Protective effects of 'Khamira Abresham Hakim Arshad Wala', a unani formulation against doxorubicin-induced cardiotoxicity and nephrotoxicity

Doxorubicin is one of the most active cytotoxic agents in current use. The clinical usefulness of the doxorubicin has been precluded by its marked cardiotoxicity. The aim of the present study was to investigate the effect of Khamira Abresham Hakim Arshadwala, a well known unani cardiac tonic formulation, pre-treatment on doxorubicin-induced cardiotoxicity, and nephrotoxicity in rats. Twenty-four Wistar albino rats, divided into four groups, were used. Khamira Abresham Hakim Arshadwala was administered daily, for 7 days, and a single dose of doxorubicin (10 mg/kg, i.v.) on day 5. After 48 h of doxorubicin injection, animals were sacrificed. Lactate dehydrogenase (LDH), aspartate transaminase (AST), blood urea nitrogen (BUN), and creatinine were estimated in the serum. Heart specimens were used for biochemical estimations of lipid peroxides (MDA), reduced glutathione (GSH), catalase, and for microscopic examination of histopathological changes. Doxorubicin showed cardiotoxicity and nephrotoxicity, as evidenced by elevated activities of AST, LDH, BUN, creatinine, and MDA, depletion in GSH level, and catalase activity. Histopathological studies showed disruption of cardiac tissues in doxorubicin groups. Khamira Abresham Hakim Arshadwala pre-treatment showed a protective effect against the enzymatic changes in serum as well as cardiac and kidney tissue damage, significantly. The present findings suggest that Khamira Abresham Hakim Arshadwala significantly (p < 0.01) improved the state of markers for cardiac and kidney damage investigated in this model of doxorubicin-induced experimental cardiotoxicity and nephrotoxicity; indicating its potential in limiting doxorubicin toxicity.     

Protective role of DLalpha-lipoic acid against adriamycin-induced cardiac lipid peroxidation

The cytoprotective activity of alpha-lipoic acid against free radical toxicity manifested during adriamycin (ADR)-induced cardiotoxicity has been investigated. ADR is a potent antitumour drug known to cause severe cardiotoxicity. Although ADR generates free radicals, the role of these radicals in the development of cardiac toxicity is still not well understood. In the present study, we evaluated the influence of chronic ADR treatment on the cellular defence mechanism against free radicals and the effect of alpha-lipoic acid supplementation on ADR-induced cardiotoxicity in male Wistar rats. The increase in lipid peroxidation (LPO) and activities of serum myocardial enzymes, namely lactate dehydrogenase (LDH) and creatinephosphokinase, associated with the decrease in activities of enzymatic (SOD, CAT, GPx, G6PD and GR) and non-enzymatic (GSH, Vit C and Vit E) antioxidants levels were the salient features observed in ADR-induced cardiotoxicity. Lipoic acid pretreated groups showed significant increase in activities of both enzymatic and non-enzymatic antioxidant levels. These observations highlight the antioxidant property of alpha-lipoic acid and its cytoprotective action against ADR-induced cardiotoxicity.     

The protective effect of glutathione administration on adriamycin-induced acute cardiac toxicity in rats.

Adriamycin (ADR) is a potent antitumor antibiotic drug known to cause severe cardiac toxicity. Although ADR generates free radicals, the role of these radicals in the development of cardiac toxicity is still not well understood. In the present study, we evaluated the effect of glutathione (GSH) supplementation or depletion on ADR-induced cardiotoxicity in male Wistar rats. Cardiac toxicity was induced by a single intraperitoneal injection of ADR (20 mg kg(-1)) and manifested by an increase in heart rate, blood pressure elevation, and increased serum creatine kinase (CK) and lactate dehydrogenase (LDH). The extent of lipoprotein oxidation, lipid peroxide measured as malondialdhye (MDA), total homocysteine (tHcy), lipid profile, and atherogenic index were markedly elevated, whereas cardiac GSH content was dramatically decreased in ADR rats. Pre- and co-treatment of ADR rats with GSH (5 mm kg(-1)) (ADR +GSH) markedly reduced the levels of CK, LDH, lipoprotein oxidation susceptibility, cardiac MDA, tHcy and atherogenic index, and elevated GSH levels in cardiac tissues. In contrast, GSH depletion through administration of l-buthionine-(S,R)-sulfoximine (BSO) (15 mm kg(-1)) before and after ADR injection (ADR +BSO) greatly exacerbated ADR cardiotoxicity compared to the control and ADR groups. Finally, there were also severe cardiac histopathological changes in ADR and ADR +BSO groups, which were nearly restored by GSH treatment. These results suggest that GSH inhibits ADR cardiotoxicity and might serve as a novel combination with ADR to limit free radical-mediated organ injury.     

Spirulina attenuates cyclosporine-induced nephrotoxicity in rats

Cyclosporine (CsA) causes a dose-related decrease in renal function in experimental animals and humans. The generation of reactive oxygen species (ROS) has been implicated in CsA-induced nephrotoxicity. It was previously shown that Spirulina, a blue-green algae, with antioxidant properties effectively attenuated the doxorubicin-induced cardiotoxicity in mice and cisplatin-induced nephrotoxicity in rat. The present study investigated the nephroprotective role of Spirulina against CsA-induced nephrotoxicity in rats. Spirulina (500 mg kg(-1) b.w.) was administered orally for 3 days before and 14 days concurrently with CsA (50 mg kg-1 b.w.). Rats treated with CsA showed nephrotoxicity as evidenced from a significant elevation in plasma urea, creatinine, urinary N-acetyl-beta-D-glucosaminidase (beta-NAG) and a decrease in creatinine and lithium clearance. Pretreatment with Spirulina protected the rats from CsA-induced nephrotoxicity. The CsA-induced rise in plasma urea and creatinine and the decrease in creatinine and lithium clearance were attenuated by Spirulina. There was a significant increase in plasma and kidney tissue MDA with CsA. Spirulina prevented the rise in plasma and kidney tissue MDA. Histopathology of the kidney from CsA-treated rats showed severe isometric vacuolization and widening of the interstitium. However, pretreatment with Spirulina prevented such changes, and the kidney morphology was comparable to that of the control. Spirulina treatment did not alter the blood CsA levels. These results suggest that Spirulina has a protective effect against nephrotoxicity induced by CsA. This study further supports the crucial role of the antioxidant nature of Spirulina in protecting against CsA-induced oxidative stress.     

Angiotensin-converting enzyme inhibition and angiotensin AT1-receptor antagonism equally improve doxorubicin-induced cardiotoxicity and nephrotoxicity

Doxorubicin (Dox) is a potent anticancer agent; its clinical use is limited for its marked cardiotoxicity and nephrotoxicity. The present study investigated the possible protective effect of telmisartan, an angiotensin AT₁-receptor blocker versus captopril, an angiotensin-converting enzyme inhibitor, on Dox-induced cardiotoxicity and nephrotoxicity in rats. Rats were allocated into four groups. Control group, Dox group, Dox + telmisartan group, and Dox + captopril group. Cardiotoxicity and nephrotoxicity were assessed biochemically and histopathologically. Frozen heart and kidney specimens were used for estimation of lipid peroxides product (MDA), reduced glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD) and nitric oxide (NO). Expression of induced nitric oxide synthase (iNOS) was detected by immunohistochemistry. Coadministration of either telmisartan or captopril with Dox equally decreased the biochemical markers of both cardiotoxicity (LDH and CK–MP) and nephrotoxicity (urea and creatinine). Both telmisartan and captopril attenuated the effects of Dox on oxidative stress parameters and NO. Histopathologically, coadministration of either drug with Dox was able to attenuate Dox-induced myocardial fibrosis and renal tubular damage. Immunohistochemistry, expression of iNOS was increased in both cardiac and renal tissues. Both telmisartan and captopril significantly and equally attenuated the effect of Dox on all measured parameters. These results suggested that telmisartan has protective effects equal to that of captopril against Dox-induced cardiotoxicity and nephrotoxicity; implying that angiotensin II pathway plays a role in Dox-induced cardiac and renal damage. The protective effect of either drug relies, at least in part, on their antioxidant effects and decreased the expression of iNOS.     

Protective effects of telmisartan against acute doxorubicin-induced cardiotoxicity in rats

The therapeutic usefulness of doxorubicin (DXR), an anthracycline antibiotic, is limited by its cardiotoxicity. The present study investigated the effects of telmisartan, an angiotensin II receptor (AT1) antagonist against doxorubicin-induced cardiotoxicity in rats using biochemical and histopathological approaches. Doxorubicin (20 mg/kg) was injected intraperitoneally (ip) as a single dose and telmisartan (10 mg/kg) was administered orally for 7 days. Rats treated with DXR showed cardiotoxicity as evidenced by elevation of serum lactate dehydrogenase (LDH) activity, tissue malondialdehyde (MDA) level, catalase activity and a decrease in the level of glutathione (GSH). Pre- and post-treatment with telmisartan elicited a significant decrease in the activities of LDH and catalase in comparison with DXR-treated group. Furthermore, pretreatment with telmisartan also decreased lipid peroxidation (MDA level) and increased the GSH content in comparison with DXR group. However, the difference in lipid peroxidation and GSH content were not statistically significant in post-treated group. Histopathological studies showed disruption of cardiac tisuues in DXR groups. Pre- and post-treatment with telmisartan reduced the damage of cardiac tissue in rats. These results suggest that telmisartan treatment provides a significant protective effect against acute-doxorubicin induced cardiotoxicity in rats.     

Protective effect of lycopene on gentamicin-induced oxidative stress and nephrotoxicity in rats

A potential therapeutic approach to protect or reverse gentamicin-induced oxidative stress and nephrotoxicity would have more importance for clinical consequences. Therefore, the present study was designed to investigate the possible protective effects of lycopene against gentamicin-induced renal damage in rats. Male Sprague-Dawley rats were divided into four groups of six rats in each one; first group served as control. The other groups were treated intraperitoneally with gentamicin alone (100 mg kg(-1) per day) for six successive days, gentamicin for 6 days following 10 days of orally lycopene (4 mg kg(-1) per day) pre-treatment and 6-days of simultaneous lycopene and gentamicin. Biochemical and histopathological examinations were utilized for evaluation of the oxidative stress and renal nephrotoxicity. Creatinine, urea, Na(+) and K(+) levels in plasma and malondialdehyde (MDA), reduced glutathione (GSH) levels and glutathione peroxidase (GSH-Px) and catalase (CAT) activities were determined in kidney tissue. Administration of gentamicin to rats induced a marked renal failure, characterized by a significant increase in plasma creatinine and urea concentrations. The animals treated with gentamicin alone showed a significantly higher kidney MDA and lower GSH-Px and CAT activities but unaffected GSH concentrations when compared with the control group. Pre-treatment with lycopene produced amelioration in biochemical indices of nephrotoxicity in plasma. However, little changes were observed in the kidney MDA and GSH levels and GSH-Px and CAT activities when compared with the gentamicin treated group. The histological structures of the renal proximal tubules showed similar patterns. On the other hand, administration of simultaneous lycopene to rats produced amelioration in MDA and GSH levels and GSH-Px and CAT activities when compared with gentamicin group. In addition, simultaneous lycopene was found to reduce the degree of kidney tissue damage in histopathological findings. These results indicate that specially simultaneous treatment of lycopene might have produced amelioration in biochemical indices and oxidative stress parameters against gentamicin-induced nephrotoxicity, but pre-treatments with lycopene had no beneficial effects on these parameters. It was concluded that lycopene as a novel natural antioxidant might have protective effects against gentamicin-induced nephrotoxicity and oxidative stress in rats.     

Cisplatin-induced cardiotoxicity: Mechanisms and cardioprotective strategies

Increased oxidative stress and apoptosis have been implicated in the cardiotoxicity that limits the clinical use of cisplatin as an anti-tumoral drug. Our study was conducted to evaluate the protective potential of acetyl-l-carnitine, DL-α-lipoic acid and silymarin against cisplatin-induced myocardial injury. Eighty male albino rats were divided into eight groups. The first four groups were treated with normal saline, acetyl-l-carnitine (500 mg/kg, i.p.), DL-α-lipoic acid (100 mg/kg, p.o.) and silymarin (100 mg/kg, p.o.) respectively, for 10 successive days. The remaining groups were treated with the same doses of normal saline, acetyl-l-carnitine, DL-α-lipoic acid and silymarin, respectively, for 5 successive days before and after a single dose of cisplatin (10 mg/kg, i.p.). Serum activities of lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase isoenzyme MB (CK-MB) and plasma cardiac troponin I (cTnI) concentration were estimated. Malondialdehyde (MDA), reduced glutathione (GSH) contents, superoxide dismutase activity (SOD) and protein content in cardiac tissues were measured. Moreover, integrity of both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) was also examined. Cisplatin-treated rats experienced a significant elevation of serum activities of LDH, CK, CK-MB and cTnI plasma concentration. These effects were accompanied by a significant increase in MDA level. On the other hand, a significant decrease in GSH content, SOD activity and total protein content was observed. In addition, both mtDNA and nDNA were heavily damaged. However, acetyl-l-carnitine, DL-α-lipoic acid and silymarin significantly attenuated the cisplatin-evoked disturbances in the above-mentioned parameters. In conclusion, the former drugs were proven to be potential candidates to ameliorate cisplatin-induced cardiotoxicity.     

姜黄素对顺铂所致大鼠肾毒性的防护作用

目的研究姜黄素(CMN)对顺铂(CDDP)所致肾损害的防护作用,并探讨其可能机制。方法将42只大鼠按体重随机分6组,分别为对照组、CMN组、CDDP组、CMN(204、0和80 mg/kg) CDDP组。CMN连续给予大鼠灌胃3 d,第2天灌胃后1 h腹腔注射CDDP(5.5 mg/kg)。CDDP处理后,分别在第1、3和5天采血,测定血清尿素氮(BUN)和肌酐(CRE)。第5天采血后处死动物,测定肾脏系数、肾皮质匀浆丙二醛(MDA)、谷胱甘肽(GSH)含量和谷胱甘肽过氧化物酶(GSH-Px)活力以及肾组织铂(Pt)含量等。同时利用体外实验观察对抗增殖作用的影响。结果CMN预处理可减轻CDDP引起的肾脏系数升高及BUN、CRE水平升高;能抑制CDDP引起的MDA形成增高;并能提升CDDP引起的GSH含量和GSH-Px活力下降。CMN低剂量的上述作用明显(P<0.05或P<0.01)。CMN防护组与CDDP组的人卵巢癌细胞系和膀胱癌细胞系的半数抑制浓度差异无显著性。结论CMN经口给予能防护CDDP所致的肾损害,其机制可能与其抗氧化作用和清除自由基活性有密切关系。较高剂量CMN未见防护CDDP所致肾毒性的作用,其原因可能与其助氧化作用有关。CMN对CDDP抗肿瘤细胞增殖作用无明显影响。     

Effects of gemcitabine on cisplatin-induced nephrotoxicity in rats: schedule-dependent study.

The effects of gemcitabine (dFdC) on the lipid peroxidation and kidney histopathology in the nephrotoxicity of an antitumour drug cisplatin (CDDP) were studied in rats. dFdC was administered intraperitoneally (i.p.) at single doses of 90 mgkg(-1) while CDDP was administered i.p. at single doses of 6 mgkg(-1). Both drugs were injected either alone or sequentially in combination. In one case, CDDP preceded dFdC by 4 h and 24 h and in the other case, dFdC preceded CDDP by 4 h and 24 h. Seven days after CDDP administration, the nephrotoxicity was manifested biochemically by elevation of serum creatinine, blood urea nitrogen and an increase in the kidney weight as a percentage of total body weight. In addition, marked decreases in serum albumin and calcium levels were observed. Lipid peroxidation in the kidney was monitored by measuring the malondialdehyde (MDA) production level and kidney glutathione (GSH) content, which were increased and depleted, respectively. Administration of dFdC 4 h and 24 h after CDDP administration did not significantly change the indices of CDDP-induced nephrotoxicity or the kidney platinum concentration levels in comparison with those animals treated with CDDP alone. On the contrary, administration of dFdC 4 h and 24 h prior to CDDP administration significantly aggravated CDDP-induced nephrotoxicity which was manifested by severe increases in the serum creatinine and blood urea nitrogen levels as well as kidney weight as a percentage of total body weight. In addition, kidney tissue showed severe GSH depletion and increases in the MDA production and platinum concentration levels. Moreover, treatment of rats with dFdC 24 h prior to CDDP resulted in much more aggravation of CDDP-induced nephrotoxicity in comparison with those animals treated with dFdC 4 h prior to CDDP. Histopathological examination demonstrated tubular atrophy, tubular necrosis and drug-induced nuclear changes in the CDDP-treated group. However, pretreatment of rats with dFdC 4 h and 24 h prior to CDDP revealed extensive interstitial nephritis, renal tubular atrophy and tubular necrosis with 'sloughing off' of the lining cells, especially with those rats treated with dFdC 24 h prior to CDDP. These results might suggest that administration of dFdC prior to CDDP enhanced the lipid peroxidation in kidney tissue and aggravated CDDP-induced nephrotoxicity.     

Prevention of acute adriamycin cardiotoxicity by dantrolene in rats

Possible preventive effect of dantrolene against the peroxidative damage in rat heart which was induced by the administration of an acute dose of adriamycin (ADR, 20 mg/kg, i.p.) has been examined. Forty-eight hours after ADR administration, biochemical changes including the activities of serum creatine kinase isoenzyme (CK-MB), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) and the levels of malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in heart tissue were measured. Pretreatment of rats with dantrolene, given i.p. 30 min prior to ADR injection, substantially reduced the peroxidative damage in the myocardium, and markedly lowered the serum CK-MB, LDH and AST. The protective effects obtained by dantrolene administration, however, were not complete and did not reach those of the control group. Dantrolene, at 5 mg/kg, was useful to obtain significant protective effects, while the protector effect of higher dantrolene dosing level (10 mg/kg) was weak or absent. These results suggest that, at least in part, due to antioxidative properties, dantrolene may provide a significant protective effect against acute ADR-induced cardiotoxicity.     

大蒜多糖对阿霉素所致小鼠心脏毒性的拮抗作用

目的　研究大蒜多糖 (GP)对中毒性心肌炎的拮抗作用并探讨其机制。方法　建立小鼠阿霉素 (ADR)中毒性心肌炎模型,测定血清、心肌多项生化指标,并观察心肌结构变化。结果　ADR(3mg·kg-1ip, qod×7)可致小鼠血清肌酸激酶(CK)、乳酸脱氢酶(LDH)、谷草转氨酶(GOT)和诱导型一氧化氮合酶(iNOS)活力升高(P<0 01),同时心肌超氧化物歧化酶(SOD)活力下降而丙二醛 (MDA)含量升高 (P<0 01),线粒体水肿明显。GP( 0 75 ~3 0g·kg-1 ig, qd×15)能逆转ADR所致的上述改变,表现为剂量相关性降低血清CK、LDH、GOT和iNOS活力,增加心肌SOD活力和降低MDA含量,尤其以GP大剂量组作用明显 (P<0 05或P<0 01)。光镜和电镜结果也证实了GP的保护作用。结论　GP能拮抗阿霉素所致的小鼠中毒性心肌炎,其作用机制与增强心肌SOD活力和抗心肌脂质过氧化有关。     

Protective effects of oral arabic gum administration on gentamicin-induced nephrotoxicity in rats.

Arabic gum (AG) is a complex polysaccharide used as suspending agent. It has been widely used by eastern folk medicine practitioners as a restorative agent and is thought to be an excellent curative for renal failure patients. We therefore tested these folkloric claims using a rat model of gentamicin (GM)-induced nephrotoxicity. AG (7.5g 100ml(-1), in drinking water) was administered orally for 8 days concurrently with GM (80mgkg(-1) per day, i.p.). Estimation of urine volume, serum creatinine and urea concentrations, kidney tissue malondialdehyde (MDA) contents and glutathione (GSH) were carried out after the last dose of GM. Kidneys were also examined for histological changes. GM caused a marked nephrotoxicity as evidenced by significant increases in urine volume (295%), serum creatinine (318%) and urea (258%) and a significant decrease in creatinine clearance (Ccr) (26%). Treatment with AG protected the rats from GM-induced nephrotoxicity as evident by normalisation of these parameters. In addition there was about 187% increase in kidney tissue MDA contents above the control with GM treatment. AG totally prevented the GM-induced rise in kidney tissue contents of MDA. Kidney histology of the tissue from GM-treated rats showed necrosis and desquamation of tubular epithelial cells in renal cortex as well as interstitial nephritis. Whereas it was very much comparable to control when AG was co-administered with GM. In conclusion, AG protected the rats from GM-induced nephrotoxicity, possibly, at least in part through inhibition of the production of oxygen free radicals that cause lipid peroxidation.     

Lycopene, a carotenoid, attenuates cyclosporine-induced renal dysfunction and oxidative stress in rats

The aim of this study was to investigate the possible protective role of antioxidant treatment with lycopene on cyclosporine A-induced nephrotoxicity using biochemical and histopatological approaches. Adult male Sprague-Dawley rats were randomly divided into four groups. The control group received physiological saline; animals in the lycopene group received only lycopene (10 mg/kg); animals in the cyclosporine A group received only cyclosporine A (15 mg/kg) and animals in cyclosporine plus lycopene group received cyclosporine and lycopene for 21 days. The effects of lycopene on cyclosporine A-induced nephrotoxicity were evaluated by plasma creatinine, urea, sodium and calcium concentrations; kidney tissue thiobarbituric acid reactive species, reduced glutathione (GSH), glutathione peroxidase (GSH-Px) and catalase activities and histopatological examinations. Administration of cyclosporine A to rats induced a marked renal failure, characterized with a significant increase in plasma creatinine and urea concentrations. Cyclosporine A also induced oxidative stress as indicated by increased kidney tissue concentrations of thiobarbituric acid reactive species and GSH, and reduced activities of GSH-Px and catalase. Moreover, the kidneys of cyclosporine A-treated rats showed tubular necrosis, degeneration, dilatation, thickened basement membranes, luminal cast formation and inter-tubular fibrosis. Lycopene markedly reduced elevated plasma creatinine, urea levels and counteracted the deleterious effects of cyclosporine A on oxidative stress markers. In addition, lycopene ameliorated cyclosporine A-induced pathological changes including tubular necrosis, degeneration, thickened basement membranes and inter-tubular fibrosis when compared to the alone cyclosporine A group. These data indicate that the natural antioxidant lycopene might have protective effect against cyclosporine-induced nephrotoxicity and oxidative stress in rat.     

Cardiotoxic effects of arsenic trioxide/imatinib mesilate combination in rats

Cardiotoxicity is an important consideration in the evaluation of cancer chemotherapy, because chemotherapy-induced myocardial damage might be irreversible and lethal. This in-vivo study investigated the cardiotoxicity of either arsenic trioxide or imatinib mesilate, or a combination of both drugs, following repeated administration in male Wistar rats. Both arsenic trioxide and imatinib mesilate were administered daily at a dose of 5 mg kg(-1) intraperitoneally and 30 mg kg(-1) orally for 10 days, respectively. Cardiotoxicity was evaluated by biochemical and histopathological examination 48 h after the last dose. Treatment with either arsenic or imatinib, or both, resulted in significant increases in serum creatine kinase isoenzyme (CK-MB), glutathione peroxidase (GPx), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) activity levels. Cardiac tissue of rats treated with arsenic showed significant increases in levels of reduced glutathione (GSH) content, GPx activity, malondialdehyde (MDA) and total nitrate/nitrite (NOx), whereas imatinib treatment significantly increased cardiac GSH content and MDA production level and decreased GPx activity level and NOx content. A combination of arsenic and imatinib produced significant increases in cardiac GSH content, GPx activity and MDA production levels, in addition to a reduction in NOx content. Combination arsenic/imatinib treatment extensively increased GPx activity and MDA production levels compared with imatinib treatment alone. Moreover, rats treated with arsenic or imatinib, or both, showed a significant increase in serum bilirubin, creatinine and urea levels. Histopathological examination of cardiac tissue of the combination-treated group revealed fibroblastic proliferation, myocardial disorganization and myocardial necrosis. Liver peroxidative alterations revealed that treatment with either arsenic or imatinib, or the two combined, increased levels of reduced-GSH and MDA production levels. However, imatinib treatment depleted liver GPx activity level contrary to treatment with the combination. Rats treated with arsenic alone or arsenic/imatinib combination showed significant elevation in liver NOx. In conclusion, both arsenic trioxide and imatinib mesilate might have significant cardiotoxicity and cardiac function should be monitored during treatment with them alone or in combination, as well as in the presence of pre-existing cardiac dysfunction.     

Rhein protects against acetaminophen-induced hepatic and renal toxicity

This study investigated the possible protective effects and mechanism of rhein on Acetaminophen (APAP)-induced hepatotoxicity and nephrotoxicity in rats. Treatment of rats with APAP resulted in severe liver and kidney injuries, as demonstrated by drastic elevation of serum glutamate-pyruvate transaminase (GPT), glutamate-oxaloacetic transaminase (GOT), total bilirubin (TBIL), creatinine (CREA), urea nitrogen (UREA) levels and typical histopathological changes including necrosis, phlogocyte infiltration and fatty degeneration in liver, tubules epithelium swelling and severe vacuolar degeneration in kidney. APAP caused oxidative stress, as evidenced by increased reactive oxygen species (ROS) production, nitric oxide (NO) and malondiadehyde (MDA) levels, together with depleted glutathione (GSH) concentration in the liver and kidney of rats. However, rhein can attenuate APAP-induced hepatotoxicity and nephrotoxicity in a dose-dependent manner. Our results showed that GPT, GOT, UREA and CREA levels and ROS production were reduced dramatically, NO, MDA, GSH contents were restored remarkedly by rhein administration, as compared to the APAP alone treated rats. Moreover, the histopathological damage of liver and kidney were also significantly ameliorated by rhein treatment. These findings suggested that the protective effects of rhein against APAP-induced liver and kidney injuries might result from the amelioration of APAP-induced oxidative stress.     

The preventive role of deferoxamine against acute doxorubicin-induced cardiac, renal and hepatic toxicity in rats.

The iron chelating activity of deferoxamine (DFO) has been exploited to obtain protection against the peroxidative damage in rat heart which was induced by the administration of an acute dose of doxorubicin (DXR, 25 mg x kg(-1), i.v.). The peroxidative lesions were evaluated both biochemically and histopathologically, 48 h after DXR administration. Abnormal biochemical changes including a marked increase in the levels of serum creatine kinase isoenzyme (CK-MB), and lactate dehydrogenase (LDH), as well as elevated serum creatinine, blood urea nitrogen and transaminases (ALT and AST) levels were observed. Myocardial tissue from DXR treated rats showed a marked increase in malondialdehyde (MDA) production and depletion of reduced glutathione (GSH) contents. Similar results were also observed in both kidney and liver tissues. Pretreatment of rats with DFO, given i.p. 30 min prior to DXR injection, substantially reduced the peroxidative damage in the myocardium, hepatic and renal tissues and markedly lowered the serum CK-MB, LDH and the other biochemical variables. The protective effects obtained by DFO administration, however, were not complete and did not reach those of the control group. The significant protection against DXR-induced cardiomyopathy by DFO was evident from the histopathological findings observed by light microscopy. DFO at a dosing level equivalent to 10-fold of that of DXR was useful to obtain protective effects. Higher DFO dosing levels did not, however, show more improvement in the DXR-induced cardiotoxicity and at the same time exhibited hepatoxicity which was confirmed by microscopical examination. These results strongly suggest that DFO protects against acute DXR-induced cardiotoxicity in a dose-dependent manner with recognizing the presence of mild DFO-related biochemical and cytological hepatic toxicity.     

Mechanism of the cardioprotective effects of docetaxel pre-administration against adriamycin-induced cardiotoxicity

We revealed that pre-treatment with docetaxel (DOC) 12 h before adriamycin (ADR) administration significantly reduced ADR-induced toxic death compared with the simultaneous dosing schedule that was commonly used in previous studies. We considered that pre-treatment with DOC relieves ADR-induced cardiotoxicity. In this study, we investigated the influence of DOC on the pharmacokinetics and pharmacodynamics of ADR in order to clarify the mechanism by which DOC pre-treatment relieves ADR-induced cardiotoxicity. When ADR and/or DOC was intravenously administered, the DOC pre-treatment (DOC-ADR) group showed significantly less toxic death than the ADR-alone group. We examined hepatopathy, nephropathy, leukopenia, and cardiotoxicity, all of which can cause toxic death. Of these toxicities, ADR-induced cardiotoxicity was significantly relieved in the DOC-ADR group. To elucidate the mechanism by which DOC pre-treatment relieved ADR-induced cardiotoxicity, lipid peroxidation as a proxy for the free radical level and the pharmacokinetics of ADR were measured. There was no difference in the pharmacokinetics of ADR between the ADR and DOC-ADR groups. On the other hand, the DOC-ADR group showed significantly inhibited lipid peroxidation in the heart compared with the ADR group. It was considered that DOC pre-administration inhibited ADR-induced free radicals and decreased cardiotoxicity.     

The effect of manganese chloride on gentamicin-induced nephrotoxicity in rats

The aim of this study was to investigate the effects of manganese chloride on gentamicin-induced nephrotoxicity in rats. Thirty-six adult Wistar Albino rats were divided into six equal groups. They were injected with gentamicin sulfate (100 mg kg⁻¹per day i.p.) and manganese chloride (2 or 20 mg kg⁻¹ per day i.p.) and gentamicin together with manganese chloride for 6 days. The animals were killed 24 h after the last injection. Nephrotoxicity was biochemically and histopathologically evaluated. The concentrations of creatinine, urea, sodium and potassium in plasma, malondialdehyde (MDA) and reduced glutathione (GSH) levels, glutathione peroxidase (GSH-Px) and catalase (CAT) activities in kidney tissue were determined. Administration of gentamicin to rats induced a marked renal failure, characterized with a significant increase in plasma creatinine and urea concentrations. A significant increase in kidney MDA and a decrease in GSH concentrations were observed in gentamicin-treated rats. No change was observed in the activities of GSH-Px and CAT in rats treated with gentamicin alone. Administration of the low dose of manganese (Mn²⁺) produced amelioration in biochemical indices of nephrotoxicity in plasma and kidney tissue when compared to gentamicin group. The histological signs of renal proximal tubules followed a similar pattern. The high dose of Mn²⁺ (20 mg kg⁻¹) caused an opposite effect on nephrotoxicity induced by gentamicin, causing exacerbation in the tubular necrosis. The results suggest that low dose of Mn²⁺ may have an antioxidant effect in kidneys of gentamicin administrated rats, but its high doses had no beneficial effect.     

Propionyl-L-carnitine as protector against adriamycin-induced cardiomyopathy.

Propionyl- l -carnitine (PLC) is a naturally occurring compound that has been considered for the treatment of many forms of cardiomyopathies. In this study, the possible mechanisms whereby PLC could protect against adriamycin (ADR)-induced cardiomyopathy were carried out. Administration of ADR (3 mg kg(-1)i.p., every other day over a period of 2 weeks) resulted in a significant two-fold increase in serum levels of creatine phosphokinase, lactate dehydrogenase and glutamic oxaloacetic transaminase, whereas daily administration of PLC (250 mg kg(-1), i.p. for 2 weeks) induced non-significant change. Daily administration of PLC to ADR-treated rats resulted in complete reversal of ADR-induced increase in cardiac enzymes except lactate dehydrogenase which was only reversed by 66%. In cardiac tissue homogenate, ADR caused a significant 53% increase in malonedialdehyde (MDA) and a significant 50% decrease in reduced glutathione (GSH) levels, whereas PLC induced a significant 33% decrease in MDA and a significant 41% increase in GSH levels. Daily administration of PLC to ADR-treated rats completely reversed the increase in MDA and the decrease in GSH induced by ADR to the normal levels. In rat heart mitochondria isolated 24 h after the last dose, ADR induced a significant 48% and 42% decrease in(14)CO(2)released from the oxidation of [1-(14)C]palmitoyl-CoA and [1-(14)C]palmitoylcarnitine, respectively, whereas PLC resulted in a significant 66% and 54% increase in the oxidation of both substrates, respectively. Interestingly, administration of PLC to ADR-treated rats resulted in complete recovery of the ADR-induced decrease in the oxidation of both substrates. In addition, in rat heart mitochondria, the oxidation of [1-(14)C]pyruvate, [1-(14)C]pyruvate and [1-(14)C]octanoate were not affected by ADR and/or PLC treatment. Moreover, ADR caused severe histopathological lesions manifested as toxic myocarditis which is protected by PLC. Worth mentioning is that PLC had no effect on the antitumour activity of ADR in solid Ehrlich carcinoma. Results from this study suggest that: (1) in the heart, PLC therapy completely protects against ADR-induced inhibition of mitochondrial beta -oxidation of long-chain fatty acids; (2) PLC has and/or induces a powerful antioxidant defense mechanism against ADR-induced lipid peroxidation of cardiac membranes; and finally (3) PLC has no effect on the antitumour activity of ADR.