3D Printing Technologies in Personalized Medicine, Nanomedicines, and Biopharmaceuticals.

3D printing technologies enable medicine customization adapted to patients' needs. There are several 3D printing techniques available, but majority of dosage forms and medical devices are printed using nozzle-based extrusion, laser-writing systems, and powder binder jetting. 3D printing has been demonstrated for a broad range of applications in development and targeting solid, semi-solid, and locally applied or implanted medicines. 3D-printed solid dosage forms allow the combination of one or more drugs within the same solid dosage form to improve patient compliance, facilitate deglutition, tailor the release profile, or fabricate new medicines for which no dosage form is available. Sustained-release 3D-printed implants, stents, and medical devices have been used mainly for joint replacement therapies, medical prostheses, and cardiovascular applications. Locally applied medicines, such as wound dressing, microneedles, and medicated contact lenses, have also been manufactured using 3D printing techniques. The challenge is to select the 3D printing technique most suitable for each application and the type of pharmaceutical ink that should be developed that possesses the required physicochemical and biological performance. The integration of biopharmaceuticals and nanotechnology-based drugs along with 3D printing ("nanoprinting") brings printed personalized nanomedicines within the most innovative perspectives for the coming years. Continuous manufacturing through the use of 3D-printed microfluidic chips facilitates their translation into clinical practice.

Extended-Release Naltrexone and Case Management for Treatment of Alcohol Use Disorder in the Emergency Department.

STUDY OBJECTIVE: To assess the feasibility of initiating treatment for alcohol use disorder with extended-release naltrexone and case management services in the emergency department (ED) and measure the intervention's impact on daily alcohol consumption and quality of life. METHODS: This is a 12-week prospective open-label single-arm study of a multimodal treatment for alcohol use disorder consisting of monthly extended-release naltrexone injections and case management services initiated at an urban academic ED. Participants were actively drinking adult patients in ED with known or suspected alcohol use disorder and an AUDIT-C score more than 4. The main feasibility outcomes included the rates of participant enrollment, retention in the study, and continuing treatment after study completion. Efficacy outcomes were the change in daily alcohol consumption (drinks per day; 14 g ethanol per drink), measured by a 14-day timeline followback, and the change in quality of life measured with a single-item Kemp quality of life scale. RESULTS: One hundred seventy-nine patients were approached, and 32 were enrolled (18%). Of the 32 enrolled patients, 25 (78%) completed all visits, and 22 (69%) continued naltrexone after the trial. The mean baseline daily alcohol consumption was 7.6 drinks per day (interquartile range, 4.5, 13.4), and the mean quality of life was 3.6 (SD 1.7) on a 7-point scale. The median daily alcohol consumption change was -7.5 drinks per day (Hodges-Lehmann 95% confidence interval -8.6, -5.9). The mean quality of life change was 1.2 points (95% confidence interval 0.5, 1.9; P<.01). CONCLUSION: We found that initiation of treatment of alcohol use disorder with extended-release naltrexone and case management is feasible in an ED setting and observed significant reductions in drinking with improved quality of life in the short term. Multicenter randomized controlled trials are needed to further validate these findings.

Drug Stability: ICH versus Accelerated Predictive Stability Studies.

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), along with the World Health Organization (WHO), has provided a set of guidelines (ICH Q1A-E, Q3A-B, Q5C, Q6A-B) intended to unify the standards for the European Union, Japan, and the United States to facilitate the mutual acceptance of stability data that are sufficient for registration by the regulatory authorities in these jurisdictions. Overall, ICH stability studies involve a drug substance tested under storage conditions and assess its thermal stability and sensitivity to moisture. The long-term testing should be performed over a minimum of 12 months at 25 °C ± 2 °C/60% RH ± 5% RH or at 30 °C ± 2 °C/65% RH ± 5% RH. The intermediate and accelerated testing should cover a minimum of 6 months at 30 °C ± 2 °C/65% RH ± 5% RH (which is not necessary if this condition was utilized as a long-term one) and 40 °C ± 2 °C/75% RH ± 5% RH, respectively. Hence, the ICH stability testing for industrially fabricated medicines is rigorous and tedious and involves a long period of time to obtain preclinical stability data. For this reason, Accelerated Predictive Stability (APS) studies, carried out over a 3-4-week period and combining extreme temperatures and RH conditions (40-90 °C)/10-90% RH, have emerged as novel approaches to predict the long-term stability of pharmaceutical products in a more efficient and less time-consuming manner. In this work, the conventional ICH stability studies versus the APS approach will be reviewed, highlighting the advantages and disadvantages of both strategies. Furthermore, a comparison of the stability requirements for the commercialization of industrially fabricated medicines versus extemporaneous compounding formulations will be discussed.

Screen for Small-Molecule Modulators of Circadian Rhythms Reveals Phenazine as a Redox-State Modifying Clockwork Tuner.

A high-throughput cell-based screen identified redox-active small molecules that produce a period lengthening of the circadian rhythm. The strongest period lengthening phenotype was induced by a phenazine carboxamide (VU661). Comparison to two isomeric benzquinoline carboxamides (VU673 and VU164) shows the activity is associated with the redox modulating phenazine functionality. Furthermore, ex vivo cell analysis using optical redox ratio measurements shows the period lengthening phenotype to be associated with a shift to the NAD/FAD oxidation state of nicotinamide and flavine coenzymes.

Rare-Earth Supported Nickel Catalysts for Alkyne Semihydrogenation: Chemo- and Regioselectivity Impacted by the Lewis Acidity and Size of the Support.

Bimetallic catalysts of nickel(0) with a trivalent rare-earth ion or Ga(III), NiML3 (where L is [iPr2PCH2NPh]-, and M is Sc, Y, La, Lu, or Ga), were investigated for the selective hydrogenation of diphenylacetylene (DPA) to (E)-stilbene. Each bimetallic complex features a relatively short Ni-M bond length, ranging from 2.3395(8) Å (Ni-Ga) to 2.5732(4) Å (Ni-La). The anodic peak potentials of the NiML3 complexes vary from -0.48 V to -1.23 V, where the potentials are negatively correlated with the Lewis acidity of the M(III) ion. Three catalysts, Ni-Y, Ni-Lu, and Ni-Ga, showed nearly quantitative conversions in the semihydrogenation of DPA, with NiYL3 giving the highest selectivity for (E)-stilbene. Initial rate studies were performed on the two tandem catalytic reactions: DPA hydrogenation and (Z)-stilbene isomerization. The catalytic activity in DPA hydrogenation follows the order Ni-Ga > Ni-La > Ni-Y > Ni-Lu > Ni-Sc. The ranking of catalysts by (Z)-stilbene isomerization initial rates is Ni-Ga ≫ Ni-Sc > Ni-Lu > Ni-Y > Ni-La. In operando 31P and 1H NMR studies revealed that in the presence of DPA, the Ni bimetallic complexes supported by Y, Lu, and La form the Ni(η2-alkyne) intermediate, (η2-PhC≡CPh)Ni(iPr2PCH2NPh)2M(κ2-iPr2PCH2NPh). In contrast, the Ni-Ga resting state is the Ni(η2-H2) species, and Ni-Sc showed no detectable binding of either substrate. Hence, the mechanism of Ni-catalyzed diphenylacetylene semihydrogenation adheres to two different kinetics: an autotandem pathway (Ni-Ga, Ni-Sc) versus temporally separated tandem reactions (Ni-Y, Ni-Lu, Ni-La). Collectively, the experimental results demonstrate that modulating a base-metal center via a covalently appended Lewis acidic support is viable for promoting selective alkyne semihydrogenation.

Multiple Bonds in Uranium-Transition Metal Complexes.

Novel heterobimetallic complexes featuring a uranium atom paired with a first-row transition metal have been computationally predicted and analyzed using density functional theory and multireference wave function based methods. The synthetically inspired metalloligands U{(iPr2PCH2NAr)3tacn} (1) and U(iPr2PCH2NPh)3 (2) are explored in this study. We report the presence of multiple bonds between uranium and chromium, uranium and manganese, and uranium and iron. The calculations predict a 5-fold bonding between uranium and manganese in the UMn(iPr2PCH2NPh)3 complex, which is unprecedented in the literature.

Bimetallic nickel-lutetium complexes: tuning the properties and catalytic hydrogenation activity of the Ni site by varying the Lu coordination environment.

We present three heterobimetallic complexes containing an isostructural nickel center and a lutetium ion in varying coordination environments. The bidentate iPr2PCH2NHPh and nonadentate (iPr2PCH2NHAr)3tacn ligands were used to prepare the Lu metalloligands, Lu(iPr2PCH2NPh)3 (1) and Lu{(iPr2PCH2NAr)3tacn} (2), respectively. Reaction of Ni(COD)2 (where COD is 1,5-cyclooctadiene) and 1 afforded NiLu(iPr2PCH2NPh)3 (3), with a Lu coordination number (CN) of 4 and a Ni-Lu distance, d(Ni-Lu), of 2.4644(2) Å. Complex 3 can further bind THF to form 3-THF, increasing both the Lu CN to 5 and d(Ni-Lu) to 2.5989(4) Å. On the other hand, incorporation of Ni(0) into 2 provides NiLu{(iPr2PCH2NAr)3tacn} (4), in which the Lu coordination environment is more saturated (CN = 6), and the d(Ni-Lu) is substantially elongated at 2.9771(5) Å. Cyclic voltammetry of the three Ni-Lu complexes shows an overall ∼410 mV shift in the Ni(0/I) redox couple, suggesting tunability of the Ni electronics across the series. Computational studies reveal polarized bonding interactions between the Ni 3d z 2 (major) and the Lu 5d z 2 (minor) orbitals, where the percentage of Lu character increases in the order: 4 (6.0% Lu 5d z 2 ) < 3-THF (8.5%) < 3 (9.3%). All three Ni-Lu complexes bind H2 at low temperatures (-30 to -80 °C) and are competent catalysts for styrene hydrogenation. Complex 3 outperforms 4 with a four-fold faster rate. Additionally, adding increasing THF equivalents to 3, which would favor build-up of 3-THF, decreases the rate. We propose that altering the coordination sphere of the Lu support can influence the resulting properties and catalytic activity of the active Ni(0) metal center.

Características de exámenes escritos, asignaturas de patología, carrera medicina, Universidad Nacional Autónoma de Honduras / Characteristics of written examinations, Pathology courses, medical career, National Autonomous University of Honduras

Los exámenes escritos como parte de la evaluación de los aprendizajes son un mecanismo regulador del proceso educativo, que permite comprobar si se adquirieronlas habilidades y destrezas planificadas. Objetivo: Determinar las características y habilidadescognitivas valoradas enlos exámenes escritos de las asignaturas de Patología, Carrera de Medicina. Material y Métodos: Estudio transversal descriptivo. La unidad de análisis consistió en exámenes escritosde la asignatura de Patología I con 49 preguntas y Patología II con 46, realizados en el primer semestre del 2017. El número de secciones fueron 14; 6 en Patología I y 8 en Patología II, con un total de 433 estudiantes. Losexámenes revisados fueron del primer y último parcial 862; 296 en Patología I y 566 en Patología II. Se revisaron 1 324 preguntas, clasificándose según habilidad cognitiva memoria, compresión, análisis y síntesis. Para el análisis de los datos se utilizaronlos programas SPSS y Excel. Resultados: En las asignaturas de Patología I y II, se aplicaron exámenes escritos unificados; se emplearon 3 tipos de reactivos; selección única 30(61%) y 30(65%); completación 15(31%) y 10(22%);enumeración 4(8%) y 6(13%), respectivamente. Las habilidades cognitivas: memoria 71(72.5%)y 74(80.5%); comprensión 22(22.5%) y 17(18.5%);1Profesor Titular II, Departamento de Psiquiatría, UNAH.2 Profesor Titular IV, Departamento de Patología, UNAH.3 Pedagoga UTES, UNAH.4 Profesor Titular I, Departamento Ciencias Morfológicas, UNAH. 5 Asistente Técnico UTES, UNAH.Autor de correspondencia: nsabillon2002@yahoo.esRecibido: 25/6/18 Aceptado: 6/11/18análisis 5( 5%) y 1(1%). El número de preguntas acertadas en las habilidades cognitivas de patología 1 fue: memoria 7 250, comprensión 2 206 y análisis 468. El porcentaje de aciertos por habilidades cognitivas, fue: 50% y 57.3% en memoria; 15.2 % y 12.2 % en comprensión; 3.2 % y 1.1% en análisis. Conclusión: En la evaluación de los aprendizajes, mediante exámenes escritos en las asignaturas de Patología, el tipo de pregunta de mayor frecuencia fue selección única yla habilidad cognitiva más evaluada y acertada fue memoria...(AU)

A strategy for dual inhibition of the proteasome and fatty acid synthase with belactosin C-orlistat hybrids.

The proteasome, a validated cellular target for cancer, is central for maintaining cellular homeostasis, while fatty acid synthase (FAS), a novel target for numerous cancers, is responsible for palmitic acid biosynthesis. Perturbation of either enzymatic machine results in decreased proliferation and ultimately cellular apoptosis. Based on structural similarities, we hypothesized that hybrid molecules of belactosin C, a known proteasome inhibitor, and orlistat, a known inhibitor of the thioesterase domain of FAS, could inhibit both enzymes. Herein, we describe proof-of-principle studies leading to the design, synthesis and enzymatic activity of several novel, ß-lactone-based, dual inhibitors of these two enzymes. Validation of dual enzyme targeting through activity-based proteome profiling with an alkyne probe modeled after the most potent inhibitor, and preliminary serum stability studies of selected derivatives are also described. These results provide proof of concept for dual targeting of the proteasome and fatty acid synthase-thioesterase (FAS-TE) enabling a new approach for the development of drug-candidates with potential to overcome resistance.

Polystyrenesulfonate-catalyzed synthesis of novel pyrroles through Paal-Knorr reaction.

BACKGROUND: The classical Paal-Knorr reaction is one of the simplest and most economical methods for the synthesis of biologically important and pharmacologically useful pyrrole derivatives. RESULTS: Polystyrenesulfonate-catalyzed simple synthesis of substituted pyrroles following Paal-Knorr reaction has been accomplished with an excellent yield in aqueous solution. This method also produces pyrroles with multicyclic polyaromatic amines. CONCLUSIONS: The present procedure for the synthesis of N-polyaromatic substituted pyrroles will find application in the synthesis of potent biologically active molecules.