Contribution of Different Patient Information Sources to Create the Best Possible Medication History.

INTRODUCTION: Obtaining the best possible medication history is the crucial step in medication reconciliation. Our aim was to evaluate the potential contributions of the main data sources available - patient/caregiver, hospital medical records, and shared electronic health records - to obtain an accurate 'best possible medication history'. MATERIAL AND METHODS: An observational cross-sectional study was conducted. Adult patients taking at least one medicine were included. Patient interview was performed upon admission and this information was reconciled with hospital medical records and shared electronic health records, assessed retrospectively. Concordance between sources was assessed. In the shared electronic health records, information was collected for four time-periods: the preceding three, six, nine and 12-months. The proportion of omitted data between time-periods was analysed. RESULTS: A total of 148 patients were admitted, with a mean age of 54.6 ± 16.3 years. A total of 1639 medicines were retrieved. Only 29% were collected simultaneously in the three sources of information, 40% were only obtained in shared electronic health records and only 5% were obtained exclusively from patients. The total number of medicines gathered in shared electronic health records considering the different time frames were 778 (three-months), 1397 (six-months), 1748 (nine-months), and 1933 (12-months). DISCUSSION: The use of shared electronic health records provides data that were omitted in the other data sources available and retrieving the information at six months is the most efficient procedure to establish the basis of the best possible medication history. CONCLUSION: Shared electronic health records should be the preferred source of information to supplement the patient or caregiver interview in order to increase the accuracy of best possible medication history of the patient, particularly if collected within the prior six months.

Introdução: A obtenção da melhor história farmacoterapêutica possível é uma etapa crucial da reconciliação da medicação. O objetivo foi avaliar as potenciais contribuições das principais fontes de informação disponíveis ­ doente/cuidador, Processo Único, Plataforma de Dados da Saúde e ­ para obter uma mais exacta melhor história farmacoterapêutica possível. Material e Métodos: Foi realizado um estudo transversal observacional. Incluíram-se doentes adultos a tomar pelo menos um medicamento. A entrevista com o doente foi realizada na admissão e os dados do Processo Único e da Plataforma de Dados da Saúde recolhidos retrospetivamente. A concordância entre as fontes de informação foi avaliada. Na plataforma de dados da saúde, os dados foram recolhidos em quatro janelas temporais: os últimos três, seis, nove e 12- meses. Os dados omitidos entre os diferentes tempos foram analisados. Resultados: Participaram 148 doentes, com uma idade média de 54,6 ± 16,3 anos. Foram recolhidos 1639 medicamentos. Destes, 29% foram obtidos simultaneamente nas três fontes de informação, 40% foram obtidos apenas na Plataforma de Dados da Saúde e 5% foram obtidos exclusivamente a partir do doente. O número total de fármacos recolhidos na Plataforma de Dados da Saúde nos diferentes tempos foi 778 (três meses), 1397 (seis meses), 1748 (nove meses) e 1933 (12 meses). Discussão: A consulta da Plataforma de Dados da Saúde permite obter dados omitidos nas outras fontes de informação e a recolha dos seis meses precedentes é o procedimento mais eficiente para constituir a base da melhor história farmacoterapêutica possível. Conclusão: A Plataforma de Dados da Saúde deve ser a fonte de informação preferencial para complementar a entrevista do doente/cuidador de forma a aumentar a exatidão da melhor história farmacoterapêutica possível, particularmente se a informação for recolhida em relação aos seis meses precedentes.

Developing an adherence in hypertension questionnaire short version: MUAH-16.

The Maastricht Utrecht Adherence in Hypertension (MUAH) questionnaire provides clinicians with information about the causes of a patient's poor adherence to antihypertensive drugs. In this study, the authors aimed to develop and validate a short version of the MUAH questionnaire. After an exploratory factor analysis, the number of MUAH items was reduced. The original MUAH questionnaire (model 1) was compared with the 16-item MUAH short version (model 2). Next, this short version of MUAH (MUAH-16) with all factors correlated (model 2a) was compared with the short version of MUAH with four subscales that contribute to a global factor of adherence (model 2b). Model 1 had a poor fit to the data (χ2 269 = 663.41, P < .001, comparative fit index = 0.695, root mean square error of approximation = 0.06), and model 2 had a very good fit to the data (χ2 100 = 171.07, P < .001, comparative fit index = 0.92, root mean square error of approximation = 0.04). When comparing model 2a with model 2b, the chi-square difference of the model (Δχ2 2 = 4.06; P = .067) revealed that the fits of both models were not significantly different. These findings suggest that MUAH-16 better represents a patient's adherence to antihypertensive medication than the original MUAH questionnaire.

Influence of the mode of administration on the results of medication adherence questionnaires.

INTRODUCTION AND OBJECTIVES: Adherence to medication regimen is commonly assessed through questionnaires, some of which are validated via self-administration. The inadequate health literacy of elderly people pushes researchers to the use of interviews as a method of administration. The aims of this study were to compare the results obtained with an interviewer-administered and a self-administered medication adherence questionnaire and to evaluate the consequences of the adherence status classification of individuals. METHODS: A cross-sectional study was performed in which the Medida de Adesão aos Tratamentos adherence questionnaire was administered to adult patients who were taking at least 1 antihypertensive drug. The data were collected in 7 community pharmacies in central Portugal between March 2014 and September 2015 in 2 different phases: in the first phase, the questionnaire was applied during a healthcare professional interview, and the second phase involved a self-report administration. A confirmatory factor analysis was conducted, and the measurement and structural invariances across the application methods were examined. RESULTS: A sample of 425 patients with a mean age of 68.21 ± 10.56 years participated in the study. The confirmatory factor analysis revealed that both the interview and self-report had a good fit with the original model, although the self-report results exhibited a better fit. In the interview administration, we obtained lower values for skewness and higher levels of kurtosis. The patients subjected to the interview administration presented with a 9.7% higher tendency to answer "never" when compared with the self-administered application, which overestimated adherence. CONCLUSIONS: The interview administration method induced bias that led to a higher percentage of "never" answers and a subsequent overestimation of adherence levels. Self-report administration should be preferred in the application of medication adherence questionnaires.

Cross-cultural adaptation of Hypertension Knowledge Test into European Portuguese

ABSTRACT We aim to validate a European-Portuguese version of the Hypertension Knowledge Test (HKT) questionnaire and examine its factorial structure with a confirmatory factor analysis (CFA). A process of translation and back-translation was performed. A cross-sectional study was developed in which all adult patients taking at least one antihypertensive drug were invited to participate. Data on personal and family history were collected, and the HKT, Strelec, and the Batalla questionnaires were administered. We enrolled 304 patients with a mean age of 68.12±10.83 years. The mean score of HKT was 15.33±2.79. CFA indicated that the construct being tested was unidimensional, and Cronbach's alpha (α=0.65) showed that the instrument had an acceptable internal consistency. When evaluating concurrent validity, HKT was significantly correlated with the Batalla and Strelec scores. Thus, the Portuguese version of HKT (HKT-pt-PT) can be used either in research or in clinical practice. With this version, a potential standard exists to evaluate knowledge about hypertension, which could avoid the practice of using non-validated questionnaires in Portugal and allow the cross-sectional and longitudinal comparability of studies.

[Pharmacovigilance in Portugal: Activity of the Central Pharmacovigilance Unit]. / Farmacovigilância em Portugal: Atividade da Unidade Regional do Centro.

INTRODUCTION: The aim of this study was to characterize the spontaneous reports of adverse events that were received by the Central Portugal Regional Pharmacovigilance Unit. MATERIAL AND METHODS: Spontaneous reports received between 01/2001 and 12/2013 were considered. The annual reporting ratios were estimated. The cases were characterized according to their seriousness, previous description, causality assessment, origin and professional group of the reporter, type of adverse event and pharmacotherapeutic groups of the suspected drugs most frequently reported. RESULTS: The Pharmacovigilance Unit received 2408 reports that contained 5749 adverse events. In 2013, the reporting rate was estimated at 171 reports per million inhabitants. Fifty-five percent of the reports were assessed as serious. Ninety percent of the cases were assessed as being at least possibly related with the suspected drug. The suspected drugs most frequently reported were anti-infectives for systemic use (n = 809, 33%). The most frequently reported adverse events were "Skin and subcutaneous tissue disorders" (n = 1139, 20%). There were 154 (6.4%) reports resulting in life-threatening situations and/or death, and 88 (3.6%) containing at least one adverse event assessed as serious, unknown and certain or probable. DISCUSSION: The present results are in line with those found in other studies, namely the seriousness and type of the adverse events and the pharmacotherapeutic groups of the most frequently reported suspected drugs. CONCLUSION: In the last years, the Central Portugal Regional Pharmacovigilance Unit has registered a growth in the reporting rate in general, as well as an increase in the reporting of unknown and serious adverse drug reactions.

Introdução: Caracterizar as notificações espontâneas de eventos adversos a medicamentos recebidas pela Unidade de Farmacovigilância do Centro.Material e Métodos: Consideraram-se todas as notificações reportadas entre 01/2001 e 12/2013. Estimaram-se taxas de notificação anuais. Os casos foram caracterizados quanto à gravidade, conhecimento prévio, causalidade imputada, origem e grupo profissional do notificador, tipo de evento adverso e grupos farmacoterapêuticos onde se incluem os medicamentos suspeitos com maior prevalência de notificação.Resultados: A Unidade recebeu 2408 notificações, que continham 5749 eventos adversos. No ano de 2013 foi registada uma taxa de notificação de 171 notificações/milhão de habitantes. Do total de notificações, 55% foram classificadas como graves. Das notificações com causalidade imputada, 90% tinham uma relação pelo menos possível com o medicamento suspeito. Os medicamentos que originaram maior número de notificações foram os anti-infeciosos para uso sistémico (n = 809; 33%), e os eventos adversos mais frequentemente notificados foram as âÄúAfeções dos tecidos cutâneos e subcutâneosâÄù (n = 1139; 20%). Registaram-se 154 (6,4%) casos de risco de vida e/ou morte e 88 (3,6%) continham pelo menos um evento adverso classificado simultaneamente como grave, desconhecido e definitivo ou provável.Discussão: Os resultados deste estudo são consistentes com os de outros estudos, designadamente no que diz respeito à gravidade, aos grupos farmacoterapêuticos onde se incluem os medicamentos suspeitos e aos tipos de eventos adversos reportados.Conclusão: Ao longo do período avaliado, a UFC solidificou a sua atividade, tendo verificado um crescimento da taxa de notificação em geral e um aumento da notificação de reações adversas graves e desconhecidas.

Assessing the impact of multi-compartment compliance aids on clinical outcomes in the elderly: a pilot study.

BACKGROUND: Medication non-adherence is a major problem for elderly people. Multicompartment compliance aids (MCAs) have been advocated as a solution for this problem. OBJECTIVE: To assess the impact of using MCAs in self-reported adherence and clinical biomarkers of elderly patients followed in a community pharmacy. SETTING: One community pharmacy at Sabugal (Portugal). METHODS: A four-month prospective, non-randomised, controlled study was performed. Autonomous patients aged 65 or more using 3 or more medicines and under follow-up in the pharmacy were invited to participate. All patients were offered to receive their medication in MCAs prepared in the pharmacy. Patients refusing the MCA were used as control. The intervention consisted of providing 4 weekly MCAs during the monthly visit. All patients received regular pharmacy counselling. Blood pressure (BP), lipid profile and glycaemia were assessed at baseline and monthly for all the patients. Morisky self-reported scale was applied at baseline and at the end of the study. Bivariate analysis and generalized estimation equations (GEE) were used. MAIN OUTCOME MEASURE: Self-reported medication adherence, clinical biomarkers: BP, lipid profile, glycaemia. RESULTS: 54 patients between 65 and 90 years were under follow-up. 44 patients accepted the MCA, constituting the intervention group. No difference in the baseline biomarkers between both groups was found. The bivariate pre-post analysis yielded significant improvements in the intervention groups, but not in the control, for glycaemia (p < 0.001), HDL-c (p = 0.018), and systolic (p < 0.001) and diastolic (p = 0.012) BP. However, when introducing the 'time in follow-up' in the GEE model, all the differences became non-significant, except systolic BP, but the time remained significant for all the biomarkers. CONCLUSION: MCAs apparently improve several clinical biomarkers in a cohort of patients under pharmacist's follow-up. When including the time in pharmacist's followup in a GEE, the effect of the MCA disappeared, remaining only the time as a significant variable. Not considering the time in follow-up may be overestimating the effect of MCAs.

Factores associados à hipertensão arterial nos utentes de farmácias em Portugal / Factores asociados con la hipertensión arterial en los usuarios de farmacias en Portugal / Factors associated with arterial hypertension in pharmacy

OBJETIVO: Estimar a prevalência, tratamento e controlo da hipertensão e identificar factores associados em utentes de farmácias comunitárias. MÉTODOS: Estudo transversal com 1.042 utentes de 40 a 65 anos em 60 farmácias comunitárias de Portugal Continental entre outubro de 2005 e janeiro de 2006. Os dados foram obtidos pela aplicação de questionário e medição de parâmetros biológicos. Foram realizadas três regressões logísticas sequenciais para verificar associação entre as variáveis. RESULTADOS: A idade média foi de 53,7 anos e a razão homem/mulher foi 0,68. A prevalência da hipertensão arterial foi de 54,8 por cento. Cerca de 70 por cento dos hipertensos encontravam-se sob tratamento anti-hipertensivo e, destes, 47,7 por cento estavam controlados. A hipertensão esteve positivamente associada à idade mais elevada, sexo masculino, ser casado, apresentar índice de massa corporal e nível de colesterol total mais alto, ser diabético, ter doença cardiovascular pessoal ou familiar precoce e reportar mais consultas médicas por ano. A hipertensão tratada mostrou-se positivamente associada a ser mulher, não casado, ser diabético, viver numa área urbana e reportar mais de três consultas médicas por ano. Nos hipertensos tratados, estar controlado foi positivamente associado a ter comportamento aderente à terapêutica anti-hipertensiva (auto-reporte), percepcionar o efeito desta medicação e ser de baixo risco cardiovascular. Os modelos preditivos apresentaram áreas sob as respectivas curvas ROC entre 0,72 e 0,78, com capacidade discriminatória aceitável. CONCLUSÕES: A prevalência da hipertensão foi elevada, mas similar à encontrada em outros estudos realizados em Portugal. A proporção de doentes tratados foi satisfatória, em contraste com o nível insuficiente de controlo.

OBJETIVO: Estimar la prevalencia de la hipertensión, tratamiento y control, así como identificar factores asociados en usuarios de farmacias comunitarias.MÉTODOS: Estudio transversal con 1.042 usuarios de 40 a 65 años en 60 farmacias comunitarias de Portugal Continental entre octubre de 2005 y enero de 2006. Los datos fueron obtenidos por la aplicación de cuestionario y medición de parámetros biológicos. Se realizaron tres regresiones logísticas secuenciales para verificar asociación entre las variables.RESULTADOS: La edad promedio fue de 53,7 años y el cociente hombre/mujer fue 0,68. La prevalencia de la hipertensión arterial fue de 54,8%. Cerca de 70% de los hipertensos se encontraban bajo tratamiento anti-hipertensivo y, de estos, 47,7% estaban controlados. La hipertensión estuvo positivamente asociada con la edad más elevada, sexo masculino, ser casado, presentar índice de masa corporal y nivel de colesterol total más alto, ser diabético, tener enfermedad cardiovascular personal o familiar precoz y reportar más consultas médicas por año. La hipertensión tratada se mostró positivamente asociada a ser mujer, no casado, ser diabético, vivir en un área urbana y reportar más de tres consultas médicas por año. En los hipertensos tratados, estar controlado fue positivamente asociado a tener comportamiento adherente a la terapia anti-hipertensiva (auto-reportada), tener percepción del efecto de este medicamento y ser de bajo riesgo cardiovascular. Los modelos predictivos presentaron áreas bajo las respectivas curvas ROC entre 0,72 y 0,78, con capacidad discriminatoria aceptable. CONCLUSIONES: La prevalencia de la hipertensión fue elevada, más similar a la encontrada en otros estudios realizados en Portugal. La proporción de enfermos tratados fue satisfactoria, en contraste con el nivel insuficiente de control.

Factors associated with arterial hypertension in pharmacy users in Portugal.

OBJECTIVE: To estimate the prevalence, treatment and control of hypertension, and to identify factors associated in community pharmacy users. METHODS: A cross-sectional study was conducted with 1,042 pharmacy users, aged between 40 and 65 years, in 60 community pharmacies of continental Portugal, between October 2005 and January 2006. Data were obtained with the application of a questionnaire and measurement of biological parameters. A total of three sequential logistic regressions were performed to verify an association among variables. RESULTS: Mean age was 53.7 years and the male/female ratio was 0.68. Prevalence of arterial hypertension was 54.8%. Approximately 70% of hypertensive individuals were undergoing antihypertensive treatment and, of these, 47.7% were controlled. Hypertension was positively associated with older age, male sex, being married, higher body mass index and higher total cholesterol level, being a diabetic, having a family or personal history of premature cardiovascular disease, and reporting more medical visits per year. When treated, hypertension was found to be positively associated with the female sex, not being married, being a diabetic, living in an urban area, and reporting more than three medical visits per year. In hypertensive users who were treated, being controlled was positively associated with self-reporting adherent behavior towards antihypertensive treatment, perceiving the effect of these drugs and having a low cardiovascular risk. The predictive models showed areas under the respective ROC curves between 0.72 and 0.78, with an acceptable discriminatory power. CONCLUSIONS: The prevalence of hypertension was high, although similar to that found in other studies conducted in Portugal. The proportion of hypertensive individuals under treatment was satisfactory, in contrast to an insufficient level of control.

Disposition of eslicarbazepine acetate in the mouse after oral administration.

Eslicarbazepine acetate is a promising antiepileptic drug structurally related to carbamazepine and oxcarbazepine, which is in the final phase of clinical development. The metabolism of eslicarbazepine acetate is clearly species dependent and, in this case, among small laboratory animals, the mouse seems to be the most relevant species to humans. Hence, the aim of this study was to investigate the plasma, brain and liver disposition of eslicarbazepine acetate in mice to better understand its disposition in humans. Adult male CD-1 mice were treated orally with a single dose of eslicarbazepine acetate 350 mg/kg. Blood samples, brain and liver tissues were taken at 0.25, 0.5, 0.75, 1, 2, 4, 6, 10, 16 and 24 h post-dose. Plasma and tissue levels of eslicarbazepine acetate and its metabolites (S-licarbazepine, R-licarbazepine and oxcarbazepine) were assessed by using high-performance liquid chromatography-ultraviolet detection. Both eslicarbazepine acetate and R-licarbazepine concentrations were below the limit of quantification of the assay in all matrices. Eslicarbazepine acetate was rapidly and extensively metabolized to S-licarbazepine (major metabolite), which was oxidized to oxcarbazepine to a small extent. The brain/plasma ratios suggest that the brain exposure to S-licarbazepine and oxcarbazepine was approximately 30% of their total systemic exposure. However, S-licarbazepine crossed the blood-brain barrier (BBB) less efficiently than oxcarbazepine. On the other hand, the liver/plasma ratios support the notion that S-licarbazepine undergoes hepatic accumulation, whereas oxcarbazepine appears to leave this compartment twice as fast as S-licarbazepine. Thus, the diffusion through the BBB is favourable to oxcarbazepine and the liver acts like a deposit of the pharmacologically active metabolite of eslicarbazepine acetate (S-licarbazepine).

CA-125 AUC as a predictor for epithelial ovarian cancer relapse.

PURPOSE: The aim of the present work was to evaluate the usefulness of CA-125 normalized in time area under the curve (CA-125 AUC) to signalise epithelial ovarian cancer relapse. PATIENTS AND METHODS: Data from a hundred and eleven patients were submitted to two different approaches based on CA-125 AUC increase values to predict patient relapse. In Criterion A total CA-125 AUC normalized in time value (AUC(i)) was compared with the immediately previous one (AUC(i-1)) using the formulae AUC(i) > or = F * AUC(i-1) (several F values were tested) to find the appropriate close related increment associated to patient relapse. In Criterion B total CA-125 AUC normalised in time was calculated and several cut-off values were correlated with patient relapse prediction capacity. RESULTS: In Criterion A the best accuracy was achieved with a factor (F) of 1.25 (increment of 25% from the previous status), while in Criterion B the best accuracies were achieved with cut-offs of 25, 50, 75 and 100 IU/mL. The mean lead time to relapse achieved with Criterion A was 181 days, while with Criterion B they were, respectively, 131, 111, 63 and 11 days. CONCLUSION: Based on our results we believe that conjugation and sequential application of both criteria in patient relapse detection should be highly advisable. CA-125 AUC rapid burst in asymptomatic patients should be firstly evaluated using Criterion A with a high accuracy (0.85) and with a substantial mean lead time to relapse (181 days). If a negative answer was obtained then Criterion B should performed to confirm the absence of relapse.

Stereoselective disposition of S- and R-licarbazepine in mice.

The stereoselective disposition of S-licarbazepine (S-Lic) and R-licarbazepine (R-Lic) was investigated in plasma, brain, liver, and kidney tissues after their individual administration (350 mg/kg) to mice by oral gavage. Plasma, brain, liver, and kidney concentrations of licarbazepine enantiomers and their metabolites were determined over the time by a validated chiral HPLC-UV method. The mean concentration data, attained at each time point, were analyzed using a non-compartmental model. S-Lic and R-Lic were rapidly absorbed from gastrointestinal tract of mouse and immediately distributed to tissues supplied with high blood flow rates. Both licarbazepine enantiomers were metabolized to a small extent, each parent compound being mainly responsible for the systemic and tissue drug exposure. The stereoselectivity in the metabolism and distribution of S- and R-Lic was easily identified. An additional metabolite was detected following R-Lic administration and S-Lic showed a particular predisposition for hepatic and renal accumulation. Stereoselective processes were also identified at the blood-brain barrier, with the brain exposure to S-Lic almost twice that of R-Lic. Another finding, reported here for the first time, was the ability of the mouse to perform the chiral inversion of S- and R-Lic, albeit to a small extent.

Simultaneous and enantioselective liquid chromatographic determination of eslicarbazepine acetate, S-licarbazepine, R-licarbazepine and oxcarbazepine in mouse tissue samples using ultraviolet detection.

Herein is reported, for the first time, a simple and reliable chiral reversed-phase liquid chromatographic method coupled to ultraviolet (UV) detection for simultaneous determination of eslicarbazepine acetate (ESL) and its metabolites, S-licarbazepine (S-LC), R-licarbazepine (R-LC) and oxcarbazepine (OXC), in mouse plasma and brain, liver and kidney tissue homogenates. All analytes and the internal standard were extracted from plasma and tissue homogenates by a solid-phase extraction procedure using Waters Oasis hydrophilic-lipophilic balance cartridges. The chromatographic separation was performed by isocratic elution with water/methanol (88:12, v/v), pumped at a flow rate of 0.7 mL min(-1), on a LichroCART 250-4 ChiraDex (beta-cyclodextrin, 5 microm) column at 30 degrees C. The UV detector was set at 225 nm. Calibration curves were linear (r2 > or = 0.996) in the ranges 0.4-8 microg mL(-1), 0.1-1.5 microg mL(-1) and 0.1-2 microg mL(-1) for ESL and OXC and in the ranges 0.4-80 microg mL(-1), 0.1-15 microg mL(-1) and 0.1-20 microg mL(-1) for R-LC and S-LC in plasma, brain and liver/kidney homogenates, respectively. The overall precision not exceeded 11.6% (%CV) and the accuracy ranged from -3.79 to 3.84% (%bias), considering all analytes in all matrices. Hence, this method will be a useful tool to characterize the pharmacokinetic disposition of ESL in mice.

Enantioselective HPLC-UV method for determination of eslicarbazepine acetate (BIA 2-093) and its metabolites in human plasma.

Eslicarbazepine acetate (BIA 2-093) is a novel central nervous system drug undergoing clinical phase III trials for epilepsy and phase II trials for bipolar disorder. A simple and reliable chiral reversed-phase HPLC-UV method was developed and validated for the simultaneous determination of eslicarbazepine acetate, oxcarbazepine, S-licarbazepine and R-licarbazepine in human plasma. The analytes and internal standard were extracted from plasma by a solid-phase extraction using Waters Oasis HLB cartridges. Chromatographic separation was achieved by isocratic elution with water-methanol (88:12, v/v), at a flow rate of 0.7 mL/min, on a LichroCART 250-4 ChiraDex (beta-cyclodextrin, 5 microm) column at 30 degrees C. All compounds were detected at 225 nm. Calibration curves were linear over the range 0.4-8 microg/mL for eslicarbazepine acetate and oxcarbazepine, and 0.4-80 microg/mL for each licarbazepine enantiomer. The overall intra- and interday precision and accuracy did not exceed 15%. Mean relative recoveries varied from 94.00 to 102.23% and the limit of quantification of the assay was 0.4 microg/mL for all compounds. This method seems to be a useful tool for clinical research and therapeutic drug monitoring of eslicarbazepine acetate and its metabolites S-licarbazepine, R-licarbazepine and oxcarbazepine.

Performance of gentamicin population kinetic parameters in Portuguese neonates.

AIM: To evaluate the performance of eight different sets of gentamicin populational pharmacokinetic parameters, regarding potential implementation in clinical pharmacokinetic software as prior information. METHODS: The study involved 49 patients of 31.3+/-4.1 weeks of gestational age (GA), receiving gentamicin, and for whom peak and trough concentrations were obtained. Accuracy and precision were assessed by mean prediction error (ME), mean squared prediction error (MSE) and root mean squared prediction error (RMSE). Weighted prediction-error analysis was carried out in order to evaluate peak and trough concentrations together (ME(w), MSE(w) and RMSE(w)). RESULTS: The analysis showed CL=0.036 l/h/kg (< 34 weeks GA) or CL=0.051 l/h/kg (> or = 34 weeks GA), and V ( d )=0.5 l/kg (< or = 37 weeks GA) or Vd = 0.4 l/kg (>37 weeks of GA) as the most accurate and precise set of pharmacokinetic parameters (Set 4), presenting the highest percentage of clinically acceptable estimates (Error(Peak)<1 microg/ml, and Error(Trough) <0.375 microg/ml). CONCLUSION: The adoption of the previously mentioned set of parameters as population estimates seems to be the best option, bearing in mind the obtained results. However, we strongly believe that pharmacokinetic parameter determination of gentamicin should be carried out whenever possible in order to improve the rationale and cost-effectiveness of therapy.

Complexos de inclusão de indometacina com hidroxipropil-beta-ciclodextrina: estudos de dissolução e coeficiente de partição / Inclusion compounds of indomethacin with hydroxypropyl-beta-cyclodextrin: dissolution profile and partition coefficient evaluation

A indometacina, antiinflamatório não-esteróide, é praticamente insolúvel em água. A hidroxipropil-beta-ciclodextrina confere aos fármacos nela incluídos melhores características de solubilidade. A formação de complexos com indometacina protege da hidrólise, aumentando a solubilidade. O objetivo desse trabalho foi estudar a influência da complexação por liofilização e por spray-dried, na dissolução e coeficiente de partição. Os resultados dos estudos de dissolução dos complexos de inclusão obtidos por liofilização quando comparados com os obtidos por spray-dryer, apresentam quer maior velocidade de dissolução quer melhor eficiência de dissolução. Os resultados da análise do coeficiente de partição, com ambos os métodos de complexação, confirmam a teoria de que são várias as forças intervenientes neste processo e não é só a fração livre de fármaco que condiciona o transporte para a fase orgânica, reforçando a importância do pH do meio. No estudo com o tampão fosfato pH 7,0, as variações no grau de transporte pela adição de ciclodextrina são muito pequenas, não ocorrendo alteração significativa dos valores de Log P*, verificando-se alterações mais significativas quando se utiliza o tampão fosfato pH 5,5. A complexação aumentou a capacidade de solubilização e dissolução da indometacina, a qual tem caráter lipófilo, sem alterar as características que lhe permitem ter boa capacidade de difusão através de membranas biológicas.

Aspectos biofarmacêuticos da formulação de medicamentos para neonatos. Fundamentos da complexação de indometacina com hidroxipropil-"beta"-ciclodextrina para tratamento oral do fechamento do canal arterial / Biopharmaceutical aspects of drugs formulations for neonatology. Rational for indomethacin's complexation with hydroxypropyl-

A terapêutica farmacológica em recém-nascidos confronta-se, por um lado, com um organismo sujeito a marcadas alterações biológicas, resultantes da composição orgânica e da maturação funcional, que decorre a diferentes graus em crianças com a mesma idade, determinando modificações no perfil farmacocinético e farmacodinâmico e, por outro lado, com a necessidade efetiva da utilização de fármacos. Para dar resposta à necessidade de tratamento destes doentes, recorre-se à utilização de medicamentos off label, sendo esta uma prática com um elevado risco de segurança e de eficácia, na ausência de informação acerca da estabilidade, solubilidade e biodisponibilidade...

Relationship between plasma and brain levels and the anticonvulsant effect of lamotrigine in rats.

The aims of the present research were to characterize the plasma and brain concentration-time profiles of lamotrigine after its acute administration and to establish the relationship between these profiles and the anticonvulsant effect of lamotrigine in rats. Adult male Wistar rats were given 10 mg/kg of lamotrigine intraperitoneally. The lamotrigine profiles in plasma and brain were determined at predetermined times over 120-h post-dose. The anticonvulsant profile against maximal electroshock seizure stimulation was determined over 48 h after dosing. After injection, lamotrigine rapidly appeared in both plasma and brain, suggesting ready penetration of the blood-brain barrier. A linear relationship was established between lamotrigine plasma and brain levels. A linear relationship was also defined between lamotrigine brain levels and the anticonvulsant response. The correspondent plasma levels were also well correlated with the anticonvulsant effect from the moment that the plasma-brain system had reached equilibrium.