Role of Biotransformation Studies in Minimizing Metabolism-Related Liabilities in Drug Discovery

Metabolism-related liabilities continue to be a major cause of attrition for drug candidates in clinical development. Such problems may arise from the bioactivation of the parent compound to a reactive metabolite capable of modifying biological materials covalently or engaging in redox-cycling reactions leading to the formation of other toxicants. Alternatively, they may result from the formation of a major metabolite with systemic exposure and adverse pharmacological activity. To avert such problems, biotransformation studies are becoming increasingly important in guiding the refinement of a lead series during drug discovery and in characterizing lead candidates prior to clinical evaluation. This article provides an overview of the methods that are used to uncover metabolism-related liabilities in a pre-clinical setting and offers suggestions for reducing such liabilities via the modification of structural features that are used commonly in drug-like molecules

PLANTAS HOSPEDEIRAS DE Thyrinteina arnobia (LEPIDOPTERA: GEOMETRIDAE) AFETAM O DESENVOLVIMENTO DO PARASITOIDE Palmistichus elaeisis (HYMENOPTERA: EULOPHIDAE)1

O objetivo deste trabalho foi avaliar a eficiência do parasitismo e a biologia da prole do parasitoide Palmistichus elaeisis Delvare e La Salle (Hymenoptera: Eulophidae) em pupas de Thyrinteina arnobia Stoll (Lepidoptera: Geometridae) quando criadas em plantas de Psidium guajava ou Eucalyptus cloeziana. Ovos de T. arnobia foram coletados e colocados em sacos de tecido tipo organza envolvendo galhos de plantas de P. guajava (T1) e E. cloeziana (T2) até as lagartas alcançarem a fase de pupa. Trinta pupas de cada tratamento foram individualizadas em tubos de vidro e expostas ao parasitismo por quatro fêmeas de P. elaeisis por 24 h. Avaliaram-se a emergência da progênie do parasitoide por pupa; a porcentagem de parasitismo, pupas mortas e de adultos de T. arnobia emergidos; a duração do ciclo de vida (ovo-adulto);a longevidade; a razão sexual; e o tamanho da cápsula cefálica e do corpo do parasitoide. A porcentagem de parasitismo, a emergência de P. elaeisis por pupa, a longevidade das fêmeas e o tamanho da cápsula cefálica e do corpo dos machos do parasitoide foram menores quando seu hospedeiro foi criado em plantas de eucalipto. Isso pode ter ocorrido devido à grande quantidade de compostos do metabolismo secundário presentes nesta planta, que podem ser acumulados no corpo do herbívoro ao se alimentar, afetando negativamente o inimigo natural. Palmistichus elaeisis mostrou-se mais adaptado à mirtácea nativa da América P. guajava

"Delirium Day": A nationwide point prevalence study of delirium in older hospitalized patients using an easy standardized diagnostic tool

Background: To date, delirium prevalence in adult acute hospital populations has been estimated generally from pooled findings of single-center studies and/or among specific patient populations. Furthermore, the number of participants in these studies has not exceeded a few hundred. To overcome these limitations, we have determined, in a multicenter study, the prevalence of delirium over a single day among a large population of patients admitted to acute and rehabilitation hospital wards in Italy. Methods: This is a point prevalence study (called "Delirium Day") including 1867 older patients (aged 65 years or more) across 108 acute and 12 rehabilitation wards in Italian hospitals. Delirium was assessed on the same day in all patients using the 4AT, a validated and briefly administered tool which does not require training. We also collected data regarding motoric subtypes of delirium, functional and nutritional status, dementia, comorbidity, medications, feeding tubes, peripheral venous and urinary catheters, and physical restraints. Results: The mean sample age was 82.0 \ub1 7.5 years (58 % female). Overall, 429 patients (22.9 %) had delirium. Hypoactive was the commonest subtype (132/344 patients, 38.5 %), followed by mixed, hyperactive, and nonmotoric delirium. The prevalence was highest in Neurology (28.5 %) and Geriatrics (24.7 %), lowest in Rehabilitation (14.0 %), and intermediate in Orthopedic (20.6 %) and Internal Medicine wards (21.4 %). In a multivariable logistic regression, age (odds ratio [OR] 1.03, 95 % confidence interval [CI] 1.01-1.05), Activities of Daily Living dependence (OR 1.19, 95 % CI 1.12-1.27), dementia (OR 3.25, 95 % CI 2.41-4.38), malnutrition (OR 2.01, 95 % CI 1.29-3.14), and use of antipsychotics (OR 2.03, 95 % CI 1.45-2.82), feeding tubes (OR 2.51, 95 % CI 1.11-5.66), peripheral venous catheters (OR 1.41, 95 % CI 1.06-1.87), urinary catheters (OR 1.73, 95 % CI 1.30-2.29), and physical restraints (OR 1.84, 95 % CI 1.40-2.40) were associated with delirium. Admission to Neurology wards was also associated with delirium (OR 2.00, 95 % CI 1.29-3.14), while admission to other settings was not. Conclusions: Delirium occurred in more than one out of five patients in acute and rehabilitation hospital wards. Prevalence was highest in Neurology and lowest in Rehabilitation divisions. The "Delirium Day" project might become a useful method to assess delirium across hospital settings and a benchmarking platform for future surveys