Guía internacional para una dosificación más segura de la clozapina en adultos mediante el uso de 6 titulaciones personalizadas de dosis basados en la etnicidad, la proteína C reactiva y los niveles de clozapina / An international adult guideline for making clozapine titration safer by using six ancestry-based personalized dosing titrations, CRP, and clozapine levels

Esta guía internacional propone mejorar los prospectos de la clozapina en todo el mundo mediante la inclusion de información sobre la titulación del fármaco en función de la ascendencia del paciente. Las bases de datos de reacciones adversas a medicamentos (RAM) sugieren que la clozapina es el tercer fármaco más tóxico en los Estados Unidos de América (EE. UU.) y que produce una mortalidad por neumonía en todo el mundo 4 veces mayor que la correspondiente a la agranulocitosis o la miocarditis. El rango terapéutico de referencia para las concentraciones séricas estables de clozapina es estrecho, de 350 a 600 ng/ml, con potencial de toxicidad y reacciones adversas más fecuentes a medida que aumentan las concentraciones. La clozapina se metaboliza principalmente por CYP1A2 (las mujeres no fumadoras requieren la dosis más baja y los hombres fumadores la dosis más alta). A través de la conversión fenotípica, la prescripción conjunta de inhibidores del metabolismo de la clozapina (incluidos los anticonceptivos orales y el valproato), la obesidad o la inflamación con elevaciones de la proteína C reactiva (PCR), pueden convertir al paciente en un metabolizador lento/pobre (MP). Las personas de ascendencia asiática (de Pakistán a Japón) o los habitantes originarios de las Américas tienen menor actividad de CYP1A2 y requieren dosis más bajas de clozapina para alcanzar concentraciones de 350 ng/ml. En los EE. UU. se recomiendan dosis diarias de 300-600 mg/día. La dosificación personalizada lenta puede prevenir RAM tempranas (incluidos el síncope, la miocarditis y la neumonía). La esencia de esta guía se fundamenta en 6 esquemas de titulaciones personalizadas para pacientes hospitalizados...(AU)

This is the Spanish translation of an international guideline which proposes improving clozapine package inserts worldwide by using ancestry-based: 1) dosing and 2) titration. Adverse drug reaction (ADR) databases suggest clozapine: 1) is the third most toxic drug in the United States (US), and 2) produces worldwide pneumonia mortality four times greater than that of agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers require the lowest dose and male smokers the highest dose). Poor metabolizer (PM) status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity or inflammation with C-reactive protein (CRP) elevations. People with ancestry from Asia (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/ml. Daily doses of 300-600 mg/day are recommended in the US. Slow personalized titration may prevent early ADRs (including syncope, myocarditis and pneumonia). The core of this guideline consists of six personalized titration schedules for inpatients...(AU)

Valoración del volumen testicular mediante resonancia magnética / The reliability of magnetic resonance imaging for the evaluation of testicular volume

Objetivo. El objetivo de nuestro trabajo es evaluar la cuantificación del volumen testicular mediante segmentación en resonancia magnética (RM) y compararla con la fórmula propuesta por Lambert en ecografía (0,71×ancho×alto×largo), que es el método utilizado como referencia. Material y métodos. Se realiza un estudio prospectivo de pacientes que acuden a la consulta de urología. Se estudian un total de 27 pacientes (49 testículos) con una edad media de 38,7±11,0años (rango: 21 a 58años). Se determina en todos ellos la volumetría mediante los dos métodos expresando los valores en cm3. El análisis estadístico se desarrolló en el paquete estadístico SPSS versión 19 para Windows y STATA. Resultados. El volumen medio testicular utilizando la fórmula de Lambert es de 25,3cm3, y con el método de segmentación es de 18,1cm3. El coeficiente de correlación lineal de Pearson entre ambos métodos es de 0,91. Sin embargo, la fórmula de Lambert proporciona valores sistemáticamente superiores, como muestra el análisis de Bland y Altman. Conclusiones. La técnica de segmentación con RM permite un cálculo fiable del volumen testicular (AU)

Objective. To determine the capability of segmentation by magnetic resonance imaging (MRI) in the quantification of testicular volume and to compare it with the formula proposed by Lambert (0.71×width×height×length), which has been used as a reference method. Material and methods. A prospective study of patients attending the urology is made. A total of 27 patients (49 testes) were included with a mean age of 38.7±11.0years (range: 21-58years). The volume was determined in both methods. All parameters were expressed as mean and standard deviation in cm3. Statistical analysis was conducted using SPSS version 19 for Windows and STATA. Results. The mean testicular volume using Lambert's formula was 25.3cm3 and with the segmentation MRI it was 18.1cm3. A strong correlation was found between the methods with a Pearson's coefficient of 0.91. However, Lambert's formula provided consistently higher values as it was revealed by Bland and Altman's analysis. Conclusions. MRI segmentation technique allows a reliable calculation of testicular volume (AU)

The 'strip method': a simple method for plaque pH assessment.

AIM: The aim of the study was to evaluate if pH indicator strips could be used for measurements of plaque pH acidogenicity in situ. METHOD: Interproximal plaque pH was measured before and up to 60 min after a 10% sucrose rinse in 30 healthy volunteers using pH indicator strips and the microtouch method in parallel. RESULTS: It was found that the 'strip method' could determine changes in plaque pH to the same extent as the microtouch method (correlation coefficient 0.99). CONCLUSION: Since the 'strip method' is inexpensive and easy to handle, it may be applicable for assessment of plaque acidogenicity in the clinic.

Error assessment in recombinant baculovirus titration: evaluation of different methods.

The success of baculovirus/insect cells system in heterologous protein expression depends on the robustness and efficiency of the production workflow. It is essential that process parameters are controlled and include as little variability as possible. The multiplicity of infection (MOI) is the most critical factor since irreproducible MOIs caused by inaccurate estimation of viral titers hinder batch consistency and process optimization. This lack of accuracy is related to intrinsic characteristics of the method such as the inability to distinguish between infectious and non-infectious baculovirus. In this study, several methods for baculovirus titration were compared. The most critical issues identified were the incubation time and cell concentration at the time of infection. These variables influence strongly the accuracy of titers and must be defined for optimal performance of the titration method. Although the standard errors of the methods varied significantly (7-36%), titers were within the same order of magnitude; thus, viral titers can be considered independent of the method of titration. A cost analysis of the baculovirus titration methods used in this study showed that the alamarblue, real time Q-PCR and plaque assays were the most expensive techniques. The remaining methods cost on average 75% less than the former methods. Based on the cost, time and error analysis undertaken in this study, the end-point dilution assay, microculture tetrazolium assay and flow cytometric assay were found to be the techniques that combine all these three main factors better. Nevertheless, it is always recommended to confirm the accuracy of the titration either by comparison with a well characterized baculovirus reference stock or by titration using two different methods and verification of the variability of results.

Quantitative high-throughput screening: a titration-based approach that efficiently identifies biological activities in large chemical libraries.

High-throughput screening (HTS) of chemical compounds to identify modulators of molecular targets is a mainstay of pharmaceutical development. Increasingly, HTS is being used to identify chemical probes of gene, pathway, and cell functions, with the ultimate goal of comprehensively delineating relationships between chemical structures and biological activities. Achieving this goal will require methodologies that efficiently generate pharmacological data from the primary screen and reliably profile the range of biological activities associated with large chemical libraries. Traditional HTS, which tests compounds at a single concentration, is not suited to this task, because HTS is burdened by frequent false positives and false negatives and requires extensive follow-up testing. We have developed a paradigm, quantitative HTS (qHTS), tested with the enzyme pyruvate kinase, to generate concentration-response curves for >60,000 compounds in a single experiment. We show that this method is precise, refractory to variations in sample preparation, and identifies compounds with a wide range of activities. Concentration-response curves were classified to rapidly identify pyruvate kinase activators and inhibitors with a variety of potencies and efficacies and elucidate structure-activity relationships directly from the primary screen. Comparison of qHTS with traditional single-concentration HTS revealed a high prevalence of false negatives in the single-point screen. This study demonstrates the feasibility of qHTS for accurately profiling every compound in large chemical libraries (>10(5) compounds). qHTS produces rich data sets that can be immediately mined for reliable biological activities, thereby providing a platform for chemical genomics and accelerating the identification of leads for drug discovery.

Simulating titration to goal clinical trials with statins.

Many countries have local guidelines on the management of subjects' lipid levels with and without pharmaceutical intervention. The statin class of drugs is the preferred class for reducing low density lipoprotein cholesterol (LDL-C). Different statins have different potencies and different dose ranges. It is of interest to simulate clinical trials in which subjects are titrated through the dose ranges of various statins in accordance with local guidelines, in order to estimate the proportion of subjects who reach treatment goal of LDL-C at any particular dose of any particular statin.

Acidimetric titration of medicines being salts of weak acids and determining the end-point based on the iodate(V)-iodide reaction.

A sample being a salt of weak acid in a solvent is determined with hydrochloric acid in the presence of iodate, iodide and starch. The excess acid colours the solution blue.

A novel view of pH titration in biomolecules.

When individual titratable sites in a molecule interact with each other, their pH titration can be considerably more complex than that of an independent site described by the classical Henderson-Hasselbalch equation. We propose a novel framework that decomposes any complex titration behavior into simple standard components. The approach maps the set of N interacting sites in the molecule onto a set of N independent, noninteracting quasi-sites, each characterized by a pK'(a) value. The titration curve of an individual site in the molecule is a weighted sum of Henderson-Hasselbalch curves corresponding to the quasi-sites. The total protonation curve is the unweighted sum of these Henderson-Hasselbalch curves. We show that pK'(a) values correspond to deprotonation constants available from methods that can be used to assess total proton uptake or release, and establish their connection to protonation curves of individual residues obtained by NMR or infrared spectroscopy. The new framework is tested on a small molecule diethylenetriaminepentaacetate (DTPA) exhibiting nonmonotonic titration curves, where it gives an excellent fit to experimental data. We demonstrate that the titration curve of a site in a group of interacting sites can be accurately reconstructed, if titration curves of the other sites are known. The application of the new framework to the protein rubredoxin demonstrates its usefulness in calculating and interpreting complicated titration curves.

Anti-pneumococcal antibody response in normal subjects: a meta-analysis.

BACKGROUND: The diagnosis of anti-polysaccharide antibody deficiency is based on the presence of normal serum immunoglobulin levels and the lack of specific antibody response to polysaccharide antigens, such as the pneumococcal vaccine. However, a normal response to pneumococcal vaccine is not well defined. "Modified meta-analysis" was undertaken in an attempt to define the normal antibody response to pneumococcal vaccine. METHODS: Studies identified by a MEDLINE search were selected. Data of the normal control groups, rather than the patient groups, were collated for analysis. RESULTS: Twenty-three studies fulfilled the selection criteria. Prevaccination antibody titers, postvaccination titers, and post- to prevaccination titer ratios varied widely. On the basis of weighted mean ratios, serotype 8 appeared to be the most antigenic. It appeared that normal subjects do not mount a response of even a twofold increase in antibody titer to all the serotypes present in the vaccine. Moreover, no minimal absolute antibody level that could be of diagnostic value, either before or after vaccination, was evident. CONCLUSION: Response to pneumococcal vaccine among normal subjects varies widely. Better designed and prospective studies are needed to define the parameters of a normal antibody response to pneumococcal vaccine so that uniform guidelines of interpretation can be formulated.