Drug-drug interactions of immunosuppressants and other drugs in kidney post-transplant recipients

Introduction: Immunosuppressants (ISS) are the most crucial tools used in the therapeutic regimens of transplant recipients. Nevertheless, these drugs are not the only ones adopted by patients; therefore, knowing the possible drug-drug interactions (DDIs) between immunosuppressants and other drugs commonly used in kidney transplant recipients is essential to ensure the effectiveness and safety of treatments. In this way, the objective is analyzing the DDIs between the immunosuppressants and other commonly used medications on kidney transplant adult recipients with active medical records undergoing post-transplant follow-up for 4.4 years (mean). Methods: First, we performed a cross-sectional study based on patients' records, in which the patient's profile and drugs used were examined, and after we analyzed DDIs by the Micromedex Drug Interactions® database. Results: We analyzed 176 patients with a mean age of 47.6(± 12.5); most were male (67.7%), and the majority received a kidney from a deceased donor (81.4%). Patients were exposed to 15.0 (± 5.4) different medicines after the transplantation, and 7.4 (± 4.0) of these medicines were simultaneous. After analyzing the DDIs according to the severity of interaction, documentation quality interaction effect, clinical management and probable interaction mechanism, the most frequent interaction was with tacrolimus, classified as moderate, and the 3 major causes of interaction occurred with azathioprine according to the Micromedex database. The primary medicines involved with immunosuppressant interactions were proton pump inhibitors, ranitidine, domperidone, amlodipine, enalapril, allopurinol, cyclobenzaprine, amitriptyline, fluoxetine, and ciprofloxacin. These DDIs' effects were related to, mainly, increase their immunosuppressant activity. Conclusion: Although the immunosuppressants analyzed lacked many clinical DDIs significance with other medicines, the healthcare team needs to monitor their DDIs' effects to prevent and minimize side effects in transplanted recipients.

Chinese consensus guidelines for therapeutic drug monitoring of polymyxin B, endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Polymyxin B, which is a last-line antibiotic for extensively drug-resistant Gram-negative bacterial infections, became available in China in Dec. 2017. As dose adjustments are based solely on clinical experience of risk toxicity, treatment failure, and emergence of resistance, there is an urgent clinical need to perform therapeutic drug monitoring (TDM) to optimize the use of polymyxin B. It is thus necessary to standardize operating procedures to ensure the accuracy of TDM and provide evidence for their rational use. We report a consensus on TDM guidelines for polymyxin B, as endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society. The consensus panel was composed of clinicians, pharmacists, and microbiologists from different provinces in China and Australia who made recommendations regarding target concentrations, sample collection, reporting, and explanation of TDM results. The guidelines provide the first-ever consensus on conducting TDM of polymyxin B, and are intended to guide optimal clinical use.

Principios de estadística Bayesiana y su relación con la farmacocinética aplicada / Principles of Bayesian statistics and its relationship with applied pharmacokinetics

La metodología estadística Bayesiana permite, si se conoce la probabilidad poblacional de que un suceso ocurra, modificar su valor cuando se dispone de nueva información individual. Aunque las metodologías Bayesiana y frecuentista (clásica) tienen idénticos campos de aplicación, la primera se aplica cada vez más en investigación científica y análisis de big data. En la farmacoterapia moderna, la farmacocinética clínica ha sido responsable de la expansión de la monitorización, facilitada por desarrollos técnico-analíticos y matemático-estadísticos. La farmacocinética poblacional ha permitido identificar y cuantificar las características fisiopatológicas y de tratamiento en una población de pacientes determinada, en particular en pediatría y neonatología, y otros grupos vulnerables, explicando la variabilidad farmacocinética interindividual. Asimismo, la estimación Bayesiana resulta importante como herramienta estadística aplicada en programas informáticos de optimización farmacoterapéutica cuando la monitorización farmacológica se basa en la interpretación farmacocinética clínica. Aunque con ventajas y limitaciones, la optimización farmacoterapéutica basada en la estimación Bayesiana es cada vez más usada en la actualidad, siendo el método de referencia. Esto es particularmente conveniente para la práctica clínica de rutina debido al limitado número de muestras requeridas por parte del paciente, y a la flexibilidad en cuanto a los tiempos de muestreo de sangre para cuantificación de fármacos. Así, la aplicación de los principios Bayesianos a la práctica de la farmacocinética clínica resulta en la mejora de la atención farmacoterapéutica.

If one knows the probability of an event occurring in a population, Bayesian statistics allows mo difying its value when there is new individual information available. Although the Bayesian and frequentist (classical) methodologies have identical fields of application, the first one is increasin gly applied in scientific research and big data analysis. In modern pharmacotherapy, clinical phar macokinetics has been used for the expansion of monitoring, facilitated by technical-analytical and mathematical-statistical developments. Population pharmacokinetics has allowed the identification and quantification of pathophysiological and treatment characteristics in a specific patient popu lation, especially in the pediatric and neonatal population and other vulnerable groups, explaining interindividual variability. Likewise, Bayesian estimation is important as a statistical tool applied in pharmacotherapy optimization software when pharmacological monitoring is based on clinical phar macokinetic interpretation. With its advantages and despite its limitations, pharmacotherapeutic op timization based on Bayesian estimation is increasingly used, becoming the reference method today. This characteristic is particularly convenient for routine clinical practice due to the limited number of samples required from the patient and the flexibility it shows regarding blood sampling times for drug quantification. Therefore, the application of Bayesian principles to the practice of clinical phar macokinetics has led to the improvement of pharmacotherapeutic care.

Development and validation of a method for phenobarbital in serum: anticonvulsant pharmacotherapy monitoring

The therapeutic drug monitoring (TDM) is an important strategy for the effectiveness and safety of long-term pharmacotherapy, such as the use of phenobarbital as an anticonvulsant drug in epilepsy. In this sense, HLPC has been presented as a technique for the measurement of phenobarbital in serum. However, the ideal conditions for carrying out the method must be established for each laboratory reality. An analytical method using HPLC was developed and validated in order to identify and quantify Phenobarbital in blood. The chromatographic conditions were C-18 column (Shimpack XR-ODS 50L x 3.0), acetonitrile-water mobile phase (30:70, v v-1), 0.2 mL min-1 flow and reading wavelength of 210 nm. Linearity was established in the range of 2.5 to 80 µg mL-1, the linear correlation coefficient was 0.9981. The average of the coefficient of variation of the precision was 5.30%. The relative standard error of the accuracy was -2.17% and of the recovery coefficient was 97.83%. In all eleven patients, phenobarbital concentrations were below the therapeutic range. The tested method was selective, linear, precise, accurate and showed good recovery.(AU)

Monitoramento prospectivo do uso de medicamentos: lesão hepática induzida por medicamentos em um centro municipal de saúde / Prospective monitoring of drug use: drug-induced liver injury in a primary healthcare center

ABSTRACT BACKGROUND: Drug-induced liver injury is still misunderstood in Brazil due to diagnostic difficulties or lack of reporting incidents. OBJECTIVE: To assess the frequency of adverse events related to the use of medicines in a primary healthcare unit, in a city locate southwestern of the state of Bahia, Brazil. METHODS: Prospective study conducted at the Primary Center for Specialized Health (CEMEA), February at August of 2013 in Vitoria da Conquista, Bahia, Brazil. Interviews were conducted with patients over 18 years old, and their clinical and laboratorial data were collected. The CIOMS scale was used to validate the cases. RESULTS: A total of 149 patients, mainly Afro-Brazilian women, received follow-up. Among these patients, three cases of hepatotoxicity were identified, and the medicines associated to drug-induced liver injuries were: nimesulide, budesonide and valacyclovir. CONCLUSION: Drug-induced liver injury is rare in primary healthcare units. It also allowed estimating the incidence of hepatotoxicity induced by allopathic medicines which are standardized by public healthcare authorities.

RESUMO CONTEXTO: As lesões hepáticas induzidas por drogas (DILI), ainda são mal compreendidas no Brasil devido a dificuldades diagnósticas ou à falta de relatos. OBJETIVO: Avaliar a frequência de eventos adversos relacionados ao uso de medicamentos em uma unidade básica de saúde, em uma cidade do sudoeste baiano. MÉTODOS: Estudo prospectivo realizado no período de fevereiro a agosto de 2013 em Vitória da Conquista, Bahia, Brasil. Entrevistas foram realizadas com pacientes maiores de 18 anos; os dados clínicos e laboratoriais foram coletados. A escala do CIOMS foi usada para avaliar causalidade dos casos. RESULTADOS: Um total de 149 pacientes, principalmente mulheres afro-brasileiras, receberam acompanhamento. Entre esses pacientes, três casos de hepatotoxicidade foram identificados e os medicamentos associados à DILI foram: nimesulida, budesonida e valaciclovir. CONCLUSÃO: DILI é raro em unidades básicas de saúde. Os três casos foram todos reversíveis, sem necessidade de internação hospitalar. Políticas de saúde que fomentam a prática da farmacovigilância são extremamente importantes para a prevenção e detecção de DILI.

Diagnostic accuracy of thromboelastometry and its correlation with the HPLC-MS/MS quantification test

The aim of the study was to evaluate the diagnostic accuracy of thromboelastometry for assessing rivaroxaban concentrations. The accuracy of thromboelastometry was compared with the high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method, which is the gold standard for drug plasma monitoring (the reference standard). Forty-six clinically stable patients were treated with 10, 15, or 20 mg of rivaroxaban once daily (OD group) or 15 mg twice a day (BID group) (no particular indication for treatment). Patient samples were collected 2 h after the use of the medication (peak) and 2 h before the next dose (trough). The rivaroxaban plasma concentrations were determined via HPLC-MS/MS, and thromboelastometry was performed using a ROTEM® delta analyzer. There were significant prolongations in clotting time (CT) for the 10, 15, and 20 mg of rivaroxaban treatments in the OD groups. In the 15 mg BID group, the responses at the peak and trough times were similar. At the peak times, there was a positive correlation between the plasma concentration of rivaroxaban and CT (Spearman correlation rho=0.788, P<0.001) and clot formation time (rho=0.784, P<0.001), and a negative correlation for alpha angle (rho=−0.771, P<0.001), amplitude after 5 min (rho=−0.763, P<0.001), and amplitude after 10 min (rho=−0.680, P<0.001). The CT presented higher specificity and sensitivity using the cut-off determined by the receiver characteristics curve. ROTEM has potential as screening tool to measure possible bleeding risk associated with rivaroxaban plasma levels.

Effective vancomycin concentrations in children: a cross-sectional study / Concentrações efetivas de vancomicina em crianças: estudo transversal

ABSTRACT Objective Analyze the microbiological effectiveness, based on the pharmacokinetics/pharmacodynamics correlation of vancomycin in pediatric patients, and to propose dose adjustment. Methods This is an observational, cross-sectional study, conducted in a pediatric hospital, over a 1-year period (2016 to 2017). Children of both sexes, aged 2 to 12 years, were included in the study; burn children, and children in renal replacement therapy were excluded. For the pharmacokinetic analysis, two samples of 2mL of whole blood were collected, respecting the 2-hour interval between each withdrawal. Results Ten pediatric patients with median age of 5.5 years and interquartile range (IQR) of 3.2-9.0 years, median weight of 21kg (IQR: 15.5-24.0kg) and median height of 112.5cm (IQR: 95-133cm), were included. Only one child achieved trough concentrations between 10µg/mL and 15µg/mL. Conclusion The empirical use of vancomycin in the children studied did not achieve the therapeutic pharmacokinetic/pharmacodynamic target for minimum inhibitory concentration of 1µg/mL.

RESUMO Objetivo Analisar a efetividade microbiológica considerando a correlação farmacocinética/farmacodinâmica de vancomicina em crianças e propor uma estimativa de ajuste na dose. Métodos Trata-se de um estudo observacional, transversal, realizado em hospital pediátrico, no período de 1 ano (2016 a 2017). Foram incluídas crianças de 2 a 12 anos de ambos os sexos, tendo sido excluídas crianças queimadas ou submetidas à terapia renal substitutiva. Para análise farmacocinética, foram coletadas duas amostras de 2mL de sangue total, respeitando o intervalo de 2 horas entre cada coleta. Resultados Foram incluídos dez pacientes pediátricos com idade de 5,5 anos (mediana) e intervalo interquartil (IQ) de 3,2-9,0 anos, peso de 21kg (mediana; IQ: 15,5-24,0kg) e altura de 112,5cm (mediana; IQ: 95-133cm). Apenas uma criança alcançou concentrações mínimas entre 10µg/mL e 15µg/mL. Conclusão A utilização empírica de vancomicina na população de crianças não alcançou o alvo farmacocinético/farmacodinâmico terapêutico para concentração inibitória mínima de 1μg/mL.

Utilidad de la monitorización terapéutica de infliximab en el manejo de la enfermedad inflamatoria intestinal / Usefulness of therapeutic monitoring of infliximab in the treatment of inflammatory bowel disease

Background: Primary non-response and secondary loss of response (LOR) are significant problems of biological therapy for inflammatory bowel disease (IBD). Therapeutic drug monitoring (TDM) in IBD patients receiving these drugs can improve outcomes. Aim: To measure serum infliximab levels and anti-infliximab antibodies (ATI) in patients with IBD post-induction phase and during maintenance therapy assessing the clinical course of IBD. Patients and Methods: Prospective study of IBD patients receiving infliximab between July 2016-May 2017. Group-A included patients who received induction therapy while Group-B included patients who were in maintenance therapy. TDM was performed in serum samples collected at weeks-14 and 30 in Group-A and before the infliximab maintenance dose in Group-B. Clinical scores, fecal calprotectin and endoscopic score were also evaluated. Results: Of 14 patients in Group-A, 57% achieved endoscopic response. Median serum infliximab concentrations at week-14 and 30 were 2.65 AU/mL (0.23-32.58) and 2.3 AU/mL (0.3-16.8), respectively. Patients with mucosal healing had non-significantly higher median infliximab concentrations at week- 14, as compared to week 30 (median 3.2 vs 2.2 AU/ml, respectively, p 0.6). ATI >10 ug/mL were found in one and seven patients at week-14 and 30, respectively. At 52 weeks of follow-up, four patients (31%) had LOR. Group-B included 36 patients, 33% had LOR. Median serum concentrations of infliximab were 1.4 AU/mL (0.27-7.03). No significant differences in serum infliximab concentration were observed between patients in remission and those with inflammatory activity. Seventeen patients had ATI >10 ug/mL. Conclusions: Clinical algorithms using TDM might help to optimize the pharmacological therapy of IBD.

Preventable adverse drug events in critically ill HIV patients: Is the detection of potential drug-drug interactions a useful tool?

OBJECTIVES: The aim of this study was to develop a strategy to identify adverse drug events associated with drug-drug interactions by analyzing the prescriptions of critically ill patients. METHODS: This retrospective study included HIV/AIDS patients who were admitted to an intensive care unit between November 2006 and September 2008. Data were collected in two stages. In the first stage, three prescriptions administered throughout the entire duration of these patients' hospitalization were reviewed, with the Micromedex database used to search for potential drug-drug interactions. In the second stage, a search for adverse drug events in all available medical, nursing and laboratory records was performed. The probability that a drug-drug interaction caused each adverse drug events was assessed using the Naranjo algorithm. RESULTS: A total of 186 drug prescriptions of 62 HIV/AIDS patients were analyzed. There were 331 potential drug-drug interactions, and 9% of these potential interactions resulted in adverse drug events in 16 patients; these adverse drug events included treatment failure (16.7%) and adverse reactions (83.3%). Most of the adverse drug reactions were classified as possible based on the Naranjo algorithm. CONCLUSIONS: The approach used in this study allowed for the detection of adverse drug events related to 9% of the potential drug-drug interactions that were identified; these adverse drug events affected 26% of the study population. With the monitoring of adverse drug events based on prescriptions, a combination of the evaluation of potential drug-drug interactions by clinical pharmacy services and the monitoring of critically ill patients is an effective strategy that can be used as a complementary tool for safety assessments and the prevention of adverse drug events.

Espectro dos efeitos cardiovasculares da dobutamina - de voluntários saudáveis a pacientes em choque séptico / The spectrum of cardiovascular effects of dobutamine - from healthy subjects to septic shock patients

RESUMO A dobutamina é o inotrópico mais comumente utilizado em pacientes com choque séptico, com o objetivo de aumentar o débito cardíaco e corrigir a hipoperfusão. Embora alguns ensaios clínicos tenham demonstrado que a dobutamina pode melhorar a hemodinâmica sistêmica e regional, outras pesquisas identificaram que seus efeitos são heterogêneos e imprevisíveis. Nesta revisão, analisamos as propriedades farmacodinâmicas da dobutamina e seus efeitos fisiológicos. Nosso objetivo foi demonstrar que os efeitos da dobutamina podem diferir entre voluntários saudáveis, estudos experimentais e insuficiência cardíaca clínica, em modelos de estudo em animais e em pacientes com choque séptico. Discutimos as evidências que suportam a afirmativa de que a dobutamina utilizada no tratamento do choque séptico frequentemente se comporta como fármaco cronotrópico e vasodilatador, sem evidências de ação inotrópica. Como seus efeitos colaterais são muito comuns e os benefícios terapêuticos não são claros, sugerimos que ela deve ser utilizada com cautela no choque séptico. Antes de uma decisão terapêutica definitiva, a eficácia e a tolerabilidade da dobutamina devem ser avaliadas por um tempo curto com monitoramento estrito de seus efeitos positivos e efeitos colaterais negativos.

ABSTRACT Dobutamine is the inotrope most commonly used in septic shock patients to increase cardiac output and correct hypoperfusion. Although some experimental and clinical studies have shown that dobutamine can improve systemic and regional hemodynamics, other research has found that its effects are heterogenous and unpredictable. In this review, we analyze the pharmacodynamic properties of dobutamine and its physiologic effects. Our goal is to show that the effects of dobutamine might differ between healthy subjects, in experimental and clinical cardiac failure, in animal models and in patients with septic shock. We discuss evidence supporting the claim that dobutamine, in septic shock, frequently behaves as a chronotropic and vasodilatory drug, without evidence of inotropic action. Since the side effects are very common, and the therapeutic benefits are unclear, we suggest that dobutamine should be used cautiously in septic shock. Before a definitive therapeutic decision, the efficacy and tolerance of dobutamine should be assessed during a brief time with close monitoring of its positive and negative side effects.

Conversion to Mycophenolate Mofetil Monotherapy in Liver Recipients: Calcineurin Inhibitor Levels are Key

Abstract: The use of calcineurin inhibitors (CNI) after liver transplantation is associated with post-transplant nephrotoxicity. Conversion to mycophenolate mofetil (MMF) monotherapy improves renal function, but is related to graft rejection in some recipients. Our aim was to identify variables associated with rejection after conversion to MMF monotherapy. Conversion was attempted in 40 liver transplant recipients. Clinical variables were determined and peripheral mononuclear blood cells were immunophenotyped during a 12-month follow- up. Conversion was classified as successful (SC) if rejection did not occur during the follow-up. MMF conversion was successful with 28 patients (70%) and was associated with higher glomerular filtration rates at the end of study. It also correlated with increased time elapsed since transplantation, low baseline CNI levels (Tacrolimus ≤ 6.5 ng/mL or Cyclosporine ≤ 635 ng/mL) and lower frequency of tacrolimus use. The only clinical variable independently related to SC in multivariate analysis was low baseline CNI levels (p = 0.02, OR: 6.93, 95%, CI: 1.3-29.7). Mean baseline fluorescent intensity of FOXP3+ T cells was significantly higher among recipients with SC. In conclusion, this study suggests that baseline CNI levels can be used to identify recipients with higher probability of SC to MMF monotherapy. Clinicaltrials.gov identification: NCT01321112.

Fases pré-analítica, analítica e pós-analítica no monitoramento laboratorial da anticoagulação com antagonistas da vitamina K / Pre-analytical, analytical, and post-analytical phases in laboratory monitoring of anticoagulant therapy with vitamin K antagonists

A trombose é uma doença caracterizada por eventos de hipercoagulabilidade. A terapêutica anticoagulante oral com antagonistas da vitamina K (AVKs) é amplamente indicada para prevenção e/ou controle de distúrbios da coagulação. O manuseio de administração dos AVKs é difícil devido à complexidade da definição da dose. Em geral, o monitoramento de indivíduos submetidos à terapêutica com AVK é realizado pela determinação do tempo de protrombina, em que se avalia o grau de anticoagulação através do coeficiente internacional normatizado. Invariavelmente, o fluxo do processamento laboratorial, que compreende as fases pré-analítica, analítica e pós-analítica, é importante para a fidedignidade dos resultados, repercutindo na conduta médica de forma determinante. O objetivo deste estudo foi a realização de uma revisão da literatura científica descritiva utilizando bases de dados eletrônicos para busca de materiais científicos, como Google Scholar, MEDLINE, LILACS, PubMed, SciELO e Science Direct. Abordamos alguns aspectos relacionados ao fluxo analítico da monitoração laboratorial em um laboratório de análises clínicas. Em conclusão, é necessária uma apropriada condução das fases analíticas para que seja possível o sucesso terapêutico com uso dos AVKs (AU)

Thrombosis is a disease characterized by hypercoagulable events. Oral anticoagulant therapy with vitamin K antagonists (VKAs) is widely indicated for prevention and/or control of coagulation disorders. The administration of VKAs is difficult because of the complexity of dose setting. In general, individuals submitted to VKA therapy are monitored by prothrombin time, in which the degree of anticoagulation is assessed by the international normalized ratio. Invariably, the flow of laboratory processing, which comprises pre-analytical, analytical, and post-analytical phases, is of importance to the trustworthiness of results, with significant consequences to the medical practice. The purpose of this study was to carry out a review of the scientific literature using electronic databases to search for scientific materials, such as Google Scholar, MEDLINE, LILACS, PubMed, SciELO, and Science Direct. We discuss some aspects related to the analytical flow of laboratory monitoring in a clinical laboratory. In conclusion, appropriate management of the analytical phases is necessary so that therapeutic success using VKAs is possible (AU)

Esquema posológico atualmente utilizado para vancomicina falha em obter níveis terapêuticos em 40% dos pacientes internados em unidade de terapia intensiva / Currently used dosage regimens of vancomycin fail to achieve therapeutic levels in approximately 40% of intensive care unit patients

RESUMO Objetivo: Avaliar se a posologia atualmente utilizada de vancomicina para tratamento de infecções bacterianas graves causadas por microrganismos Gram-positivos em pacientes admitidos à unidade de terapia intensiva proporcionam níveis plasmáticos de vale de vancomicina em nível terapêutico, e examinar possíveis fatores associados com níveis de vale de vancomicina adequados nesses pacientes. Métodos: Estudo prospectivo descritivo com amostra de conveniência. Os pacientes que cumpriam os critérios de inclusão tiveram seus dados coletados a partir das anotações da enfermagem e dos registros médicos entre setembro de 2013 e julho de 2014. Incluíram-se 83 pacientes. Os níveis plasmáticos de vale iniciais de vancomicina foram obtidos imediatamente antes da quarta dose de vancomicina. Definiu-se lesão renal aguda como um aumento de, pelo menos, 0,3mg/dL na creatinina sérica dentro de 48 horas. Resultados: Considerando os níveis de vale plasmáticos de vancomicina recomendados para o tratamento de infecções graves por Gram-positivos (15 - 20µg/mL), os pacientes foram categorizados em grupos como níveis de vale de vancomicina baixos, adequados e elevados, respectivamente divididos em 35 (42,2%), 18 (21,7%), e 30 (36,1%) pacientes. Os pacientes com lesão renal aguda tiveram níveis plasmáticos de vale de vancomicina significantemente mais elevados (p = 0,0055, com significância para tendência, p = 0,0023). Conclusão: Preocupantemente, mais de 40% dos pacientes não obtiveram níveis plasmáticos de vale de vancomicina considerados eficazes. São necessários estudos de farmacocinética e de regimes posológicos de vancomicina em pacientes admitidos em unidades de terapia intensiva, para contornar esta elevada proporção de falhas na obtenção de níveis de vale iniciais adequados de vancomicina. Deve ser desencorajado o uso de vancomicina sem monitoramento dos níveis de vale plasmáticos.

ABSTRACT Objective: This study aimed to assess whether currently used dosages of vancomycin for treatment of serious gram-positive bacterial infections in intensive care unit patients provided initial therapeutic vancomycin trough levels and to examine possible factors associated with the presence of adequate initial vancomycin trough levels in these patients. Methods: A prospective descriptive study with convenience sampling was performed. Nursing note and medical record data were collected from September 2013 to July 2014 for patients who met inclusion criteria. Eighty-three patients were included. Initial vancomycin trough levels were obtained immediately before vancomycin fourth dose. Acute kidney injury was defined as an increase of at least 0.3mg/dL in serum creatinine within 48 hours. Results: Considering vancomycin trough levels recommended for serious gram-positive infection treatment (15 - 20µg/mL), patients were categorized as presenting with low, adequate, and high vancomycin trough levels (35 [42.2%], 18 [21.7%], and 30 [36.1%] patients, respectively). Acute kidney injury patients had significantly greater vancomycin trough levels (p = 0.0055, with significance for a trend, p = 0.0023). Conclusion: Surprisingly, more than 40% of the patients did not reach an effective initial vancomycin trough level. Studies on pharmacokinetic and dosage regimens of vancomycin in intensive care unit patients are necessary to circumvent this high proportion of failures to obtain adequate initial vancomycin trough levels. Vancomycin use without trough serum level monitoring in critically ill patients should be discouraged.

Impact of Angiotensin Converting Enzyme Inhibitor versus Angiotensin Receptor Blocker on Incidence of New-Onset Diabetes Mellitus in Asians

PURPOSE: Angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) are associated with a decreased incidence of new-onset diabetes mellitus (NODM). The aim of this study was to compare the protective effect of ACEI versus ARBs on NODM in an Asian population. MATERIALS AND METHODS: We investigated a total of 2817 patients who did not have diabetes mellitus from January 2004 to September 2009. To adjust for potential confounders, a propensity score matched (PSM) analysis was performed using a logistic regression model. The primary end-point was the cumulative incidence of NODM, which was defined as having a fasting blood glucose > or =126 mg/dL or HbA1c > or =6.5%. Multivariable cox-regression analysis was performed to determine the impact of ACEI versus ARB on the incidence of NODM. RESULTS: Mean follow-up duration was 1839+/-1019 days in all groups before baseline adjustment and 1864+/-1034 days in the PSM group. After PSM (C-statistics=0.731), a total 1024 patients (ACEI group, n=512 and ARB group, n=512) were enrolled for analysis and baseline characteristics were well balanced. After PSM, the cumulative incidence of NODM at 3 years was lower in the ACEI group than the ARB group (2.1% vs. 5.0%, p=0.012). In multivariate analysis, ACEI vs. ARB was an independent predictor of the lower incidence for NODM (odd ratio 0.37, confidence interval 0.17-0.79, p=0.010). CONCLUSION: In the present study, compared with ARB, chronic ACEI administration appeared to be associated with a lower incidence of NODM in a series of Asian cardiovascular patients.

Promoting adverse drug reaction reporting: comparison of different approaches / Promoção da notificação de reações adversas a medicamentos: comparação de estratégias

ABSTRACT OBJECTIVE To describe different approaches to promote adverse drug reaction reporting among health care professionals, determining their cost-effectiveness. METHODS We analyzed and compared several approaches taken by the Northern Pharmacovigilance Centre (Portugal) to promote adverse drug reaction reporting. Approaches were compared regarding the number and relevance of adverse drug reaction reports obtained and costs involved. Costs by report were estimated by adding the initial costs and the running costs of each intervention. These costs were divided by the number of reports obtained with each intervention, to assess its cost-effectiveness. RESULTS All the approaches seem to have increased the number of adverse drug reaction reports. We noted the biggest increase with protocols (321 reports, costing 1.96 € each), followed by first educational approach (265 reports, 20.31 €/report) and by the hyperlink approach (136 reports, 15.59 €/report). Regarding the severity of adverse drug reactions, protocols were the most efficient approach, costing 2.29 €/report, followed by hyperlinks (30.28 €/report, having no running costs). Concerning unexpected adverse drug reactions, the best result was obtained with protocols (5.12 €/report), followed by first educational approach (38.79 €/report). CONCLUSIONS We recommend implementing protocols in other pharmacovigilance centers. They seem to be the most efficient intervention, allowing receiving adverse drug reactions reports at lower costs. The increase applied not only to the total number of reports, but also to the severity, unexpectedness and high degree of causality attributed to the adverse drug reactions. Still, hyperlinks have the advantage of not involving running costs, showing the second best performance in cost per adverse drug reactions report.

RESUMO OBJETIVO Descrever diferentes abordagens de promoção da notificação de reações adversas a medicamentos entre os profissionais de saúde, determinando o seu custo-eficácia. MÉTODOS Foram analisadas e comparadas estratégias adotadas pela Unidade de Farmacovigilância do Norte (Portugal) para promoção da notificação de reações adversas a medicamentos. As estratégias foram comparadas quanto ao número e relevância das notificações de reações adversas a medicamentos obtidas e quanto aos custos envolvidos. Os custos por notificação foram calculados somando os custos iniciais e os custos de manutenção de cada estratégia. Esses custos foram então divididos pelo número de notificações obtidas em cada intervenção, para avaliar o seu custo-eficácia. RESULTADOS Todas as abordagens aumentaram o número de notificações de reações adversas a medicamentos. O maior aumento foi observado com os protocolos (321 notificações de reações adversas a medicamentos ganhas, custando 1,96 € cada), seguidos pela primeira abordagem educacional (265 notificações, 20,31 € cada) e pela colocação de hyperlinks (136 notificações, 15,59 € cada). Com relação à gravidade das reações adversas a medicamentos, os protocolos foram a estratégia mais eficiente, custando 2,29 € cada notificação, seguida da colocação de hyperlinks (30,28 € cada, sem custos de manutenção). Quanto às reações adversas a medicamentos inesperadas, o melhor resultado pertenceu aos protocolos (5,12 € cada notificação), seguido por uma primeira abordagem educativa (38,79 € cada notificação). CONCLUSÕES Os autores recomendam a implementação de protocolos em outros centros de farmacovigilância. De fato, estes parecem ser a intervenção mais eficaz, permitindo receber notificações de RAM com custos mais baixos, aplicando-se este aumento tanto ao número total de notificações de reações adversas a medicamentos, como à gravidade, imprevisibilidade e alto grau de causalidade atribuído a elas. Ainda assim, a colocação de hyperlinks apresenta a vantagem de não envolver custos de manutenção, por isso tem o segundo melhor desempenho no indicador custo por notificação de reações adversas a medicamentos.

Risk factors for recurrent wheezing in infants: a case-control study / Fatores de risco para sibilância recorrente em lactentes: estudo caso-controle

ABSTRACT OBJECTIVE To evaluate the association between recurrent wheezing and atopy, the Asthma Predictive Index, exposure to risk factors, and total serum IgE levels as potential factors to predict recurrent wheezing. METHODS A case-control study with infants aged 6-24 months treated at a specialized outpatient clinic from November 2011 to March 2013. Evaluations included sensitivity to inhalant and food antigens, positive Asthma Predictive Index, and other risk factors for recurrent wheezing (smoking during pregnancy, presence of indoor smoke, viral infections, and total serum IgE levels). RESULTS We evaluated 113 children: 65 infants with recurrent wheezing (63.0% male) with a mean age of 14.8 (SD = 5.2) months and 48 healthy infants (44.0% male) with a mean age of 15.2 (SD = 5.1) months. In the multiple analysis model, antigen sensitivity (OR = 12.45; 95%CI 1.28-19.11), positive Asthma Predictive Index (OR = 5.57; 95%CI 2.23-7.96), and exposure to environmental smoke (OR = 2.63; 95%CI 1.09-6.30) remained as risk factors for wheezing. Eosinophilia ≥ 4.0% e total IgE ≥ 100 UI/mL were more prevalent in the wheezing group, but failed to remain in the model. Smoking during pregnancy was identified in a small number of mothers, and secondhand smoke at home was higher in the control group. CONCLUSIONS Presence of atopy, positive Asthma Predictive Index and exposure to environmental smoke are associated to recurrent wheezing. Identifying these factors enables the adoption of preventive measures, especially for children susceptible to persistent wheezing and future asthma onset.

RESUMO OBJETIVO Avaliar a associação entre a sibilância recorrente e atopia, o Índice Preditivo para Asma, exposição a fatores de risco e dosagem de IgE sérica total como possíveis fatores preditores de sibilância recorrente. MÉTODOS Estudo caso-controle com crianças de seis a 24 meses de idade atendidas em ambulatório especializado entre novembro de 2011 e março de 2013. Foram avaliados a sensibilização a antígenos inaláveis e alimentares, positividade para o Índice Preditivo para Asma e outros fatores de risco para sibilância recorrente (tabagismo durante a gravidez, presença de fumaça na residência, infecções virais e dosagem de IgE total). RESULTADOS Foram avaliadas 113 crianças, sendo 65 lactentes sibilantes recorrentes (63,0% do sexo masculino) com média de idade de 14,8 (DP = 5,2) meses e 48 lactentes saudáveis (44,0% do sexo masculino) com média de idade de 15,2 (DP = 5,1) meses. No modelo de análise múltipla, a sensibilização a antígenos (OR = 12,45; IC95% 1,28-19,11), Índice Preditivo para Asma positivo (OR = 5,57; IC95% 2,23-7,96) e exposição à fumaça ambiental (OR = 2,63; IC95% 1,09-6,30) permaneceram como fatores de risco para sibilância. Eosinofilia ≥ 4,0% e IgE total ≥ 100 UI/mL foram mais prevalentes no grupo sibilante, mas não permaneceram no modelo. O tabagismo na gestação foi identificado em pequeno número de mães e o tabagismo domiciliar foi maior no grupo controle. CONCLUSÕES A presença de atopia, a positividade ao Índice Preditivo para Asma e a exposição à fumaça ambiental estão associadas à sibilância recorrente. A identificação desses fatores permite a adoção de medidas preventivas, especialmente nas crianças susceptíveis à persistência de sibilância e ao surgimento de asma no futuro.

Early monitoring for detection of antituberculous drug-induced hepatotoxicity

BACKGROUND/AIMS: We investigated the time of onset of antituberculous drug-induced hepatotoxicity (ADIH) and related characteristics. METHODS: Adult patients (n = 1,031) treated with first-line antituberculous drugs between February 2009 and January 2013 were enrolled. RESULTS: Of the 1,031 patients, 108 patients (10.5%) developed ADIH a mean of 39.6 +/- 43.7 days after treatment initiation. Twenty-eight patients (25.9%) developed ADIH within 7 days, 73 (67.6%) within 30 days, and the rest after 30 days. The 30-day group. In subgroup analysis, the 40 IU/L (odds ratio [OR], 2.995; 95% confidence interval [CI], 1.580 to 5.680; p = 0.001) and presence of anti-hepatitis C virus (OR, 4.204; 95% CI, 1.822 to 9.700, p = 0.001) were independent risk factors for development of ADIH. CONCLUSIONS: Approximately 70% of the cases of ADIH occurred in the first month of antituberculous treatment, and were associated with continuation of the first-line drug regimen.

Elderly men over 65 years of age with late-onset hypogonadism benefit as much from testosterone treatment as do younger men

PURPOSE: To investigate the potential benefits of testosterone administration to elderly men (>65 years) with late-onset hypogonadism (LOH) in comparison with younger men and to assess the safety of testosterone administration to elderly men. MATERIALS AND METHODS: A total of 561 hypogonadal men from two registry studies were divided into age groups of 65 years (group O, n=111; range, 66-84 years). Following an initial 6-week interval, all men were treated with 3-month injections of parenteral testosterone undecanoate for up to 6 years. RESULTS: Over the 6 years, there was a progressive decrease of body weight and waist circumference. Beneficial effects on lipids and other metabolic factors and on psychological and sexual functioning progressed over the first 24 to 42 months and were sustained. Rather than a deterioration, there was an improvement of urinary parameters. Prostate volume and prostate-specific antigen increased moderately. Hematocrit levels increased but remained within safe margins. CONCLUSIONS: The benefits of restoring serum testosterone in men with LOH were not significantly different between men older than 65 years of age and younger men. There were no indications that side effects were more severe in elderly men. The effects on prostate and urinary function and hematocrit were within safe margins. Age itself need not be a contraindication to testosterone treatment of elderly men with LOH.

Response-Guided Therapy for Hepatitis C Virus Recurrence Based on Early Protocol Biopsy after Liver Transplantation

Hepatitis C virus (HCV) recurrence after liver transplantation (LT) is universal and progressive. Here, we report recent results of response-guided therapy for HCV recurrence based on early protocol biopsy after LT. We reviewed patients who underwent LT for HCV related liver disease between 2010 and 2012. Protocol biopsies were performed at 3, 6, and 12 months after LT in HCV recurrence (positive HCV-RNA). For any degree of fibrosis, > or = moderate inflammation on histology or HCV hepatitis accompanying with abnormal liver function, we treated with pegylated interferon and ribavirin. We adjusted treatment period according to individual response to treatment. Among 41 HCV related recipients, 25 (61.0%) who underwent protocol biopsies more than once were enrolled in this study. The mean follow-up time was 43.1 (range, 23-55) months after LT. Genotype 1 and 2 showed in 56.0% and 36.0% patients, respectively. Of the 25 patients, 20 (80.0%) started HCV treatment after LT. Rapid or early virological response was observed in 20 (100%) patients. Fifteen (75.0%) patients finished the treatment with end-of-treatment response. Sustained virological response (SVR) was in 11 (55.0%) patients, including 5 (41.7%) of 12 genotype 1 and 6 (75.0%) of 8 non-genotype 1 (P = 0.197). Only rapid or complete early virological response was a significant predictor for HCV treatment response after LT (100% in SVR group vs. 55.6% in non-SVR group, P = 0.026). Overall 3-yr survival rate was 100%. In conclusion, response-guided therapy for HCV recurrence based on early protocol biopsy after LT shows encouraging results.