Cost saving, patient centered algorithm for progenitor cell mobilization for autologous hematopoietic cell transplantation.

Administration of plerixafor with granulocyte-colony stimulating factor (G-CSF) mobilizes CD34+ cells much more effectively than G-CSF alone, but cost generally limits plerixafor use to patients at high risk of insufficient CD34+ cell collection based on low peripheral blood (PB) CD34+ counts following 4 days of G-CSF. We analyzed costs associated with administering plerixafor to patients with higher day 4 CD34+ cell counts to decrease apheresis days and explored the use of a fixed split dose of plerixafor instead of weight-based dosing. We analyzed 235 patients with plasma cell disorders or non-Hodgkin's lymphoma who underwent progenitor cell mobilization and autologous hematopoietic cell transplantation (AHCT) between March 2014 and December 2017. Two hundred ten (89%) received G-CSF plus Plerixafor and 25 (11%) received G-CSF alone. Overall, 180 patients (77%) collected in 1 day, 53 (22%) in 2 days and 2 (1%) in 3 days. Based on our data, we present a probabilistic algorithm to identify patients likely to require more than one day of collection using G-CSF alone. CD34+ cell yield, ANC and platelet recovery were not significantly different between fixed and standard dose plerixafor. Plerixafor enabled collection in 1 day and with estimated savings of $5000, compared to patients who did not receive plerixafor and required collection for three days. While collection and processing costs and patient populations vary among institutions, our results suggest re-evaluation of current algorithms.

Sample preparation composite and replicate strategy for assay of solid oral drug products.

In pharmaceutical analysis, the results of drug product assay testing are used to make decisions regarding the quality, efficacy, and stability of the drug product. In order to make sound risk-based decisions concerning drug product potency, an understanding of the uncertainty of the reportable assay value is required. Utilizing the most restrictive criteria in current regulatory documentation, a maximum variability attributed to method repeatability is defined for a drug product potency assay. A sampling strategy that reduces the repeatability component of the assay variability below this predefined maximum is demonstrated. The sampling strategy consists of determining the number of dosage units (k) to be prepared in a composite sample of which there may be a number of equivalent replicate (r) sample preparations. The variability, as measured by the standard error (SE), of a potency assay consists of several sources such as sample preparation and dosage unit variability. A sampling scheme that increases the number of sample preparations (r) and/or number of dosage units (k) per sample preparation will reduce the assay variability and thus decrease the uncertainty around decisions made concerning the potency of the drug product. A maximum allowable repeatability component of the standard error (SE) for the potency assay is derived using material in current regulatory documents. A table of solutions for the number of dosage units per sample preparation (r) and number of replicate sample preparations (k) is presented for any ratio of sample preparation and dosage unit variability.

An Elemental Impurities Excipient Database: A Viable Tool for ICH Q3D Drug Product Risk Assessment.

To support the practical implementation of the International Council for Harmonisation (ICH) Q3D guideline, which describes a risk-based approach to the control of elemental impurities in drug products, a consortium of pharmaceutical companies has established a database to collate the results of analytical studies of the levels of elemental impurities within pharmaceutical excipients. This database currently includes the results of 26,723 elemental determinations for 201 excipients and represents the largest known, and still rapidly expanding, collection of data of this type. Analysis of the database indicates good coverage of excipients relevant to real-world drug product formulations and tested element profiles consistent with ICH Q3D recommendations. The database includes the results from multiple analytical studies for an excipient and thus incorporates within it an indication of both excipient supplier and batch-to-batch variability as well as any variability associated with the different testing organizations and methods employed. The data confirm the findings of earlier smaller studies that elemental impurity concentrations in excipients are generally low and when used in typical proportions in formulated drug products are unlikely to pose a significant patient safety risk. The database is now in active use as one line of evidence in ICH Q3D risk assessments.

Comparison of extraction techniques for spray dried dispersion tablet formulations.

Non-traditional sample preparation/extraction techniques that utilized the Caliper Life Sciences Tablet Processing Workstation II (TPW II), Microwave Assisted Extraction (MAE), and Accelerated Solvent Extraction (ASE) were evaluated for the extraction of Compound A from a 50 mgA, 15% Spray Dried Dispersion (SDD) immediate released (IR) tablet formulation. The TPW II consistently provided complete recoveries with very short preparation/extraction times (approximately 30 min). MAE also provided complete recovery of the API from the tablet formulation, but required approximately twice the extraction time, while ASE provided the lowest recovery of the three non-traditional techniques. The sample preparation/extraction efficiencies of the three non-traditional techniques were compared to that of the 5.5 h long manual method.

Direct determination of cadmium and lead in pharmaceutical ingredients using anodic stripping voltammetry in aqueous and DMSO/water solutions.

A new electrochemical method has been developed to detect and quantify the elemental impurities, cadmium(II) (Cd(2+)) and lead(II) (Pb(2+)), either simultaneously or individually in pharmaceutical matrices. The electro-analytical approach, involving the use of anodic stripping voltammetry (ASV) on an unmodified glassy carbon electrode, was performed in both aqueous and in a 95/5 dimethyl sulfoxide (DMSO)/water solutions, without acid digestion or dry ashing to remove organic matrices. Limits of detection (LODs) in the µg L(-1) [or parts per billion (ppb), mass/volume] range were obtained for both heavy metals - in the presence and absence of representative pharmaceutical components. To the best of our knowledge, the work demonstrates the first analysis of heavy metals in DMSO/water solutions through ASV. The strong reproducibility and stability of the sensing platform, as well as obviation of sample pretreatment show the promise of utilizing ASV as a sensitive, robust, and inexpensive alternative to inductively-coupled-plasma (ICP)-based approaches for the analysis of elemental impurities in, e.g., pharmaceutical-related matrices.

Identification of low-level degradants from low dose tablets.

A multifaceted approach was successfully used to identify three of four unknown degradants in degraded low dose tablets. Accelerated solvent extraction (ASE) was found to be an invaluable tool in this multifaceted approach. ASE was capable of extracting four individual degradants of an active pharmaceutical component from 10 tablets into 15 mL of solvent with approximately 100% recovery for each degradant. Using ASE instead of manual extraction led to the extraction and isolation of the degradants in 1 day instead of 7 days. One of the degradants was extracted by ASE, isolated by semi-prep HPLC, and identified by LC-MS and NMR spectroscopy. The structures of two of the remaining three degradants were confirmed by synthesis of authentic samples, while the fourth degradant is yet to be identified.

Metabolism of a serotonin-4 receptor partial agonist 4-{4-[4-tetrahydrofuran-3-yloxy)-benzo[d]isoxazol-3-yloxymethyl]-piperidin-1-ylmethyl}-tetrahydropyran-4-ol (TBPT): identification of an unusual pharmacologically active cyclized oxazolidine metabolite in human.

4-{4-[4-Tetrahydrofuran-3-yloxy)-benzo[d]isoxazol-3-yloxymethyl]-piperidin-1-ylmethyl}-tetrahydropyran-4-ol (PF-4995274, TBPT) is a new agent that is a partial agonist of the human serotonin-4 (5-HT4) receptor and is under investigation for neurological disorders. Metabolism of TBPT was examined in vitro in human liver microsomes and human hepatocytes. Metabolites were also identified in the plasma of healthy human subjects in a phase 1 clinical study. Human-derived metabolite profiles were compared with corresponding profiles obtained in laboratory animal species. There were two major routes of metabolism in vitro: N-dealkylation of the methyltetrahydropyran moiety (M1) and hydroxylation at the seven position of the benzisoxazole moiety (M4). These were also observed in human plasma; however, in that matrix, the major metabolite was an unusual cyclized oxazolidine entity (M2). M2 was proposed to be formed via generation of an intermediate 4° iminium ion on the piperidine ring followed by spontaneous cyclization by attack of the ß-hydroxyl substituent of the tetrahydropyran ring to form a cyclized oxazolidine product. An authentic standard of the metabolite was generated using a methylene-blue-sensitized photochemical oxidation reaction as well as microbial transformation. Further investigation of this metabolite showed that it also possessed 5-HT4 agonism activity similar to the parent. The metabolite was 150-fold more highly protein bound in human plasma than TBPT, which is consistent with its presence as a major circulating metabolite while being only a minor metabolite in in vitro systems. Overall, this illustrates the importance of understanding the complex dispositional properties of a pharmacologically active metabolite.

¿Estamos preparados para enfrentar el parto vaginal posterior a cesárea? / Are we ready to face vaginal delivery after cesarean section?

Se realizó un estudio descriptivo, mediante encuesta a las pacientes con el antecedente de cesárea, en el último cuatrimestre de 1993 en el Hospital "Clodomira Acosta Ferrales", para explorar el grado de conocimiento y la aceptabilidad del método de parto vaginal posterior a cesárea. Se realizó también una encuesta a 100 obstetras de la Ciudad de La Habana, para conocer su disposición a un cambio de conducta en favor de este método. El 40 porciento de las pacientes se muestra a favor de intentar el parto vaginal, y cuando se les ofreció explicaciones sobre las ventajas del parto vaginal, entonces el 75,65 porciento se inclinó por el parto transpelviano. El 80 porciento de los obstetras se muestran decididos a enfrentar un cambio de conducta, y están dispuestos a permitir el intento de parto a las pacientes con cesárea anterior

Parto vaginal poscesárea. Primeros casos en Cuba / Post cesarean vaginal delivery. First cases in Cuba

El incremento de la operación cesárea ha estimulado la búsqueda de alternativas para intentar reducir su frecuencia, entre ellas el parto vaginal poscesárea. En Cuba, por primera vez, se trabaja sobre este controvertido tema, y desde 1995 funciona en el Hospital Ginecoobstétrico Docente "Clodomira Acosta Ferrales" una Consulta Especializada de Cesárea, en la cual se seleccionan los casos con el antecedente de haberse realizado una operación cesárea, que reúnan las condiciones requeridas para intentar el parto transpelviano. Se muestran en este trabajo los primeros resultados de esta consulta, que incluyen la satisfacción de los primeros partos vaginales después de cesárea que se logran de forma programada en nuestro país, así como un análisis de los aspectos que impidieron un mayor número de casos en esta primera etapa de trabajo

Mosaico Turner y Embarazo. Presentación de un caso / Turner mosaic and pregnancy. Report of 1 case

La constitución cromosómica más frecuente del síndrome de Turner es 45XO, pero también han sido descritas variantes de éste, como los casos con mosaico Turner con fórmula cromosómica XX/XO, descrita por Ford. En la literatura se plantea que casos con esta variante no suelen lograr embarazo, pues traen aparejada una alta indicencia de esterilidad. El objetivo del presente trabajo es presentar una paciente de 22 años de edad, con historia clínica de baja talla y estigmas de disgenesia gonadal turneriana, que a los 10 años se le diagnosticó un mosaico Turner con cariograma 46XX 45XO; a los 16 años de edad tuvo la menarquía, a los 22 se le diagnosticó un embarazo y tuvo un parto normal. Este es el primer caso que se reporta en nuestro país

Complicaciones del parto vaginal en pelviana versus cesárea / Complications of pelvic vaginal delivery versus cesarean section

Se realiza un estudio retrospectivo de los nacimientos en presentación pelviana, ocurridos entre 1990 y 1996 en el Hospital ginecoobstétrico docente "Clodomira Acosta Ferrales ". En el período se produjeron 566 nacimientos en presentación pelviana: 146 partos transpelvianos y 420 cesáreas. Fueron excluidos los casos con embarazo gemelar y/o muerte fetal anteparto, por lo que se analizan 120 partos y 368 cesáreas. Mediante selección aleatoria, por muestreo sistemático con intervalo fraccional y selección en 2 fases, se obtuvo un número similar de cesáreas. Se comparan diferentes variables, mediante los métodos chi cuadrado y prueba de comparación de proporciones, obteniendo como resultado que algunos factores considerados desfavorables para el parto transpelviano, en pacientes con presentación pelviana, no se relacionaron de modo significativo con la vía del nacimiento; y como aspectos relevantes, que la morbimortalidad perinatal resultó similar en los 2 grupos de pacientes, mientras que se observa un incremento alarmante de la morbilidad materna en el grupo de pacientes que fueron operadas