Sex-related <em>in vitro/in vivo</em> and PK/PD correlations after oral single dose furosemide administration

Background: The goal of this study was to develop an in vivo-in vitro (IVIV) correlation, both in men and women, which allows constructing a model to predict bioequivalence assessments for drugs with narrow absorption windows. Besides, pharmacokinetic and pharmacodynamic equivalences were also investigated. Furosemide was chosen as a prototype.Methods: Twelve healthy Caucasian volunteers (8 women and 4 men) participated in a relative bioavailability study. Two oral formulations [Lasix® (Reference, R) and Furosemide EFA® (Test, T)] were administered under fasting conditions. Urinary excretion of unchanged drug (PK), and of chloride, sodium and potassium (PD) wasmonitored throughout time. PK and PD parameters were calculated from each respective excretion rate versus time curve. In vitro dissolution testing of both formulations was carried out using the USP apparatus 2 and 4 with fixed and variable dissolution media.Results: T and R could be considered bioequivalent since the 90% confidence intervals for the T/R ratio of geometric means for the area under the urinary drug excretion rate versus time curve and for the maximum excretion rate were within the 0.80-1.25 bioequivalence interval. However, T had faster initial absorption and higher levels in women, while R displayed such characteristics in men. Closer IVIV correlations in women were obtained when apparatus 4 with variable biorelevant dissolution media were used [going from fasting state simulated gastric fluid to fasting state simulated intestinal fluid]. Since R had faster disintegration time than T, a shorter stay of R under gastric conditions was required in order to obtain a good IVIV correlation in men. Saluretic effect displayed a typical clockwise hysteresis loop for the PKPD correlation assessed through chloride-versus-furosemide urinary excretion rates. Even though a higher amount of furosemide was excreted with the urine in men, differences in the excretion of electrolytes between sexes were almost negligible.Conclusions: Sex-differences in the gastrointestinal transit of formulations, under fasting conditions, determined the extent and the rate of furosemide absorption. The prolongation of the absorption process by mean of slowing the gastric emptying would make the formulation more effective. The USP-4 apparatus with variable dissolution media was able to discriminate the formulations even between sexes, becoming a promissory in vitro dissolution testing to predict bioequivalence.<br/

Sex-related <em>in vitro/in vivo</em> and PK/PD correlations after oral single dose furosemide administration

Background: The goal of this study was to develop an in vivo-in vitro (IVIV) correlation, both in men and women, which allows constructing a model to predict bioequivalence assessments for drugs with narrow absorption windows. Besides, pharmacokinetic and pharmacodynamic equivalences were also investigated. Furosemide was chosen as a prototype.Methods: Twelve healthy Caucasian volunteers (8 women and 4 men) participated in a relative bioavailability study. Two oral formulations [Lasix® (Reference, R) and Furosemide EFA® (Test, T)] were administered under fasting conditions. Urinary excretion of unchanged drug (PK), and of chloride, sodium and potassium (PD) wasmonitored throughout time. PK and PD parameters were calculated from each respective excretion rate versus time curve. In vitro dissolution testing of both formulations was carried out using the USP apparatus 2 and 4 with fixed and variable dissolution media.Results: T and R could be considered bioequivalent since the 90% confidence intervals for the T/R ratio of geometric means for the area under the urinary drug excretion rate versus time curve and for the maximum excretion rate were within the 0.80-1.25 bioequivalence interval. However, T had faster initial absorption and higher levels in women, while R displayed such characteristics in men. Closer IVIV correlations in women were obtained when apparatus 4 with variable biorelevant dissolution media were used [going from fasting state simulated gastric fluid to fasting state simulated intestinal fluid]. Since R had faster disintegration time than T, a shorter stay of R under gastric conditions was required in order to obtain a good IVIV correlation in men. Saluretic effect displayed a typical clockwise hysteresis loop for the PKPD correlation assessed through chloride-versus-furosemide urinary excretion rates. Even though a higher amount of furosemide was excreted with the urine in men, differences in the excretion of electrolytes between sexes were almost negligible.Conclusions: Sex-differences in the gastrointestinal transit of formulations, under fasting conditions, determined the extent and the rate of furosemide absorption. The prolongation of the absorption process by mean of slowing the gastric emptying would make the formulation more effective. The USP-4 apparatus with variable dissolution media was able to discriminate the formulations even between sexes, becoming a promissory in vitro dissolution testing to predict bioequivalence.<br/

Gelatinasas como marcadores de consumo crônico de álcool: Um estúdio piloto em Urugua

El consumo crónico de alcohol en Uruguay es un problemacreciente, sin embargo, las determinaciones de biomarcadoresconsensuados no se realizan sistemáticamente ni se investiganotros marcadores potenciales. Para validar la hipótesis de quelas metaloproteinasas de matriz con actividad gelatinasa sonbiomarcadores de consumo crónico de alcohol, se evaluaronmuestras de sangre de 100 alcohólicos que comenzaron aatenderse en la Unidad de Trastornos Relacionados con el Alcoholy de 50 donantes sanos no alcohólicos. Las muestras de alcohólicospresentaron actividad de gelatinasas que triplicaron la de loscontroles y aumentos pequeños pero significativos en los niveles degama-glutamil transferasa, aspartato-aminotransferasa y volumencorpuscular medio. Los valores de transferrina deficiente encarbohidratos fueron menores en alcohólicos que en controles. Estosresultados permiten proponer a las gelatinasas como los indicadoresmás sensibles del consumo sostenido de alcohol en la poblaciónanalizada ya que las enzimas hepáticas y el volumen corpuscularmedio muestran una tendencia acorde con la literatura pero noalcanzaron valores asociados a la patología. Dado que la transferrinadeficiente en carbohidratos es considerada el biomarcador indirectomás sensible y específico de consumo crónico de alcohol, los valoresmenores obtenidos en alcohólicos respecto de controles sugierenproblemas metodológicos que podrían subsanarse aplicando otrastécnicas de medida o la presencia de interferencias que deben seridentificadas. Finalmente, estos hallazgos justifican una extensiónde este trabajo piloto, así como estudios adicionales centrados enla participación de las metaloproteinasas de matriz con actividadgelatinasa en las cascadas de daño asociadas al consumo crónicode alcohol.Chronic alcohol consumption in Uruguay is a growing problem, however, determinations of consensual biomarker are not performed systematically neither potential markers are explored. To validate the hypothesis that matrix metalloproteinases with gelatinase activity are biomarkers of chronic alcohol consumption, blood samples of 100 alcoholics that began medical treatment at the Unidad de Trastornos Relacionados con el Alcohol and 50 healthy non-alcoholic donors were evaluated. Alcoholic samples showed gelatinase activity that tripled that of controls and small but significant increases in levels of gamma-glutamyl transferase, aspartate-aminotransferase and mean cellular volume. Carbohydrate deficient transferrin values were lower in alcoholics than in controls. These results allow proposing gelatinases as the most sensitive indicators of sustained alcohol consumption in the population analyzed since hepatic enzymes and mean cellular volume showed a tendency consistent with the literature but did not reach values associated with the pathology. Since carbohydrate-deficient transferrin is considered the most sensitive and specific indirect biomarker of chronic alcohol consumption, lower values in alcoholics related to controls suggest methodological problems that could be solved by applying other measurement techniques or the presence of yet unknown interferences. Finally, these findings justify an extension of this pilot work, as well as additional studies focused on the participation of matrix metalloproteinases with gelatinase activity in the cascades of damage associated with chronic alcohol consumption.O consumo crônico de álcool no Uruguai é um problema crescente, no entanto, as determinações consensuais de biomarcadores não são realizadas sistematicamente ou os potenciais marcadores são explorados. Para validar a hipótese de que as metaloproteinases de matriz com atividade gelatinase são biomarcadores do consumo crônico de álcool, foram avaliadas amostras de sangue cd 100 alcoólatras que começaram a ser tratadas na Unidad de Trastornos Relacionados con el Alcohol e 50 doadores não-alcoólatras saudáveis. As amostras alcoólicas apresentaram atividade de gelatinase que triplicou a dos controles e pequenos más significativos aumentos nos níveis de gama-glutamil transferase, aspartato-aminotransferase e volume médio celular. Os valores de transferrina deficientes em carboidratos foram menores nos alcoolistas que nos controles. Esses resultados permitem que as gelatinases sejam propostas como os indicadores mais sensíveis do consumo sustentado de álcool na população analisada, uma vez que as enzimas hepáticas e o volume celular médio apresentam uma tendência consistente com a literatura, mas não alcançaram valores associados à patologia. Como a transferrina deficiente em carboidratos é considerada o biomarcador indireto mais sensível e específico do consumo crônico de álcool, os valores mais baixos em alcoólatras do que em controles sugerem problemas metodológicos que poderiam ser sanados pela aplicação de outras técnicas de mensuração a presença de interferências que deben identificadas. Finalmente, esses achados justificam uma extensão deste trabalho piloto, bem como estudos adicionais voltados para a participação de metaloproteinases de matriz com atividade de gelatinase nas cascatas de danos associados ao consumo crônico de álcool.Fil: Marco, Marta. Universidad de la República. Facultad de Química; UruguayFil: Boragno, Daniela. Universidad de la República. Facultad de Química; UruguayFil: Rodriguez, Paola. Universidad de la República. Facultad de Química; UruguayFil: Mestre Cordero, Victoria Evangelina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Ciencias Biológicas. Cátedra de Fisiología Humana; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Metabolismo del Fármaco. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Metabolismo del Fármaco; ArgentinaFil: Pereira, Natalia Romina. Universidad de la República. Facultad de Química; UruguayFil: Berasain, Patricia. Universidad de la Republica. Facultad de Medicina. Hospital de Clínicas "dr. Manuel Quintela".; UruguayFil: Cadenas, Florencia. Universidad de la Republica. Facultad de Medicina. Hospital de Clínicas "dr. Manuel Quintela".; UruguayFil: Rodriguez, Cecilia. Universidad de la Republica. Facultad de Medicina. Hospital de Clínicas "dr. Manuel Quintela".; UruguayFil: Moreira, Alejandra. Universidad de la Republica. Facultad de Medicina. Hospital de Clínicas "dr. Manuel Quintela".; UruguayFil: Simoff, Ximena. Universidad de la Republica. Facultad de Medicina. Hospital de Clínicas "dr. Manuel Quintela".; UruguayFil: Bianchi, Virginia. Universidad de la Republica. Facultad de Medicina. Hospital de Clínicas "dr. Manuel Quintela".; UruguayFil: Barindelli, Anna. Universidad de la Republica. Facultad de Medicina. Hospital de Clínicas "dr. Manuel Quintela".; UruguayFil: Fielitz, Pablo. Universidad de la Republica. Facultad de Medicina. Hospital de Clínicas "dr. Manuel Quintela".; UruguayFil: Olivera Bravo, Silvia. Universidad de la República. Facultad de Química; Urugua

Am I Allowed to Play here? : A Qualitative Interview Study Including Accessibility to Leisure Activities for Children with Disabilities

Barn med funktionsnedsättning tar inte del av fritidsaktiviteter i samma utsträckning som barn utan funktionsnedsättning. Det finns en önskan hos barn med funktionsnedsättning att få ta del av fler aktiviteter. Studien är en kvalitativ intervjustudie med kommuner i Sverige. Syftet med studien är att undersöka hur kommuner i Sverige arbetar med tillgängligheten till fritidsaktiviteter för barn funktionsnedsättning. Frågeställningarna är; 1), Hur hanterar kommunerna barn och unga med funktionsnedsättningars olika behov vid fritidsaktiviteter? 2) Hur utvecklar kommuner fritidsaktiviteter? 3) Hur arbetar kommunerna för att kommunicera och informerar gällande sina fritidsaktiviteter? Den teoretiska utgångpunkten för resultat och analys är Antonovskys teori om känslan av sammanhang. Resultaten visar på en övergripande vilja hos kommunerna att ha aktiviteter som ska vara tillgängliga för alla, oavsett stödbehov. Öppna fritidsaktiviteter kan nyttjas som ett främjande verktyg för barnen att utveckla nya sociala relationer. Svårigheter med att anpassa fritidsaktiviteterna vid behov återfinns i kommunerna, trots den övergripande vilja om öppna verksamheter. Bristande kompetens inom verksamheterna kan vara en faktor som motverkar tillgängligheten. Resultatet visar även att kommunerna upplever en svårighet att nå ut till barn med funktionsnedsättning. Tillgänglighet vid information och kommunikation beskrev kommunerna som faktorer som kunde förbättras. Kommunerna uttrycker ett stort intresse för att utbilda sig i barnkonventionen. En av de mest betydande faktorerna för att aktivt utveckla verksamheterna är barnkonventionen. Barnkonventionen ställer utvecklingskrav på kommunerna och det medför att kommunerna skapar gemensamma mål

Am I Allowed to Play here? : A Qualitative Interview Study Including Accessibility to Leisure Activities for Children with Disabilities

Barn med funktionsnedsättning tar inte del av fritidsaktiviteter i samma utsträckning som barn utan funktionsnedsättning. Det finns en önskan hos barn med funktionsnedsättning att få ta del av fler aktiviteter. Studien är en kvalitativ intervjustudie med kommuner i Sverige. Syftet med studien är att undersöka hur kommuner i Sverige arbetar med tillgängligheten till fritidsaktiviteter för barn funktionsnedsättning. Frågeställningarna är; 1), Hur hanterar kommunerna barn och unga med funktionsnedsättningars olika behov vid fritidsaktiviteter? 2) Hur utvecklar kommuner fritidsaktiviteter? 3) Hur arbetar kommunerna för att kommunicera och informerar gällande sina fritidsaktiviteter? Den teoretiska utgångpunkten för resultat och analys är Antonovskys teori om känslan av sammanhang. Resultaten visar på en övergripande vilja hos kommunerna att ha aktiviteter som ska vara tillgängliga för alla, oavsett stödbehov. Öppna fritidsaktiviteter kan nyttjas som ett främjande verktyg för barnen att utveckla nya sociala relationer. Svårigheter med att anpassa fritidsaktiviteterna vid behov återfinns i kommunerna, trots den övergripande vilja om öppna verksamheter. Bristande kompetens inom verksamheterna kan vara en faktor som motverkar tillgängligheten. Resultatet visar även att kommunerna upplever en svårighet att nå ut till barn med funktionsnedsättning. Tillgänglighet vid information och kommunikation beskrev kommunerna som faktorer som kunde förbättras. Kommunerna uttrycker ett stort intresse för att utbilda sig i barnkonventionen. En av de mest betydande faktorerna för att aktivt utveckla verksamheterna är barnkonventionen. Barnkonventionen ställer utvecklingskrav på kommunerna och det medför att kommunerna skapar gemensamma mål