The Investigation of Therapeutic Implications of Mast Cell Stabilizer Cromolyn Sodium on Cholestasis and Cholestatic Pruritus in Experimental Cholestasis.

BACKGROUND: Relevant studies have indicated that hepatic mast cells may have potential roles in the progression of cholestasis and cholestasis-induced itch. We aimed to compare the effects of cromolyn sodium and other medications on cholestatic pruritus, serum biochemistry, histamine, total bile acids, autotaxin, liver histopathology, and mast cell distribution in tissues in an experimental cholestasis model conducted by bile duct ligation. METHODS: Rats received the determined treatment consecutively for 10 days in addition to bile duct ligation. On the 5th and 10th days of the experiment, the rats' itching behaviors were observed for 5 minutes. After 10 days, blood and tissue samples were taken. RESULTS: Significant decreases in serum histamine and autotaxin levels, plasma total bile acids, total bilirubin, and biliary enzymes were reported only in cromolyn sodium-treated rats compared to the control group. In immunohistochemistry of the liver samples, the peribiliary mast cells stained positive for autotaxin. Except for bile duct infarctus, all histopathological findings of cholestasis significantly improved only in cromolyn sodium-treated and sertraline-treated rats. The liver and peritoneal mast cells significantly decreased only in cromolyn sodium-treated rats compared to the control group. On the 10th day of the experiment, the mean duration of itching was significantly lower in all groups, except for naloxone- and ondansetron-treated rats. CONCLUSION: Cromolyn sodium has promising antipruritic efficacy and provides biochemical and histopathological recovery of the relevant parameters of cholestasis induced by bile duct ligation. For the first time in the literature, we showed that peribiliary mast cells can produce autotaxin, which is a very important pruritogenic signal in the setting of cholestasis.

Histopathologic evaluation of anti-ulcerogenic effect of montelukast in indomethacin-induced experimental ulcer model.

BACKGROUND/AIMS: The effects of anti-ulcerogenic drugs are dependent on the increase in prostaglandin production and reduction in leukotriene production in the gastric mucosa. Montelukast is an anti-asthmatic drug, a selective reversible cysteinyl leukotriene D4 receptor antagonist. In this study, we aimed to evaluate the anti-ulcerogenic effect of montelukast and to investigate the relationship between its anti-ulcerogenic effect and polymorphonuclear leukocyte infiltration in the gastric tissues. MATERIALS AND METHODS: Male Sprague-Dawley rats were separated into five groups. Distilled water (control group), famotidine (40 mg/kg), and montelukast (5, 10 and 20 mg/kg) were given orally (gavage). Thirty minutes later, indomethacin (25 mg/kg) was administered to all the groups. Six hours later, the animals were sacrificed by decapitation. The ulcer indexes for each stomach and the ulcer inhibition rates for each group were calculated, and the stomachs were later evaluated histopathologically (polymorphonuclear leukocyte infiltration). RESULTS: Ulcer inhibition rates were as follows: famotidine 96.14% and montelukast 59.96%, 72.65% and 76.97% (5, 10 and 20 mg/kg, respectively). Montelukast (10 and 20 mg/kg) showed effects similar to those of famotidine histopathologically. CONCLUSIONS: In this study, it was observed that there was a relationship between the anti-ulcerogenic effect of montelukast and polymorphonuclear leukocyte infiltration in the gastric mucosa, and montelukast behaved as an anti-ulcerogenic drug both macroscopically and microscopically.

Effects of statins in an indomethacin-induced gastric injury model in rats.

BACKGROUND/AIMS: Statins have additional pleiotropic effects beyond their lipid-lowering effects. In this study, the effects of statins were evaluated in an indomethacin-induced gastric injury model in rats. MATERIALS AND METHODS: Animals were divided into eight groups. Distilled water (control group), omeprazole (30 mg/kg), atorvastatin (20 and 40 mg/kg), simvastatin (20 and 40 mg/kg), and rosuvastatin (20 and 40 mg/kg) were given orally (gavage). Thirty minutes later, indomethacin (25 mg/kg) was administered orally to all groups. Six hours later, the animals were sacrificed by decapitation. The mean ulcer indexes for each group were calculated, and the stomachs were evaluated histopathologically. RESULTS: The ulcer indexes were as follows: control 1.72 ± 0.16, omeprazole 0 ± 0.00, and atorvastatin, simvastatin and rosuvastatin (at 20 and 40 mg/kg doses, respectively) 4.28 ± 0.39, 4.99 ± 0.96, 1.72 ± 0.73, 1.90 ± 0.48, 1.85 ± 0.26, and 1.67 ± 0.18. Atorvastatin significantly increased the indomethacin-induced ulcer index at both doses and the erosion score at 40 mg/kg dose. Although the 20 mg/kg dose of simvastatin inhibited mononuclear leukocyte infiltration, the 40 mg/kg dose induced hyperemia. Rosuvastatin did not decrease mononuclear leukocyte or neutrophil infiltrations at 20 mg/kg dose, and only neutrophil infiltration at the 40 mg/kg dose. CONCLUSIONS: In patients with gastric discomfort, statins must be used carefully. If statin therapy is needed, we recommend to avoid using atorvastatin and to use the other statins only in the minimum effective dose.

Anticonvulsant and hypnotic effects of amiodarone.

Amiodarone hydrochloride is a potent anti-arrhythmic agent, known as a multiple ion-channel blocker in the heart. Although it has been detected in the rat brain, there are no data related to its central nervous system (CNS) effects. In this study, we evaluated anticonvulsant and hypnotic effects of amiodarone. Convulsions were induced by phentylenetetrazole (PTZ) (100 mg/kg) or caffeine (300 mg/kg) in mice. In both models, amiodarone prolonged both latency period and time to death, and acted as an anticonvulsant drug. It was found to be more effective in the PTZ model than in the caffeine model; none of the animals treated with 150 mg/kg dose amiodarone had died in the PTZ model. For hypnotic effect, sleeping was induced with pentobarbital (35 mg/kg) in rats. Amiodarone dose-dependently increased the sleeping time (677.7%-725.9%). In the sleeping test, all rats in 200 mg/kg amiodarone group died. In conclusion, anticonvulsant and hypnotic effects of amiodarone have shown the depressant effects on CNS. These effects may be dependent on its pharmacological properties.

Role of polymorphonuclear leukocyte infiltration in the mechanism of anti-inflammatory effect of amiodarone.

In many physiological bodily functions, and in the pathogenesis of inflammation, ions are exchanged between intracellular and extracellular areas. Amiodarone is a multiple ion channel (Ca++, Na+, K+) blocking drug, effective anti-arrhythmic drug, and phospholipase inhibitor. The aim of this study is to examine a role of polymorphonuclear leukocyte infiltration in amiodarone's anti-inflammatory effect on experimental paw inflammation. After rats had been assigned to groups, their normal right hind paw volumes were measured using a plethysmometer. Amiodarone (25, 50 and 100 mg/kg) and distilled water were administrated to the experimental and control groups, respectively, by ip route. Thirty minutes later, paw edema was induced in rats by subplantar injection of 0.1 ml of histamine (0.1%) to those paws. Subsequent volume readings for those paws were carried out at 30-min intervals. Results were expressed as percentages of change from the initial volumes. After the final measurements, the animals were killed by decapitation and their paw tissues were cut for pathological investigation. Amiodarone dose-dependently decreased the paw edema (25.05, 48.71 and 74.97%), and reduced polymorphonuclear leukocyte infiltration in the paw tissue (55.65, 69.76 and 84.58%). Our findings support the view that amiodarone dose-dependently exerts a powerful anti-inflammatory activity. This effect of amiodarone may be due to the activation of nitric oxide resulting from its calcium channel antagonistic effects, to the inhibition of phospholipase A2 and/or to a reduction in neutrophil movement and activation, which may reduce free radical production and proteolytic enzyme release.

Effects of Momordica charantia L. (Cucurbitaceae) on indomethacin-induced ulcer model in rats.

BACKGROUND/AIMS: Fruits of Momordica charantia L.-cucurbitaceae have been frequently used in folk medicine for rapid healing of cutaneous lesions and peptic ulcer, especially in Western Anatolia in Turkey. METHODS: The anti-ulcerogenic effect of the oily extract of Momordica charantia fruits was investigated in male Sprague-Dawley rats. Animals were separated into six groups. Distilled water (control group), famotidine (40 mg/kg), oily extracts (5 and 10 ml/kg), and vehicles (olive oil -5 and 10 ml/kg) were given orally (gavage). Thirty minutes later indomethacin (25 mg/kg) was administrated to all the groups. Six hours later, animals were killed with decapitation. For each stomach, ulcerated and total areas were measured (mm2). The ulcer indexes for each stomach and the ulcer inhibition rates for each group were calculated, after which the stomachs were evaluated pathologically (polymorphonuclear leukocytes infiltration). RESULTS: Ulcer inhibition rates were as follows: famotidine -91.54%, oily extract (5 ml/kg) -53.80%, oily extract (10 ml/kg) -98.04%, vehicle (olive oil -5 ml/kg) -18.40%, and vehicle (olive oil -10 ml/kg) -88.02%. According to polymorphonuclear leukocytes infiltration, oily extract (10 ml/kg) and vehicle (10 ml/kg) had similar effects to famotidine. CONCLUSIONS: The olive oil extract of M. charantia fruit did show a protective effect macroscopically.