Incidence of liver injury among cancer patients receiving chemotherapy in an integrated health system.

PURPOSE: Using liver laboratory tests (LLTs), Hy's law is a method used to identify drug-induced liver injury (DILI), after excluding other causes. Elevated LLTs in chemotherapy-exposed patients may result from tumor effects or comorbidities. This study evaluated incidence of Hy's law in chemotherapy-treated cancer patients. METHODS: We identified breast, colorectal, and lung cancer patients diagnosed in 1 January 2000 to 31 December 2007 at a Midwestern health system. Using automated data, potential Hy's law (PHL) cases were defined by patterns of elevated LLTs suggestive of DILI. Among those treated with chemotherapy, we excluded PHL patients with pre-existing conditions that could cause liver injury, producing a cohort meeting Hy's law criteria, according to automated data. Medical record review, conducted among these automated data-derived Hy's law patients, further excluded those with causes of liver injury other than chemotherapy. RESULTS: Using automated data, among chemotherapy-exposed patients (N = 2788), 91 (3.3%) met PHL criteria using LLTs and 64 (2.3%) met Hy's law after excluding underlying liver injury using the International Classification of Diseases, 9th Revision codes. After a medical record review, 62 of 64 patients qualifying as Hy's law through automated data had other potential causes, leaving two patients (0.07%; 95%CI: 0.01-0.24%) with chemotherapy as a likely alternative cause of liver injury. CONCLUSIONS: Abnormal LLTs are common in chemotherapy-treated patients. Medical record review showed that the incidence of Hy's law events is rare. These data provide context for evaluating DILI in clinical trials and postmarketing surveillance of anticancer therapies, understanding that automated data alone may substantially overestimate the number of Hy's law cases.

Minireview: Challenges and opportunities in development of PPAR agonists.

The clinical impact of the fibrate and thiazolidinedione drugs on dyslipidemia and diabetes is driven mainly through activation of two transcription factors, peroxisome proliferator-activated receptors (PPAR)-α and PPAR-γ. However, substantial differences exist in the therapeutic and side-effect profiles of specific drugs. This has been attributed primarily to the complexity of drug-target complexes that involve many coregulatory proteins in the context of specific target gene promoters. Recent data have revealed that some PPAR ligands interact with other non-PPAR targets. Here we review concepts used to develop new agents that preferentially modulate transcriptional complex assembly, target more than one PPAR receptor simultaneously, or act as partial agonists. We highlight newly described on-target mechanisms of PPAR regulation including phosphorylation and nongenomic regulation. We briefly describe the recently discovered non-PPAR protein targets of thiazolidinediones, mitoNEET, and mTOT. Finally, we summarize the contributions of on- and off-target actions to select therapeutic and side effects of PPAR ligands including insulin sensitivity, cardiovascular actions, inflammation, and carcinogenicity.

Drug-induced liver injury: the role of drug metabolism and transport.

Many studies have pinpointed the significant contribution of liver-mediated drug metabolism and transport to the complexity of drug-induced liver injury (DILI). Phase I cytochrome P450 (CYP450) enzymes can lead to altered drug metabolism and formation of toxic metabolites, whilst Phase II enzymes are also associated with DILI. The emerging role of hepatic transporters in regulating the movement of endogenous and exogenous chemicals (e.g., bile acids and drugs) across cellular and tissue membranes is critical in determining the pathophysiology of liver disease as well as drug toxicity and efficacy. Genetic and environmental factors can have a significant impact on drug metabolism and transporter proteins, consequently increasing the risk of DILI in susceptible individuals. The assessment of these factors therefore represents an important approach for predicting and preventing DILI, by better understanding the pharmacological profile of a specific drug. This review focuses on the mechanisms of DILI associated with drug metabolism and hepatic transport, and how they can be influenced by underlying factors.

Examining the safety of PPAR agonists - current trends and future prospects.

INTRODUCTION: The peroxisome proliferator-activated receptor (PPAR)-α and -γ agonists, fibrates and glitazones, are effective treatments for dyslipidemia and type 2 diabetes mellitus, respectively, but exhibit class-related, as well as compound-specific safety characteristics. AREAS COVERED: This article reviews the profiles of PPAR-α, PPAR-γ, and dual PPAR-α/γ agonists with regard to class-related and compound-specific efficacy and adverse effects. We explore how learnings from first-generation drugs are being applied to develop safer PPAR-targeted therapies. EXPERT OPINION: The finding that rosiglitazone may increase risk for cardiovascular events has led to regulatory guidelines requiring demonstration of cardiovascular safety in appropriate outcome trials for new type 2 diabetes mellitus drugs. The emerging data on the possibly increased risk of bladder cancer with pioglitazone may prompt the need for post-approval safety studies for new drugs. Since PPAR-α and -γ affect key cardiometabolic risk factors (diabetic dyslipidemia, insulin resistance, hyperglycemia, and inflammation) in a complementary fashion, combining their benefits has emerged as a particularly attractive option. New PPAR-targeted therapies that balance the relative potency and/or activity toward PPAR-α and -γ have shown promise in retaining efficacy while reducing potential side effects.

Current challenges and controversies in drug-induced liver injury.

Current key challenges and controversies encountered in the identification of potentially hepatotoxic drugs and the assessment of drug-induced liver injury (DILI) are covered in this article. There is substantial debate over the classification of DILI itself, including the definition and validity of terms such as 'intrinsic' and 'idiosyncratic'. So-called idiosyncratic DILI is typically rare and requires one or more susceptibility factors in individuals. Consequently, it has been difficult to reproduce in animal models, which has limited the understanding of its underlying mechanisms despite numerous hypotheses. Advances in predictive models would also help to enable preclinical elimination of drug candidates and development of novel biomarkers. A small number of liver laboratory tests have been routinely used to help identify DILI, but their interpretation can be limited and confounded by multiple factors. Improved preclinical and clinical biomarkers are therefore needed to accurately detect early signals of liver injury, distinguish drug hepatotoxicity from other forms of liver injury, and differentiate mild from clinically important liver injury. A range of potentially useful biomarkers are emerging, although so far most have only been used preclinically, with only a few validated and used in the clinic for specific circumstances. Advances in the development of genomic biomarkers will improve the prediction and detection of hepatic injury in future. Establishing a definitive clinical diagnosis of DILI can be difficult, since it is based on circumstantial evidence by excluding other aetiologies and, when possible, identifying a drug-specific signature. DILI signals based on standard liver test abnormalities may be affected by underlying diseases such as hepatitis B and C, HIV and cancer, as well as the concomitant use of hepatotoxic drugs to treat some of these conditions. Therefore, a modified approach to DILI assessment is justified in these special populations and a suggested framework is presented that takes into account underlying disease when evaluating DILI signals in individuals. Detection of idiosyncratic DILI should, in some respects, be easier in the postmarketing setting compared with the clinical development programme, since there is a much larger and more varied patient population exposure over longer timeframes. However, postmarketing safety surveillance is currently limited by the quantity and quality of information available to make an accurate diagnosis, the lack of a control group and the rarity of cases. The pooling of multiple healthcare databases, which could potentially contain different types of patient data, is advised to address some of these deficiencies.

Superação de dormência em sementes de Gleditschia amorphoides Taub. / Overcoming of seed dormancy in Gleditschia amorphoides Taub.

O trabalho teve como objetivo avaliar métodos para a superação da dormência de sementes de sucará. As sementes receberam os seguintes tratamentos: 1) testemunha; 2) escarificação mecânica; 3) escarificação mecânica + água/24h; 4) escarificação mecânica + água quente/24h; 5) água quente/24h; 6) ácido sulfúrico (H2SO4)/1h; 7) H2SO4/2h; 8) H2SO4/1h + água/24h; 9) H2SO4/30min + água corrente/4h; 10) escarificação mecânica + água corrente/4h. O teste de germinação foi conduzido em rolos de papel Germitest acondicionados em câmara de germinação, à 25°C, com fotoperíodo de 12h por 26 dias. Avaliou-se também o tempo e a velocidade média de germinação. O delineamento experimental foi inteiramente casualizado, com quatro repetições de 25 sementes. O melhor desempenho germinativo foi registrado para as sementes submetidas à escarificação mecânica e química, com médias entre 76 e 98 por cento de germinação, respectivamente, 2,17 a 2,88 dias para tempo médio de germinação e 0,46 a 0,47 sementes/dia para velocidade média de germinação, demonstrando serem estes os melhores métodos para superação da dormência de sementes dessa espécie.

The objective of this research was to evaluate methods to overcome dormancy of seeds of Gleditschia amorphoides. For dormancy's overcoming the seeds received the following treatments: 1) control; 2) mechanical scarfication 3) mechanical scarfication + water/24h; 4) mechanical scarfication + hot water/24h; 5) hot water/24h; 6) sulfuric acid (H2SO4)/1h; 7) H2SO4/2h; 8) H2SO4/1h + water/24h; 9) H2SO4/30min + flowing water/4h; 10) mechanical scarfication + flowing water/4h. Germination was done in rolls of Germitest conditioned in a germination chamber under 25°C, during 12h for 26 days. Percentage, time and average speed of germination were evaluated. The experimental design was completely casual with 10 treatments, 4 repetitions and 25 seeds. The best results were recorded for treatments with mechanical and chemical scarification with averages between 76 and 98 percent of germination, from 2.17 to 2.88 days for medium time for germination and 0.46 to 0.48 seeds/day for average speed of germination, demonstrating that these are the best methods to overcome dormancy of seeds.

Risk reduction and tolerability of fluvastatin in patients with the metabolic syndrome: a pooled analysis of thirty clinical trials.

OBJECTIVE: This pooled analysis of 30 completed clinical trials assessed the efficacy and safety profile in reducing cardiovascular disease (CVD) risk of fluvastatin in the treatment of dyslipidemia in patients with and without the metabolic syndrome (metS). METHODS: Data from 30 double-blind, randomized, placebo-controlled or fluvastatin-controlled trials with > or =6 weeks of active treatment and daily fluvastatin doses of 20, 40, and 80 mg were pooled. Patients received fluvastatin or placebo. Linear contrasts from an analysis of covariance model containing factors for trial and treatment group (immediate-release fluvastatin 20, 40, 80 mg; extended-release fluvastatin 80 rag; or placebo), and using the baseline value as covariate, were used to compare the percentage changes from baseline to the first postbaseline assessment of all lipid parameters. A Cox regression analysis compared the all-fluvastatin group to the placebo group with regard to the time to occurrence of clinical end points from 5 pooled studies, each with a mean treatment duration >1 year wherein clinical end points were reviewed by an adjudication committee. These analyses were performed separately for patients with and without metS. RESULTS: This pooled analysis included data from 7043 patients (4095 men, 2948 women; all-fluvastatin group with and without metS, 2529 and 2052 patients, respectively; placebo group with and without metS, 1514 and 948 patients, respectively). Patients with metS in the pooled fluvastatin group had a greater mean reduction in triglyceride levels (24.1% vs 6.7%), a greater mean increase in high-density lipoprotein cholesterol levels (10.3% vs -0.6%), and a similar mean reduction in low-density lipoprotein cholesterol levels (26.8% vs 26.7%) compared with the subgroup of patients without metS. Treatment with fluvastatin was associated with a significantly lower incidence of major adverse cardiovascular events (MACEs) (16.4% vs 22.0%) and an increase in the time to first MACE in patients with metS compared with placebo (hazard ratio = 0.728; P = 0.001). The incidences of adverse events, particularly those of concern (ie, myalgia and/ or increased blood creatine phosphokinase, alanine aminotransferase, and/or aspartate aminotransferase) with lipid-lowering therapy, were statistically similar between the patients who received fluvastatin and those who received placebo in the 2 subgroups. CONCLUSION: The results from this pooled analysis found that fluvastatin was effective in reducing CVD risk in the treatment of dyslipidemia in these patients with metS.

Propagação vegetativa via estaquia de azaléia-arbórea (Rhododendron Tomsonii HOOK.f.) / Vegetative propagation by cuttings of azaléia tree(Rhododendron thomsonii HOOK. f.) / Vegetative propagation by cuttings of azalélia tree (Rhododendron thomsonii HOOK.f. )

Rhododendron thomsonii (Ericaceae) é uma espécie lenhosa, ornamental originária da China cujas sementes são utilizadas exclusivamente para produção de híbridos, sendo a propagação vegetativa uma ferramenta viável para a produção de mudas em larga escala. Com a finalidade de avaliar o enraizamento desta espécie para estacas colhidas na primavera (setembro/2004), foram selecionadas plantas-matrizes adultas situadas no município de Curitiba-PR. As estacas semilenhosas foram obtidas com comprimento aproximado de 12cm, cortadas em bisel na parte inferior e em corte reto na parte superior, com duas folhas reduzidas à metade. O tratamento fitossanitário foi realizado utilizando-se imersão das estacas em hipoclorito de sódio 0,5 (10 minutos) seguida de lavagem em água corrente (5 minutos). Posteriormente as bases das estacas foram imersas em soluções alcoólicas (50) com diferentes concentrações de ácido indol butírico (IBA), (),1000,2000 e 4000mgL-1), e em talco (0,1000,2000 e 4000mgKg-1), totalizando 8 tratamentos com 4 repetições de 9 estacas por parcela. O delineamento experimental utilizado foi o arranjo fatorial (4 X 2) entre as dosagens utilizadas e as formas de aplicação. As estacas foram plantadas em tubetes contendo vermiculita de granulometria média e mantidas em casa-de-vegetação climatizada por 70 dias. As avaliações compreenderam porcentagens de estacas enraizadas, com calos (sem raiz e com calos), vivas (sem raízes e sem calos) e mortas. Não houve enraizamento para estacas coletadas nesta época do ano. A análise de variância revelou que os fatores dosagens e formas de aplicação não apresentaram interação. Na comparação de médias para porcentagens de estacas vivas e mortas, os tratamentos não apresentaram diferenças estatisticamente significativas.

Rhododendron thomsonii (Ericaceae) is a chinese ornamental hardwood species. The seeds are usedjust for hybrids production, therefore, vegetative propagation is an appropriate way for large scale plantproduction. The rooting potential was evaluated in cuttings collected in spring/2004 from stock plants localized in Curitiba, Paraná. The stem cuttings were produced with 12 cm long, right cut upper and bevelbellow, with two half leaves and treated with sodium hypochlorite for ten minutes and current water forfive minutes. The cuttings basis were dipped in IBA treatments (0, 1000, 2000, 4000mgL-1) in alcoholicsolutions and talc (0, 1000, 2000, 4000 mgKg-1), totalling eight treatments with four replications of ninecuttings. Mean separation were made using a pair wise design (4X2) in a association between dosageand application ways. The cuttings were planted in vermiculite medium and maintained in greenhousefor 70 days. The evaluation included percentage of rooting, callus cuttings (without root with callus),alive and dead cuttings. No rooting was verified in cuttings collected in this season. The varianceanalysis showed no interactions between dosage and application ways