Nonlinear Refraction, Excited State Absorption, and Multiphoton Absorption of 1,3-Thiazolium-5-thiolate Mesoionic Compound.

We synthesized the mesoionic compound 2-(4-chlorophenyl)-3-methyl-4-(4-methylphenyl)-1,3-thiazole-5-thiolate and measured its refractive and absorptive nonlinear optical response in different temporal and spectral regimes. The experiments were performed by using the Z-scan technique with two pulsed light sources: the second harmonic (at 532 nm) of a mode-locked and Q-switched Nd-YAG laser (100 ps, 10 Hz) and a Ti: Sapphire laser system (100 fs, 1 kHz) operating at 800 nm. The observation and characterization of nonlinear refraction, two- and three-photon absorption, and excited state absorption of the mesoionic compound dissolved in dimethyl sulfoxide, in different concentrations, are presented and discussed with basis on the population redistribution in a three-energy-level model that allows the determination of the parameters which characterize the nonlinear response.

Effect of 2-chloro-N-(4-fluoro-3-nitrophenyl)acetamide in combination with antibacterial drugs against Klebsiella pneumoniae.

Klebsiella pneumoniae is a species of Gram-negative bacteria related to a wide range of infections and high rates of drug resistance. The combined use of antibacterial agents is one of the strategies that has been analyzed in recent years as part of the alternatives in the treatment of drug-resistant infections. Recently, the antibacterial activity of of 2-chloro-N-(4-fluoro-3-nitrophenyl)acetamide has been demonstrated against K. pneumoniae, also indicating that this acetamide did not show significant cytotoxic potential in preliminary tests. Thus, it becomes an interesting substance for future studies that explore its antimicrobial capacity, including investigating its association with antibacterial drugs. Based on this, this research aimed to analyze the effects of the association of 2-chloro-N-(4-fluoro-3-nitrophenyl)acetamide (CFA) with ciprofloxacin, cefepime, ceftazidime, meropenem and imipenem against K. pneumoniae strains. The results showed additivity when the substance was combined with ciprofloxacin and cefepime, indifference when associated with ceftazidime and synergistic effect when combined with meropenem and imipenem. Thus, the acetamide was able to optimize the effects of antibacterial drugs, reducing the concentrations necessary to cause bacterial death. These data indicate a potential future clinical use of these combinations, and further studies are needed to analyze this viability.

Antifungal activity of 2-chloro-N-phenylacetamide, docking and molecular dynamics studies against clinical isolates of Candida tropicalis and Candida parapsilosis.

AIMS: This study evaluated the antifungal, antibiofilm and molecular docking of 2-chloro-N-phenylacetamide against clinical isolates of Candida tropicalis and Candida parapsilosis. METHODS AND RESULTS: Minimum inhibitory concentration (MIC) of the test drugs was determined by microdilution. A1Cl obtained MIC values ranging from 16 and 256 µg/ml. Fluconazole MIC ranging from 16 and 512 µg/ml. MIC of A1Cl showed fungicide activity, emphasizing the solid antifungal potential of this drug. An association study was performed with A1Cl and fluconazole (checkerboard), revealing indifference by decreasing. Thus, we conducted this study using A1Cl isolated. In the micromorphological assay, the test drugs reduced the production of virulence structures compared to the control (concentration-dependent effect). A1Cl inhibited in vitro biofilm formation at all concentrations tested (1/4MIC to 8 × MIC) (p < 0.05) and reduced mature biofilm biomass (p < 0.05) against C. tropicalis and C. parapsilosis. In the ex vivo biofilm susceptibility testing (human nails fragments), A1Cl inhibited biofilm formation and reduced mature biofilm biomass (p < 0.05) more than 50% at MIC. Fluconazole had a similar effect at 4 × MIC. In silico studies suggest that the mechanism of antifungal activity of A1Cl involves the inhibition of the enzyme dihydrofolate reductase (DHFR) rather than geranylgeranyltransferase-I. CONCLUSIONS: The results suggest that A1Cl is a promising antifungal agent. Furthermore, this activity is related to attenuation of expression of virulence factors and antibiofilm effects against C. tropicalis and C. parapsilosis. SIGNIFICANCE AND IMPACT OF THE STUDY: Our study provides the first evidence that A1Cl, a novel synthetic drug, has fungicidal effects against C. tropicalis and C. parapsilosis. Furthermore, in vitro and ex vivo biofilms assays have demonstrated the potential antibiofilm of A1Cl. The mechanism of action involves inhibiting the enzyme DHFR, which was supported by in silico analyses. Therefore, this potential can be explored as a therapeutic alternative for onychomycosis and, at the same time, contribute to decreasing the resistance of clinical isolates of C. tropicalis and C. parapsilosis.

Cardiovascular characterization of the novel organic mononitrate NDIBP in rats.

Organic nitrates are widely used to restore endogenous nitric oxide (NO) levels reduced by endothelial nitric oxide synthase dysfunction. However, these drugs are associated with undesirable side effects, including tolerance. This study aims to investigate the cardiovascular effects of the new organic nitrate 1,3-diisobutoxypropan-2-yl nitrate (NDIBP). Specifically, we assessed its effects on blood pressure, vascular reactivity, acute toxicity, and the ability to induce tolerance. In vitro and ex vivo techniques showed that NDIBP released NO both in a cell-free system and in isolated mesenteric arteries preparations through a process catalyzed by xanthine oxidoreductase. NDIBP also evoked endothelium-independent vasorelaxation, which was significantly attenuated by 2-phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl 3-oxide (PTIO, 300 µM), a nitric oxide scavenger; 1-H-[1,2,4] oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ, 10 µM), a soluble guanylyl cyclase inhibitor; tetraethylammonium (TEA, 3 mM), a potassium channel blocker; febuxostat (500 nM), a xanthine oxidase inhibitor; and proadifen (10 µM), an inhibitor of cytochrome P450 enzyme. Furthermore, this organic nitrate did not induce tolerance in isolated vessels and presented low toxicity following acute oral administration. In vivo changes on cardiovascular parameters were assessed using normotensive and renovascular hypertensive rats. NDIBP evoked a reduction of blood pressure that was significantly higher in hypertensive animals. Our results suggest that NDIBP acts as a NO donor, inducing blood pressure reduction without having the undesirable effects of tolerance. Those effects seem to be mediated by activation of NO-sGC-cGMP pathway and positive modulation of K+ channels in vascular smooth muscle.

Antifungal activity and mechanism of action of 2-chloro-N -phenylacetamide: a new molecule with activity against strains of Aspergillus flavus.

Aspergillus genus causes many diseases, and the species Aspergillus flavus is highly virulent. Treatment of aspergillosis involves azole derivatives such as voriconazole and polyenes such as amphotericin B. Due to an increase in fungal resistance, treatments are now less effective; the search for new compounds with promising antifungal activity has gained importance. The aims of this study were to evaluate the effects of the synthetic amide 2-chloro-N-phenylacetamide (A1Cl) against strains of Aspergillus flavus and to elucidate its mechanism of action. Thus, the minimum inhibitory concentration, minimum fungicidal concentration, conidial germination, associations with antifungal agents, cell wall activities, membrane activities and molecular docking were evaluated. A1Cl presented antifungal activity against Aspergillus flavus strains with a minimum inhibitory concentration of between 16 and 256 µg/mL and a minimum fungicidal concentration between 32 and 512 µg/mL. The minimum inhibitory concentration of A1Cl also inhibited conidial germination, but when associated with amphotericin B and voriconazole, it promoted antagonistic effects. Binding to ergosterol on the fungal plasma membrane is the likely mechanism of action, along with possible inhibition of DNA synthesis through the inhibition of thymidylate synthase. It is concluded that the amide 2-chloro-N-phenylacetamide has promising antifungal potential.

The new organic nitrate 2-nitrate-1,3-diocthanoxypropan (NDOP) induces nitric oxide production and vasorelaxation via activation of inward-rectifier potassium channels (KIR).

INTRODUCTION: Cardiovascular diseases are coupled to decreased nitric oxide (NO) bioavailability, and there is a constant search for novel and better NO-donors. Here we synthesized and characterized the cardiovascular effects of the new organic nitrate 2-nitrate-1,3-dioctanoxypropan (NDOP). METHODS: A combination of in vitro and in vivo experiments was performed in C57BL/6 mice and Wistar rats. Thus, the ability of NDOP in donating NO in a cell-free system and in vascular smooth muscles cells (VSMC) and its ability to induce vasorelaxation in aortic rings from mice were evaluated. In addition, changes in blood pressure and heart rate to different doses of NDOP were evaluated in conscious rats. Finally, acute pre-clinical toxicity to oral administration of NDOP was assessed in mice. RESULTS: In cell-free system, NDOP increased NO levels, which was dependent on xanthine oxidoreductase (XOR). NDOP also increased NO levels in VSMC, which was not influenced by endothelial NO synthase. Furthermore, incubation with the XOR inhibitor febuxostat blunted the vasorelaxation in aortic ring preparations. In conscious rats, NDOP elicited dose-dependent reduction in blood pressure accompanied with increased heart rate. In vessel preparations, NDOP (10-8-10-3 mol/L) induced endothelium-independent vasorelaxation, which was inhibited by the NO scavengers 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide and hydroxocobalamin or by inhibition of soluble guanylyl cyclase using H- [1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one. To investigate if NDOP acts through potassium channels, selective blockers were used. Inhibition of BKCa, Kv or KATP subtypes of potassium channels had no effect, but inhibition of inward-rectifier potassium channels (KIR) significantly reduced NDOP-mediated vasorelaxation. Lastly, NDOP showed low toxicity (LD50 ~5000 mg/kg). CONCLUSION: Bioactivation of NDOP involves functional XOR, and this new organic nitrate elicits vasorelaxation via NO-cGMP-PKG signaling and activation of KIR channels. Future studies should further characterize the underlying mechanism and evaluate the therapeutic benefits of chronic NDOP treatment in relevant cardiovascular disease models.

Synthesis of New Cyclic Imides Derived from Safrole, Structure- and Ligand-based Approaches to Evaluate Potential New Multitarget Agents Against Species of Leishmania.

BACKGROUND: Leishmaniasis is a neglected disease that does not have adequate treatment. It affects around 12 million people around the world and is classified as a neglected disease by the World Health Organization. In this context, strategies to obtain new, more active and less toxic drugs should be stimulated. Sources of natural products combined with synthetic and chemoinformatic methodologies are strategies used to obtain molecules that are most likely to be effective against a specific disease. Computer-Aided Drug Design has become an indispensable tool in the pharmaceutical industry and academia in recent years and has been employed during various stages of the drug design process. OBJECTIVES: Perform structure- and ligand-based approaches, synthesize and characterize some compounds with materials available in our laboratories to verify the method's efficiency. METHODS: We created a database with 33 cyclic imides and evaluated their potential anti- Leishmanial activity (L. amazonensis and L. donovani) through ligand- and structure-based virtual screening. A diverse set selected from ChEMBL databanks of 818 structures (L. donovani) and 722 structures (L. amazonensis), with tested anti-Leishmanial activity against promastigotes forms, were classified according to pIC50 values to generate and validate a Random Forest model that shows higher statistical indices values. The structures of four different L. donovani enzymes were downloaded from the Protein Data Bank and the imides' structures were submitted to molecular docking. So, with available materials and technical feasibility of our laboratories, we have synthesized and characterized seven compounds through cyclization reactions between isosafrole and maleic anhydride followed by treatment with different amines to obtain new cyclic imides to evaluate their anti-Leishmanial activity. RESULTS: In silico study allowed us to suggest that the cyclic imides 516, 25, 31, 24, 32, 2, 3, 22 can be tested as potential multitarget molecules for leishmanial treatment, presenting activity probability against four strategic enzymes (Topoisomerase I, N-myristoyltransferase, cyclophilin and Oacetylserine sulfhydrylase). The compounds synthesized and tested presented pIC50 values less than 4.7 for Leishmania amazonensis. CONCLUSION: After combined approach evaluation, we have synthesized and characterized seven cyclic imides by IR, 1H NMR, 13C-APT NMR, COSY, HETCOR and HMBC. The compounds tested against promastigote forms of L. amazonensis presented pIC50 values less than 4.7, showing that our method was efficient in predicting true negative molecules.

The novel organic mononitrate NDHP attenuates hypertension and endothelial dysfunction in hypertensive rats.

RATIONALE: Development and progression of cardiovascular diseases, including hypertension, are often associated with impaired nitric oxide synthase (NOS) function and nitric oxide (NO) deficiency. Current treatment strategies to restore NO bioavailability with organic nitrates are hampered by undesirable side effects and development of tolerance. In this study, we evaluated NO release capability and cardiovascular effects of the newly synthesized organic nitrate 1, 3-bis (hexyloxy) propan-2-yl nitrate (NDHP). METHODS: A combination of in vitro and in vivo approaches was utilized to assess acute effects of NDHP on NO release, vascular reactivity and blood pressure. The therapeutic value of chronic NDHP treatment was assessed in an experimental model of angiotensin II-induced hypertension in combination with NOS inhibition. RESULTS: NDHP mediates NO formation in both cell-free system and small resistance arteries, a process which is catalyzed by xanthine oxidoreductase. NDHP-induced vasorelaxation is endothelium independent and mediated by NO release and modulation of potassium channels. Reduction of blood pressure following acute intravenous infusion of NDHP was more pronounced in hypertensive rats (two-kidney-one-clip model) than in normotensive sham-operated rats. Toxicological tests did not reveal any harmful effects following treatment with high doses of NDHP. Finally, chronic treatment with NDHP significantly attenuated the development of hypertension and endothelial dysfunction in rats with chronic NOS inhibition and angiotensin II infusion. CONCLUSION: Acute treatment with the novel organic nitrate NDHP increases NO formation, which is associated with vasorelaxation and a significant reduction of blood pressure in hypertensive animals. Chronic NDHP treatment attenuates the progression of hypertension and endothelial dysfunction, suggesting a potential for therapeutic applications in cardiovascular disease.

Synthesis and characterization of a novel organic nitrate NDHP: Role of xanthine oxidoreductase-mediated nitric oxide formation.

In this report, we describe the synthesis and characterization of 1,3-bis(hexyloxy)propan-2-yl nitrate (NDHP), a novel organic mono nitrate. Using purified xanthine oxidoreductase (XOR), chemiluminescence and electron paramagnetic resonance (EPR) spectroscopy, we found that XOR catalyzes nitric oxide (NO) generation from NDHP under anaerobic conditions, and that thiols are not involved or required in this process. Further mechanistic studies revealed that NDHP could be reduced to NO at both the FAD and the molybdenum sites of XOR, but that the FAD site required an unoccupied molybdenum site. Conversely, the molybdenum site was able to reduce NDHP independently of an active FAD site. Moreover, using isolated vessels in a myograph, we demonstrate that NDHP dilates pre-constricted mesenteric arteries from rats and mice. These effects were diminished when XOR was blocked using the selective inhibitor febuxostat. Finally, we demonstrate that NDHP, in contrast to glyceryl trinitrate (GTN), is not subject to development of tolerance in isolated mesenteric arteries.

Nitric oxide generation by the organic nitrate NDBP attenuates oxidative stress and angiotensin II-mediated hypertension.

BACKGROUND AND PURPOSE: NO deficiency and oxidative stress are crucially involved in the development or progression of cardiovascular disease, including hypertension and stroke. We have previously demonstrated that acute treatment with the newly discovered organic nitrate, 2-nitrate-1,3-dibuthoxypropan (NDBP), is associated with NO-like effects in the vasculature. This study aimed to further characterize the mechanism(s) and to elucidate the therapeutic potential in a model of hypertension and oxidative stress. EXPERIMENTAL APPROACH: A combination of ex vivo, in vitro and in vivo approaches was used to assess the effects of NDBP on vascular reactivity, NO release, NADPH oxidase activity and in a model of hypertension. KEY RESULTS: Ex vivo vascular studies demonstrated NDBP-mediated vasorelaxation in mesenteric resistance arteries, which was devoid of tolerance. In vitro studies using liver and kidney homogenates revealed dose-dependent and sustained NO generation by NDBP, which was attenuated by the xanthine oxidase inhibitor febuxostat. In addition, NDBP reduced NADPH oxidase activity in the liver and prevented angiotensin II-induced activation of NADPH oxidase in the kidney. In vivo studies showed that NDBP halted the progression of hypertension in mice with chronic angiotensin II infusion. This was associated with attenuated cardiac hypertrophy, and reduced NADPH oxidase-derived oxidative stress and fibrosis in the kidney and heart. CONCLUSION AND IMPLICATIONS: The novel organic nitrate NDBP halts the progression of angiotensin II-mediated hypertension. Mechanistically, our findings suggest that NDBP treatment is associated with sustained NO release and attenuated activity of NADPH oxidase, which to some extent requires functional xanthine oxidase.

The new nitric oxide donor cyclohexane nitrate induces vasorelaxation, hypotension, and antihypertensive effects via NO/cGMP/PKG pathway.

We investigated the cardiovascular effects induced by the nitric oxide donor Cyclohexane Nitrate (HEX). Vasodilatation, NO release and the effects of acute or sub-chronic treatment with HEX on cardiovascular parameters were evaluated. HEX induced endothelium-independent vasodilatation (Maximum effect [efficacy, ME] = 100.4 ± 4.1%; potency [pD2] = 5.1 ± 0.1). Relaxation was attenuated by scavenging nitric oxide (ME = 44.9 ± 9.4% vs. 100.4 ± 4.1%) or by inhibiting the soluble guanylyl cyclase (ME = 38.5 ± 9.7% vs. 100.4 ± 4.1%). In addition, pD2 was decreased after non-selective blockade of K(+) channels (pD2 = 3.6 ± 0.1 vs. 5.1 ± 0.1) or by inhibiting KATP channels (pD2 = 4.3 ± 0.1 vs. 5.1 ± 0.1). HEX increased NO levels in mesenteric arteries (33.2 ± 2.3 vs. 10.7 ± 0.2 au, p < 0.0001). Intravenous acute administration of HEX (1-20 mg/kg) induced hypotension and bradycardia in normotensive and hypertensive rats. Furthermore, starting at 6 weeks after the induction of 2K1C hypertension, oral treatment with the HEX (10 mg/Kg/day) for 7 days reduced blood pressure in hypertensive animals (134 ± 6 vs. 170 ± 4 mmHg, respectively). Our data demonstrate that HEX is a NO donor able to produce vasodilatation via NO/cGMP/PKG pathway and activation of the ATP-sensitive K(+) channels. Furthermore, HEX acutely reduces blood pressure and heart rate as well as produces antihypertensive effect in renovascular hypertensive rats.

Nitric oxide as a target for the hypotensive and vasorelaxing effects induced by (Z)-ethyl 12-nitrooxy-octadec-9-enoate in rats.

The cardiovascular effects induced by a new organic nitrate were investigated in rats. The (Z)-ethyl 12-nitrooxy-octadec-9-enoate (NCOE) was synthesized from ricinoleic acid, the major compound of the castor oil. NCOE induced significant and dose-dependent hypotension and bradycardia in normotensive rats. In rats pretreated with NCOE (60 mg/kg, i.v., once a day) for 4 consecutive days, hypotension induced by the nitrate was similar to that observed in rats that were not pretreated with the compound. The vasorelaxation induced by the compound was concentration-dependent (10(-10)-10(-3) M) in rat mesenteric artery rings, pre-contracted with phenylephrine (1 µM), with or without endothelium. Pre-incubation with PTIO (300 µM), a free radical form of NO (NO) scavenger, attenuated the NCOE vasorelaxation potency. However, in the presence of L-cysteine (3 mM), a reduced form of NO (NO-) scavenger, NCOE response was potentiated. NCOE effect was not changed in the presence of an inhibitor of cytochrome P450, proadifen (10 µM). On the other hand, the vasodilation was reduced in the presence of mitochondrial aldehyde dehydrogenase inhibitor (mtALDH), cyanamide (1 mM); soluble guanylyl cyclase inhibitor (sGC), ODQ (10 µM); and non-selective K+ channels blocker, TEA (3 mM). In addition the NCOE-induced vasorelaxation was reduced by BKCa (iberiotoxin, 100 nM) and KATP selective (glibenclamide, 10 µM) blockers, however the effect was not modified by a KV blocker (4-aminopyridine, 1 mM). Furthermore, NCOE increased NO levels in rat aortic smooth muscle cultured cells, detected by NO-sensitive probe DAF-2DA, by flow cytometry. These results together suggest that NCOE induces short-lasting hypotension and bradycardia, and promotes vasorelaxation due to NO release through the compound metabolism via mtALDH and consequent sGC, KATP and BKCa activation. Furthermore, the compound was not able to induce tolerance.

Synthesis and preliminary ex vivo evaluation of the spasmolytic activity of 1,3-thiazolium- and 1,3,4-thiadiazolium-5-methylthio- and 5-thioacetate derivatives.

Seven new compounds have been synthetized in satisfactory yields (51-78 %) through the treatment of mesoionic 1,3-thiazolium-5-thiolate (4a-d) and 1,3,4-thiadiazolium- 5-thiolate (10a,b) with chloroacetic acid or methyl iodide: 1,3,4-thiadiazolium-5-methylthio- (11) and 5-thioacetate (12). The structure of the title compounds was elucidated by elemental analysis, IR, (1)H and (13)C NMR spectroscopy. The newly synthesized compounds 5a, 6a, 11 and 12 were evaluated for their ex vivo spasmolytic potential on four isolated smooth muscles (rat aorta and uterus, guinea pig ileum and trachea) and compared with scopolamine. Some of the compounds exhibited potent spasmolytic activity equal to or stronger than scopolamine.

2-(5-Methyl-1,3,4-oxa-diazol-2-yl)phenyl acetate.

In the title compound, C11H10N2O3, which is a potential bioactive compound, the benzene and oxa-diazole rings are approximately coplanar, with an inter-ring dihedral angle of 4.14 (2)°, while the ester plane is rotated out of the benzene plane [dihedral angle = 82.69 (9)°]. In the crystal, the mol-ecules form layers down the a axis with weak π-π inter-actions between the oxa-diazole and benzene rings [minimum ring centroid separation = 3.7706 (14) Å].

The new nitric oxide donor 2-nitrate-1,3-dibuthoxypropan alters autonomic function in spontaneously hypertensive rats.

Previously, we found that the nitrate synthesized from glycerin, 2-nitrate-1,3-dibuthoxypropan (NDBP), increased NO levels in rat aortic smooth muscle cells, inducing vasorelaxation in mesenteric artery. However, its effects on blood pressure and heart rate as well as on autonomic function were not investigated. This study evaluated the action of NDBP on these cardiovascular parameters in spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats. We found that NDBP causes a biphasic response: hypotension and bradycardia followed by hypertension and tachycardia in WKY and SHR rats. Atropine (2mg/kg) blunted the hypotension induced by NDBP (15 mg/kg) in WKY and SHR (-75 ± 9 vs -12 ± 3 mmHg, n=6; -101 ± 6 vs -7 ± 2 bpm, n=6; respectively, p<0.05) and the pressor response to the compound was potentiated. Furthermore, vagotomy reduced the bradycardia in WKY and SHR (-136 ± 8 vs -17 ± 2, n=4, p<0.05; -141 ± 9 vs -8 ± 2, n=6, p<0.05). Moreover, hexamethonium (30 mg/kg) reduced both bradycardia (-278 ± 23 vs -48 ± 3 in WKY; -285 ± 16 vs -27 ± 19 in SHR, n=4; p<0.05) and pressor response (28 ± 8 vs -9 ± 5-WKY, n=6; 42 ± 7 vs -19 ± 8-SHR, n=5; p<0.05). In addition, administration of methylene blue (4 mg/kg) attenuated the hypotensive and bradycardic responses to the NDBP in all groups. In conclusion, NDBP induces bradycardia by direct vagal stimulation and pressor response by increasing sympathetic outflow to the periphery.

The 2-nitrate-1,3-dibuthoxypropan, a new nitric oxide donor, induces vasorelaxation in mesenteric arteries of the rat.

The reduced availability of nitric oxide (NO) is associated with cardiovascular diseases. Therefore, NO donors such as organic nitrates are useful for the treatment of these disorders. The 2-nitrate-1,3-dibuthoxypropan (NDBP) is an organic nitrate synthesized from glycerin, which the pharmacological effects have not been investigated. In this study we evaluated the vasorelaxant effect induced by NDBP in superior mesenteric artery from rats. In phenylephrine pre-contracted artery rings, NDBP (10(-8)-10(-4)M) elicited concentration-dependent and endothelium-independent relaxation, which were attenuated by hydroxocobalamin-HDX (30 µM), a NO extracellular scavenger, and 1-H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one-ODQ (10 µM), an inhibitor of soluble guanylyl cyclase (sGC). In addition, the NDBP-induced relaxation was reduced by non-selective K(+) channels blocker KCl (20 mM) or selective K(+) channels blockers such as tetraethylammonium-TEA (B(KCa), 1 mM), charybdotoxin-ChTX (B(KCa), 100 nM), glibenclamide (K(ATP), 1µM) and 4-aminopyridine-4-AP (K(V), 1mM). In preparations with ODQ (10 µM) plus TEA (1 mM), the response was virtually abolished. In rat smooth muscle cells culture, NDBP (10(-6)-10(-4)M) caused concentration-dependent increases in NO levels. These findings suggest that NDBP causes vasorelaxation through NO generation and activation of the sCG/cGMP/PKG pathway.

Bioactivities from marine algae of the genus Gracilaria.

Seaweeds are an important source of bioactive metabolites for the pharmaceutical industry in drug development. Many of these compounds are used to treat diseases like cancer, acquired immune-deficiency syndrome (AIDS), inflammation, pain, arthritis, as well as viral, bacterial, and fungal infections. This paper offers a survey of the literature for Gracilaria algae extracts with biological activity, and identifies avenues for future research. Nineteen species of this genus that were tested for antibacterial, antiviral, antifungal, antihypertensive, cytotoxic, spermicidal, embriotoxic, and anti-inflammatory activities are cited from the 121 references consulted.

Influência do local de nascimento e do transporte sobre a morbimortalidade de recém-nascidos prematuros / Effect of place of birth and transport on morbidity and mortality of preterm newborns

OBJETIVO: Verificar a influência do local de nascimento e do transporte sobre a morbimortalidade de recém-nascidos prematuros na Região Sul do Brasil. MÉTODOS: Estudo de coorte com recém-nascidos prematuros transferidos para a unidade de tratamento intensivo de referência (grupo transporte = 61), tendo sido acompanhados até a alta. Os dados sobre o atendimento no hospital de origem e transporte foram obtidos no momento da internação. Esse grupo foi comparado com neonatos da maternidade de referência, pareados por idade gestacional (grupo controle = 123), tendo como desfecho primário o óbito e desfechos secundários as alterações da glicemia, temperatura e saturação de oxigênio no momento da internação e a incidência de enterocolite necrosante, displasia broncopulmonar e sepses. Na associação entre as variáveis e o desfecho, foi utilizado o risco relativo. Foi adotado um nível de significância de α = 5 por cento e β = 90 por cento. RESULTADOS: A distância média percorrida foi de 91 km. A idade gestacional média foi de 34 semanas. Entre os recém-nascidos transferidos, 23 por cento (n = 14) não tiveram atendimento pediátrico na sala de parto. No transporte, 33 por cento dos recém-nascidos foram acompanhados por pediatra, e os equipamentos utilizados foram: incubadora (57 por cento), bomba de infusão (13 por cento), oxímetro (49 por cento) e aparelho para aferição da glicemia (21 por cento). O grupo transporte apresentou maior incidência de hiperglicemia, risco relativo (RR) = 3,2 (2,3-4,4), hipoglicemia, RR = 2,4 (1,4-4,0), hipertermia, RR = 2,5 (1,6-3,9), e hipoxemia, RR = 2,2 (1,6-3,0). Foram observados 18 por cento de óbitos no grupo dos transferidos e 8,9 por cento no grupo controle, RR = 2,0 (1,0-2,6). CONCLUSÕES: A pesquisa expõe deficiências no atendimento e transporte dos recém-nascidos, sendo necessária uma melhor organização do atendimento perinatal e do transporte na região nordeste do Rio Grande do Sul.

OBJECTIVE: To evaluate the effect of place of birth and transport on morbidity and mortality of preterm newborns in the southern region of Brazil. METHODS: This cohort study included preterm newborns transported to a reference intensive care unit (transport group = 61) and followed up until discharge. Data about care in hospital of origin and transport were obtained at admission. This group was compared with infants born in the maternity ward of the reference hospital paired according to gestational age (control group = 123). Primary outcome was death, and secondary outcomes were changes in blood glucose, temperature and oxygen saturation at admission and the incidence of necrotizing enterocolitis, bronchopulmonary dysplasia and sepsis. Relative risk (RR) was used to evaluate the association between variables and outcome. The level of significance was set at α = 5 percent and β = 90 percent. RESULTS: Mean travel distance was 91 km. Mean gestational age was 34 weeks. Of the neonates in the transport group, 23 percent (n = 14) did not receive pediatric care in the delivery room. During transportation, 33 percent of newborns were accompanied by a pediatrician, and the equipment available was: incubator (57 percent), infusion pump (13 percent), oximeter (49 percent) and device for blood glucose test (21 percent). The transport group had a greater incidence of hyperglycemia (RR = 3.2; 2.3-4.4), hypoglycemia (RR = 2.4; 1.4-4.0), hyperthermia (RR = 2.5; 1.6-3.9), and hypoxemia (RR = 2.2; 1.6-3.0). The percentage of deaths was 18 percent in the transport group and 8.9 percent in the control group (RR = 2.0; 1.0-2.6). CONCLUSIONS: This study revealed deficiencies in neonatal care and transport. Perinatal care and transport should be better organized in the northeastern region of Rio Grande do Sul, Brazil.

Effect of place of birth and transport on morbidity and mortality of preterm newborns.

OBJECTIVE: To evaluate the effect of place of birth and transport on morbidity and mortality of preterm newborns in the southern region of Brazil. METHODS: This cohort study included preterm newborns transported to a reference intensive care unit (transport group = 61) and followed up until discharge. Data about care in hospital of origin and transport were obtained at admission. This group was compared with infants born in the maternity ward of the reference hospital paired according to gestational age (control group = 123). Primary outcome was death, and secondary outcomes were changes in blood glucose, temperature and oxygen saturation at admission and the incidence of necrotizing enterocolitis, bronchopulmonary dysplasia and sepsis. Relative risk (RR) was used to evaluate the association between variables and outcome. The level of significance was set at α = 5% and ß = 90%. RESULTS: Mean travel distance was 91 km. Mean gestational age was 34 weeks. Of the neonates in the transport group, 23% (n = 14) did not receive pediatric care in the delivery room. During transportation, 33% of newborns were accompanied by a pediatrician, and the equipment available was: incubator (57%), infusion pump (13%), oximeter (49%) and device for blood glucose test (21%). The transport group had a greater incidence of hyperglycemia (RR = 3.2; 2.3-4.4), hypoglycemia (RR = 2.4; 1.4-4.0), hyperthermia (RR = 2.5; 1.6-3.9), and hypoxemia (RR = 2.2; 1.6-3.0). The percentage of deaths was 18% in the transport group and 8.9% in the control group (RR = 2.0; 1.0-2.6). CONCLUSIONS: This study revealed deficiencies in neonatal care and transport. Perinatal care and transport should be better organized in the northeastern region of Rio Grande do Sul, Brazil.

Prevalência de polinose em soldados do exército no sul do Brasil / Prevalence of pollinosis in Brazilian Army soldiers in southern Brazil

Objetivo: Estabelecer a prevalência de polinose (rinite sazonal), em soldados do Exército Brasileiro, em áreas com agricultura modificada pela introdução extensiva de Lolium multiflorum (Missões) e outra não-modificada (Pampa), localizadas no Estado do Rio Grande do Sul. Métodos: Utilizou-se o questionário escrito do International Study of Asthma and Allergies in Childhood modificado e previamente validado em Curitiba. A amostra foi de 3.028 militares do exército brasileiro; 1.392 pertenciam à região das Missões, e 1.636, à região do Pampa. A análise estatística para cálculo de prevalência foi limitada para residência (≥ 2 anos na região e permanência ≥ 4 dias na cidade/semana). Resultados: Presença de sintomas nasais e oculares nos últimos doze meses, com respostas afirmativas foram em Missões (31,4%; IC95%: 28,9-33,9) e Pampa (18,5%; IC95%: 16,6-20,5). Nos sintomas nasais em setembro, outubro e novembro (primavera), a frequência afirmativa foi, respectivamente, em Missões (20,8%, 12,2% e 5,8%) e Pampa (6,1%, 4,1% e4,2%). Responderam “sim” sobre a alergia ao pólen na primavera, em Missões (24,6%) e Pampa (11,2%). Conclusões: Os sintomas naso-oculares, associados à resposta afirmativa para alergia ao pólen na primavera, nos meses de setembro, outubro e novembro, permitem estabeleceruma prevalência de polinos e (21,6%; IC95%:19,1-24,3) em Missões e (3,2%; IC95%: 2,3-4,3) para a região do Pampa. A elevada prevalência de polinose encontrada em Missões poderia estar relacionada com a cultura atual extensiva de Lolium multiflorum.

Objective: To verify the prevalence of pollinosis (seasonal rhinitis) among Brazilian Army soldiers in an area with modified agriculture by introduction of Lolium multiflorum (Missões)compared to a non-modified environment (Pampa), both located in the state of Rio Grande do Sul Methods: The written questionnaire of the International Study of Asthma and Allergies in Childhood previously adapted and validated in Curitiba, was applied to a total of 3.028 soldiers, being 1.392 subjects living in the Missões region and 1.636 located at the Pampa region. Statistical analysis for prevalence was limited only to residents in those regions (≥ 2years living in the region and ≥ 4 days/week in the area). Results: The prevalence of nasal and ocular symptoms in the last 12 months was (31.4%: 95% CI: 28.9 – 33.9) in the Missões area versus (18.5%; 95% CI: 16,6 – 20,5) in the Pampa. Specifically, when the evaluation of nasal symptoms was limited to the spring season (September, October and November), positive responses were observed in (20.8%: 12.2%:5.8%) in the Missões region and (6.1%: 4:1%: 4,2%) in the Pampa. Regarding the presence of pollen allergy in the spring, 24.6% of all questionnaires described positive answers in Missões area compared to 11.2% in the Pampa region Conclusions: Positive answers regarding the presence of nasal and ocular symptoms associated with spring pollen allergy allow the definition of the pollinosis rates in the Missões area (21.6%; 95%CI: 19.1 – 24.3) and in Pampa (3.2%; 95%CI: 2.3 – 4.3). The higher prevalence of pollinosis found in Missões could be related to the current extensive cultivation of Lolium multiflorum.