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 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