Encefalitis por inhibidores del punto de control inmunitario / Encephalitis associated to immune checkpoint inhibitors

Resumen Los inhibidores del punto de control inmunitario han demostrado mejorar el pronóstico de múltiples enfer medades oncológicas. Recientemente se han reportado eventos adversos relacionados a la inmunoterapia. La to xicidad neurológica es poco frecuente. Se presenta el caso de un paciente con encefalitis relacionada con inhibido res del punto de control inmunitario.

Abstract Immune checkpoint inhibitors have been shown to improve the prognosis of multiple oncological diseases. Recently, adverse events related to immunotherapy have been reported. Neurologic toxicity is infrequent. We pre sent the case of a patient with encephalitis associated to immune checkpoint inhibitors.

[Encephalitis associated to immune checkpoint inhibitors]. / Encefalitis por inhibidores del punto de control inmunitario.

Immune checkpoint inhibitors have been shown to improve the prognosis of multiple oncological diseases. Recently, adverse events related to immunotherapy have been reported. Neurologic toxicity is infrequent. We present the case of a patient with encephalitis associated to immune checkpoint inhibitors.

Los inhibidores del punto de control inmunitario han demostrado mejorar el pronóstico de múltiples enfermedades oncológicas. Recientemente se han reportado eventos adversos relacionados a la inmunoterapia. La toxicidad neurológica es poco frecuente. Se presenta el caso de un paciente con encefalitis relacionada con inhibidores del punto de control inmunitario.

Competencies for quality spiritual care in palliative care in Latin America: from the Spirituality Commission of the Latin American Association for Palliative Care.

Spiritual care is an essential part of quality palliative care. However, the literature regarding spiritual care competencies in Latin America is limited. Herein we propose the basic quality standards for spiritual care in palliative care according to best professional practices and provide a common vocabulary and required competencies for quality clinical spiritual care. Both elements, quality standards and a common vocabulary, are part of an essential step implementing continuous educational initiatives among interdisciplinary palliative care teams in Latin America. Members of the Spirituality Commission of the Latin American Association for Palliative Care and three members of independent professional palliative care organizations identified and reviewed our proposed spiritual care competencies and created a consensus document describing the competencies for general spiritual care. In the context of palliative care in Latin America, general spiritual care is provided by members of interdisciplinary teams. We proposed six competencies for high-quality general spiritual care and their observable behaviors that every member of an interdisciplinary palliative care team should have to provide quality clinical spiritual care in their daily practice: (I) personal, spiritual, and professional development; (II) ethics of spiritual care; (III) assessment of spiritual needs and spiritual care interventions; (IV) empathic and compassionate communication; (V) supportive and collaborative relationships among the interdisciplinary team; and (VI) inclusivity and diversity.

Solvent-Casted Films to Assist Polymer Selection for Amorphous Solid Dispersions During Preclinical Studies: In-vitro and In-vivo Exploration.

PURPOSE: The use of two solvent-casted film methods to select optimal polymer compositions for amorphous solid dispersions prepared to support preclinical pharmacokinetic and toxicology studies is described. METHODS: Evaporation of solvent from cover slips by using nitrogen flow, and solvent removal from vials by using rotary evaporation were employed. The films prepared on cover slips were evaluated under the microscope to determine crystallinity. The methods were validated by scaling up corresponding SDDs, evaluating SDD's dissolution, and comparing those results to the dissolution of drug-polymer films. Subsequently, SDD suspensions were prepared and dosed orally to rats to determine pharmacokinetic parameters. This was done by using three compounds from our pipeline and evaluating multiple polymers. RESULTS: The dissolution of generated films showed good agreement with the dissolution of spray dried dispersions when the films were fully amorphous (Compound A and B). In contrast, there was disagreement between film and SDD dissolution when the films had crystallized (Compound C). The in vivo exposure results indicated that the polymer choice based on the film screening methods would have been accurate for drug-polymer films that were amorphous (Compound A and B). Two additional case studies (Compound D and E) are presented, showing good agreement between in vivo and in vitro results. CONCLUSION: This study established the ability of two film casting screening methods to predict the in vitro and in vivo performance of corresponding SDDs, provided that the films are fully amorphous.

Ripple Effects of a Community-Based Randomized Trial for Rural Women: Strong Hearts, Healthy Communities.

OBJECTIVE: This study aimed to examine (1) whether the Strong Hearts, Healthy Communities intervention (SHHC) improved social network members' (SNMs') weight, exercise, and diet and (2) whether SNMs' weight and behavioral changes were modified by their relationship closeness and/or spatial closeness with trial participants. METHODS: Eight towns received the SHHC intervention, which focused on building individual healthy behaviors and creating supportive social and built environments for exercise and healthy eating. Eight towns received an education-only control intervention. SNMs (n = 487) were recruited to complete a questionnaire at baseline and at 6 months that asked about demographics, weight, height, exercise, and eating habits. RESULTS: SHHC's effect on SNMs differed depending on their relationship closeness with trial participants. Among SNMs who had a very close relationship with trial participants, those associated with the intervention group lost more weight and decreased BMI more than those associated with the control group (weight [kilograms] between-group difference: Δ = -1.68; 95% CI: -3.10 to -0.25; P = 0.021; BMI between-group difference: Δ = -0.60; 95% CI: -1.16 to -0.04; P = 0.034). Spatial closeness did not modify any of SHHC's ripple effects. CONCLUSIONS: Relationship closeness, rather than spatial closeness, played an important role in influencing a rural community-based intervention's ripple effects.

Efecto de cocción en horno convencional y microondas sobre rancidez, pérdida por cocción y diferencia sensorial de hamburguesas / Effect of conventional oven versus microwave cooking on rancidity, cooking loss and sensory difference of hamburger patties

El uso de microondas está muy extendido a nivel doméstico gracias a su rapidez y facilidad de uso. El objetivo del presente trabajo es comparar el efecto de cocción de hamburguesas de distintos tipos de carne, en microondas y en horno convencional, sobre la pérdida de peso y estabilidad oxidativa. Además, determinar si existen diferencias desde el punto de vista sensorial aplicando una prueba triangular, comparando 2 productos presentados en tríos, uno que corresponde a hamburguesa cocida en microondas y otro a hamburguesa cocida en horno convencional. Se adquirieron hamburguesas de pollo, pavo, cerdo y vacuno en el comercio, se cocinaron en horno convencional y en microondas. Se calculó pérdida por cocción, se evaluó la rancidez y diferencias sensoriales entre hamburguesas del mismo tipo de carne, cocidas en distinto tipo de horno. La pérdida por cocción fue menor en hamburguesas cocidas en microondas. La acidez e índice de peróxido aumentaron en las muestras cocidas en ambos tipos de hornos respecto a hamburguesas crudas. La acidez fue mayor en hamburguesas cocidas en horno convencional, y el índice de peróxido fue mayor en hamburguesas cocidas en microondas, llegando a 10,6 meq O2/kg. En el análisis sensorial se encontraron diferencias significativas (p<0,05) entre las hamburguesas cocidas en horno convencional y en microondas. Resulta mejor opción cocinar hamburguesas en horno convencional, ya que el índice de peróxidos es menor que al cocinar en microondas; dentro del tipo de hamburguesas, son más estables las de vacuno y cerdo frente a la oxidación.

The use of microwaves is very widespread at the domestic level thanks to its speed and ease of use. The aim of this study was to compare cooking loss, rancidity and sensory differences for hamburger patties cooked in conventional versus microwave ovens. We also determined sensorial differences with the triangular test, comparing two products presented in threesomes, one that corresponded to a patty cooked in the microwave and the other in a conventional oven. Chicken, turkey, pork and beef patties were purchased commercially, cooked in a conventional oven and in microwaves. Cooking loss was calculated, rancidity and sensory differences were evaluated between patties of the same type of meat and cooked in the different oven types. Cooking loss was lower in patties cooked in microwaves compared to those cooked in conventional ovens. For both oven types, acidity and peroxide index increased with respect to raw ones. Acidity was higher in hamburgers cooked in conventional ovens and the peroxide index was higher in burgers cooked in microwaves, reaching 10.6 meq O2/kg. In sensory analysis, significant differences were found (p<0.05) between patties cooked in a conventional oven and in microwaves. It is a better option to cook patties in a conventional oven, because the peroxide index is smaller than in microwaves; and within types of patties, beef and pork are more stable against oxidation.

Tunable Two-Compartment On-Demand Sustained Drug Release Based on Lipid Gels.

The binary-lipid system of soybean phosphatidylcholine (SPC) and glycerol dioleate (GDO) can hydrate to gels on contacting with aqueous mediums, which has emerged as a versatile and promising delivery matrix for extended drug release applications. In the present work, we have characterized the gelation process of this SPC/GDO lyotropic gel (SGLG) system by rheology and evaluated the drug release profiles from the SGLG formulations with different SPC/GDO mass ratios. Our study has demonstrated that simply adjusting the SPC/GDO mass ratio can tune the lipid gelation behavior and modulate the drug release profiles. More importantly, the drug release from the SGLG formulations follows a two-compartment (fast and slow release compartments) release kinetics that has not been reported before. We posit that the fast release compartment corresponds to the passive diffusion of the drug during the early stage of the gel formation. After the boundary gel phase generation, the drug release is then dominated by the slow diffusion process from SGLG. The pharmacokinetic studies in rats match well with the in vitro studies, suggesting that the binary-lipid formulation is an excellent candidate for on-demand sustained drug delivery system.

A polychromatic turbidity microplate assay to distinguish discovery stage drug molecules with beneficial precipitation properties.

A material sparing microplate screening assay was developed to evaluate and compare the precipitation of discovery stage drug molecules as a function of time, concentration and media composition. Polychromatic turbidity time course profiles were collected for cinnarizine, probucol, dipyridamole as well as BMS-932481, and compared with turbidity profiles of monodisperse particle size standards. Precipitation for select sample conditions were further characterized at several time points by size, morphology, amount and form via laser diffraction, microscopy, size based particle counting and X-ray diffraction respectively. Wavelength dependent turbidity was found indicative of nanoprecipitate, while wavelength independent turbidity was consistent with larger microprecipitate formation. A transition from wavelength dependent to wavelength independent turbidity occurred for nanoparticle to microparticle growth, and a decrease in wavelength independent turbidity correlated with continued growth in size of microparticles. Other sudden changes in turbidity signal over time such as rapid fluctuation, a decrease in slope or a sharp inversion were correlated with very large or aggregated macro-precipitates exceeding 100µm in diameter, a change in the rate of precipitate formation or an amorphous to crystalline form conversion respectively. The assay provides an effective method to efficiently monitor and screen the precipitation fates of drug molecules, even during the early stages of discovery with limited amounts of available material. This capability highlights molecules with beneficial precipitation properties that are able to generate and maintain solubility enabling amorphous or nanoparticle precipitates.

Improving Metabolic Stability with Deuterium: The Discovery of BMT-052, a Pan-genotypic HCV NS5B Polymerase Inhibitor.

Iterative structure-activity analyses in a class of highly functionalized furo[2,3-b]pyridines led to the identification of the second generation pan-genotypic hepatitis C virus NS5B polymerase primer grip inhibitor BMT-052 (14), a potential clinical candidate. The key challenge of poor metabolic stability was overcome by strategic incorporation of deuterium at potential metabolic soft spots. The preclinical profile and status of BMT-052 (14) is described.

The discovery of a pan-genotypic, primer grip inhibitor of HCV NS5B polymerase.

The development of a series of novel 7-azabenzofurans exhibiting pan-genotype inhibition of HCV NS5B polymerase via binding to the primer grip site is presented. Many challenges, including poor oral bioavailability, high clearance, bioactivation, high human serum shift, and metabolic stability were encountered and overcome through SAR studies. This work culminated in the selection of BMS-986139 (43) as a preclinical candidate.

Discovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily Dosing.

The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (2) is described. The objective of this work was the identification of a drug with antiviral properties and toxicology parameters similar to 2, but with a preclinical pharmacokinetic (PK) profile that was predictive of once-daily dosing. Critical to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compounds that, like 2, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 (1) from clinical trials. Structure-activity relationships (SARs) at each of the structural subsites in 2 were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Additional modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 (29).

Adaptation and Validation of the Instrument Treatment Outcomes Profile to the Chilean Population.

This study aims to psychometrically validate the Chilean version of the treatment outcomes profile (TOP), an instrument that can be used by treatment centers to monitor the results of drug and alcohol treatments. Specifically, this study is interested in evaluating the inter-rater reliability, concurrent validity, change sensitivity and discriminant and construct validity of this instrument. The TOP was modified to reflect the Chilean context and then applied in three successive stages: an initial application at the beginning of treatment, a retest after 1week, and a follow up after a month. The sample was composed of 411 users of different types of drugs who were in treatment centers in the three largest regions of the country. The TOP reliability was greater than .75 for most items. Regarding concurrent validity, all the coefficients were in the expected direction and statistically significant. Change over time, as measured by Cohen's d statistic and the Reliable Change Index, was significant for most items. Users in treatment for less than 3months showed higher alcohol consumption (odds ratio [OR]=1.07; 95% confidence interval [95% CI]: 1.01-1.13), poorer psychological health (OR=0.94; 95% CI: 0.87-1.00), fewer days worked (0.56; 0.95-0.99) and poorer housing conditions (OR=2.76; 95% CI: 1.22-6.23) than did their counterparts who had more than 3months of treatment. Researchers extracted six components with eigenvalues greater than one, accounting for 69.0% of the total variance. In general, the Chilean TOP is a reliable and valid mechanism to monitor outcomes of people treated for problems with drug and alcohol abuse in Chile, but further validation work is required in some dimensions.

The discovery of asunaprevir (BMS-650032), an orally efficacious NS3 protease inhibitor for the treatment of hepatitis C virus infection.

The discovery of asunaprevir (BMS-650032, 24) is described. This tripeptidic acylsulfonamide inhibitor of the NS3/4A enzyme is currently in phase III clinical trials for the treatment of hepatitis C virus infection. The discovery of 24 was enabled by employing an isolated rabbit heart model to screen for the cardiovascular (CV) liabilities (changes to HR and SNRT) that were responsible for the discontinuation of an earlier lead from this chemical series, BMS-605339 (1), from clinical trials. The structure-activity relationships (SARs) developed with respect to CV effects established that small structural changes to the P2* subsite of the molecule had a significant impact on the CV profile of a given compound. The antiviral activity, preclincial PK profile, and toxicology studies in rat and dog supported clinical development of BMS-650032 (24).

P2X1 receptors localized in lipid rafts mediate ATP motor responses in the human vas deferens longitudinal muscles.

To assess the role of the P2X1 receptors (P2X1R) in the longitudinal and circular layers of the human vas deferens, ex vivo-isolated strips or rings were prepared from tissue biopsies to record isometric contractions. To ascertain its membrane distribution, tissue extracts were analyzed by immunoblotting following sucrose gradient ultracentrifugation. ATP, alpha,beta-methylene ATP, or electrical field stimulation elicited robust contractions of the longitudinal layer but not of the circular layer which demonstrated inconsistent responses. Alpha,beta-methylene ATP generated stronger and more robust contractions than ATP. In parallel, prostatic segments of the rat vas deferens were examined. The motor responses in both species were not sustained but decayed within the first minute, showing desensitization to additional applications. Cross-desensitization was established between alpha,beta-methylene ATP or ATP-evoked contractions and electrical field stimulation-induced contractions. Full recovery of the desensitized motor responses required more than 30 min and showed a similar pattern in human and rat tissues. Immunoblot analysis of the human vas deferens extracts revealed a P2X1R oligomer of approximately 200 kDa under nonreducing conditions, whereas dithiothreitol-treated extracts showed a single band of approximately 70 kDa. The P2X1R was identified in ultracentrifugation fractions containing 15%-29% sucrose; the receptor localized in the same fractions as flotillin-1, indicating that it regionalized into smooth muscle lipid rafts. In conclusion, ATP plays a key role in human vas deferens contractile responses of the longitudinal smooth muscle layer, an effect mediated through P2X1Rs.

The effective effect-site propofol concentration for induction and intubation with two pharmacokinetic models in morbidly obese patients using total body weight.

BACKGROUND: Most pharmacokinetic (PK) models used for propofol administration are based on studies in normal-weight patients. Extrapolation of these models for morbidly obese patients is controversial. Using 2 PK models and a target-controlled infusion system, we determined the predicted propofol effect-site concentration (Ce) needed for induction of anesthesia in morbidly obese subjects using total body weight. METHODS: Sixty-six morbidly obese subjects from 18 to 50 years of age were randomized to receive propofol to reach and maintain a predetermined propofol Ce, based on the PK models of either Marsh or Schnider. All patients were monitored with a Bispectral Index electroencephalographic monitor. Fentanyl 3 µg/kg total body weight was administered before starting the propofol infusion. After loss of consciousness, vecuronium was administered to facilitate endotracheal intubation. Groups of 6 patients each received propofol at a different, predetermined target propofol Ce. An "effective Ce" (ECe) was defined as the propofol Ce that provided adequate hypnosis (Bispectral Index <60) during the complete induction period (45 seconds after reaching the predetermined target Ce until 5 minutes after tracheal intubation). Heart rate and arterial blood pressure were measured every 1 minute throughout the study period. Probit regression analysis was performed to calculate the effective propofol Ce values to induce hypnosis in 50% (ECe(50)) and 95% (ECe(95)) of patients with 95% confidence intervals (CIs). RESULTS: Patient characteristics were similar between models and across the propofol target concentration groups. The ECe(50) of propofol was 3.4 µg/mL (95% CI: 2.9, 3.7 µg/mL) with the Marsh model and 4.5 µg/mL (95% CI: 4.1, 4.8 µg/mL) with the Schnider model (P < 0.001). The ECe(95) values were 4.2 µg/mL (95% CI: 3.8, 6.2 µg/mL) and 5.5 µg/mL (95% CI: 5.0, 7.2 µg/mL) with Marsh and Schnider models, respectively. At the ECe(95), hemodynamic effects were similar with the 2 PK models. CONCLUSION: Different propofol target concentrations for each PK model must be used for induction when using total body weight in morbidly obese patients.

Surfactant choice and the physical stability of nanosuspensions as a function of pH.

Nanosuspensions of the example compounds ketoconazole and itraconazole were shown to aggregate upon reducing the pH to levels comparable to that known to exist in the stomach. Manipulation of the surfactant/polymer ratio in the suspension vehicle did not elucidate the cause of the aggregation. X-ray diffraction on ketoconazole solids failed to identify a form change as causative. Ultimately, ketoconazole intrinsic dissolution rate experiments implicated surface salt formation between ketoconazole and the vehicle surfactant as the cause of the aggregation. The generality of the phenomenon is discussed.

[Primary left atrial hemangiopericytoma. Report of one case]. / Hemangiopericitoma de aurícula izquierda. Caso clínico.

We report a 41-year-old male presenting with progressive dyspnea lasting one month. A CAT scan disclosed a left atrial mass, that was surgically excised. The pathological study of the surgical piece showed a primary hemangiopericytoma. One month later, the patient consulted for cervical pain and a positron emission tomography showed multiple metastases. The patient died two months later.

Hemangiopericitoma de aurícula izquierda: Caso clínico / Primary left atrial hemangiopericytoma: Report of one case

We report a 41-year-old male presenting with progressive dyspnea lasting one month. A CAT scan disclosed a left atrial mass, that was surgically excised. The pathological study of the surgical piece showed a primary hemangiopericytoma. One month later, the patient consulted for cervical pain and a positron emission tomography showed multiple metastases. The patient died two months later.