Theoretical analysis of the effects of counterions on the supramolecular arrangement of sulfamethoxazole.

Active pharmaceutical ingredients are formulated as the salt form, aiming to modulate their physicochemical properties. In this regard, the optimization and choice of the salt former have a strong influence on toxicity, therapeutic efficiency, and bioavailability. Sulfamethoxazole (SMZ) salts with Na+, Cl-, and Br- counterions influence in the supramolecular arrangement as well as in their thermodynamic and kinetic parameters. Herein, we analyzed the interactions of the Na+, Cl-, and Br- counterions on the supramolecular arrangement of the sulfamethoxazole salts by Hirshfeld surfaces, fingerprint plots, and theoretical methods-quantum theory of atoms in molecules and natural bond orbitals. Moreover, we evaluated their electronic structure by density functional theory using calculation of the frontier molecular orbitals. Molecular electrostatic potential maps were also obtained to predict the interactions of the counterions along crystalline arrangements. We observed that the structures of [SMZ]+ and [SMZ]- ions differ slightly from the SMZ. The chemical reactivity indices show that the SMZ is kinetically more stable than its respective ions, while its anion is more polarizable, and its cation has a higher global electrophilicity index. The molecular electrostatic potential maps show high charge density in the sulfonyl group (nucleophilic region) and the heterocyclic amino group (electrophilic region). Although the molecular skeleton is identical among the three SMZ species and the presence of different counterions in the formation of the crystalline structure of the salts results in supramolecular arrangements with different patterns of intermolecular interactions, despite being very similar in terms of intensities.

Evaluation of Gastroprotective Activity of Linoleic Acid on Gastric Ulcer in a Mice Model.

BACKGROUND: Gastric ulcer has been a major cause of morbidity and mortality worldwide, and it has been linked to factors such as nutritional deficiency, smoking, stress, and continuous intake of non-steroidal antiinflammatory drugs (NSAIDs). The search for new anti-ulcer therapeutic agents has been the subject of several studies. Recently, the gastroprotective effect of Celtis iguanaea has been reported, with linoleic acid (LA) responsible for many of the therapeutic effects of this medicinal plant. AIMS: This study aims to investigate the gastroprotective activity and the possible mechanisms in which LA may be involved through different experimental assays in mice. METHODS: The gastroprotective activity of LA was evaluated in the ulcer induced by indomethacin, HCl/EtOH, hypothermic-restraint stress and pyloric ligation. For the investigation of gastroprotective mechanisms, the quantification of the volume (mL), pH and total acidity of gastric secretion were considered. RESULTS: The oral administrations of 25 mg/kg, 50 mg/kg or 100 mg/kg of body weight of LA were capable of protecting the gastric mucosa against HCl/ethanol (10 mL/kg p.o.), and oral/intraduodenal treatment administrations of 50 mg/kg LA showed protection from ulcers induced by indomethacin, hypothermic-restraint stress and pyloric ligation. CONCLUSION: The results of this study show the gastroprotective role of LA in gastric mucosal damage induced by all assayed distresses. The observed gastroprotection possibly occurs due to the mediated increase of mucosal defensive factors.

Insights on a new sulfonamide chalcone with potential antineoplastic application.

Chalcones (E)-1,3-diphenyl-2-propene-1-ones, a class of biosynthetic precursor molecules of flavonoids, have a wide variety of biological applications. Besides the natural products, many synthetic derivatives and analogs became an object of continued interest in academia and industry. In this work, a synthesis and an extensive structural study were performed on a sulfonamide chalcone 1-Benzenesulfonyl-3-(4-bromobenzylidene)-2-(2-chlorophenyl)-2,3-dihydro-1H-quinolin-4-one with potential antineoplastic application. In addition, in silico experiments have shown that the sulfonamide chalcone fits well in the ligand-binding site of EGFR with seven µ-alkyl binding energy interactions on the ligand-binding site. Finally, the kinetic stability and the pharmacophoric analysis for EGFR indicated the necessary spatial characteristics for potential activity of sulfonamide chalcone as an antagonist.

Donor cell engineering with GSK3 inhibitor-loaded nanoparticles enhances engraftment after in utero transplantation.

Host cell competition is a major barrier to engraftment after in utero hematopoietic cell transplantation (IUHCT). Here we describe a cell-engineering strategy using glycogen synthase kinase-3 (GSK3) inhibitor-loaded nanoparticles conjugated to the surface of donor hematopoietic cells to enhance their proliferation kinetics and ability to compete against their fetal host equivalents. With this approach, we achieved remarkable levels of stable, long-term hematopoietic engraftment for up to 24 weeks post-IUHCT. We also show that the salutary effects of the nanoparticle-released GSK3 inhibitor are specific to donor progenitor/stem cells and achieved by a pseudoautocrine mechanism. These results establish that IUHCT of hematopoietic cells decorated with GSK3 inhibitor-loaded nanoparticles can produce therapeutic levels of long-term engraftment and could therefore allow single-step prenatal treatment of congenital hematological disorders.

The gastroprotective effect of Memora nodosa roots against experimental gastric ulcer in mice.

Memora nodosa is popularly known as "caroba" and widely found in the Cerrado regions of Brazil. In traditional medicine, the leaves and stems are used for the healing of external ulcer and the roots for abdominal pain. This study investigated the effect of ethanolic roots extract of Memora nodosa (EMN) on the gastric mucosa of mice. In the indomethacin induced gastric ulcer model, the treatments of the animals with EMN at doses of 100, 300 and 1000 mg/kg, p.o., markedly reduced the index of lesions. In the gastric ulcer models induced by ethanol and cold restraint-stress the previous treatment with EMN at dose of 300 mg/kg showed 69% and 43% of protection, respectively. Seven days after food-restriction, the animals treated with EMN (300 mg/kg p.o.) showed reduction in the index of lesion by 65% as compared to control group. The intraduodenal administration of EMN (300 mg/kg) did not alter the gastric acid secretion parameters. The treatment with EMN (300 mg/kg p.o.) did not alter glutathione levels (GSH), but showed an increase of adhered gastric mucus as compared to the control group with lesion. These results showed that EMN has gastroprotective activity probably due with an increase of adhered gastric mucus.

Antinociceptive and anti-inflammatory effects of Memora nodosa and allantoin in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: The leaves and stems bark of Memora nodosa (Silva Manso) Miers (Bignoniaceae) are used in Brazilian traditional medicine in the treatment of external ulcers and wounds; its roots are used to treat abdominal pain and scabies. AIM OF THE STUDY: Our aim was to evaluate the antinociceptive and anti-inflammatory activities of Memora nodosa roots ethanolic extract (EMN) and allantoin, a secondary metabolite isolated from this plant. MATERIALS AND METHODS: The EMN and allantoin antinociceptive activity were evaluated in mice using both chemical and heat-induced pain models such as acetic acid-induced writhing, formalin and tail-flick tests. In the formalin test, a pre-treatment with naloxone was used to verify an involvement of opioid receptor in the antinociceptive effect of EMN and allantoin. Pre-treatment with glibenclemide was used to verity an involvement of ATP-sensitive K(+)channel in the allantoin antinociceptive effect. EMN and allantoin anti-inflammatory activity were assessed by carrageenan-induced paw edema and pleurisy tests. RESULTS: The treatment with EMN (250, 500 and 1000mg/kg, p.o.) inhibit the acetic acid and formalin (both phases)-induced nociception. However, just at doses 500 and 1000mg/kg increased the latency time in tail-flick test. These results suggest the involvement of both peripheral and central antinociceptive mechanisms. The treatment with allantoin (40, 60 and 80mg/kg p.o.) produced a dose-dependent antinociceptive effect in both phases of formalin-induced nociception test; allantoin (60mg/kg) was not able to increase the latency time in tail flick-test. The pre-treatment with naloxone completely reversed the EMN (1000mg/kg) and allantoin (60mg/kg) effect in the first phase of formalin test; and glibenclamide reversed the allantoin effect. The administration of EMN (250, 500 and 1000mg/kg) and allantoin (60mg/kg) showed significant anti-inflammatory activity in the whole carrageenan-induced paw edema. Furthermore, EMN and allantoin reduced the leukocytes migration and pleural exudate to the pleural cavity. CONCLUSION: EMN have significant antinociceptive and anti-inflammatory effects, which appear to be, at least in part, due to the presence of allantoin. However, allantoin is not responsible for the EMN central antinociceptive activity. Allantoin has peripheral antinociceptive activity that involves the opioid receptor and ATP-sensitive K(+)channels. Opioid receptors are also involved in the EMN antinociceptive activity. These findings support the use of Memora nodosa in popular medicine and demonstrate that this plant has therapeutic potential for the development of antinociceptive and anti-inflammatory phytomedicines.

Involvement of monoaminergic systems in the antidepressant-like properties of Lafoensia pacari A. St. Hil.

ETHNOPHARMACOLOGICAL RELEVANCE: Lafoensia pacari A. St.-Hil. (Lythraceae), known popularly as "pacari" or "mangaba-brava" is popularly used in the state of Goiás, Brazil. The stem bark or leaves are used to treat cancer, gastric disorders, inflammation and as a tonic to treat loss of enthusiasm. AIM OF THE STUDY: Previous results suggest that the ethanol:water 7:3 extract of the stem bark of L. pacari (PEx) has antidepressant-like activity in male mice. Our aim was to perform the PEx׳s bioguided fractionation and evaluate the monoaminergic system involvement in the antidepressant effect as well as progress in the study of L. pacari mechanism of action. MATERIAL AND METHODS: Mice (30-35g) orally treated (24, 5 and 1h) with PEx (100, 300 or 1000mg/kg), chloroform (ChloF-70mg/kg), ethyl acetate (180mg/kg), n-butanol (370mg/kg) and aqueous (1g/kg) fractions were submitted to the forced swimming test. To assess the mechanism of action, different groups of mice were pretreated with p-chlorophenylalanine (PCPA-100mg/kg, 4 days, i.p.) and alpha-methyl-p-tyrosine (AMPT-100mg/kg, 4h, i.p.) to assess the involvement of serotoninergic and catecholaminergic systems in the ChloF effects, respectively. A putative in vitro inhibition of monoamine oxidase (MAO) activity as well as the ex vivo hippocampal brain-derived neurotrophic factor (BDNF) quantification were carried out. Phytochemical screening, spectroscopy and chromatography analysis were used for identification of compounds present in ChloF. RESULTS AND DISCUSSION: After the fractionation, the ChloF 70mg/kg was the most active fraction, reducing the immobility time by 22%. Pre-treatments with both PCPA and AMPT abolished the ChloF effects, suggesting that ChloF antidepressant-like effect is dependent on serotonergic and catecholaminergic systems. ChloF did not inhibited MAO-A or MAO-B activity, excluding this as possible mechanism of action. ChloF augmented hippocampal BDNF level, which could be accounted for its antidepressant-like effect. Phytochemical screening showed the presence of saponins, tannins, steroids and triterpene in the PEx, and the presence of triterpene and steroids in ChloF. The spectroscopy and chromatography analysis identified lupeol, ß-sitosterol and stigmasterol in ChloF. CONCLUSION: ChloF is the fraction that better retained the crude extract active constituents. ChloF presents antidepressant-like effect that involves both serotonergic and catecholaminergic systems without inhibiting MAO enzymatic activity; this fraction also increases the hippocampal BDNF levels.

Medicinal species with gastroprotective activity found in the Brazilian Cerrado.

Peptic and/or duodenal ulcers are characterized by diverse acute and chronic ulcerative lesions that commonly arise in any portion of the gastric mucosa that is exposed to the aggressive action of gastric acid. The pathophysiology of peptic ulcers has been attributed to an imbalance between aggressive and protective factors. In Brazil, medicinal plants are commonly used to treat this ailment. A country with great biodiversity, Brazil is considered a rich source of therapeutic products. There have been popular and pharmacological reports on the medicinal relevance of the Brazilian cerrado plant species, including Ananas ananassoides, Celtis iguanaea, Encholirium spectabile, Hymenaea stigonocarpa, Lafoensia pacari, Qualea grandiflora, Qualea parvifora, Mouriri pusa, Solanum lycocarpum, Solanum paniculatum, Serjania erecta, and Vochysia tucanorum, in the treatment of stomach disorders. The aim of the present review was to report on some of the Brazilian cerrado plants that are used in folk medicine because of their gastroprotective potential and to encourage novel studies in the search and preservation of plants with this therapeutic potential.

Congenital thickening and shortening of the round ligament of the liver causing gastric outlet obstruction.

This report describes a case of congenital thickening and shortening of the round ligament of the liver, a rare cause of gastric outlet obstruction. There are few published cases in the literature and these were generally diagnosed at a late stage and were mostly among adults. The patient underwent exploratory laparotomy, which showed gastric compression in the distal antrum, close to the pylorus, caused by the round ligament, which was shortened and thickened. The round ligament was suture ligated and divided, and the patient's symptoms resolved. Comments on this abnormality and its rarity are presented.

Sacral ratio and fecal continence in children with anorectal malformations.

OBJECTIVE: To evaluate the sacral ratio (SR) in patients with an anorectal malformation (ARM) and verify whether it has predictive value for fecal continence. PATIENT AND METHODS: From January 1990 to April 2002, 42 patients (aged 3-14 years) with an ARM and having already been operated on were reassessed and enrolled in the study. Patients with solid or paste-like stools but no soiling were deemed continent, those with similar stool and episodes of soiling partially continent, and those with no sphincter control, incontinent. The fecal continence was always analysed by the same observer. Sacral radiographic images were reviewed and the SR calculated from anteroposterior and images in the lateral position. All images were obtained before surgery and analysed by the same observer, while a third analysed the results. Results were considered statistically significant at P < 0.001. RESULTS: Seventeen patients were deemed continent, seven partially continent and 18 incontinent; there was no significant difference in SR among the three groups. When fecal continence was analysed in relation to changes in the findings on computed tomography of the lumbosacral spine, patients with sacral agenesis had a significantly higher frequency of fecal incontinence than the others, and all had a SR below 'normal'. CONCLUSION: Although the SR was different in patients with sacral agenesis it was no different in continent, partially continent or incontinent patients, and thus it is of no practical value in identifying patients likely to have fecal incontinence.

Tratamento cirúrgico do megacólon congênito pela técnica de Duhamel, utilizando-se pinças ou grampeador cirúrgico / Surgical treatment of Hirschsprung's disease by Duhamel's technique using surgical nippers or stapler

No período de setembro de 1981 a janeiro de 1998, 43 pacientes foram submetidos ao tratamento cirúrgico do megacólon congênito clássico (M.C.), 23.pacientes (53,5 por cento) e de segmento longo (M.L.), 20 pacientes (46,5 por cento), na Disciplina de Cirurgia Pediátrica da UNIFESP-EPM, sendo 30 do sexo masculino (69,7 por cento) e 13 do sexo feminino (30,3 por cento); 30 brancos (69,7 por cento) e 13 näo-brancos (30,3 por cento), com média etária de 44 meses no momento do abaixamento. O abaixamento de cólon ganglionar foi realizado pela técnica de Duhamel sendo que em 21 pacientes utilizou-se a técnica das pinças, grupo com pinças (G.P), e nos outros 22, utilizou-se grampeador cirúrgico, grupo com grampeador (G.Gr). Não houve mortalidade peri-operatória. Houve complicaçöes pós-operatórias graves em 6 pacientes (13,9 por cento), todos pertencentes ao G.P. (28,6 por cento). Nos pacientes do G.Gr, a média de internaçäo foi de 5,5 dias, ao passo que no G.P., 19,5 dias. Em 12 pacientes (27,9 por cento), houve a recidiva da sintomatologia de obstipaçäo e o manchar de roupas íntimas, devidos à presença de esporäo, sendo 8 do G.P (38.1 por cento). e 4 do G.Gr (18,2 por cento). Ocorreram estenoses da anastomose colorretal em 3 pacientes (6,97 por cento), sendo 2 do G.Gr. (9,1 por cento) e 1 do G.P. (4,8 por cento). Dada a menor permanência hospitalar, ausência de complicaçöes pós-operatórias e tendência à menor incidência de esporäo pós-operatório, acreditamos que o uso de grampeador cirúrgico resulta em nítida vantagem sobre a técnica das pinças.

Hamartoma mesenquimal hepatico no recem-nascido / Hepatic mesenchimal hamartoma in neonates

Objetivo: Abordar o diagnóstico e conduta em duas formas distintas de hamartoma mesenquimal hepático no período neonatal. Métodos: relato de 2 casos raros de hamartoma mesenquimal hepático (HMH) em recém-nascidos e revisäo de literatura (MEDLINE, LILACS). Resultados: Säo apresentados dois casos de recém-nascidos con grandes massas abdominais, um deles complicado por rotura e hmorragia durante manipulaçäo em exames, evoluindo para choque. A operaçäo de de urgência no caso 1 evidenciou enorme tumor cístico hepático roto com conteúdo sero-hemorrágico. Após ressecçäo da lesäo em cunha, no pós-operatório a criança evoluiu sem anormalidades. O exame anátomo-patológico e imuno-histoquímico do cisto demonstraram HMH. No caso 2, com suspeita de tumor hepático pelo ultrason pré-natal, a lesäo aumentou progressivamente,...