Hematological and renoprotective effects of folic acid and lentil extract in diclofenac sodium exposed rats / Efeitos hematológicos e renoprotetores do ácido fólico e do extrato de lentilha em ratos expostos ao diclofenaco de sódio

Excessive intake of non-steroidal anti-inflammatory drugs such as, diclofenac sodium (DS) may lead to toxicity in the rats. In this work, we aimed to examine the protective impact of lentil extract (LE) and folic acid (FA) on the hematological markers, the kidney tissue oxidative stress and the renal function against diclofenac sodium (DS) in male albino rats. The rats (120-150 g) were divided into four equal groups randomly, the first group kept as the untreated control. The second group was administrated with DS (11.6 mg/kg b.wt. orally once/day). The third group was received DS+FA (11.6 mg/kg b.wt.+76.9 microgram/kg b.wt.) orally once/day. The fourth group was treated with DS+LE (11.6 mg/kg b.wt.+500 mg/kg b.wt.) orally once/day. After four weeks, the results revealed that DS produced a significant decrease in the values of red blood cells (RBCs), hemoglobin concentration (Hb), hematocrit (HCT) and white blood cells (WBCs). On the other hand, there was a significant increase in the platelets count. Also, DS induced a renal deterioration; this was evidenced by the significant increase in the serum levels of urea, creatinine, uric acid, Na, Ca, Mg as well as the nitric oxide (NO) level in the kidney tissue. Also, there were a significant reduction in the serum levels of potassium (K) and reduced glutathione (GSH) in the kidney homogenates. Moreover, the findings in the rats treated by DS+LE or DS+FA showed a potential protection on the hematological markers, oxidative stress in the kidney tissue and the renal function disturbed by DS. LE and FA could play a potent role for the prevention the adverse hematological, the kidney tissue oxidative stress and the renal dysfunction caused by DS via their anti-oxidative and bioactive phytochemicals.

A ingestão excessiva de anti-inflamatórios não esteroidais, como o diclofenaco de sódio (DS), pode causar toxicidade em ratos. Neste trabalho, objetivamos examinar o impacto protetor do extrato de lentilha (LE) e ácido fólico (AF) em marcadores hematológicos, no estresse oxidativo do tecido renal e na função renal contra o diclofenaco de sódio (DS) em ratos albinos machos. Os ratos (120-150 g) foram divididos em quatro grupos iguais aleatoriamente, sendo o primeiro grupo mantido como controle não tratado. O segundo grupo foi administrado com DS (11,6 mg / kg de peso corporal por via oral uma vez / dia). O terceiro grupo recebeu DS + FA (76,9 mg / kg de peso corporal por via oral uma vez / dia). O quarto grupo foi tratado com DS + LE (500 mg / kg de peso corporal por via oral uma vez / dia). Após quatro semanas, os resultados revelaram que o DS produziu uma diminuição significativa nos valores de glóbulos vermelhos (RBCs), concentração de hemoglobina (Hb), hematócrito (HCT) e glóbulos brancos (WBCs). Por outro lado, houve um aumento significativo na contagem de plaquetas. Além disso, o DS induziu uma deterioração renal; isso foi evidenciado pelo aumento significativo dos níveis séricos de ureia, creatinina, ácido úrico, Na, Ca, Mg e também do nível de óxido nítrico no tecido renal. Além disso, houve uma redução significativa nos níveis séricos de potássio (K) e glutationa reduzida (GSH) nos homogenatos renais. Além disso, os achados nos ratos tratados com DS + LE ou DS + FA mostraram uma proteção potencial sobre os marcadores hematológicos, estresse oxidativo no tecido renal e função renal perturbada pelo DS. LE e AF podem desempenhar um papel potente na prevenção do estresse hematológico adverso, do estresse oxidativo do tecido renal e da disfunção renal causada pelo DS por meio de seus fitoquímicos antioxidantes e bioativos.

Hematological and renoprotective effects of folic acid and lentil extract in diclofenac sodium exposed rats / Efeitos hematológicos e renoprotetores do ácido fólico e do extrato de lentilha em ratos expostos ao diclofenaco de sódio

Abstract Excessive intake of non-steroidal anti-inflammatory drugs such as, diclofenac sodium (DS) may lead to toxicity in the rats. In this work, we aimed to examine the protective impact of lentil extract (LE) and folic acid (FA) on the hematological markers, the kidney tissue oxidative stress and the renal function against diclofenac sodium (DS) in male albino rats. The rats (120-150 g) were divided into four equal groups randomly, the first group kept as the untreated control. The second group was administrated with DS (11.6 mg/kg b.wt. orally once/day). The third group was received DS+FA (11.6 mg/kg b.wt.+76.9 microgram/kg b.wt.) orally once/day. The fourth group was treated with DS+LE (11.6 mg/kg b.wt.+500 mg/kg b.wt.) orally once/day. After four weeks, the results revealed that DS produced a significant decrease in the values of red blood cells (RBCs), hemoglobin concentration (Hb), hematocrit (HCT) and white blood cells (WBCs). On the other hand, there was a significant increase in the platelets count. Also, DS induced a renal deterioration; this was evidenced by the significant increase in the serum levels of urea, creatinine, uric acid, Na, Ca, Mg as well as the nitric oxide (NO) level in the kidney tissue. Also, there were a significant reduction in the serum levels of potassium (K) and reduced glutathione (GSH) in the kidney homogenates. Moreover, the findings in the rats treated by DS+LE or DS+FA showed a potential protection on the hematological markers, oxidative stress in the kidney tissue and the renal function disturbed by DS. LE and FA could play a potent role for the prevention the adverse hematological, the kidney tissue oxidative stress and the renal dysfunction caused by DS via their anti-oxidative and bioactive phytochemicals.

Resumo A ingestão excessiva de anti-inflamatórios não esteroidais, como o diclofenaco de sódio (DS), pode causar toxicidade em ratos. Neste trabalho, objetivamos examinar o impacto protetor do extrato de lentilha (LE) e ácido fólico (AF) em marcadores hematológicos, no estresse oxidativo do tecido renal e na função renal contra o diclofenaco de sódio (DS) em ratos albinos machos. Os ratos (120-150 g) foram divididos em quatro grupos iguais aleatoriamente, sendo o primeiro grupo mantido como controle não tratado. O segundo grupo foi administrado com DS (11,6 mg / kg de peso corporal por via oral uma vez / dia). O terceiro grupo recebeu DS + FA (76,9 mg / kg de peso corporal por via oral uma vez / dia). O quarto grupo foi tratado com DS + LE (500 mg / kg de peso corporal por via oral uma vez / dia). Após quatro semanas, os resultados revelaram que o DS produziu uma diminuição significativa nos valores de glóbulos vermelhos (RBCs), concentração de hemoglobina (Hb), hematócrito (HCT) e glóbulos brancos (WBCs). Por outro lado, houve um aumento significativo na contagem de plaquetas. Além disso, o DS induziu uma deterioração renal; isso foi evidenciado pelo aumento significativo dos níveis séricos de ureia, creatinina, ácido úrico, Na, Ca, Mg e também do nível de óxido nítrico no tecido renal. Além disso, houve uma redução significativa nos níveis séricos de potássio (K) e glutationa reduzida (GSH) nos homogenatos renais. Além disso, os achados nos ratos tratados com DS + LE ou DS + FA mostraram uma proteção potencial sobre os marcadores hematológicos, estresse oxidativo no tecido renal e função renal perturbada pelo DS. LE e AF podem desempenhar um papel potente na prevenção do estresse hematológico adverso, do estresse oxidativo do tecido renal e da disfunção renal causada pelo DS por meio de seus fitoquímicos antioxidantes e bioativos.

A study on the toxic effect of different doses of diclofenac sodium on the development of the kidney in the postnatal period / Estudio sobre el efecto tóxico de diferentes dosis de diclofenaco sódico en el desarrollo del riñón en el período postnatal

The toxic effects of different doses of diclofenac sodium (DS) on the kidney on the postnatal period (0-7 days) by morphometrical and immunohistochemical methods were investigated. For this purpose, 15 female adult wistar albino rats were used and divided into 5 main groups. Group Ia served as normal control, physiologic group Ib received normal saline, group II received low dose (3.9 mg/kg), group III received medium dose (9 mg/kg) and group IV received high dose (18 mg/kg). Male offspring's from 0-7 days after birth were used in this study. On the 8th day of postnatal life, all animals were anesthetized. Then, the kidney samples were analyzed. Haematoxylin and eosin staining showed degeneration and necrosis, apparent atrophy of the glomeruli, mononuclear cell infiltration, congested vessels, increased fibrous tissue and distortion of the proximal convoluted tubules with interruption of the brush margin of the DS treated group. Increased level of Caspase-3 and upregulation of TNF-α with different doses of DS. In light of our findings, DS may lead to adverse effects that are dose-dependent in the prenatal subjected kidney to this drug.

Se investigaron los efectos tóxicos de diferentes dosis de diclofenaco sódico (DS) en el riñón de ratas, durante su período postnatal (0-7 días), por métodos morfométricos e inmunohistoquímicos. Para este propósito, se utilizaron 20 crías macho, de ratas Wistar albinas, y se dividieron en 5 grupos principales. El grupo Ia sirvió como control normal, el grupo fisiológico Ib recibió solución salina normal, el grupo II recibió una dosis baja de DS (3,9 mg/kg), el grupo III recibió una dosis media de DS (9 mg/kg) y el grupo IV recibió una dosis alta de DS (18 mg/kg). Se administraron los medicamentos de 0 a 7 días después del nacimiento de las ratas. En el octavo día de vida postnatal, todos los animales fueron sacrificados. Luego, se analizaron las muestras de riñón. Mediante hematoxilina-eosina se evidenció degeneración y necrosis, aparente atrofia de los glomérulos, infiltración de células mononucleares, vasos congestionados, aumento del tejido fibroso y distorsión de los túbulos contorneados proximales, con interrupción del margen en cepillo del grupo tratado con DS. Se detectó un aumento del nivel de caspasa-3 y regulación al alza de TNF-α con diferentes dosis de DS. A la luz de nuestros hallazgos, la DS puede provocar efectos adversos en el riñón, que dependen de la dosis de este medicamento administrada en el período posnatal.

comparative study on liver toxicity profile of diclofenac sodium and piroxicam on rabbits

Aim of this study was to determine the clinical hepatotoxicity of diclofenac sodium and of piroxicam, and to evaluate whether these drugs could elicit liver cell destruction and anemia, and which drug is comparatively safer for prolong use. This study was conducted in the department of Pharmacology, Faculty of pharmacy, University of Karachi, Karachi. Duration of study was 30 days. Male 40 rabbits were equally divided into 4 groups, group A was served as control and the group B and C was diclofenac sodium [0.8mg/kg/day and 1.5 mg/kg/day], and group D was of piroxicam [0.31 mg/kg/day] treated. All the animals were caged in pair in an iron caged with free access to grass and hay of standard diet and tap water for a period of 30 days. Diclofenac sodium in 2 different doses 0.8mg/kg/day, 1.5 mg/kg/day and similarly Piroxicam [0.31mg/kg/day] dissolved in drinking water and was given orally for a period of 30 days. Control rabbits were given tap water. At the end of 30 days blood was collected through cardiac puncture from each rabbit and was analyzed to determine the levels of SGOT, SGPT, Bilirubin, ESR and Erythrocyte count. It was found that these drugs can induce severe hepatic damage but the ratio of liver toxicity is different, as evident by the elevation of serum aminotransferases, bilirubin and changes in hematological profile. The experimental results suggest that SGOT and SGPT levels were significantly increased in diclofenac sodium treated rabbits after 10 and 30 days [P> 0.01], while piroxicam treated rabbits showed significant result, [P<0.05] only after 30 days of treatment. The level of bilirubin was significantly increased in diclofenac sodium treated rabbits after 10 days and 30 days [P<0.01] and piroxicam also showed significant result [P<0.05] after 30 days treatment. Erythrocyte count decreased in both control and treated rabbits after 10 days but control results are not significant. After 30 days diclofenac sodium showed highly significant decrease in count of erythrocytes [P<0.01], but piroxicam showed less significant results [P<0.05]. E.S.R values significantly increased in diclofenac sodium and piroxicam treated rabbits after 10 days and 30 days. It can be concluded that diclofenac sodium and piroxicam both can play a role in inducing hepatocellular damage, but a greater increase in liver toxicity was seen in diclofenac sodium treated rabbits rather than piroxicam treated rabbits

Diclofenac inhibits proliferation but not NGF-induced differentiation of PC 12 cells

Diclofenac is a non-steroidal anti-inflammatory drug that is prescribed for treatment of rheumatic diseases and as an analgesic. Although the information about these side effects has been widely reported, little is know about the effect of diclofenac on the neural cells. In this study, we investigated the effects of diclofenac on the proliferation and differentiation of PC12 cells. The cell proliferation was evaluated by using XTT assay in the both free-serum neurobasal medium supplemented with B27 supplement and DMEM/F12 medium containing 10% FBS. The nerve growth factor [NGF]-induced differentiation was assessed by measuring the neurite length. The drug toxicity was exhibited at the concentrations more than 310 microM in the supplemented neurobasal medium. The treatment of cells in the DMEM/F12 medium increased their sensitivity to diclofenac, with 40% and 75% growth inhibition at the 155 and 310 microM concentrations, respectively. The NGF-induced differentiation was not reduced by toxic and subtoxic concentrations of diclofenac. The results of this study indicated that diclofenac may be able to exhibit its neurotoxic effects through growth inhibition, but not differentiation inhibition. Supplement of B27 has several antioxidant compounds. Therefore, the difference of diclofenac cytotoxic effects in two culture media suggest that drug cytotoxicity may be related to the oxidative stress

Protective effect of taurine and quercetin against renal dysfunction associated with the combined use of gentamycin and diclofenac.

The potential protective effects of taurine and quercetin against gentamycin (GM)/diclofenac (DC) combined nephrotoxicity were investigated in rats. The results showed that administration of DC alone at an oral dose of 5 mg/kg b.wt/day for 28 days had no significant effect on the measured parameters, except for marked increase in urinary uronic acid excretion. Administration of GM alone at a dose of 100 mg/kg b.wt/day i.p. for 8 days resulted in obvious nephrotoxicity. Combined GM-DC treatment led to the most pronounced nephrotoxicity, as indicated by greater elevations in serum urea, creatinine and urinary N-acetyl-beta-D-glucosaminidase (NAG), together with severe depression of renal cortical Na , K+-ATPase, compared to GM-treated group. Moreover, only combined treatment resulted in significant decrease in urinary potassium and renal cortical glutathione peroxidase (GSHPx), together with an increase in renal cortical lipid peroxidation products (LPOs). Co-administration of taurine or quercetin normalized creatinine clearance and ameliorated the elevations in urinary proteins, uronic acids, NAG and renal cortical LPOs in GM/DC treated rats. The study justifies the use of taurine and quercetin as renoprotective agents against the nephrotoxicity caused by GM/DC therapy.