Persistence in the Methadone Maintenance Program and Its Relationship with the Medication Regimen Complexity Index in Opioid-Dependent Patients.

It has been shown that the Medication Regimen Complexity Index (MRCI) is a useful and reliable tool for calculating the complexity of the pharmacotherapeutic regimen (CPR). Furthermore, a high MRCI is associated with lower adherence. However, the MRCI of opioid-dependent patients (ODP) has not been studied. The aim of this study is to calculate the Methadone Maintenance Program (MMP) persistence and the MRCI score in a ODP cohort. Second, to analyze its relationship and association with other variables. To accomplish this research, an observational study including adults with a confirmed diagnosis of opiate-dependency according to the DSM-5 in a MMP center was carried out. To define MMP-persistence, a group was created by the researchers who defined five weighted items according to their agreed importance. Our first contribution was to create a new definition of MMP-persistence. This study also identified age, comorbidities, and received methadone maintenance doses as successful predictors for MMP-persistence. We have also shown that the MRCI does not seem to be a useful tool to determine MMP-persistence, probably because there are multiple factors that influence it in addition to the CPR. It is necessary to continue searching for more precise selection and stratification tools for ODP to improve their persistence.

Physicochemical and Microbiological Stability of Two Oral Solutions of Methadone Hydrochloride 10 mg/mL.

In this article, we studied physicochemical and microbiological stability and determined the beyond-use date of two oral solutions of methadone in three storage conditions. For this, two oral solutions of methadone (10 mg/mL) were prepared, with and without parabens, as preservatives. They were packed in amber glass vials kept unopened until the day of the test, and in a multi-dose umber glass bottle opened daily. They were stored at 5 ± 3 °C, 25 ± 2 °C and 40 ± 2 °C. pH, clarity, and organoleptic characteristics were obtained. A stability-indicating high-performance liquid chromatography method was used to determine methadone. Microbiological quality was studied and antimicrobial effectiveness testing was also determined following European Pharmacopoeia guidelines. Samples were analyzed at days 0, 7, 14, 21, 28, 42, 56, 70, and 91 in triplicate. After 91 days of storage, pH remained stable at about 6.5-7 in the two solutions, ensuring no risk of methadone precipitation. The organoleptic characteristics remained stable (colorless, odorless, and bitter taste). The absence of particles was confirmed. No differences were found with the use of preservatives. Methadone concentration remained within 95-105% in all samples. No microbial growth was observed. Hence, the two oral methadone solutions were physically and microbiologically stable at 5 ± 3 °C, 25 ± 2 °C, and 40 ± 2 °C for 91 days in closed and opened amber glass bottles.

Development and validation of a HPLC-UV method for methadone hydrochloride quantification in a new oral solution with preservatives to be implemented in physicochemical stability studies.

PURPOSE: The Pharmacy Service of the Infanta Leonor University Hospital acquires, compounds, distributes and dispenses more than 3000 L of methadone oral solution to Drug Addiction Patients Centers per year. Our purpose is to develop and validate an improved high performance liquid chromatography (HPLC) method to quantify methadone hydrochloride in a new oral solution with methylhydroxybenzoate (methylparaben) and propylhydroxybenzoate (propylparaben) to be implemented in physicochemical stability studies that allow to provide more information and even to increase the beyond-use date. METHODS: A HPLC-Agilent® 1100 equipment, comprising a quaternary pump and an ultraviolet diode-array-detector (DAD) was used. An analytical method development and validation was completed. The curve was constructed from methadone working concentrations of 75-125% (7.5, 9.0, 10.0, 11.0 and 12.5 mg/mL) to assess the linear relationship between the concentration of the analyte and the obtained areas. Precision and accuracy were calculated. Detection and quantification limit (LD, LQ) were estimated using the EURACHEM method. Forced-degradation studies were also performed. RESULTS: Chromatographic conditions were: flow rate 1.6 mL/min; mobile phase 55% acetonitrile and 45% sodium phosphate 25 mM (pH = 10); injection volume was 5 µL. The column was a Waters-XTerra™ RP18, maintained at 40 °C. DAD was λ = 254 nm. Retention times for methadone, methylparaben and propylparaben were 4.34, 0.70 and 0.88 min respectively. The method was linear (y = 284.3x - 97.8, r = 0.996). Instrumental precision was 0.33% for standards (n = 10); intra-assay precision 0.53% (n = 6) and inter-assay precision 1.95% (n = 12). The relative standard deviation percentage for accuracy was 1.28%. The recovery percentage was 101.5 ± 1.5%. LQ and LD were 2.18 µg/mL and 2.0 µg/mL respectively. The most destabilizing conditions were oxidizing and alkaline. The chromatograms confirmed no interference with the methadone signal. CONCLUSIONS: The HPLC method has proved to be valid and reproducible for methadone quantification in a new oral solution with methylparaben and propylparaben. This assay is a rapid, simple and reliable technique that can be used in daily analysis and physicochemical stability studies.

Centralization of the methadone maintenance plan in a hospital pharmacy department in the Community of Madrid.

In February 2018, Resolution 189/2018 was published in the Autonomous Community of Madrid with the objective of centralizing the  procedure for the acquisition, preparation, distribution, and dispensing of methadone to Centres for the Comprehensive Care of Drug Addiction Patients  within the Madrid Health Service under the responsibility of a Hospital Pharmacy  Service. The Hospital Pharmacy Service began this activity in March 2018. This is the first time that the comprehensive management of a methadone  maintenance plan has been centralized in an Hospital Pharmacy Service for the care of drug-dependent patients in the Autonomous Community of Madrid. At the beginning of the Project, the previous workflow was analysed, the pharmaceutical laboratory was adapted, and the methadone acquisition procedure was designed. A communication channel with the Centres  for the Comprehensive Care of Drug Addiction Patients was implemented and application forms were designed. Corresponding control procedures were established given that the medication under consideration was a narcotic. Standard procedures for the acquisition of methadone, of containers for personalized dosing in Centres for the Comprehensive Care of Drug Addiction  Patients, and transport routes were designed and contracted out through public  tender in compliance with the Public Administration Contract Law. A tender has  also been awarded for the implementation of a computerized management  system and automated dispensing systems, which are currently undergoing  installation. The pharmacotherapeutic protocol of the Methadone Maintenance Plan of the Autonomous Community of Madrid is also being updated. Over 18  months, 5,300 L of methadone solution have been prepared and 2,844 individual prescriptions have been dispensed. High levels of perceived satisfaction were  reported via a questionnaire administered to the Centre for the Comprehensive  Care of Drug Addiction Patients staff. The response rate was 92%. Overall  satisfaction was very satisfied/quite satisfied (91%) and satisfied (9%). These  results highlight the high level of satisfaction (quite satisfied or very satisfied:  81.8%) with the effectiveness and speed of resolution of incidents by the  Hospital Pharmacy Service staff. This process incorporates the knowledge and  experience of hospital pharmacists into this healthcare field, as well as taking  advantage of existing resources, facilities, and procedures. All these aspects lead to an efficient, effective, and safe approach to this clinical-care activity and  enable a change in the pharmacotherapeutic health care model for opioid- dependent patients.

En febrero de 2018 se publicó en la Comunidad de Madrid la Resolución 189/2018 con el objetivo de centralizar el procedimiento de  adquisición, elaboración, distribución y dispensación de metadona a los Centros de Atención Integral a Drogodependientes del Servicio Madrileño de Salud bajo la responsabilidad de un servicio de farmacia hospitalaria. El  servicio de farmacia hospitalaria inició esta actividad en marzo de 2018, siendo  la primera vez que se centraliza en un servicio de farmacia hospitalaria la  gestión integral del plan de mantenimiento con metadona para la atención de  pacientes drogodependientes en la Comunidad de Madrid. Al inicio del proyecto  se analizó el circuito anterior, se adaptó el laboratorio de farmacotecnia y se  diseñó el procedimiento de adquisición de metadona. Se implementó una vía de  comunicación con los Centros de Atención Integral a Drogodependientes,  diseñándose formularios de solicitud y se establecieron los correspondientes  procedimientos de control derivados de su naturaleza estupefaciente. Se han  diseñado y adjudicado, cumpliendo la Ley de Contratos de la Administración  Pública, procedimientos normalizados para la adquisición de metadona, envases  para la dosificación personalizada en los Centros de Atención Integral a  Drogodependientes y rutas de transporte. Asimismo, se ha adjudicado un  concurso para la implementación de un sistema informático de gestión y  sistemas automatizados de dispensación, actualmente en vías de instalación. También se está actualizando el protocolo farmacoterapéutico del Plan de  mantenimiento con metadona de la Comunidad de Madrid. En año y medio se  han elaborado 5.300 litros de metadona solución y se han dispensado 2.844  prescripciones individualizadas. Disponemos de resultados de calidad percibida  por los profesionales de los Centros de Atención Integral a Drogodependientes  mediante una encuesta de satisfacción. La tasa de respuesta fue del 92%. El  grado de satisfacción global fue: 91% muy satisfecho/bastante satisfecho y 9%  satisfecho. Destaca el alto grado de satisfacción (bastante o muy satisfecho) del  81,8% con la eficacia y rapidez de la resolución de incidencias por parte de los  profesionales del servicio de farmacia. Este proceso permite incorporar el  conocimiento y experiencia de los farmacéuticos especialistas a este ámbito  asistencial, así como aprovechar recursos, instalaciones y procedimientos ya  existentes. Todo ello redunda en un abordaje eficiente, eficaz y seguro de esta  actividad clínico-asistencial y posibilitar un cambio de modelo de asistencia  farmacoterapéutica de los pacientes dependientes de opiáceos.

Muscular contraction frequency does not affect plasma homocysteine concentration in response to energy expenditure- and intensity-matched acute exercise in sedentary males.

Acute exercise seems to increase total plasma homocysteine (tHcy); since this variable associated with cardiovascular risk, it is important to understand the determinants of its response to all types of exercise. The aim of this study was to examine the impact of cycling at 2 different rates of muscle contraction on the complete tHcy kinetics. Eight young sedentary males were required to complete 2 isocaloric (400 kcal) acute exercise trials at 50% peak oxygen uptake on separate occasions at 50 or 80 rpm. Blood samples were drawn at different points before (4 h before exercise and immediately before exercise), during (10, 20, 30, 45, and 60 min during exercise), and after exercise (immediately and 19 h after exercise). Dietary and lifestyle factors were controlled during the research. Maximum tHcy occurred during exercise for both conditions (50 rpm: 11.4 ± 2.7 µmol·L-1; 80 rpm: 10.8 ± 3.2 µmol·L-1). From this point onwards tHcy declined until the cessation of exercise and continued descending below pre-exercise values at 19 h postexercise (p < 0.05). No hyperhomocysteinemia were observed at any sampling point in both trials. In conclusion, the different muscular contraction frequency during exercise has no impact on tHcy during an acute bout of exercise in sedentary individuals, when at least 400 kcal are spent during exercise and the nutritional status for folate, B12, and B6 is adequate. This information is relevant to further inform healthy exercise prescription, not only in terms of duration and intensity of exercise, but also taking into account frequency of contraction.

Exploring drug solubility in fasted human intestinal fluid aspirates: Impact of inter-individual variability, sampling site and dilution.

One of the main factors defining intestinal drug absorption is the solubility of the compound in the gastrointestinal environment. This study reports the solubility of a series of 27 commonly used acidic, neutral and basic drugs in human intestinal fluid samples collected from the duodenum or jejunum of healthy volunteers under fasted state conditions. The interindividual variability as well as the impact of factors such as pH, sampling site and bile salts on the solubility in human intestinal fluids was investigated. The solubility measurements were evaluated using a statistical experimental design. Variability in solubility across volunteers and sampling sites was highly compound-specific and appeared to be substantial for weak acids and bases and for lipophilic drugs. Both pH of the samples and the abundance of amphiphilic components were responsible for the variability observed in the solubility values obtained. The results confirm strong interindividual differences in intraluminal solubility, especially for compounds with high lipophilicity and/or compounds with a pKa value within the physiological pH range. It is important to recognize this variability in intestinal drug solubility as it may considerably influence the therapeutic outcome among patients.

Study of 5 Volatile Organic Compounds in Exhaled Breath in Chronic Obstructive Pulmonary Disease. / Estudio de 5 compuestos orgánicos volátiles en aire exhalado en la enfermedad pulmonar obstructiva crónica.

INTRODUCTION: A major risk factor for chronic obstructive pulmonary disease (COPD) is tobacco smoke, which generates oxidative stress in airways, resulting in the production of volatile organic compounds (VOC). The purpose of this study was to identify VOCs in exhaled breath and to determine their possible use as disease biomarkers. METHOD: Exhaled breath from 100 healthy volunteers, divided into 3groups (never smokers, former smokers and active smokers) and exhaled breath from 57 COPD patients were analyzed. Samples were collected using BioVOC® devices and transferred to universal desorption tubes. Compounds were analyzed by thermal desorption, gas chromatography and mass spectrometry. VOCs analyzed were linear aldehydesand carboxylic acids. RESULTS: The COPD group and healthy controls (never smokers and former smokers) showed statistically significant differences in hexanal concentrations, and never smokers and the COPD group showed statistically significant differences in nonanal concentrations. CONCLUSIONS: Hexanal discriminates between COPD patients and healthy non-smoking controls. Nonanal discriminates between smokers and former smokers (with and without COPD) and never smokers.

Volatile organic compounds in exhaled breath in a healthy population: effect of tobacco smoking.

INTRODUCTION: Tobacco smoke is a source of free radicals and reactive oxygen and nitrogen species, which are the main causes of oxidative stress. The analysis of volatile organic compounds (VOC) in exhaled breath is an indirect method of measuring the level of oxidative stress that occurs in the airways caused by tobacco consumption. The aim of this study was to determine whether smoking influences the production of VOC, in a clinically healthy population. METHODS: Exhaled breath from 89 healthy volunteers, divided into three groups (non-smokers, ex-smokers and smokers) was analysed. Samples were collected using Bio-VOC® devices and transferred to universal desorption tubes. Chemical compounds were analysed by thermal desorption, gas chromatography and mass spectrometry. We analysed hexanal, heptanal, octanal, nonanal, nonanoic acid and propanoic acid, all identified by retention time and mass spectra referenced in the NIST 08 mass spectral library; confirmation was carried out using reference standards of the pure chemical compound. RESULTS: These VOC were found in very low concentrations. Only nonanal showed significant quantitative and qualitative statistical differences among the study groups. Nonanal concentration is dependent on smoking, but is independent of the amount of tobacco consumed, age and gender. CONCLUSIONS: Nonanal in exhaled breath is associated with tobacco consumption, current or previous. Nonanal is a sub-product of the destruction of the cell membrane, and its finding may be indicative of cell damage in smokers. This result appears in many farmers who smoke.