Acute and Chronic Toxicity of Carbamazepine on the Release of Chitobiase, Molting, and Reproduction in Daphnia similis.

As one of the most frequently detected pharmaceutical compounds in aquatic environments, carbamazepine (CBZ) has recently been shown to cause acute and chronic toxicity in a variety of non-target aquatic organisms. However, little is known about the ecotoxicological effects it has on the molting and reproduction of crustaceans. The aim of the present work was to evaluate the acute and chronic toxic responses to CBZ in the crustacean Daphnia similis. After acute exposure (4 days), CBZ did not cause lethal toxicity at the tested concentrations. However, CBZ did inhibit the molting and release of chitobiase at concentrations higher than 6.25 µg/L, with 96 h EC50 (median effective concentration) values of 864.38 and 306.17 µg/L, respectively. The results of chronic exposure showed that the mean number of molts, size of the first brood, mean number of offspring per brood, mean number of broods per female, and total offspring per female decreased significantly with increasing CBZ concentrations. Significant effects of CBZ on the molting or fecundity in D. similis were observed even at concentrations as low as 0.03 µg/L. In conclusion, CBZ can cause inhibition of molting, delayed reproduction, and reduced fecundity in D. similis. CBZ toxicity to D. similis depends on the timing and duration of the exposure. Moreover, our results indicated that CBZ would act as an endocrine disrupter in D. similis, as with vertebrates (e.g., fish).

[Effect of zhuhong ointment on renal antioxidant capability in skin ulcer model rats].

OBJECTIVE: To study the effect of repeated administration of Zhuhong ointment on renal antioxidant capability of ulcerous skin in rats, in order to further discuss the mechanism of mercury contained in Zhuhong ointment on the antioxidant capability of kidney in skin ulcer rats. METHOD: Eighty SD rats were randomly divided into eight groups: Zhuhong ointment A, B, C, D, E (1.219, 0.609, 0.305, 0.152, 0.76 g x kg(-1)) groups, the vaseline group, the ulcer model group and the impairment control group. The levels of NAG and RBP of toxicity for early kidney tubular injury and T-AOC, SOD, GSH-PX and GSH in kidney were determined after consecutive administration for 14 days. RESULT: Compared with ulcer model group, the levels of RBP in groups A, B, C and D increased, while the levels of NAG increased only in the group A. The level of T-AOC increased in groups A, B and C. The level of T-SOD increased in the group E, while it dropped down greatly in the group A. The level of GSH-PX increased in groups A, B and C. The content of GSH increased in every dose groups. CONCLUSION: Antioxidant capacity in rats can be increased in a reasonable dose of Zhuhong ointment, but some antioxidant activity can be notably inhibited by with the increase of dose.

[Effects of zhuhong ointment on mercury cumulation and renal organization modality in skin-impaired model rat].

OBJECTIVE: To study the effects of Zhuhong ointment on accumulation in the body of mercury and the pathological morphology changes of kidney, via the measurement of related indicators of the skin-impaired model rat. METHOD: Eighty-eight SD rats were randomly divided into the impairment control group, and high-, middle-, low-dose Zhuhong ointment groups. Each group was treated by corresponding methods for 4 weeks, and recovering for 4 weeks. Urinary potein (PRO), pH, Beta N-acetyl aminoglycosidase enzymes (NAG) and beta2-microglobulin (beta2-MG) contents in urine were taken as monitoring indexes, blood urea nitrogen (BUN) and serum creatinine (SCr) in blood and the levels of mercury in urine, blood and kidney were tested, and the pathological morphology changes of kidney were observed. RESULT: After treatment for 4 weeks, compared with impairment control group, the levels of mercury in urine, blood and kidney in every dose group increased significantly (P < 0.01). And the relation exists between toxicity and dose on Zhuhong ointment. After recovery for 4 weeks, the levels of mercury in urine and blood in every dose group restore normal, while the level of mercury in kidney in high- dose group still increased (P < 0.01). The level of NAG increased only in high-dose group. There was no significant difference in NAG contents between Zhuhong ointment groups and the impairment control group (P < 0.05). CONCLUSION: Excess using Zhuhong ointment repeatedly may lead to accumulation of mercury and pathological morphology changes of kidney. So the levels of mercury in the body and related indicators of renal functions should be tested in clinical when long-term using Zhuhong ointment.

Effect of bicarbonate administration on cyclosporine-induced nephrotoxicity in rats.

BACKGROUND: Cyclosporine (CsA) is known to cause metabolic and distal tubular acidosis. There is some evidence that CsA reduces net HCO(3)(-) absorption. The aim of this study was to elucidate whether bicarbonate administration prevented CsA-induced functional or structural nephrotoxicity. METHODS: Seven days after uninephrectomy, 20 rats were divided into 4 groups. NaHCO(3) (0.28 mol/L) was added in drinking water for 7 days, whereas control rats received regular tap water. The bicarbonate pretreated rats were administered either CsA (50 mg/kg intraperitoneally) or vehicle daily for a week. At the end of the procedure, animals were placed in metabolic cages for 24 hours after which we measured creatinine clearance (Ccr), urinary total proteins, pH, and N-acetyl-beta-D-glucosaminidase (NAG) activity. The kidney was fixed in formaldehyde. RESULTS: Ccr was significantly affected by the administration of CsA. The effects of CsA on serum pH and HCO(3)(-) concentration were prevented by pretreatment with NaHCO(3). However, it did not affect the CsA-induced increased urinary NAG activity or decreased Ccr. There was no protection of CsA-induced changes in renal tissues by NaHCO(3). CONCLUSION: Overall NaHCO(3) administration did not prevent CsA-induced changes in Ccr and NAG activity. These data suggested involvement of factors other than acid-base status in CsA-induced nephrotoxicity. However, correction of acidosis should still be considered for patients receiving CsA because acidosis exacerbates tissue damage.

Assessment of novel avian renal disease markers for the detection of experimental nephrotoxicosis in pigeons (Columba livia).

Renal disease is a major cause of illness in captive and wild avian species. Current renal disease markers (e.g., uric acid, blood urea nitrogen, and creatinine) are insensitive. Two endogenous markers, creatine and N-acetyl-beta-D-glucosaminidase (NAG), were selected for study in the pigeon (Columba livia). Representative organs from four pigeons were surveyed to determine those exhibiting the highest level of each marker. In a separate study, NAG and creatine from plasma and urine were assayed before and after gentamicin (50 mg/kg twice daily), administration for up to 9 days. Observer-blinded pathologic scoring (five saline solution controls, 17 treated birds) was used to verify the presence of renal disease that corresponded to marker increases. The first study revealed that kidney tissue had the highest NAG activity (by approximately six times), and pectoral muscle had the most creatine (>900 times). In response to gentamicin, plasma creatine (>five times) and NAG increased (approximately six times), which paralleled uric acid (>10 times). Urine creatine (approximately 60 times) and NAG increased dramatically (approximately 50 times) in response to gentamicin. In conclusion, NAG, especially in the urine, may be of value to noninvasively detect renal toxin exposures and to monitor potentially nephrotoxic drugs, and might be of value to screen free-ranging birds in large exhibits or in the wild by assaying fresh urate samples at feeding stations.

Measurement of urinary N-acetyl-b-D-glucosaminidase in adult patients with cystic fibrosis: before, during and after treatment with intravenous antibiotics.

BACKGROUND: Patients with cystic fibrosis (CF) are at high risk from the nephrotoxic effects of intravenous antibiotics due to repeated and prolonged courses of therapy. Routine methods of monitoring renal injury are insensitive. N-acetyl-b-d-glucosaminidase (NAG) is a lysosomal enzyme present in the renal proximal tubular cells, with increased excretion an indicator of renal tubular dysfunction. METHODS: Urinary NAG, creatinine, serum creatinine, electrolytes and BUN were measured on days 1, 14 and at the first out-patient visit following treatment with tobramycin or colistin. Urinary NAG levels were corrected for urinary creatinine and expressed as a NAG ratio. Patients who received>1 course of intravenous antibiotics during the study period were included in a separate analysis of the cumulative effect of treatment. RESULTS: 88 patients (44 female, 31 with CFRD) completed a single course of intravenous antibiotics. 71 patients had urinary NAG levels at follow-up. The median time to follow-up was 50 days. Serum electrolytes, creatinine and BUN were normal throughout. A 3.5-fold increase in urinary NAG excretion was observed between day 1 and 14 and 46% of patients had an elevated NAG level at follow-up. A highly significant difference in NAG excretion was observed on day 14 for tobramycin vs. colistin (median 2.24 vs. 0.98, p<0.001). A significant difference in NAG excretion was seen in patients with CFRD at all measured time points. Patients with CFRD had a significantly worse clinical status and had received more days of intravenous antibiotics over the previous 6 years. In 20 (80%) of 25 patients who received>1 course of treatment during the study period, baseline NAG levels were significantly higher in subsequent courses (p<0.001). There was a significant correlation between previous exposure to colistin and baseline NAG levels (r=0.389, p<0.001). CONCLUSIONS: Both tobramycin and colistin cause acute renal tubular injury with a significant rise in urinary NAG excretion. Patients with CFRD seem to be at greatest risk of renal tubular damage. Cumulative damage is evident with repeated dosing. Previous exposure to nephrotoxic antibiotics, especially colistin, is associated with elevated baseline NAG levels. We recommend that colistin is reserved for patients with resistant Pseudomonas aeruginosa or those who are intolerant to tobramycin. Serial longitudinal NAG measurements may be useful in patients with CF, especially those with CFRD, to identify patients at risk of developing renal disease.

N-acetyl-beta-D-glucosaminidase--a marker of reperfusion and a prognostic indicator in patients with acute myocardial infarction.

OBJECTIVE: N-acetyl-beta-D-glucosaminidase (NAG) is a lysosomal enzyme of which the activity in plasma is increased in a number of conditions including myocardial infarction. Plasma levels of cardiac proteins, such as myoglobin, troponin and creatine kinase, have been used as markers of myocardial reperfusion as well as for the prognosis of the disease. The aim of this study is to investigate whether NAG could be used as an additional biochemical marker to predict myocardial reperfusion and to find out if its release following thrombolysis has a prognostic value as well. METHOD: Streptokinase (SK) in a dose of 1.5 million units was administered intravenously to 75 patients with acute myocardial infarction (AMI) and the response to SK was assessed over a period of 90 minutes. Plasma NAG activity was monitored before (0 min) and 90 min after SK treatment. RESULTS: The mean NAG activity values were found to be 8.6 +/- 4.8 U/I and 10.95 +/- 7.3 U/I, respectively, and when compared using paired samples t-test revealed a significant increase (p = 0.0001) following thrombolytic therapy. The increase appears perfusion related as rabbits injected with SK failed to show any increase in plasma NAG activity. There was an association between plasma NAG activity and clinical response to SK treatment (p = 0.045). A follow-up of 66 patients over a period of 18 months, revealed increased survival in AMI patients having significantly more activity/release of plasma NAG after thrombolytic treatment (p = 0.001). CONCLUSION: NAG appears to be another potential biochemical marker of reperfusion. Moreover, NAG release profile during thrombolysis could be of value in predicting prognosis of the disease.

Differential effects of antiangiogenic compounds in neovascularization, leukocyte recruitment, VEGF production, and tumor growth in mice.

Angiogenesis and inflammation play critical roles in tumor growth. Using an in vivo tumor model, we report that thalidomide (100 mg kg(-1)day(-1)) or clotrimazole (120 mg kg(-1) day(-1)), inhibit blood vessel formation (determined by hemoglobin content), leukocyte recruitment [myeloperoxidase (MPO) activity; N-acetylglucosa-minidase (NAG) activity], and vascular endothelial growth factor production. Inhibition of angiogenesis ranged from 35% to 65%. Clotrimazole was the most potent antiangiogenic compound and the agent capable of inhibiting tumor growth. Thalidomide was able to reduce the inflammatory reaction (MPO and NAG activities) by 50% to 70%, but was unable to delay tumor development. These results suggest that for this type of solid tumor the degree of neovascularization, rather than inhibition of inflammatory cell recruitment, is a determinant factor in tumor development. As the contribution of angiogenesis and inflammation to cancer progression vary markedly among different tumor types, it may be relevant to consider these factors in cancer therapy using antiangiogenesis/antiinflammatory approaches.

Effect of once-daily dosing vs. multiple daily dosing of tobramycin on enzyme markers of nephrotoxicity.

OBJECTIVE: To determine the incidence of nephrotoxicity of once-daily dosing (ODD) and multiple daily dosing (MDD) regimens of tobramycin in critically ill patients. DESIGN: Randomized, prospective clinical trial. SETTING: : Adult intensive care units at two university hospitals. PATIENTS: Fifty-eight critically ill patients with a suspected or documented aerobic Gram-negative infection. INTERVENTIONS: Patients were randomized to receive tobramycin by ODD (7 mg/kg) or MDD. Baseline urine aliquots and 24-hr urine collections were collected on days 3, 7, and 11 during therapy and on days 3, 7, and 11 following discontinuation of therapy for measurement of alanine aminopeptidase (AAP), N-acetyl-beta-d-glucosaminidase (NAG), and creatinine. MEASUREMENTS AND MAIN RESULTS: Fifty-four patients were evaluable (ODD n = 25; MDD n = 29). The groups were similar with regard to demographic and clinical variables. The tobramycin dose was higher in the ODD group compared with the MDD group (425 +/- 122.5 mg vs. 312.8 +/- 116.6 mg, p <.001). Patients in the MDD group received a mean of 3.89 +/- 1.14 mg.kg(-1)day(-1) at intervals of 11.92 +/- 3.12 hrs. In the ODD group, patients had a higher measured creatinine clearance at the end of therapy compared with MDD group (70 +/- 18.6 vs. 64.8 +/- 17.5 mL/min, p =.047). Fewer patients in the ODD group developed nephrotoxicity than the MDD group (5 vs. 12, p =.142). Although there were increases in urinary enzymes in both treatment groups (AAP, 8.7 +/- 2.9 vs. 5.2 +/- 2.1 units/24 hrs, p <.01 MDD vs. ODD; NAG, 14.7 +/- 4.9 vs. 6.8 +/- 3.1, p <.01 MDD vs. ODD), the increases in the ODD group were significantly lower than in the MDD group. CONCLUSIONS: : The ODD tobramycin regimen appeared to be less nephrotoxic than the MDD regimen despite significantly higher doses. Tobramycin administered by ODD may be the preferred dosing method in selected critically ill medical patients to reduce the incidence and extent of renal damage.

Clinical characteristics of normotensive renal transplant recipients with microalbuminuria and effects of angiotensin II type I receptor antagonist on urinary albumin excretion.

AIM: Microalbuminuria is typically observed in renal transplant recipients with systemic hypertension. The effects of angiotensin II type 1 receptor antagonist (losartan) on the hypertensive recipients have been evaluated. However, the clinical background of normotensive recipients with microalbuminuria and the effect of losartan administration in those subjects have not been clarified. One of the two purposes for the present study was to investigate the clinical characteristics of normotensive recipients with microalbuminuria. The other was to evaluate the effect of losartan on urinary excretion of albumin in these patients. METHODS: The clinical data and the change of the single kidney glomerular filtration rate (GFR) for the graft by radionuclide study were assessed in 13 normotensive recipients with microalbuminuria. These were compared with the data of 13 normotensive patients without microalbuminuria. The 13 recipients with microalbuminuria were treated with losartan for one year and urine excretion of albumin, N-acetyl-beta-D-glucosaminidase (NAG) and serum creatinine (S-Cr) levels were measured. RESULTS: The GFR of the grafts from donors to recipients significantly increased (30.9 to 55.2 mL/min) in microalbuminuric recipients, but did not significantly increase in the non-microalbuminuric recipients. Decreases of the urinary excretion rate of albumin (351 +/- 261 at baseline to 158 +/- 14 mg/gCr at 12 months), NAG (13 +/- 5 to 10 +/- 3 IU/gCr) and S-Cr (1.7 +/- 0.6 to 1.5 +/- 0.4 mg/DL) were observed in the microalbuminuric recipients with losartan administration. CONCLUSIONS: The present study suggests that an increased single kidney GFR of the graft from the donor in situ to the recipient might be a cause of microalbuminuria in normotensive recipients. The one-year effects of losartan were observed in terms of the decrease in urinary excretion of albumin, NAG and S-Cr levels.

Effect of simvastatin and fenofibrate on endothelium in Type 2 diabetes.

Statins and fibrates influence endothelial activity and consequently atherogenesis but the mechanisms are not well understood. Twenty Type 2 diabetic patients with dyslipidemia were treated 3 months with simvastatin (20 mg daily) and then 3 months with fenofibrate (200 mg daily) with 2 months of wash-out between the two treatments. Laboratory parameters of oxidative stress, fibrinolysis and endothelial function were evaluated before and at the end of each treatment period. The significant decrease in serum total and LDL-cholesterol concentrations (P<0.0001) caused by simvastatin was associated with an increase in serum N-acetyl-beta-glucosaminidase activity (P<0.001), ascorbic acid (P<0.001), plasminogen activator inhibitor (PAI-1) (P<0.01), vonWillebrand factor (P<0.05), E-selectin (P<0.01) and vascular endothelial growth factor (P<0.05) concentrations and with a decrease in plasma glutathione (P<0.01) levels. Fenofibrate caused a significant decrease in serum triglyceride concentration (P<0.0001) associated with a decrease in plasma malondialdehyde (P<0.001) and an increase in plasma PAI-1 (P<0.05) and P-selectin (P<0.05) concentrations. We conclude that simvastatin and fenofibrate interact, by different mechanisms, with oxidative stress, a key factor in the modification of fibrinolysis and endothelial function in Type 2 diabetes.

Formulation dependent pharmacokinetics, bioavailability and renal toxicity of a selective cyclooxygenase-1 inhibitor SC-560 in the rat.

PURPOSE: To delineate formulation dependent pharmacokinetics and bioavailability of SC-560, a relatively new cycloooxygenase-1 (COX-1) specific inhibitor, in the rat and examine its influence on the renal tubular enzyme, N-acetyl-beta-D-glucosaminidase (NAG), and urinary electrolytes. METHODS: The pharmacokinetics of SC-560 was studied in Sprague-Dawley rats (n = 5 per group) after a single intravenous (i.v.) and oral dose (10 mg/kg) in polyethylene glycol (PEG) 600 and a single oral dose (10 mg/kg) in 1% methylcellulose (MC). Serial blood samples were collected via a catheter inserted in the right jugular vein and serum samples were analysed for SC-560 using reverse phase HPLC. After oral administration of SC-560 in PEG, urine was also collected for 24 h and analysed for urinary sodium, chloride, and potassium as well as NAG. RESULTS: After an iv dose (10 mg/kg) of SC-560, serum AUC, t(1/2), CL and Vd were 9704 +/- 4038 ng h/mL, 5.4 +/- 0.8 h, 1.15 +/- 0.46 L/h/kg and 9.1 +/- 4.6 L/kg (mean +/- SD, n = 5), respectively. Oral administration of 10 mg/kg SC-560-PEG and MC (n=5 rats) yielded serum AUC, C max, t (max )and t (1/2) of 1203.4 +/- 130.3 and 523 +/- 208 ng h/mL, 218.5 +/- 86.9 and 119.8 +/- 15.5 ng/mL, 1.00 +/- 1.8 and 2.0+/- 0 h, 3.7 +/- 1.6 and 2.7 +/- 1.7 h (mean +/- SD, n = 5), respectively. A single oral dose 10 mg/kg of SC-560 in PEG resulted in an increase in NAG excretion in urine and a reduction in 0-24 h urinary sodium, potassium, and chloride excretion. CONCLUSIONS: SC-560 extensively distributes into rat tissues, and has a CL approaching hepatic plasma flow. The drug displays low <15% and formulation dependent bioavailability after oral administration and demonstrates kidney toxicity.

The influence of lipoic acid on adriamycin induced nephrotoxicity in rats.

Adriamycin, which is widely used in the treatment of various neoplastic conditions, exerts toxic effects in several organs. Adriamycin nephrotoxicity has been recently documented in a variety of animal species. The present study was designed to investigate the effect of lipoic acid on the nephrotoxic potential of adriamycin. The study was carried out with adult male albino rats of Wistar strain. Test animals were divided into four groups of six rats each as follows: Group I (control) received only normal saline throughout the course of the experiment. Group II (ADR) received intravenous injections of adriamycin through the tail vein (1 mg kg(-1) body wt day(-1)) once a week for a period of 12 weeks. Group III (LA) received lipoic acid (35 mg kg(-1) body wt day(-1)) intraperitoneally once a week for a period of 12 weeks. Group IV (ADR + LA) received a single injection of lipoic acid intraperitoneally 24 h prior to the administration of adriamycin through the tail vein once a week for a period of 12 weeks. Intravenous injections of adriamycin resulted in decreased activities of the glycolytic enzymes; hexokinase, phosphoglucoisomerase, aldolase and lactate dehydrogenase in the rat renal tissue. The gluconeogenic enzymes, glucose-6-phosphatase and fructose-1,6-diphosphatase, showed a decline in their activities on adriamycin administration. The transmembrane enzymes namely the Na+,K+-ATPase, Ca2+-ATPase, Mg2+-ATPase and the brush-border enzyme alkaline phosphatase also showed a decrease in their activities. This decrease in the activities of ATPases and alkaline phosphatase suggests basolateral and brush-border membrane damage. Decreased activities of the TCA cycle enzymes isocitrate dehydrogenase, succinate dehydrogenase and malate dehydrogenase, suggest a loss in mitochondrial function and integrity. Nephrotoxicity was evident from the increased excretions of N-acetyl-beta-D-glucosaminidase and gamma-glutamyl transferase in the urine of adriamycin administered rats. These biochemical disturbances were effectively counteracted on pre-treatment with lipoic acid, which brought about an increase in the activities of glycolytic enzymes, ATPases and the TCA cycle enzymes. On the other hand, the gluconeogenic enzymes showed a further decrease in their activities on lipoic acid pretreatment. LA pretreatment also restored the activities of the urinary enzymes to normal. These observations shed light on the nephroprotective action of lipoic acid rendered against experimental aminoglycoside toxicity.

The influence of lipoic acid on adriamycin-induced hyperlipidemic nephrotoxicity in rats.

Adriamycin widely used in the treatment of neoplastic conditions is nephrotoxic. In the present study the protective effect of lipoic acid was investigated in adriamycin-induced nephrotoxicity in adult male albino Wistar rats. Adriamycin-induced nephrotoxicity was characterized by hyperlipidemia, proteinuria, and hypoproteinemia, by decreased activities of the enzymes N-acetyl-beta-D-glucosaminidase and cathepsin D, by increased lipid peroxidation and decreases in serum catalase and glutathione activities, and by increased urinary and serum urea, creatinine and urinary glycosaminoglycans. Pretreatment with lipoic acid restored the changes, indicating that lipoic acid is renoprotective in adriamycin nephrotoxicity.

Fluoride ion toxicity in rabbit kidney thick ascending limb cells.

BACKGROUND AND OBJECTIVE: Some halogenated agents, especially methoxyflurane, because of a higher level of fluoride production, induce a renal concentrating defect that could be related to an ascending limb impairment. We investigated the mechanisms of fluoride toxicity on an immortalized cell line. METHODS: Cells were cultured for 2, 6 or 24 h in the presence of fluoride. Toxicity evaluation was based on: cell numbers, protein content, leucine-incorporation, lactate dehydrogenase (LDH) and N-acetyl-beta-glucosaminidase (NAG) releases, Na-K-ATPase and Na-K-2Cl activities, electron microscope studies. Infrared analysis and fluoride microdetermination allowed crystal components. RESULTS: At 5 mmol after 24 h, fluoride decreased cell numbers (-14%, *P < 0.05), protein content (-16%*), leucine incorporation (-54%*), Na-K-2Cl activity (-84%*), increased LDH (+145%*) and NAG release (+190%*). Na-K-ATPase was more sensitive and impaired from 1 mmol for 24h and after 2 h at 5 mmol. Crystal formation in mitochondria occurred after 6 h at 5 mmol. Infra-red analysis and fluoride microdetermination established that crystals contained sodium, phosphate and fluoride. CONCLUSIONS: The results suggest that the Na-K-ATPase pump is a major target for fluoride toxicity in Henle's loop.

[Monitoring of renal function in epileptic children and teenagers treated with valproic acid or carbamazepine in concomitant therapy with tiagabine]. / Monitorowanie czynnosci nerek u dzieci i mlodziezy chorych na padaczke leczonych kwasem walproinowym lub karbamazepina w terapii skojarzonej z tiagabina.

The aim of the study was the evaluation of the influence of 4-month concomitant tiagabine (TGB) and valproic acid (VPA) or carbamazepine (CBZ) therapy on renal function of epileptic children and teenagers. Initial parameter values, indicated on renal disfunction, were compared with these obtained after VPA and TGB or CBZ and TGB therapy and with values in healthy children and teenagers. Investigation group was composed of 22 children and teenagers with drug-resistant focal epilepsy. We observed that in the time of concomitant VPA and TGB therapy increased the NAG/g creatinine activity index. In spite the fact of statistical significance of these changes, they were not outside the normal range. beta 2-microglobulin concentrations in urine of epileptic children treated with VPA in monotherapy before concomitant therapy with TGB were higher than in control group. That difference was statistically significant. Addition of TGB to the therapy normalized this parameter. During concomitant VPA and TGB or CBZ and TGB therapy we didn't observe statistically significant changes of parameters indicating on glomerular disfunction. In the VPA therapy before concomitant treatment with tiagabine the disfunction of tubules and glomerules was observed. On the other side in the concomitant VPA and TGB therapy the disfunction of tubules and glomerules didn't occurred. We can conclude that concomitant therapy VPA or CBZ with tiagabine don't affect the renal function in clinical significant manner. Therapy with VPA could leads to minimal disfunction of tubules what is represented by increasing of beta 2-microglobulin level in urine.

Attenuation of oxalate-induced nephrotoxicity by eicosapentaenoate-lipoate (EPA-LA) derivative in experimental rat model.

Hyperoxaluria is one of the major risk factors for the formation of urinary calcium oxalate stones. Calcium oxalate crystals and their deposition have been implicated in inducing renal tubular damage. Lipoic acid (LA) and eicosapentaenoic acid (EPA) have been shown to ameliorate the changes associated with hyperoxaluria. This prompted us to investigate the nephroprotectant role of EPA-LA, a new derivative, in vivo in hyperoxaluric rats. Elevation in the levels of calcium, oxalate and phosphorus, the stone-forming constituents, were observed in calculogenic rats as a manifestation of crystal deposition. Tubular damage to the renal tissue was assessed byassaying the excretion of marker enzymes in the urine. Damage to the tubules was indicated by increased excretion of alkaline phosphatase (ALP), lactate dehydrogenase (LDH), gamma-glutamyl transferase (gamma-GT), beta-Glucuronidase (beta-GLU) and N-Acetyl beta-D glucosaminidase (NAG). Fibrinolytic activity was found to be reduced. Administration of EPA, LA and EPA-LA reduced the tubular damage and decreased the markers of crystal deposition markedly, which was substantiated by the reduction in weight of bladder stone formed. Our results highlight that EPA-LA is the most effective drug in inhibiting stone formation and mitigating renal damage caused by oxalate toxicity, thus confirming it as a nephroprotectant. Further work in this direction is warranted to establish the therapeutic effectiveness of this new derivative.

The combined effect of cyclosporine a and gentamicin on enzymuria in the Sprague-Dawley rat.

Male Sprague-Dawley rats (8 per group) were administered a single oral dose of cyclosporine A (10, 30 and 50 mg/day) for 5 days or vehicle (corn oil, 1.5 mL/kg) and urinary enzymes excretion was monitored. Only minor changes in enzymuria were observed in the 10 and 30 mg/kg group. However, in the 50 mg/kg group, nephrotoxicity was evident by significant increase in the excretion of N-acetyl-beta-D-glucosaminidase (NAG), glutamate dehydrogenase (GDH), and lactate dehydrogenase (LDH on day 2 of treatment. As chemotherapeutic drug interaction with cyclosporine A (CyA) is thought to aggravate its nephrotoxicity, the effect of combined CyA (30 mg/kg) and the antibiotic gentamicin (50 mg/kg) for 5 days was investigated. Gentamicin alone caused a significant enzymuria, whilst co-treatment of rats with CyA gave rise to increased changes in enzymuria on days 1 and 2, between the groups receiving gentamicin+vehicle and those receiving CyA+gentamicin. This was particularly marked by significant changes in LDH excretion. In contrast these observed differences were not paralleled by changes in serum creatinine and other functional parameters. Treatment with gentamicin, appears to enhance CyA nephrotoxicity, but only in the first 2 days, after this there was no significant differences between the two groups. Our data suggest that urinary enzyme measurements could serve as a valuable non-invasive means of monitoring renal performance in animals or humans who may be exposed to combination of drugs. CyA is found not to potentiate the nephrotoxic effect of gentamicin in the animal model used in this study. It therefore appears safe to use the combined therapy particularly in the treatment of transplant patients.

Protective effects of vitamin e and probucol against gentamicin-induced nephrotoxicity in rats.

Gentamicin (GM) is widely used as a bactericidal agent for the treatment of severe gram negative infections, however, its clinical use is partially limited due to its nephrotoxicity. Recent evidence suggests a role of reactive oxygen metabolites in GM nephrotoxicity. The present study was designed to investigate a possible potential protective role of vitamin E and/or probucol against GM nephrotoxicity. GM was administered to rats in a single dose of (150 mg kg(-1)i.p.), while vitamin E (250 mg kg(-1)i.m.) and/or probucol (60 mg kg(-1)i.m.) were given once daily for 3 consecutive days prior to GM administration. GM-induced nephrotoxicity was evidenced by marked elevations in serum urea and creatinine levels, urinary activity of N-acetyl-beta- d -glucosaminidase (NAG) and gamma-glutamyl-transferase (gamma-GT). Also, GM caused significant increases in kidney content of malondialdehyde (MDA), and significant decreases in kidney content of reduced non-protein sulphydryls (NPSH) and superoxide dismutase (SOD) activity. Vitamin E pretreatment significantly lowered the elevated serum urea and creatinine levels, and urinary activity of NAG and gamma-GT. In addition, vitamin E ameliorated the rise in renal content of MDA and enhanced the renal NPSH content as well as SOD activity. Similarly, probucol significantly inhibited the elevations in urea and creatinine levels and enhanced renal NPSH content and SOD activity. Simultaneous use of vitamin E and probucol was more effective in mitigating disturbances in the assessed parameters. The present work indicates that, due to their antioxidant activity, vitamin E and probucol have potential protective effects against GM nephrotoxicity.

Effects of fosfomycin and imipenem-cilastatin on the nephrotoxicity of vancomycin and cisplatin in rats.

The nephrotoxicity of vancomycin and cisplatin and the protective effects of fosfomycin and imipenem-cilastatin on renal function have been studied in rats. The renal clearance of vancomycin after the induction of renal dysfunction was also evaluated by calculating the glomerular filtration rate (GFR) and its secretory clearance. Plasma concentrations of creatinine and urea nitrogen increased dose-dependently after vancomycin injection. No such increases were observed after co-treatment with fosfomycin or imipenem-cilastatin. Changes of N-acetyl-beta-D-glucosaminidase activity in the urine of vancomycin-treated rats were not remarkable compared with those in cisplatin-treated animals. The reduced renal clearance of vancomycin in rats with acute renal failure induced by vancomycin was because of a decrease in both GFR and secretory clearance. However, the changes in GFR and secretory clearance were not proportional-the change in GFR was more pronounced than that of secretory clearance in the experimental groups. In addition, the renal clearance of vancomycin was maintained at the control level after co-administration of fosfomycin or imipenem-cilastatin with vancomycin. These results suggest that vancomycin impairs glomerular filtration more markedly than renal tubular function as compared with cisplatin. Co-administration with fosfomycin or imipenem-cilastatin confers significant protection against the nephrotoxic effects of vancomycin.