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Rocio M Suarez Ordoñez,1 Jorgelina Cesolari,2 Casas Ofelia,2 Ivonne Villavicencio,1 Hendrée E Jones31Research Department, Institute of Cognitive Neuroscience INECO Oroño, 2Neonatology Department, Martin Maternity, Rosario, Santa Fe, Argentina; 3UNC Horizons and Department of Obstetrics and Gynecology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USAAbstract: Untreated behavioral disorders in pregnant women and in women of childbearing age pose physical and psychological safety concerns and are barriers to the well-being of both mother and neonate. The present paper underlines the importance of screening in Argentina for behavioral problems in women of childbearing age, particularly pregnant women and their newborns. Emphasized is the need to formalize this comprehensive screening in a protocol that includes domains of mental disorders, behavioral disorders, education, social environment, employment, desire for maternity, substance use including non-prescription use of prescription medications, eating disorders, suicide risk, interpersonal violence, stress, and trauma. Implementation of such a model would require agreement and cooperation between the public and private health sectors as well as in the development of research for validation of the various screening and interventions tools that would be adopted for general use. Keywords: pregnancy, substance use, assessment, measures

The anti-inflammatory effect of Bioflora probiotic administered orally or subcutaneously with viable or nonviable bacteria was analyzed in two experimental models of randomly selected female Wistar rats. The use of indomethacin at a dose of 50 mg/kg was associated with gastric necrotic lesions and multiple erosions of the small intestine, with marked mucosal neutrophil infiltrate measured by myeloperoxidase (MPO). Probiotics prevented both gastrointestinal lesions and neutrophil infiltrate (p < 0.001). In the model of carrageenin-induced plantar edema in the rat, the oral or subcutaneous administration of Bioflora with live or dead bacteria proved to prevent plantar edema (p < 0.001). We concluded that Bioflora probiotic given orally or subcutaneously with live or dead bacteria has an anti-inflammatory effect.

In randomized groups of Wistar rats, the effect inhibitor of selective NASAID over the COX-1, COX-2 and COX-3 the synchronizes inhibition of COX-1 and COX-2, COX-1 and COX-3, COX-2 and COX-3, and COX-1, COX-2 and COX-3 were studied. The conclusions were that the selective inhibition of COX-1, COX-2 and COX-3 no given gastrointestinal damage; the synchronizes inhibition of COX-1 and COX-2 given preferential gastric damage; in contrast the inhibition of COX-2 and COX-3 given massive necrosis preferential in small intestine.

Dexketoprofene (De) NSAID was studied as a selective COX-1 inhibitor in comparison with Ketorolac (Ke), a mainly COX-1 inhibitor. De and Ke were administered to different groups of animals in a dose-dependent manner, i.e., 3-15 and 25 mgs/kg. The gastrointestinal mucosa damage was macroscopically and microscopically quantified at 24 hs, as well as leukocyte infiltration (LI) and neosinophilia. Similarly, Indomethacin (Indo) damage (COX-1-COX-2), with 25 mgs/kg. Dose was compared. On the other hand, De and Ke at inhibitory selective COX-1 dose (3 mg/kg) plus Celecoxib, selective COX-2 inhibitor, yielding no gastrointestinal damage, with decreased LI and without neutrophilia, the same as Ke (n.s.). Similarly De at higher dose (2.5 mgs/kg), produced minimal gastrointestinal lesions, showing a preferential COX-1 inhibitor behavior. Ke and Indo produced important gastrointestinal necrotic and erosive lesions with remarkable LI and neutrophilia (p < 0.001). On the other hand, COX-1 De dose plus Celecoxib produced evident gastrointestinal lesions, increased LI and neutrophilia, the same as Indo, pointing out that the gastrointestinal damage is due to COX-1 and COX-2 inhibition.

The aim of the present work was to study in vivo COX-2-COX-1 selectivity of 16 nonsteroidal anti-inflammatory drugs (NSAIDs) in equipotent ulcerogenic doses in two in vivo experimental models. Indomethacin, ibuprofen, nimesulide, aceclofenac, aspirin, sodium diclofenac, meloxicam, naproxene, paracetamol, piroxicam, tenoxicam, nabumetone, ketoprofen, mefenamic acid, etodolac, and ketorolac were administered to female Wistar rats (N = 10 each group). In experiment I, solid food plus subcutaneous NSAIDs were given. In experiment II, NSAIDs were given by oral gavage and in bolus. Macroscopic gastric antral ulcer area (30%) and intestinal erosiva area (295 mm2) in experiment I and necrotic gastric fundus area (65%) and erosive intestinal area (182 mm2), "in vivo" the NSAIDs COX-1 was showed. Neutrofilia assessed in gastric intestinal mucosa where also ibuprofen and paracetamol not given neotrophilic infiltration. In conclusion, COX-2-COX-1 selectivity was demonstrated in vivo with the drugs aceclofenac, nabumetone, meloxicam, nimesulide, and paracetamol.

In 5 random groups of Wistar rats (n = 15 for each group), ulcerogenic doses of NSAIDs COX-1-COX-2 inhibitors such as indomethacin were compared with Celecoxib (COX-2 inhibitor); the production of antrum gastric ulcers and bowel and colon necrotic areas was studied. Celecoxib was given each 12 hs orally and subcutaneously during 5 days and gastrointestinal lesions were not found; in contrast, Celecoxib given after indomethacin aggravated antrum gastric ulcers (p < 0.001); intestinal massive necrosis and death were observed in all the rats. We conclude that Celecoxib does not induce gastrointestinal lesions in healthy mucosa; in contrast, Celecoxib amplifies the gastrointestinal lesions induced by indomethacin.

Unlabelled: Five experimental models were carried out in different groups of Wistar rats (n = 15) in order to study selective (cyclo-oxygenase) COX-2 non-steroid antiinflammatory inhibitors, such as celecoxib and rofecoxib, as follows: 1) Dose-dependent oral celecoxib and rofecoxib for 5 days, and 24 hours after oral indomethacin. 2) Same as 1, but subcutaneously. 3) Gastric ulcer induced by means of glacial acetic acid. 4) Duodenal ulcer induced by means of cysteamine. 5) Stress due to being kept under restraint and immersion in water at 15 degrees C for 6 hours. Celecoxib and rofecoxib, either orally or subcutaneously, did not produce necrotic injuries in healthy gastrointestinal mucosa (0%), showing normal histology. On the other hand, the injuries previously induced by indomethacin worsened (90%, p < 0.001). Total necrosis of small intestine as well as increased ulcer and perforation of gastric and duodenal ulcers induced by acetic acid and cysteamine were observed. There was also worsening of gastric necrotic area with stress (60-90%, p < 0.05). Celecoxib and rofecoxib showed neutrophilia (5,000/mm3) similar to that presented by indomethacin, but there was no leukocyte infiltration in the gastric mucosa; thus we can consider it a COX-2 selective NSAID (non-steroidal anti-inflammatory drug)., Conclusion: Dose-dependent administration of celecoxib and rofecoxib as COX-2 inhibitors and non-COX-1 inhibitors, respectively, did not produce toxic injuries on healthy gastrointestinal mucosa, thus providing a broad therapeutic spectre. On the other hand, when administered in presence of altered gastrointestinal mucosa, they worsened and complicated gastric ulcers, and also induced necrosis in the small intestine, thereby restricting their clinical use.

The role of the autonomic nervous system on gastric stress was studied in different groups of Wistar rats (n = 10). The experimental stress model consisted of immobilization and immersion in 15 degrees C water during 6 hours. The percentage of the gastric mucosa macroscopic lesional area was tabulated, and at the same time cortisol, melatonin, noradrenaline, adrenaline, dopamine and serotonin blood levels were measured. The stress control showed a necrotic area (80%) and in blood there was only and increase in noradrenaline and adrenaline. The following dose dependent drugs were studied: beta adrenergics agonists and antagonists, alpha 1 postsinaptical adrenergic antagonists, anticholinergics and cholinergics, endorphin and GABA receptors. Isoproterenol, prazosim, doxasine, tramadol and vigabatrin yielded a remarkable gastric mucosa protection in stress with an area close to 0% (p < 0.001). In contrast, propanolol, acetylholine, atropine, naloxone and flumazenil showed no difference in control stress (p > 0.5). All the drugs under study yielded similar vasoactive amines than the control stress. It is concluded that the protective gastric mechanism of the autonomic nervous system in stress, could be linked to its receptors with an increase in the splanchnic microcirculation.

Unlabelled: This work was aimed to study COX-1 and COX-2 selectivity in 16 non-steroidal anti-inflammatory drugs (NSAIDs), at ulcerogenic doses in 2 experimental models: 1) provided subcutaneously (sc), after solid food(SF), (antrum ulcers and intestinal erosions); and 2) orally (O) (fundic and intestinal erosions)., Methods: 17 groups of female Wistar rats (n = 7 each group), weighing 200 g, 36 h fasting with water ad libitum, were submitted to the following experiments: 1. SF (Cargill chow) during 1 h, and then sc: 1.1 ml saline; 2. diclofenac (Di); 3. indomethacine (Indo); 4. Ketorolac (Ke); 5. meloxicam (Mel); 6. Pyroxicam (P); 7. tenoxicam (T). The dose for the aforementioned drugs was 60 mg/kg; 8. aceclofenac (Ace); 9. 200 mg/kg nimesulide (Ni); 10. mefenamic acid (Mac); 11. aspirin (A); 12. etodolac (E); 13. ibuprophen (Ibu); 14. nabumetone (Na); 15. naproxene (Nap); 16. ketoprophen (Ket); 17. paracetamol (Pa), 500 mg/kg. II. The drugs where administered by orogastric tubing to the same groups of fasting animals. After 24 h the animals were killed by ether overdose. Laparotomy was performed and the stomach and the small intestine was removed. The percentage of antum ulcer, and fundic and intestinal erosion (mm2) was tabulated by planimetry. Blood and histological samples were obtained., Results: The NSAIDs Indo, Ibu, Ke, Ket, P and Te yielded an antrum ulcer area: 5-29% and intestinal erosion, 101-395 mm2, similar to Indo (p > 0.50). In contrast there were neither ulcers nor intestinal erosions with Mac, A, Di, E and Nap (p > 0.50). While there were absence of ulcers with Ace, Me, Na, Ni and Pa and slight intestinal erosion (0-23 mm2; p < 0.01). II. There were differences in the following oral (NAIDs: Ace, Me, NA, Ni and Pa, yielding 0-5% fundic erosion and 0-22 mm2 intestinal erosion (p < 0.001). The other NSADs yielded 33-90% fundic erosion and 116-550 mm2 intestinal erosion, similarly to Indo (p > 0.50)., Histology: Leukocyte infiltrate in the gastrointestinal mucosa with all the NSADs, except Ibu and Pa. There was also neutrophilia (5000-20,000), but not with Ibu and Pa (700-1200)., Conclusions: COX-2-COX-1 selectivity was demonstrated "in vivo" in aceclofenac, meloxicam, nabumetone, nimesulide and paracetamol.

In groups of female Wistar rats, someted to stress by immobilization and immersion in 18 degrees C water during 6 hrs, the role of nitric oxide (NO) in its pathophysiologic was studied. Agonist and antagonist of the isoforms Constitutive NO Synthase (cNOS) and of the inducible NO Synthase (iNOS) were used. Was found that the overdose of L-arginine aggravated of stress acute gastric lesions. The agonist of iNOS the NMDA and the antagonists dexamethasone and aminoguanidine were used. The NMDA aggravated the stress acute gastric lesions; in contrast, dexamethasone and aminoguanidine given a evident protection of the gastric mucosa in stress. Was concluded that the production of NO given by iNOS, play a role important in the pathophysiologic in stress acute gastric lesions.

Objective: To verify wether a cytoprotective or a antisecretant drug is effective on stress acute gastric., Method: Female Wistar rats (n=7), 200 g, 24 h fasted, water ad lib. were used. Experiment I. Stress (s) by immobilization and immersion in 181/3 C water, 6 h (control). 30 min pretreatment with 2 ml 800 mg/Kg in OG bolus Sucralfate. 800 mg/Kg OG Magaldrate. 800 mg/Kg OG AIMgOH. 800 mg/Kg OH Hydrotalcite. 100 aeg/Kg OG Misoprostol (antisecretant). 125 mg/Kg s.c. Somatostatine (Octeotride). 30 mg/Kg i.p. Ranitidine. 30 mg/Kg i.p. Omeprazole and 30 mg/Kg i.p. Lanzoprazole. The rats were sacrificed by ether overdose, and laparotomy was performed to remove stomach and to assess the percentage gastric lesional area by computerized planimetry and histological examination. Experiment II. With the same scheme above described and previous anesthesia, laparatomy and pylorus ligature, the acid gastric secretion was studied. Results Exp. I. Percentage of gastric lesional area: C: 80.5 +/- 5.1; Sucralfate: 25.6 +/- 4.1 (p < 0.05). Magaldrate: 51.6 +/- 7.1 (NS). AIMgOH 78.6 +/- 7.1. Hydrotalcite; 85.6 +/- 5.1. Misoprostol (cytoprotector) 59.5 +/- 6.1 (NS). Misoprostol (antisecretant) 1 +/- 0.1 (p < 0.001). Somatostatine: 20.3 +/- 5.1 (p < 0.01). Ranitidine: 46.5 +/- 7.8 (NS). Omeprazole: 1 +/- 0.1 and Lanzoprazole: 1 +/- 0.1 (p < 0.001). Histological examination demonstrated gastric cytoprotection in the groups pretreated with Omeprazole and Lanzoprazole. Exp. II. 6 h m/Mol HCl output: C: 0.22 +/- 0.09. Sucralfate: 0.2 +2- 0.07 (NS). Magaldrate: 0.19 +/- 0.08. AIMgOH: 0.18 +/- 0.07. Hydrotalcite: 0.19 +/- +/- 0.10. Misoprostol (cytoprotector): 0.23 +/- 0.07. Misoprostol (anti-secretor): 0.11 +2- 0.05 (p < 0.05). Somatostatin: 0.09 +/- 0.04. Ranitidine: 0.08 +/- 0.05. Omeprazole: 0.02 +/- 0.01 (p < 0.001) and Lanzoprazole: 0.02 +/- 0.01., Conclusion: In the prevention of stress acute gastric lesions Sucralfate might be indicated as a partial cytoprotector and Omeprazole or Lanzoprazole as antisecretant and lesion preventive drugs.

The effect of Molsidomine as a gastric mucosa protector against absolute ethanol was studied in Wistar rats. It was found that Molsidomine provided an important gastric cytoprotection and it behaved in a similar way as the nitric oxide (NO), the latter verified by specific NO antagonist, namely the NG-monomethyl-L arginine. It was also demonstrated that the cytoprotector mechanism of Molsidomine, as well as of other nitroderivates was sulfhydryl and HEM dependent regarding the guanylate-cyclase enzyme. It can be concluded that both Molsidomine and the NO behaved as modulator of the gastric microcirculation, venous and arterial vasodilator and that their gastric cytoprotective mechanism was endogenous prostaglandin dependent.

The role of sucralphate in prevention of acute gastric injuries and its comparison with free radical blockers such as allopurinol, soybean trypsin inhibitor and superoxidase dismutase in the ischemia-reperfusion model by total occlusion of the coeliac artery in Wistar rats, was studied. The gross gastric mucosal necrotic area was 80%. In contrast with the antioxidant drugs the necrotic area attained was between 7 to 15%, while with sucralphate, an antioxidant-cytoprotective drug that enhances the gastric defensive barrier, the prevention of the secondary aggression induced by free radicals was more important.

In Wistar rats, four experiments were carried out, studying specific inhibitors for ACE (angiotensin-converting enzyme), such as captopril, enalapril, lisinopril, ramipril and cilazapril, in presence of 20% and 95% ethanol induced gastric lesions. The effect of lisinopril and angiotensin I on the same injury was also studied. Subsequently, drugs with known role in gastric mucosa cytoprotection, such as enprostil, paracetamol, ketotiphen, levamisole, diazepam, bromocriptine, dopamine and clonidine, before and after absolute ethanol gastric injury were also studied. Finally, to examine the potential role of ACE in gastric cytoprotection, pretreatment with enalapril, followed by cytoprotective drugs, was carried out. We conclude that all ACE blockers aggravate the gastric lesion induced by 20% and 95% ethanol and are similar to the findings with angiotensin I. The gastric ACE probably plays an important role in the gastric mucosa defense. On the other hand, gastric ACE, as a physiologic regulator of microcirculation, acts by a double mechanism. a) converting the vasopressor amine, angiotensin I in angiotensin II. b) activating vasoactive peripheric receptors such as DA 2 dopaminergic and alfa 2 adrenoreceptors.

The role of Sucralfate in prevention of acute gastric injuries and its comparison with free radicals blockers as Allopurinol, Soybean Trypsin Inhibitor and Superoxide Dismutase was studied in the ischemia-reperfusion model by total occlusion of the celiac axis in Wistar rats. In control rats, the gross gastric mucosal necrotic area was of 80%; in contrast, the antioxidant drugs resulted in a necrotic area of 7%-15% and Sucralfate resulted in a necrotic area of only a 4%. It was concluded that Sucralfate, as antioxidant-cytoprotective drug, by enhancing the gastric defensive barrier was more important than the secondary aggression induced by free radicals.

Six percent hydrogen peroxide (H2O2) was used as a generator of the *OH free radical, and as an aggressor of gastric mucosa, in 100 Wistar rats. The mucosal cytoprotector effect of sucralfate, misoprostol, enprostil, cimetidine, ranitidine, famotidine and 10% aluminum sulphate yielded almost complete macroscopic and histological protection to the gastric mucosa. Misoprostol or enprostil gave partial protection whereas the H2 blockers aggravated the gastric necrotic lesions produced by the H2O2. We conclude that sucralfate is a true anti-oxidant that protects the gastric mucosa through its aluminum and sulphydril components, the increment of gastric mucins and endogenous PGs.

The unknown mechanism of adaptative gastric cytoprotection (AGC) induced by 20% ethanol and subsequent injury with 70% ethanol was studied in wistar rats. Pretreatment with indomethacin or HgII2 did not prevent the AGC, there suggesting that neither endogenous PGS nor gastric mucus take part in its mechanism. On the other hand, ranitidine pretreatment blocked and even aggravated the damage induced by ethanol-ethanol. In contrast, the latter phenomenon was reverted by 20% acidified ethanol. It is concluded that a back diffusion of H+ and bicarbonate play important roles in the AGC mechanism.

In groups of white Wistar rats, the cytoprotective effect induced by TDB on the gastric mucosa against the ethanol injury, was studied; where macroscopic protection and histologic cytoprotection in gastric corpus was found, and no in antrum mucosa. The cytoprotective mechanism give by TDB, were studied by the test of Indomethacin, Cl2Hg, Domperidone, Chlorpromazine and Acetazolamide, where each drug was given as pretreatment. Was conclude that TDB give gastric cytoprotection by the mechanism of the nonprotein sulfhydryl, by to be one peripheral agonist of the neuronal dopamine receptors, by increase of endogenous prostaglandin, by little increment of cAMP and no participate the gastric bicarbonate secretion.

In Wistar rats, the acid factor, the peripheral dopaminergic mechanism and the role of Brunner gland (BG), in the prevention of the Cysteamine duodenal ulcer (CDU) were studied. It was found that Bromocriptine; a peripheral dopaminergic neuronal receptor agonist (DA2), produced prevention of the CDU and blocked of PAS depletion of the BG; in contrast, SCH23390, a peripheral dopaminergic vascular receptor antagonist (DA1), and SAMe, a peripheral and central antidopaminergic; induced aggravation of CDU and total depletion of the BG. In conclusion, the HCl factor, a peripheral dopaminergic mechanism and impaired Brunners gland secretion of PAS mucus, in the pathogenesis of the CDU was postulated.

The cytoprotective effects on the gastric mucosa of the Bromocriptine, a peripheral dopaminergic receptor agonist compared with Misoprostol against ethanol-induced injury were studied. Pretreatment with SCH 23390 (a DA1 receptor antagonist) and Domperidone (a DA2 receptor antagonist), showed that Misoprostol was peripheral dopaminergic receptor dependent in the gastric cytoprotective mechanism, and that Bromocriptine was a selective peripheral DA2 receptor agonist in the gastric cytoprotection mechanism; as well as, indomethacin pretreatment, showed that peripheral DA2 receptors were endogenous prostaglandin dependent. In conclusion, a prostaglandin-dopaminergic mechanism was postulated in gastric cytoprotection.