Interaction of Some Amino-Nitrile Derivatives with Vascular Endothelial Growth Factor Receptor 1 (VEGFR1) Using a Theoretical Model.

BACKGROUND: Some studies indicate that the angiogenesis process is related to vascular endothelial growth factor, which can interact with endothelial cell surface receptors (VEGF-R1, VEGF-R2, and VEGF-R3); this biochemical process and other factors result in the promotion and growth of new blood vessels under normal conditions. However, some studies indicate that this phenomenon could also occur in cancer cells. It is important to mention that some amino derivatives have been prepared as VEGF-R1 inhibitors; however, their interaction with VEGF-R1 is not clear, perhaps due to different experimental approaches or differences in their chemical structure. OBJECTIVE: The aim of this study was to evaluate the theoretical interaction of several amino-nitrile derivatives (Compounds 1 to 38) with VEGF-R1. METHODS: The theoretical interaction of amino-nitrile derivatives with VEGF-R1 was carried out using the 3hng protein as the theoretical model. In addition, cabozantinib, pazopanib, regorafenib, and sorafenib were used as controls in the DockingServer program. RESULTS: The results showed different amino acid residues involved in the interaction of amino-nitrile derivatives with the 3hng protein surface compared with the controls. In addition, the inhibition constant (Ki) was lower for Compounds 10 and 34 than for cabozantinib. Other results show that Ki for Compounds 9, 10, 14, 27-29 and 34-36 was lower in comparison with pazopanib, regorafenib, and sorafenib. CONCLUSIONS: All theoretical data suggest that amino-nitrile derivatives could produce changes in the growth of some cancer cell lines through VEGFR-1 inhibition. Therefore, these amino-nitrile derivatives could be a therapeutic alternative to treat some types of cancer.

Evaluation of Biological Activity Exerted by Dibenzo[b,e]Thiophene-11(6H)-One on Left Ventricular Pressure Using an Isolated Rat Heart Model.

BACKGROUND: Some studies show that some Dibenzo derivatives can produce changes in the cardiovascular system; however, its molecular mechanism is not very clear. OBJECTIVE: The objective of this investigation was to evaluate the inotropic activity of ten Dibenzo derivatives (compounds 1 to 10) on either perfusion pressure or left ventricular pressure. METHODS: Biological activity produced by the Dibenzo derivatives on either perfusion pressure or coronary resistance was evaluated using an isolated rat heart. In addition, the molecular mechanism of biological activity produced by compound 4 (Dibenzo[b,e]thiophene-11(6H)-one) on left ventricular pressure was determined using both Bay-k8644 and nifedipine as pharmacological tools in an isolated rat heart model. RESULTS: The results showed that Dibenzo[b,e]thiophene-11(6H)-one increases perfusion pressure and coronary resistance at a dose of 0.001 nM. Besides, other data display that Dibenzo[b,e]thiophene-11(6H)-one increases left ventricular pressure in a dose-dependent manner (0.001 to 100 nM) and this effect was similar to biological activity produced by Bay-k8644 drug on left ventricular pressure. However, the effect exerted by Dibenzo[b,e]thiophene-11(6H)-one was inhibited in the presence of nifedipine at a dose of 1 nM. CONCLUSIONS: All these data suggest that Dibenzo[b,e]thiophene-11(6H)-one increase left ventricular pressure through calcium channel activation. In this way, Dibenzo[b,e]thiophene-11(6H)-one could be a good candidate as positive inotropic agent to heart failure.

Synthesis, Characterization, and Preliminary In Vitro Cytotoxic Evaluation of a Series of 2-Substituted Benzo [d] [1,3] Azoles.

A series of benzo [d] [1,3] azoles 2-substituted with benzyl- and allyl-sulfanyl groups were synthesized, and their cytotoxic activities were in vitro evaluated against a panel of six human cancer cell lines. The results showed that compounds BTA-1 and BMZ-2 have the best inhibitory effects, compound BMZ-2 being comparable in some cases with the reference drug tamoxifen and exhibiting a low cytotoxic effect against healthy cells. In silico molecular coupling studies at the tamoxifen binding site of ERα and GPER receptors revealed affinity and the possible mode of interaction of both compounds BTA-1 and BMZ-2.

Facile Synthesis of a Series of Non-Symmetric Thioethers Including a Benzothiazole Moiety and Their Use as Efficient In Vitro anti-Trypanosoma cruzi Agents.

A series of 2-benzylsulfanyl benzothiazole (BTA) derivatives were synthesized and fully characterized and in vitro tested against two strains of T. cruzi (NINOA and INC-5), exhibiting good activities at low concentrations.

Staphylococcus epidermidis lipoteichoic acid: exocellular release and ltaS gene expression in clinical and commensal isolates.

PURPOSE: Staphylococcus epidermidis ATCC12228 lipoteichoic acid (LTA) inhibits TNFα production from keratinocytes that are activated with poly I:C. However, this effect has not been proven in clinical or commensal isolates. METHODOLOGY: The <10 kDa fractions of S. epidermidis isolates from ocular infections (n=56), healthy skin (n=35) and healthy conjunctiva (n=32) were obtained. TNFα production was determined by elisa in HaCaT keratinocytes stimulated with poly I:C and with the <10 kDa fractions. LTA in the cytoplasmic membrane and in the <10 kDa fractions of the isolates was determined during bacterial growth by flow cytometry, Western blot and electrospray ionization mass spectrometry. The expression levels of ugtP, ltaA and ltaS were evaluated. RESULTS: Two populations of isolates were found: a population that inhibited TNFα production (TNFα-inhibitor isolates) and a population that did not inhibit it (TNFα non-inhibitor isolates). The cells from the TNFα-inhibitor isolates had less LTA in the cytoplasmic membrane compared to the cells from the TNFα non-inhibitor isolates (P<0.05). Similarly, LTA was detected in the supernatants of TNFα-inhibitor isolates, and it was absent in TNFα non-inhibitor isolates. High expression levels of the ugtP and ltaA genes in the 1850I (TNFα-inhibitor isolate) and 37HS (TNFα non-inhibitor isolate) isolates were found during bacterial growth. However, the ltaS gene had a low expression level (P<0.05) in the 37HS isolate. CONCLUSION: The TNFα-inhibitor isolates release LTA due to high expression of the LTA synthesis genes. By contrast, TNFα non-inhibitor isolates do not release LTA due to low expression level of the ltaS gene.

Design and synthesis of a new steroid-macrocyclic derivative with biological activity.

The aims of this study were to evaluate the positive inotropic effect of a new macrocyclic derivative (compound 11) and characterize the molecular mechanism involved in its biological activity. The first step was achieved by synthesis of a macrocyclic derivative involving a series of reactions for the preparation of several steroid derivatives such as (a) steroid-pyrimidinone (3 and 4), (b) steroid-amino (5), (c) steroid-imino (6), (d) ester-steroid (7 and 8), and (e) amido-steroid (9 and 10). Finally, 11 was prepared by removing the tert-butyldimethylsilane fragment of 10. The biological activity of compounds on perfusion pressure and vascular resistance was evaluated on isolated rat heart using the Langendorff model. The inotropic activity of 11 was evaluated in presence of prazosin, metoprolol, indomethacin, nifedipine, and flutamide to characterize its molecular mechanism. Theoretical experiments were carried out with a Docking model, to assess potential interactions of androgen receptor with 11. The results showed that only this macrocyclic derivative exerts changes on perfusion pressure and vascular resistance translated as the positive inotropic effect, and this effect was blocked with flutamide; these data indicate that the positive inotropic activity induced by this macrocyclic derivative was via androgen receptor activation. The theoretical results indicated that the interaction of the macrocyclic derivative with the androgen receptor involves several amino acid residues such as Leu704, Asn705, Met780, Cys784, Met749, Leu762, Phe764, Ser778, and Met787. In conclusion, all these data suggest that the positive inotropic activity of the macrocyclic derivative may depend on its chemical structure.

Experimental, Theoretical and Biological Activity of a Triazonine- Derivative on Left Ventricular Pressure.

BACKGROUND: There are data indicating that several azonine-derivatives may exert effects on some biological systems; however, there is very low information on the biological activity induced by these compounds on left ventricular pressure. OBJECTIVE: The aim of this study was to synthesize and evaluate the biological activity of new triazoninederivative on left ventricular pressure. MATERIAL AND METHODS: The first stage involved: 1) preparation of two azepine-benzamide derivatives (Z or E) by reaction of the nitrobenzoyl azide with adrenosterone; and 2) reaction of (Z)-azepine-benzamide derivative with ethylenediamine to form the triazonine derivative. The structure of compounds was confirmed by spectroscopy and spectrometry data. The second stage involved the biologic activity on left ventricular pressure was evaluated in a model of rat heart isolated. In addition, some physicochemical parameters were evaluated to characterize the possible molecules involved in its effect. RESULTS: The results showed that only the triazonine increased left ventricular pressure via androgen receptor. CONCLUSIONS: In conclusion, this phenomenon is conditioned by the functional groups involved in the chemical structure of triazonine derivative and their interaction with residues of amino acids involved on the androgen receptor surface.

Different sensitivity levels to norspermidine on biofilm formation in clinical and commensal Staphylococcus epidermidis strains.

Biofilm formation on medical and surgical devices is the main virulence factor of Staphylococcus epidermidis. A recent study has shown that norspermidine inhibits and disassembles the biofilm in the wild-type Bacillus subtilis NCBI3610 strain. In this study, the effect of norspermidine on S. epidermidis biofilm formation of clinical or commensal strains was tested. Biofilm producing strains of S. epidermidis were isolated from healthy skin (HS; n = 3), healthy conjunctiva (HC; n = 9) and ocular infection (OI; n = 19). All strains were treated with different concentrations of norspermidine, spermidine, putrescine, and cadaverine (1, 10, 25, 50 and 100 µM), and the biofilm formation was tested on microtiter plate. Besides, cell-free supernatants of S. epidermidis growth at 4 h and 40 h were analyzed by gas chromatography coupled to mass spectrometry (GC-MS) to detect norspermidine. Results showed that norspermidine at 25 µM and 100 µM prevented the biofilm formation in 45.16% (14/31) and 16.13% (5/31), respectively; only in one isolate from OI, norspermidine did not have effect. Other polyamines as spermidine, putrescine and cadaverine did not have effect on the biofilm formation of the strains tested. Norspermidine was also capable to disassemble a biofilm already formed. Norspermidine was detected in the 40 h cell-free supernatant of S. epidermidis by GC-MS. Norspermidine inhibited the biofilm development of S. epidermidis on the surface of contact lens. In this work, it was demonstrated that S. epidermidis produces and releases norspermidine causing an inhibitory effect on biofilm formation. Moreover, this is the first time showing that clinical S. epidermidis strains have different sensitivity to norspermidine, which suggest that the composition and structure of the biofilms is varied. We propose that norspermidine could potentially be used in the pre-treating of medical and surgical devices to inhibit the biofilm formation.

D-Amino acids inhibit biofilm formation in Staphylococcus epidermidis strains from ocular infections.

Biofilm formation on medical and surgical devices is a major virulence determinant for Staphylococcus epidermidis. The bacterium S. epidermidis is able to produce biofilms on biotic and abiotic surfaces and is the cause of ocular infection (OI). Recent studies have shown that d-amino acids inhibit and disrupt biofilm formation in the prototype strains Bacillus subtilis NCBI3610 and Staphylococcus aureus SCO1. The effect of d-amino acids on S. epidermidis biofilm formation has yet to be tested for clinical or commensal isolates. S. epidermidis strains isolated from healthy skin (n = 3), conjunctiva (n = 9) and OI (n = 19) were treated with d-Leu, d-Tyr, d-Pro, d-Phe, d-Met or d-Ala and tested for biofilm formation. The presence of d-amino acids during biofilm formation resulted in a variety of patterns. Some strains were sensitive to all amino acids tested, while others were sensitive to one or more, and one strain was resistant to all of them when added individually; in this way d-Met inhibited most of the strains (26/31), followed by d-Phe (21/31). Additionally, the use of d-Met inhibited biofilm formation on a contact lens. The use of l-isomers caused no defect in biofilm formation in all strains tested. In contrast, when biofilms were already formed d-Met, d-Phe and d-Pro were able to disrupt it. In summary, here we demonstrated the inhibitory effect of d-amino acids on biofilm formation in S. epidermidis. Moreover, we showed, for the first time, that S. epidermidis clinical strains have a different sensitivity to these compounds during biofilm formation.

Efecto inotrópico positivo ejercido por el derivado de brucina en un modelo de corazón aislado de rata / Inotropic effect exerted by the brucine derivativein an isolated rat heart mode / Efeito inotrópico exercida pelo derivado de brucinaem um modelo de corações isolados de ratos

Existen pocos datos con respecto a los efectos de la brucina y sus derivados en el aparato cardiovascular; además, el mecanismo molecular y su sitio de acción celular no son claros. Para proporcionar información adicional acerca de este fenómeno, en este trabajo fue evaluado el efecto inducido por un derivado de la brucina sobre la presión de perfusión, la resistencia vascular y la presión ventricular izquierda en corazón aislado de rata a flujo constante (modelo de Langendorff). Los resultados mostraron que; 1) el derivado brucina (1×10-9 mM) incrementa la presión de perfusión y la resistencia vascular en comparación con la brucina (1×10-9 mM) y las condiciones de control; 2) los efectos del derivado de brucina en dosis de 1×10-9 a 1×10-4 mM sobre la presión intraventricular no fueron inhibidos por metoprolol, prazosina o nifedipino a dosis de 1×10-6 mM; y 3) la furosemida a dosis de 1×10-6 mM bloquea los efectos ejercidos por el derivado de brucina (1×10-9 a 1×10-4 mM) sobre la presión intraventricular. En conclusión, la actividad ejercida por el derivado de brucina sobre la presión ventricular izquierda, involucra inhibición de la bomba Na+/K+-ATPasa, lo que trae indirectamente cambios en los niveles de calcio intracelular y subsecuentemente un efecto inotrópico positivo.

Few data exist with respect to the effects of brucine and its derivatives at a cardiovascular level; furthermore, the molecular mechanism and its site of cellular action are still unclear. In order to provide additional information about this phenomenon, the effect induced by a brucine derivative on perfusion pressure, vascular resistance and left ventricular pressure was evaluated in anisolated rat heart at constant flow (Langendorff model). The results showed that: 1) The brucine derivative [1×10-9 mM] increased perfusion pressure and vascular resistance in comparison with the brucine [1×10-9 mM] and the control conditions; 2) the effects of brucine derivative [1×10-9 to 1×10-4 mM] on intraventricular pressure were not inhibited by metoprolol, prazosin or nifedipine at a 1×10-6 mM dose; 3) furosemide [1×10-6 mM] blocked the effects exerted by the brucine derivative [1×10-9 a 1×10-4 mM] on intraventricular pressure. In conclusion, the activity exerted by the brucine derivative on perfusion pressure, vascular resistance and left ventricular pressure, involves inhibition of Na+/K+-ATPase, consequently resulting in indirect changes in intracellular calcium levels and subsequently inducing a positive inotropic effect.

Existem poucos dados no que diz respeito aos efeitos da brucina e seus derivados no nível cardiovascular; além disso, o mecanismo molecular e seu local de ação celular não são claros. Para fornecer informações adicionais sobre este fenômeno, neste trabalho foi avaliado o efeito induzido por um derivado de brucina sobre a pressão de perfusão, a resistência vascular e a pressão ventricular esquerda em coração isolado de ratos em fluxo constante (modelo Langendorff). Os resultados mostraram que: 1) o derivado brucina (1×10-9 mM) aumenta a pressão de perfusão e a resistência vascular em comparação com a brucina (1×10-9 mM) e as condições de controle; 2) os efeitos do derivado de brucina em doses de 1×10-9 a 1×10-4 mM sobre a pressão intraventricular não foram inibidos por metoprolol, prazosina ou nifedipino em doses de 1×10-6 mM; e 3) a furosemida, em doses de 1×10-6 mM, bloqueia os efeitos exercidos pelo derivado de brucina (1×10-9 a 1×10-4 mM) sobre a pressão intraventricular. Em conclusão, a atividade exercida pelo derivado de brucina sobre a pressão ventricular esquerda, envolve a inibição da bomba de Na+/K+-ATPase, o que indiretamente traz alterações nos níveis de cálcio intracelular e, subsequentemente, um efeito inotrópico positivo.

Efecto inotrópico positivo ejercido por el derivado de brucina en un modelo de corazón aislado de rata / Inotropic effect exerted by the brucine derivativein an isolated rat heart mode / Efeito inotrópico exercida pelo derivado de brucinaem um modelo de coraþ§es isolados de ratos

Existen pocos datos con respecto a los efectos de la brucina y sus derivados en el aparato cardiovascular; además, el mecanismo molecular y su sitio de acción celular no son claros. Para proporcionar información adicional acerca de este fenómeno, en este trabajo fue evaluado el efecto inducido por un derivado de la brucina sobre la presión de perfusión, la resistencia vascular y la presión ventricular izquierda en corazón aislado de rata a flujo constante (modelo de Langendorff). Los resultados mostraron que; 1) el derivado brucina (1Î10-9 mM) incrementa la presión de perfusión y la resistencia vascular en comparación con la brucina (1Î10-9 mM) y las condiciones de control; 2) los efectos del derivado de brucina en dosis de 1Î10-9 a 1Î10-4 mM sobre la presión intraventricular no fueron inhibidos por metoprolol, prazosina o nifedipino a dosis de 1Î10-6 mM; y 3) la furosemida a dosis de 1Î10-6 mM bloquea los efectos ejercidos por el derivado de brucina (1Î10-9 a 1Î10-4 mM) sobre la presión intraventricular. En conclusión, la actividad ejercida por el derivado de brucina sobre la presión ventricular izquierda, involucra inhibición de la bomba Na+/K+-ATPasa, lo que trae indirectamente cambios en los niveles de calcio intracelular y subsecuentemente un efecto inotrópico positivo.(AU)

Few data exist with respect to the effects of brucine and its derivatives at a cardiovascular level; furthermore, the molecular mechanism and its site of cellular action are still unclear. In order to provide additional information about this phenomenon, the effect induced by a brucine derivative on perfusion pressure, vascular resistance and left ventricular pressure was evaluated in anisolated rat heart at constant flow (Langendorff model). The results showed that: 1) The brucine derivative [1Î10-9 mM] increased perfusion pressure and vascular resistance in comparison with the brucine [1Î10-9 mM] and the control conditions; 2) the effects of brucine derivative [1Î10-9 to 1Î10-4 mM] on intraventricular pressure were not inhibited by metoprolol, prazosin or nifedipine at a 1Î10-6 mM dose; 3) furosemide [1Î10-6 mM] blocked the effects exerted by the brucine derivative [1Î10-9 a 1Î10-4 mM] on intraventricular pressure. In conclusion, the activity exerted by the brucine derivative on perfusion pressure, vascular resistance and left ventricular pressure, involves inhibition of Na+/K+-ATPase, consequently resulting in indirect changes in intracellular calcium levels and subsequently inducing a positive inotropic effect.(AU)

Existem poucos dados no que diz respeito aos efeitos da brucina e seus derivados no nível cardiovascular; além disso, o mecanismo molecular e seu local de aþÒo celular nÒo sÒo claros. Para fornecer informaþ§es adicionais sobre este fen¶meno, neste trabalho foi avaliado o efeito induzido por um derivado de brucina sobre a pressÒo de perfusÒo, a resistÛncia vascular e a pressÒo ventricular esquerda em coraþÒo isolado de ratos em fluxo constante (modelo Langendorff). Os resultados mostraram que: 1) o derivado brucina (1Î10-9 mM) aumenta a pressÒo de perfusÒo e a resistÛncia vascular em comparaþÒo com a brucina (1Î10-9 mM) e as condiþ§es de controle; 2) os efeitos do derivado de brucina em doses de 1Î10-9 a 1Î10-4 mM sobre a pressÒo intraventricular nÒo foram inibidos por metoprolol, prazosina ou nifedipino em doses de 1Î10-6 mM; e 3) a furosemida, em doses de 1Î10-6 mM, bloqueia os efeitos exercidos pelo derivado de brucina (1Î10-9 a 1Î10-4 mM) sobre a pressÒo intraventricular. Em conclusÒo, a atividade exercida pelo derivado de brucina sobre a pressÒo ventricular esquerda, envolve a inibiþÒo da bomba de Na+/K+-ATPase, o que indiretamente traz alteraþ§es nos níveis de cálcio intracelular e, subsequentemente, um efeito inotrópico positivo.(AU)

Effect of progesterone-carbachol derivative on perfusion pressure and coronary resistance in isolated rat heart: via activation of the M2 muscarinic receptor.

AIM: The present study was designed to investigate the effects of progesterone-carbachol derivative on perfusion pressure and coronary resistance in rats. An additional aim was to identify the molecular mechanisms involved. METHODS: The Langendorff model was used to measure perfusion pressure and coronary resistance changes in isolated rat heart after progesterone-carbachol derivative alone and after the following compounds; mifepristone (progesterone receptor blocker), yohimbine (α2 adreno-receptor antagonist), ICI 118,551 (selective ß2 receptor blocker), atropine (non-selective muscarinic receptor antagonist), methoctramine (antagonist of M2 receptor) and L-NAME (inhibitor of nitric oxide synthase). RESULTS: The results show that progesterone-carbachol derivative [10(-9) mM] significantly decreased perfusion pressure (P=0.005) and coronary resistance (P=0.006) in isolated rat heart. Additionally, the effect of progesterone-carbachol on perfusion pressure [10(-9) to 10(-4) mM] was only blocked in the presence of methoctramine and L-NAME. CONCLUSIONS: These data suggest that progesterone derivative exert its effect on perfusion pressure via activation of the M2 muscarinic. In addition, this phenomenon involves stimulation of nitric oxide synthase (NOS).

Glibenclamide-pregnenolone derivative has greater hypoglycemic effects and biodistribution than glibenclamide-OH in alloxan-rats.

AIM: The present study was designed to investigate the activity of two glibenclamide derivatives on glucose concentration. An additional aim was to identify the biodistribution of glibenclamide derivatives in different organs in a diabetic animal model. METHODS: The effects of two glibenclamide derivatives on glucose concentration were evaluated in a diabetic animal model. In addition, glibenclamide derivatives were bound to Tc-99m using radioimmunoassay methods. To evaluate the pharmacokinetics of the glibenclamide derivatives over time (15, 30, 45 and 60 min) the Tc-99m-glibenclamide conjugates were used. RESULTS: The results showed that glibenclamide-pregnenolone had greater hypoglycemic activity than glibenclamide or glibenclamide-OH. The data also showed that the biodistribution of Tc-99m-glibenclamide-OH in all organs was less than that of the Tc-99m-glibenclamide-pregnenolone derivative. CONCLUSIONS: The glibenclamide-pregnenolone derivative had greater hypoglycemic effects and its biodistribution was wider than glibenclamide-OH. The data suggest that the steroid nucleus may be important to the hypoglycemic activity of the glibenclamide-pregnenolone derivative and this could be related to the degree of lipophilicity induced by the steroid nucleus in the chemical structure of glibenclamide-pregnenolone.

[Inotropic activity induced by carbamazepine-alkyne derivative in an isolated heart model and perfused to constant flow]. / Actividad inotrópica inducida por el derivado carbamacepina-alquino en un modelo de corazón aislado y perfundido a flujo constante.

Inotropic activity induced by carbamazepine-alkyne derivative in an isolated heart model and perfused to constant flow Introduction. Few data exist with respect to the effects of carbamazepine and its derivatives at cardiovascular level; furthermore, the molecular mechanisms and cellular site of action are still unclear. Objective. The effects induced by carbamazepine-alquine derivative on perfusion pressure, vascular resistance and left ventricular pressure were evaluated. Materials and methods. The effects of carbamazepine and carbamazepine-alquine on the perfusion pressure, vascular resistance and left ventricular pressure were examined in isolated rat hearts (Langendorff model). Results. Four results were obtained: (1) The carbamazepine-alquine derivative 10-9 mM increased the perfusion pressure and vascular resistance in comparison with the carbamazepine 10-9 mM; (2) the effect of carbamazepine-alquine derivative 10-9-10-4 mM on left ventricular pressure not was inhibited by metoprolol or prazosin at a dose of 10-6 mM; (3) nifedipine 10-6 mM blocked the effects exerted by the carbamazepine-alquine derivative 10-9-10--4 mM on left ventricular pressure, and (4) the carbamazepine-alquine derivative at dose of 10-9 mM increased the concentration of intracellular calcium over a time period of 3-18 min; nevertheless, in presence of nifedipine 10-6 mM this effect was inhibited significantly (p=0.005). Conclusions. The activity exerted by carbamazepine-alquine derivative on perfusion pressure, vascular resistance and left ventricular pressure involved activation of calcium channel type-L, brought indirectly changes in the intracellular calcium levels and subsequently induced a positive inotropic effect.

Actividad inotrópica inducida por el derivado carbamacepina-alquino en un modelo de corazón aislado y perfundido a flujo constante / Inotropic activity induced by carbamazepine-alkyne derivative in an isolated heart model and perfused to constant flow

Introducción. Existen pocos datos con respecto a los efectos de la carbamacepina y sus derivados en el aparato cardiovascular; además, el mecanismo molecular y su sitio de acción celular no son claros. Objetivo. Evaluar los efectos inducidos por el derivado carbamacepina-alquino sobre la presión de perfusión, la resistencia vascular y la presión ventricular izquierda. Materiales y métodos. Los efectos de la carbamacepina y del derivado carbamacepina-alquino sobre la presión de perfusión, la resistencia vascular y la presión ventricular izquierda fueron evaluados en un modelo de corazón aislado de rata (Langendorff). Resultados. Se encontró que: 1) el derivado carbamacepina-alquino (1x10 -9 mM) incrementa la presión de perfusión y la resistencia vascular en comparación con la carbamacepina (1×10 -9 mM); 2) los efectos del derivado carbamacepina-alquino (1×10 -9 -1×10 -4 M) sobre la presión intraventricular no fueron inhibidos por metoprolol o prazosina (1×10 -6 mM); 3); el nifedipino (1×10 -6 mM) bloquea los efectos ejercidos por el derivado carbamacepina-alquino (1×10 -9 -1×10 -4 M) sobre la presión intraventricular, y 4) el efecto del derivado de carbamacepina (1×10 -9 mM) incrementa la concentración de calcio intracelular a través del tiempo (3 a 18 minutos); sin embargo, en presencia de nifedipino (1×10-6 mM), este efecto disminuye significativamente (p=0,005). Conclusiones. La actividad ejercida por el derivado carbamacepina-alquino sobre la presión de perfusión, la resistencia vascular y la presión intraventricular, involucra la activación del canal de calcio de tipo L, lo que trae como consecuencia indirecta cambios en los niveles de calcio intracelular y, subsecuentemente, induce un efecto inotrópico positivo.

Efectos del danazol y hemisuccinato de danazol sobre la presión de perfusión y resistencia vascular / Effects of danazol and danazol hemisuccinate on perfusión pressure and vascular resistance

Estudios clínicos y epidemiológicos sugieren que el danazol ha sido considerado como un factor de riesgo para desarrollar hipertensión. Para proporcionar información adicional acerca de este fenómeno, en este trabajo fue caracterizado el efecto inducido por el danazol y el hemisuccinato de danazol sobre la presión de perfusión y la resistencia vascular en corazón aislado de rata a flujo constante (modelo de Langendorff). Los resultados, mostraron que; 1) el hemisuccinato de danazol [10-9 M] incrementa la presión de perfusión en comparación con el danazol [10-9 M]; 2) los efectos del derivado de danazol [10-9 M - 10-4 M] sobre la presión de perfusión fueron inhibidos por flutamida [10-6 M]; 3) la nifedipina [10-6 M], bloqueó los efectos ejercidos por el hemisuccinato de danazol [10-9 M -10-4 M] sobre la presión de perfusión y 4) el efecto del derivado de danazol [10-9 M - 10-4 M] sobre la presión de perfusión en presencia del montelukast [10-6 M] fue inhibido significativamente (p=0,008). En conclusión, los efectos inducidos por el danazol y hemisuccinato de danazol sobre la presión de perfusión y la resistencia vascular podrían depender de su estructura química. Este fenómeno podría involucrar la interacción del receptor de andrógenos e indirectamente la activación de la síntesis de leucotrienos D4 (LTD4) y consecuentemente inducir variaciones en la presión de perfusión.

Epidemiological and clinical studies suggest that danazol has been considered a risk factor for hypertension development. In order to provide additional information about this phenomenon, the effect induced by both danazol and hemisuccinate of danazol on perfusion pressure and vascular resistance was characterized in isolated rat heart at constant flow (Langendorff model) and it was evaluated in this work.The results showed that; 1) hemisuccinate of danazol [10-9 M] increases perfusion pressure and vascular resistance in comparison with danazol [10-9 M]; 2) the effects of danazol-derivative [10-9 M - 10-4 M] on perfusion pressure were inhibited by flutamide [10-6 M]; 3) nifedipine [10-6 M] blockaded the effects exerted by hemisuccinate of danazol [10-9 M -10-4 M] on perfusion pressure; and 4) the effect of danazol-derivative [10-9 M - 10-4 M] on perfusion pressure in presence of montelukast [10-6 M] was significantly inhibited (p=0.008). In conclusion, the effects induced by both danazol and hemisuccinate of danazol on perfusion pressure and vascular resistance could depend on their chemical structure. This phenomenon could involve the interaction of androgene steroid-receptor and indirect activation of leukotriene D4 (LTD4) synthesis and consequently, induce variations in the perfusion pressure.

Efectos inducidos por Ruta graveolens L., Cnidoscolus chayamansa McVaugh y Citrus aurantium L. sobre los niveles de glucosa, colesterol y triacilglicéridos en un modelo de rata diabética / Efeitos induzidos por Ruta graveolens L., Rutaceae, Cnidoscolus chayamansa McVaugh, Euphorbiaceae, e Citrus aurantium L., Rutaceae, nos níveis de glucose, colesterol e triacilglicerídeos num modelo do rato diabético / Induced effects by Ruta graveolens L., Rutaceae, Cnidoscolus chayamansa McVaugh, Euphorbiaceae, and Citrus aurantium L., Rutaceae, on glucose, cholesterol and triacylglycerides levels in a diabetic rat model

Varias plantas con propiedades hipoglucemicas se han utilizado en medicina popular y sistemas curativos tradicionales en todo el mundo. El propósito de este trabajo fue evaluar los efectos inducidos por Ruta graveolens L., Rutaceae, Cnidoscolus chayamansa McVaugh, Euphorbiaceae, y Citrus aurantium L., Rutaceae, en un modelo de rata diabética, a la que se le cuantificaron los niveles de glucosa cada 24 horas por un mes después de la administración gástrica del extracto de las plantas. Además, el colesterol y los triglicéridos fueron evaluados usando técnicas enzimáticas. Los resultados mostraron que la administración de Cnidoscolus chayamansa a dosis de 0.5 a 1.5 g/kg induce un aumento hipoglucemico (< 200 mg/dL). Otros datos indican que Cnidoscolus chayamansa ejerce variaciones en los niveles de triacilglicéridos (80-90 mg/dL) y colesterol (88-96 mg/dL). Sin embargo, la administración de Citrus aurantium en las mismas dosis no fue suficiente para disminuir los niveles de glucosa (> 200 mg/dL). Otros resultados, mostraron que Citrus aurantium ejerce cambios en la concentración de triacilglicéridos (158-172 mg/dL) y colesterol (120-128 mg/dL). Finalmente, la administración de Ruta graveolens a dosis de 0.5 g/kg induce un efecto hipoglucemico (< 200 mg/dL). Además, Ruta graveolens a dosis de 0.5 a 1.5 g/kg induce variaciones en los niveles de triacilglicéridos (110-120 mg/dL) y colesterol (116-124 mg/dL). En conclusión la administración de Cnidoscolus chayamansa ejerce efectos hipoglucemicos en una manera dosis dependiente en comparación con Ruta graveolens y Citrus aurantium. Además, las plantas evaluadas inducen cambios en los niveles de lípidos dependiente de la dosis.

Diversas plantas com propriedades hipoglicêmicas foram usadas na medicina popular e em sistemas tradicionais de curas em torno do mundo. A finalidade deste trabalho foi avaliar os efeitos induzidos por Ruta graveolens L, Rutaceae, Cnidoscolus chayamansa McVaugh, Euphorbiaceae, e Citrus aurantium L., Rutaceae, em modelo do rato diabético onde níveis da glucose foram determinados a cada 24 h em um mês antes da administração gástrica do extrato das plantas. Colesterol e triacilglicerídeos foram avaliados usando técnicas enzimáticas. Os resultados mostraram que a administração de Cnidoscolus chayamansa a dose de 0,5 a 1,5 g/kg induz um aumento hipoglicêmico (< 200 mg/dL). Outros dados indicam que Cnidoscolus chayamansa exerce variações nos níveis de triacilglicerídeos (80-90 mg/dL) e colesterol (88-96 mg/dL). A administração de Citrus aurantium nas mesmas doses não foi suficiente para diminuir os níveis de glucose (> 200 mg/dL). Outros resultados, mostraram que Citrus aurantium exerce mudanças na concentração de triacilglicerídeos (158-172 mg/dL) e colesterol (120-128 mg/dL). Finalmente, a administração de Ruta graveolens na dose de 0.5 g/kg induziu um efeito hipoglicêmico (< 200 mg/dL). Ruta graveolens, na dose de 0.5 a 1.5 g/kg, induziu variações nos níveis de triacilglicerídeos (110-120 mg/dL) e colesterol (116-124 mg/dL). Em conclusão, a administração de Cnidoscolus chayamansa exerce efeitos hipoglicêmicos numa maneira dose dependente em comparação com Ruta graveolens e Citrus aurantium. As plantas avaliadas induzem mudanças nos níveis de lipídeos dependente da dose.

Several plants with hypoglycemic properties have been used in folk medicine and traditional healing systems around the world. The purpose of this work was to evaluate the effects of Ruta graveolens L., Rutaceae, Cnidoscolus chayamansa McVaugh, Euphorbiaceae, and Citrus aurantium L., Rutaceae, in a diabetic rat model to which the glucose levels were quantified every 24 hours by one month before of gastric administration of plants extract. Additionally, the cholesterol and triacylglycerides were evaluated using standard enzymatic techniques. The results showed that increases in the dose (0.5 to 1.5 g/kg) of Cnidoscolus chayamansa induce a high hypoglycemic effect (< 200 mg/dL). Another data indicate that Cnidoscolus chayamansa exerts variations in triacylglycerides (80-90 mg/dL) and cholesterol (88-96 mg/dL). Nevertheless, the administration of Citrus aurantium in the same doses was not sufficient for diminish the glucose levels (> 200 mg/dL). Other results, showed that Citrus aurantium exert changes in the concentration of triacylglycerides (158-172 mg/dL) and cholesterol (120-128 mg/dL). Finally, the administration of Ruta graveolens at dose of 0.5 mg/kg induces a hypoglycemic effect (< 200 mg/dL). Additionally, Ruta graveolens at dose of 0.5 to 1.5 g/kg induce variations in the triacylglycerides (110-120 mg/dL) and cholesterol (116-124 mg/dL) levels. In conclusion the administration of Cnidoscolus chayamansa it exerts hypoglycemic effects in a manner dose-dependent in comparison with both Ruta graveolens and Citrus aurantium. In addition, the plants evaluated induce changes in lipids levels dose-dependent.

Crystal structures of N,N'-(m-tolyl)thiourea and N,N'-(p-tolyl)thiourea.

C15H16N2S is monoclinic [orthorhombic], P2(1)/c [Pbcn]. Unit-cell dimensions at 293 K are a = 9.506(1), b = 7.629(1), c = 20.077(1)A, beta = 99.93(1) degrees, V= 1434.2(2)A(3), D(x) = 1.187 g/cm3, and Z = 4 [a = 11.806(2), b = 13.954(2), c = 8.466(1)A, V = 1394.7(3)A(3), D(x) = 1.221 g/cm3, and Z = 8]. The R value is 0.049 [0.045] for 1620 [1229] observed reflections. The dihedral angle between the tolyl rings is 53.6(1) degrees [47.9(1)degrees]. The crystal structures are stabilized by N-H...S hydrogen bonds and van der Waals forces.