RESUMEN
Laser-localized structures have been observed in several experiments based on broad-area semiconductor lasers. They appear as bounded regions of laser light emission which can exist independently of each other and are expected to be commuted via external optical perturbations. In this work, we perform a statistical analysis of time-resolved commutation experiments in a system of coupled lasers and show the role of wavelength, polarization and pulse energy in the switching process. Furthermore, we also analyse the response of the system outside of the stability region of laser-localized states in search of an excitable response. We observe not only a threshold separating two types of responses, but also a strong variability in the system's trajectory when returning to the initial stable fixed point.
RESUMEN
In a semiconductor laser with saturable absorber, solitons may spontaneously drift and/or oscillate. We study three different regimes characterized by strong intensity oscillations, both periodic and chaotic. We show that (i) soliton dynamics may be similar to that of passively Q-switched lasers, (ii) solitons may drift and oscillate simultaneously, and (iii) chaotic solitons may coexist with stationary ones and with the laser off solution.
RESUMEN
In spite of numerous theoretical and experimental reports of excitability in lasers with injected signal based on the locking-unlocking transition, the response of the system to controlled external perturbations (which is at the basis of the definition of excitable systems) has not been experimentally studied yet. In the following, we analyze the response of an injection-locked semiconductor laser to different external perturbations. We demonstrate the existence of a perturbation threshold beyond which the response of the system is independent of the strength of the stimulation and, thus, demonstrate its excitable character. We show that optically perturbing such an excitable system via the control of the phase of the injection beam can be useful for optical pulse generation.
RESUMEN
Excitable localized states, spatial structures which possess both the features of temporal excitable pulses and of transverse cavity solitons, have been theoretically predicted in model systems as single pulses of light localized in space with a finite and deterministic duration. We study experimentally the nucleation of laser localized structures on a device defect and its motion along a spatial gradient. We demonstrate that in the reference frame of the drifting localized structure, the resulting dynamics presents the typical features of excitable systems. In particular, for specific parameter values, we observe that the nucleation of laser localized structures is triggered by noise, while the drift of the localized structure up to a spatial region where it vanishes provides the deterministic orbit which brings the system back to its initial rest state. The control of such structures may open the way to novel applications of localized structures beyond that of simple stationary bits.
RESUMEN
The formation of long stationary filaments resulting in uniform high density plasma strings in air using short pulse UV laser Bessel beams is shown. The length and the electron density of the plasma strings can be easily tuned by adjusting the conical Bessel wavefront angle. It is shown that in this regime the length of the plasma string can be extended over meter-long scales without any compromise in the string uniformity or any temporal evolution of the filamented laser pulse.
Asunto(s)
Aire , Gases/química , Gases/efectos de la radiación , Rayos Láser , Modelos Teóricos , Rayos Ultravioleta , Simulación por Computador , Calor , Luz , Dispersión de RadiaciónRESUMEN
BACKGROUND: Changes in flow to the gut and the kidney during hemorrhage and resuscitation contribute to organ dysfunction and outcome. We evaluated regional and splanchnic oxygen (O2) flow distribution and calculated oxygen supply distribution during hemorrhage and reperfusion and compared them with global measures. METHODS: Seven anesthetized pigs were instrumented to evaluate global hemodynamics, visceral blood flow, and oxygen transport. Tonometric pH probes were positioned in the stomach and jejunum. Animals were bled to 45 mm Hg for 1 hour. Crystalloids and blood were infused during the following 2 hours to normalize blood pressure, heart rate, urine output, and hemo- globin. RESULTS: During hemorrhage, mesenteric flow and O2 consumption were significantly decreased, whereas systemic consumption remained normal. Renal flow was reduced, but renal O2 consumption remained normal. After resuscitation, despite normal hemodynamics, neither systemic, mesenteric, nor renal O2 delivery returned to baseline. Lactate remained significantly increased. Arterial pH, base excess, and gastric and jejunal pH were all decreased. CONCLUSION: During hemorrhage, the gut is more prone than other regions to O2 consumption supply dependency. After resuscitation, standard clinical parameters do not detect residual O2 debt. Lactate, arterial pH, base excess, and intramucosal gut pH are all markers of residual tissue hypoperfusion.
Asunto(s)
Consumo de Oxígeno/fisiología , Circulación Renal/fisiología , Daño por Reperfusión/fisiopatología , Resucitación , Choque Hemorrágico/fisiopatología , Circulación Esplácnica/fisiología , Equilibrio Ácido-Base/fisiología , Animales , Femenino , Fluidoterapia , Determinación de la Acidez Gástrica , Hemodinámica/fisiología , Ácido Láctico/sangre , PorcinosAsunto(s)
Corticoesteroides/uso terapéutico , Antioxidantes/uso terapéutico , Depuradores de Radicales Libres/uso terapéutico , Peroxidación de Lípido/efectos de los fármacos , Insuficiencia Multiorgánica/tratamiento farmacológico , Pregnatrienos/uso terapéutico , Animales , Antiinflamatorios/uso terapéutico , Ensayos Clínicos como Asunto , Humanos , Inyecciones Intraperitoneales , Metilprednisolona/uso terapéutico , Insuficiencia Multiorgánica/mortalidad , Estudios Prospectivos , Conejos , Ensayos Clínicos Controlados Aleatorios como Asunto , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Sepsis/tratamiento farmacológico , Choque Séptico/tratamiento farmacológico , Zimosan/administración & dosificaciónRESUMEN
The majority of cancer of the pancreas-about 70%-arise in the head of the gland and only 20-30% in the body and tail. The latter usually have grown to a large size by the diagnosis is made, due to absence of symptoms. Jaundice is seldom present and pain is the main symptom. We reviewed recent literature, which present homogeneous data. Cancers of the body and tail are rarely resectable, with 30% morbidity and a much lower morbidity-0-10%-in specialized centres. If the lesion is localized and the patient in good physical condition, a laparotomy can be performed, with or without a preliminary laparoscopy to detect distant metastases. Distal pancreatectomy and splenectomy is the treatment of choice. In our experience, only tumors different from ductal adenocarcinoma have a good prognosis. Pain can be managed by surgical or chemical splanchnicectomy and, in selected cases, thoracoscopically.
Asunto(s)
Adenocarcinoma/cirugía , Neoplasias Pancreáticas/cirugía , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , PronósticoRESUMEN
Both the enantiomeric forms of DAU 5750, a novel muscarinic receptor antagonist, have been synthesized in order to assess the relevance of configurational/conformational features for high affinity binding to muscarinic receptor subtypes. The attribution of absolute stereochemistry and conformational analysis by means of molecular modelling and NMR techniques are also reported.
Asunto(s)
Antagonistas Muscarínicos/síntesis química , Quinolinas/síntesis química , Receptores Muscarínicos/metabolismo , Tropanos/síntesis química , Quimotripsina/metabolismo , Espectroscopía de Resonancia Magnética , Conformación Molecular , Estructura Molecular , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/metabolismo , Quinolinas/química , Quinolinas/metabolismo , Estereoisomerismo , Tropanos/química , Tropanos/metabolismoRESUMEN
The 5-HT4 receptor antagonist action of DAU 6285 was investigated in vivo in anesthetized pigs. DAU 6285 (0.3-3 mg/kg i.v.) dose dependently antagonized 5-hydroxytryptamine (5-HT)-induced tachycardiac responses. In contrast, the 5-HT3 receptor antagonist, ondansetron (0.3-3 mg/kg i.v.) did not influence the tachycardia induced by 5-HT. These results indicate that DAU 6285 is a potent antagonist of 5-HT4 receptor-mediated responses in vivo.
Asunto(s)
Bencimidazoles/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes , Compuestos Bicíclicos con Puentes/farmacología , Antagonistas de la Serotonina/farmacología , Serotonina/toxicidad , Taquicardia/inducido químicamente , Taquicardia/prevención & control , Animales , Relación Dosis-Respuesta a Droga , Masculino , PorcinosRESUMEN
Three chemical classes of serotonin 5-HT4 receptor agonists have been identified so far: 5-substituted indoles (e.g. 5-HT), benzamides (e.g. renzapride) and benzimidazolones (e.g. BIMU 8). In a search for 5-HT4 receptor antagonists, we have discovered that the benzimidazolone derivative DAU 6285 (for structure see text), is 3-5 times more potent than tropisetron in blocking 5-HT, renzapride and BIMU 8 induced stimulation of adenylate cyclase activity in mouse embryo colliculi neurons. Schild plot analysis yielded Ki values of 220, 181 and 255 nmol/l, respectively. In addition, DAU 6285 showed poor activity as a 5-HT3 receptor ligand with respect to tropisetron, as demonstrated by in vitro binding studies (Ki, 322 vs 2.8 nmol/l) and by its antagonistic activity in the Bezold-Jarisch reflex test (ID50, 231 vs 0.5 micrograms/kg, i.v.). No significant binding (Ki greater than 10 mumol/l) of DAU 6285 to serotonergic 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, and 5-HT2 receptors as well as to adrenergic alpha 1, alpha 2, dopaminergic D1, D2 or muscarinic M1-M3 receptor subtypes was found. The data indicate that DAU 6285 has a somewhat higher affinity than tropisetron for 5-HT4 receptors, a property confirmed in functional tests, and much lower affinity than tropisetron for 5-HT3 receptors. The compound represents a new interesting tool for investigating the pharmacological and physiological properties of 5-HT4 receptors.
Asunto(s)
Bencimidazoles/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes , Compuestos Bicíclicos con Puentes/farmacología , Antagonistas de la Serotonina , Animales , Benzamidas/farmacología , Encéfalo/citología , Encéfalo/ultraestructura , Células Cultivadas , AMP Cíclico/biosíntesis , Embrión de Mamíferos , Frecuencia Cardíaca/efectos de los fármacos , Indoles/farmacología , Cinética , Mesencéfalo/citología , Mesencéfalo/ultraestructura , Ratones , Ratas , Receptores de Serotonina/clasificación , Receptores de Serotonina/metabolismo , Reflejo/efectos de los fármacos , Serotonina/farmacología , Antagonistas de la Serotonina/farmacología , Estimulación Química , TropisetrónRESUMEN
The antagonistic properties of DAU 6285, an azabicycloalkyl benzimidazolone derivative, at putative 5-hydroxytryptamine4 (5-HT4) receptors were investigated in in vitro preparations of guinea-pig ileum and human atrium, in comparison to ICS 205-930. DAU 6285 behaved as a competitive antagonist in all the preparations examined. Its affinity (pA2) ranged between 6.50 and 7.12 in the test models considered. The affinity of ICS 205-930 was 2-3 fold lower. At variance with ICS 205-930, DAU 6285 displayed a weak affinity for 5-HT3 receptors (pKi = 6.1, rat cortex; pA2 less than 5, guinea-pig ileum). In the guinea-pig ileum, DAU 6285 (10 microM) did not exert antimuscarinic, antihistaminic, antinicotinic or myolytic activity. Moreover, it did not bind to other 5-HT receptor subtypes, or to adrenergic, dopaminergic, benzodiazepine, nicotine, GABA receptors. DAU 6285 may represent a suitable tool for studies in the field of 5-HT4 receptors.
Asunto(s)
Bencimidazoles/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes , Compuestos Bicíclicos con Puentes/farmacología , Antagonistas de la Serotonina , Animales , Cobayas , Humanos , Íleon/efectos de los fármacos , Técnicas In Vitro , Indoles/farmacología , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , TropisetrónRESUMEN
The pharmacological profile of six representative members of a novel class of 5-HT3 receptor antagonists is described. The compounds are esters and amides of benzimidazolone-1-carboxylic acid with a basic azabicycloalkyl moiety (compounds 1-3) and their respective ethyl derivatives (compounds 4-6). In isolated preparations (rabbit heart and guinea pig ileum) all compounds antagonized the 5-HT3 receptor-mediated effects of serotonin, with potencies comparable with those of the reference compounds, ICS 205.930 and GR 38032F (-log IC50 9.30-11.9 and 6.8-8.20, in heart and ileum, respectively). In the anaesthetised rat, all agents potently inhibited the Bezold-Jarisch reflex whether given i.v. or i.d. I.v. administration of compounds prevented cisplatin-induced emesis in dogs (ID50 ranging from 3.7 to 147 micrograms/kg). All agents accelerated gastric emptying of solids in rats (ED50 about 10-160 micrograms/kg i.p.). In addition, compounds 4 and 5 were able to stimulate 5-HT4 receptors in the isolated guinea pig ileum, as well as enhance contractile activity in the Heidenhain gastric pouch of dogs, showing clearcut prokinetic properties.
Asunto(s)
Bencimidazoles/farmacología , Antagonistas de la Serotonina , Animales , Cisplatino/efectos adversos , Perros , Relación Dosis-Respuesta a Droga , Femenino , Vaciamiento Gástrico/efectos de los fármacos , Cobayas , Corazón/efectos de los fármacos , Íleon/efectos de los fármacos , Técnicas In Vitro , Masculino , Contracción Muscular/efectos de los fármacos , Conejos , Ratas , Ratas Endogámicas , Serotonina/farmacología , Estómago/efectos de los fármacos , Vómitos/inducido químicamente , Vómitos/prevención & controlRESUMEN
A series of malonamic acid esters with suitable amino alcohols, typical of antimuscarinic compounds, was synthesized and the affinities for the three pharmacologically defined muscarinic receptor subtypes, namely M1, M2 and M3, were evaluated by radioligand displacement experiments. It was found that the esters with 3-quinuclidinol 7b, 7f-g, 8 and 9 are ligands with intermediate to high affinity for the M1 receptors, for which they show a preferential binding. Unexpectedly, the ester 7a with tropine bound with negligible affinity to all the receptors investigated. The introduction of a phenyl group on the carboxamido moiety of 7b gave compound 9, which showed an affinity for the M1 receptor comparable with that of the reference drug Pirenzepine 1.
Asunto(s)
Malonatos/farmacología , Antagonistas Muscarínicos , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Técnicas In Vitro , Malonatos/síntesis química , Miocardio/metabolismo , Pirenzepina/farmacología , Ratas , Relación Estructura-Actividad , Glándula Submandibular/efectos de los fármacos , Glándula Submandibular/metabolismoRESUMEN
Two classes of compounds, bearing a cyclic amidino moiety instead of the tertiary amino group of the classical antimuscarinic drugs like hexahydrodifenidol 3 were synthesized. Affinities (KD) for the three pharmacologically defined M1, M2 and M3 mAChR subtypes were measured in radioligand binding assays and in functional in vitro studies (KB) in guinea pig ileum and left atrium. The results showed that the replacement of the tertiary amino group in structural analogues of 3 with a cyclic amidino moiety afforded potent antimuscarinic compounds. The selectivity shown for smooth muscle preparations suggests their usefulness as antispasmodics.
Asunto(s)
Amidinas/síntesis química , Antagonistas Muscarínicos , Amidinas/química , Amidinas/farmacología , Animales , Cationes/química , Cobayas , Técnicas In Vitro , Músculo Liso/efectos de los fármacos , Parasimpatolíticos/síntesis química , Parasimpatolíticos/farmacología , Ensayo de Unión Radioligante , Ratas , Receptores Muscarínicos/metabolismoRESUMEN
Recent experimental evidence indicates that central 5-HT4 receptors which are positively coupled to adenylate cyclase, are stimulated by a family of 2-methoxy-4-amino-5-chloro substituted benzamide derivatives. These compounds are also potent stimulants of the gastro-intestinal motility. In this study the ability of three azabicycloalkyl benzimidazolone derivatives, BIMU 1, BIMU 8, and DAU 6215 (structural formulas are given in the text), to stimulate cAMP formation in colliculi neurons in primary culture have been tested. Two of the compounds, BIMU 1 and BIMU 8, which show prokinetic activity in various animal models, were also good agonists at the 5-HT4 receptors, whereas DAU 6215, a drug devoid of prokinetic activity, was only a weak, partial agonist at 5-HT4 receptors. The rank order of their potencies as compared with those of 5-HT and cisapride was as follows: BIMU 8 = cisapride greater than 5-HT greater than BIMU 1 greater than DAU 6215. The efficacies of BIMU 8 and cisapride were comparable (133 +/- 9% and 124 +/- 8% of the maximal 5-HT efficacy, respectively), whereas BIMU 1 and DAU 6215 elicited, respectively, only 72 +/- 11% and 16 +/- 4% of the maximal 5-HT effect. The activities of the azabicycloalkyl benzimidazolone derivatives and 5-HT on cAMP formation were not additive and ICS 205-930 antagonized the stimulatory effect of these compounds with low potency (pKi = 6.1-6.4), further strengthening the notion of interaction with 5-HT4 receptors. In addition, cross desensitization between the effects of 5-HT and the azabicycloalkyl benzimidazolones on adenylate cyclase was noted, another argument in favor of an interaction of these drugs on 5-HT4 receptors.
Asunto(s)
Adenilil Ciclasas/metabolismo , Bencimidazoles/farmacología , Encéfalo/enzimología , Compuestos Bicíclicos Heterocíclicos con Puentes , Receptores de Serotonina/metabolismo , Animales , Compuestos Bicíclicos con Puentes/farmacología , Cisaprida , AMP Cíclico/biosíntesis , Interacciones Farmacológicas , Indoles/farmacología , Ratones , Neuronas/metabolismo , Piperidinas/farmacología , Receptores de Serotonina/efectos de los fármacos , Serotonina/farmacología , Antagonistas de la Serotonina/farmacología , TropisetrónRESUMEN
The antiemetic activity of DAU 6215, a novel antagonist of 5-HT3 receptors, was investigated in animal models of cytotoxic treatment-evoked emesis and compared with the antiemetic activity of ondansetron and metoclopramide. In dogs, vomiting was induced by i.v. cisplatin; in ferrets, the emetic response was elicited by i.v. doxorubicin or X-ray exposure. Pretreatment with 0.1-1 mg/kg DAU 6215 given i.v. or p.o. prevented the vomiting response to the different emetic agents. In the dog, the antiemetic potency of metoclopramide was 30 times lower than that of DAU 6215. Ondansetron was less potent than DAU 6215 against cisplatin and doxorubicin but was equally effective in the radiotherapy protocol. In this model, lengthening of the pretreatment time to 2 h did not affect the antiemetic efficacy of DAU 6215, whereas it decreased that of ondansetron. The results demonstrate that DAU 6215 is a highly effective and long-lasting inhibitor of cytotoxic treatment-induced emesis in different animal species.
Asunto(s)
Antieméticos/uso terapéutico , Bencimidazoles/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes , Compuestos Bicíclicos con Puentes/uso terapéutico , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/radioterapia , Antagonistas de la Serotonina/uso terapéutico , Animales , Cisplatino/efectos adversos , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Doxorrubicina/efectos adversos , Evaluación Preclínica de Medicamentos , Femenino , Hurones , Imidazoles/uso terapéutico , Masculino , Metoclopramida/uso terapéutico , Neoplasias Experimentales/complicaciones , Ondansetrón , Factores de Tiempo , Vómitos/etiología , Vómitos/prevención & controlRESUMEN
A series of 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid esters and amides containing a basic azacyclo- or azabicycloalkyl moiety has been synthesized and evaluated for 5-HT3 antagonistic activity in a radioligand binding assay ([3H]ICS 205930) and in the 5-HT-induced von Bezold-Jarisch reflex in the rat. It was found that endo-substituted azabicycloalkyl derivatives (e.g. 7a, 12a, 12b) were much more active than the corresponding exo analogues (e.g. 7b, 12h, 12i) or azacycloalkyl compounds. Amidic derivatives 12a, 12b, 12c, 12e, 13b, and 13c proved to be about 10 times more active than the corresponding ester derivatives 7a, 11a, 7c, 7d, 8a, and 8b. In particular, compound 12a (DA 6215) showed a Ki = 3.8 nM in the binding test and an ED50 = 1 nM/kg iv in the von Bezold-Jarisch reflex assay, an activity comparable to that of the reference compound 2 (ICS 205930, Ki = 2 nM, ED50 = 2.1 nM/kg). IR spectroscopy studies in the solid state and in CHCl3 solution revealed the existence of an intramolecular hydrogen bond in 13b, taken as a model compound for this class of substances. A molecular modeling study showed that 12a, in its internal hydrogen-bound conformation, well matches a recently proposed pharmacophoric model for 5-HT3 antagonist activity.
Asunto(s)
Bencimidazoles/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes , Compuestos Bicíclicos con Puentes/farmacología , Hidrocarburos Aromáticos con Puentes/farmacología , Antagonistas de la Serotonina/farmacología , Animales , Bencimidazoles/síntesis química , Bencimidazoles/metabolismo , Unión Competitiva , Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Bicíclicos con Puentes/metabolismo , Corteza Cerebral/metabolismo , Fenómenos Químicos , Química , Simulación por Computador , Enlace de Hidrógeno , Indoles/metabolismo , Modelos Moleculares , Estructura Molecular , Ensayo de Unión Radioligante , Ratas , Receptores de Serotonina/metabolismo , Reflejo/efectos de los fármacos , Antagonistas de la Serotonina/síntesis química , Relación Estructura-Actividad , TropisetrónRESUMEN
The muscarinic receptors responsible for two effects elicited by McN-A-343, i.e. the relaxation of the rat duodenum and the inhibition of the twitch contraction of rabbit vas deferens, were investigated by use of derivatives of 4-diphenyl acetoxy-N-methyl piperidine methobromide (4-DAMP). Both receptors had been previously identified as M1 on the basis of the high affinity shown towards pirenzepine. Schild analysis of antagonism revealed that the affinities of 4-DAMP and three of its analogues in the rat duodenum were significantly different from those estimated in rabbit vas deferens. These data indicate that distinct receptor subtypes mediate duodenal relaxation and vas deferens inhibition of twitch contraction and suggest that receptors classified as M1 by means of pirenzepine affinity constitute a heterogeneous population.
Asunto(s)
Parasimpaticomiméticos , Piperidinas , Receptores Muscarínicos/metabolismo , Cloruro de (4-(m-Clorofenilcarbamoiloxi)-2-butinil)trimetilamonio/farmacología , Animales , Duodeno/efectos de los fármacos , Técnicas In Vitro , Contracción Isotónica/efectos de los fármacos , Masculino , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Parasimpaticomiméticos/farmacología , Piperidinas/farmacología , Pirenzepina/farmacología , Conejos , Ratas , Ratas Endogámicas , Receptores Muscarínicos/efectos de los fármacos , Conducto Deferente/efectos de los fármacosRESUMEN
A series of derivatives of rifamycin P, an antibiotic produced by fermentation of a mutant strain of Nocardia mediterranea or by chemical modification of rifamycin S, have been prepared. The structures of these compounds were determined by 1H NMR, IR, UV, and LC/MS. Their in vitro and in vivo antibacterial activities in comparison with rifampicin and two other rifamycins under investigation were evaluated. The derivatives were more active than rifamycin P against Mycobacterium avium complex and other slowly and rapidly growing nontuberculous mycobacteria which frequently cause systemic infection in patients with AIDS. 2'-(Diethylamino)rifamycin P (P/DEA) appears suitable for further investigation.