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Antifungal drugs such as amphotericin B (AmB) interact with lipids and phospholipids located on fungal cell membranes to disrupt them and create pores, leading to cell apoptosis and therefore efficacy. At the same time, the interaction can also take place with cell components from mammalian cells, leading to toxicity. AmB was selected as a model antifungal drug due to the complexity of its supramolecular chemical structure which can self-assemble in three different aggregation states in aqueous media: monomer, oligomer (also known as dimer) and poly-aggregate. The interplay between AmB self-assembly and its efficacy or toxicity against fungal or mammalian cells is not yet fully understood. To the best of our knowledge, this is the first report that investigates the role of excipients in the supramolecular chemistry of AmB and the impact on its biological activity and toxicity. The monomeric state was obtained by complexation with cyclodextrins resulting in the most toxic state, which was attributed to the greater production of highly reactive oxygen species upon disruption of mammalian cell membranes, a less specific mechanism of action compared to the binding to the ergosterol located in fungal cell membranes. The interaction between AmB and sodium deoxycholate resulted in the oligomeric and poly-aggregated forms which bound more selectively to the ergosterol of fungal cell membranes. NMR combined with XRD studies elucidated the interaction between drug and excipient to achieve the AmB aggregation states, and ultimately, their diffusivity across membranes. A linear correlation between particle size and the efficacy/toxicity ratio was established allowing to modulate the biological effect of the drug and hence, to improve pharmacological regimens. However, particle size is not the only factor modulating the biological response but also the equilibrium of each state which dictates the fraction of free monomeric form available. Tuning the aggregation state of AmB formulations is a promising strategy to trigger a more selective response against fungal cells and to reduce the toxicity in mammalian cells.

Adherence to Enhanced Recovery Protocols (ERPs) is associated with faster functional recovery, better patient satisfaction, lower complication rates and reduced length of hospital stay. Understanding institutional barriers and facilitators is essential for improving adherence to ERPs. The purpose of this study was to identify institutional factors associated with adherence to an ERP for colorectal surgery.A secondary analysis of a nationwide study was conducted including 686 patients who underwent colorectal surgery across twenty-one institutions in Spain. Adherence to ERPs was calculated based upon the components recommended by the Enhanced Recovery After Surgery (ERAS®) Society. Institutional characteristics (i.e., case volume, ERP duration, anesthesia staff size, multidisciplinary meetings, leadership discipline) were captured from each participating program. Multivariable regression was performed to determine characteristics associated with adherence.The median adherence to ERAS was 68.2% (IQR 59.1%-81.8%). Multivariable linear regression revealed that anesthesiologist leadership (+5.49%, 95%CI +2.81% to +8.18%, P 0.01), duration of ERAS implementation (+0.46% per year, 95%CI +0.06% to +0.86%, P 0.01) and the use of regular multidisciplinary meetings (+4.66%, 95%CI +0.06 to +7.74%, P 0.01) were independently associated with greater adherence. Case volume (-2.38% per 4 cases weekly, 95%CI -3.03 to -1.74, P 0.01) and number of anesthesia providers (-1.19% per 10 providers, 95%CI +2.23 to -8.18%, P 0.01) were negatively associated with adherence.Adherence to ERPs is strongly associated with anesthesiology leadership, regular multidisciplinary meetings, and program duration, whereas case volume and the size of the anesthesia staff were potential barriers. These findings highlight the importance of strong leadership, experience and establishing a multidisciplinary team when developing an ERP for colorectal surgery.

Amphotericin B (AmB) is a high-molecular weight poorly soluble drug with a high efficacy in the treatment of infectious caused by Leishmania spp. parasites, which possesses a very low topical bioavailability. Transferosomes (TFs) are ultradeformable vesicles that consist of drugs lipids, an edge activator, and a low amount of ethanol (

Este artículo se encuentra disponible en la siguiente URL: https://pubs.acs.org/doi/10.1021/acsinfecdis.0c00293 Nota de Fondos: Esta versión preprint del artículo se encuentra a texto completo en el CEU Repositorio Institucional. En esta investigación también participan: Francisco Bolás-Fernández, Maria Paloma Ballesteros, Marcia Dalastra Laurenti, Luiz F. D. Passero, Aikaterini Lalatsa y Dolores R. Serrano. This is the pre-peer reviewed version of the following article: Fernández-García, R., Statts, L., Jesús, J.A., Dea-Ayuela, M.A., Bautista, L., Simao, R. et al. (2020). Ultradeformable lipid vesicles localize Amphotericin B in the dermis for the treatment of infectious skin diseases. ACS Infectious Diseases, vol. 6, i. 10 (18 aug.), pp. 2647-2660, which has been published in final form at https://doi.org/10.1021/acsinfecdis.0c00293 Este es el pre-print del siguiente artículo: Fernández-García, R., Statts, L., Jesús, J.A., Dea-Ayuela, M.A., Bautista, L., Simao, R. et al. (2020). Ultradeformable lipid vesicles localize Amphotericin B in the dermis for the treatment of infectious skin diseases. ACS Infectious Diseases, vol. 6, i. 10 (18 aug.), pp. 2647-2660, que se ha publicado de forma definitiva en https://doi.org/10.1021/acsinfecdis.0c00293 Cutaneous fungal and parasitic diseases remain challenging to treat, as available therapies are unable to permeate the skin barrier. Thus, treatment options rely on systemic therapy, which fail to produce high drug local concentrations but can lead to significant systemic toxicity. Amphotericin B (AmB) is highly efficacious in the treatment of both fungal and parasitic diseases such as cutaneous leishmaniasis, but is only reserved for parenteral administration in patients with severe pathophysiology. Here, we have designed and optimised AmB-transfersomes [93.5 % encapsulation efficiency, size of 150 nm, and good colloidal stability (-35.02 mV)] that can remain physicochemically stable (>90 % drug content) at room temperature and 4 °C over 6 months when lyophilised and stored under desiccated conditions. AmBtransfersomes possessed good permeability across mouse skin (4.91 ± 0.41 μg/cm2/h) and 10-fold higher permeability across synthetic Strat-M® membranes. In vivo studies after a single topical application in mice showed permeability and accumulation within the dermis (>25 μg AmB /g skin at 6 h post-administration) indicating the delivery of therapeutic amounts of AmB for mycoses and cutaneous leishmaniasis, while a single daily administration in Leishmania (Leishmania) amazonensis infected mice over 10 days resulted in excellent efficacy (98 % reduction in Leishmania parasites). Combining the application of AmB-transfersomes with metallic microneedles in vivo increased levels in the SC and dermis but is unlikely to elicit transdermal levels. In conclusion, AmB-transfersomes are promising and stable topical nanomedicines that can be readily translated for parasitic and fungal infectious diseases.

Fixed-dose combination (FDC) products containing at least two different active pharmaceutical ingredients are designed to treat more effectively different pathologies as they have demonstrated to enhance patient compliance. However, the combination of multiple drugs within the same dosage form can bring many physicochemical and pharmacodynamic interactions. The manufacturing process of FDC products can be challenging, especially when it is required to achieve different drug release profiles within the same dosage form to overcome physicochemical drug interactions. Monolithic, multiple-layer, and multiparticulate systems are the most common type of FDCs. Currently, the main manufacturing techniques utilized in industrial pharmaceutical companies rely on the use of combined wet and dry granulation, hot-melt extrusion coupled with spray coating, and compression of bilayered tablets. Nowadays, personalized medicines are gaining importance in clinical settings and 3D printing is taking a highlighted role in the manufacturing of complex and personalized 3D solid dosage forms that could not be manufactured using conventional techniques. In this review, it will be discussed in detail current marketed FDC products and their application in several diseases with an especial focus on antimicrobial drugs. Current industrial conventional techniques will be compared with 3D printing manufacturing of FDCs. Graphical Abstract.

Amphotericin B possesses high activity against Candida spp. with low risk of resistance. However, Amphotericin B&rsquo, s high molecular weight compared to other antifungal drugs, such as miconazole and clotrimazole, and poor water solubility hampers its efficacy at the physiological conditions of the oropharyngeal cavity (saliva pH, limited volume for dissolution) and thereby limits its clinical use in oropharyngeal candidiasis. We have prepared fast-dissolving orodispersible films with high loading (1% w/w) using solvent casting that enables amphotericin B to remain solubilised in saliva in equilibrium between the monomeric and dimeric states, and able to produce a local antifungal effect. Optimisation of the amphotericin B-loaded orodispersible films was achieved by quality by design studies combining dextran and/or maltodextrin as dextrose-derived-polymer film formers with cellulose-derived film formers (hydroxypropylmethyl/hydroxypropyl cellulose in a 1:4 weight ratio), sorbitol for taste masking, microcrystalline cellulose (Avicel 200) or microcrystalline cellulose-carboxymethylcellulose sodium (Avicel CL-611) for enhancing the mechanical strength of the film, and polyethylene glycol 400 and glycerol (1:1 w/w) as plasticizers. The optimised amphotericin B orodispersible films (containing 1% AmB, 25% dextran, 25% maltodextrin, 5% sorbitol, 10% Avicel 200, 10% polyethylene glycol 400, 10% glycerol, 3% hydroxypropylmethyl cellulose acetate succinate, 12% hydroxypropyl cellulose) possessed a fast disintegration time (60 &plusmn, 3 s), quick release in artificial saliva (&gt, 80% in 10 min), high burst strength (2190 mN mm) and high efficacy against several Candida spp. (C. albicans, C. parapsilosis and C. krusei) (&gt, 15 mm inhibition halo). Amphotericin B orodispersible films are stable for two weeks at room temperature (25 &deg, C) and up to 1 year in the fridge. Although further toxicological and in vivo efficacy studies are required, this novel Amphotericin B orodispersible films is a promising, physicochemically stable formulation with potential wide application in clinical practice, especially for immunocompromised patients suffering from oropharyngeal candidiasis.

Leishmaniasis is a neglected tropical disease affecting more than 12 million people worldwide, which in its visceral clinical form (VL) is characterised by the accumulation of parasites in the liver and spleen, and can lead to death if not treated. Available treatments are not well tolerated due to severe adverse effects, need for parenteral administration and patient hospitalisation, and long duration of expensive treatments. These treatment realities justify the search for new effective drugs, repurposing existing licensed drugs towards safer and non-invasive cost-effective medicines for VL. In this work, we provide proof of concept studies of butenafine and butenafine self-nanoemulsifying drug delivery systems (B-SNEDDS) against Leishmania infantum. Liquid B-SNEDDS were optimised using design of experiments, and then were spray-dried onto porous colloidal silica carriers to produce solid-B-SNEDDS with enhanced flow properties and drug stability. Optimal liquid B-SNEDDS consisted of Butenafine:Capryol 90:Peceol:Labrasol (3:49.5:24.2:23.3 w/w), which were then sprayed-dried with Aerosil 200 with a final 1:2 (Aerosil:liquid B-SNEDDS w/w) ratio. Spray-dried particles exhibited near-maximal drug loading, while maintaining excellent powder flow properties (angle of repose &lt, 10&deg, ) and sustained release in acidic gastrointestinal media. Solid-B-SNEDDS demonstrated greater selectivity index against promastigotes and L. infantum-infected amastigotes than butenafine alone. Developed oral solid nanomedicines enable the non-invasive and safe administration of butenafine as a cost-effective and readily scalable repurposed medicine for VL.

Recently an increase in both the prevalence and incidence of invasive fungal infections have been reported. The number of fungal species that can cause systemic mycoses are higher and current antifungal therapies are still far from ideal. The emergence of antifungal resistances has a major clinical impact when using azoles and echinocandins leading to possible treatment failure and ultimately putting the patient's life at risk. Amphotericin B can play a key role in treating severe invasive mycoses as the incidence of antifungal resistance is very low combined with a high efficacy against a wide range of fungi. However, the use of this drug is limited due to its high toxicity and the infusion-related side effects often necessitating patient hospitalisation. New medicines based on lipid-based systems have been commercialised in the last decade, these treatments are able to reduce the toxicity of the drug but intravenous administration is still required. An oral or topically self-administered amphotericin B formulation can overcome these challenges, however such a product is not yet available. Several drug delivery systems such as cochleates, nanoparticulate and self-emulsifying systems are under development in order to enhance the solubility of the drug in aqueous media and promote oral absorption and cutaneous permeation across the skin. In this review, the type of drug delivery system and the effect of particle size on efficacy, toxicity and biodistribution will be discussed.

BACKGROUND: Postoperative respiratory failure (PRF) is the most frequent respiratory complication following surgery. OBJECTIVE:/nThe objective of this study was to build a clinically useful predictive model for the development of PRF. DESIGN: A prospective observational study of a multicentre cohort. SETTING: Sixty-three hospitals across Europe. PATIENTS: Patients undergoing any surgical procedure under general or regional anaesthesia during 7-day recruitment periods. MAIN OUTCOME MEASURES: Development of PRF within 5 days of surgery. PRF was defined by a partial pressure of oxygen in arterial blood (PaO2) less than 8 kPa or new onset oxyhaemoglobin saturation measured by pulse oximetry (SpO2) less than 90% whilst breathing room air that required conventional oxygen therapy, noninvasive or invasive mechanical ventilation./nRESULTS: PRF developed in 224 patients (4.2% of the 5384 patients studied). In-hospital mortality [95% confidence interval (95% CI)] was higher in patients who developed PRF [10.3% (6.3 to 14.3) vs. 0.4% (0.2 to 0.6)]. Regression modelling identified a predictive PRF score that includes seven independent risk factors: low preoperative SpO2; at least one preoperative respiratory symptom; preoperative chronic liver disease; history of congestive heart failure; open intrathoracic or upper abdominal surgery; surgical procedure lasting at least 2 h; and emergency surgery. The area under the receiver operating characteristic curve (c-statistic) was 0.82 (95% CI 0.79 to 0.85) and the Hosmer-Lemeshow goodness-of-fit statistic was 7.08 (P = 0.253). CONCLUSION: A risk score based on seven objective, easily assessed factors was able to predict which patients would develop PRF. The score could potentially facilitate preoperative risk assessment and management and provide a basis for testing interventions to improve outcomes.The study was registered at ClinicalTrials.gov (identifier NCT01346709). The PERISCOPE study was funded and supported through the European Society of Anaesthesiology’s Clinical Trials Network.

Nebulised antibiotics offer great advantages over intravenously administered antibiotics and other conventional antibiotic formulations. However, their use is not widely standardized in the current clinical practice. This is the consequence of large variability in the performance of nebulisers, patient compliance and a deficiency of robust preclinical and clinical data. Nebulised antibiotherapy may play a significant role in future pulmonary drug delivery treatments as it offers the potential to achieve both a high local drug concentration and a lower systemic toxicity. In this review, the physicochemical parameters required for optimal deposition to the lung in addition to the main characteristics of currently available formulations and nebuliser types are discussed. Particular attention will be focused on emerging nanotechnology based approaches which are revolutionizing inhaled therapies used to treat both infections and lung cancer. Promising carriers such as Trojan-Horse microparticles, liposomes, polymeric and lipid nanoparticulate systems have been investigated and proposed as viable options. In order to achieve site-specific targeting and to optimize the PK/PD balance critical nanoscale design parameters such as particle size, morphology, composition, rigidity and surface chemistry architecture must be controlled. Development of novel excipients to manufacture these nanomedicines and assessment of their toxicity is also a keystone and will be discussed in this review.

La falta de seguridad del paciente es un problema de salud pública a nivel mundial que afecta todos los países independientemente de su nivel de desarrollo. La Alianza Mundial para la Seguridad del Paciente (World Alliance for Patient Safety) promueve esfuerzos mundiales encaminados a mejorar la seguridad de la atención de los pacientes de todos los Estados Miembros de la Organización Mundial de la Salud (OMS). La Anestesiología comparte responsabilidades para la calidad y la seguridad en Anestesia, Cuidados Intensivos, Medicina de Urgencias y Medicina del Dolor, incluido todo el proceso perioperatorio, así como en muchas otras situaciones dentro y fuera del hospital en las que los pacientes son más vulnerables. Todas las instituciones deberían apoyar la “Safe Surgery Lives Initiative” (“Iniciativa la Cirugía Segura Salva Vidas”) de la OMS y su lista de verificación (check-list del paciente quirúrgico).

La cateterización de la vía subclavia suele verse como un procedimiento peligroso que puede producir complicaciones comprometedoras para la vida del paciente. Aunque se ha descrito como fiable, relativamente seguro y fácil de realizar, esta opinión no es uniformemente compartida. Los estudios acerca de las complicaciones de este abordaje en el caso de pacientes sometidos a ventilación mecánica son realmente inexistentes. La vía supraclavicular, introducida en la práctica clínica a mediados de los años 60 del siglo pasado, perdió adeptos tras la popularización de la yugular interna, por su menor riesgo de complicaciones en general y, en especial, de neumotórax en pacientes con ventilación mecánica. Actualmente, no hay acuerdo acerca de cuál es el mejor abordaje central ni en qué situaciones es mejor uno u otro.

"El desarrollo de la arquitectura salomónica en la Nueva España se explica a partir de la influencia que ejercieron los tres principales tratadistas del "orden salomónico": Ricci, Caramuel y Guarini. A consecuencia de que los tratados de Ricci no fueron publicados sino hasta el año de 1930, ha motivado la creencia de que sus ideas pudieron ser difundidas a través de Guarini; sin embargo, la presencia de obras novohispanas con elementos ondeantes anteriores a las ediciones del tratado del teatino, abre interrogantes de interés respecto a la posible presencia de Ricci a través de otro tipo de fuentes. Más segura es la influencia de Caramuel, muy especialmenteen el siglo XVII cuando, pese a las interpretaciones propias de la región, resulta muy claro el conocimiento que tuvieron de su arquitectura recta y oblicua."

En este artículo se revisa la fisiología básica del gasto cardíaco y sus componentes para entender mejor los efectos de las alteraciones cardiovasculares en el paciente crítico y la mejor manera de tratarlo. El aporte de oxígeno (oxygen delivery, DO2) se determina por el gasto cardiaco y por el contenido arterial de oxígeno, que a su vez está determinado por la concentración de hemoglobina y por la saturación arterial de oxígeno. El gasto cardíaco tiene cuatro determinantes: frecuencia cardíaca, contractilidad, precarga y postcarga. Para entender al paciente y el impacto combinado de estos cuatro componentes, el Dr. Vincent sugiere una simple analogía que equipara el gasto cardíaco, es decir, la cantidad de sangre bombeada por el corazón en un período de tiempo, a la velocidad de una bicicleta. La frecuencia cardíaca equivale a la velocidad de pedaleo. El aumento de la frecuencia cardíaca puede afectar al llenado del ventrículo izquierdo y por tanto, reducir el volumen de eyección pudiendo ser perjudicial dado que, la frecuencia cardíaca es un determinante fundamental en la demanda de oxígeno miocárdico. La frecuencia cardiaca óptima para cada paciente es difícil de determinar ya que depende de la contractilidad intrínseca, del volumen intravascular, del estado adrenérgico y de la función diastólica. La contractilidad depende de la fuerza muscular de la contracción. Sin embargo, la fuerza de contracción es también un determinante de las demandas miocárdicas de oxígeno y un aumento rápido puede dar lugar a fatiga, como sucede al ciclista que pedalea y tiene que reducir para finalmente detenerse. La precarga es el grado de distensión del miocardio. Depende del volumen intravascular, de la función diastólica y del tiempo (y por tanto, de la frecuencia cardíaca). La postcarga representa los elementos contra los cuales el ventrículo debe trabajar con el fin de extraer la sangre, y depende de la presión arterial y del tono vascular.

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Historia del Arte

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tesis que para obtener el grado de Doctorado en Historia del Arte, presenta Oscar Molina Palestina ; asesora Martha Fernández García295 páginas : ilustracionesDoctorado en Historia del Arte UNAM, Facultad de Filosofía y Letras, 2012

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