Lactose drives Enterococcus expansion to promote graft-versus-host disease.

Disruption of intestinal microbial communities appears to underlie many human illnesses, but the mechanisms that promote this dysbiosis and its adverse consequences are poorly understood. In patients who received allogeneic hematopoietic cell transplantation (allo-HCT), we describe a high incidence of enterococcal expansion, which was associated with graft-versus-host disease (GVHD) and mortality. We found that Enterococcus also expands in the mouse gastrointestinal tract after allo-HCT and exacerbates disease severity in gnotobiotic models. Enterococcus growth is dependent on the disaccharide lactose, and dietary lactose depletion attenuates Enterococcus outgrowth and reduces the severity of GVHD in mice. Allo-HCT patients carrying lactose-nonabsorber genotypes showed compromised clearance of postantibiotic Enterococcus domination. We report lactose as a common nutrient that drives expansion of a commensal bacterium that exacerbates an intestinal and systemic inflammatory disease.

Ahmed glaucoma drainage implant surgery in the management of refractory uveitic glaucoma: Long-term follow up. / Implante de válvula de Ahmed para el manejo del glaucoma uveítico refractario: seguimiento a largo plazo.

OBJECTIVE: To examine the long-term efficacy, safety and complications of Ahmed glaucoma drainage implant surgery in patients with refractory uveitic glaucoma. METHODS: Retrospective review of consecutive cases of patients with refractory uveitic glaucoma who underwent Ahmed glaucoma drainage implant surgery between 2004-2014. Demographic characteristics of the study population, visual acuity, intraocular pressure (IOP), number of antiglaucoma medications and operative and postoperative complications were recorded. Complete success was defined as IOP≥5 and ≤18mmHg without any medication, as qualified success if IOP≤18mmHg with one or more medications. Patients with less than 12 months of follow-up were excluded. RESULTS: 21 patients (26 eyes) were included. The mean postoperative follow-up was 53.5±31 months. Eight eyes (30%) had at least one previously failed glaucoma surgery. IOP was reduced from a mean of 30.0mmHg to 14.0mmHg at the last follow-up visit (P<.001). The number of IOP-lowering medications was reduced from a median of 2.9 preoperatively to 1.1 at the last follow-up (P<.001). Overall, 7 eyes (27%) were classified as complete success, 13 eyes (50%) were considered as qualified success, and 6 eyes (23%) met the criteria for failure. The most common postoperative complication was hypertensive phase in 12 eyes (46%). Kaplan-Meier life-table analysis showed a cumulative probability of success after Ahmed glaucoma valve implantation of 65% at 84 months. CONCLUSIONS: Ahmed glaucoma drainage implant surgery may be considered a long-term effective and safety surgical option for patients with refractory uveitic glaucoma.

Study of Ras/MAPK pathway gene variants in Chilean patients with Cryptorchidism.

Cryptorchidism is one of the most common congenital disorders in boys, and several genetic, hormonal, and environmental factors have been proposed as possible causes for this genitourinary defect. Genetic factors have been intensively searched, but relatively few pathogenic variants have been described. Cryptorchidism is a frequent finding in patients with RASopathies, a group of syndrome caused by mutations in genes of the Ras/MAPK pathway. Our aim was to determine whether patients with isolated cryptorchidism (IC) exhibit Ras/MAPK pathway gene variants associated with RASopathies. Two hundred thirty-nine patients with IC were recruited after orchidopexy. Determination of Ras/MAPK pathway gene variants was performed by high-resolution melting (HRM) analysis followed by sequencing. Restriction or allele-specific amplification assay was applied to (i) variant confirmation; (ii) search in healthy controls; and (iii) segregation analysis. Controls correspond to 100 healthy Chilean adults without a history of cryptorchidism. Molecular analysis showed one synonymous substitution (BRAF_p.Q456Q) in two patients and four missense substitutions (SOS1_ p.R497Q, BRAF_ p.F595L, NRAS_ p.T50I, and MAP2K2_ p.Y134C) in five patients. Our results suggest that some patients with isolated cryptorchidism, but with no evidence of dysmorphic features suggestive of RASopathies, may harbor Ras/MAPK pathway gene alterations.

Long-term prognosis for 1-year relapse-free survivors of CD34+ cell-selected allogeneic hematopoietic stem cell transplantation: a landmark analysis.

CD34+ cell selection significantly improves GvHD-free survival in allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, specific information regarding long-term prognosis and risk factors for late mortality after CD34+ cell-selected allo-HSCT is lacking. We conducted a single-center landmark analysis in 276 patients alive without relapse 1 year after CD34+ cell-selected allo-HSCT for AML (n=164), ALL (n=33) or myelodysplastic syndrome (n=79). At 5 years' follow-up after the 1-year landmark (range 0.03-13 years), estimated relapse-free survival (RFS) was 73% and overall survival (OS) 76%. The 5-year cumulative incidence of relapse and non-relapse mortality (NRM) were 11% and 16%, respectively. In multivariate analysis, Hematopoietic Cell Transplantation Comorbidity Index score⩾3 correlated with marginally worse RFS (hazard ratio (HR) 1.78, 95% confidence interval (CI) 0.97-3.28, P=0.06) and significantly worse OS (HR 2.53, 95% CI 1.26-5.08, P=0.004). Despite only 24% of patients with acute GvHD within 1 year, this also significantly correlated with worse RFS and OS, with increasing grades of acute GvHD associating with increasingly poorer survival on multivariate analysis (P<0.0001). Of 63 deaths after the landmark, GvHD accounted for 27% of deaths and was the most common cause of late mortality, followed by relapse and infection. Although prognosis is excellent for patients alive without relapse 1 year after CD34+ cell-selected allo-HSCT, risks of late relapse and NRM persist, particularly due to GvHD.

Handgrip strength and weight predict long-term mortality in acute kidney injury patients.

INTRODUCTION: Surviving acute kidney (AKI) patients have a higher late mortality compared with those admitted without AKI. The negative impact of malnutrition on the early outcome of AKI patients has recently been confirmed by various studies. However, its impact after hospital discharge has not been studied. The objective of the study was to determine the role of anthropometric measurements and handgrip strength as predictors of mortality 180 days after discharge. METHODOLOGY: Eighty-two survivors AKI patients who were older than 18 y old and followed by AKI team were prospectively evaluated. Patient's characteristics were recorded, anthropometric measurements were taken, handgrip strength (HGS) was measured, subjective global assessment and bioimpedance were applied and blood samples were collected during hospitalization at first and last nephrologist evaluation and in after hospital discharge at 1 month, 3 and 6 months. Multivariable logistic regression was used to adjust confounding and selection bias. RESULTS: Age was 62.3 ± 14.7 years, prevalence of hospitalization in medical wards of 71.6%, index of severity of AKI (ATN-ISS) was 28% and late mortality rates was 25.6%. Risk factors associated with late mortality were the number of comorbidities (HR = 1.79, 95% CI = 1.45-2.46, p = 0.04), cancer (HR = 1.89, 95 CI% = 1.48-3.16, p = 0.01), sepsis (HR = 1.47, 95% CI = 1.18-2.38, p = 0.03), no recovery of renal function at hospital discharge (HR = 1.46, 95% CI = 1.02-2.16, p = 0.03), malnutrition at first evaluation (HR = 1.58, 95% CI = 1.14-2.94, p = 001), the HGS value at the moment of last evaluation by nephrologist (HR = 1.81, 95% CI = 1.17-2.31, p = 0.04) and gain weigh < 1 kg between the moment at first evaluation by nephrologist and one month after hospital discharge (HR = 1.95, 95 CI% = 1.29-3.3, p = 0.02). CONCLUSION: HGS and gain weight were identified as predictors of late mortality. Simple and ease methods can be applied in AKI patients during and after hospitalization to diagnose nutritionally patients who are at higher risk for poor prognosis and, consequently intervention measures can be performed to improve survival in long-term.

Autoimmune hemolysis and immune thrombocytopenic purpura after cord blood transplantation may be life-threatening and warrants early therapy with rituximab.

Autoimmune hemolysis (AH) and immune thrombocytopenic purpura (ITP) are recognized complications after cord blood transplantation (CBT). We evaluated the incidence and characteristics of AH/ITP after double-unit CBT in a day 100 landmark analysis of 152 patients (median age 36 years, range 0.9-70 years) transplanted for hematologic malignancies with myeloablative or nonmyeloablative conditioning and calcineurin inhibitor (CNI)/mycophenolate mofetil. With a median 5.2-year (range 1.6-9.7 years) survivor follow-up, 10 patients developed autoimmune cytopenias (8 AH, 1 ITP, 1 both) at a median of 10.4 months (range 5.8-24.5) post CBT for a 7% cumulative incidence 3 years after the day 100 landmark. Six patients presented with severe disease (hemoglobin ⩽6 g/dL and/or platelets <20 × 109/L). All AH patients were direct antiglobulin test positive. All 10 cases developed during immunosuppression taper with 8 having prior acute GVHD. All 10 patients received rituximab 2-18 days after diagnosis, and corticosteroids combined with rituximab within <7 days was the most effective. No patient died of AH/ITP. AH/ITP occurs infrequently after CBT but may be life-threatening requiring emergency therapy. Rituximab combined with corticosteroids at diagnosis is warranted in patients with severe disease.

[Myomectomy and uterine desarterialization as conservative treatment for uterine fibroids: Review of clinic case]. / Miomectomía y desarterialización uterina como tratamiento conservador de la miomatosis de grandes elementos: reporte de un caso.

BACKGROUND: Uterine fibroids are the most common gynecological tumors; the prevalence increases with age. They can cause symptoms (20-50%). Myomectomy is an alternative for women who wish to preserve their fertility, increased risk of blood loss and longer operative time. Since 2000, a significant number of surgeons have performed occlusion of uterine arteries prior to myomectomy successfully. CASE REPORT: We report the case of a 24-year-old patient, with a history of premature birth; and starts her condition after obstetric event with abnormal uterine bleeding and postcoital bleeding, accompanied by intense, oppressive and stabbing abdominal pain and increased ab-dominal volume. At physical examination an enlarged abdominal wall by a tumor involving, abdominal pain on palpation, at the gynecological examination: frankly enlarged uterus, about 25 x 20 cm, painful and tenderness. Prior to myomectomy, uterine externalization takes place and proceeds to dearterialization of uterine arteries under the García-González technique, removing the tumor without complications, with an estimated 100 cc bleeding. The bilateral uterine artery ligation, is one of the methods used to re-duce intraoperative blood loss. It is a quick, simple technique, whose theoretical basis is that 90% of the irrigation of the uterus comes from the uterine arteries.

Análisis comparativo de la cinética de liberación de diclofenaco sódico a partir de matrices hidrofílicas en medios de disolución convencionales y biorrelevantes / A comparative analysis of the release kinetics of sodium diclofenac from hydrophilic matrices in conventional dissolution media and biorelevant media is carried out

Se utilizaron dos polímeros hidrofílicos comúnmente empleados en la formulación de matrices de liberación extendida, hidroxipropil-metil-celulosa (HPMC, hipromelosa) y óxido de polietileno (PEO), junto con celulosa microcristalina y lactosa, con el objetivo de estudiar la cinética de liberación del diclofenaco sódico en los aparatos II y III de la USP, en un medio de disolución compendial y en medios biorrelevantes. La cinética de liberación predominante en el aparato II fue uno y en el aparato III, cero. El valor de las constantes n y k aplicando la ley del exponente, indicaron tanto para el aparato II como para el III, que no se presenta el efecto "burst" y que el mecanismo predominante en la liberación del fármaco, es la relajación y la erosión del polímero. Los resultados sugieren que la metodología de disolución en un medio biorrelevante es apropiada para discriminar entre formulaciones y para predecir el desempeño in vivo de tabletas de liberación extendida de diclofenaco sódico.

Two hydrophilic polymers commonly employed on the development of extended release products, hydroxypropyl-methyl-cellulose (HPMC, hypromellose) and polyethylene oxide (PEO) were formulated with microcrystalline cellulose or lactose in order to investigate the release kinetics of sodium diclofenac on USP apparatus II and III using a compendial or biorelevant media, respectively. The dominant release kinetic on apparatus II was first order and zero on apparatus III. The values of the kinetic constant (k) and the release exponent (n) from the Power Law Model indicated that there was no burst effect in none of the studied formulations, relaxation and polymer erosion was the dominant mechanism of drug release in both methods. The results suggest that biorelevant dissolution methodology is appropriate for the discrimination of formulations and prediction of in vivo performance of MR diclofenac sodium matrices.

[Conjunctival impression cytology in patients with normal and impaired OSDI scores]. / Citología de impresión conjuntival en pacientes con valores OSDI normales y alterados.

PURPOSE: To describe goblet cell density and Nelson grading in different areas of the ocular surface using conjunctival impression cytology (CIC) among patients with normal and impaired Ocular Surface Disease Index (OSDI) scores. MATERIAL AND METHODS: Patients (n=166) under assessment for dry eye were recruited between 2011 and 2012 and classified according to the OSDI score in 4 categories (normal and impaired). Cytological study (CIC plus Papanicolaou staining) using the Nelson grading system, with modifications in staging, and goblet cell counting were performed on the nasal, temporal, inferior, and superior bulbar conjunctival surfaces. RESULTS: Nelson grading was significantly higher in patients with a severely impaired OSDI score (1.41±0.14) compared to normal patients (0.86±0.09) (P<.01). Goblet cell density was significantly reduced in patients with a severely impaired OSDI score (310.24±56.24 cells per sample) compared with normal subjects (497.31±50.07 cells per sample) (P<.001). Compared with the photoexposed bulbar conjunctiva, goblet cell density on the non-photoexposed conjunctiva was significantly higher both in patients with mild (P<.01) and moderate (P<.001) OSDI scores. CONCLUSION: Patients with severely impaired OSDI scores have less goblet cells and a higher Nelson grade. Goblet cells are more abundant on the non-photoexposed conjunctiva.

Donor-recipient allele-level HLA matching of unrelated cord blood units reveals high degrees of mismatch and alters graft selection.

The feasibility of selecting cord blood (CB) units at high-resolution HLA match has not been investigated. We analyzed the high-resolution donor-recipient HLA match of 100 double-unit 4-6/6 HLA-A,-B antigen, -DRB1 allele-matched CB grafts (units 1a and 1b) and their back-up units (n=377 units in total). The median cryopreserved graft dose was 2.9 × 10(7)/kg/unit, and at high resolution these units had a median donor-recipient HLA-allele match of 5/8 (range 2-8/8) and 6/10 (range 2-9/10), respectively. We then evaluated how often use of high-resolution HLA-match criteria would change the original graft selection to substitute one or both of the back-up units for units 1a and/or 1b. On using a model in which both a higher eight-allele HLA match and a cell dose ⩾ 2.0 × 10(7)/kg/unit were required, graft selection changed in 33% of transplants with minimal effect on cell dose (8.3% reduction). In summary, while units chosen based on HLA-A,-B antigen and -DRB1 allele match have substantial mismatch at higher resolution, CB selection based on high-resolution HLA match is possible in a significant proportion of patients without compromise in cell dose.

Hsp90 activity is necessary to acquire a proper neuronal polarization.

Chaperones are critical for the folding and regulation of a wide array of cellular proteins. Heat Shock Proteins (Hsps) are the most representative group of chaperones. Hsp90 represents up to 1-2% of soluble protein. Although the Hsp90 role is being studied in neurodegenerative diseases, its role in neuronal differentiation remains mostly unknown. Since neuronal polarity mechanisms depend on local stability and degradation, we asked whether Hsp90 could be a regulator of axonal polarity and growth. Thus, we studied the role of Hsp90 activity in a well established model of cultured hippocampal neurons using an Hsp90 specific inhibitor, 17-AAG. Our present data shows that Hsp90 inhibition at different developmental stages disturbs neuronal polarity formation or axonal elongation. Hsp90 inhibition during the first 3h in culture promotes multiple axon morphology, while this inhibition after 3h slows down axonal elongation. Hsp90 inhibition was accompanied by decreased Akt and GSK3 expression, as well as, a reduced Akt activity. In parallel, we detected an alteration of kinesin-1 subcellular distribution. Moreover, these effects were seconded by changes in Hsp70/Hsc70 subcellular localization that seem to compensate the lack of Hsp90 activity. In conclusion, our data strongly suggests that Hsp90 activity is necessary to control the expression, activity or location of specific kinases and motor proteins during the axon specification and axon elongation processes. Even more, our data demonstrate the existence of a "time-window" for axon specification in this model of cultured neurons after which the inhibition of Hsp90 only affects axonal elongation mechanisms.

Graft-versus-host disease after double-unit cord blood transplantation has unique features and an association with engrafting unit-to-recipient HLA match.

Manifestations of and risk factors for graft-versus-host disease (GVHD) after double-unit cord blood transplantation (DCBT) are not firmly established. We evaluated 115 DCBT recipients (median age, 37 years) who underwent transplantation for hematologic malignancies with myeloablative or nonmyeloablative conditioning and calcineurin inhibitor/mycophenolate mofetil immunosuppression. Incidence of day 180 grades II to IV and III to IV acute GVHD (aGVHD) were 53% (95% confidence interval, 44 to 62) and 23% (95% confidence interval, 15 to 31), respectively, with a median onset of 40 days (range, 14 to 169). Eighty percent of patients with grades II to IV aGVHD had gut involvement, and 79% and 85% had day 28 treatment responses to systemic corticosteroids or budesonide, respectively. Of 89 engrafted patients cancer-free at day 100, 54% subsequently had active GVHD, with 79% of those affected having persistent or recurrent aGVHD or overlap syndrome. Late GVHD in the form of classic chronic GVHD was uncommon. Notably, grades III to IV aGVHD incidence was lower if the engrafting unit human leukocyte antigen (HLA)-A, -B, -DRB1 allele match was >4/6 to the recipient (hazard ratio, 0.385; P = .031), whereas engrafting unit infused nucleated cell dose and unit-to-unit HLA match were not significant. GVHD after DCBT was common in our study, predominantly affected the gut, and had a high therapy response, and late GVHD frequently had acute features. Our findings support the consideration of HLA- A,-B,-DRB1 allele donor-recipient (but not unit-unit) HLA match in unit selection, a practice change in the field. Moreover, new prophylaxis strategies that target the gastrointestinal tract are needed.

Estandarización de celdas de Franz para la realización de ensayos de liberación de fármacos a partir de complejos con polielectrolitos / Standardization of Franz cells to evaluate drugs release from drug-polyelectrolyte complexes

En el presente estudio se realizó la estandarización de las condiciones de operación de algunas celdas de Franz, sistema que permite realizar la evaluación de la liberación de compuestos biológicamente activos como una de sus aplicaciones. Para ello se seleccionaron y caracterizaron dos complejos obtenidos entre Eudragit® y ácido benzoico como modelos a emplear, de acuerdo con su solubilidad. Se evaluó su comportamiento de liberación en diferentes condiciones operacionales del ensayo y los resultados se evaluaron empleando el modelo de Korsmeyer-Peppas y el análisis estadístico correspondiente. El análisis de Korsmeyer-Peppas demostró que el mecanismo de liberación del ácido benzoico se ajusta a la ley de difusión de Fick, en algunos casos. Las condiciones operacionales definidas para el ensayo de liberación en las celdas de Franz fueron las siguientes: la concentración del ácido benzoico en la dispersión de complejo en el compartimento donor, 0,07%; la velocidad de agitación, 400 rpm; el volumen de muestreo, 1 mL y la frecuencia de muestreo según un esquema determinado. Se demostró la reproducibilidad del ensayo de liberación en las condiciones operacionales definidas, mediante análisis de varianza.

This paper presents the studies carried out about the standardization of the operational conditions of some Franz Cells; this system allows evaluating the drug release, among others. To this purpose, two Eudragit E- benzoic acid complexes were selected and characterized, as models due to their solubility. After that, the outstanding operational variables were established and evaluated at different levels. The delivery profiles analysis applying the Korsmeyer-Peppas model showed that the release mechanism of benzoic acid was Fick diffusion, in some cases. The operational conditions: benzoic concentration in the complex dispersion in the donor compartment, 0,07%; agitation speed, 400 rpm; volume (1 mL) and frequency sampling according to specific scheme, were determined. The delivery assay reproducibility was demonstrated in the established operational conditions by statistically analysis (ANOVA).

Preparación y caracterización fisicoquímica de complejos polielectrolito-diclofenaco / Preparation and physicochemical characterization of some polyelectrolyte-diclofenac complexes

La interacción ácido-base entre un polielectrolito y un fármaco ionizable podría conllevar a la formación de complejos iónicos. Este tipo de nano-estructuras permitiría obtener propiedades fisicoquímicas diferentes a las del fármaco original, que se podría reflejar en variaciones de la solubilidad, de la estabilidad y del comportamiento de liberación del fármaco, entre otras. Este estudio se realizó para establecer si la solubilidad del diclofenaco podría verse modificada por la formación de complejos polielectrolito-fármaco con el Eudragit® E. Los complejos se elaboraron mediante el método de evaporación del solvente; se caracterizaron al estado sólido por espectroscopía infrarroja y difracción de rayos X y se les determinó la solubilidad aparente. Los resultados evidenciaron la formación del complejo en cada caso, denominados EuD50, EuD50Cl10, EuD50Cl25 y EuD50Cl35. Los valores de solubilidad aparente, fueron 431 y 1498 veces más altos para los complejos EuD50Cl25 y EuD50Cl35, respectivamente, cuando se empleó el agua como solvente; y 3674 y 10412 veces mayor en solución fisiológica, al compararlas con el fármaco sin complejar. Se concluyó que los complejos formados poseen solubilidades diferentes a la del fármaco original, con potencial aplicación en el diseño de formas farmacéuticas líquidas homogéneas.

Enfermedad de Paget mamaria: caso clínico y revisión de la literatura / Paget’s disease of the breast: clinical case and literature review

La enfermedad de Paget mamaria es una patología poco común en la mama, sin embargo, tiene gran importancia por su alta asociación a carcinoma mamario y porque requiere de un alto índice de sospecha. Se presenta el caso de una mujer de 56 años con enfermedad de Paget mamaria con focos microscópicos de invasión y compromiso linfonodal masivo. Se realiza una revisión de esta patología, con especial énfasis en la sospecha, diagnóstico, manejo, estadificación, tratamiento y pronóstico desde el punto de vista médico y quirúrgico.

Cáncer de piel no melanoma e inmunosupresión / Non-melanoma skin cancer and inmunosuppressive therapy

El cáncer de piel no melanoma es la neoplasia más frecuente en el ser humano, sin embargo su incidencia es aún mayor en individuos trasplantados usuarios de inmunosupresión prolongada, representado en ellos el 95 por ciento de los cánceres de piel, con un comportamiento más agresivo y mayor probabilidad de recidiva. A diferencia de la población general, en la cual el cáncer basocelular es el más común, en estos pacientes el carcinoma de células escamosas es el más habitual. El papel del tratamiento inmunosupresor en la génesis del cáncer de piel no melanoma es vastamente reconocido. Los cánceres de piel resultan tanto de una disminución de la actividad inmunológica, como de los efectos oncogénicos directos vinculados a algunos inmunosupresores. La carga tumoral específica parece estar vinculada con el tipo, dosis y duración de la inmunosupresión. En este artículo presentamos una revisión sistemática actualizada de la literatura acerca de esta interesante entidad patológica, con especial énfasis en la epidemiología, factores de riesgo, patogénesis y terapia.

Mecanismos generales de cesión de principios activos a partir de matrices monolíticas hidrofílicas preparadas con éteres de celulosa / Overall mechanisms that rule the active pharmaceutical ingredient’s delivery process from hydrophilic matrices elaborated with ether cellulose

Las matrices hidrofílicas son uno de los sistemas de liberación controlados más empleados a escala mundial. El reconocido éxito global de este tipo de sistemas está ligado a su manufactura por medio de tecnología convencional para la obtención de comprimidos, además de su bajo costo. Estos sistemas han sido objeto de investigación desde hace ya algunas décadas, mediante el uso de técnicas como la creación de imágenes a partir de resonancia magnética, calorimetría de barrido diferencial y la espectroscopia dieléctrica de baja frecuencia, entre otras. Varios autores han estudiado los diferentes estados del agua dentro de una matriz, así como el estado y los cambios en los estados de los materiales en el tiempo, con el fin de estudiar los mecanismos de cesión de los activos a partir de las matrices, así como para buscar modelos matemáticos que describan la evolución de la concentración en el tiempo. En la actualidad se cuenta con modelos matemáticos de gran utilidad que permiten identificar dichos mecanismos a partir de un análisis de los parámetros de los modelos y que conducen finalmente a predecir la velocidad de liberación a partir de estos sistemas.

The hydrophilic matrices are one of the most used controlled delivery systems in the world, due to the simple technology and low cost. A number of publications, over the last decades, have reported investigations in regard with the mechanisms of drug release from hydrophilic matrices. Nevertheless, the mechanisms of drug release from these systems continue to be a matter of debate. Differential scanning calorimetry, low frequency dielectric spectroscopy and nuclear magnetic resonance have been used to examine the distribution of water within ether cellulose matrices, as well as to describe the state of the materials inside the device. The objective is to study the release and hydration rate of hydrophilic matrices in order to contribute to the rationalization of the design of these controlled release systems through mathematical modeling and to obtain a better knowledge of the processes that occur during the release of the drug.

Importancia y fundamentación del sistema de clasificación biofarmacéutico, como base de la exención de estudios de biodisponibilidad y bioequivalencia in vivo / The biopharmaceutic drug classification, the theoretical basis and its importance in the biowaiver studies

El Sistema de Clasificación Biofarmacéutica (SCB), publicado por Gordon Amidon y cols. en 1995, se basa en un sólido fundamento científico para clasificar un fármaco considerando los parámetros de solubilidad y permeabilidad, factores estrechamente relacionados con el proceso de absorción, y plantea como objetivo, la posibilidad de establecer correlaciones in vitro-in vivo que permitan sustituir los ensayos realizados en humanos por ensayos de disolución in vitro, de acuerdo con la clasificación obtenida para el fármaco. Actualmente la aplicación del SCB está enfocada a los estudios de bioequivalencia para demostrar intercambio de medicamentos, presentados en forma sólida de liberación inmediata, de administración peroral y al aseguramiento de que los cambios realizados durante el escalonamiento o en las formulaciones o procesos de éstos, una vez aprobados, no tengan incidencia en su comportamiento in vivo. La proyección de la aplicación del SCB se está dando hacia su implantación como herramienta en el desarrollo de nuevos fármacos, en el diseño y desarrollo de medicamentos y en la posibilidad de bioexenciones para los sistemas de liberación controlada.

The Biopharmaceutics Classification System (BCS), published in 1995 by Gordon Amidon and coworkers, is proposed based on recognizing the underlying process that is controlling the drug absorption rate and extent, namely, drug solubility and intestinal membrane permeability, classifying a drug according to this. Its objective is the possibility to set standards for in vitro drug dissolution testing methodology which will correlate with the in vivo process, avoiding human studies. The BCS can be used to classify drugs and set standards for scale-up and post-approval changes to show that the efficacy has not been altered, as well as standards for in vitro/in vivo correlation for bioequivalence studies, for solid oral immediate release products. About this, exists discusses for further potential applications of the BCS in the development of new drugs and drug products and in the possibility of biowaivers for controlled-release products.

Artificial insemination in black-handed spider monkey (Ateles geoffroyi).

Artificial insemination (AI) was performed in spider monkeys; these primates are vulnerable to extinction and usually do not reproduce spontaneously in captivity. Uterine cycles were followed by daily assessment of vaginal cytology, and corroborated a posteriori by concentrations of 17-beta estradiol and progesterone, measured by radioimmunoassay (RIA), in fecal samples collected once daily. Five females between 13 to 27 years old were inseminated intravaginally (with fresh semen) twice each during the periovulatory phase (Days 9-12 of the menstrual cycle; Day 0, first day of menstrual bleeding), from September to the first 3 weeks of November (most fertile months). Transcervical AI was not useful in this primate because the liquid portion of the semen completely solidified instead of liquefying as in other primates. Pregnancies were apparently achieved in 5 of 14 attempts. One female became pregnant after the first round of inseminations, delivered a healthy infant, was inseminated and got pregnant again (subsequently aborted). One female aborted, apparently due to an intramural uterine leiomyoma. Another two females stopped menstruating for a few months, then restarted menstruating (these females may have been pregnant and aborted). In conclusion, in spider monkeys: (1) captivity-induced stress did not inhibit reproduction; (2) fecal steroid hormones were useful to assess cyclicity; (3) the semen coagulum, which apparently is a tightly packed and large reservoir of spermatozoa, must not be discarded but used in AI; (4) old female spider monkeys did not have cessation of reproductive function.