Hepatic and renal damage induced by oxidative stress are improved by administration of enalapril and nicorandil in diabetic rats

Oxidative stress plays a crucial role in tissue damage occurring in diabetes mellitus [DM]. A number of studies reported that antioxidants can attenuate the complications of DM. The present work was undertaken to study the histopathological and biochemical effects of oxidative stress on hepatic and renal tissue in streptozotocin-induced DM in rats, and to evaluate the role of enalapril and nicorandil and their combination in combating oxidative stress-induced pathological effects. Diabetic rats were divided into groups of six rats and received 10mgkg, intraperitoneally of enalapril [an angiotensin-converting enzyme [ACE] inhibitor that is used in the treatment of hypertension], 10lmg/kg, orally of nicorandil [a potassium channel opener which is effective in the treatment of hypertension and angina pectoris] and their combination once daily for one month. Analysis of plasma and tissue parameters of oxidative stress was done. In addition, specimens were taken from the liver and kidney for histopathological examination. Plasma of diabetic rats showed significant elevation of glucose level and alteration in oxidative stress parameters, Cytochernical studies on hepatic and renal tissues showed altered levels of oxidative stress parameters. Histopathological examination of hepatic and renal specimens showed degenerative changes. Treatments of the diabetic rats with enalapril, nicorandil and their combination led,to improvement of the abnormalities in oxidative stress parameters and also in the histopathological abnormalities of the liver may be and kidney. These results indicate that oxidative stress an important cause of the structural damage occurring in many organs in DM, even in early stages of the disease. The antioxidant activities of enalapril, nicorandil and their combination may play an important role in protection against oxidative stress in DM

Modification of the antinflammatory, antipyretic and analgesic effects of meloxicam with omeprazol or ranitidine in exeperimental animals

The potential modification of the anti-inflammatory, antipyretic and analgesic effects of meloxicam in concurrent administration of omeprazole or ranitidine was assessed. This study was divided into two sets of experiments. In the first set of experiments, male albino rats were divided into 2 main groups: Group I: to study the anti-inflammatory activity of the tested drugs by induction of inflammation by subcutaneous injection of 0.1mI of 20% brewer's yeast suspension into planter surface of the right hind paw and measuring the rats paw thickness according to the treatment received. Group II: to study the anti-pyretic activity of the tested drugs by induction of pyrexia by subcutaneous injection of 2. 5m1 of 20% aqueous suspension of yeast dorsally and ventrally and recording the rectal temperature according to the treatment received. In the second set of experiments, mice were divided into two main groups: Group I: The analgesic activity of the tested drugs was evaluated by chemical method [p-benzoquinon induced-writhing response]. Group II: The analgesic activity of the tested drugs was evaluated by thermal method [hot plate method]. Intraperitoneal [i.p.] administration of meloxicain produced a significant reduction in the rat paw edema [P<0. 05]. Combined i.p. injection of meloxicam and ranitidine caused a significant decrease in the rats paw edema [P<0. 05]. Also, the combined i.p injection of meloxicam and omeprazole caused a significant reduction in the rat's paw edema [P<0. 05]. Intraperitoneal administration of meloxicam into hyperthermic rats led to a remarkable reduction in body temperature of rats. Combined administration of meloxicam and ranitidine or meloxicam and omeprazole produced a significant decrease in the body temperature [P<0. 05]. The i.p administration of meloxicam before the injection of P-benzoquinon [PBQ] protected the animals against writhing response. The concurrent administration of meloxicam and ranitidine or meloxicam and omeprazole resulted in protection of animals from PBQ-induced writhing response which was significant [P<0. 05]. Furthermore, the combined administration of meloxicam and ranitidine or meloxicam and omeprazole caused a significant increase in the reaction time to thermal stimulus [P<0. 05]. On the other hand, i.p. injection of ranitidine or omeprazole alone caused non significant change in the rat's paw edema or yeast induced pyrexia, but ranitidine caused a significant decrease in PBQ-induced writhing response and in hot plate-induced pain [P<0.05]. In addition, omeprazol produced non significant change in PBQ-induced writhing response and in hot plate-induced pain. It could be suggested that in choice of the use of one of antiulcer drugs with meloxicam we prefer to use ranitidine over omeprazole as ranitidine potentiated the analgesic effect of meloxicam

Role of allium sativum in the protection against oxidative stress and associated biochemical changes in streptozotocin-induced diabetes in rats

Oxidative stress is involved in both pathogenesis and complications of diabetes. The need to identify agents with a potential for preventing such damage and complication has assumed great importance. The present study was devoted to the assessment of the effect of chronic oral administration of raw garlic homogenate on oxidative stress and associated biochemical changes in streptozotocin [STZ]-induced diabetic rats. Male Sprague- Dawley rats weighing 180-200 g were used. Rats were divided into four groups 6 rats each. Group 1: is a control group in which rats received only 0.5 ml of vehicle [citrate buffer pH 4.5] as a single intraperitoneal [i.p.] dose. Group II: in which rats were treated orally with 20% raw garlic homogenate in distilled water in a dose of 500 mg/kg once a day for 30 days. Group III: rats were treated with 0.5 ml 2.4% solution STZ in citrate buffer in a single i.p. dose of 60 mg/kg. Group IV: rats were treated with 0.5 ml 2.4% solution STZ in citrate buffer in a single i.p. dose of 60 mg/kg, plus orally with 20% raw garlic homogenate in distilled water in a dose of 500 mg/kg once a day for 30 days. Blood aliquots were collected for serum separation. Serum levels of glucose, aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase [ALP], bilirubin, urea and creatinine as well as total cholesterol, LDL-cholesterol, VLDL-cholesterol and triglycerides were evaluated. HDL-cholesterol was also determined. The animals were then sacrificed and specimens were taken from the liver and kidney tissues and tissue homogenates were separated for determination of oxidative stress and antioxidant parameters such as malondialdehyde [MDA], reduced glutathione [GSH] and catalase [CAT] levels. Chronic oral administration of raw garlic homogenate produced a significant reduction in the serum levels of glucose[P<0.01], AST [P<0.05], ALT[P<0.05], ALP [P<0.05], bilirubin [P<0.01], urea [P<0.01] and creatinine [P<0.05] in STZ-induced diabetic rats. Furthermore,there was a significant decrease in total serum cholesterol [P<0.05], LDL-cholesterol [P<0.01], VLDL-cholesterol [P<0.05], and triglycerides [P<0.05] and a significant increase in HDL-cholesterol [P<0.01] as compared to STZ -induced diabetic group. On the other hand, hepatic and renal MDA were significantly reduced, [P<0.01] and [P<0.05], respectively. Also, there was a significant increase in both hepatic [P<0.01] and renal [P<0.05] GSH levels and catalase activity [P<0.001] as compared to STZ-induced diabetic rats. Chronic oral administration of raw garlic homogenate attenuates oxidative stress and associated biochemical changes in STZ-induced diabetic rats

Role of copper complexes in the protection against stress-induced gastric ulcer in rats

Copper complexes achieve an anti-ulcer activity, several investigations were submitted to clarify the possible mode of action of these copper complexes as potent anti-ulcer drugs. These agents have a wide range of pharmacological activities that could be explained on the basis of the activation of copper dependant enzymes and their physiochemical properties. Copper complexes are reported to have potent anti-inflammatory and anti-ulcer effects. All of these copper complexes were found to be more active than either inorganic copper salts or their parent completing agents, Copper complexes were effective in reducing ulcer number as well as ulcer severity, they have an antisecretory activity. To further clarify this point, the present study was conducted to evaluate anti-ulcer activity of two types of copper complexes which are: Cu [l]-[nicotinic acid][2]Cl complex and Cu[II] [glycinate][2] complexe and their combination in water immersion-restraint stressed [WIRS] ulcer rat model. The present study was conducted on 25 mule Wister albino rats, that were randomly divided info three groups:Group I: Control non-stressed group: in which animals were received only an intragastric dose of 0, 5ml of vehicle [0.25% Tween -80 in saline solution]. Group II: Non-pretreated WIRS group; in which rats were subjected to restraining by WIRS and received an intragastric dose of 0.5ml of vehicle. Group III: Treated WIRS groups: in which rats were subjected to restraining and subdivided according to the received drug into: Subgroup A: received an intragastric dose of 8 mg/kg body mass Cu[I]-[nicotinic acid][2]Cl complex, in 0.5ml of vehicle immediately prior to stress. Subgroup B: received an intragastric dose of 5 mg/kg body mass Cu[II][glycinate]2 complex, in 0.5ml of vehicle immediately prior to stress. Subgroup C: received an intragastric dose of 5 mg/kg body mass Cu[II] [glycinate][2] complex + 8 mg/kg body mass Cu[T]-[nicotinic acid][2]CI complex, in 0.5 ml of vehicle immediately prior to stress.Group II and III were subjected to restraining by fixing I he four limbs to a metal board, and placed in a water bath maintained to the level of the xiphoid process at a temperature of 23 +/- 1 °C for 3 to 5 hours.Blood samples were taken from all groups as plasma for determination of total superoxide dismutase [SOD] activity or serum for determination of total nitrite level. After withdrawal of the blood samples, their stomachs were removed and opened along the greater curvature. All the stomachs were formalin fixed and paraffin embedded, for assessment of histopathological changes affecting these structures using light microscopical examination. Administration of intragastric copper complexes increased plasma level of SOD from 0.54 +/- 0.02 unit/ml and 0.32 +/- 0.63 unit/ml for control non-stressed group and non-pretreated WIRS group to 0.84+0.10 unit/ml 1.39 +/- 0.15 unit/ml and 2.27 +/- 0.13 unit/ml for Cu[I]-[nicotinic acid][2]Cl complex, Cu[II][glycinate][2] complex and combination of two types of copper complexes, respectively. In the other hand, WIRS was associated with a significant increase in total serum nitrite level with a mean of 70.11 +/- 6.12 micro mol/1 in a comparison with non stressed group [32.09 +/- 2.05 micro mol/l]. Pretreatment of WIRS animals with both types of copper complexes; Cu[I]-[nicotinic acid][2]Cl complex and Cu[Il] [glycinate][2] complex and their combinations intragastrically did not produce a significant reduction of nitrite level, compared to WIRS group, with means 59 +/- 1.90 micro mol/L, 64.93 +/- 2.66pmol/L and 63.20+1.78 micro mol/L for both [Cu[l]-[nicotinic acid][2]Cl complex and Cu[II] [glycinate][2] complex and their combined mixture respectively. The histopathological findings of the light microscopical examination demonstrated that there was no microscopic abnormality in the gastric mucosae in the non-stressed control group [group I]. Moderate to severe gastric erosion was seen in the examined cases, with denudation of parts of the gastric mucosae of different thickness. A complete gastric ulceration with complete necrosis of parts of the gastric mucosaeseen in the most severe forms of non-pretreated WIRS group [group II]. Either no histopathologic abnormality or mild erosion was seen in WIRS groups treated with Cu[I]-[nicotinic acid][2]Cl, Cu[II][glycinate]2 complexes and their combined mixture [group III], From these results It can be concluded that both intragastrically injected copper complexes and their combined mixture exerted protective effect on the gastric mucosa of WIRS induced ulcer in rats. This is confirmed by the incosistantly measured biochemical parameters [plasma SOD and serum nitrite levels] and the histopathological examination of the gastric mucosa

Modification of antiinflammatory, antipyretic and analgesic effects of celecoxib with some antiulcer drugs in experimental animals

Patients under antiulcer therapy may suffer from a concurrent disease which requires the use of one of NSAIDs, In such cases, these patients are likely to receive a combination of one of the antiulcer drugs plus the NSAIDs. Accordingly, the simultaneous use of one of the NSAIDs with one of the antiulcer drugs may lead to drug-drug interaction. The present work was devoted to the assessment of the modification of the anti-inflammatory, antipyretic and analgesic effects of celecoxib after the concurrent administration of the antiulcer drugs, omeprazole and ranitidine. This study was performed on two animal species, rats and mice. Rats were used to detect the anti-inflammatory and the antipyretic activities of the investigated drugs. Mice were utilized to study the analgesic activity of the same drugs.Male albino rats were divided into 2 main groups: Group I. rats were divided into 5 subgroups, to study the anti-inflammatory activity of the tested drugs by induction of inflammation by subcutaneous injection of 0.1 ml of 20% brewer's yeast suspension into planter surface of the right hid paw and measuring the rats paw thickness according to the treatment received. Group II: rats were divided into 5 subgroups, to study the anti-pyretic activity of the tested drugs by induction of pyrexia by subcutaneous injection of 2.5ml of 20% aqueous suspension of yeast dorsally and ventrally and recording the rectal temperature according to the treatment received. GroupIII: mice were divided into two set of experiment each of which divided into 5 subgroups. The analgesic activity of the drugs was evaluated by chemical method [p-benzoquinon induced -writhing response and the thermal method [hot plate method]. Intraperitoneal [i.p.] administration of celecoxib produced highly significant reduction in the rat's paw edema. Intraperitoneal injection of celecoxib and ranitidine caused highly significant decrease in the rat's paw edema. Similarly the combined i.p injection of celecoxib and omeprazole gave a highly significant reduction in the rat's paw edema. Intraperitoneal administration of celecoxib Into hyper-thermic rats led to a remarkable reduction in body temperature of rats. Combined administration of celecoxib and ranitidine produced highly significant decrease in body temperature. The combined i.p administration of celecoxib and omeprazole caused a highly significant decrease. In body temperature. The i.p administration of celecoxib before the injection of P-benzoquinon [PBQ] protected the animals against writhing response. Intraperitoneal injection of celecoxib and ranitidine resulted in protection of animals from PBQ-induced writhing response which was highly significant. The simultaneous administration of celecoxib and omeprazole protected the animals from PBQ-induced writhing response which was highly significant. Intraperitoneal injection of celecoxib revealed a highly significant increase in the reaction time. The combined administration of celecoxib and ranitidine caused highly significant increase in the reaction time. Intraperitoneal administration ofcelecoxib and omeprazole also produced highly significant increase in the reaction time to thermal stimulus. Intraperitoneal injection of ranitidine or omeprazole caused non significant change in the rat's paw edema or yeast induced pyrexia, but ranitidine caused a significant decrease in PBQ-induced writhing response and in hoi plate-induced pain. On the other hand omeprazol produced non significant change in PBQ-induced writhing response and in hot plate-induced pain. It could be suggested that ranitidine is a relatively better drug than omeprazole with respect to anti-inflammatory, antipyretic and analgesic actions when used concurrently with a selective COXII inhibitor

Role of drugs affecting potassium channels on morphine analgesia in mice

The modification of antinociceptive effect of morphine by either K[+] channel blockers such as glibenclamide or K[+] channel openers such as diazoxide and minoxidil was evaluated. Antinociceptive activity of morphine was measured by tail-immersion test and hot plate test in mice. The intraperitoneal administration of morphine [5 mg/kg] elicited a time-dependent antinociceptive effect [after 15, 30, 60 and 120 minutes post injection]. The selective blockers of ATP -senstive K[+] channels glibenclamide [15mg, IP] antagonized the spinal [tail-immersion test] and supraspinal [hot plate lest] antinociception induced by 5 mg/kg morphine IP. In contrast the antinociceptive effect of morphine was enhanced by intraperitoneal administration of either diazoxide [140 mg/kg] or minoxidil [14 mg/kg] [K[+] channels openers] in a time dependent manner [after 15, 30, 60 and 120 minutes post injection]. These results suggested that K[+] channels openers as diazoxide and minoxidil potentiated the spinal and supraspinal analgesia induced by morphine. In addition the selective blockers of ATP -senstive K[+] channels glibenclamide antagonized the spinal and supraspinal analgesia induced by morphine in time dependent manners

Ropivacaine 0.2% pharm following caudal block in children

Ropivacaine is a long -acting amide local anasetheic that is available as a pure S-enantiomer.Several clinical studies have shown that ropivacaine is a suitable drug for epidural anaesthesia [1]. There has little published on the use of caudally administered ropivacaine in children. The aim of this study was to evaluate the pharmacokinetics of ropivacaine after caudal block in children, comparing infants [children aged between I and 5 years]. Thirty male children as a grade 1 and scheduled for subumblical surgery were enrolled in this prospective study after informed parent consent. The children were grouped according to age [15 [infant] aged less than 1 year and 15 [toddlers] aged 1-5 years. After induction of general anaesthesia .caudal epidural injection using ropivacaine 0.2% 1 ml/kg was performed .Plasma concentrations of ropivacaine in the first 2 hours after injection were determined by reversed -phase high-pressure liquid chromatography. Caudal blockade with ropivacaine 2mg/ml resulted in mean [ +/- SD] peak plasma concentrations of 0.69 micro g/ml [ +/- 0.29] in infants and 0.46 micro g/ml [ +/- 0.23] in toddlers [p<0.01].Maximum plasma concentrations occurred after a median range period of 60 [15-90] minutes and 53 [30-120] in infants and toddlers respectively. No clinical signs of local anaesthetic toxicity were observed. The results of the present study suggest that, caudal blockade using ropivacaine 0.2% 1mI/kg, from a pharmacokinetic point of view, can be considered a safe technique in children i.e.in infants as well as in toddlers

Protective effects of oleanolic acid and vitamine E on thyroid dysfunction and lipid peroxidation in cadmium- induced toxicity in rats

The effect of oleanolic acid or vit. E on heavy metal [cadmium] -induced thyroid dysfunction and lipid peroxidation in male rats was studied. The animals divided into 3 groups each of which 6 rats. The first group were injected with 1mg/kg/day cadmium chloride, 1% solution in distilled water subcutaneously daily for 30 days. The second group were injected simultaneously with equivalent dose of cadmium chloride [1mg/kg/day] subcutaneously and oleanolic acid in a dose of 5 mg/kg/day, 2% suspension in 2% tween 80 intramuscularly for 30 days. The third group were injected simultaneously with equivalent dose of cadmium chloride [1mg/kg/day] subcutaneously and vit. E, in a dose of 100mg/kg [5% solution in saline] intramuscularly for 30 days. The control groups were divided into 3 groups. The first group was treated with distilled water, the second one was treated with tween 80 and lastly the third group was trated with saline. Cadmium chloride treatment alone led to decrease in concentrations of serum thyroid hormones, zinc and copper concentration [p<0.01]. In addition, a significant increase in both malondialdyhyde [MDA] levels and thyroid stimulating hormone [TSH] has been observed by Cd-treatment alone [p<0.01]. Treatment with either oleanolic acid or vit.E improved the metal-induced decrease in serum thyroid function. Treatment with oleanolic acid lead to decrease in levels of blood and hepatic malondialdyhyde but remain higher than normal rates [47.14 +/- 0.82 micro mol/L and 119 +/- 0.86 micro mol/g wet tissue, respectively]. However, treatment with Cd and vit. E restored blood and hepatic malondialdyhyde levels toward normal values [34.7 +/- 0.65 micro mol/L and 100.4 +/- 1.44 micro mol/g wet tissue, respectively]. The effect of vit. E combined with cadmium is significant compared with the effect of oleanolic acid treatment with cadmium [p<0.01]. The protective effect of each oleanolic acid or vit. E against cadmium-induced thyroid dysfunction is mediated through its antioxidative action

Effects of henna leaf [lawsonia inermis] on biochemical and pathological alterations in chemically-induced cancer breast in albino female rats

Breast cancer is one of the most common and treatable of all-human malignancies. The development of breast cancer is associated with oxidative stress, Henna leaf [Lawsonia inermis,] has anti-inflammatory, antimicrobial, antipyretic, analgesic, antioxidant and anticarcinogenic effect as well. This study is designed to investigate the effects of henna leaf on the chemically-induced cancer breast in albino female rats. Thirty albino female rats of 45 F days age were used. The animals were divided into three groups 10 animals each. Group I [control group], group II received the carcinogenic substance 7, 12-dimethyl benz [a] anthracene [DMBA,] intraperitonially, in single dose of 10 mg that can induce palpable mammary masses within 90 days and group III received the carcinogenic substance by the same concentrations, duration and the same route as in group II till induced palpable mammary masses then treated orally once daily for one month with 200 mg/kg body weight of henna leaf extract. Blood samples were collected from the three groups and the serum used for determination of estradiol hormone and lipid bound sialic acid. The animals then sacrificed and specimens were taken from the breast tumor tissues and tissue homogenate was done for determination of nitric oxide [NO] and total glutathione. Another specimen was taken from the breast tumor tissues and processed for histopathological examination. RESULTS: Group II showed that DMBA administration caused a significant increase in the serum level of both estradiol and lipid bound sialic acid, Also, DMBA induced a significant increase in the level of NO and a significant decrease in the level of total glutathione in breast tumor tissues homogenate. The palpable masses were rubbery in consistency, whitish cut surface with focal ulceration of the overlying skin. Mammary adenocarcinomas with a prevailing cribriform pattern were seen in DMBA treated group. Group III showed that treatment with henna induced a significant decrease of serum estradiol level as well as a decrease in the serum level of lipid bound sialic acid. Also henna caused a significant decrease in NO and a significant increase in the level of total glutathione in breast tumor tissues homogenate. As regard the lesions size there were marked reduction in them in all animals. Histologically, group III breast masses showed extensive areas of necrosis, and exhibited stromal reaction composed of admixture of lymphocytes, plasma cells, histiocytes, and fibroblasts [signs of regression,]. Histopathological assessment also demonstrated cellular morphological features of apoptosis in both malignant and dysplastic cells. We can conclude that the effects of henna leaf on breast cancer induced chemically by DMBA are incomplete and exerted mainly through a decrease of free radicals and increase in the antioxidant level

Age related changes and melatonin

Melatonin [N-acetyl-5-methoxy-tryptamine] is a neurohormone that is secreted by a small gland in the center of the brain called the pineal gland. Aging is accompanied by changes in the morphology and physiology of organs and tissues. This process might be due to the accumulation of oxidative damage induced by reactive oxygen [ROS] and reactive nitrogen species [RNS]. To assess age - related changes that occur in the lung, liver and kidney of the rat and to investigate the protective role of exogenous melatonin against these changes. Thirty five male albino rats were classified into 3 groups. Group 1 [non aged] acted as the control group, injected with normal saline intraperitoneal 3 times / week and sacrificed when aged 3 months. Group II remained untreated and sacrificed when aged 18 months. Group III was treated with melatonin [1 mg/kg] intraperitoneal 3 times / week and sacrificed when aged 18 months. The antioxidant effect of melatonin was also detected by measuring the level of nitric oxide in all groups. Group II showed marked age-related changes in the examined organs. The lung showed thickening in the wall of the alveoli with increased phagocytic and lymphocytic infiltration. The liver showed vaculation of the cytoplasm and increased phagocytic infiltration .The kidney showed atrophic glomeruli. Most of these changes were reduced in group III [treated with melatonin] except increasing the number of phagocyte especially in the lung. Melatonin also decreased the level of nitric oxide. Melatonin seems to have beneficial effects against age- related changes in the lung, liver and kidney

Role of oxidative stress in cisplatin - induced nephrotoxicity in rats

Cisplatin [cis diammine dichloroplatinum] is a potent antitumor drug. Expansion of the clinical utility of cisplatin has been limited by its toxicity where acute and chronic forms of renal injury have been described due to apoptosis. The mechanism by which it activates the myriad of apoptotic pathways remains unclear. Several studies have now documented the importance of reactive oxygen metabolites [ROM] in cisplatin-induced renal cell apoptosis. To further clarify this point the present study was conducted to evaluate the oxidative stress induced by cisplatin. Rats were treated either by high single intraperiotoneal dose [7mg/kg] or by repeated small doses [4mg/kg] twice weekly for one month. Rats were sacrificed by decapitation after 48 hours of high dose intake or 24 hours after intake repeated small doses. Kidney tissues were removed for histopathological examination, after homogenization these tissues were removed for determination of glutathione [GSH]. Blood samples were taken from rats for determination of serum level of creatinine, blood urea nitrogen [BUN] and nitric oxide [NO]. Histopathological examination of kidney tissue revealed degenerative changes with tubular change, especially in the proximal convoluted tubules. Significant elevation in serum creatinine [2.24 +/- 0.18 vs 2.12 +/- 0.18] and BUN [146 +/- 10.6 vs132 +/- 11.2] levels were observed. Administration of cisplatin in large dose or small repeated doses causes significant elevation in serum [NO] level [10.4 +/- 0.8 micro mol/l and 9 +/- 0.53 micro mol/l respectively] as well as depletion in renal [GSH] tissue levels [1.02 +/- 0.09 micro mol/l w.wt wet, weight] and 1.12 +/- 0.08 micro mol/g w.wt, respectively]. From these results, it can be concluded that single high dose or small repeated doses of cisplatin-induced nephrotoxicity was associated with induction of oxidative stress. Use of antioxidants in conjunction with cisplatin could be a value in minimizing its toxicity