The Salutary Effects of Diminazene, Lisinopril or Valsartan on Cisplatin - Induced Acute Kidney Injury in Rats: A Comparative Study.

Nephrotoxicity as a cause of acute kidney injury (AKI) induced by cisplatin (CP), limits its usefulness as an anticancer agent. Diminazene, an angiotensin converting enzyme 2 activator, exhibited renoprotective properties on rat models of kidney diseases. This research aims to investigate the salutary effect of diminazene in comparison with lisinopril or valsartan in CP-induced AKI. The first and second groups of rats received oral vehicle (distilled water) for 9 days, and saline injection or intraperitoneal CP (6 mg/kg) on day 6, respectively. Third, fourth, and fifth groups received intraperitoneal injections of CP on day 6 and diminazene (15 mg/kg/day, orally), lisinopril (10 mg/kg/day, orally), or valsartan (30 mg/kg/day, orally), for 9 days, respectively. 24h after the last day of treatment, blood and kidneys were removed under anesthesia for biochemical and histopathological examination. Urine during the last 24 h before sacrificing the rats was also collected. CP significantly increased plasma urea, creatinine, neutrophil gelatinase-associated lipocalin, calcium, phosphorus, and uric acid. It also increased urinary albumin/creatinine ratio, N-Acetyl-beta-D-Glucosaminidase/creatinine ratio, and reduced creatinine clearance, as well the plasma concentrations of inflammatory cytokines [plasma tumor necrosis factor-alpha, and interleukin-1beta], and significantly reduced antioxidant indices [catalase, glutathione reductase , and superoxide dismutase]. Histopathologically, CP treatment caused necrosis of renal tubules, tubular casts, shrunken glomeruli, and increased renal fibrosis. Diminazine, lisinopril, and valsartan ameliorated CP-induced biochemical and histopathological changes to a similar extent. The salutary effect of the three drugs used is, at least partially, due to their anti-inflammatory and antioxidant effects. Keywords: Cisplatin, Diminazene, ACE2 activator, Lisinopril, Valsartan, Acute kidney injury.

Waterpipe smoke inhalation induces lung injury and aortic endothelial dysfunction in mice.

Waterpipe tobacco smoking (WPS) inhalation has been shown to trigger endothelial dysfunction and atherosclerosis. However, the mechanisms underlying these effects are still unknown. Here, we assessed the impact and underlying mechanism of WPS exposure for one month on endothelial dysfunction using aortic tissue of mice. The duration of the session was 30 min/day and 5 days/week. Control mice were exposed to air. Inhalation of WPS induced an increase in the number of macrophages and neutrophils and the concentrations of protein, tumor necrosis factor alpha (TNF alpha), interleukin (IL)-1beta, and glutathione in bronchoalveolar lavage fluid. Moreover, the concentrations of proinflammatory cytokines (TNF alpha, IL-6 and IL-1beta), adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin and P-selectin) and markers of oxidative stress (lipid peroxidation, glutathione, superoxide dismutase and nitric oxide) in aortic homogenates of mice exposed to WPS were significantly augmented compared with air exposed mice. Likewise, the concentration of galectin-3 was significantly increased in the aortic homogenates of mice exposed to WPS compared with control group. WPS inhalation induced vascular DNA damage assessed by comet assay and apoptosis characterized by a significant increase in cleaved caspase-3. While the aortic expression of phosphorylated nuclear factor kappaB (NF-kappaB) was significantly increased following WPS inhalation, the concentration of sirtuin 1 (SIRT1) was significantly decreased in WPS group compared with air-exposed group. In conclusion, our study provided evidence that WPS inhalation triggers lung injury and endothelial inflammation, oxidative stress and apoptosis which were associated with nuclear factor-kappaB activation and SIRT1 down-regulation.

Osteoradionecrosis of the lamina papyracea leading to recurrent orbital infections-A case study.

Osteoradionecrosis (ORN) is a well-known complication of radiotherapy (RT) to the sino-nasal cavity and nasopharynx. Here, we report a case of recurrent orbital infections secondary to ORN of the lamina papyracea (LP). A 66-year-old female presented to our unit with right periorbital swelling and pain after having undergone chemotherapy and proton beam irradiation to her ethmoid sinuses for sino-nasal undifferentiated carcinoma (SNUC) 5 years prior. She had also undergone endoscopic sinus surgery for chronic rhinosinusitis about a year prior to the current presentation. Her post-operative course was notable for recurrent episodes of pre-septal cellulitis occurring about 3 months apart that were increasingly severe. Examination revealed right proptosis, and endoscopy showed an exposed and denuded LP with scant crusting of the ethmoid sinuses. Microbial studies did not yield any significant growth, and imaging showed enhancement of the right orbit. The working diagnosis was acute right orbital cellulitis secondary to ORN of the right LP. She was treated with broad spectrum intravenous antibiotics and systemic steroids, but experienced minimal symptomatic improvement. She then underwent endoscopic resection of the right LP, and histopathological examination showed osteonecrosis on an inflammatory background. Post-operatively, all orbital symptoms resolved and she was well at 6 months' follow up. In the discussion, we highlight additional factors in our patient that may have contributed to this clinical presentation, and hope that this report raises awareness of a rare complication of RT to the sino-nasal cavity.

Insulin resistance in nondiabetic Egyptian patients with chronic hepatitis C virus. / Resistencia a la insulina en pacientes egipcios no diabéticos infectados con el virus de hepatitis C crónica.

INTRODUCTION AND OBJECTIVE: Insulin resistance and diabetes mellitus are frequently associated with chronic hepatitis C virus (HCV) infection, and it is thought that the presence of insulin resistance aggravates liver disease. We aimed to evaluate insulin resistance in nondiabetic Egyptian patients with chronic HCV infection. MATERIALS AND METHODS: Sixty nondiabetic patients with chronic HCV infection and 30 healthy nondiabetic non-HCV-infected volunteers were enrolled in our study. They were divided into 3 groups: group 1 included 30 patients with chronic HCV infection with no cirrhosis, group 2 included 30 patients with chronic HCV infection and cirrhosis of the liver, and group 3 included 30 healthy volunteers as controls. The entire study population underwent a detailed clinical history and physical examination, weight and height measurement, routine laboratory tests, and viral marker determination that included hepatitis B surface antigen and HCV antibodies. PCR analysis was carried out on the patients with positive HCV antibodies. Fasting blood sugar and fasting insulin levels were measured in all the patients, and insulin resistance was calculated according to the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: Patients with cirrhosis of the liver (2 patients with Child class A, 12 patients with Child class B, and 16 patients with Child class C) showed higher insulin resistance levels (2.76±0.97) than the patients with chronic HCV infection and no cirrhosis (2.03±0.743) and the control group (1.22±0.38). The p value was significantly different between the 3 groups. There were direct and significant correlations between insulin resistance, fasting blood sugar, and fasting insulin levels. Patients with chronic HCV infection showed significantly higher fasting insulin and glucose levels than the control group. CONCLUSION: Chronic HCV-infected patients showed significantly higher insulin resistance levels than the normal population, even in the absence of hepatic dysfunction and cirrhosis.

Ameliorative effect of sesamin in cisplatin-induced nephrotoxicity in rats by suppressing inflammation, oxidative/nitrosative stress, and cellular damage.

Nephrotoxicity of cisplatin (CP) involves renal oxidative stress and inflammation, and sesamin (a major liganin in many plants) has strong antioxidant and antiinflammatory actions. Therefore, we investigated here the possible mitigative action of sesamin on CP nephrotoxicity in rats. Sesamin was given orally (5 mg/kg/day, 10 days), and on the 7th day, some of the treated rats were injected intraperitoneally with either saline or CP (5 mg/kg). On the 11th day, rats were sacrificed, and blood and urine samples and kidneys were collected for biochemical estimation of several traditional and novel indices of renal damage in plasma and urine, several oxidative and nitrosative indices in kidneys, and assessment of histopathological renal damage. CP significantly and adversely altered all the physiological, biochemical and histopathological indices of renal function measured. Kidneys of CP-treated rats had a moderate degree of necrosis. This was markedly lessened when CP was given simultaneously with sesamin. Sesamin treatment did not significantly alter the renal CP concentration. The results suggested that sesamin had ameliorated CP nephrotoxicity in rats by reversing the CP-induced oxidative stress and inflammation. Pending further pharmacological and toxicological studies sesamin may be considered a potentially useful nephroprotective agent.

Effect of diesel exhaust particles on renal vascular responses in rats with chronic kidney disease.

Several recent studies have indicated the possible association between exposure to particulate air pollution and the increased rate of morbidity and mortality in patients with kidney diseases. The link of this observation to vascular damage has not been adequately addressed. Therefore, this study aims to investigate possible vascular damage that might be associated with exposure to diesel exhaust particles (DP) in adenine (AD)-induced chronic kidney disease (CKD) in rats, and the possible ameliorative effect of gum acacia (GA). CKD was induced by feeding AD (0.75%, w/w), and DP (0.5 mg/kg) was instilled intratracheally every second day and GA was given concomitantly in the drinking water at a dose of 15% w/v. All treatments were given concomitantly for 28 days. Changes in renal blood flow (RBF) and systolic and diastolic blood pressure were monitored in these animals after anesthesia, together with several other endpoints. Exposure to DP significantly reduced RBF and this was significantly potentiated in AD-treated rats. Phenylephrine-induced decreases in RBF and increases in systolic and diastolic blood pressure were severely potentiated in rats exposed to DP, and these actions were significantly augmented in AD-treated rats. GA did not significantly affect the vascular impairment induced by AD and DP given together. This study provides experimental evidence that exposure to particulate air pollution can exacerbate the vascular damage seen in patients with CKD. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 541-549, 2017.

The in vivo effects of adenine-induced chronic kidney disease on some renal and hepatic function and CYP450 metabolizing enzymes.

Adenine-induced model of chronic kidney disease (CKD) is a widely used model especially in studies testing novel nephroprotective agents. We investigated the effects of adenine-induced CKD in rats on the activities of some xenobiotic metabolizing enzymes in liver and kidneys, and on some in vivo indicators of drug metabolism (viz pentobarbitone sleeping time, and plasma concentration of theophylline 90 min post administration). CKD was induced by orally feeding adenine (0.25 % w/w) for 35 days. Adenine induced all the characteristics of CKD, which was confirmed by biochemical and histological findings. Glutathione concentration and activities of some enzymes involved in its metabolism were reduced in kidneys and livers of rats with CKD. Renal CYP450 1A1 activity was significantly inhibited by adenine, but other measured isoenzymes (1A2, 3A4 and 2E1) were not significantly affected. Adenine significantly prolonged pentobarbitone-sleeping time and increased plasma theophylline concentration 90 min post administration. Adenine also induced a moderate degree of hepatic damages as indicated histologically and by significant elevations in some plasma enzymes. The results suggest that adenine-induced CKD is associated with significant in vivo inhibitory activities on some drug-metabolizing enzymes, with most of the effect on the kidneys rather than the liver.

Gum acacia mitigates genetic damage in adenine-induced chronic renal failure in rats.

BACKGROUND: Subjects with chronic renal failure (CRF) exhibit oxidative genome damage, which may predispose to carcinogenesis, and Gum acacia (GumA) ameliorates this condition in humans and animals. We evaluated here renal DNA damage and urinary excretion of four nucleic acid oxidation adducts namely 8-oxoguanine (8-oxoGua), 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), 8-oxoguanosine (8-oxoGuo) and 8-hydroxy-2-deoxyguanisone (8-OHdg) in rats with adenine (ADE)-induced CRF with and without GumA treatment. MATERIALS AND METHODS: Twenty-four rats were divided into four equal groups and treated for 4 weeks. The first group was given normal food and water (control). The second group was given normal food and GumA (15% w/v) in drinking water. The third group was fed powder diet containing adenine (ADE) (0·75% w/w in feed). The fourth group was fed like in the third group, plus GumA in drinking water (15%, w/v). RESULTS: ADE feeding induced CRF (as measured by several physiological, biochemical and histological indices) and also caused a significant genetic damage and significant decreases in urinary 8-oxo Gua and 8-oxoGuo, but not in the other nucleic acids. However, concomitant GumA treatment reduced the level of genetic damage in kidney cells as detected by Comet assay and significantly reversed the effect of adenine on urinary 8-oxoGuo. CONCLUSIONS: Treatment with GumA is able to mitigate genetic damage in renal tissues of rats with ADE-induced CRF.

Influence of treatment with gum acacia on renal vascular responses in a rat model of chronic kidney disease.

OBJECTIVE: This study was conducted in order to investigate the effects of adenine-induced chronic kidney disease (CKD) on renal blood flow and biochemical changes in rats, and to assess the effect of treatment with gum acacia (GA) thereon. MATERIALS AND METHODS: CKD was induced by feeding rats with adenine (0.25% w/w, five weeks). Concomitantly, some of these rats were also given gum acacia (GA) (15% w/v in the drinking water). Before animals were sacrificed, changes in renal blood flow (RBF) were monitored in anaesthetized rat preparations. Several biochemical and histological renal function tests were also conducted. RESULTS: Adenine-induced CKD significantly impaired the vasopressor actions of acetylcholine, sodium nitroprusside and phenylephrine and concomitant treatment with GA abated these responses. Additionally, plasma concentrations of urea, creatinine, uric acid, indoxyl sulfate, nitrite and nitrate and urinary excretion of protein were all significantly increased by adenine. GA significantly mitigated the severity of adenine-induced changes. CONCLUSIONS: Adenine-induced CKD in rats significantly impaired renal vascular responses to acetylcholine, sodium nitroprusside and phenylephrine and this was mitigated by treatment with GA. This provides another experimental evidence for the usefulness of GA in the amelioration of CKD.

High-mobility group box-1 protein in adenine-induced chronic renal failure and the influence of gum arabic thereon.

Pathogenesis of adenine-induced chronic renal failure may involve inflammatory, immunological and/or oxidant mechanisms. Gum arabic (GA) is a complex polysaccharide that acts as an anti-oxidant which can modulate inflammatory and/or immunological processes. Therefore, we tested here the effect of GA treatment (15 % in the drinking water for 4 weeks) in plasma and urine of rats, on a novel cytokine that has been shown to be pro-inflammatory, viz, DNA-binding high-mobility group box-1 protein (HMGB1). Adenine (0.75 % in the feed, 4 weeks) significantly increased indoxyl sulphate, urea and creatinine concentrations in plasma, and significantly decreased the creatinine clearance. GA significantly abated these effects. The concentrations of HMGB1 in urine before the start of the experiment were similar in all four groups. However, 24 h after the last treatment, adenine treatment increased significantly the concentration of HMGB1 when compared with the control. GA treatment did not affect the HMGB1 concentration in urine. Moreover, the concentration of HMGB1 in plasma obtained 24 h after the last treatment in rats treated with adenine was drastically reduced compared with the control group. This may explain its significant rise in urine. In conclusion, HMGB1 can be considered a potentially useful biomarker in adenine induced CRF and its treatment.

Anemia in adenine-induced chronic renal failure and the influence of treatment with gum acacia thereon.

Anemia frequently complicates chronic kidney disease (CKD). We investigated here the effect of adenine-induced CKD in rats on erythrocyte count (EC), hematocrit (PCV) and hemoglobin (Hb) concentration, as well as on the activity of L-gamma-glutamyl transferase (GGT) and the concentrations of iron (Fe), transferrin (Tf), ferritin (F), total iron binding capacity (TIBC) / unsaturated iron binding capacity (UIBC) and hepcidin (Hp) in serum and erythropoietin (Epo) in renal tissue. Renal damage was assessed histopathologically, and also by measuring the serum concentrations of the uremic toxin indoxyl sulfate (IS), creatinine, and urea, and by creatinine clearance. We also assessed the influence of concomitant treatment with gum acacia (GA) on the above analytes. Adenine feeding induced CKD, accompanied by significant decreases (P<0.05) in EC, PCV, and Hb, and in the serum concentrations of Fe, Tf, TIBC, UIBC and Epo. It also increased Hp and F levels. GA significantly ameliorated these changes in rats with CKD. A general improvement in the renal status of rats with CKD after GA is shown due to its anti-inflammatory and anti-oxidant actions, and reduction of the uremic toxin IS, which is known to suppress Epo production, and this may be a reason for its ameliorative actions on the indices of anemia studied.

Motor and behavioral changes in mice with cisplatin-induced acute renal failure.

We have previously shown that chronic renal failure in rats induces changes in motor activity and behavior. Similar work on the possible effects of acute renal failure (ARF) induced by cisplatin (CP) is lacking. This is the subject matter of the current work. CP was injected intraperitoneally (i.p.) at a single dose of 20 mg/kg to induce a state of ARF, and three days later, its effects on motor activity, thermal and chemical nociceptive tests, neuromuscular coordination, pentobarbitone-sleeping time, exploration activity and two depression models were investigated. The platinum concentration in the kidneys and brains of mice was also measured. The occurrence of CP-induced ARF was ascertained by standard physiological, biochemical and histo-pathological methods. CP induced all the classical biochemical, physiological and histopathological signs of ARF. The average renal platinum concentration of CP-treated mice was 5.16 ppm, but there was no measurable concentration of platinum in the whole brains. CP treatment significantly decreased motor and exploration activities, and increased immobility time in depression models, suggesting a possible depression-like state. There was also a significant decrease in neuromuscular coordination in CP-treated mice. CP, given at a nephrotoxic dose, induced several adverse motor and behavioral alterations in mice. Further behavioral tests and molecular and biochemical investigations in the brains of mice with CP-induced ARF are warranted.

Some physiological and histological aspects of the gastrointestinal tract in a mouse model of chronic renal failure.

INTRODUCTION: It has been reported that mice with 5/6 nephrectomy- induced chronic renal failure (CRF) have reduced gastrointestinal transit (GIT) and increased fecal moisture content (FMC). We have recently shown that feeding adenine (0.2%, w/w) to mice can be used as a model of CRF. Here, we investigated the possible effects of adenine-induced CRF on several in vivo and in vitro aspects of GIT physiology and histology of the stomach, duodenum, ileum and colon in mice. METHODS: The effects of CRF induced by feeding adenine (0.2%, w/w for 2 or 4 weeks) on the gastric emptying index (GEI), GIT, FMC and bead expulsion test (BET) were investigated. GIT was measured by the charcoal meal test and GEI by the difference between full and empty stomach weights. Fresh and dried feces were weighed to calculate the FMC. Renal function was assessed histologically, and biochemically in plasma and urine. The light microscopic histology of the different parts of the gut, as well as the in vitro contractility of the isolated ileum was also assessed. RESULTS: Feeding adenine for 2 or 4 weeks resulted in CRF. The BET was significantly increased in mice given adenine for 2 but not 4 weeks, while the GEI was significantly increased in mice treated with adenine for 4 but not 2 weeks. No significant differences between control and adenine-treated mice were found in GIT, FMC or the histology of the different parts of the gut. Acetylcholine-induced contractions of the ileum of adenine-treated rats were not significantly different from those of the controls. DISCUSSION: Feeding adenine for either 2 or 4 weeks resulted in CRF, but it would appear that this model produces effects on the gastrointestinal tract that are milder than those reported before in animal models with 5/6 nephrectomy-induced-CRF.

Antimicrobial agent prescription patterns for chemotherapy-induced febrile neutropenia in patients with hematological malignancies at Sultan Qaboos University Hospital, Oman.

OBJECTIVES: The aim of this study was to describe the antimicrobial prescription patterns of patients with hematological malignancies who developed febrile neutropenia (FN) at Sultan Qaboos University Hospital (SQUH) in Oman. METHODS: This was a retrospective observational study covering a period of 3 years (January 2007-February 2010). FN episodes were studied in patients with hematological malignancies in three different wards at SQUH. RESULTS: A total of 176 FN episodes were analyzed. Overall, 64% of the 107 patients studied experienced at least 2 episodes during the analysis period. Approximately, 69% of the febrile neutropenia episodes had severe neutropenia. The duration of neutropenia was less than 1 week in the majority of the episodes (57%). The mean duration of treatment was approximately 7 days, with no significant difference between specialties or different types of malignancies. Only 34 (19%) episodes had positive cultures, and most of these were from blood samples (30 episodes, 88%). The majority of isolates were gram-negative organisms (63%). The initial empirical treatment included monotherapy (37%), dual therapy (60%) and triple therapy (3%). CONCLUSIONS: This study demonstrates that there is a large variation in the antimicrobial treatment of FN episodes in patients with hematological malignancies at SQUH. All chosen drugs were within international guideline recommendations.

Ellagic acid protects against cisplatin-induced nephrotoxicity in rats: a dose-dependent study.

BACKGROUND: The anticancerdrug cisplatin (CP) causes nephrotoxicity through different mechanisms, including generation of free radicals. Ellagic acid (EA) is a polyphenolic antioxidant found in fruits and nuts. AIM: This study aimed to investigate the ability of different doses of EA to ameliorate CP nephrotoxicity in rats. MATERIALS AND METHODS: Animals were randomly divided into six groups and treated with saline; CP alone (6 mg/kg); two doses of EA, both alone (10 and 30 mg/kg) or with CP. RESULTS: Treatment with CP alone reduced body weight, water intake, urine output, and renal total antioxidant and reduced glutathione (GSH) concentrations (p < 0.01). In addition, it increased relative kidney weight, plasma creatinine, and blood urea nitrogen (BUN) concentrations (p < 0.01). However, a dose of 30 mg/kg EA mitigated most of the CP-induced actions, but no effect was seen for the 10 mg/kg dose. Histopathologically, rats given CP+EA30 showed < 25% necrotic lesions in the renal cortical area compared with > 60% in rats treated with CP alone. Molecular analysis showed that clusterin (Clu) mRNA and protein were expressed in all treated groups, meanwhile kidney injury molecule-1 (Kim-1) mRNA and protein were only expressed in the CP and CP+EA treated rats. CONCLUSIONS: EA (30 mg/kg) ameliorated most of the physiological, histological, and biochemical markers of CP nephrotoxicity. The molecular findings in this work did not completely tally with the conventional method used. The overexpression of the molecular markers may be related to the EA induced repair mechanism.

Comparative efficacy of three brands of gum acacia on adenine-induced chronic renal failure in rats.

Gum acacia (GA) is used in pharmaceutical, cosmetic and food industries as an emulsifier and stabilizer, and in some countries in the traditional treatment of patients with chronic kidney disease (CKD). We have previously found that GA ameliorates adenine-induced chronic renal failure (CRF) in rats. Different brands of GA are commercially available, but their comparative efficacy against adenine-induced CKD is unknown. Here, we explored the effects of three different brands of GA (Sudanese GA, Supergum and GA from BDH) on some physiological, biochemical, and histological effects of adenine-induced CRF in rats. Adenine (0.75 %, w/w in feed, four weeks) reduced body weight, and increased urine output. It also induced significant increases in blood pressure, and in creatinine, urea, several inflammatory cytokines in plasma, and indices of oxidative stress, and caused histological damage in kidneys. Treatment of rats concomitantly with any of the three GA brands, significantly, and to a broadly similar extent, mitigated all the signs of CRF. The results suggested equivalent efficacy of these brands in antagonizing the CRF in this animal model. However, to enable standardization of different brands between laboratories, the use of the chemically well-characterized GA preparation (such as Supergum) is recommended.

Comparative protective effect of N-acetyl cysteine and tetramethylpyrazine in rats with gentamicin nephrotoxicity.

Gentamicin (GM) is used against serious and life-threatening infections, but its use is limited by the occurrence of nephrotoxicity, which involves the generation of free radicals. In this work we tested the effect of a compound with antioxidant properties, tertamethylpyrazine (TMP), a major constituent of the Chinese medicinal plant Lingusticum wallichi, on GM-induced nephrotoxicity, and compared it with an established anti-oxidant compound N-acetyl cysteine (NAC). Six groups of rats were studied: (1) control, treated orally (p.o.) and intraperitoneally (i.p.) with saline; (2) treated i.p. with GM (80 mg kg(-1) per day for 6 days); (3) TMP, given p.o. (100 mg kg(-1) per day for 10 days) + GM (same dose as above during the last 6 days); (4) NAC, given i.p. (500 mg kg(-1) per day for 10 days) + GM as above; (5) TMP (100 mg kg(-1) per day for 10 days) + saline; (6) NAC (500 mg kg(-1) per day for 10 days) + saline. GM nephrotoxicity was characterized by reduced creatinine clearance, increased creatinine and urea concentrations in plasma, increased urinary excretion of N-acetyl-beta-d-glucosaminidase (NAG) and total protein. These functional and structural alterations were prevented or ameliorated by NAC treatment, while TMP had only a slight mitigating effect that was less marked than that produced by NAC. The concentration of GM in the renal cortex of the rats given GM + NAC (but not TMP) was lower than that found in rats treated with GM alone by about 25%. The mechanism by which NAC and, to a lesser extent TMP, protected against GM-induced nephrotoxicity may be related, at least in part, to the decrease in oxidative stress in renal cortex.

Ontogenic aspects of cisplatin-induced nephrotoxicity in rats.

A multi-age rat model was evaluated to identify a potential age-related difference in kidney injury following administration of cisplatin (CP). Different age groups of Wistar rats (aged 3, 7, 11 and 24 weeks) were given CP intraperitoneally (6 mg/kg) and sacrificed 6 days thereafter. CP-induced nephrotoxicity caused significant decreases in body weight, creatinine clearance, urine osmolality, plasma total anti-oxidant status, cortical glutathione (GSH) concentration and superoxide dismutase activity. It increased kidney weight and plasma concentrations of creatinine and urea. It increased urinary N-acetyl-beta-D-glucosaminidase activity and protein concentration. Most of the above actions were more marked as the animals advanced in age, except for the changes in GSH, which were similar in all age groups. CP produced necrosis in renal tubules and epithelial vacuolization, the extent of which was more evident as the rats grew older. Renal CP concentration was increased with the increased age of the animal, and the cortical CP concentration in 3 week-old rats was nearly half that of 24 week-old rats. This study showed that the vulnerability profile of each age group was different, suggesting that a multi-age pediatric/geriatric animal model is appropriate to assess, more completely, age-dependent changes in drug toxicity.

Amelioration of cisplatin-induced nephrotoxicity in rats by tetramethylpyrazine, a major constituent of the Chinese herb Ligusticum wallichi.

Nephrotoxicity of the anticancer drug, cisplatin (CP) involves enhanced renal generation of reactive oxygen metabolites and lipid peroxidation caused by decreased levels of antioxidants and antioxidant enzymes. Tetramethylpyrazine (TMP) is known to act as a strong antioxidant. Therefore, in the present work, we aimed at testing the possible protective or palliative effect of TMP on CP nephrotoxicity in rats. TMP was given orally at a dose of 80 mg . kg(- 1) . day(- 1) for 7 days. Some of these rats were given a single intraperitoneal injection of CP (or vehicle) at a dose of 6 mg/kg on Day 6 of treatment. Animals were sacrificed 6 days after CP (or vehicle) treatment, and blood, urine, and kidneys were obtained. Nephrotoxicity was assessed biochemically by measuring creatinine and urea in serum, reduced glutathione (GSH) concentration in renal cortex, by urinalysis, and histopathologically by light microscopy. CP significantly increased the concentration of urea and creatinine (P < 0.05) by about 128% and 170%, respectively; increased urine volume and N-acetyl-beta-D-glucosaminidase (NAG) activity; and significantly decreased osmolality and protein concentrations. CP treatment reduced GSH by about 34% (P < 0.05) and superoxide dismutase (SOD) and total antioxidant activity (TOX) by about 28% and 21%, respectively (P < 0.05). TMP pretreatment significantly mitigated all of these effects. Sections from saline- and TMP-treated rats showed apparently normal proximal tubules. However, kidneys of CP-treated rats had a moderate degree of necrosis. This was markedly reduced when CP was given after pretreatment with TMP. CP cortical concentration was not significantly altered by TMP treatment. The results suggest that TMP ameliorated the histological, physiological, and biochemical indices of nephrotoxicity in rats. Pending further pharmacological and toxicological studies, TMP may potentially be useful as a nephroprotective agent.

The ameliorative effect of cysteine prodrug L-2-oxothiazolidine-4-carboxylic acid on cisplatin-induced nephrotoxicity in rats.

Pathogenesis of nephrotoxicity of the synthetic anticancer drug cisplatin (CP) involves generation of reactive oxygen species and free radicals in the kidney cortex, and cysteine prodrug l-2-oxothiazolidine-4-carboxylic acid (OTC) has been confirmed to have a strong antioxidant action. Therefore, in the present work, we aimed at testing the possible protective or palliative effect of OTC on CP nephrotoxicity in rats. OTC was given at an oral dose of 150 mg/kg/day for 7 days. On day 7, some of these rats were given a single intraperitoneal injection of CP (or vehicle) at a dose of 6 mg/kg. Rats were killed, blood and urine samples were collected, and the kidneys were removed 6 days after CP treatment. Nephrotoxicity was evaluated histopathologically by light microscopy, and biochemically by measuring the concentrations of creatinine and urea in serum, reduced glutathione (GSH) concentration and superoxide dismutase (SOD) activity in renal cortex, and by urinalyses. CP significantly increased the concentrations of urea and creatinine (P < 0.05) by about 128% and 170% respectively. CP treatment reduced cortical GSH concentration by about 34% (P < 0.05), and the activity of SOD by about 28% (P < 0.05). CP treatment significantly increased urine volume and N-acetyl-beta-D-glucosaminidase (NAG) activity, and significantly decreased osmolality and protein concentrations. OTC significantly mitigated all these effects. Sections from saline- and OTC-treated rats showed apparently normal proximal tubules. However, kidneys of CP-treated rats had a moderate degree of necrosis. This appeared to be lessened when CP was given simultaneously with OTC. The concentration of CP in the cortical tissues was not significantly altered by OTC treatment. The results suggested that OTC had ameliorated the histopathological and biochemical indices of nephrotoxicity in rats. Pending further pharmacological and toxicological studies, OTC may potentially be useful as a nephroprotective agent.