The Effects of Spironolactone in Preventing Bile Duct Ligation-induced Hepatitis in A Rat Model.

Cholestasis is associated with the accumulation of bile acids and bilirubin in the hepatocytes and leads to liver injury. Pregnane X Receptor (PXR) coordinates protective hepatic responses to toxic stimuli, and this receptor was reported to stimulate bile secretion by increasing MRP2 expression. Since PXR activators were reported to be anti-inflammatory in the liver, PXR was proposed as a drug target for the treatment of chronic inflammatory liver diseases. We investigated the potential protective effect of spironolactone (SPL), an enzyme inducer, in hepatotoxicity induced by bile duct ligation in rats. Wistar Albino (250-300 g) rats were divided into the control group and the bile duct ligated (BDL) group. BDL group was divided into three subgroups; following BDL, for 3 days, the first group received propylene glycol (vehicle of SPL) (blinded), the second subgroup received spironolactone (SPL) (200 mg/kg oral), and the third subgroup received SPL for 3 days, starting 3 days after the bile duct ligation, in order to investigate if it has a healing effect after hepatitis had developed. The control group was sham-operated and received saline. At the end of the experiment, blood and tissue samples were collected. Serum TNF-α, NF-ĸB, bilirubin, IL-6 levels, ALT, AST, ALP activities and tissue MPO activity and oxidant damage increased after the bile duct ligation was significantly decreased following SPL administration. PXR and MRP2 activity showed an increase in the hepatocytes as a result of the treatment. In conclusion, it was observed that SPL administration significantly decreases liver inflammation and damage related to BDL.

Knowledge and attitudes of the pharmacists, prescribers and patients towards generic drug use in Istanbul - Turkey.

UNLABELLED: The use of generic drugs has increased significantly in recent years. Since generic drugs are available at a lower cost, they provide an opportunity for savings in drug expenditure. Thus, use of generic drugs is encouraged especially in developing countries. There are only a few studies concerning the perceptions and attitudes of the healthcare providers and patients towards generic drug use. METHODS: The present study was conducted by a face to face questionnaire in the Kadikoy district of Istanbul in April 2010. From randomly chosen respondents, 68 pharmacists, 56 prescribers and 101 patients consented to participate in the study. RESULTS: Thirty one and 32 % of the pharmacists and prescribers, respectively, expressed that they believed that the generics did not differ from the original drugs, whereas only 24% of the patients believed so. Forty percent of the pharmacists and 82% of the prescribers told that they were unsure about the bioequivalence of the generics. Ten percent of the patients claimed that they immediately accept generic substitution by the pharmacist, while 26% accepted it if it was substituted by the prescriber. Cost was the most important factor taken into consideration about generic substitution (92% for prescribers; 83% for patients and 82% for pharmacists). CONCLUSIONS: Our findings demonstrated that healthcare providers as well as the drug consumers have insufficient knowledge about generic drugs. Therefore, they should be better educated with respect to generic substitution.

A study comparing the effects of rosiglitazone and/or insulin treatments on streptozotocin induced diabetic (type I diabetes) rat aorta and cavernous tissues.

Our aim was to investigate the role of oxidative stress and inflammation on the functional and biochemical changes caused by hyperglycemia in the aorta and corpus cavernosum tissues of streptozotozin diabetic rats and to determine if rosiglitazone and/or insulin treatment has any preventive effect on organ dysfunction. Wistar Albino rats were divided into 2 groups. I) Control group: a) Vehicle, 0.1 M citrate buffer, the solvent of streptozotocin injected intraperitoneally (i.p) and b) Rosiglitazone group: (4 mg/kg/day, i.p.) for 8 weeks. II) Diabetic group: streptozotocin (60 mg/kg) was administered i.p. to induce diabetes. 48 h after streptozotocin injection, animals were divided into 4 subgroups (n=6 for each group); a) no treatment group (D), b) treated with rosiglitazone (4 mg/kg/day) (DR), c) treated with insulin (6 U/kg/day) (DI) and d) treated with insulin and rosiglitazone (DRI) for 8 weeks. At the end of the experimental period, animals were decapitated and tissue samples were collected for in vitro experiments and biochemical studies. Endothelium dependent relaxation induced by acetylcholine in the aorta and corpus cavernosum tissues were attenuated in the diabetic group, whereas phenylephrine induced contractile responses were reduced. These responses were restored after rosiglitazone and/or insulin treatment, the combination being the most efficient treatment. Malondialdehyde and TNF-α levels were increased in diabetic rats while glutathione levels were decreased. All treatments prevented these changes in biochemical parameters, rosiglitazone and insulin combination again being the most efficient treatment. Our results suggested that supplementing diabetic patients receiving insulin treatment with adjunct therapy of rosiglitazone may have some benefit for controlling diabetic complications.

Changes in caveolin-1 expression and vasoreactivity in the aorta and corpus cavernosum of fructose and streptozotocin-induced diabetic rats.

Hyperglycemia is a common defining feature in the development of endothelial dysfunction which plays a key role in the pathogenesis of both type 1 and type 2 diabetes. Caveolin-1 is the main structural component of caveolae which might be involved in the pathophysiology of macrovascular complications of diabetes. In this study we aimed to observe the effect of caveolin-1 on functional responses of aorta and corpus cavernosum in the streptozotocin and fructose-induced diabetes groups. Type 1 diabetes was induced by intraperitoneal administration of streptozotocin (60 mg/kg),. Type 2 diabetes by adding fructose in the rat's drinking water (10% (w/v)) for 8 weeks. For insulin treatment; rats were treated with insulin (6 U/kg) for 8 weeks. In Type I and Type II diabetic groups the contractile responses of corpus cavernosum strips to phenylephrine (EC(50):1.82 x 10(-5)M;1.47 x 10(-5)M, respectively)and relaxation responses to acetylcholine (EC(50):7.5 x 10(-5)M;4.48 x 10(-5)M, respectively)were significantly impaired. Contractile responses of aorticstrips to phenylephrine in diabetic groups were markedly decreased (EC(50):3.7.10(-7)M;2.61.10(-7)M respectively) and dose-dependent relaxation responses to acetylcholine were also attenuated (EC(50):3.23.10(-6)M; 2.0.10(-6)M respectively). Treatment with insulin improved the functional responses in the aorta and corpus cavernosum. Protein expression of caveolin-1 was increased in the aorta and corpus cavernosum of the diabetic groups, but this increase seen in the streptozotocin group was more significant than the fructose group. Our findings indicate that an attenuation of the functional responses in both diabetes groups were probably associated with an enhanced expression of caveolin-1, and therefore a decrease in the eNOS activity with a concomitant decrease in NO synthesis.

Rosiglitazone, a PPAR-gamma ligand, protects against burn-induced oxidative injury of remote organs.

Severe burn induces the activation of an inflammatory cascade that contributes to the development of subsequent immunosuppression, increased susceptibility to sepsis, as well as generation of reactive oxygen radicals and lipid peroxidation, leading to multiple organ failure. In the present study, we investigated whether rosiglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligand is protective against burn-induced remote organ injury. Under brief ether anaesthesia, shaved dorsum of the rats were exposed to 90 degrees C (burn group) or 25 degrees C (control group) water bath for 10s. Rosiglitazone (4 mg/kg) or saline was administered intraperitoneally immediately after and at the 12th hour of the burn. Rats were decapitated 24h after injury and the tissue samples from lung, liver, and kidney were taken for the determination of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen contents. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) levels, and creatinine, blood urea concentrations (BUN) were determined to assess liver and kidney function, respectively. Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and lactate dehydrogenase (LDH) were also assayed. Severe skin scald injury (30% of total body surface area) caused a significant decrease in GSH level, and significant increases in MDA level, MPO activity and collagen content of tissues. Similarly, serum ALT, AST and BUN levels, as well as LDH, IL-1 beta and TNF-alpha were elevated in the burn group as compared to the control group. Rosiglitazone treatment reversed all these biochemical indices. According to the findings of the present study, rosiglitazone possesses a anti-inflammatory effect that prevents burn-induced damage in remote organs and protects against organ damage.

Pharmacoeconomic comparison of Helicobacter pylori eradication regimens.

BACKGROUND: Helicobacter pylori is the most important etiologic agent for development of peptic ulcer, chronic gastritis and gastric carcinomas. It is now well established that H. pylori eradication treatment is more cost-effective than acid suppressing therapies alone for the treatment of peptic ulcer disease. However, the comparative cost-effectiveness of various H. pylori eradication regimens is still not clear. OBJECTIVE: This study was designed to make a pharmacoeconomic comparison of different H. pylori eradication regimens in patients with peptic ulcer disease or chronic gastritis, using real-world cost and effectiveness data. SETTING: Istanbul University Hospital and Marmara University Hospital. METHOD: A total of 75 patients diagnosed as H. pylori (+) by endoscopy were randomized to receive one of the seven H. pylori treatment protocols. These protocols were as follows: (LAC) = 'lansoprazole 30 mg bid + amoxicillin 1 g bid + clarithromycin 500 mg bid' for 7 days and (OCM) = 'omeprazole 20 mg bid + clarithromycin 250 mg bid + metronidazole 500 mg bid'; (OAM) = 'omeprazole 40 mg qd + amoxicillin 500 mg tid + metronidazole 500 mg tid'; (MARB) = 'metronidazole 250 mg tid + amoxicillin 500 mg qid + ranitidine 300 mg hs + bismuth 300 mg qid'; (OAC) = omeprazole 20 mg bid + amoxicillin 1 g bid + clarithromycin 500 mg bid'; (OCA) = omeprazole 40 mg bid + clarithromycin 500 mg bid + amoxicillin 1 g bid'; (OAB) = 'omeprazole 20 mg bid + amoxicillin 500 mg tid + bismuth 300 mg qid' each for 14 days. Only direct costs were included in the analysis. Effectiveness was measured in terms of "successful eradication". The cost-effectiveness ratios of the regimens were calculated using these effectiveness and cost data. The perspective of the study was assumed as the Government's perspective. MAIN OUTCOME MEASURE: Cost-effectiveness ratios of eradication regimens. RESULTS: MARB and OCA regimens were found to be more cost-effective than the other treatment regimens. The eradication rates and cost-effectiveness ratios calculated for these protocols were 90% (158.7 euros) for MARB and 90% (195.8 euros) for OCA regimen. CONCLUSION: This study confirms the importance of using local pharmacoeconomic data. Analyses such as this give decision-makers the tools to choose a better treatment option which is both highly effective yet and has a low cost.

Pressure ulcer-induced oxidative organ injury is ameliorated by beta-glucan treatment in rats.

Pressure ulcers (PU) cause morphological and functional alterations in the skin and visceral organs. In this study we investigated the role of oxidative damage in PUs and the probable beneficial effect of beta-glucan treatment against this damage. beta-glucan is known to have immunomodulatory effects. Experiments were carried on Wistar albino rats. PU was induced by applying magnets over steel plates that were implanted under the skin, to compress the skin and cause ischemia where removing the magnets cause reperfusion of the tissue. Within the first 12 h, rats were subjected to 5 cycles of ischemia/reperfusion (I/R), followed by 12 h ischemia. This protocol was repeated for 3 days. In treatment groups, twice a day during reperfusion periods, beta-glucan was either applied locally (25 mg/kg) as an ointment on skin, or administered orally (50 mg/kg) as a gavage. At the end of the experimental periods, tissue samples (skin, liver, kidney, lung, stomach, and ileum) were taken for the measurement of malondialdehyde (MDA)--an index of lipid peroxidation--and glutathione (GSH)--a key antioxidant--levels. Neutrophil infiltration was evaluated by the measurement of tissue myeloperoxidase activity, while collagen contents were measured for the evaluation of tissue fibrosis. Skin tissues were also examined microscopically. Liver and kidney functions were assayed in serum samples. Local treatment with beta-glucan inhibited the increase in MDA and MPO levels and the decrease in GSH in the skin induced by PU, but was less efficient in preventing the damage in visceral organs. However, systemic treatment prevented the damage in the visceral organs. Significant increases in creatinine, BUN, ALT, AST, LDH and collagen levels in PU group were prevented by beta-glucan treatment. The light microscopic examination exhibited significant degenerative changes in dermis and epidermis in the PU group. Tissue injury was decreased especially in the locally treated group. Thus, supplementing geriatric and neurologically impaired patients with adjuvant therapy of beta-glucan may have some benefits for successful therapy and improving quality of life.

Melatonin protects against pressure ulcer-induced oxidative injury of the skin and remote organs in rats.

Pressure ulcers (PU) cause morphological and functional alterations in the skin and visceral organs; the damage is believed to be due to ischemia/reperfusion (I/R) injury. In this study, we examined the role of oxidative damage in PU and the beneficial effect of treatment with the antioxidant melatonin. PU were induced by applying magnets over steel plates that were implanted under the skin of rats; this compressed the skin and caused ischemia. Within a 12-hr period, rats were subjected to five cycles of I/R (2 and 0.5 hr respectively), followed by an additional 12 hr of ischemia (to simulate the period at sleep at night). This protocol was repeated for 3 days. In treatment groups, twice a day during reperfusion periods, melatonin (5 mg per rat) was either applied locally as an ointment on skin, or administered i.p. (10 mg/kg). At the end of the experimental period, blood and tissue (skin, liver, kidney, lung, stomach, and ileum) samples were taken for determination of biochemical parameters and for histological evaluation. Local treatment with melatonin inhibited the increase in malondialdehyde levels; an index of lipid peroxidation, myeloperoxidase activity; an indicator of tissue neutrophil infiltration, and the decrease in glutathione; a key antioxidant, in the skin induced by PU, but was less efficient in preventing the damage in visceral organs. However, systemic treatment prevented the damage in the visceral organs. Significant increases in creatinine, blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and collagen levels in animals with PU were prevented by melatonin treatment. The light microscopic examination exhibited significant degenerative changes in dermis and epidermis in the PU rats. Tissue injury was decreased especially in the locally treated group. Findings of the present study suggest that local and/or systemic melatonin treatment may prove beneficial in the treatment of PU.

Protective effect of melatonin and omeprazole against alendronat-induced gastric damage.

Alendronate causes serious gastrointestinal adverse effects. We aimed to investigate if free radicals have any role in the damage induced by alendronate and if melatonin or omeprazole is protective against this damage. Rats were administered 20 mg/kg alendronate by gavage for 4 days, either alone or following treatment with melatonin or omeprazole. On the last day, following drug administration, pilor ligation was performed, and 2 hr later rats were killed and stomachs were removed. Gastric acidity and tissue ulcer index values, lipid peroxidation, and myeloperoxidase and glutathione levels, as well as the histologic appearance of the stomach tissues, were determined. Chronic oral administration of alendronate induced significant gastric damage, increasing lipid peroxidation and myeloperoxidase activity, while tissue glutathione levels decreased. Treatment with omeprazole or melatonin prevented this damage as well as the changes in biochemical parameters, and melatonin appeared to be more efficient than omeprazole in protecting the mucosa. Intraperitoneal administration of alendronate did not cause much gastric irritation. Findings of the present study suggest that alendronate induces oxidative gastric damage by a local irritant effect and that melatonin and omeprazole are protective against this damage due to their antioxidant properties.

Protective effects of MESNA (2-mercaptoethane sulphonate) against acetaminophen-induced hepatorenal oxidative damage in mice.

Acetaminophen, a widely used analgesic and antipyretic, is known to cause hepatic and renal injury in humans and experimental animals when administered in high doses. It was reported that these toxic effects of acetaminophen are due to oxidative reactions that take place during its metabolism. In this study we aimed to investigate the possible beneficial effect of 2-mercaptoethane sulphonate (MESNA), an antioxidant agent, against acetaminophen toxicity in mice. Balb-c mice were injected i.p. with: vehicle (the control group); a single dose of 150 mg kg(-1) MESNA (MES group); a single dose of 900 mg kg(-1) i.p. acetaminophen (AA4h and AA24h groups); and MESNA, at a dose of 150 mg kg(-1) after acetaminophen injection (AA4h-MES and AA24h-MES groups). The MESNA injection was repeated once more 12 h after the first injection in the AA24h-MES group. Blood urea nitrogen, serum creatinine, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in blood and glutathione (GSH) and malondialdehyde (MDA) levels, myeloperoxidase (MPO) activity and collagen contents in liver and kidney tissues were measured. Tissues also were examined microscopically. Blood urea nitrogen and serum creatinine, which were increased significantly (P < 0.001) following acetaminophen treatment were decreased significantly (P < 0.05-0.001) after treatment with MESNA. The ALT and AST levels were also increased significantly (P < 0.001) after acetaminophen treatment but were not reduced with MESNA. Acetaminophen treatment caused a significant (P < 0.05-0.001) decrease in GSH levels whereas MDA levels and MPO activity were increased in both tissues. These changes were reversed by MESNA treatment. Collagen contents of the liver and kidney tissues were increased by acetaminophen treatment (P < 0.001) and reversed back to the control levels with MESNA. Our results imply that acetaminophen causes oxidative damage in hepatic and renal tissues and that MESNA, via its antioxidant effects, protects these tissues. Therefore, its therapeutic role as a 'tissue injury-limiting agent' must be elucidated further in drug-induced oxidative damage.

Protective effect of taurine against alendronate-induced gastric damage in rats.

Alendronate (ALD) causes serious gastrointestinal adverse effects. The aim of this study was to investigate whether taurine (TAU), a semi-essential amino acid and an antioxidant, improves the alendronate-induced gastric injury. Rats were administered 20 mg/kg ALD by gavage for 4 days, either alone or following treatment with TAU (50 mg/kg, i.p.). On the last day of treatment, following drug administration, pylorus ligation was performed and 2 h later, rats were killed and stomachs were removed. Gastric acidity and tissue ulcer index values, lipid peroxidation and glutathione (GSH) levels, myeloperoxidase (MPO) activity as well as the histologic appearance of the stomach tissues were determined. Chronic oral administration of ALD induced significant gastric damage, increasing lipid peroxidation, MPO activity and collagen content, as well as decreasing tissue GSH levels. Treatment with TAU prevented the damage and also the changes in biochemical parameters. Findings of the present study suggest that ALD induces oxidative gastric damage by a local irritant effect, and that TAU ameliorates this damage by its antioxidant and/or membrane-stabilizing effects.

Gastroprotective effect of leukotriene receptor blocker montelukast in alendronat-induced lesions of the rat gastric mucosa.

Alendronate causes serious gastrointestinal adverse effects. We aimed to investigate if montelukast, a leukotriene receptor antagonist, is protective against this damage. Rats were administered 20 mg/kg alendronate by gavage for 4 days, either alone or following treatment with montelukast (10 mg/kg). On the last day, following drug administration, pilor ligation was performed and 2 h later, rats were killed and stomach, liver and kidney tissues were removed. Gastric acidity, gastric tissue ulcer index values and malondialdehyde (MDA); an end product of lipid peroxidation, and glutathione (GSH) levels; a key antioxidant, as well as myeloperoxidase (MPO) activity; an indirect marker of tissue neutrophil infiltration were determined, and the histologic appearance of the stomach, liver and kidney tissues were studied. Chronic oral administration of alendronate induced significant gastric damage, increasing myeloperoxidase activity and lipid peroxidation, while tissue glutathione levels decreased. Similarly, in the alendronate group MDA levels and MPO activities of liver and kidney tissues were increased and GSH levels were decreased. Treatment with montelukast prevented the damage as well as the changes in biochemical parameters in all tissues studied. Findings of the present study suggest that alendronate is a local irritant that causes inflammation through neutrophil infiltration and oxidative damage in tissues, and that montelukast is protective against this damage by its anti-inflammatory effect.

Melatonin treatment protects against diabetes-induced functional and biochemical changes in rat aorta and corpus cavernosum.

Enhanced oxidative stress due to diabetes is accepted to lead to endothelial dysfunction, and this is known to play a key role in the pathogenesis of diabetic vascular diseases and complications. This study was designed to determine the possible protective effect of melatonin and/or insulin treatment on the functional and biochemical changes caused by hyperglycemia in aorta and corpus cavernosum of diabetic rats. Wistar albino male rats were rendered diabetic by injecting streptozotocin (60 mg/kg, intraperitoneally (i.p.)). Melatonin (10 mg/kg, i.p.) and/or insulin (6 U/kg, subcutaneously (s.c.)) were administered for 8 weeks. In the diabetic group, the contractile responses of aortic strips to phenylephrine were significantly impaired (EC(50) 5.5 x 10(-7) M in diabetic and EC(50) 1.47 x 10(-7) M in the control group, P<0.001). Treatment with melatonin (EC(50) 4.6 x 10(-7) M) or insulin+melatonin (EC(50) 1.68 x 10(-7) M, P<0.001) improved the contractile responses. Acetylcholine caused a dose-dependent relaxation response (EC(50) 1.58 x 10(-7) M) which was impaired in the diabetic group (EC(50) 26 x 10(-7) M, P<0.001). There was less impairment in melatonin-, insulin- and insulin+melatonin-treated groups (EC(50) 11.61 x 10(-7), 7.3 x 10(-7) and 1.41 x 10(-7) M, respectively, P<0.01). Contractile responses to phenylephrine were also impaired in the corpus cavernosum strips (EC(50) 2.06 x 10(-5) M in diabetic and 0.94 x 10(-5) M in the control group, P<0.001). In the melatonin- (EC(50) 1.59 x 10(-5) M) and insulin+melatonin-treated (EC(50) 1.53 x 10(-5) M, P<0.5) groups contractile responses were improved. In the diabetic group, the relaxation responses of corpus cavernosum strips to acetylcholine were impaired (EC(50) 24.12 x 10(-5) M, P<0.001), and treatment with melatonin (EC(50) 0.68 x 10(-5) M), insulin (EC(50) 0.53 x 10(-5) M) or insulin+melatonin (0.98 x 10(-5) M, P<0.001) restored the responses to acetylcholine. In diabetic tissues, malondialdehyde levels were increased while glutathione levels were decreased, demonstrating oxidative damage. This was also prevented by treatment with melatonin or the melatonin and insulin combination. The diabetic state enhances the generation of free radicals, and both melatonin and insulin treatments reduced this oxidative stress; however, treatment with the combination was the most efficient in preventing diabetes-induced damage. Thus, our results suggested that giving diabetic patients adjuvant therapy with melatonin may have some benefit in controlling diabetic complications.

Melatonin ameliorates chronic renal failure-induced oxidative organ damage in rats.

Chronic renal failure (CRF) is associated with oxidative stress that promotes production of reactive oxygen species (ROS). Melatonin, the chief secretory product of the pineal gland, was recently found to be a potent free radical scavenger and antioxidant. The aim of this study was to examine the role of melatonin in protecting the aorta, heart, corpus cavernosum, lung, diaphragm, and kidney tissues against oxidative damage in a rat model of CRF, which was induced by five of six nephrectomy. Male Wistar albino rats were randomly assigned to either the CRF group or the sham-operated control group, which had received saline or melatonin (10 mg/kg, i.p.) for 4 wk. CRF was evaluated by serum blood urea nitrogen (BUN) level and creatinine measurements. Aorta and corporeal tissues were used for contractility studies, or stored along with heart, lung, diaphragm, and kidney tissues for the measurement of malondialdehyde (MDA, an index of lipid peroxidation), protein carbonylation (PC, an index for protein oxidation), and glutathione (GSH) levels (a key antioxidant). Plasma MDA, PC, and GSH levels and erythrocytic superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities were studied to evaluate the changes of antioxidant status in CRF. In the CRF group, the contraction and the relaxation of aorta and corpus cavernosum samples decreased significantly compared with controls (P < 0.05-0.001). Melatonin treatment of the CRF group restored these responses. In the CRF group, there were significant increases in tissue MDA and PC levels in all tissues with marked reductions in GSH levels compared with controls (P < 0.05-0.001). In the plasma, while MDA and PC levels increased, GSH, SOD, CAT, and GSH-Px activities were reduced. Melatonin treatment reversed these effects as well. In this study, the increase in MDA and PC levels and the concomitant decrease in GSH levels of tissues and plasma and also SOD, CAT, GSH-Px activities of plasma demonstrate the role of oxidative mechanisms in CRF-induced tissue damage, and melatonin, via its free radical scavenging and antioxidant properties, ameliorates oxidative organ injury. CRF-induced dysfunction of the aorta and corpus cavernosum of rats was reversed by melatonin treatment. Thus, supplementing CRF patients with adjuvant therapy of melatonin may have some benefit.

Octreotide ameliorates alendronate-induced gastric injury.

Alendronate causes serious gastrointestinal adverse effects. The aim of this study was to investigate whether octreotide, a synthetic somatostatin analogue, improves the alendronate-induced gastric injury. Rats were administered 20mg/kg alendronate by gavage for 4 days, either alone or following treatment with octreotide (0.1 ng/kg, i.p.). On the last day, following drug administration, pilor ligation was performed and 2h later, rats were killed and stomachs were removed. Gastric acidity and tissue ulcer index values, lipid peroxidation (as assessed by malondialdehyde, MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity as well as the histologic appearance of the stomach tissues were determined. Chronic oral administration of alendronate induced significant gastric damage, increasing lipid peroxidation (37.1+/-3.2 nmol/g) and myeloperoxidase activity (57.6+/-3.7 U/g), while tissue glutathione levels (09.+/-0.1 micromol/g) decreased. Treatment with octreotide prevented this damage as well as the changes in biochemical parameters (MDA: 23.4+/-1.3 nmol/g; MPO: 31.68 U/g; GSH: 15.+/-0.1 micromol/g). Findings of the present study suggest that alendronate induces oxidative gastric damage by a local irritant effect, and that octreotide ameliorates this damage by inhibiting neutrophil infiltration and reducing lipid peroxidation. Therefore, its therapeutic role as a "ulcer healing" agent must be further elucidated in alendronate-induced gastric mucosal injury.

Melatonin reverses urinary system and aorta damage in the rat due to chronic nicotine administration.

We have evaluated the changes in contractile activity and oxidant damage of corpus cavernosum, urinary bladder, kidney and aorta after chronic nicotine administration in rats. The effects of melatonin on these parameters were investigated also. Male Wistar albino rats were injected intraperitoneally with nicotine hydrogen bitartrate (0.6 mg kg(-1) daily for 21 days) or saline. Melatonin (10 mg kg(-1), i.p.) was administered either alone or with nicotine injections. Corpus cavernosum, bladder and aorta were used for contractility studies, or stored with kidneys for the measurement of malondialdehyde and glutathione levels. Corpus cavernosum, bladder, and aorta samples were examined histologically and the extent of microscopic tissue damage was scored. In the nicotine-treated group, the contraction of corpus cavernosum, bladder and aorta samples and the relaxation of corporeal and aorta tissues decreased significantly compared with controls. However, melatonin treatment restored these responses. In the nicotine-treated group, there was a significant increase in the malondialdehyde levels of the corporeal tissue, bladder, kidney and aorta, with marked reductions in glutathione levels compared with controls. Melatonin treatment reversed these effects also. Melatonin administration to nicotine-treated animals caused a marked reduction in the microscopic damage of the tissues compared with those of the untreated group. In this study, nicotine-induced dysfunction of the corpus cavernosum, bladder and aorta of rats was reversed by melatonin treatment. Moreover, melatonin, as an antioxidant, abolished elevation in lipid peroxidation products, and reduction in the endogenous antioxidant glutathione, and protected the tissues from severe damage due to nicotine exposure.

Melatonin treatment protects against sepsis-induced functional and biochemical changes in rat ileum and urinary bladder.

Sepsis is commonly associated with enhanced generation of reactive oxygen metabolites, which lead to multiple organ dysfunction. The aim of this study was to examine the role of melatonin, a potent antioxidant, in protecting the intestinal and bladder tissues against damage in a rat model of sepsis. Sepsis was induced by cecal ligation and perforation (CLP) in Wistar Albino rats. Sham operated (control) and CLP group received saline or melatonin (10 mg/kg, ip) 30 minutes prior to and 6 hours after the operation. Sixteen hours after the surgery, rats were decapitated and the intestinal and urinary bladder tissues were used for contractility studies, or stored for the measurement of malondialdehyde (MDA) content -an index of lipid peroxidation-, glutathione (GSH) levels -a key antioxidant- and myeloperoxidase (MPO) activity- an index of neutrophil infiltration-. Ileal and bladder MDA levels in the CLP group were significantly increased (p < 0.001) with concomitant decreases in GSH levels (p < 0.01 - p < 0.001) when compared to the control group. Similarly, MPO activity was significantly increased (p < 0.001) in both ileum and bladder tissues. On the other hand, melatonin treatment significantly reversed (p < 0.001) the elevations in MDA and MPO levels, while reduced GSH levels were increased back to the control levels (p < 0.01 - p < 0.001). In the CLP group, the contractility of the ileal and bladder tissues decreased significantly compared with controls. Melatonin treatment of the CLP group restored these responses. In this study, CLP induced dysfunction of the ileal and bladder tissue of rats was reversed by melatonin treatment. Moreover, melatonin, as an antioxidant, abolished the elevation in lipid peroxidation products and myeloperoxidase activity, and reduction in the endogenous antioxidant glutathione and thus protected the tissues against sepsis-induced oxidative damage.

Melatonin protects against mercury(II)-induced oxidative tissue damage in rats.

Mercury exerts a variety of toxic effects in the body. Lipid peroxidation, DNA damage and depletion of reduced glutathione by Hg(II) suggest an oxidative stress-like mechanism for Hg(II) toxicity. Melatonin, the main secretory product of the pineal gland, was recently found to be a potent free radical scavenger and antioxidant. N-Acetylcysteine, a precursor of reduced glutathione and an antioxidant, is used in the therapy of acute heavy metal poisoning. In this study the protective effects of melatonin in comparison to that of N-acetylcysteine against Hg-induced oxidative damage in the kidney, liver, lung and brain tissues were investigated. Wistar albino rats of either sex (200-250 g) were divided into six groups, each consisting of 8 animals. Rats were intraperitoneally injected with 1) 0.9% NaCl, control (C) group; 2) a single dose of 5 mg/kg mercuric chloride (HgCl2), Hg group; 3) melatonin in a dose of 10 mg/kg, 1 hr after HgCl2 injection, Hg-melatonin group; 4) melatonin in a dose of 10 mg/kg one day before and 1 hr after HgCl2 injection, melatonin-Hg-melatonin group; 5) N-acetylcysteine in a dose of 150 mg/kg, 1 hr after HgCl2 injection, Hg-N-acetylcysteine group, and 6) N-acetylcysteine in a dose of 150 mg/kg one day before and 1 hr after HgCl2 injection, N-acetylcysteine-Hg-N-acetylcysteine group. Animals were killed by decapitation 24 hr after the injection of HgCl2. Tissue samples were taken for determination of malondialdehyde, an end-product of lipid peroxidation; glutathione (GSH), a key antioxidant, and myeloperoxidase activity, an index of neutrophil infiltration. The results revealed that HgCl2 induced oxidative tissue damage, as evidenced by increases in malondialdehyde levels. Myeloperoxidase activity was also increased, and GSH levels were decreased in the liver, kidney and the lungs. All of these effects were reversed by melatonin or N-acetylcysteine treatment. Since melatonin or N-acetylcysteine administration reversed these responses, it seems likely that melatonin or N-acetylcysteine can protect all these tissues against HgCl2-induced oxidative damage.

Protective effects of melatonin, vitamin E and N-acetylcysteine against acetaminophen toxicity in mice: a comparative study.

Acetaminophen (AA) is a commonly used analgesic and antipyretic drug; however, when used in high doses, it causes fulminant hepatic necrosis and nephrotoxic effects in both humans and experimental animals. It has been reported that the toxic effects of AA are the result of oxidative reactions that take place during its metabolism. In this study we investigated if melatonin, vitamin E or N-acetylcysteine (NAC) are protective against AA toxicity in mice. The doses of the antioxidants used were as follows: melatonin (10 mg/kg), vitamin E (30 mg/kg) and NAC (150 mg/kg). Blood urea nitrogen (BUN), serum creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels in blood, and glutathione (GSH), malondialdehyde (MDA), oxidized protein levels and myeloperoxidase (MPO) activity in liver and kidney tissues were measured. BUN and serum creatinine, ALT and AST levels which were increased significantly following AA treatment decreased significantly after pretreatment with either vitamin E, melatonin or NAC; however, they were not reduced to control levels. ALT and AST levels were significantly higher at 4 hr compared with the 24 hr levels after AA administration. However, BUN and creatinine levels were significantly elevated only at 24 hr. GSH levels were reduced while MDA, MPO and oxidized protein levels were increased significantly following AA administration. These changes were reversed by pretreatment with either melatonin, vitamin E or NAC. Liver toxicity was higher at 4 hr, whereas nephrotoxicity appeared to be more severe 24 hr after treatment with AA. Vitamin E was the least efficient agent in reversing AA toxicity while melatonin, considering it was given as at lower dose than either vitamin E or NAC, was the most effective. This may be the result of the higher efficacy of melatonin in scavenging various free radicals and also because of its ability in stimulating the antioxidant enzymes.

Melatonin and N-acetylcysteine have beneficial effects during hepatic ischemia and reperfusion.

This study was designed to study the effects of Melatonin (Mel) and N-Acetylcystein (NAC) on hepatic ischemia/reperfusion (I/R) injury in rats. For this purpose Wistar albino rats were subjected to 45 minutes of hepatic ischemia followed by 60 minutes of reperfusion period. Melatonin (10 mg/kg) or NAC (150 mg/kg) were administered alone or in combination, intraperitoneally, 15 minutes prior to ischemia and just before reperfusion. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were determined to assess liver functions. Liver tissues were taken for determination of malondialdehyde (MDA) levels, an end product of lipid peroxidation; glutathione (GSH) levels, a key antioxidant; protein carbonyl concentration (protein oxidation) (PO), a specific marker of oxidative damage of proteins; and myeloperoxidase (MPO) activity, as an indirect index of neutrophil infiltration. Plasma ALT and AST activities were higher in ischemia/reperfusion group than in control. They were decreased in the groups given Mel, NAC or the combination. Hepatic GSH levels, significantly depressed by I/R, were elevated to control levels in the combination group, whereas treatment with Mel or NAC alone provided only a limited protection. Hepatic MDA and PO levels, and MPO activity were significantly increased by I/R. The increase in these parameters were partially decreased by Mel or NAC alone, whereas treatment with the combination reduced these values back to control levels. In conclusion, considering the dosages used, Mel appeared to be significantly more potent than NAC in reversing the oxidative damage induced by I/R. Our findings show that Mel and NAC have beneficial effects against the I/R injury and due to their synergistic effects, when administered in combination, may have a more pronounced protective effects on the liver.