Inclusion Complex Of S(-) Bupivacaine And 2-hydroxypropyl- β-cyclodextrin: Study Of Morphology And Cytotoxicity

Local anesthetics (LA) belong to a class of pharmacological compounds that attenuate or eliminate pain by binding to the sodium channel of excitable membranes, blocking the influx of sodium ions and the propagation of the nerve impulse. S (-) bupivacaine (S(-) bvc) is a local anesthetic of amino-amide type, widely used in surgery and obstetrics for sustained peripheral and central nerve blockade. This article focuses on the characterization of an inclusion complex of S(-) bvc in 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). Differential scanning calorimetry, scanning electron microscopy and X-Ray diffraction analysis showed structural changes in the complex. In preliminary toxicity studies, the cell viability tests revealed that the inclusion complex decreased the toxic effect (p<0.001) produced by S(-) bvc. These results suggest that the S(-) bvc:HP-β-CD inclusion complex represents a promising agent for the treatment of regional pain.273207212Araújo, D.R., Cereda, C.M., Brunetto, G.B., Pinto, L.M.A., Santana, M.H., de Paula, E., Encapsulation of mepivacaine prolongs the analgesia provided by sciatic nerve blockade in mice (2004) Can J Anaesth, 51, pp. 566-572Araújo, D.R., Fraceto, L.F., Braga, A.F.A., de Paula, E., Drug-delivery systems for racemic bupivacaine (S50-R50) and bupivacaine enantiomeric mixture (S75-R25):cyclodextrins complexation effects on sciatic nerve blockade in mice (2005) Rev Bras Anestesiol, 55, pp. 316-328Araújo, D.R., Moraes, C.M., Fraceto, L.F., Braga, A.F.A., de Paula, E., Cyclodextrin-bupivacaine enantiomeric mixture (S75-R25) inclusion complex and intrathecal anesthesia in rats (2006) Rev Bras Anestesiol, 56, pp. 495-506Bibby, D., Davies, N.M., Tueker, I.G., Mechanisms by which cyclodextrins modify drug release from polymeric drug delivery systems (2000) Int J Pharm, 197, pp. 1-11Covino, B.G., Vassalo, H.G., (1976) Local anesthetics: Mechanisms of action and clinical use, , New York: Grune and Stratton;, 255pFoster, R.H., Markham, A., Levobupivacaine. A review of its pharmacology and use as a local anaesthetic (2000) Drugs, 59, pp. 551-579Grant, G.J., Bansinath, M., Liposomal delivery systems for local anesthetics (2001) Reg Anesth Pain Med, 26, pp. 61-63Gristwood, R.W., Cardiac and CNS toxicity of levobupivacaine: Strengths of evidence for advantage over bupivacaine (2002) Drug Saf, 25, pp. 153-163Hirayama, F., Uekama, K., Cyclodextrin-based controlled drug release system (1999) Adv Drug Deliv Rev, 36, pp. 125-141Huang, Y.F., Pryor, M.E., Mather, L.E., Veering, B.T., Cardiovascular and central nervous system effects of intravenous S-bupivacaine and bupivacaine in sheep (1998) Anesth Analg, 86, pp. 797-804Jong, R.H., (1994) Local anesthetics, , Springfield: CC. Thomas;, 325pKohata, S., Jyodi, K., Ohyoshi, A., Thermal decomposition of cyclodextrins (α -, β-, γ, and modified β-CyD) and of metal-(β-CyD) complex in the solid phase (1993) Thermochim Acta, 217, pp. 187-198Loftsson, T., Brewster, M.E., Pharmaceutical application of Cyclodextrin. 1. Drug solubilization and stabilization (1996) J Pharm Sci, 85, pp. 1017-1025Loukas, Y.L., Vraka, V., Gregoriadis, G., Novel non-acidic formulations of haloperidol complexed with beta-cyclodextrin derivatives (1997) J Pharm Biomed Anal, 16, pp. 263-268Mather, L.E., McCall, P., McNicol, P.L., Bupivacaine enantiomer pharmacokinetics after intercostal neural blockade in liver transplant patients (1995) Anesth Analg, 80, pp. 328-335Michaud, M., Icart, S., Determination of the substitution of hydroxypropylbetadex using fourier transform infrared spectrophotometry (2001) PharmEuropa, 13, pp. 714-716Naidu, N.B., Chowdary, K.P.R., Murthy, K.V.R., Satyanarayana, V., Hayman, A.R., Becket, G., Physicochemical characterization and dissolution properties of meloxicam-cyclodextrin binary systems (2004) J Pharm Biomed Anal, 35, pp. 75-86Pinto, L.M.A., Fraceto, L.F., Santana, M.H.A., Pertinhez, T.A., Oyama, S., de Paula, E., Physico-chemical characterization of benzocaine-β-cyclodextrin inclusion complexes (2005) J Pharm Biomed Anal, 39, pp. 956-963Ren, X., Xue, Y., Liu, J., Zhang, K., Zheng, J., Lou, G., Gou, C., Shen, J., A novel cyclodextrin-deri ved tellurium compound with glutathione peroxidase (2002) Chembiochem, 3, pp. 363-365Rose, J.S., Neal, J.M., Kopacz, D.J., Extended-duration analgesia: Update on microspheres and liposomes (2005) Reg Anesth Pain Med, 30, pp. 275-285Strichartz, G.R., Ritchie, J.M., (1987) Local anesthetics: Handbook of experimental pharmacology, , Berlin: Springer-Verlag;, 445pThompson, D.O., Cyclodextrin-enabling excipients: Their present and future use in pharmaceuticals (1997) Crit Rev Ther Drug Carrier Syst, 14, pp. 1-10

Nanocarriers as a tool for the treatment of colorectal cancer

Experimentele farmacotherapi

Maximizing the potency of oxaliplatin coated nanoparticles with folic acid for modulating tumor progression in colorectal cancer

One of the challenges of nanotechnology is to improve the efficacy of treatments for diseases, in order to reduce morbidity and mortality rates. Following this line of study, we made a nanoparticle formulation with a small size, uniform surfaces, and a satisfactory encapsulation coefficient as a target for colorectal cancer cells. The results of binding and uptake prove that using the target system with folic acid works: Using this system, cytotoxicity and cell death are increased when compared to using free oxaliplatin. The data show that the system maximized the efficiency of oxaliplatin in modulating tumor progression, increasing apoptosis and decreasing resistance to the drug. Thus, for the first time, our findings suggest that PLGA-PEG-FA increases the antitumor effectiveness of oxaliplatin by functioning as a facilitator of drug delivery in colorectal cancer.Radiolog

Cholesterol-functionalized carvedilol-loaded PLGA nanoparticles: anti-inflammatory, antioxidant, and antitumor effects

The inflammation has been identified as factor of tumor progression, which has increased the interest and use of molecules with anti-inflammatory and antioxidant activities in the cancer treatment. In this study, the antioxidant, anti-inflammatory, and antitumor potentials of carvedilol was explored in a different approach. The cholesterol (CHO) was investigated as facilitated agent in the action of carvedilol-loaded nanoparticles. Different formulations exhibited spherical and stable nanoparticle with mean diameter size < 250 nm. The cholesterol changed the copolymer-drug interactions and the encapsulation efficiency. The in vitro cancer study was performed using murine colorectal cancer cell line (CT-26) to observe the cell viability and apoptosis on MTS assay and flow cytometry, respectively. The experiments have demonstrated that cholesterol improved the performance of drug-loaded nanoparticles, which was much better than free drug. The in vivo inflammation peritonitis model revealed that carvedilol-loaded nanoparticles increased the level of glutathione and leukocyte migration mainly when the functionalized drug-loaded nanoparticles were tested, in a lower dose than the free drug. As hypothesized, the experimental data suggest that cholesterol-functionalized carvedilol-loaded PLGA nanoparticles can be a novel and promising approach in the inflammation-induced cancer therapy since showed anti-inflammatory, antioxidant, and antitumor effects.Graphical abstractRadiolog

The Psychedelic State Induced By Ayahuasca Modulates The Activity And Connectivity Of The Default Mode Network

The experiences induced by psychedelics share a wide variety of subjective features, related to the complex changes in perception and cognition induced by this class of drugs. A remarkable increase in introspection is at the core of these altered states of consciousness. Self-oriented mental activity has been consistently linked to the Default Mode Network (DMN), a set of brain regionsmore active during rest than during the execution of a goal-directed task. Here we used fMRI technique to inspect the DMN during the psychedelic state induced by Ayahuasca in ten experienced subjects. Ayahuasca is a potion traditionally used by Amazonian Amerindians composed by a mixture of compounds that increase monoaminergic transmission. In particular, we examined whether Ayahuasca changes the activity and connectivity of the DMN and the connection between the DMN and the task-positive network (TPN). Ayahuasca caused a significant decrease in activity throughmost parts of the DMN, including its most consistent hubs: the Posterior Cingulate Cortex (PCC)/Precuneus and the medial Prefrontal Cortex (mPFC). Functional connectivity within the PCC/Precuneus decreased after Ayahuasca intake. No significant change was observed in the DMN-TPN orthogonality. Altogether, our results support the notion that the altered state of consciousness induced by Ayahuasca, like those induced by psilocybin (another serotonergic psychedelic), meditation and sleep, is linked to the modulation of the activity and the connectivity of the DMN.102Watts, A., Psychedelics and religious experience (1968) California Law Review, 56, pp. 74-85Shanon, B., (2002) The Antipodes of the Mind: Charting the Phenomenology of the Ayahuasca Experience, 6, p. 475. , OxfordNew York: Oxford University PressDos Santos, R.G., Grasa, E., Valle, M., Ballester, M.R., Bouso, J.C., Pharmacology of ayahuasca administered in two repeated doses (2012) Psychopharmacology, 219, pp. 1039-1053. , PMID: 21842159Callaway, J.C., McKenna, D.J., Grob, C.S., Brito, G.S., Raymon, L.P., Pharmacokinetics of Hoasca alkaloids in healthy humans (1999) Journal of Ethnopharmacology, 65, pp. 243-256. , PMID: 10404423Fontanilla, D., Johannessen, M., Hajipour, A.R., Cozzi, N.V., Jackson, M.B., The hallucinogen N, N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator (2009) Science, 323, pp. 934-937. , PMID: 19213917Mckenna, D.J., Towers, G.H.N., Abbott, F., Monoamine-oxidase inhibitors in South-American hallucinogenic plants-tryptamine and beta-carboline constituents of ayahuasca (1984) Journal of Ethnopharmacology, 10, pp. 195-223. , PMID: 6587171De Araujo, D.B., Ribeiro, S., Cecchi, G.A., Carvalho, F.M., Sanchez, T.A., Seeing with the eyes shut: Neural basis of enhanced imagery following ayahuasca ingestion (2012) Human Brain MappingRiba, J., Valle, M., Urbano, G., Yritia, M., Morte, A., Human pharmacology of ayahuasca: Subjective and cardiovascular effects, monoamine metabolite excretion, and pharmacokinetics (2003) Journal of Pharmacology and Experimental Therapeutics, 306, pp. 73-83. , PMID: 12660312Riba, J., Rodriguez-Fornells, A., Urbano, G., Morte, A., Antonijoan, R., Subjective effects and tolerability of the South American psychoactive beverage Ayahuasca in healthy volunteers (2001) Psychopharmacology, 154, pp. 85-95. , PMID: 11292011Bouso, J.C., Fabregas, J.M., Antonijoan, R.M., Rodriguez-Fornells, A., Riba, J., Acute effects of ayahuasca on neuropsychological performance: Differences in executive function between experienced and occasional users (2013) Psychopharmacology, 230, pp. 415-424. , PMID: 23793226Riba, J., Romero, S., Grasa, E., Mena, E., Carrio, I., Increased frontal and paralimbic activation following ayahuasca, the pan-amazonian inebriant (2006) Psychopharmacology, 186, pp. 93-98. , PMID: 16575552Sheline, Y.I., Barch, D.M., Price, J.L., Rundle, M.M., Vaishnavi, S.N., The default mode network and self-referential processes in depression (2009) Proceedings of the National Academy of Sciences of the United States of America, 106, pp. 1942-1947. , PMID: 19171889Sood, A., Jones, D.T., On mind wandering, attention, brain networks, and meditation (2013) Explore: The Journal of Science and Healing, 9, pp. 136-141. , PMID: 23643368Buckner, R.L., Andrews-Hanna, J.R., Schacter, D.L., The brain's default network. 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(2009) Neuroimage, 44, pp. 893-905. , PMID: 18976716Weissenbacher, A., Kasess, C., Gerstl, F., Lanzenberger, R., Moser, E., Correlations and anticorrelations in resting-state functional connectivity MRI: A quantitative comparison of preprocessing strategies (2009) Neuroimage, 47, pp. 1408-1416. , PMID: 19442749Keller, C.J., Bickel, S., Honey, C.J., Groppe, D.M., Entz, L., Neurophysiological investigation of spontaneous correlated and anticorrelated fluctuations of the BOLD signal (2013) The Journal of Neuroscience, 33, pp. 6333-6342. , PMID: 23575832Brefczynski-Lewis, J.A., Lutz, A., Schaefer, H.S., Levinson, D.B., Davidson, R.J., Neural correlates of attentional expertise in long-term meditation practitioners (2007) Proceedings of the National Academy of Sciences of the United States of America, 104, pp. 11483-11488. , PMID: 17596341James, W., (1902) The Varieties of Religious Experiencea Study in Human Nature, 12, p. 534. , New York etc.: Longmans, Green, and co, 5311. pRinpoche, Y.M., (2007) The Joy of Living, , New York: Three Rivers, PMID: 25506957Hasenkamp, W., Wilson-Mendenhall, C.D., Duncan, E., Barsalou, L.W., Mind wandering and attention during focused meditation: A fine-grained temporal analysis of fluctuating cognitive states (2012) Neuroimage, 59, pp. 750-760. , PMID: 21782031Hasenkamp, W., Barsalou, L.W., Effects of meditation experience on functional connectivity of distributed brain networks (2012) Frontiers in Human Neuroscience, p. 6. , PMID: 23419982Ray, T.S., Psychedelics and the human receptorome (2010) PLoS One, 5, p. e9019. , PMID: 20126400Su, T.-P., Hayashi, T., Vaupel, D.B., When the endogenous hallucinogenic trace amine n, n-dimethyltryptamine meets the sigma-1 receptor (2009) Science Signaling, 2, p. e12Young, R., Biggs, J., Ziegler, V., Meyer, D., A rating scale for mania: Reliability, validity and sensitivity (1978) The British Journal of Psychiatry, 133, pp. 429-435. , PMID: 728692Boveroux, P., Vanhaudenhuyse, A., Bruno, M.A., Noirhomme, Q., Lauwick, S., Breakdown of within- and between-network resting state functional magnetic resonance imaging connectivity during propofol-induced loss of consciousness (2010) Anesthesiology, 113, pp. 1038-1053. , PMID: 20885292Josipovic, Z., Dinstein, I., Weber, J., Heeger, D.J., Influence of meditation on anti-correlated networks in the brain (2012) Frontiers in Human Neuroscience, p. 5. , PMID: 22363273Fox, M.D., Zhang, D., Snyder, A.Z., Raichle, M.E., The global signal and observed anticorrelated resting state brain networks (2009) Journal of Neurophysiology, 101, pp. 3270-3283. , PMID: 1933946

A probabilistic method for the operation of three-phase unbalanced active distribution networks

YesThis paper proposes a probabilistic multi-objective optimization method for the operation of three-phase distribution networks incorporating active network management (ANM) schemes including coordinated voltage control and adaptive power factor control. The proposed probabilistic method incorporates detailed modelling of three-phase distribution network components and considers different operational objectives. The method simultaneously minimizes the total energy losses of the lines from the point of view of distribution network operators (DNOs) and maximizes the energy generated by photovoltaic (PV) cells considering ANM schemes and network constraints. Uncertainties related to intermittent generation of PVs and load demands are modelled by probability density functions (PDFs). Monte Carlo simulation method is employed to use the generated PDFs. The problem is solved using ɛ-constraint approach and fuzzy satisfying method is used to select the best solution from the Pareto optimal set. The effectiveness of the proposed probabilistic method is demonstrated with IEEE 13- and 34- bus test feeders