Antisecretory Activity Research Articles

OA01.03. Antisecretory and antiulcer activities of eclipta alba linn. In rats

Purpose: Eclipta alba Linn. (Asteraceae) is used traditionally in Indian system of medicine as anti inflammatory, hepatoprotective, hypoglycemic, immunomodulator, in wound healing, and as a potent hair growth promoter. The study was aimed to evaluate the antisecretory and gastroprotective effects of 50% ethanol extract of Eclipta alba. Method: Eclipta alba extract (EAE) at 50, 100 and 200 mg/kg was administered orally, twice daily for 5 days to prevent from, cold restraint stress (CRS), and pylorus ligation (PL) induced ulcers. Antioxidant studies were performed in CRS induced ulcer model. Gastric wall mucus and secretion parameters like volume of gastric juice, acid output and pH were estimated in PL induced ulcer model. Ranitidine (50mg/kg, p.o.) was used as positive control for comparison. Result: A dose dependent and significant (p <0.05) reduction in lesion index was observed in ulcer-induced rats treated with EAE at various doses when compared with control group in both the models. Gastric wall mucus production was significantly (p<0.05) elevated in EAE treated rats. Significant attenuation in lipid peroxidation, superoxide dismutase activity was observed, whereas, catalase enzyme levels were elevated in EAE treated groups. Antisecretory activity of EAE was evidenced by significant reduction in gastric volume, acid output and increase in gastric pH when compared to their control values. The findings were further supported by histopathological examination of stomach in both EAE treated and control rats. Conclusion: The results of the present investigation suggest that ethanol extract of Eclipta alba possesses potent antisecretory and gastroprotective activity. The exact mechanism to be evaluated further but in preliminary observation it was thought to be mediated through free radical scavenging activity.

Protective Effect of ECQ on Rat Reflux Esophagitis Model

This study was designed to determine the protective effect of Rumex Aquaticus Herba extracts containing quercetin-3-β-D-glucuronopyranoside (ECQ) on experimental reflux esophagitis. Reflux esophagitis was induced by surgical procedure. The rats were divided into seven groups, namely normal group, control group, ECQ (1, 3, 10, 30 mg/kg) group and omeprazole (30 mg/kg) group. ECQ and omeprazole groups received intraduodenal administration. The Rats were starved for 24 hours before the experiments, but were freely allowed to drink water. ECQ group attenuated the gross esophagitis significantly compared to that treated with omeprazole in a dose-dependent manner. ECQ decreased the volume of gastric juice and increased the gastric pH, which are similar to those of omeprazole group. In addition, ECQ inhibited the acid output effectively in reflux esophagitis. Significantly increased amounts of malondialdehyde (MDA), myeloperoxidase (MPO) activity and the mucosal depletion of reduced glutathione (GSH) were observed in the reflux esophagitis. ECQ administration attenuated the decrement of the GSH levels and affected the MDA levels and MPO activity. These results suggest that the ECQ has a protective effect which may be attributed to its multiple effects including anti-secretory, anti-oxidative and anti-inflammatory actions on reflux esophagitis in rats.

Pathogenesis of NSAID-induced gastric damage: Importance of cyclooxygenase inhibition and gastric hypermotility

This article reviews the pathogenic mechanism of non-steroidal anti-inflammatory drug (NSAID)-induced gastric damage, focusing on the relation between cyclooxygenase (COX) inhibition and various functional events. NSAIDs, such as indomethacin, at a dose that inhibits prostaglandin (PG) production, enhance gastric motility, resulting in an increase in mucosal permeability, neutrophil infiltration and oxyradical production, and eventually producing gastric lesions. These lesions are prevented by pretreatment with PGE₂ and antisecretory drugs, and also via an atropine-sensitive mechanism, not related to antisecretory action. Although neither rofecoxib (a selective COX-2 inhibitor) nor SC-560 (a selective COX-1 inhibitor) alone damages the stomach, the combined administration of these drugs provokes gastric lesions. SC-560, but not rofecoxib, decreases prostaglandin E₂ (PGE₂) production and causes gastric hypermotility and an increase in mucosal permeability. COX-2 mRNA is expressed in the stomach after administration of indomethacin and SC-560 but not rofecoxib. The up-regulation of indomethacin-induced COX-2 expression is prevented by atropine at a dose that inhibits gastric hypermotility. In addition, selective COX-2 inhibitors have deleterious influences on the stomach when COX-2 is overexpressed under various conditions, including adrenalectomy, arthritis, and Helicobacter pylori-infection. In summary, gastric hypermotility plays a primary role in the pathogenesis of NSAID-induced gastric damage, and the response, causally related with PG deficiency due to COX-1 inhibition, occurs prior to other pathogenic events such as increased mucosal permeability; and the ulcerogenic properties of NSAIDs require the inhibition of both COX-1 and COX-2, the inhibition of COX-1 upregulates COX-2 expression in association with gastric hypermotility, and PGs produced by COX-2 counteract the deleterious effect of COX-1 inhibition.

Enaminones as Building Blocks in Heterocyclic Preparations: Synthesis of Novel Pyrazoles, Pyrazolo[3,4-d]pyridazines, Pyrazolo[1,5-a]pyrimidines, Pyrido[2,3-d]pyrimidines Linked to Imidazo[2,1-b]thiazole System

The unreported 2-[E-3-(N,N-dimethylamino)acryloyl]-3-methyl-5,6diphenylimidazo[2,1-b]thiazole 3 was prepared via the reaction of 2-acetyl-3methyl-5,6-diphenylimidazo[2,1-b]thiazole 2 with dimethylformamide dimethyl acetal (DMF-DMA). Enaminone 3 underwent regioselective 1,3-dipolar cycloaddition with nitrilimines 5a-f, to afford the corresponding pyrazoles 7a-f. The reaction of 7a,d,g with hydrazine hydrate, afforded the pyrazolo[3,4d]pyridazines 8a-c, respectively. Enaminone 3 also reacted with a hydrazines, hydroxylamine hydrochloride, 5-aminopyrazole 11, 6-aminothiouracil 15 and hippuric acid 22. The structures of the newly synthesized compounds were confirmed by spectral data and elemental analyses. Enaminones are poly-dentate reagents that have been utilized extensively in this decade as building blocks in organic synthesis. Furthermore, many enaminones were found to exhibit several biological activities as antitumor, antibacterial and anticonvulsant agents. On the other hand, imidazoles possess important biological, pharmacological and therapeutic activities, where midazoles are present in compounds that have antiasthmatic, anti-inflammatory, antiulcerative, antithrombotic, fungicidal and herbicidal activities. Furthermore, some imidazo[2,1b]thiazoles were active against various cancer cell lines. Much interest has also been focused on the chemistry and anticonvulsant, analgesic, antibacterial and antisecretory activities displayed by HETEROCYCLES, Vol. 85, No. 9, 2012 2291

Morphologic and pharmacological investigations in the epicatechin gastroprotective effect.

Previous studies of the gastroprotective activity of plants have highlighted the importance of the polyphenolic compound epicatechin (EC) in the treatment of gastric ulcers. This paper aimed to evaluate and characterize the gastroprotective mechanism of action of EC using male rats. The gastroprotective action of EC was analyzed in gastric ulcers induced by ethanol or indomethacin. The involvement of sulfhydryl (SH) groups, K+ ATP channels, α 2 adrenoceptors, gastric antisecretory activity, and the amount of mucus in the development of gastric ulcers were investigated. The lowest effective dose of EC providing gastroprotective effects was 50 mg/kg in the ethanol-induced gastric ulcers and 25 mg/kg in the indomethacin-induced gastric ulcers. The gastroprotection seen upon treatment with EC was significantly decreased in rats pretreated with a SH compound reagent or an α 2-receptor antagonist, but not with a K+ ATP channel blocker. Furthermore, oral treatment with EC increased mucus production and decreased H+ secretion. Immunohistochemistry demonstrated the involvement of superoxide dismutase (SOD), nitric oxide (NO), and heat shock protein-70 (HSP-70) in the gastroprotection. These results demonstrate that EC provides gastroprotection through reinforcement of the mucus barrier and neutralization of gastric juice and this protection occurs through the involvement of SH compounds, α 2-adrenoceptors, NO, SOD, and HSP-70.

Gastroprokinetic Activity of Nizatidine during the Digestive State in the Dog and Rat

The present study was undertaken to clarify a prokinetic activity of nizatidine (CAS 76963-41-2) during the digestive state as well as gastric emptying of a solid test meal in comparison with cimetidine (CAS 51481-61-9), famotidine (CAS 76842-35-6) and cisapride (CAS 81098-60-4). Intravenous administration of nizatidine (0.3-3 mg/kg) enhanced the motility of the gastric antrum and duodenum during the digestive state. With cimetidine (1-10 mg/kg) and famotidine (0.1-1 mg/kg) enhancement of gastric motility was observed only with the highest dose of cimetidine, and famotidine had no effect. Marked enhancement of gastric motility was observed with cisapride (0.1-0.5 mg/kg). After intraduodenal administration of nizatidine (10 and 20 mg/kg) and cisapride (0.25 and 0.5 mg/kg), they also amplified the contractile activity of the gastric antrum. Gastric emptying of a solid test meal was accelerated by intraperitoneal administration of nizatidine (1-10 mg/kg) to the same extent as cisapride (0.1-1 mg/kg). In addition, even in a model of delayed gastric emptying induced by clonidine, nizatidine, like cisapride, improved the rate of gastric emptying. Neither cimetidine (3-30 mg/kg) nor famotidine (0.3-3 mg/kg) affected the gastric emptying of a solid meal or delayed gastric emptying. These results suggest that nizatidine enhanced gastric motility even during the digestive state, and accelerated gastric emptying of a solid meal, similar to cisapride. Furthermore, nizatidine improved clonidine-induced delayed gastric emptying. These prokinetic activities of nizatidine may by useful for the treatment of abdominal symptoms due to dysmotility and delayed gastric emptying in patients with gastritis and non-ulcer dyspepsia (NUD). In comparison with famotidine and cimetidine, nizatidine may be different from other histamine H2-receptor antagonists and has unique properties other than its gastric antisecretory activity.

Synthesis and antisecretory activity of 6-substituted 5-cyanomethylimidazo[2,1-b]thiazoles and 2,6-dimethyl-5-hydroxymethylimidazo[2,1-b][1,3,4]thiadiazole.

The synthesis of imidazo[2,1-b]thiazole and imidazo[2,1-b][1,3,4]thiadiazole derivatives, related to known antiulcer agents, is reported. 5-Cyanomethyl-6-methylimidazo[2,1-b]thiazole showed significant antisecretory activity in the isolated rabbit gastric glands assay.

Antiulcerogenic effect of some gastrointestinally acting plant extracts and their combination.

Extracts from the plants Iberis amara, Melissa officinalis, Matricaria recutita, Carum carvi, Mentha x piperita, Glycyrrhiza glabra, Angelica archangelica, Silybum marianum and Chelidonium majus, singly and combined in the form of a commercial preparation, STW 5 (Iberogast) and a modified formulation, STW 5-II, lacking the last 3 constituents, were tested for their potential anti-ulcerogenic activity against indometacin induced gastric ulcers of the rat as well as for their antisecretory and cytoprotective activities. All extracts produced a dose dependent anti-ulcerogenic activity associated with a reduced acid output and an increased mucin secretion, an increase in prostaglandin E2 release and a decrease in leukotrienes. The effect on pepsin content was rather variable and did not seem to bear a relationship with the anti-ulcerogenic activity. The most beneficial effects were observed with the combined formulations STW 5 and STW 5-II in a dose of 10 ml/kg b.w., comparable with cimetidine in a dose of 100 mg/kg b.w. The anti-ulcerogenic activity of the extracts was also confirmed histologically. The cytoprotective effect of the extracts could be partly due to their flavonoid content and to their free radical scavenging properties.

Effects of IY-81149, a newly developed proton pump inhibitor, on gastric acid secretion in vitro and in vivo.

The inhibitory effects of IY-81149 (2-[[(4-methoxy-3-methyl)-2- pyridinyl]methyl-sulfinyl]-5-(1H-pyrol-1-yl)-1H-benzimidazole, CAS 172152-36-2), a newly developed proton pump inhibitor (PPI) on gastric acid secretion were investigated in vitro and in vivo. In rabbit parietal cell preparation, IY-81149 irreversibly inhibited H+/K(+)-ATPase in dose-dependent manner with an IC50 of pump inhibitory activity of 6.0 x 10(-6) mol/l and that of omeprazole (CAS 73590-58-6) was 1 x 10(-4) mol/l at pH 7.4. On cumulation of 14C-aminopyrine in histamine stimulated parietal cells, the IC50 of IY-81149 was 9.0 x 10(-9) mol/l and that of omeprazole was 1.9 x 10(-8) mol/l. The inhibition rates of IY-81149 and omeprazole at a concentration of 1 x 10(-9) mol/l in human parietal cells were 137% and 64%, respectively. In pylorus-ligated rats, IY-81149 showed a 2-3 times stronger inhibitory activity than omeprazole against gastric acid secretion. The ED50 of IY-81149 and omeprazole administered intraduodenally was 1.6 mg/kg and 3.8 mg/kg. In the case of oral administration, the ED50 of IY-81149 and omeprazole was 1.94 mg/kg and 5.64 mg/kg, respectively. But after 24 h administration, the anti-secretory activity of IY-81149 was lower than that of omeprazole at all doses tested. In anesthetized rats, IY-81149 dose-dependently increased gastric pH which was lowered by histamine infusion. In the case of i.v. injection, the ED50 of IY-81149 and omeprazole was 1.2 and 1.4 mg/kg and in the case of i.d. administration, the ED50 of IY-81149 and omeprazole was 3.9 and 4.1 mg/kg, respectively. IY-81149 also significantly inhibited pentagastrin-stimulated gastric secretion. Its ED50 was 2.1 mg/kg and that of omeprazole was 3.5 mg/kg with i.d. administration. In the case of i.v. injection, IY-81149 was equipotent to omeprazole. IY-81149 also inhibited gastric acid secretion strongly in fistular rats. The ED50 of IY-81149 administered intraduodenally was 0.43 mg/kg and that of omeprazole was 0.68 mg/kg. In Heidenhain pouch dogs, the acid output was completely blocked at 0.3 mg/kg, 135 min after i.v. administration. Omeprazole showed a similar effect as IY-81149. The histamine induced increase of acid output in the Heidenhain pouch dog was blocked by 71% 150 min after oral administration of enteric-coated IY-81149 at a dose of 3 mg/kg, and omeprazole showed similar effects. In conclusion, IY-81149 revealed the characteristics as a strong proton pump inhibitor, and its potency against gastric acid secretion was superior to that of the reference drug, omeprazole.

Safety pharmacology of CKD-602, a novel anticancer agent.

CKD-602 ((20S)-7-[2-(N-isopropylamino)-ethyl]-camptothecin.HCl, CAS 213819-48-8) is a new class of anticancer drug that belongs to the topoisomerase inhibitors. Its effect on the central nervous system (CNS), general behavior, cardiovascular-respiratory system and the other organ systems were studied. When intravenously administered, CKD-602 up to doses of 5 mg/kg caused an increase of body temperature, increase of respiration rate, decrease of gastrointestinal transport, showed analgesic action and produced antisecretory action in pylorus ligated rats. However, CKD-602 showed no effects on general behavior, motor coordination, spontaneous locomotor activity, hexobarbital sleeping time, convulsion, cardiovascular, smooth muscle and urinary tract system. These findings demonstrate that CKD-602 in doses up to 5 mg/kg has minor effects on the CNS in animals. However, CKD-602 does not exert any general pharmacological effects at the dose of 1 mg/kg except the effects on gastric secretion.

Dose–response relationships of rabeprazole 5, 10, 20, and 40 mg once daily on suppression of gastric acid secretion through the night in healthy Japanese individuals with different CYP2C19 genotypes

This study was designed to investigate the antisecretory activity of rabeprazole administered once daily in doses of 5, 10, 20, and 40 mg and different cytochrome P450 2C19 (CYP2C19) genotypes on gastric pH in healthy individuals. Additional objectives were delineating the nighttime from the daytime effect and determining the relationships between the pharmacokinetics and pharmacodynamics of rabeprazole. Eight individuals of each of the three genotypes of CYP2C19-homozygous extensive metabolizers (homo-EMs), heterozygous EMs (hetero-EMs), and poor metabolizers (PMs)-were recruited. Twenty-four individuals received a once-daily dose, with dosing interval 24 h of 5, 10, 20, or 40 mg rabeprazole for 5 days in a 4-period crossover fashion. Twenty-four-hour intragastric pH and plasma rabeprazole concentrations were determined on day 5. A dose-dependent increase in median pH and in pH 4 holding time was observed across all CYP2C19 genotypes. When rabeprazole was increased from 20 mg to 40 mg, the differences and 95% confidence intervals (CIs) of nighttime pH 4 holding time between 40 mg and 20 mg in homo-EMs, hetero-EMs, and PMs were 8.0% (-5.0% -21.0%), 28.7% (15.7% -41.6%), and 16.9% (3.9% -29.9%), respectively. The relationship between the area under the plasma concentration-time curve up to the last time point at which rabeprazole was quantifiable (AUC(0-t)) and the pH 4 holding time could be described using a sigmoid maximum effect (E(max)) model. Our data demonstrate that increasing rabeprazole dose up to 40 mg once daily results in an increasing pharmacodynamic effect, which is most apparent for the control of nocturnal gastric acid secretion.

Mechanisms of action underlying the gastric antiulcer activity of the Rhizophora mangle L.

Ethnopharmacological relevanceRhizophora mangle, the red mangrove, has long been known as a traditional antiulcer medicine. The present work evaluated the mechanisms of action involved in the anti-ulcer properties of the Rhizophora mangle bark extracts. Materials and methodsGastroprotection of Rhizophora mangle was evaluated in rodent experimental models (ethanol). To elucidate the mechanisms of action the antisecretory action and involvement of NO, SH, mucus and PGE2 were evaluated. The acetic acid-induced gastric ulcer model, Western blotting assay (COX-1, COX-2 and EGF) and immunohistochemical localization of HSP-70, PCNA and COX-2 were also used to evaluate the Rhizophora mangle healing properties. ResultsResults showed that Rhizophora mangle bark crude extract (CE), as well as ethyl acetate (EtOAc) and butanolic fractions (BuOH) provided significant gastroprotection at all the tested doses. Thereby, the following protocols were performed using the lowest dose capable of producing the most effective gastroprotection, which was the BuOH 0.5mg/kg (P<0.001). Several mechanisms are involved in the antiulcer activity of Rhizophora mangle, such as, participation of NO, SH and mucus. The enhancement of PGE2 levels and the upregulation of COX-2 and EGF seem to be directly linked to the antisecretory, cytoprotective and healing effects of BuOH. HSP-70 and PCNA are also involved in this cicatrisation process. No sign of toxicity was observed in this study, considering the analyzed parameters. ConclusionOur study reinforces its traditional medicinal use. Considering that the current therapies are based on the use of antisecretory or cytoprotective drugs, the Rhizophora mangle arises as a promising alternative antiulcer therapy.

Sexual dimorphism and oestrogen regulation of KCNE3 expression modulates the functional properties of KCNQ1 K+ channels

The KCNQ1 potassium channel associates with various KCNE ancillary subunits that drastically affect channel gating and pharmacology. Co-assembly with KCNE3 produces a current with nearly instantaneous activation, some time-dependent activation at very positive potentials, a linear current-voltage relationship and a 10-fold higher sensitivity to chromanol 293B. KCNQ1:KCNE3 channels are expressed in colonic crypts and mediate basolateral K(+) recycling required for Cl(-) secretion. We have previously reported the female-specific anti-secretory effects of oestrogen via KCNQ1:KCNE3 channel inhibition in colonic crypts. This study was designed to determine whether sex and oestrogen regulate the expression and function of KCNQ1 and KCNE3 in rat distal colon. Colonic crypts were isolated from Sprague-Dawley rats and used for whole-cell patch-clamp and to extract total RNA and protein. Sheets of epithelium were used for short-circuit current recordings. KCNE1 and KCNE3 mRNA and protein abundance were significantly higher in male than female crypts. No expression of KCNE2 was found and no difference was observed in KCNQ1 expression between male and female (at oestrus) colonic crypts. Male crypts showed a 2.2-fold higher level of association of KCNQ1 and KCNE3 compared to female cells. In female colonic crypts, KCNQ1 and KCNE3 protein expression fluctuated throughout the oestrous cycle and 17β-oestradiol (E2 10 nM) produced a rapid (<15 min) dissociation of KCNQ1 and KCNE3 in female crypts only. Whole-cell K(+) currents showed a linear current-voltage relationship in male crypts, while K(+) currents in colonic crypts isolated from females displayed voltage-dependent outward rectification. Currents in isolated male crypts and epithelial sheets were 10-fold more sensitive to specific KCNQ1 inhibitors, such as chromanol 293B and HMR-1556, than in female. The effect of E2 on K(+) currents mediated by KCNQ1 with or without different β-subunits was assayed from current-voltage relations elicited in CHO cells transfected with KCNQ1 and KCNE3 or KCNE1 cDNA. E2 (100 nM) reduced the currents mediated by the KCNQ1:KCNE3 potassium channel and had no effect on currents via KCNQ1:KCNE1 or KCNQ1 alone. Currents mediated by the complex formed by KCNQ1 and the mutant KCNE3-S82A β-subunit (mutation of the site for PKCδ-promoted phosphorylation and modulation of the activity of KCNE3) showed rapid run-down and insensitivity to E2. Together, these data suggest that oestrogen regulates the expression of the KCNE1 and KCNE3 and with it the gating and pharmacological properties of the K(+) conductance required for Cl(-) secretion. The decreased association of the KCNQ1:KCNE3 channel complex promoted by oestrogen exposure underlies the molecular mechanism for the sexual dimorphism and oestrous cycle dependence of the anti-secretory actions of oestrogen in the intestine.

Comparative Evaluation Of Efficiency Of Proton Pomp Inhibitors Of The First And Second Generations In Treating Gastroesophageal Reflux Disease

Comparative assessment of clinical efficiency of omeprazole and rabeprazole in treating gastroesophageal reflux disease (GERD). 65 patients with a verified diagnosis GERD were examined. Comparative clinical investigations of using ofomeprazole and rabeprazole have revealed effectiveness of both drugs in the therapy of GERD. However, rabeprazoleshowed antisecretory action in the earlier periods, providing stable clinical remission of GERD and early scarring of erosivelesions of the esophageal mucosa, compared with omeprazole

Short-term effects of tolvaptan on renal function and volume in patients with autosomal dominant polycystic kidney disease

Tolvaptan and related V(2)-specific vasopressin receptor antagonists have been shown to delay disease progression in animal models of polycystic kidney disease. Slight elevations in serum creatinine, rapidly reversible after drug cessation, have been found in clinical trials involving tolvaptan. Here, we sought to clarify the potential renal mechanisms to see whether the antagonist effects were dependent on underlying renal function in 20 patients with autosomal dominant polycystic kidney disease (ADPKD) before and after 1 week of daily split-dose treatment. Tolvaptan induced aquaresis (excretion of solute-free water) and a significant reduction in glomerular filtration rate (GFR). The serum uric acid increased because of a decreased uric acid clearance, and the serum potassium fell, but there was no significant change in renal blood flow as measured by para-aminohippurate clearance or magnetic resonance imaging (MRI). No correlation was found between baseline GFR, measured by iothalmate clearance, and percent change in GFR induced by tolvaptan. Blinded post hoc analysis of renal MRIs showed that tolvaptan significantly reduced total kidney volume by 3.1% and individual cyst volume by 1.6%. Preliminary analysis of this small cohort suggested that these effects were more noticeable in patients with preserved renal function and with larger cysts. No correlation was found between changes of total kidney volume and body weight or estimated body water. Thus, functional and structural effects of tolvaptan on patients with ADPKD are likely due to inhibition of V(2)-driven adenosine cyclic 3',5'-monophosphate generation and its aquaretic, hemodynamic, and anti-secretory actions.

The flavonone naringenin inhibits chloride secretion in isolated colonic epithelia

Studies investigating the activating and inhibitory actions of bioflavonoids on colonic function have yielded conflicting results. At low concentrations, flavonoids may stimulate chloride secretion while at higher concentrations they may have antisecretory actions in the colon. Naringenin (4′,5,7-trihydroxyflavanone), found predominantly in citrus fruits, confers a protective effect against colorectal cancer and is purported to modulate secretory function in colonic cell lines. The aim of this study was to investigate the effects of naringenin on ion transport in rat and human colonic mucosae.Naringenin inhibited basal and stimulated chloride secretion in rat and human colonic mucosae mounted in Ussing chambers (IC50 330μMol/L and 360μMol/L respectively) and did not alter intracellular cAMP generation. Naringenin inhibited chloride secretion in MQAE (N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide) loaded crypts stimulated with forskolin. In BCECF (2′,7′-bis-(2-carboxyethyl)-5-(and 6)-carboxyfluorescein acetoxymethyl ester) loaded crypts, naringenin caused an intracellular acidification (ΔpH/min=0.05±0.004) which was sensitive to the Na-K-Cl co-transporter (NKCC) inhibitor bumetanide. In addition, the antisecretory effect of naringenin was not inhibited by blockade of barium sensitive basolateral K+ transporters or by inhibition of Na+/H+ exchange by amiloride.We propose that the antisecretory action of naringenin is due to inhibition of basolateral NKCC1 in rat and human colon.

Somatostatin in breast cancer

In man, somatostatin is a hormone mostly produced by hypothalamus. It plays different parts in hormonal regulation through many specific receptors in human body. It has also two interesting actions such as an anti-secretory activity, mostly on the gastrointestinal system and an antiproliferative action on tumor cells. Many synthetic somatostatin analogues, more stable than the natural one, have been developed and are already used in digestive surgery to treat postoperative digestive fistula. Also, the development of specific polyclonal antibodies allowed the identification of five specific somatostatin receptors and their localization in different cell species. The presence of the five receptors in breast cancer cells has than been demonstrated. The purpose of this literature review is to clarify the potential antitumor effect of somatastatin analogues in breast cancer; its use as a preventive agent on lymphorrhea after breast surgery and its employment in imaging for early breast cancer detection.

Gastroprotective activity of Zanthoxylum rhoifolium Lam. in animal models

The stem barks of Zanthoxylum rhoifolium Lam. (Rutaceae), locally known as "mamica de cadela", are popularly used in dyspepsies, stomachic, tonic, antitumoral, antipyretic and are used in treating flatulence and colic. The objective of this study was to evaluate the gastroprotective effect of the ethanolic extract of Zanthoxylum rhoifolium (EEZR) stem barks in acute gastric lesion models, investigating their possible mechanisms. Mice were used for the evaluation of the acute toxicity, and mice and rats to study the gastroprotective activity. The gastroprotective action of EEZR was analyzed in the absolute ethanol, HCl/ethanol and indomethacin-induced gastric lesion models in mice, hypothermic-restraint stress, and ischemia/reperfusion in rats. In the investigation of the gastroprotective mechanisms of EEZR, the participation of the NO-synthase pathway, ATP-sensitive potassium channels (K(ATP)), the levels of the non-protein sulfhydril groups (NP-SH) and the catalase activity using the ethanol-induced gastric mucosa lesion model and the quantification of the gastric mucus and the antisecretory activity through pylorus ligature model in rats were analyzed. The animals did not present any signs of acute toxicity for the EEZR (up to the 4 g/kg dose, po), and it was not possible to calculate the DL(50). EEZR (125-500 mg/kg) exhibited a significant gastroprotective effect in absolute ethanol, HCl/ethanol, hypothermic-restraint stress, and ischemia/reperfusion-induced gastric lesion models. EEZR (250 and 500 mg/kg) exhibited still a gastroprotective activity in the indomethacin-induced ulcer model. Gastroprotection of EEZR was significantly decreased in pre-treated mice with l-NAME or glibenclamide, the respective nitric oxide synthase and K(ATP) channels inhibitors. Our studies revealed that EEZR (500 mg/kg) prevented the decrease of the non-protein sulfhydril groups (NP-SH) and increased the catalase levels in ethanol-treated animals. Furthermore, the extract (500 mg/kg) significantly increased the mucus production, however, the gastric secretion parameters (volume, [H(+)], pH) did not show any alteration. Our results indicate that the ethanolic extract of Zanthoxylum rhoifolium exhibits a significant gastroprotection, because it inhibits the formation of gastric lesions using different models. The release of the nitric oxide, the opening of the K(ATP) channels, the participation of the non-protein sulfhydril groups (NP-SH), catalase and the increase of mucous secretion seem to be involved in the gastroprotection activity of the EEZR. Nevertheless, this activity does not seem to be related to antisecretory mechanisms.

Indigofera suffruticosa Mill as new source of healing agent: Involvement of prostaglandin and mucus and heat shock proteins

Indigofera suffruticosa is specie typical of the "Cerrado" or Brazilian savannah; it is a member of the Fabaceae family - in folkmedicine is used for gastric disorders, infection and inflammation. Ethyl acetate fraction (AcF) and aqueous fraction (AqF) of the methanolic extract of I. suffruticosa leaves were evaluated against acute gastric ulcer. The AcF fraction was selected to assess its activity in ulcer healing and its gastroprotective effects via mucus and gastric secretion. The gastroprotective action of AcF and AqF fractions were evaluated in a rodent experimental model. The action mechanisms, involvements of the antisecretory action, mucus and prostaglandin production, toxicological and healing activity of the AcF (100mg/kg, p.o.) were evaluated. We also used histological analysis (HE and PAS) and immunohistochemical (PCNA and HSP-70) assays to evaluate the effects of I. suffruticosa. AcF significantly inhibited the gastric mucosal damage caused by ethanol. This effect was statistically significant in 100mg/kg group compared vehicle. AcF did not interfered with gastric secretion, significantly increased the PGE(2) and mucus production (validated in PAS technique). The gastroprotection was attenuated by pretreatment with N-ethylmaleimide, but not L-NAME. In acid-acetic-induced ulcer model AcF accelerated ulcer healing. Immunohistochemistry analysis showed induction of proliferating cell (PCNA) and heat shock protein (HSP 70). These results showed that AcF acted as gastroprotective agent stimulating prostaglandin, mucus and HSP70.

Antisecretory actions of Baccharis trimera (Less.) DC aqueous extract and isolated compounds: Analysis of underlying mechanisms

Baccharis trimera (Less.) DC. (Asteraceae) is a species native to South America used in Brazilian folk medicine to treat gastrointestinal and liver diseases, kidney disorders and diabetes. Previous studies from this laboratory confirmed the antacid and antiulcer activities of the plant aqueous extract (AE) in rat and mouse models. To investigate the mechanisms involved in the antacid action of AE and isolated compounds from Baccharis trimera. AE was assayed in vivo in cold-restraint stress gastric ulcers and in pylorus-ligated mice. Nine fractions (F2-F10) previously isolated from AE were assayed in vitro on acid secretion measured as [(14)C]-aminopyrine ([(14)C]-AP) accumulation in rabbit gastric glands, and on gastric microsomal H(+), K(+)-ATPase preparations. Chlorogenic acids (F2, F3, F6, F7), flavonoids (F9), an ent-clerodane diterpene (F8) and a dilactonic neo-clerodane diterpene (F10) have been identified in these fractions. Intraduodenal injection of AE (1.0 and 2.0 g/kg) in 4h pylorus-ligated mice decreased the volume (20 and 50%) and total acidity (34 and 50%) of acid secretion compared to control values. Administered orally at the same doses AE protected against gastric mucosal lesions induced in mice by restraint at 4°C. Exposure of isolated rabbit gastric glands to fractions F8 (10-100 μM) and F9 (10-300 μg/ml) decreased the basal [(14)C]-AP uptake by 50 and 60% of control (Ratio=6.2±1.1), whereas the remaining fractions were inactive. In the presence of the secretagogues F2 and F4 (30-300 μg/ml) decreased the [(14)C]-AP uptake induced by histamine (His) with a 100-fold lower potency than that of ranitidine. F5 and F6 reduced the [(14)C]-AP uptake stimulated by carbachol (CCh), but they were 10 to 20-fold less potent than atropine. F8 (diterpene 2) and F9 (flavonoids) decreased both the His- and CCh-induced [(14)C]-AP uptake, whereas F10 (diterpene 1) was inactive against the [(14)C]-AP uptake stimulated by secretagogues. Diterpene 2 was the most active of all tested compounds being 7-fold less potent than ranitidine and equipotent to atropine in reducing acid secretion in vitro. This compound also reduced the gastric H(+), K(+)-ATPase activity by 20% of control, while the remaining fractions were inactive on the proton pump in vitro. The results indicate that Baccharis trimera presents constituents that inhibit gastric acid secretion by acting mainly on the cholinergic regulatory pathway. The plant extract also contains compounds that exert moderate inhibition of the histaminergic regulatory pathway of acid secretion and the gastric proton pump. Altogether these active constituents appear to provide effective inhibition of acid secretion in vivo, which may explain the reputed antiulcer activity of the plant extract.