT cell cultures, did not reduce cisplatin toxicity. In contrast to published findings inhibition of C-S lyase did not prevent the nephrotoxicity of cisplatin in vivo or cellular toxicity in vitro. These data demonstrate that the biotransformation enzymes AP-N, RDP and C-S lyase are not implicated in the metabolism of cisplatin to a nephrotoxic metabolite as has been previously hypothesised. Instead, our data demonstrate that gamma glutamyltranspeptidase is a key enzyme involved in mediating cisplatin nephrotoxicity, which potentially acts to cleave cisplatin-GSH conjugates to a toxic metabolite.     

Effect of glucarolactam on ototoxicity of aminoglycoside antibiotics in guinea-pigs

Intramuscular administration of glucarolactam in the form of aminoglycoside salt to guinea-pigs protected the experimental ototoxicity caused by high dosing of aminoglycoside antibiotics. The protection was evidenced by the pinna reflex threshold and histochemical examinations of hair cells of cochlea as well as body weight gain. The degree of protection differed with the aminoglycosides, and high protection was observed for dibekacin, gentamicin, tobramycin, followed by kanamycin and bekanamycin. However, protection was weak or not observed when glucarolactam was administered as a mixture of glucarolactam potassium and aminoglycoside sulfate. Serum analysis of the guinea-pigs on day 14 post-administration as a measure of nephrotoxicity revealed that glucarolactam suppressed the elevation of BUN and serum creatinine caused by the aminoglycosides. The protective effect of glucarolactam on the aminoglycoside-induced nephrotoxicity in the dehydrated rats did not differ between the salt and the mixture. No difference in the in vivo antibiotic activity against bacterial infections of mice was observed between the salt and the mixture.     

Nephrotoxicity of a novel antineoplastic platinum complex, nedaplatin: a comparative study with cisplatin in rats

The present study was designed to characterize the nephrotoxicity induced by the antineoplastic platinum complex nedaplatin (NDP) in rats of different ages in comparison with cisplatin (CDDP). A single dose of 15 mg/kg NDP or 7.5 mg/kg CDDP was administered intravenously to 8-, 11-, or 15-week-old male and female SD rats, which were then sacrificed after ten days. Body weight decreases were observed for both drugs, in direct relation to age. CDDP treatment markedly increased urinary excretion of NAG, -GTP, LDH and protein, with peaks on day 4 and complete or partial recovery on day 7; NDP increased NAG, LDH and protein excretion, but to a lesser extent, and these elevations were generally more marked for females. CDDP increased plasma creatinine and BUN in males and females of all age groups at necropsy. No apparent changes were seen following NDP treatment except in the 15-week-old rats. These results also show that NDP is less nephrotoxic than CDDP. CDDP-treated rats showed remarkable proximal tubular lesions in the renal cortex and corticomedullary region, and the papillary lesions were minor. On the other hand, the NDP-induced nephrotoxicity was morphologically characterized by hyaline droplet changes (electron microscopically, hyperplasia of lysosomes), necrosis or hyperplasia of the collecting duct epithelium in the renal papilla and the epithelium covering the papilla. Cortical lesions, indicated by slight tubular dilatation, were found only in the animals with papillary lesions. In summary, NDP is a promising second-generation platinum complex with reduced nephrotoxicity.     

Diltiazem enhances gentamicin nephrotoxicity in rats

The effect of the calcium antagonist, diltiazem, was examined in gentamicin-induced nephrotoxicity states in rats. Animals were injected for 5 days with diltiazem intraperitoneally (40 mg/kg/day), or gentamicin subcutaneously (100 mg/kg/day) or simultaneously with both preparations using the same doses. At the time of sacrifice, the urea and creatinine clearances, as well as urine osmolality were determined and the renal tissues were processed for examination by light microscopy. Gentamicin-injected rats demonstrated the typical pattern of aminoglycoside nephrotoxicity characterized by poliuric renal failure and necrosis of the proximal tubular epithelium. Rats injected with diltiazem revealed only mild depression of urine osmolality. There was no elevation of blood urea nitrogen and serum creatinine or depression of urea and creatinine clearances, and no focal tubular cell necrosis was detected. However, concomitant administration of both compounds considerably increased nephrotoxicity by according both histological indications and renal function measurements. Thus, we conclude that the combination of diltiazem and gentamicin must be used carefully in human clinical practice.     

Quercetin, a bioflavonoid, protects against oxidative stress-related renal dysfunction by cyclosporine in rats.

Nephrotoxicity is the most common and clinically important side effect of cyclosporine (CsA). Recent evidence suggests that reactive oxygen species (ROS) play an important role in CsA nephrotoxicity. This study was designed to demonstrate the role of oxidative stress and its relation to renal dysfunction and to investigate the effects of quercetin, a bioflavonoid with antioxidant properties, in CsA-induced nephrotoxicity. Quercetin (0.5 and 2.0 mg/kg i.p.) was administered 24 h before and concurrently with CsA (20 mg/kg s.c.) for 21 days. Tissue lipid peroxidation was measured as thiobarbituric acid reacting substances (TBARS). Renal function was assessed by estimating plasma creatinine, blood urea nitrogen (BUN), creatinine and urea clearance. Renal morphological alterations were assessed histopathologically. Pretreatment with CsA (20 mg/kg s.c.) for 21 days produced elevated levels of TBARS and deteriorated renal function as assessed by increased plasma creatinine, BUN and decreased creatinine and urea clearance as compared to vehicle-treated rats. The kidneys of CsA-treated rats showed severe striped interstitial fibrosis, arteriopathy, glomerular basement thickening, tubular vacuolization and hyaline casts. Quercetin (2 mg/kg) markedly reduced elevated levels of TBARS and significantly attenuated renal dysfunction and morphological changes in CsA-treated rats. It is likely that quercetin, due to its antioxidant properties, prevented CsA-induced ROS and consequently CsA nephrotoxicity. These results clearly demonstrate the pivotal role of oxidative stress and its relation to renal dysfunction, and also point to the therapeutic potential of the natural antioxidant quercetin in CsA-induced nephrotoxicity.     

Protective effect of fleroxacin against the nephrotoxicity of isepamicin in rats

The protective effect of fleroxacin on isepamicin-induced nephrotoxicity was investigated. Wistar rats were administered either fleroxacin 100 mg/kg orally, isepamicin 300 mg/kg subcutaneously, or fleroxacin and isepamicin in combination for 14 d. The animals given 300 mg/kg of isepamicin showed a significant increase in urine N-acetyl-beta-D-glucosaminidase (NAG) levels as compared with the control animals which received saline (p<0.01). However, the increase in NAG level was markedly less when isepamicin was administered in combination with fleroxacin (p<0.01). Fleroxacin alone had no effect on urine NAG activity. Serum creatinine and blood urea nitrogen (BUN) levels were significantly higher in animals treated with isepamicin alone than in the control animals (p<0.01) or animals receiving the isepamicin fleroxacin combination (p<0.01). Histopathologically, fleroxacin induced very few cellular alterations, but considerably reduced the manifestation of typical signs of isepamicin nephrotoxicity. This investigation demonstrates that fleroxacin protects animals against isepamicin-induced nephrotoxicity.     

Toxicological studies on isepamicin (HAPA-B). II. Intramuscular subacute toxicity test in the rat

Subacute toxicity in the rat of isepamicin (HAPA-B), a new aminoglycoside antibiotic, was examined in comparison with amikacin (AMK). Daily doses of 12.5, 25, 100 and 300 mg/kg of HAPA-B or 25 and 100 mg/kg of AMK were injected intramuscularly for 28 days. No animal died and there were no changes in general symptoms except for hemorrhage at injection sites of both drugs. Decreases in body weight gain and food consumption were observed in males and females in the HAPA-B 300 mg/kg dose group. Water consumption was increased in males in the HAPA-B 300 mg/kg and AMK 100 mg/kg dose groups. Elevations of serum creatinine and/or BUN in males and females were occasionally observed in the HAPA-B 300 mg/kg and AMK 100 mg/kg dose groups, and elevation of GOT, which seemed to be due to muscle injuries, was occasionally observed in a no dose-dependent manner with either drug. Increases in kidney and caecum weights of males and females in the HAPA-B 100, 300 mg/kg and AMK 25, 100 mg/kg dose groups and increases in adrenal relative-weights in males and females in the HAPA-B 300 mg/kg dose group were observed. At necropsy, discoloration and enlargement of the kidney were observed in a dose-dependent manner at or above 100 mg/kg with either drug. Histopathological findings indicated degeneration and necrosis in epithelial cells of the proximal convolute tubuli and thickening of basement membrane. Electron microscopic findings indicated an increase in number of large lysosomes containing myeloid bodies in the epithelial cells of the proximal convolute tubuli with both drugs. The above results suggest that HAPA-B has renal toxicity like other aminoglycoside antibiotics but its toxicity was lower than AMK. The non-toxic dose of HAPA-B in this test was 12.5 mg/kg.     

Renal toxicity of the antitumor drug N2-methyl-9-hydroxyellipticinium acetate in the wistar rat

Celiptium (N2-methyl-9-hydroxy-ellipticinium) is an antitumoral agent used to treat bone metastases from breast carcinomas. This new drug appeared to be of great interest because of the absence of hepato-or myelotoxicity. Three different investigators recently mentioned cases of celiptium-induced renal failure. We therefore undertook a study of renal function and morphology in female Wistar rats. Two single i.v. doses (10 or 20 mg/kg) were administered and animals were sacrificed 4, 8, 15, 28 and 60 days after injection. One group of rats received multiple doses, 5 mg/kg/week for 8 weeks. No mortality was observed. With the 10 mg/kg single dose creatinine clearance (Ccr) and urinary enzymes did not change, and tubular lesions were rare. With the 20 mg/kg single dose CCr decreased on day 4 and returned to normal on day 28. Urinary enzyme excretion (AAP, NAG, GT) increased. Renal lesions were diffuse with tubular necrosis, luminal dilation and later (day 28) interstitial cellular infiltration. These lesions persisted on day 60 and appeared to be irreversible. Ultrastructural studies showed numerous large fat droplets in proximal tubular cells. Glycerol concentrations in renal cortex homogenates were increased while phospholipids are slightly decreased. With 5 mg/kg every week (multiple doses) Ccr decreased and tubular lesions similar to the observed with the 20 mg/kg single dose were seen. Thus celiptium induced dose-dependent nephrotoxicity in rats with prolonged tubular alterations. Since it has been shown that renal tubular cells metabolized celiptium in vitro into electrophilic intermediates, we suggest that free radicals and quinone derivatives may contribute to peroxidation of unsaturated fatty acids and play a role in the nephrotoxicity of the drug.     

Proximal tubule damage in patients treated with gentamicin or amikacin

The present study aimed to determine the relationships between time of administration and dose of aminoglycosides, the extent of proximal tubule damage, evaluated by the urine N-acetyl-beta-D-glucosaminidase (NAG) activity, and to compare proximal tubule dysfunction in the patients treated with gentamicin and those receiving amikacin. The measurement of activity of NAG in urine was chosen to monitor of proximal tubule function. The studies were performed in 25 patients, who had to be administered gentamicin or amikacin by intramuscular injections. In both groups, the maximum NAG activities in urine were detected most frequently after the 7th day of the therapy. A significant difference in NAG activities in urine was noted between the values observed in the course of treatment with aminoglycosides and those determined before start of the treatment. NAG activity in urine significantly decreased following discontinuation of aminoglycoside antibiotic administration. The activities did not decrease quite to the pretreatment level but the remaining difference proved to be insignificant. In the course of aminoglycoside treatment, 7 patients demonstrated an increase in serum creatinine levels exceeding 0.4 mg%. It should be stressed that no pronounced differences in nephrotoxicity and, in particular, in their potential to induce injury to the proximal tubule have been disclosed between gentamicin and amikacin. Their significant, damaging effect on integrity of proximal tubule was demonstrated, which was evidenced by the clear increase in urinary NAG activity during administration of either drug. Nevertheless, only in a small fraction of such cases (12-16%), the increase promoted development of renal insufficiency, usually of a transient character. Monitoring of the increase in urinary NAG activities in line with observations on creatinine levels permits to distinguish a subgroup of patients who may be suspected of development of overt nephrotoxicity. In such cases cessation of aminoglycoside administration is required.     

Effect of thromboxane synthetase inhibition and angiotensin converting enzyme inhibition on acute cyclosporin A nephrotoxicity

One component of cyclosporin A (CsA) nephrotoxicity is thromboxane (Tx) A2 induced renal vasoconstriction. This study was designed to investigate whether coadministration of angiotensin converting enzyme inhibitors (ACEI) and thromboxane synthetase inhibition (TSI) could act synergistically to improve the glomerular filtration rate in CsA treated animals. CsA administration (50 mg/kg/day p.o.) to Sprague-Dawley rats for 14 days caused a significant decline in creatinine clearance (CCR), an increase in N-acetyl-beta-D-glucosaminidase (NAG) enzymuria and renal tubulointerstitial damage. These changes were associated with a ten-fold increase in urinary TxB2 excretion (from pretreatment values of 17.2 +/- 6.0 ng/day to 174.9 +/- 65.4 ng/day on day 14). Treatment with TSI normalized TxB2 excretion; this was associated with partial protection against CsA induced changes in CCR and NAG enzymuria and the complete prevention of acute proximal tubular vacuolation. However, the coadministration of both TSI and ACEI removed the protective effects exerted by TSI alone and resulted in elevated urinary TxB2 levels similar to those observed in other CsA treated groups. Treatment with ACEI alone did not affect CsA nephrotoxicity. We suggest that elevated TxB2 synthesis is in part responsible for some aspects of renal functional and morphological damage, but that CsA nephrotoxicity is multifactorial and may result from direct cellular toxicity in addition to vascular changes.     

Functional and structural alterations of the rat kidney induced by the naturally occurring organonitrile 2S-1-cyano-2-hydroxy-3,4-epithiobutane

The organonitriles, 2S-1-Cyano-2-hydroxy-3,4-epithiobutane (erythro and threo) (CHEB), isolated from the seed of Crambe abyssinica were administered by gavage to male Fischer-344 rats. Rats given 50 mg/kg/day were killed at 24, 48, and 72 hr. The rats given 100 mg/kg/day were killed at 48 and 72 hr. Serum urea nitrogen and creatinine were increased by 48 hr and further elevated by 72 hr. Glomerular filtration rate (GFR) of the 50 mg/kg CHEB rats was elevated at 24 hr but fell to subnormal values by 72 hr. The GFR of the 100-mg/kg group was decreased at 48 and 72 hr. Urine output of the 50-mg/kg group increased continuously through 72 hr, while urine output of the 100-mg/kg group was increased to a lesser degree. Urinary N-acetyl-beta-D-glucosaminidase (NAG) activity (nmol/hr/mg creatinine) was significantly elevated in both groups by 48 hr, and further increased by 72 hr. Twenty-four hours after administration of 50 mg/kg, renal proximal tubular epithelial cells of some rats had fine cytoplasmic vacuolation. At 48 and 72 hr, necrosis and coarse vacuolation of proximal tubular epithelial cells occurred in both dose groups. The necrosis was most severe at the apexes of the medullary rays and the coarse vacuolation extended deeply toward the outer stripe of the outer zone of the medulla. Higher doses and/or longer times of CHEB administration resulted in a more extensive lesion distribution. It is concluded that CHEB induces nephrotoxicity in rats characterized by nonoliguric, acute renal failure, and morphological lesions preferentially involving the pars recta of the proximal tubules.     

Calcium channel blockade in experimental aminoglycoside nephrotoxicity

Calcium channel blocker therapy has proved protective in certain models of ischemic-induced acute renal failure. This effect may be related to the prevention of calcium influx into injured cells or by the vasodilatory effects of verapamil that may result in an improvement in renal blood flow. In the current study, the effect of verapamil treatment on the development of renal insufficiency and renal tissue calcium accumulation following aminoglycoside administration was investigated. The degree of functional damage and cortical tissue calcium accumulation after six or nine days of gentamicin administration (120 mg/kg body weight/day) was not significantly different in rats whose drinking water contained verapamil (10 mg/100 cc) than corresponding values in control animals. The tissue calcium accumulation correlated with the degree of reduction of creatinine clearance and probably reflects the extent of lethal tubular cell injury.