Sherif Y. Saad

Protection effects of Taurine supplementation against cisplatin-induced nephrotoxicity in rats.

Backgound: Taurine, which is the major intracellular free β-amino acid, is known to be an antioxidant and a membrane-stabilizing agent. This study was designed to investigate the protective role of taurine supplementation against cisplatin-induced nephrotoxicity. Methods: Male Wistar rats were divided into six groups and treated as follows: (1) saline-treated control drinking tap water, (2) saline-treated plus taurine-supplemented (1.5% taurine in the drinking water), (3) saline-treated plus taurine-depleted (3% β-alanine in the drinking water), (4) cisplatin-treated, CDDP 6 mg/kg intraperitoneally, (5) taurine-supplemented plus CDDP-treated and (6) taurine-depleted plus CDDP-treated. Rats were sacrificed 7 days after CDDP treatment, and serum as well as kidneys were isolated and analyzed. Results: CDDP-treated rats showed increased kidney weight as a percentage of total body weight, serum creatinine and BUN levels and decreased serum albumin and calcium levels. Also, CDDP treatment resulted in a depletion of kidney GSH content, a reduction in the kidney glutathione peroxidase (GSH-Px) activity and increased kidney MDA production level. Taurine supplementation attenuated CDDP-induced nephrotoxicity which was manifested by jeopardizing the elevation in serum creatinine and BUN levels and the reduction in serum albumin and calcium levels. Moreover, taurine supplementation restored kidney GSH content and GSH-Px activity and reduced platinum accumulation and MDA production levels in the kidney tissue following CDDP treatment. Histopathological examination of the kidney of CDDP-treated rats revealed tubular atrophy, tubular necrosis and desquamation of renal tubular cells. However, taurine supplementation protected against CDDP-induced histopathological changes. Conclusions: The data suggest that taurine supplementation effectively attenuates the accumulation of platinum within kidney tissue and counteracts the deleterious effect of CDDP on the renal tubular function.

Role of non-selective adenosine receptor blockade and phosphodiesterase inhibition in cisplatin-induced nephrogonadal toxicity in rats

1. It is well documented that cisplatin (CDDP) treatment increases the expression of adenosine A1 receptors in both kidney and testes. However, the effect of adenosine at these receptors is controversial. Adenosine A1 receptors have been documented to be involved in either cytoprotection or aggravation of nephrotoxicity. The aim of the present study was to examine the effect of the non‐selective adenosine receptor inhibitor theophylline and the phosphodiesterase inhibitor pentoxifylline on CDDP‐induced renal and testicular toxicity.

Inhibition of Nitric Oxide Synthase Aggravates Cisplatin-Induced Nephrotoxicity: Effect of 2-Amino-4-Methylpyridine

Background: Nitric oxide (NO) has been shown to play a role in maintaining normal renal function. However, the role of NO in cisplatin (CDDP)-induced nephrotoxicity is still unclear. The aim of the present work was to examine the effect of the NO synthase (NOS) inhibitor, 2-amino-4-methylpyridine, on the severity of CDDP-induced nephrotoxicity. Methods: Male Wistar rats were divided into six groups. Three control groups received plain drinking water or water containing 1.5% L-arginine. One of the two groups receiving plain water was treated with an intraperitoneal injection of 2-amino-4-methylpyridine (1 mg/kg in normal saline), and the other two control groups were injected intraperitoneally with normal saline. Another three groups were treated in the same manner and injected with CDDP (6 mg/kg, i.p.). CDDP was injected 1 h after 2-amino-4-methylpyridine treatment. Rats were sacrificed 7 days after CDDP treatment, and serum as well as kidneys were isolated and analysed. Results: CDDP-treated rats showed increases in the kidney weight as a percentage of the total body weight and serum creatinine and urea levels and decreases in serum albumin and calcium levels. Also, CDDP treatment induced reductions in the kidney total nitrate/nitrite (NOx), reduced glutathione (GSH) and glutathione peroxidase activity (GSH-Px) levels and an increase in the kidney malondialdehyde (MDA) production level. In contrast, 2-amino-4-methylpyridine treatment 1 h prior to CDDP injection induced marked exacerbation of CDDP-induced nephrotoxicity, as manifested by severe aggravation of the indices of nephrotoxicity. Also, 2-amino-4-methylpyridine plus CDDP-treated rats showed exaggeration of the reduction in the kidney total NOx content and GSH-Px activity and elevation of the kidney platinum accumulation level with normalization of the kidney MDA production level and rebound in the kidney GSH content. Histopathologically, CDDP-treated rats showed marked interstitial nephritis, tubular atrophy and tubular necrosis. However, treatment with 2-amino-4-methylpyridine 1 h prior to CDDP injection revealed marked exacerbation of CDDP-induced histopathological changes. Conclusions: The present findings suggest that NO plays a role in CDDP-induced nephrotoxicity. Administration of 2-amino-4-methylpyridine, an NOS inhibitor, exacerbates CDDP-induced nephrotoxicity.

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.

Cisplatin pharmacokinetics and its nephrotoxicity in diabetic rabbits

Background: This study was designed to investigate the relationship between the attenuation of cisplatin (CDDP)-induced nephrotoxicity in experimental diabetic rabbits and the plasma pharmacokinetics of the free ultrafilterable and total plasma platinum (Pt) levels. Methods: Two groups of age-matched male New Zealand white rabbits were used; the first group consisted of rabbits with streptozotocin-induced diabetes (single i.v. bolus dose of streptozotocin of 65 mg/kg in citrate buffer, pH 4.6), and the second group of nondiabetic rabbits treated with the same volume of citrate buffer. Both groups were treated with CDDP (5 mg/kg, single i.v. bolus dose) 3 days after induction of the diabetic state in the first group. The plasma Pt levels were followed for 4 h after CDDP administration, in which the free ultrafilterable and total plasma Pt concentrations were determined by atomic absorption spectrometry. The pharmacokinetic parameters of free ultrafilterable plasma Pt were determined using a noncompartment pharmacokinetic model of analysis. Results: The total plasma Pt levels declined in a biphasic manner and were adequately described by a two-compartment model. No significant change was observed in the pharmacokinetics of either the free ultrafilterable or total plasma Pt levels in the diabetic group in comparison with the control nondiabetic group (p > 0.05). However, 4 h after CDDP administration, the total plasma Pt level of the nondiabetic group was significantly higher than that of the diabetic rabbits (p < 0.001). Indices of nephrotoxicity were determined 7 days after CDDP administration. The results revealed that the diabetic state protected against CDDP-induced nephrotoxicity. The nondiabetic rabbits exhibited highly significant elevations in the serum creatinine and urea levels and a decrease in the serum albumin level (p < 0.001) in comparison with the diabetic group. Conclusions: These findings might suggest that the reduction in CDDP-induced nephrotoxicity in diabetic rabbits is not due to a change in the plasma pharmacokinetic profile within the drug follow-up period. It could be anticipated that the rapid decline in the total plasma Pt level after CDDP administration to diabetic rabbits, as well as the reduction in the terminal elimination half-life of the total plasma Pt level might be responsible for the reduction in CDDP-induced nephrotoxicity. Also, alterations in the how kidneys of diabetics deal with the renal excretion of Pt and reduction of its accumulation in kidney tissue are not excluded.

Mechanism and implication of cephalosporin penetration into oropharyngeal mucosa.

The aim of this study was to explore the mechanism(s) by which oral cephalosporins penetrate into human oropharyngeal mucosa, and thus, the availability of sufficient concentrations at the site of infection. Two oral cephalosporin prototypes, cephalexin (first generation) and cefixime (third generation), were administered to five healthy subjects at two different visits with a 1-week washout period. Plasma and saliva samples were collected and drug concentrations were measured using an appropriate HPLC method. The maximum plasma concentrations (Cmax) of cefixime and cephalexin were 2.97 ± 0.24 μg ml−1 and 77.65 ± 18.91 μg ml−1, respectively. These concentrations were associated with a maximum salivary concentration (CSmax) of 0.56 μg ml−1 for cefixime and 3.34 μg ml−1 for cephalexin. Such levels exceed the reported minimal inhibitory concentration (MIC) for Streptococcus pyogenes and Streptococcus pneumoniae. The average concentration of cefixime in saliva corresponded to its plasma free fraction (saliva/plasma [S/P] ratio; 0.34). However, this observation was not true for cephalexin, for which antibiotic concentrations in the saliva did not appear to correspond to its plasma free fraction (0.8–0.85), with an S/P ratio of only 0.092. Our findings indicate that an active transport mechanism exists for cefixime excretion into human oropharyngeal mucosa, whereas cephalexin is passively diffused, although to a limited extent, as measured by its salivary concentrations.

Pharmacokinetic Profile of Methotrexate and 5-Fluorouracil in Normal and Bilharzial-infested Mice

The pharmacokinetics of two commonly used anticancer drugs, methotrexate (MTX) and 5-fluorouracil (5-FU), were investigated in normal and bilharzial-infested mice. Liver glucose-6-phosphatase activity and antipyrine clearance were used as parameters of liver function. Liver glucose-6-phosphatase activity was significantly reduced in bilharzial-infested mice compared with the normal controls. Bilharzial infestation caused a significant reduction in the elimination (beta) and clearance rate (Cl) of antipyrine, whereas its elimination half-life (t1/2 beta) was increased in comparison with the normal controls. A similar pattern was also obtained after MTX and 5-FU administration in bilharzial mice, compared to controls. These results indicate that hepatic bilharziasis causes a significant reduction in the hepatic clearance and elimination of MTX and 5-FU, whereas their areas under the concentration-time curve were significantly increased. These findings may have to be considered in the treatment of bilharzial cancer patients.