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BACKGROUND: Although videolaryngoscopy has been proposed as a default technique for tracheal intubation in children, published evidence on universal videolaryngoscopy implementation programmes is scarce. We aimed to determine if universal, first-choice videolaryngoscopy reduces the incidence of restricted glottic views and to determine the diagnostic performance of the Cormack and Lehane classification to discriminate between easy and difficult videolaryngoscopic tracheal intubations in children. METHODS: We conducted a prospective observational study within a structured universal videolaryngoscopy implementation programme. We used C-MAC™ (Karl Storz, Tuttlingen, Germany) videolaryngoscopes in all anaesthetised children undergoing elective tracheal intubation for surgical procedures. The direct and videolaryngoscopic glottic views were classified using a six-stage grading system. RESULTS: There were 904 tracheal intubations in 809 children over a 16-month period. First attempt and overall success occurred in 607 (67%) and 903 (> 99%) tracheal intubations, respectively. Difficult videolaryngoscopic tracheal intubation occurred in 47 (5%) and airway-related adverse events in 42 (5%) tracheal intubations. Direct glottic view during laryngoscopy was restricted in 117 (13%) and the videolaryngoscopic view in 32 (4%) tracheal intubations (p < 0.001). Videolaryngoscopy improved the glottic view in 57/69 (83%) tracheal intubations where the vocal cords were only just visible, and in 44/48 (92%) where the vocal cords were not visible by direct view. The Cormack and Lehane classification discriminated poorly between easy and difficult videolaryngoscopic tracheal intubations with a mean area under the receiver operating characteristic curve of 0.68 (95%CI 0.59-0.78) for the videolaryngoscopic view compared with 0.80 (95%CI 0.73-0.87) for the direct glottic view during laryngoscopy (p = 0.005). CONCLUSIONS: Universal, first-choice videolaryngoscopy reduced substantially the incidence of restricted glottic views. The Cormack and Lehane classification was not a useful tool for grading videolaryngoscopic tracheal intubation in children.
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BACKGROUND: It is not certain whether the blade geometry of videolaryngoscopes, either a hyperangulated or Macintosh shape, affects glottic view, success rate and/or tracheal intubation time in patients with expected difficult airways. We hypothesised that using a hyperangulated videolaryngoscope blade would visualise a higher percentage of glottic opening compared with a Macintosh videolaryngoscope blade in patients with expected difficult airways. METHODS: We conducted an open-label, patient-blinded, randomised controlled trial in adult patients scheduled to undergo elective ear, nose and throat or oral and maxillofacial surgery, who were anticipated to have a difficult airway. All airway operators were consultant anaesthetists. Patients were allocated randomly to tracheal intubation with either hyperangulated (C-MAC D-BLADE™) or Macintosh videolaryngoscope blades (C-MAC™). The primary outcome was the percentage of glottic opening. First attempt success was designated a key secondary outcome. RESULTS: We assessed 2540 adults scheduled for elective head and neck surgery for eligibility and included 182 patients with expected difficult airways undergoing orotracheal intubation. The percentage of glottic opening visualised, expressed as median (IQR [range]), was 89 (69-99 [0-100])% with hyperangulated videolaryngoscope blades and 54 (9-90 [0-100])% with Macintosh videolaryngoscope blades (p < 0.001). First-line hyperangulated videolaryngoscopy failed in one patient and Macintosh videolaryngoscopy in 12 patients (13%, p = 0.002). First attempt success rate was 97% with hyperangulated videolaryngoscope blades and 67% with Macintosh videolaryngoscope blades (p < 0.001). CONCLUSIONS: Glottic view and first attempt success rate were superior with hyperangulated videolaryngoscope blades compared with Macintosh videolaryngoscope blades when used by experienced anaesthetists in patients with difficult airways.
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Manejo de la Vía Aérea , Intubación Intratraqueal , Laringoscopios , Laringoscopía , Humanos , Laringoscopía/métodos , Laringoscopía/instrumentación , Masculino , Femenino , Persona de Mediana Edad , Intubación Intratraqueal/instrumentación , Intubación Intratraqueal/métodos , Adulto , Manejo de la Vía Aérea/métodos , Manejo de la Vía Aérea/instrumentación , Anciano , Grabación en Video , Glotis , Diseño de Equipo , Método Simple Ciego , Procedimientos y Técnicas Asistidas por VideoRESUMEN
This report describes a patient with Goldenhar syndrome undergoing anesthesia for whom Macintosh videolaryngoscopy failed, as the epiglottis was adhered to the posterior pharynx and could not be lifted with a tracheal introducer (Cormack-Lehane grade 3B). Hyperangulated videolaryngoscopy revealed only the arytenoids (Cormack-Lehane grade 2B), even after direct lifting of the epiglottis, and endotracheal tube advancement failed due to unclear tissue resistance. Hyperangulated videolaryngoscopy was combined with a tube-mounted camera (VivaSight single lumen tube). The combination of both camera perspectives was successfully used to allow placement of the endotracheal tube underneath the epiglottis and through the vocal cords.
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Síndrome de Goldenhar , Laringoscopios , Síndrome de Goldenhar/complicaciones , Síndrome de Goldenhar/cirugía , Humanos , Intubación Intratraqueal , LaringoscopíaRESUMEN
BACKGROUND: Giardia lamblia is a common cause of diarrhoea in returning travellers. Failure of the recommended first-line treatment, metronidazole, has frequently been observed. Recommendations for treatment of metronidazole-refractory giardiasis lack clarity and evidence. METHODS: We conducted a retrospective data analysis of returned travellers with confirmed giardiasis at the Bernhard-Nocht-Clinic in Hamburg, Germany, between 2007 and 2016. RESULTS: We identified 339 cases of giardiasis, mostly acquired in South Asia (n = 157). 308 patients received metronidazole as first-line treatment, leading to treatment failure in 93 cases. Statistical analysis suggested by far the highest risk of metronidazole treatment failure for travellers returning from South Asia (Odds Ratio 8.73). Second-line therapy consisted of various different therapy regimens. Combination therapy as second-line treatment seemed to be more effective than monotherapy. A repeat course of metronidazole proved to be futile. CONCLUSION: This study reveals a strikingly low effectiveness of metronidazole, especially in patients returning from South Asia. Second-line treatment showed inconsistency of regimens and yielded unsatisfactory results. These findings require reconsideration of treatment strategies for giardiasis. Large prospective trials are urgently needed to assess new first-line treatment options and to help implement advice for effective, agreed second-line treatment strategies. Translational projects should be created to link the understanding of resistance mechanisms with epidemiological data and clinical outcome.
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Antiprotozoarios , Giardia lamblia , Giardiasis , Antiprotozoarios/uso terapéutico , Giardiasis/tratamiento farmacológico , Giardiasis/epidemiología , Humanos , Metronidazol/uso terapéutico , Estudios Prospectivos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Background: Tracheal intubation in patients with an expected difficult airway may be facilitated by videolaryngoscopy (VL). The VL viewing axis angle is specified by the blade shape and visualization of the larynx may fail if the angle does not meet anatomy of the patient. A tube with an integrated camera at its tip (VST, VivaSight-SL) may be advantageous due to its adjustable viewing axis by means of angulating an included stylet. Methods: With ethics approval, we studied the VST vs. VL in a prospective non-inferiority trial using end-tidal oxygen fractions (etO2) after intubation, first-attempt success rates (FAS), visualization assessed by the percentage of glottis opening (POGO) scale, and time to intubation (TTI) as outcome parameters. Results: In this study, 48 patients with a predicted difficult airway were randomized 1:1 to intubation with VST or VL. Concerning oxygenation, the VST was non-inferior to VL with etO2 of 0.79 ± 0.08 (95% CIs: 0.75-0.82) vs. 0.81 ± 0.06 (0.79-0.84) for the VL group, mean difference 0.02 (-0.07 to 0.02), p = 0.234. FAS was 79% for VST and 88% for VL (p = 0.449). POGO was 89 ± 21% in the VST-group and 60 ± 36% in the VL group, p = 0.002. TTI was 100 ± 57 s in the VST group and 68 ± 65 s in the VL group (p = 0.079). TTI with one attempt was 84 ± 31 s vs. 49 ± 14 s, p < 0.001. Conclusion: In patients with difficult airways, tracheal intubation with the VST is feasible without negative impact on oxygenation, improves visualization but prolongs intubation. The VST deserves further study to identify patients that might benefit from intubation with VST.
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Pharmaceutical legislation provides a legal framework to ensure the safe and effective use of medicines. This framework requires national regulatory authorities (NRAs) to establish and maintain a pharmacovigilance system (PV system) stating and enforcing the regulatory commitments that key stakeholders, including marketing authorisation holders (MAHs), are required to fulfil. In recent years, national legislative bodies and NRAs across the world have issued a significant amount of legislation and guidance enforcing the obligation to perform pharmacovigilance activities. In countries where the NRA is a member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), safety management requirements are generally consistent with ICH guidelines. In a number of countries beyond this scope, requirements may deviate from internationally agreed standards, adding a substantial complexity and increasing burden on the stakeholders involved, whilst the benefit for patients' safety may not be evident. Committed to fulfilling safety-regulatory obligations in any country where a product licence is held, global pharmaceutical companies have accumulated a broad and deep experience acquired whilst meeting the expectations of a large array of diverse PV systems across the world. These range from sub-optimal frameworks, according to the World Health Organization (WHO) Global Benchmarking Tool, to highly effective resource-optimised PV systems. In order to support countries creating or further developing their PV systems, especially where infrastructure and resources are limited, the European Federation of Pharmaceutical Industries and Associations (EFPIA) International Pharmacovigilance Group (IPVG) has developed consensus recommendations consistent with harmonised standards for the development and step-wise implementation of key PV system components. These recommendations endorsed by the EFPIA membership constitute the focus of this review article.
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Industria Farmacéutica , Farmacovigilancia , Consenso , Humanos , Seguridad del Paciente , Organización Mundial de la SaludRESUMEN
Imiquimod, a toll-like receptor 7 (TLR7) agonist, is an active pharmaceutical ingredient (API) established for the topical treatment of several dermal cancerous and precancerous skin lesions. Within this work, the immunostimulatory effect of imiquimod is further exploited in a transcutaneous immunization (TCI) approach based on a solid nanoemulsion (SN) formulation. SN contains a combination of imiquimod with the model peptide antigen SIINFEKL as a novel approach to omit needle and syringe and optimize dermal antigen administration. Excipients including sucrose fatty acid esters and the pharmaceutically acceptable oils MCT (middle chain triglycerides), avocado oil, jojoba wax and squalene are high pressure homogenized together with the antigen SIINFEKL. Freeze drying was performed to eliminate water and to achieve spreadable properties of the formulation for dermal administration. The influence of the different oil components was assessed regarding in vitro drug permeation in a Franz diffusion cell model using a murine skin setup. In vivo performance in terms of cytotoxic T-cell response was assessed in a C57BL/6 mouse model. Whereas Aldara® cream contains imiquimod in a dissolved state, the SN formulations carry the active in a suspended state. This resulted in a reduction of imiquimod permeation across murine skin from the SN when compared to Aldara® cream. In spite of this permeation rate reduction, each SN induced an in vivo immune response by specific T-cell lysis. A stabilized solid nanosuspension containing squalene/tocopherol exhibited a significantly higher performance (p⩽0.05) in comparison with Aldara® cream. MCT based SN exerted an in vivo effect comparable to Aldara®. In conclusion, anhydrous highly dispersed vehicles containing imiquimod in a submicron particle size distribution can represent promising formulations for TCI. The choice of the oil component has a strong influence on SN performance, independent of in vitro drug permeation.
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Adyuvantes Inmunológicos/administración & dosificación , Aminoquinolinas/uso terapéutico , Antineoplásicos/uso terapéutico , Sistemas de Liberación de Medicamentos , Células de Langerhans/inmunología , Nanoestructuras/administración & dosificación , Lesiones Precancerosas/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adyuvantes Inmunológicos/química , Administración Cutánea , Animales , Química Farmacéutica , Humanos , Imiquimod , Inmunización , Ratones , Ratones Endogámicos C57BL , Nanoestructuras/química , Aceites/química , VacunaciónRESUMEN
BACKGROUND: Neutron capture therapy for glioblastoma has focused mainly on the use of (10)B as neutron capture isotope. However, (157)Gd offers several advantages over boron, such as higher cross section for thermal neutrons and the possibility to perform magnetic resonance imaging during neutron irradiation, thereby combining therapy and diagnostics. We have developed different liposomal formulations of gadolinium-DTPA (Magnevist®) for application in neutron capture therapy of glioblastoma. The formulations were characterized physicochemically and tested in vitro in a glioma cell model for their effectiveness. METHODS: Liposomes entrapping gadolinium-DTPA as neutron capture agent were manufactured via lipid/film-extrusion method and characterized with regard to size, entrapment efficiency and in vitro release. For neutron irradiation, F98 and LN229 glioma cells were incubated with the newly developed liposomes and subsequently irradiated at the thermal column of the TRIGA reactor in Mainz. The dose rate derived from neutron irradiation with (157)Gd as neutron capturing agent was calculated via Monte Carlo simulations and set in relation to the respective cell survival. RESULTS: The liposomal Gd-DTPA reduced cell survival of F98 and LN229 cells significantly. Differences in liposomal composition of the formulations led to distinctly different outcome in cell survival. The amount of cellular Gd was not at all times proportional to cell survival, indicating that intracellular deposition of formulated Gd has a major influence on cell survival. The majority of the dose contribution arises from photon cross irradiation compared to a very small Gd-related dose. CONCLUSIONS: Liposomal gadolinium formulations represent a promising approach for neutron capture therapy of glioblastoma cells. The liposome composition determines the uptake and the survival of cells following radiation, presumably due to different uptake pathways of liposomes and intracellular deposition of gadolinium-DTPA. Due to the small range of the Auger and conversion electrons produced in (157)Gd capture, the proximity of Gd-atoms to cellular DNA is a crucial factor for infliction of lethal damage. Furthermore, Gd-containing liposomes may be used as MRI contrast agents for diagnostic purposes and surveillance of tumor targeting, thus enabling a theranostic approach for tumor therapy.
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Neoplasias Encefálicas/radioterapia , Proliferación Celular/efectos de la radiación , Glioma/radioterapia , Liposomas , Terapia por Captura de Neutrón , Neutrones , Neoplasias Encefálicas/patología , Medios de Contraste/farmacocinética , Gadolinio DTPA/farmacocinética , Glioma/patología , Humanos , Técnicas In Vitro , Imagen por Resonancia Magnética/métodos , Método de Montecarlo , Células Tumorales CultivadasRESUMEN
The [(18)F]fluoroethyl moiety has been widely utilized in the synthesis of (18)F-labelled compounds. The aim of this work was the reliable synthesis of [(18)F]FEtOTf with a novel strategy to increase the reactivity of the commonly used [(18)F]FEB and [(18)F]FEtOTos. [(18)F]FEtOTf and the intermediate [(18)F]FEtOH were synthesized in high RCY (78% and 85%, respectively) and purified by SPE. The high potency of [(18)F]FEtOTf was shown by the efficient alkylation of the deactivated nucleophile aniline under mild conditions, as well as by the synthesis of [(18)F]FEC.
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Radioisótopos de Flúor/química , Radioisótopos de Flúor/aislamiento & purificación , Marcaje Isotópico/métodos , Mesilatos/síntesis química , Mesilatos/aislamiento & purificación , Radiofármacos/síntesis química , Radiofármacos/aislamiento & purificación , Compuestos de Vinilo/químicaRESUMEN
For studying proliferation and determination of survival of cancer cells after irradiation, the multiple MTT assay, based on the reduction of a yellow water soluble tetrazolium salt to a purple water insoluble formazan dye by living cells was modified from a single-point towards a proliferation assay. This assay can be performed with a large number of samples in short time using multi-well-plates, assays can be performed semi-automatically with a microplate reader. Survival, the calculated parameter in this assay, is determined mathematically. Exponential growth in both control and irradiated groups was proven as the underlying basis of the applicability of the multiple MTT assay. The equivalence to a clonogenic survival assay with its disadvantages such as time consumption was proven in two setups including plating of cells before and after irradiation. Three cell lines (A 549, LN 229 and F 98) were included in the experiment to study its principal and general applicability.
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Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular/efectos de la radiación , Glioblastoma/patología , Neoplasias Pulmonares/patología , Ensayo de Tumor de Célula Madre , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Supervivencia Celular/efectos de la radiación , Rayos gamma , Glioblastoma/tratamiento farmacológico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Células Tumorales CultivadasRESUMEN
The directionality of interaction of electron-deficient π systems with spherical anions (e.g,. halides) can be controlled by secondary effects like NH or CH hydrogen bonding. In this study a series of pentafluorophenyl-substituted salts with polyhalide anions is investigated. The compounds are obtained by aerobic oxidation of the corresponding halide upon crystallization. Solid-state structures reveal that in bromide 2, directing NH-anion interactions position the bromide ion in an η(1)-type fashion over but not in the center of the aromatic ring. The same directing forces are effective in corresponding tribromide salt 3. In the crystal, the bromide ion is paneled by four electron-deficient aromatic ring systems. In addition, compounds 4 and 6, which have triiodide and the rare tetraiodide dianion as anions, are described. Computational studies reveal that the latter is highly unstable. In the present case it is stabilized by the crystal lattice, for example, by interaction with electron-deficient π systems.
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Monastrol is the first characterised small molecule inhibitor of the motor protein Eg5 involved in bipolar mitotic spindle assembly. Eg5 localises to microtubules in mitosis, but not to interphase microtubules, suggesting that Eg5 inhibitors may be useful to specifically target proliferating tumour tissue, thereby avoiding dose-limiting neuropathy observed with other antimicrotubule agents like taxanes or vinca alkaloids. Because other antimicrotubule agents fail in multidrug resistance associated with P-glycoprotein (Pgp) over-expression, we investigated the interaction of monastrol with Pgp in vitro. By means of the calcein assay (with P388/dx cells and primary porcine brain capillary endothelial cells) and confocal laser-scanning microscopy (with L-MDR1 cells) we demonstrated that monastrol is a weak inhibitor of Pgp in vitro, with f2 values being about two orders of magnitude greater than those of the well-known inhibitors verapamil and quinidine. Monastrol also induces Pgp in vitro as measured by mRNA expression in LS180 cells after incubation with monastrol. However, its effect is weak compared to rifampicin. Whilst it reveals weak inhibitory and inductive characteristics, monastrol appears to be not transported by Pgp, as indicated by the lack of difference in the antiproliferative effect of this compound in cell lines with and without over-expression of Pgp. The observed interaction profile of monastrol with Pgp is promising for the development of other more potent Eg5 inhibitors.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Antimitóticos/farmacología , Cinesinas/antagonistas & inhibidores , Pirimidinas/farmacología , Tionas/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Fluoresceínas/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Células LLC-PK1 , Ratones , Microscopía Confocal , Paclitaxel/farmacología , ARN Mensajero/metabolismo , Porcinos , Tubulina (Proteína)/metabolismoRESUMEN
Eniporide (EMD 96 875) is a novel and selective inhibitor of the Na+-H+ exchange (NHE-1) inhibitor. The study objectives were to identify a structural model for population pharmacokinetic analysis of eniporide and its metabolite (EMD 112 843) using nonlinear mixed-effects modeling after short-term infusion (dose: 2.5-400 mg) in healthy subjects and patients undergoing myocardial reperfusion therapy. Pooled concentrations of eniporide and its metabolite from healthy subjects (n = 153; 4815 observations) and patients (n = 304; 1465 observations) were included in the pharmacokinetic analysis. Population estimates of clearance and volume of distribution of eniporide were 29.2 L/h (24.1% coefficient of variation [CV], healthy), 20.8 L/h (28.0% CV, patients) and 20.4 L (13.1% CV, healthy), 16.9 L (24.9% CV, patients), respectively. Statistical significance was achieved for the effect of age on clearance and creatinine clearance on volume of distribution of eniporide. The impact of the covariates on eniporide pharmacokinetics is minimal to warrant any dosage adjustments in patient population.