Monoamine oxidase inhibitory activity of 2-aryl-4H-chromen-4-ones.

A series of twenty 2-aryl-4H-chromen-4-one (flavones) derivatives (3a-3s) were synthesized and tested for hMAO inhibitory activity. Fifteen compounds (3a, 3c, 3e-3h, 3j-3p, 3r, 3s) were found to be selective towards MAO-B, while 3d was selective towards MAO-A, and 3b, 3i and 3q were non-selective. Experimental Selectivity Index for MAO-B ranges from 2.0 (3g, 3p) to 30.0 (3j). Compound 3j, which is carrying 3,4-di-OMeC6H3 groups at R position on the molecule, was found to be potent MAO-B inhibitor amongst the fifteen with Ki value for MAO-B of 0.16±0.01 µM comparable to that of standard drug, Selegiline (Ki for MAO-B is 0.16±0.01 µM). Compound 3j also appeared as the most selective MAO-B inhibitor according to its best selectivity index (30.0), which is comparable to that of Selegiline (SIMAO-B=35.0). Molecular docking and molecular dynamics simulation studies were carried out using Autodock-4.0 and Amber12 to understand the molecular level interaction and energy relation of MAO isoforms with selective inhibitors (3d and 3j). Simulation results are in good agreement with the experimental results. Leads identified may further be explored to develop potent isoform specific inhibitors of MAO.

The combined use of brachial artery flow-mediated dilatation and carotid artery intima-media thickness measurements may be a method to determine vasculogenic erectile dysfunction.

The aim of this study was to investigate the relationship between penile color Doppler sonography (CDS) findings and sonographic endothelial parameters in patients with erectile dysfunction (ED), including intima-media thickness (IMT) of common carotid arteries (CCA) and flow-mediated dilatation (FMD) of brachial artery. Fifty-six ED patients were included in the study. Penile CDS, IMT of CCA and FMD of brachial artery were performed in all patients. According to penile CDS findings, 27 (48%) patients had non-vasculogenic and 29 (52%) patients had vasculogenic ED. Among 29 patients, 17 (30%) patients had cavernous veno-occlusive disease (CVOD) and 12 (22%) patients had arterial/combined insufficiency (AI). Median (interquartile range) FMD values of non-vasculogenic ED, CVOD and AI were 12.50 (6.54)%, 12.82 (7.41)% and 6.25 (7.17)%, respectively. FMD was found to be impaired significantly in AI group when compared to the other groups. FMD values of CVOD group were lower when compared to non-vasculogenic group, but the difference was not statistically significant. IMT values of vasculogenic ED patients were higher than non-vasculogenic ED patients (P<0.05). Although IMT values were higher in AI group when compared to CVOD, the difference was not statistically significant. The combined use of IMT and FMD established the diagnosis of vasculogenic ED with 100% sensitivity and 59.2% specificity. The positive predictive value was 72%, negative predictive value 100% and accuracy 80%. The combined use of brachial artery FMD and carotid arteries IMT measurements may be suggested as an alternative method to evaluate vasculogenic ED.

Plasma and platelet serotonin levels in familial Mediterranean fever.

OBJECTIVE: Familial Mediterranean fever (FMF) is the most common auto-inflammatory syndrome with exaggerated acute phase and inflammatory response. After revealing the MEFV gene mutation with the finally disturbed end product pyrin, some of the mechanisms were explained. However it is still unknown what triggers or ends these periodical attacks. Moreover, the treatment of up to 30% of the patients, that are resistant to colchicine is still a problem. In this study we investigated the role of serotonin in colchicine-resistant FMF patients. METHODS: Twenty-four FMF patients (male/female: 15/9) and 32 age- and sex-matched healthy controls (male/female: 17/15) were included into the study. Patients were subdivided into two groups. Thirteen had FMF attacks despite regular colchicine (colchicine-resistant group), other 11 had disease under control with colchicine for at least 6-months. Sampling was done both during the attack and ten days after its cessation. Plasma and platelet serotonin levels and acute phase reactants were studied in patients and controls. RESULTS: Colchicine-resistant patients had plasma serotonin (5-HT) levels of 7.85 +/- 1.0 nmol/l during acute attacks which significantly reduced to the levels of 6.3 +/- 0.6 nmol/l (p < 0.001), after 10 days of acute attacks and these levels were significantly lower than those of attack-free patients' and controls' (10.7 +/- 0.2 nmol/l and 10.1 +/- 0.3 nmol/l, respectively). Platelet 5-HT level was 6.4 +/- 0.3 nmol/10(9) platelets during acute attack, and this level was increased to 9.8 +/- 0.5 nmol/10(9) platelets on the 2(nd) sampling, 10 days after the cessation of the acute attack (p < 0.001). They were both significantly higher than those of attack-free FMF patients (5.9 +/- 0.1 nmol/10(9) platelets) and healthy controls (5.7 +/- 0.3 nmol/10(9) platelets). There was a negative correlation between plasma and platelet 5-HT levels (r=-0.77, p < 0.001). CONCLUSION: Changes in plasma and platelet 5-HT levels may be related to the disturbances in 5-HT transport mechanisms or may also be attributed to the potential role of serotonin in the inflammatory cascade. Last but not least, serotonin may have a role in the pathogenesis of FMF.

Heterogeneity of damage between segments of rat liver after inflow-outflow obstruction.

BACKGROUND: Total vascular exclusion (TVE) causes warm liver ischemia. The complete explanation of the events during inflow and outflow obstruction of the liver during selective TVE has not yet been studied. The aim of this study was to investigate the liver injury caused by inflow-outflow obstruction in the rat liver. MATERIALS AND METHODS: Forty Wistar-Albino rats were divided into four groups. Liver inflow occlusion (groups A and C) or inflow-outflow occlusion (groups B and D) was applied for 30 minutes. Samples were collected at the end of the ischemia period. We examined oxidative injury in the liver tissue and liver histopathology. RESULTS: Oxidative stress and histopathologic alterations were more prominent with TVE application. Significant alterations were shown in hepatic superoxide dismutase, glutathione, and glutathione S-transferase levels. Central segments of the rat liver were affected significantly from inflow occlusion, whereas dome segments were significantly damaged from inflow-outflow occlusion. CONCLUSIONS: Inflow-outflow occlusion of the liver caused more tissue damage compared with inflow occlusion. The pattern of distribution of the damage due to TVE seemed different from other well-known ischemia-reperfusion injuries.

Monoamine oxidase inhibitory activities of the scorpion Mesobuthus gibbosus (Buthidae) venom peptides.

In the present study, crude venom of Mesobuthus gibbosus (Buthidae), a scorpion distributed all over Anatolia was isolated and purified by the Sephadex G-50 gel filtration and high pressure liquid chromatographic (HPLC) separation. Two of the five fractions (fractions 4 and 5) obtained from the Sephadex G-50 filtration and detected as lethal on mice and Musca domestica larvae in in vivo toxicity tests, were independently subjected to the HPLC separation. Only one of seven fractions (fraction 5.5*) obtained from the HPLC separation of the fraction 5 was found to be extremely lethal. Sodium dodecylsulfate polyacrylamide gel electrophoretic (SDS-PAGE) analysis of the crude venom and its chromatographic fractions demonstrated that crude venom consisted of peptides with molecular weights of 6500-210,000 Da. The neurotoxic fraction 5.5* appeared as a single band of 28,000 Da and two bands of 6200 and 22,000 Da in SDS-PAGE under non-reducing and reducing conditions, respectively, suggesting that it might consist of two chains attached by a disulfide bridge. Fractions 5 and 5.5* inhibited monoamine oxidase A (MAO-A) of rat liver reversibly and non-competitively, in a concentration-dependent manner. Fraction 5.5* appeared as a potent and specific MAO-A inhibitor with a Ki value of 0.12 mg venom proteinml(-1). The inhibitory effect of venom peptide 5.5* on MAO-A was found to be dependent on the preincubation time suggesting that the peptide binds to some site other than the substrate-binding site. Results of the present study demonstrated that M. gibbosus venom contains a peptide with specific MAO-A inhibitory activity which may be responsible for the anxiogenic effects of the scorpion venoms on animals and humans.

Evaluation of liver damage after application of TVE in the rat model.

INTRODUCTION: The aim of this study was to investigate the effects of total vascular exclusion (TVE) on the liver during the early period of reperfusion. MATERIALS AND METHODS: Forty Wistar-Albino rats were divided into four groups. Portal pedicle clamping (groups 1 and 2) or TVE (groups 3 and 4) were applied for 10 minutes. Samples were collected at the time of clamp release (groups 1 and 3) and at 30 minutes of reperfusion (groups 2 and 4). We examined oxidative injury to and histopathology of the liver. RESULTS: Oxidative stress was more prominent with TVE application. Significant alterations were shown in hepatic superoxide dismutase, catalase, glutathione, and glutathione S-transferase levels. The levels of malondialdehyde and myeloperoxidase were not altered significantly. CONCLUSION: Inflow-outflow occlusion of the liver causes more oxidative stress compared with inflow occlusion.

Mixed-type inhibition of bovine lung angiotensin converting enzyme by lisinopril and its dansyl derivative.

The steady-state inhibition of bovine lung angiotensin converting enzyme (ACE; EC 3.4.15.1) by the slow-binding inhibitor lisinopril and its dansyl derivative conformed to a linear mixed inhibition model with inhibitor binding to ES as well as to E. Studied at pH8, 35 degrees, and using N-(3-[2-furyl]-acryloyl)phe-gly-gly as substrate, the approach to steady-state activity at different substrate concentrations pointed to slow isomerizations in both EI and EIS. While an inhibitory scheme involving a single I-binding site adequately accounts for the data presented, information relating to the primary structure of ACE brings up a two-site alternative which remains to be tested.

Serum angiotensin converting enzyme activity in pulmonary diseases: correlation with lung function parameters.

Serum angiotensin converting enzyme activity (ACE), plasma renin activity (PRA), blood pressure (BP), blood pH, blood gases and lung function parameters were measured in patients with emphysema, extrinsic and intrinsic asthma, malignant pulmonary neoplasms, active sarcoidosis and healthy adults. Serum ACE activity was significantly higher in sarcoidosis (250.22+/-34.18 U/L); in small cell carcinoma of lung (155.10+/-38.25 U/L); emphysema (149.82+/-18.31 U/L); extrinsic asthma (141.22+/-25.30 U/L) and lower in intrinsic asthma (98.12+/-15.11 U/L) and squamous cell carcinoma of lung (97.294+/-18.85 U/L) when compared with that of control subjects (108.20+/-13.15 U/L). PRA and BP values of the patients with sarcoidosis, emphysema and small cell carcinoma were markedly elevated and sACE activity was found to be correlated with PRA and mean BP in the same diagnostic groups. sACE activity, PRA and BP of smokers were higher than those of non-smokers in control subjects and in patients with emphysema, extrinsic asthma and small cell carcinoma of lung. Oxygen tensions of the patients with emphysema , extrinsic asthma and small cell carcinoma of lung were found to be significantly decreased. Negative correlations between the sACE activity and oxygen tension (r= -0.68) and between the sACE activity and lung function parameters (r= -0.69 ) were found in these diagnostic groups suggesting that increased sACE level might appeared as a response to chronic hypoxia in the patients with emphysema, extrinsic asthma and small cell carcinoma of lung.

Synthesis and monoamine oxidase inhibitory activities of some 3-(4-fluorophenyl)-5-aryl-n-substituted-4,5-dihydro-(1H)-pyrazole-1-carbothioamide derivatives.

28 new 3-(4-fluorophenyl)-5-aryl-N-substituted-4,5-dihydro-1H-pyrazole-1-carbothioamide derivatives were synthesized and evaluated in vitro for their monoamine oxidase (MAO) A and B inhibitory activity and selectivity. The derivatives substituted by halogen on the fifth position of pyrazole ring, inhibited MAO-A enzyme with a high selectivity index. On the other hand, compounds substituted with 2-naphthyl inhibited MAO-B enzyme with a moderate selectivity index. Docking studies were done to highlight the interactions of the most active derivative with the active site of MAO-A. In addition, in vivo antidepressant and anxiolytic activities of the compounds having selective MAO-A inhibitory effects, were investigated by using Porsolt forced swimming and elevated plus-maze tests respectively. 3-(4-Fluorophenyl)-5-(4-chloro-phenyl)-N-allyl-4,5-dihydro-1H-pyrazole-1-carbothio-amide has antidepressant, 3-(4-fluorophenyl)-5-(4-chlorophenyl)-N-methyl-4,5-dihydro-1H-pyrazole-1-carbothioamide and 3-(4-fluoro-phenyl)-5-(4-bromophenyl)-N-ethyl-4,5-dihydro-1H-pyrazole-1-carbothioamide have anxiolytic activity.

Monoamine oxidase inhibitory activity of 3,5-biaryl-4,5-dihydro-1H-pyrazole-1-carboxylate derivatives.

Ethyl and phenyl carbamate derivatives of pyrazoline (3a-3h) were synthesized and tested for their MAO inhibitory activity. All the compounds were found to be selective towards MAO-A. Phenyl carbamates (3e-3h) were better than ethyl carbamates (3a-3d) and displayed the best selectivity index. Compound 3f (KiMAO-A; 4.96 ± 0.21 nM) was found to be equally potent as that of standard drug, Moclobemide (KiMAO-A; 5.01 ± 0.13 nM) but with best selectivity index (8.86 × 10(-5)). Molecular docking studies with R &S conformer of 3f revealed S-enantiomer is better than R-enantiomer as reported earlier by other groups. It is proposed that VdW's radii of the substitution (bulkiness) in ring B determine the potency of phenyl carbamates.

Monoamine oxidase inhibitory activities of novel 3,4-dihydroquinolin-(1H)-2-one derivatives.

Three 3,4-dihydroquinoline-(1H)-2-one derivatives were synthesized and their monoamine oxidase (MAO) inhibitory activities were evaluated. The calculated IC(50) values revealed that compound Q (N-amino-3,4-dihydroquinoline-(1H)-2-one), which carries a free amine group in the molecule, inhibited rat liver MAO-B competitively and reversibly suggesting that this relatively small compound may interact with the active site channel of the enzyme while the compounds QB (1-(benzlyden-amino)-3,4-dihydroquinoline-(1H)-2-one), PCN (2-(3-cyano-2-oxo-4-phenyl-2H-quinolin-1-yl-N-cyclohexyl-2-(4'-chlorophenyl) acetamide) and MG (tert-butyl-N-[cyclohexylcarbamoyl-(3-hydroxyphenyl)methyl]-N-(2-benzoylphenyl)-carbamate) inhibited rat liver MAO-B non-competitively and irreversibly, suggesting that these compounds may interact with another hydrophobic binding region outside of the active site of the enzyme.

Interaction of rat lung SSAO with the novel 1-N-substituted thiocarbamoyl-3-substituted phenyl-5-(2-pyrolyl)-2-pyrazoline derivatives.

Interactions of twelve new synthesized 1-N-substituted thiocarbamoyl-3-substituted phenyl-5-pyrolyl-2-pyrazoline derivatives with rat lung semicarbazide-sensitive amine oxidase (SSAO) were assessed. Pyrazoline derivatives were synthesized according to previous methods and SSAO was purified from the crude microsomal fractions of rat lung.Three compounds (3e, 3f, 3k) with a p-methoxy group at the phenyl ring inhibited rat lung SSAO non-competitively and irreversibly, and showed higher affinity towards SSAO when expressed in terms of IC(50) for SSAO/Monoamine oxidase B (MAO-B). Since these novel pyrazoline derivatives have been found to act as suicide inhibitors of SSAO, the semicarbazide group in these molecules may be responsible for the SSAO inhibitory action. It is suggested that these compounds cannot enter the first small active site cavity of SSAO and may interact tightly with another binding site or with some other reactive groups present in the molecule. Compound 3e showed the highest inhibitory activity on rat lung SSAO. The novel pyrazoline derivatives may be used to discriminate between Cu- and FAD-containing amine oxidases and may have promising features as anti-Parkinson agents if the SSAO-inhibitory effects can be supported by in vivo studies.

Tumores pulmonares en pediatría / Pulmonary tumors in pediatrics

In patients under 15 years of age primary lung tumors are infrequent, most thoracic tumors being originated in the mediastinum or the thoracic wall. The great majority of pulmonary masses are non-neoplastic corresponding to inflammatory processes or malformations. Amongst neoplasms metastasis from solid extracraneal tumors are the predominant lesions. Other malignant neoplasms are: bronchial carcinoid, mucoepidermoid carcinoma, pulmonary lymphoma, pleuropulmonary blastoma and metastasis. In the spectrum of benign lesions the following are found: miofibroblastic inflammatory tumor, nodular lymphoid hyperplasia and hamartomas. The diagnosis of primary pulmonary neoplasms is frequently late because of its low incidence, lack of clinical suspicion and the variability of its manifestations. Radiological and tomographical signs are very proteiform and unspecific, representing a great diagnostic challenge.

En pacientes menores de 15 años los tumores pulmonares primarios son infrecuentes, generalmente los tumores torácicos son de origen mediastínico o de la pared torácica. La gran mayoría de las masas pulmonares son de origen no neoplásico, correspondiendo a procesos inflamatorios o malformaciones. Dentro de las neoplasias pulmonares, las metástasis de tumores sólidos extracraneanos son las lesiones predominantes. En el espectro de lesiones benignas se encuentran el tumor miofibroblástico inflamatorio, la hiperplasia nodular linfoidea, los síndromes linfoproliferativos y los hamartomas. Entre las neoplasias malignas se incluyen el tumor carcinoide bronquial, carcinoma mucoepidermoide, linfoma pulmonar, blastoma pleuropulmonar y las metástasis. El diagnóstico de las neoplasias primarias pulmonares frecuentemente es tardío, por su baja incidencia y la falta de sospecha clínica o por su presentación atípica. Los hallazgos radiológicos y tomográficos de los tumores pulmonares son muyproteiformes, según su estirpe y lugar de origen, y no son específicos en la mayoría de los casos, constituyendo habitualmente un gran desafo diagnóstico.