Gentamicin and tobramycin nephrotoxicity. A morphologic and functional comparison in the rat.

Fischer 344 rats were treated with tobramycin or gentamicin, 40 mg/kg/day, for up to 10 days or with tobramycin, 120 mg/kg/day, for up to 14 days. Serum creatinine and BUN at the time of sacrifice were determined, and kidney tissues were examined by light and electron microscopy. Rats receiving gentamicin demonstrated progressive renal proximal tubular necrosis which was nearly universal at the end of 10 days. Their BUN and creatinine levels rose progressively over the same period. Even at the higher dosage, tobramycin therapy resulted in only rare foci of proximal tubular necrosis and minimal elevation of BUN and creatinine. Although they occurred later and were substantially less severe, the ultrastructural changes induced by tobramycin were the same as those seen following gentamicin administration. These results indicate that the mechanism of tobramycin-induced renal injury is probably similar to that of gentamicin and that tobramycin is significantly less nephrotoxic in this experimental model.     

The optimal aminoglycoside and its dosage for the treatment of severe Enterococcus faecalis infection. An experimental study in the rabbit endocarditis model

Aminoglycosides are recommended for the treatment of Enterococcus faecalis infections, especially in severe and bacteremic infection. However, the optimal aminoglycoside or the optimal dosage remains uncertain. This study aimed to compare the activity of four aminoglycosides against E. faecalis (gentamicin, netilmicin, tobramycin, and amikacin) and two dosages of gentamicin. One clinical strain of E. faecalis was used to induce aortic endocarditis in the study rabbits. Each aminoglycoside was infused daily over 3?days with a computer-regulated flow simulating human pharmacokinetics of 15?mg/kg/day for amikacin, 6?mg/kg/day for netilmicin, and 3?mg/kg/day for gentamicin and tobramycin. Additionally, two dosages of gentamicin (simulating 3 or 6?mg/kg/day) were compared over 1 or 3?days of treatment. The in vivo efficacy was assessed according to the bacterial count in vegetations, in comparison with a control group. Of the four aminoglycosides tested, only gentamicin and netilmicin showed significant antibacterial efficacy after 3?days of treatment. After only 1?day of treatment, the high dosage of gentamicin (6?mg/kg/day) was more effective than the standard dosage (3?mg/kg/day). Among the tested aminoglycosides, gentamicin showed the best efficacy, with the best results after 24 h of treatment for the highest dosage.     

Urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) and its isoenzyme B as a marker of the nephrotoxicity of gentamicin: re-test from an animal model

A high level of NAG urinary excretion with marked isoenzyme B excretion are commonly considered as an indicator of aminoglycoside nephrotoxicity. The urinary excretion of NAG following gentamicin treatment was studied in rabbit. The rabbits received gentamicin at equivalent therapeutic (5 and 20 mg/kg/j) or toxic (50 mg/kg/j) doses during four days. Activities were measured daily and isoenzyme patterns were determined on the day of maximal urinary enzyme excretion. Isoenzyme patterns of kidney cortex, urinary control, and urinary gentamicin treated rabbits were compared. As compared with control rabbit, no changes in isoenzyme profiles appeared following the administration of gentamicin at 5-20 mg/kg/j. Thus, NAG enzymuria is constituted almost exclusively by isoenzyme A. Surprisingly, the high level of NAG excretion following the administration of gentamicin at 50 mg/kg/j is not accompanied by a marked excretion of isoenzyme B. The present results confirm controversy still exists regarding the clinical significance of urinary NAG excretion. These data indicate that increases in urinary NAG and isoenzyme B excretion following gentamicin treatment in Human are not always reliable indicators of renal tubular cell lysis.     

Pathological effects of gentamicin administered intramuscularly to day-old broiler chicks

The aim of this experimental study was to investigate the pathological effects of gentamicin in birds. Broiler chicks at 1 day of age were intramuscularly administered gentamicin at dose levels varying from 0 to 180 mg/kg. Clinical signs comprising of depression, decreased feed consumption, increased water intake, loose watery droppings and reduced body weights appeared in a dose-related manner in chicks administered 30 mg/kg or higher dose levels. Mortality was 0% and 20% in chicks given 40 mg and 50 mg/kg gentamicin. It increased in a dose-related manner and was 100% in 100 mg/kg or higher dose groups. The LD50 calculated at total deaths in 5 weeks duration was 77.56 mg/kg. Kidneys and livers of chicks given 50 mg/kg or higher doses of gentamicin were congested, enlarged and had hemorrhages on the surfaces. Microscopically kidneys exhibited acute tubular necrosis. Livers showed fatty change, vacuolar degeneration, necrotic areas and cellular infiltration around portal triads. Serum total proteins and albumin decreased while creatinine and ALT increased in chicks given 20 mg/kg and higher doses. The no observable effect level (NOEL) of a single intramuscular administration of gentamicin in day-old broiler chicks was 10 mg/kg body weight.     

Time and dose-response study of the effects of vanadate on rats: morphological and biochemical changes in organs

Vanadate at a dosage level of 0.9 mg V/kg per day produced acute toxic signs in rats when injected subcutaneously for 16 days. These signs were weakness, loss of appetite, dehydration, significant reduction in body weight, nose bleeding, and death. The pathological and biochemical changes were most severe in kidney tissue. The kidney lesions were bilateral and multifocal. At two days, degenerative and necrotic changes of the tubular and glomerular epithelium, thickening of glomerular membrane, vascular congestion, and edema were observed. At five days, proliferation of tubular epithelial and interstitial cells was observed. At 12 days, the cellular proliferation in both cortex and medulla was significantly greater. Fibrosis was observed at glomerular tuft, preglomeruli, pretubules, and interstitium (cortex and medulla). At 25 days, the collagen deposition reached the highest level in all regions, cellular proliferation decreased, and thickening of the arteriolar wall became prominent. The renal lesions were coupled with changes in the levels of protein, RNA, DNA, and hydroxyproline. At 40 days, the kidney showed signs of recovery. Blood urea nitrogen levels were significantly elevated at 2-25 days post-treatment. Stained tissue sections from liver, lung, heart, spleen, thymus, lymph nodes, testes, and adrenal glands of the treated rats were examined microscopically and appeared normal. Biochemically, significant changes (p less than .05) in protein, RNA, DNA, and hydroxyproline were also observed in these organs. At lower dosage (0.6 mg V/kg per day for 16 days), similar but less severe pathological and biochemical changes in kidneys and other organs were observed. At 0.3 mg V/kg per day for 16 days, the changes in the tissues were detected only at the biochemical level. These results indicate that the toxic effects of vanadium are cumulative and that vanadium-produced fibrosis in tissues is dose-dependent.     

Habekacin: a new aminoglycoside. Study of nephrotoxicity in rats in comparison with gentamicin, netilmicin and amikacin

Habekacin is a new aminoglycoside antibiotic. In this study we want to know the effect of increasing dose of habekacin on renal function and on renal morphology. We decide to compare the renal alterations induced by habekacin to these provoked by gentamicin, netilmicin and amikacin. Female Wistar rats received intraperitonally a single injection daily of 10, 30, 50, 150 mg/kg of habekacin for seven days. Wistar rats received also 50 mg/kg gentamicin, 50 mg/kg netilmicin and 150 mg/kg amikacin. No mortality was observed in groups treated with 10, 30, 50 mg/kg habekacin but 50 per cent of rats died with 150 mg/kg habekacin. Habekacin--30 mg/kg seven days--induced a decrease of cortical enzymatic activities, an increase of the number of lysosomes, a great accumulation of myeloid bodies, an alteration of lysosomal membranes Habekacin--50 mg/kg seven days and 150 mg/kg--induced a decrease of creatinine clearance and ultrastructural alterations of renal tubular cells. Comparative studies with other aminoglycosides showed that amikacin--150 mg/kg was the lesser nephrotoxic drug. With a same dose of 50 mg/kg, gentamicin appeared lesser nephrotoxic than habekacin and habekacin seemed to induce a same degree of renal modifications than netilmicin. With the dose of 150 mg/kg habekacin this drug was higher nephrotoxic than 50 mg/kg gentamicin. In conclusion, if it could be necessary to use habekacin and to prefer this aminoglycoside to gentamicin from an antibacterial activity point of view it is necessary to keep in mind that this drug is potentially nephrotoxic and that the dosage had to be strictly respected.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal and hepatic function in rats treated with cyclosporin A in combination with gentamicin or cephalosporin antibiotics.

Sprague-Dawley rats received cyclosporin A (25 mg/kg) together with either the aminoglycoside gentamicin (50 mg/kg) or one of 3 cephalosporin antibiotics (100 mg/kg) daily for 14 days. Only minor impairment of renal or hepatic function was observed when either cyclosporin A or gentamicin was given on its own and no abnormality was seen in response to cephalosporins. However, concomitant administration of cyclosporin A and gentamicin caused acute renal failure, accompanied by cyclosporin A-induced damage to the proximal straight tubule and gentamicin-induced proximal convoluted tubular cell necrosis. In contrast, the structural abnormalities present in the 3 groups given cephalosporins in addition to cyclosporin A were attributable only to the immune suppressant. Liver functional changes previously found only at higher doses of cyclosporin A were observed in the cyclosporin A/gentamicin group and there was some evidence of possible interactions between cyclosporin A and each cephalosporin affecting liver function. The results indicate that treatment of infection with cephalosporin antibiotics or a less nephrotoxic aminoglycoside is preferable to gentamicin in cyclosporin A-treated patients.     

Gentamicin-induced nephrotoxicity in mice: protection by loop diuretics.

Gentamicin, at doses of 50 or 100 mg/kg body wt administered daily to healthy male MF1 mice by i.p. injection for either 7 or 10 days caused proximal tubular cell damage shown both by the urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) and by electron microscopy. The tubular damage was maximal at 7 days. Concomitant administration of any of 3 diuretics-frusemide, bumetanide or piretanide at 5,0.5 and 1 mg/kg body wt/day respectively-resulted in less tubular damage than that caused by gentamicin alone. This finding of protection by diuretics contrasts with those of previous studies of combination gentamicin-diuretic therapy.     

Alterations in renal cortex cation homeostasis during mercuric chloride and gentamicin nephrotoxicity

To help better understand the role of changes in cellular cation homeostasis in the pathogenesis of renal tubular cell injury, the alterations in cation content of renal cortex and isolated renal cortical mitochondria occurring during models of nephrotoxicity secondary to gentamicin and HgCl₂ were determined both during a developing phase of injury prior to the appearance of cell necrosis and after advanced injury when cell necrosis was present. At 3 hr after 5 mg/kg HgCl₂ or after 4 daily doses of 100 mg/kg gentamicin, tubular cell integrity was still intact but mitochondrial functional changes were present. There were no alterations of renal cortex tissue electrolytes at this stage in the HgCl₂ model but tissue K⁺, and more prominently, tissue Mg²⁺ were decreased in the gentamicin model. K⁺ and Mg²⁺ contents of isolated mitochondria were slightly reduced after HgCl₂. Only K⁺ content was slightly reduced after gentamicin. No evidence for tissue or mitochondrial Ca²⁺ overload was present in either model. At 12 hr after 5 mg/kg HgCl₂ or after 10 daily 100 mg/kg doses of gentamicin, widespread areas of tubular cell necrosis were present and the function of isolated mitochondria was severely compromised. Tissue electrolytes at this stage of injury in both models were characterized predominantly by a twofold increase in Na⁺ content and five- to sixfold increases in Ca²⁺. Isolated mitochondria showed marked decreases in K⁺ content and marked increases in content of Na⁺ and Ca²⁺. These data suggest that neither cellular and mitochondrial Ca²⁺ overload nor substantial changes in cellular Na⁺ and K⁺ homeostasis can be implicated in the early stages of renal tubular cell injury produced by gentamicin and HgCl₂.     

Effects of the calcium-channel blocker diltiazem on gentamicin-induced nephrotoxicity in rats

Injection of diltiazem (40 mg/kg/d) to gentamicin (75 mg/kg/d = G 75 or 100 mg/kg/d = G 100) treated rats enhances aminoglycoside-induced nephrotoxicity. As a result of this combination, acute renal failure becomes systematic and is often irreversible. The lesion is of tubular origin and is characterized by a large increase in the urinary N-acetyl-beta-D-glucosaminidase (u-NAG) activity and its NAG-B isoenzyme level. The phenomenon is twice as marked with G 75 (u-NAG x 6.8, NAG-B x 2.2) as with G 100 (u-NAG x 3.1, NAG-B x 1.1). The effect seems to be attenuated if diltiazem is administered as a preventive treatment or in drinking water. As well as its diuretic properties, diltiazem may aggravate the renal toxicity of gentamicin by reducing the proximal tubular availability of calcium. Diltiazem inhibits reabsorption and behaves like a non-competitive inhibitor of calcium. This deficiency favours the proximal tubular binding and the non-specific penetration of gentamicin in the cytosol and cellular organelles (microsomes, mitochondria). The tubular toxic symptoms which ensure (inactivation of membranaceous enzyme, reduction of microsomal protein synthesis and ATP level, decreased of solute reabsorptive flux) lead in turn to proximal tubular necrosis and acute renal failure.     

On the effect of prednisolone on hamster bone.

Over a period of 10.8 weeks 0.4, 4.0 or 40.0 mg, respectively of prednisolone bisuccinate/kg/day were injected intramuscularly into Syrian golden hamsters with a body weight of about 100 g. The dosage of 4.0 mg of prednisolone/kg did not produce any osteoporotic changes. The modulus of elasticity and the fracture load of the bones under investigation did not differ from the values obtained in control animals. At a dosage of 0.4 mg of prednisolone/kg/day the values of analysis (density, ash/cm3, calcium/cm3 and hydroxyproline/cm3) decreased by 5-8 percent, and at a dosage of 40.0 mg of prednisolone/kg/day even by 20-34 per cent as compared with the control group. The modulus of elasticity and the fracture load were significantly changed.     

The protective effect of nitrendipine on gentamicin acute renal failure in rats

Aminoglycoside nephrotoxicity was produced in two groups of Fischer rats by intraperitoneal injection of gentamicin, 40 mg/kg/day for 2 weeks. Beginning 3 days prior to, and continuing throughout the 2-week treatment period, one of the groups (control) received the inert vehicle, polyethylene glycol, while the experimental group was given nitrendipine, a calcium channel blocker, in a dose of 25 mg/kg/day by gavage. Both groups received food and water ad libitum. Gentamicin with vehicle caused a marked decrease in inulin clearance (4.9 ml/min/kg) and paraaminohippurate (PAH) extraction (26%), and extensive renal tubular necrosis. In comparison, the nitrendipine-treated rats had a significantly increased clearance (9.8 ml/min/kg) and PAH extraction (48%), and less histopathologic damage. Renal tissue content of gentamicin was not influenced by nitrendipine after 4 days of dosing. Nitrendipine, a diisopyridine derived calcium channel blocker, offers significant functional and histologic protection against aminoglycoside nephrotoxicity in Fischer rats. Its mode of action in this regard is unknown.     

Plasma protein extravasation and vascular endothelial growth factor expression with endothelial nitric oxide synthase induction in gentamicin-induced acute renal failure in rats

Microvascular hyperpermeability to plasma proteins via vascular endothelial growth factor (VEGF) with endothelial nitric oxide synthase (eNOS) induction may contribute to wound healing through matrix remodeling. However, vascular hyperpermeability is not examined in acute renal failure (ARF), a unique form of wound healing. Subcutaneous injection of gentamicin (400 mg/kg per day for 2 days in divided doses every 8 h) in rats increased serum creatinine levels and induced tubular damage, which peaked at day 6, after the last gentamicin injection. Ki67-positive regenerating proximal tubules (PTs) peaked in number at day 6 and almost covered the bare tubular basement membrane (TBM) by day 10. Staining of fibrinogen and plasma fibronectin began to increase in the peritubular regions as early as day 0, steadily increased in TBM and tubular lumen until day 6 and then decreased. Hyperpermeable peritubular capillaries were identified by extravasation of perfused-fluoresceinated dextran (both 70 kDa and 250 kDa) into peritubular regions as early as day 0 and prominently into TBM and tubular lumen at day 6. Electron microscopy further suggested the intraendothelial pathway of dextran. Immunoreactive VEGF increased in the damaged and regenerating PTs. Immunoreactive VEGF receptors-1 and -2 did not change, but immunoreactive eNOS increased in the peritubular capillaries after induction of ARF. Western blotting for VEGF and eNOS supported the immunostaining findings. In addition, we assessed the effects of NOS inhibitor N-nitro-l-arginine methyl ester (l-NAME) on vascular hyperpermeability during the recovery phase of this model. Treatment with l-NAME (s.c. at a dose of 100 mg/kg/day from day 3 to day 6) decreased extravasation of perfused-250-kDa dextran and significantly inhibited the regenerative repair of PTs at day 6 when compared with vehicle-treated rats. In conclusion, plasma protein extravasation occurred, leading to matrix remodeling, such as the process of wound healing during the tubular repair in gentamicin-induced ARF. Since VEGF-induced vascular hyperpermeability may depend on NO production, VEGF/VEGF receptor system with eNOS induction might be responsible for this process.     

Cyclosporin A-induced nephrotoxicity in the rat: Relationship to increased plasma renin activity

Cyclosporin A (CsA; 50, 100 or 150 mg/kg) was administered by gavage, daily for 4 days, to groups of normotensive rats. An additional group of animals received the drug vehicle. CsA-induced nephrotoxicity, characterized by reduced glomerular filtration rate (GFR) and urinary sodium flow, enzymuria and proximal tubular cell damage was accompanied by elevated plasma renin activity (PRA).These changes were dose-related at 50 and 100 mg/kg CsA, but were not increased by administration of 150 mg/kg. Circulating trough drug levels were related to dosage.Four days after CsA withdrawal in animals given 50 mg/kg, there was reduced nephrotoxicity and PRA had returned to normal, even though circulating CsA levels had not diminished. Rats given 100 and 150 mg/kg, however, showed no reduction in nephrotoxicity or in PRA. Hyperglycaemia was evident at 4 days in animals given 100 and 150 mg/kg CsA and persisted 4 days after drug withdrawal.There were no accompanying abnormalities in islet cell structure.Continuous administration of CsA (50 mg/kg) to rats for 14 days caused elevated PRA on day 4 but a return to normal levels by day 7. In contrast, significant GFR impairment was evident by day 7 whilst enzymuria was significantly increased from day 4 onwards.CsA nephrotoxicity in the rat is clearly associated with activation of the renin-angiotensin-aldosterone system. Possible mechanisms leading to increased renin release are discussed.     

Dose-related protecting effects of vitamin C in gentamicin-induced rat nephrotoxicity: a histopathologic and biochemical study

Gentamicin remains the mainstay in treatment of gram-negative infections, despite its potential ototoxicity and nephrotoxicity. In this study, we investigated dose-related protecting effects of vitamin C against gentamicin-induced rat nephrotoxicity. Hence, 50 male albino Wistar rats were randomly divided into five equal groups to receive a corresponding dose of either normal saline as control, vitamin C (200 mg/kg/bw, i.m.) or gentamicin alone (80 mg/kg/bw, i.m.) or in combination with vitamin C at low dose (200 mg/kg/bw, i.m.; LVG) and high dose (600 mg/kg/bw, i.m.) for 9 days. Daily administration of gentamicin at a dose of 80 mg/kg resulted in a significant increase in oxidative stress in renal tissues and plasma and a concomitant decrease in the creatinine clearance and renal blood flow as result of early hemodynamic toxicity. Histopathological examinations revealed acute tubular necrosis with hyaline cast formation triggered by gentamicin over 9 days of experiment, in addition to interstitial nephritis and tubular epithelial loss. Further biochemical studies showed protecting effects of supplemented vitamin C at a high dose, including slowdown in the urinary enzyme activity, a significant decrease in plasma lipid peroxidation, and an increased tissue superoxide dismutase activity with recovery in the glomerular hemodynamicity and the ATPase activity up to 50% when compared to controls and low-dose rats (LVG). In high-dose animals, normal glomerular and tubular function on recovery from toxic renal failure led us to conclude that antioxidant properties of vitamin C consistently increase with dose intensity. The present study also provided evidence that high dose of vitamin C prevented both functional and histological renal changes induced by gentamicin in rats, more efficient than low dose of the vitamin.     

A light and electron microscopic analysis of gentamicin nephrotoxicity in rats.

The sequence of proximal tubular damage and repair after gentamicin sulfate administration was studied by light and electron microscopy in Fischer 344 rats. The drug was administered at a dose of 40 mg/kg for up to 14 days. Although epithelial destruction was progressive with time, the extent and degree of tubular damage varied among animals at each interval. Tubule regeneration began to occur by the tenth day despite continued drug administration. Regenerating cells appeared to originate from residual epithelial cells in areas of tubular damage. The morphologically immature regenerating cells are apparently metabolically immature as well and appear not to be susceptible to toxic effects of the drug. Tubules were repopulated by 3 days following cessation of gentamicin administration. Except for foci of tubular atrophy and interstitial fibrosis, cortical tissues were comparable to controls ultrastructurally at the end of 31 days.     

Effect of Lycopene and Rosmarinic Acid on Gentamicin Induced Renal Cortical Oxidative Stress,Apoptosis, and Autophagy in Adult Male Albino Rat

Gentamicin nephrotoxicity accounts for 10%–15% of all cases of acute renal failure. Several natural antioxidants were found to be effective against drug‐induced toxicity. The possible protective effects of lycopene (Lyc) and rosmarinic acid (RA) alone or combined on gentamicin (Gen) induced renal cortical oxidative stress, apoptosis, and autophagy were evaluated. Sixty‐three rats were randomly divided into seven groups named: control, group II received RA 50 mg/kg/day, group III received Lyc 4 mg/kg/day, group IV received Gen 100 mg/kg/day, group V (RA + Gen), group VI (Lyc + Gen), and group VII (RA + Lyc + Gen). At the end of the experiment, kidney functions were estimated then the kidneys were sampled for histopathological, immunohistochemistry, and biochemical studies. Administration of rosmarinic acid and lycopene decreased elevated serum creatinine, blood urea nitrogen, renal malondialdehyde and immunoexpression of the proapoptotic protein (Bax), autophagic marker protein (LC3/B), and inducible nitric oxide synthase (iNOS) induced by gentamicin. They increased reduced glutathione, glutathione peroxidase, superoxide dismutase, and immunoexpression of the antiapoptotic protein (Bcl2). They also improved the histopathological changes induced by gentamicin. The combination therapy of rosmarinic acid and lycopene shows better protective effects than the corresponding monotherapy. Anat Rec, 300:1137–1149, 2017. © 2016 Wiley Periodicals, Inc.     

Protective effects of corn silk extract administration on gentamicin-induced nephrotoxicity in rat

The objective of this study was to evaluate effect of corn silk against gentamicin (GM)-induced nephrotoxicity. Sixty Wistar rats were divided into ten equal groups as follow: (1) control group, 0.1 ml/kg given intraperitoneally (i.p.) per day of isotonic saline. (2) GM group, 100 mg/kg i.p. per day of GM. (3) corn silk groups (3–6), 200, 300, 400, and 500 mg/kg, i.p. (4) Corn silk + GM groups (7–10), corn silk extract was injected the same as corn silk groups and after1 h, 100 mg/kg GM was injected i.p. to rats. All animals were treated for 8 days. Plasma creatinine and urea levels significantly increased in GM group. Corn silk administration (200 and 300 mg/kg) with GM injection significantly decreased serum creatinine, but not urea, levels compared with GM group. Acute tubular necrosis (ATN), hyaline casts in tubular lumen, interstitial nephritis, and glomerular changes were histopathologically detected in the GM group. Co-treatment of corn silk with GM considerably decreased the interstitial nephritis, but not ATN and hyaline casts formation, compared with the GM group. Also, high dose of corn silk caused hyaline cast formation, apoptosis, congestion, and swelling of renal tubules. In conclusion, the results showed that corn silk may ameliorate nephropathy during prolonged therapeutic use of GM and related aminoglycosides.     

Antioxidant protecting effects of vitamin B6 at reducing hemodynamic toxicity of gentamicin in rat model of nephrotoxicity

Routine therapeutic use of gentamicin in patients with preexisting renal failure may confront us with the toxic effects of aminoglycosides in the kidney known as nephrotoxicity. It is a common and often overlooked clinical entity that presents itself in the setting of oxidative stress-associated diseases in older individuals with renal failure. In this study, we investigated the antioxidant protecting effects of vitamin B₆ in the kidney, with a view on vasoregulatory role of renal pyridoxal 5′-phosphate at reducing the hemodynamic toxicity of gentamicin. Hence, 50 male Sprague–Dawley rats were randomly assigned in five groups to receive a corresponding dose of either normal saline, vitamin B₆ (100 mg/kg/bw; i.m.) or gentamicin alone (80 mg/kg/bw; i.m.), or in combination with vitamin B₆ at low (100 mg/kg/bw; i.m.) and high dose (200 mg/kg/bw; i.m.) for 10 days as animal model of nephrotoxicity. Daily administration of gentamicin at a dose of 80 mg/kg resulted in a significant increase in local and systemic oxidative stress and a decrease in glomerular functions as result of early hemodynamic toxicity. Histopathological examinations of renal tissues revealed acute tubular necrosis with hyaline cast formation triggered by gentamicin over 9 days of the experiment, in addition to interstitial nephritis and tubular epithelial loss. Further biochemical studies in HVB group showed the protecting effects of supplemented vitamin B₆ at a high dose, including a slowdown in urinary enzyme activity, a significant decrease in plasma lipid peroxidation, and an increased tissue superoxide dismutase activity with recovery in the glomerular hemodynamicity and ATPase activity up to 50 % when compared to low-dose rats and controls. In high-dose animals, normal glomerular and tubular function on recovery from toxic renal failure led us to conclude that antioxidant properties of vitamin B₆ consistently increase with dose intensity. The present study also provided evidence that high dose of vitamin B₆ prevented both functional and histological renal changes induced by gentamicin in rats, more efficient than low dose of the vitamin.     

Effect of the hypolipidemic drug RMI 14,514 on hepatic ultrastructure of rats

The oral administration of 150 mg/kg/day of the drug RMI 14,514 (5-tetradecyloxy-2-furancarboxylic acid) to rats for 4 months resulted in a significant reduction in plasma total and esterified cholesterol, an effect more pronounced in males. After 1 month of treatment, fine structural alterations of hepatocytes first appeared as vacuoles within the matrix of the microbodies. Microbodies lacking these changes frequently exhibited one of three types of tubular formations which were of variable diameter: the most common, type 1 (690–790 Å); type 2 (370–460 Å); type 3 (1480–1680 Å). Relative to the microbody limiting membrane, these tubules were either external (types 1 or 3) or internal (type 2) and frequently protruded in apposition to other organelles. The microbodies also increased in number as well as size after 1 week of treatment with 150 mg/kg/day of RMI 14,514. Dosages of 100 or 200 mg/kg/day for 6 months produced additional findings of focal hyperplasia of the smooth and rough endoplasmic reticulum. Following a 1-month recovery period, hepatocytes from rats previously treated with a 150-mg/kg/day dosage for 4 months had a fine structure similar to controls, indicating a reversibility of drug-induced alterations.