Capsule permeability via polymer and protein ingress/egress.

Static incubation tests, where microcapsules and beads are contacted with polymer and protein solutions, have been developed for the characterization of permselective materials applied for bioartificial organs and drug delivery. A combination of polymer ingress, detected by size-exclusion chromatography, and protein ingress/ egress, assessed by gel electrophoresis, provides information regarding the diffusion kinetics, molar mass cutoff(MMCO) and permeability. This represents an improvement over existing permeability measurements that are based on the diffusion of a single type of solute. Specifically, the permeability of capsules based on alginate, cellulose sulfate, polymethylene-co-guanidine were characterized as a function of membrane thickness. Solid alginate beads were also evaluated. The MMCO of these capsules was estimated to be between 80 and 90 kDa using polymers, and between 116-150 kDa with proteins. Apparently, the globular shape of the proteins (radius of gyration (Rg) of 4.2-4.6 nm) facilitates their passage through the membrane, comparatively to the polysaccharide coil conformation (Rg of 6.5-8.3 nm). An increase of the capsule membrane thickness reduced these values. The MMCO of the beads, which do not have a membrane limiting their permselective properties, was higher, between 110 and 200 kDa with dextrans, and between 150 and 220 kDa with proteins. Therefore, although the permeability estimated with biologically relevant molecules is generally higher due to their lower radius of gyration, both the MMCO of synthetic and natural watersoluble polymers correlate well, and can be used as in vitro metrics for the immune protection ability of microcapsules and microbeads. This article shows, to the authors' knowledge, the first reported concordance between permeability measures based on model natural and biological macromolecules.

Fenilefrina intracamerular en el síndrome del iris flácido intraoperatorio

La incidència d’hipertròfia benigna de pròstata és aproximadament d’un 50 % en pacients majors de 50 anys. La Tamsulosina és el medicament més prescrit per aquesta dolència i la principal causa del síndrome d’iris flàccid intraoperatori a la cirurgia de cataractes. Els nostres dos estudis han sigut; per una banda, avaluar la toxicitat corneal i afectació cardíaca de Fenilefrina intracamerular a una concentració de 2,5% respecte la pauta de dilatació tòpica estàndard al nostre centre, i per l’altra, comparar l’ efectivitat i diferència al recompte endotelial de Fenilefrina intracamerular a una concentració de 2,5% respecte a una altra concentració del 1,66 %, mesurant els seus efectes en diverses variables.

Evaluación de la eficacia y seguridad del tratamiento con tetratiomolibdato de amonio en la enfermedad de Wilson con afectación neurológica

El tractament actual de la malaltia de Wilson amb afectació neurològica és controvertit. Els fàrmacs actuals s’associen a risc de deteriorament neurològic (50% amb penicilamina i 26% amb trientine). El nou medicament tetratiomolibdat s’està estudiant perquè sembla tenir menor freqüència d’empitjorament neurològic. S’associa a efectes secundaris lleus i generalment reversibles. A la nostra sèrie de cinc pacients vàrem observar una milloria significativa dels símptomes després del tractament amb tetratiomolibdat. No es va detectar cap empitjorament neurològic. En dos casos va haver també una millora radiològica. Un pacient va presentar lleu anèmia, leucopènia i elevació de les transaminases reversible.

Prolonged cholestasis after raloxifene and fenofibrate interaction: A case report.

Assigning causality in drug-induced liver injury is challenging particularly when more than one drug could be responsible. We report a woman on long-term therapy with raloxifen who developed acute cholestasis shortly after starting fenofibrate. The picture evolved into chronic cholestasis. We hypothesized that an interaction at the metabolic level could have triggered the presentation of hepatotoxicity after a very short time of exposure to fenofibrate in this patient. The findings of an overexpression of vascular endothelial growth factor in the liver biopsy suggest that angiogenesis might play a role in the persistence of toxic cholestasis.

Assessment of drug-induced hepatotoxicity in clinical practice: a challenge for gastroenterologists.

Currently, pharmaceutical preparations are serious contributors to liver disease; hepatotoxicity ranking as the most frequent cause for acute liver failure and post-commercialization regulatory decisions. The diagnosis of hepatotoxicity remains a difficult task because of the lack of reliable markers for use in general clinical practice. To incriminate any given drug in an episode of liver dysfunction is a step-by-step process that requires a high degree of suspicion, compatible chronology, awareness of the drug's hepatotoxic potential, the exclusion of alternative causes of liver damage and the ability to detect the presence of subtle data that favors a toxic etiology. This process is time-consuming and the final result is frequently inaccurate. Diagnostic algorithms may add consistency to the diagnostic process by translating the suspicion into a quantitative score. Such scales are useful since they provide a framework that emphasizes the features that merit attention in cases of suspected hepatic adverse reaction as well. Current efforts in collecting bona fide cases of drug-induced hepatotoxicity will make refinements of existing scales feasible. It is now relatively easy to accommodate relevant data within the scoring system and to delete low-impact items. Efforts should also be directed toward the development of an abridged instrument for use in evaluating suspected drug-induced hepatotoxicity at the very beginning of the diagnosis and treatment process when clinical decisions need to be made. The instrument chosen would enable a confident diagnosis to be made on admission of the patient and treatment to be fine-tuned as further information is collected.

Genetic variations in drug-induced liver injury (DILI): resolving the puzzle.

Despite stringent requirements for drug development imposed by regulatory agencies, drug-induced liver injury (DILI) is an increasing health problem and a significant cause for failure to approve drugs, market withdrawal of commercialized medications, and adoption of regulatory measures. The pathogenesis is yet undefined, though the rare occurrence of idiosyncratic DILI (1/100,000–1/10,000) and the fact that hepatotoxicity often recurs after re-exposure to the culprit drug under different environmental conditions strongly points toward a major role for genetic variations in the underlying mechanism and susceptibility. Pharmacogenetic studies in DILI have to a large extent focused on genes involved in drug metabolism, as polymorphisms in these genes may generate increased plasma drug concentrations as well as lower clearance rates when treated with standard medication doses. A range of studies have identified a number of genetic variants in drug metabolism Phase I, II, and III genes, including cytochrome P450 (CYP) 2E1, N-acetyltransferase 2, UDP-glucuronosyltransferase 2B7, glutathione S-transferase M1/T1, ABCB11, and ABCC2, that enhance DILI susceptibility (Andrade et al., 2009; Agundez et al., 2011). Several metabolic gene variants, such as CYP2E1c1 and NAT2 slow, have been associated with DILI induced by specific drugs based on individual drug metabolism information. Others, such as GSTM1 and T1 null alleles have been associated with enhanced risk of DILI development induced by a large range of drugs. Hence, these variants appear to have a more general role in DILI susceptibility due to their role in reducing the cell's antioxidative capacity (Lucena et al., 2008). Mitochondrial superoxide dismutase (SOD2) and glutathione peroxidase 1 (GPX1) are two additional enzymes involved in combating oxidative stress, with specific genetic variants shown to enhance the risk of developing DILI

HLA Alleles Influence the Clinical Signature of Amoxicillin-Clavulanate Hepatotoxicity.

BACKGROUND AND AIM The genotype-phenotype interaction in drug-induced liver injury (DILI) is a subject of growing interest. Previous studies have linked amoxicillin-clavulanate (AC) hepatotoxicity susceptibility to specific HLA alleles. In this study we aimed to examine potential associations between HLA class I and II alleles and AC DILI with regards to phenotypic characteristics, severity and time to onset in Spanish AC hepatotoxicity cases. METHODS High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls. RESULTS The distributions of class I alleles A*3002 (P/Pc = 2.6E-6/5E-5, OR 6.7) and B*1801 (P/Pc = 0.008/0.22, OR 2.9) were more frequently found in hepatocellular injury cases compared to controls. In addition, the presence of the class II allele combination DRB1*1501-DQB1*0602 (P/Pc = 5.1E-4/0.014, OR 3.0) was significantly increased in cholestatic/mixed cases. The A*3002 and/or B*1801 carriers were found to be younger (54 vs 65 years, P = 0.019) and were more frequently hospitalized than the DRB1*1501-DQB1*0602 carriers. No additional alleles outside those associated with liver injury patterns were found to affect potential severity as measured by Hy's Law criteria. The phenotype frequencies of B*1801 (P/Pc = 0.015/0.42, OR 5.2) and DRB1*0301-DQB1*0201 (P/Pc = 0.0026/0.07, OR 15) were increased in AC DILI cases with delayed onset compared to those corresponding to patients without delayed onset, while the opposite applied to DRB1*1302-DQB1*0604 (P/Pc = 0.005/0.13, OR 0.07). CONCLUSIONS HLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients.

Selected ABCB1, ABCB4 and ABCC2 Polymorphisms Do Not Enhance the Risk of Drug-Induced Hepatotoxicity in a Spanish Cohort.

BACKGROUND AND AIMS Flawed ABC transporter functions may contribute to increased risk of drug-induced liver injury (DILI). We aimed to analyse the influence of genetic variations in ABC transporters on the risk of DILI development and clinical presentations in a large Spanish DILI cohort. METHODS A total of ten polymorphisms in ABCB1 (1236T>C, 2677G>T,A, 3435T>C), ABCB4 (1954A>G) and ABCC2 (-1774G>del, -1549A>G, -24C>T, 1249G>A, 3972C>T and 4544G>A) were genotyped using Taqman 5' allelic discrimination assays or sequencing in 141 Spanish DILI patients and 161 controls. The influence of specific genotypes, alleles and haplotypes on the risk of DILI development and clinical presentations was analysed. RESULTS None of the individual polymorphisms or haplotypes was found to be associated with DILI development. Carriers homozygous for the ABCC2 -1774del allele were however only found in DILI patients. Hence, this genotype could potentially be associated with increased risk, though its low frequency in our Spanish cohort prevented a final conclusion. Furthermore, carriers homozygous for the ABCC2 -1774G/-1549A/-24T/1249G/3972T/4544G haplotype were found to have a higher propensity for total bilirubin elevations when developing DILI. CONCLUSIONS Our findings do not support a role for the analysed polymorphisms in the ABCB1, ABCB4 and ABCC2 transporter genes in DILI development in Spanish patients. The ABCC2 -1774deldel genotype was however restricted to DILI cases and could potentially contribute to enhanced DILI susceptibility.

The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury.

Distinguishing drug-induced liver injury (DILI) from idiopathic autoimmune hepatitis (AIH) can be challenging. We performed a standardized histologic evaluation to explore potential hallmarks to differentiate AIH versus DILI. Biopsies from patients with clinically well-characterized DILI [n = 35, including 19 hepatocellular injury (HC) and 16 cholestatic/mixed injury (CS)] and AIH (n = 28) were evaluated for Ishak scores, prominent inflammatory cell types in portal and intra-acinar areas, the presence or absence of emperipolesis, rosette formation, and cholestasis in a blinded fashion by four experienced hepatopathologists. Histologic diagnosis was concordant with clinical diagnosis in 65% of cases; but agreement on final diagnosis among the four pathologists was complete in only 46% of cases. Interface hepatitis, focal necrosis, and portal inflammation were present in all evaluated cases, but were more severe in AIH (P < 0.05) than DILI (HC). Portal and intra-acinar plasma cells, rosette formation, and emperiopolesis were features that favored AIH (P < 0.02). A model combining portal inflammation, portal plasma cells, intra-acinar lymphocytes and eosinophils, rosette formation, and canalicular cholestasis yielded an area under the receiver operating characteristic curve (AUROC) of 0.90 in predicting DILI (HC) versus AIH. All Ishak inflammation scores were more severe in AIH than DILI (CS) (P ≤ 0.05). The four AIH-favoring features listed above were consistently more prevalent in AIH, whereas portal neutrophils and intracellular (hepatocellular) cholestasis were more prevalent in DILI (CS) (P < 0.02). The combination of portal inflammation, fibrosis, portal neutrophils and plasma cells, and intracellular (hepatocellular) cholestasis yielded an AUC of 0.91 in predicting DILI (CS) versus AIH. Conclusion: Although an overlap of histologic findings exists for AIH and DILI, sufficient differences exist so that pathologists can use the pattern of injury to suggest the correct diagnosis.

Guía farmacoterapéutica de hospital : Sistema Sanitario Público de Andalucía 2014

Actualización enero de 2015. Esta guía se ha realizado en virtud de un convenio de colaboración entre el Servicio Andaluz de Salud y la Sociedad Andaluza de Famacéuticos de Hospital. Grupo hospitalario para la evaluación de medicamentos en Andalucía (GHEMA).

Use of Hy's law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury.

BACKGROUND & AIMS Hy's Law, which states that hepatocellular drug-induced liver injury (DILI) with jaundice indicates a serious reaction, is used widely to determine risk for acute liver failure (ALF). We aimed to optimize the definition of Hy's Law and to develop a model for predicting ALF in patients with DILI. METHODS We collected data from 771 patients with DILI (805 episodes) from the Spanish DILI registry, from April 1994 through August 2012. We analyzed data collected at DILI recognition and at the time of peak levels of alanine aminotransferase (ALT) and total bilirubin (TBL). RESULTS Of the 771 patients with DILI, 32 developed ALF. Hepatocellular injury, female sex, high levels of TBL, and a high ratio of aspartate aminotransferase (AST):ALT were independent risk factors for ALF. We compared 3 ways to use Hy's Law to predict which patients would develop ALF; all included TBL greater than 2-fold the upper limit of normal (×ULN) and either ALT level greater than 3 × ULN, a ratio (R) value (ALT × ULN/alkaline phosphatase × ULN) of 5 or greater, or a new ratio (nR) value (ALT or AST, whichever produced the highest ×ULN/ alkaline phosphatase × ULN value) of 5 or greater. At recognition of DILI, the R- and nR-based models identified patients who developed ALF with 67% and 63% specificity, respectively, whereas use of only ALT level identified them with 44% specificity. However, the level of ALT and the nR model each identified patients who developed ALF with 90% sensitivity, whereas the R criteria identified them with 83% sensitivity. An equal number of patients who did and did not develop ALF had alkaline phosphatase levels greater than 2 × ULN. An algorithm based on AST level greater than 17.3 × ULN, TBL greater than 6.6 × ULN, and AST:ALT greater than 1.5 identified patients who developed ALF with 82% specificity and 80% sensitivity. CONCLUSIONS When applied at DILI recognition, the nR criteria for Hy's Law provides the best balance of sensitivity and specificity whereas our new composite algorithm provides additional specificity in predicting the ultimate development of ALF.

Dificuldades e facilidades dos doentes no seguimento do tratamento da hipertensão arterial

Este estudo teve por objetivos identificar as dificuldades e as facilidades de doentes no seguimento do tratamento da hipertensão arterial; e, verificar se existem diferenças nessas dificuldades e facilidades em dois momentos dessa trajetória - no atendimento ambulatorial e na internação. Para este estudo descritivo, quantitativo, foram entrevistados 34 doentes, com diagnóstico médico de hipertensão arterial (HA) e/ou suas complicações, sendo 17 matriculados no ambulatório e 17 hospitalizados na unidade de internação de nefrologia. Os resultados revelaram que, em geral, não houve diferenças entre as dificuldades e as facilidades referidas pelos doentes para o seguimento do tratamento da HA, nos dois momentos estudados. As dificuldades e facilidades apontadas referem-se ao financiamento do tratamento (compra de medicamento e gastos com transporte); acessibilidade ao serviço (facilidade em marcar consulta médica e distância do serviço de saúde); mudança de hábito alimentar (dieta hipossódica) e a importância do apoio familiar nesta trajetória.

Administração de medicamentos injetáveis por via intramuscular: conhecimento dos ocupacionais de farmácias

Complicações advindas da aplicação incorreta das injeções intramusculares podem acarretar sérios prejuízos orgânicos, favorecer o aparecimento de infecções e aumentar a permanência do paciente na instituição ou prejudicar as funções no trabalho. Estudo anterior detectou vários casos de pacientes com complicações locais após aplicação intramuscular de diclofenaco sódico em farmácias e concluiu que a falta de conhecimento da técnica de administração desse medicamento pode ter sido uma das causas das complicações. Diante disso o estudo atual teve o objetivo de identificar e avaliar o nível de conhecimentos de ocupacionais que administram medicamentos injetáveis intramusculares à população, em farmácias de Ribeirão Preto - SP. O estudo se constituiu num levantamento, a partir de um questionário contendo 20 questões abertas e fechadas, aplicado a uma população constituída por ocupacionais atuando em farmácias, selecionadas através do método da amostragem simples casual estratificada -partilha proporcional, resultando num total de 41 sujeitos. Concluímos que a população vem recebendo medicamento s injetáveis de ocupacionais com déficit de informações a respeito da técnica de aplicação de injetáveis. Os sujeitos referiram não receber treinamento adequado para exercer esse procedimento, terminando por aprendê-lo com outro funcionário ou observando alguém que o realize. Disto resulta lacunas de conhecimento em uma amostra de ocupacionais que podem, realmente, levar ao aparecimento de complicações pós injeções intramusculares na população que utiliza os serviços desses estabelecimentos.

Conseqüências dos erros de medicação em unidades de terapia intensiva e semi-intensiva

O estudo objetivou caracterizar erros de medicação e avaliar conseqüências na gravidade dos pacientes e carga de trabalho de enfermagem em duas Unidades de Terapia Intensiva (UTI) e duas Semi-Intensiva (USI) de duas instituições hospitalares do município de São Paulo. A amostra foi constituída por 50 pacientes e os dados obtidos por meio do registro de ocorrências e prontuários, retrospectivamente. A gravidade e carga de trabalho de enfermagem foram avaliadas antes e após o erro. Do total de 52 erros, 12 (23,08%) ocorreram por omissão de dose, 11 (21,15%) e 9 (17,31%) por medicamento e dose erradas, respectivamente. Não houve mudança na gravidade dos pacientes (p=0,316), porém houve aumento na carga de trabalho de enfermagem (p=0,009). Quanto ao grupo de medicamentos envolvidos, potencialmente perigosos e não potencialmente perigosos, não houve diferenças estatisticamente significantes na gravidade (p=0,456) e na carga de trabalho de enfermagem (p=0,264), após o erro de medicação.

Os conceitos de vulnerabilidade e adesão na Saúde Coletiva

Os conceitos de Vulnerabilidade e Adesão têm sido foco de debate na Saúde Coletiva. É desafio posto pela Saúde Coletiva, propiciar tecnologias, dispositivos e instrumentos que apóiem a construção de práticas qualificadas, para responder às necessidades dos grupos sociais. Na produção do conhecimento, tem buscado inovar no desenvolvimento de instrumentos que apóiem a captação da realidade de vida e saúde e que auxiliem na leitura das necessidades e no desencadeamento e sustentação de projetos de intervenção que produzam o impacto desejado: atender os grupos sociais que mais carecem de apoio para conquistar autonomia para viver a vida com qualidade e a consecução do auto-cuidado, no cenário da equidade e da justiça social. O artigo apresenta aspectos das categorias analíticas Adesão e Vulnerabilidade, quanto à proposição de marcadores/ indicadores para o seu monitoramento, o que pode contribuir para o adensamento do conceito e para a prática do processo de produção à saúde.