Prevalence and characterization of postoperative pain in the Postanaesthesia Care Unit. / Estudio de la prevalencia y la caracterización del dolor postoperatorio inmediato en la Unidad de Recuperación Postanestésica.

INTRODUCTION: Immediate postoperative pain occurs initially after surgery, while the patient is in the Post-Anaesthesia Recovery Unit. Very few studies assess this pain in this most immediate phase. OBJECTIVE: Cross-sectional study of the prevalence and characteristics of immediate postoperative pain in patients after surgery. MATERIAL AND METHODS: Between August 2014 and February 2015, a sample of 503 patients from the Post-Anaesthesia Recovery Unit was followed. Immediate postoperative pain was assessed (by the patient and the researcher) using the visual analogue scale (VAS; range 0-10) on 5 occasions after surgery. The impact of numerous factors (age, gender, type of surgery, type of anaesthesia and analgesic) on the pain, as well as variation in vital signs and the presence of side effects, were analysed. RESULTS: Assessment of the pain showed overall VAS values of 2.2±2.8 on all occasions. Pain was reported to be of greatest intensity 20min after the patients' arrival in the Post-Anaesthesia Recovery Unit (P<.001). The VAS values reported by the researcher (1.4±2.0) were lower than those reported by the patients. Although there was a very strong correlation (R2=0.82; P<.001) and they followed a parallel distribution, there was moderate concordance (kappa=0.4). Plastic surgery and neurosurgery were the specialties with the highest percentages of VAS values in the strong intensity range (8-10). Patients with regional block techniques (with or without general anaesthesia) had lower VAS values than other general anaesthesia groups. Male patients and older patients displayed less pain than female and young patients, respectively (P<.001). CONCLUSIONS: Studying the characteristics of postoperative pain at such an early stage allows for improved management. It helps to predict, according to the type of surgery and the anaesthesia used, those patients in which higher VAS values may be seen and to better adapt analgesic therapy.

Enantiospecific semisynthesis of (+)-almuheptolide-A, a novel natural heptolide inhibitor of the mammalian mitochondrial respiratory chain.

The development of novel styryl lactone derivatives as bioactive compounds and the semisynthesis of both 4,5-dialkoxylated eight-membered-ring lactones with a heptolide skeleton (almuheptolide-A (1) type) and 7-alkoxylated delta-lactones with a saturated furanopyrone skeleton (etharvensin (8) type) have been successfully achieved from the chiral unsaturated alpha-pyrone altholactone (7). This new method is a direct and one-step enantiospecific alkoxylation of altholactone (7) in concentrated acid medium, followed by formation of the eight-membered-ring zeta-lactone. The reaction mechanism operating in the synthesis of the heptolide skeleton is postulated to be a direct Michael-type addition. Concerted opening of both the alpha-pyrone and tetrahydrofuran rings and subsequent intramolecular rearrangement with the ring closure lead to almuheptolide-A (1). This compound (1) and its diacetated derivative (1a) showed potent and selective inhibitory activity toward mammalian mitochondrial respiratory chain complex I. This mechanism of action, reported here for the first time, provides a possible explanation for the cytotoxic and antitumor activities previously described for related natural compounds.

Enantioselective syntheses of dopaminergic (R)- and (S)-benzyltetrahydroisoquinolines.

Optically pure (1S,R)- and (1R,S)-benzyltetrahydroisoquinolines (BTHIQs), 12a,b as the major diastereomers, were prepared by stereoselective reduction of the isoquinolinium salt possessing (R)- and (S)-phenylglycinol as the chiral auxiliary, respectively. The absolute configurations of (1S,R)-13a hydrochloride (O-debenzoylated derivative from 12a) and (1R,S)-12b diastereomers were unambiguously determined by single-crystal X-ray analysis. Reductive removal of the chiral auxiliary group, subsequent N-propylation, and cleavage of the methylenedioxy group furnished the optically active catecholamines (1S)-16a and (1R)-16b in good overall yield. We have separately prepared for the first time pairs of dopaminergic 1-BTHIQs enantiomers through a classical methodology in asymmetric synthesis. The (1S)-enantiomers (14a-16a) bind to D1 and D2 dopamine receptors with affinities 5-15 times higher than those of the corresponding (1R)-enantiomers (14b-16b). Moreover, (1S)-14a inhibits [3H]dopamine uptake with high affinity. It appears that synthesis and testing of (S)-enantiomers of BTHIQ are very important for the search for new active drugs at dopamine receptors.

3-acetylaltholactone and related styryl-lactones, mitochondrial respiratory chain inhibitors.

A novel furano-pyrone, 3-acetylaltholactone, and two other known styryl-lactones, altholactone and 5-acetoxyisogoniothalamin oxide, have been isolated from Goniothalamus arvensis (Annonaceae) stem bark. We report here the isolation and structural elucidation of these compounds with furane-pyrone and styryl-pyrone skeletons, postulating also for the first time their mechanism of cytotoxicity based on inhibition on mammalian mitochondrial respiratory chain.

Mechanism of vascular relaxation by thaligrisine: functional and binding assays.

In the present study we examine the mechanism by which thaligrisine, a bisbenzyltetrahydroisoquinoline alkaloid, inhibits the contractile response of vascular smooth muscle. The work includes functional studies on rat isolated aorta and tail artery precontracted with noradrenaline or KCl. In other experiments rat aorta was precontracted by caffeine in the presence or absence of extracellular Ca2+. In order to assess whether thaligrisine interacts directly with calcium channel binding sites or with alpha-adrenoceptors we examined the effect of the alkaloid on [3H]-(+)-cis diltiazem, [3H]-nitrendipine and [3H]-prazosin binding to cerebral cortical membranes. The functional studies showed that the alkaloid inhibited in a concentration-dependent manner the contractile response induced by depolarization in rat aorta (IC50 = 8.9+/-2.9 microM, n=5) and in tail artery (IC50 = 3.04+/-0.3 microM, n=6) or noradrenaline induced contraction in rat aorta (IC50 = 23.0+/-0.39 microM, n=9) and in tail artery (IC50 = 3.8+/-0.9 microM, n=7). In rat aorta, thaligrisine concentration-dependently inhibited noradrenaline-induced contraction in Ca2+-free solution (IC50 = 13.3 microM, n=18). The alkaloid also relaxed the spontaneous contractile response elicited by extracellular calcium after depletion of noradrenaline-sensitive intracellular stores (IC50 = 7.7 microM, n=4). The radioligand receptor-binding study showed that thaligrisine has higher affinity for [3H]-prazosin than for [3H]-(+)-cis-diltiazem binding sites, with Ki values of 0.048+/-0.007 microM and 1.5+/-1.1 microM respectively. [3H]-nitrendipine binding was not affected by thaligrisine. The present work provides evidence that thaligrisine shows higher affinity for [3H]-prazosin binding site than [3H]-(+)-cis-diltiazem binding sites, in contrast with tetrandrine and isotetrandrine that present similar affinity for both receptors. In functional studies thaligrisine, acted as an alpha1-adrenoceptor antagonist and as a Ca2+ channel blocker, relaxing noradrenaline or KCl-induced contractions in vascular smooth muscle. This compound specifically inhibits the refilling of internal Ca2+-stores sensitive to noradrenaline, by blocking Ca2+-entry through voltage-dependent Ca2+-channels.

Euphorbia characias as bioenergy crop: a study of variations in energy value components according to phenology and water status.

Euphorbia characias has drawn much attention as a potential bioenergy crop given its considerable amount of latex, rich in hydrocarbon-like compounds, and its ability to grow in large areas of semiarid lands. Compositions of major constituents with an energy value have been determined for the three phenological stages of this plant (preflowering, flowering, and postflowering) and different irrigation treatments. Metabolites from both nonpolar and polar extracts have been identified and quantified by GC-MS, GC-FID, HPLC-ELSD, and UPLC-PDA-MS. The results highlight that the end of the flowering period is the optimal harvesting time to maximize the yields of E. characias as a potential energy crop. The total water requirements to obtain the maximum yields of hexane- and methanol-extractables were determined for its annual development cycle.

An overview on benzylisoquinoline derivatives with dopaminergic and serotonergic activities.

Dopamine and serotonin are important neurotransmitters in the mammalian central nervous system (CNS) involved in numerous physiological and behavioural disorders such as schizophrenia, major depression, anxiety, Parkinson's and Huntington's diseases, and attention deficit hyperactivity disorder. Several natural and synthetic benzylisoquinoline derivatives have displayed affinity for dopamine and serotonin receptors in nanomolar or micromolar ranges. This review covers the last three decades of dopaminergic and serotonergic activities, and especially focuses on structure-activity relationships of natural and synthetic benzylisoquinoline derivatives. We have included aporphines, 1-benzyltetrahydroisoquinolines, bis-benzylisoquinolines, protoberberines, cularines and other structural analogues. Further molecular modelling calculations have been considered as important tools to not only obtain structural information of both neurotransmitter receptors, but to also identify their pharmacophore features. The development of selective potential ligands like benzylisoquinoline derivatives may help in the therapy of diseases related to CNS dysfunction.

Estudio de la prevalencia y la caracterización del dolor postoperatorio inmediato en la Unidad de Recuperación Postanestésica / Prevalence and characterization of postoperative pain in the Postanaesthesia Care Unit

Introducción. El dolor postoperatorio inmediato es aquel que se produce inmediatamente tras la cirugía, mientras el paciente permanece en la Unidad de Recuperación Postanestésica. Son pocos los estudios que evalúan y caracterizan el dolor postoperatorio en esta fase tan temprana. Objetivo. Estudio transversal de la prevalencia y las características del dolor postoperatorio inmediato. Material y métodos. Se analizaron 503 pacientes entre agosto de 2014 y febrero de 2015 que ingresaron en la Unidad de Recuperación Postanestésica. Se usó la escala visual analógica (EVA; rango 0-10) y se aplicó en 5 tiempos tras la cirugía, recogiéndose medidas procedentes del paciente y el investigador. Se analizaron los factores que influyen en la aparición y el mantenimiento del dolor (edad, sexo, tipo de cirugía, tipo de anestesia y analgesia), la variación de las constantes vitales y los efectos secundarios. Resultados. Globalmente, la media de la EVA valorada por el paciente fue 2,2±2,8. El tiempo de dolor más intenso fue a los 20min de llegar a la Unidad de Recuperación Postanestésica (p<0,001). Los valores de EVA del investigador (1,4±2,0) fueron inferiores a los del paciente, con buena correlación (R2=0,82; p<0,001) y distribución paralela aunque con concordancia moderada (kappa = 0,4). Cirugía plástica y neurocirugía fueron las especialidades con valores de EVA superiores. Las técnicas de bloqueo regional registraron valores más bajos de EVA. El sexo masculino y la edad avanzada registraron valores de EVA inferiores (p < 0,001). Conclusiones. El estudio de las características del dolor postoperatorio inmediato permitiría una mejor gestión en la prevención del dolor postoperatorio. Ayudaría a predecir, de acuerdo con el tipo de cirugía y anestesia utilizada, aquellos pacientes en los que pueden aparecer valores más altos de EVA para adaptar la analgesia (AU)

Introduction. Immediate postoperative pain occurs initially after surgery, while the patient is in the Post-Anaesthesia Recovery Unit. Very few studies assess this pain in this most immediate phase. Objective. Cross-sectional study of the prevalence and characteristics of immediate postoperative pain in patients after surgery. Material and methods. Between August 2014 and February 2015, a sample of 503 patients from the Post-Anaesthesia Recovery Unit was followed. Immediate postoperative pain was assessed (by the patient and the researcher) using the visual analogue scale (VAS; range 0-10) on 5 occasions after surgery. The impact of numerous factors (age, gender, type of surgery, type of anaesthesia and analgesic) on the pain, as well as variation in vital signs and the presence of side effects, were analysed. Results. Assessment of the pain showed overall VAS values of 2.2±2.8 on all occasions. Pain was reported to be of greatest intensity 20min after the patients’ arrival in the Post-Anaesthesia Recovery Unit (P<.001). The VAS values reported by the researcher (1.4±2.0) were lower than those reported by the patients. Although there was a very strong correlation (R2=0.82; P<.001) and they followed a parallel distribution, there was moderate concordance (kappa=0.4). Plastic surgery and neurosurgery were the specialties with the highest percentages of VAS values in the strong intensity range (8-10). Patients with regional block techniques (with or without general anaesthesia) had lower VAS values than other general anaesthesia groups. Male patients and older patients displayed less pain than female and young patients, respectively (P<.001). Conclusions. Studying the characteristics of postoperative pain at such an early stage allows for improved management. It helps to predict, according to the type of surgery and the anaesthesia used, those patients in which higher VAS values may be seen and to better adapt analgesic therapy (AU)

Synthesis and dopamine receptor selectivity of the benzyltetrahydroisoquinoline, (R)-(+)-nor-roefractine.

(R)-(+)-nor-Roefractine (1) was synthesized by the Bischler-Napieralski route, using asymmetric reduction of the 1, 2-didehydro precursor imine with sodium (S)-N-CBZ-prolinyloxyborohydride. Compound 1 was able to displace [3H]-raclopride (a D2 dopamine receptor-selective ligand) from its specific binding sites in rat striatum with selectivity vs [3H]-SCH23390 (D1 dopamine receptor-selective ligand).

Preparation of dopaminergic N-alkyl-benzyltetrahydroisoquinolines using a 'one-pot' procedure in acid medium.

The preparation of N-methyl-BTHIQ (4) from N-phenylethyl-phenacetamide (1) by cyclization, reduction and N-alkylation in acid medium has been achieved in good yield in a 'one-pot' procedure. Acylation of imine (2) intermediate afforded the Z and E stereoselectivity in the enamide formation. 6-Hydroxy-BTHIQ (7) shows selectivity for D2 dopamine receptors, while its N-methylated homologue (8) displays higher affinities for both D1 and D2 receptor types, with an unexpected increase in D1 dopamine receptor affinity.

Synthesis of N-diisopropyl phosphoryl benzyltetrahydroisoquinoline, a new class of mitochondrial complexes I and III inhibitors.

The synthesis of N-(O,O-diisopropylphosphoryl)-benzyltetrahydroisoquinoline (3) has been achieved in a 'one pot' procedure from imine (2) and diisopropyl-phosphorochloridate (1) generated in situ (POCl3 + iPrOH). Compound 3 is the first benzyltetrahydroisoquinoline derivative found to be a potent inhibitor of mitochondrial complexes I and III, and therefore it opens a new perspective with this series of compounds as they can be considered as new class of antitumor agents.

Semisynthesis and cytotoxicity of styryl-lactone derivatives.

The cytotoxicity and the cell-cycle action of altholactone (1), goniofufurone (2), and eight altholactone derivatives (5-12), were determined in vitro on L-1210 cells. Semisyntheses and structure-activity relationships of these compounds are described. The results of this study suggest that the cytotoxicity of altholactone (1), 11-nitro-altholactone (8), and 7-chloro-6,7-dihydroaltholactone (10) is due to the accumulation of the cells in the G2 + M phase of the cell cycle.