First Evidence of Gastroprotection by Schinus molle: Roles of Nitric Oxide, Prostaglandins, and Sulfhydryls Groups in Its Mechanism of Action.

Schinus molle is a plant traditionally used in Mexico to treat gastric disorders. However, no scientific evidence has been reported on its gastroprotective effect. The aim of the current contribution was to conduct a bioassay-guided study on S. molle to evaluate its gastroprotective activity in a model of Wistar rats given ethanol orally to induce gastric lesions. The hexane and dichloromethane extracts from the tested plant showed over 99% gastroprotection at a dose of 100 mg/kg. From the hexane extract, two of the three fractions (F1 and F2) afforded over 99% gastroprotection. The F1 fraction was subjected to column chromatography, which revealed a white solid. Based on the ESI-MS analysis, the two main compounds in this solid were identified. The predominant compound was probably a triterpene. This mixture of compounds furnished about 67% gastroprotection at a dose of 100 mg/kg. Pretreatment with L-NAME, indomethacin, and NEM was carried out to explore the possible involvement of nitric oxide, prostaglandins, and/or sulfhydryl groups, respectively, in the gastroprotective activity of the white solid. We found evidence for the participation of all three factors. No antisecretory activity was detected (tested by pylorus ligation). In conclusion, evidence is herein provided for the first time of the gastroprotective effect of S. molle.

Gastroprotection of Calein D against Ethanol-Induced Gastric Lesions in Mice: Role of Prostaglandins, Nitric Oxide and Sulfhydryls.

Peptic ulcers are currently treated with various drugs, all having serious side effects. The aim of this study was to evaluate the gastroprotective activity of calein D (from Calea urticifolia), a sesquiterpene lactone with a germacrane skeleton. Gastric lesions were induced in mice by administering ethanol (0.2 mL) after oral treatment with calein D at 3, 10 and 30 mg/kg, resulting in 13.15 ± 3.44%, 77.65 ± 7.38% and 95.76 ± 2.18% gastroprotection, respectively, to be compared with that of the control group. The effect found for 30 mg/kg of calein D was not reversed by pretreatment with NG-nitro-l-arginine methyl ester (l-NAME, 70 mg/kg, ip), indomethacin (10 mg/kg, sc) or N-ethylmaleimide (NEM, 10 mg/kg, sc). Hence, the mechanism of action of calein D does not involve NO, prostaglandins or sulfhydryl compounds. Calein D was more potent than carbenoxolone, the reference drug. The findings for the latter are in agreement with previous reports.

Evidence against the participation of a pharmacokinetic interaction in the protective effect of single-dose curcumin against gastrointestinal damage induced by indomethacin in rats.

OBJECTIVE: To determine the role of a pharmacokinetic interaction in the protective effect of curcumin against the gastric damage induced by indomethacin administration as such or as its prodrug acemetacin. METHODS: Wistar rats orally received single dose of indomethacin (30 mg/kg) with and without curcumin (30 mg/kg); gastric injury was evaluated by determining the total damaged area. Additional groups of rats received an oral single dose of indomethacin (30 mg/kg) or its prodrug acemetacin (34.86 mg/kg) in the presence or absence of curcumin (30 mg/kg). Indomethacin and acemetacin concentrations in plasma from blood draws were determined by high-performance liquid chromatography.Plasma concentration-against-time curves were constructed, and bioavailability parameters, maximal concentration (Cmax) and area under the curve to the last sampling time (AUC0-t) were estimated. RESULTS: Concomitant administration of indomethacin and curcumin resulted in a significantly reduced gastric damage compared to indomethacin alone. However, co-administration of curcumin did not produce any significant alteration in the bioavailability parameters of indomethacin and acemetacin after administration of either the active compound or the prodrug. CONCLUSION: Curcumin exhibits a protective effect against indomethacin-induced gastric damage, but does not produce a reduction of the bioavailability of this nonsteroidal anti-inflammatory drug, indomethacin. Data thus suggest that a pharmacokinetic mechanism of action is not involved in curcumin gastroprotection.

Dillapiole, isolated from Peperomia pellucida, shows gastroprotector activity against ethanol-induced gastric lesions in Wistar rats.

Peperomia pellucida is a plant used in traditional medicine to treat gastric ulcers. Although this gastroprotective activity was reported, the active compounds have not been identified. Therefore, the aim herein was to identify the most active compound in the gastroprotective activity of P. pellucida using an ethanol-induced gastric ulcer experimental rat model. A gastroprotective effect was observed when the hexane and dichloromethane extracts were tested, with the higher effect being obtained with the dichloromethane extract (82.3 ± 5.6%) at 100 mg/kg. Dillapiole was identified as the most active compound in this extract. Although there have been previous reports on dillapiole, this is the first on its gastroprotective activity. Rats treated with this compound at 3, 10, 30 and 100 mg/kg showed 23.1, 56.1, 73.2 and 85.5% gastroprotection, respectively. The effect elicited by dillapiole at 100 mg/kg was not attenuated by pretreatment with indomethacin (10 mg/kg, s.c.), a prostaglandin synthesis blocker, NG-nitro-l-arginine methyl ester (70 mg/kg, i.p.), a nitric oxide (NO) synthase inhibitor, or N-ethylmaleimide (10 mg/kg, s.c.), a blocker of sulfhydryl groups. This suggests that the gastroprotective mechanism of action of dillapiole does not involve prostaglandins, NO or sulfhydryl groups.

Bioassay-guided isolation of an anti-ulcer compound, tagitinin C, from Tithonia diversifolia: role of nitric oxide, prostaglandins and sulfhydryls.

Tithonia diversifolia is a medicinal plant from the Municipality of Suchiapa, Chiapas, Mexico, that according to local folk medicine is considered useful in the treatment of gastric ulcers. The aim of the present study was to investigate the gastroprotective activity of T. diversifolia by using an ethanol-induced gastric ulcer experimental model in male Wistar rats. The results showed that T. diversifolia had gastroprotective activity, and that the dichloromethane extract had the highest protective activity (close to 90% when using doses between 10 to 100 mg/kg), and that further the compound tagitinin C isolated from this extract was the main active gastroprotective agent. Rats treated with tagitinin C suspended in Tween 80 at 1, 3, 10 and 30 mg/kg showed 37.7, 70.1, 100, and 100% gastroprotection, respectively. The effect elicited by tagitinin C (30 mg/kg) was not attenuated by pretreatment with either N(G)-nitro-L-arginine methyl ester (70 mg/kg, i.p.), a nitric oxide (NO) synthase inhibitor, N-ethylmaleimide (10 mg/kg, s.c.), a blocker of sulfhydryl groups, or indomethacin (10 mg/kg, s.c.), a blocker of prostaglandin synthesis, which suggests that the gastroprotective mechanism of action of this sesquiterpene lactone does not involve NO, sulfhydryl groups or prostaglandins.

L-arginine reverses alterations in drug disposition induced by spinal cord injury by increasing hepatic blood flow.

High hepatic extraction drugs--such as phenacetin, methylprednisolone, and cyclosporine--exhibit an increased bioavailability after acute spinal cord injury (SCI) due to an impaired clearance. For these drugs, metabolic clearance depends on hepatic blood flow. Thus, it is possible that pharmacokinetic alterations can be reversed by increasing liver perfusion. Therefore, we evaluated the effect of L-arginine, a nitric oxide precursor, on the pharmacokinetics of a prototype drug with high hepatic extraction, and on hepatic microvascular blood flow (MVBF) after acute SCI. Pharmacokinetics of i.v. phenacetin was studied in rats 24 h after a severe T-5 spinal cord contusion; animals being pretreated with L-arginine 100 mg/kg i.v. or vehicle. MVBF was assessed under similar experimental conditions using laser Doppler flowmetry. SCI significantly altered phenacetin pharmacokinetics. Clearance was significantly reduced, resulting in a prolonged half-life and an increase in bioavailability, while volume of distribution was decreased. Pharmacokinetic alterations were reversed when injured rats were pretreated with L -arginine. It was also observed that L-arginine significantly increased hepatic MVBF in injured rats, notwithstanding it exhibited a limited effect on sham-injured animals. Our data hence suggest that L-arginine is able to reverse SCI-induced alterations in phenacetin pharmacokinetics due to an impaired hepatic MVBF, likely by increased nitric oxide synthesis leading to vasodilation. Further studies are warranted to examine the potential usefulness of nitric oxide supplementation in a clinical setting.

Gastroprotection and effect of the simultaneous administration of Cuachalalate (Amphipterygium adstringens) on the pharmacokinetics and anti-inflammatory activity of diclofenac in rats.

This work aimed to study the effect of Cuachalalate methanol extract (CME) on the anti-inflammatory activity and pharmacokinetics of diclofenac sodium, a frequently prescribed non-steroidal anti-inflammatory drug (NSAID). The gastroprotective effect of CME on the gastric injury induced by diclofenac was studied in rats. CME showed a gastroprotective effect of 15.7% at 1 mg kg(-1) and 72.5% at dose of 300 mg kg(-1). Omeprazole, used as anti-ulcer reference drug, showed gastroprotective effects of 50-89.7% at doses tested (1-30 mg kg(-1)). The value of the 50% effective dose for the anti-inflammatory effect of diclofenac sodium (ED50 = 1.14 +/- 0.23 mg kg(-1)) using carrageenan-induced rat paw oedema model, was not modified by the concomitant administration of 30 or 100 mg kg(-1) of CME. The effect of CME (30, 100 and 300 mg kg(-1), p.o.) on the pharmacokinetics of diclofenac sodium was studied. It was observed that the simultaneous administration of diclofenac sodium and 300 mg kg(-1) of CME decreased significantly the values of Cmax (7.08 +/- 1.42 microg mL(-1)) and AUC (12.67 +/- 2.97 microg h mL(-1)), but not the value of tmax (0.13 (0.1-0.25)h) obtained with the administration of diclofenac alone. The simultaneous administration of 30 or 100 mg kg(-1) of CME did not modify the pharmacokinetic parameters of diclofenac. The experimental findings in rats suggest that CME at doses lower than 100 mg kg(-1) protects the gastric mucosa from the damage induced by diclofenac sodium without altering either the anti-inflammatory activity or the pharmacokinetics of this NSAID.