Cross-species absorption, metabolism, distribution and pharmacokinetics of BI 201335, a potent HCV genotype 1 NS3/4A protease inhibitor

The present study describes the cross-species absorption, metabolism, distribution and pharmacokinetics of BI 201335, a potent HCV protease inhibitor currently in phase III clinical trials. BI 201335 showed a good Caco-II permeability (8.7 × 10(-6) cm/sec) and in vitro metabolic stability (predicted hepatic clearence (CL(hep)) <19% Q(h) in all species tested). Single dose PK revealed a clearance of 17, 3.0 and 2.6 mL/min/kg in rat, monkey and dog respectively, with a corresponding oral bioavailability of 29.1, 25.5 and 35.6%. Comparative plasma and liver PK profile in rodents showed a high liver Kp in the rat (42-fold), suggesting high target tissue distribution. Simple allometry based on animal PK predicted a human oral CL/F of 168 mL/min, within two-fold of the observed value (118 mL/min) at 240 mg in healthy volunteers. Allometry of volume of distribution generated a low exponent of 0.59, and a much lower predicted Vss/F (5-fold less than observed). Several different approaches of Vss/F prediction were evaluated and compared with the value observed in human. The averaged Vss/F from preclinical animals provides the best estimation of the observed human value (169 L vs. 175 L). Corresponding human "effective" t(1/2) values were also compared. The predicted human t(1/2) based on the CL from allometry with metabolic corrections and the averaged animal Vss represented the best estimation of the clinical data (12.1 vs. 17.2 hr). The present study demonstrated that the good preclinical ADMEPK profile of BI 201335 is consistent with that observed in the clinic. While preclinical data accurately predicted the human CL, the prediction of human Vss seems to be more challenging. The averaged Vss/F from all tested preclinical animals provided the best prediction of human Vss and the resulting "effective" t(1/2).     

The liver partition coefficient-corrected inhibitory quotient and the pharmacokinetic-pharmacodynamic relationship of directly acting anti-hepatitis C virus agents in humans

Pharmacokinetic-pharmacodynamic (PK-PD) data analyses from early hepatitis C virus (HCV) clinical trials failed to show a good correlation between the plasma inhibitory quotient (IQ) and antiviral activity of different classes of directly acting antiviral agents (DAAs). The present study explored whether use of the liver partition coefficient-corrected IQ (LCIQ) could improve the PK-PD relationship. Animal liver partition coefficients (Kp(liver)) were calculated from liver to plasma exposure ratios. In vitro hepatocyte partition coefficients (Kp(hep)) were determined by the ratio of cellular to medium drug concentrations. Human Kp(liver) was predicted using an in vitro-in vivo proportionality method: the species-averaged animal Kp(liver) multiplied by the ratio of human Kp(hep) over those in animals. LCIQ was calculated using the IQ multiplied by the predicted human Kp(liver). Our results demonstrated that the in vitro-in vivo proportionality approach provided the best human Kp(liver) prediction, with prediction errors of <45% for all 5 benchmark drugs evaluated (doxorubicin, verapamil, digoxin, quinidine, and imipramine). Plasma IQ values correlated poorly (r(2) of 0.48) with maximum viral load reduction and led to a corresponding 50% effective dose (ED(50)) IQ of 42, with a 95% confidence interval (CI) of 0.1 to 148534. In contrast, the LCIQ-maximum VLR relationship fit into a typical sigmoidal curve with an r(2) value of 0.95 and an ED(50) LCIQ of 121, with a 95% CI of 83 to 177. The present study provides a novel human Kp(liver) prediction model, and the LCIQ correlated well with the viral load reductions observed in short-term HCV monotherapy of different DAAs and provides a valuable tool to guide HCV drug discovery.     

Sémiologie du syndrome catatonique

The catatonic syndrome remains a syndrome whose definition and identification in clinical practice are little known, unfamiliar for many clinicians. The symptoms may be subtle and difficult to identify. The semiology of the catatonic syndrome results from an interaction between three groups of signs and symptoms: motor signs (immobility, stupor, mutism, fixity of gaze, withdrawal, refusal of food, posture, psychomotor agitation, impulsivity, facial expressions, stereotypy, mannerism, catalepsy, waxy flexibility, negativism, oppositionism), behavioral signs giving an impression of dependence on the environment (imitation behaviors, utilization behaviors, magnetization behaviors) and neurovegetative signs. This syndrome has become, in a widely accepted way today, a transnosographic clinical syndrome. It is imperative to recognize this semiology in order to treat it quickly. Indeed, the etiologies of this syndrome and the consequences of the syndrome, can engage the vital prognosis.     

Risk Factors of Cholera Transmission in Al Hudaydah,Yemen: Case-Control Study

BackgroundYemen has recently faced the largest cholera outbreak in the world, which started at the end of 2016. By the end of 2017, the cumulative reported cases from all governorates reached 777,229 with 2134 deaths. Al Hudaydah was one of the most strongly affected areas, with 88,741 (18%) cases and 244 (12%) deaths reported.ObjectiveThe aim of this study was to determine the risk factors associated with cholera transmission in Al Hudaydah city, Yemen.MethodsFrom December 1, 2017 to January 10, 2018, a total of 104 patients with cholera (57 women and 47 men) who presented at cholera treatment centers in Al Hudaydah city with three or more watery stools in a 24-hour period and with moderate or severe dehydration were identified for inclusion in this study. Each case was matched by age and gender with two controls who were living in the neighboring house. A semistructured questionnaire was used to collect data on behavioral and environmental risk factors such as drinking water from public wells, storing water in containers, consumption of unwashed vegetables or fruits, and sharing a toilet.ResultsThe median age of the cases and controls was 20 years (range 5-80) and 23 years (range 5-85), respectively. Only 6% of cases and 4% of controls were employed. Multivariate analysis showed that eating unwashed vegetables or fruits (odds ratio [OR] 7.0, 95% CI 1.6-30.6, P=.01), storing water in containers (OR 3.0, 95% CI 1.3-7.3, P=.01), drinking water from a public well (OR 2.5, 95% CI 1.1-5.7, P=.02), and using a public toilet (OR 5.2, 95% CI 1.1-24.4, P=.04) were significantly associated with cholera infection risk.ConclusionsThe cholera transmission risk factors in Al Hudaydah city were related to water and sanitation hygiene. Therefore, increasing awareness of the population on the importance of water chlorination, and washing fruits and vegetables through a health education campaign is strongly recommended.     

The heterogeneous functional architecture of the posteromedial cortex is associated with selective functional connectivity differences in Alzheimer's disease

The posteromedial cortex (PMC) is a key region involved in the development and progression of Alzheimer's disease (AD). Previous studies have demonstrated a heterogenous functional architecture of the region that is composed of discrete functional modules reflecting a complex pattern of functional connectivity. However, little is understood about the mechanisms underpinning this complex network architecture in neurodegenerative disease, and the differential vulnerability of connectivity‐based subdivisions in the PMC to AD pathogenesis. Using a data‐driven approach, we applied a constrained independent component analysis (ICA) on healthy adults from the Human Connectome Project to characterise the local functional connectivity patterns within the PMC, and its unique whole‐brain functional connectivity. These distinct connectivity profiles were subsequently quantified in the Alzheimer's Disease Neuroimaging Initiative study, to examine functional connectivity differences in AD patients and cognitively normal (CN) participants, as well as the entire AD pathological spectrum. Our findings revealed decreased functional connectivity in the anterior precuneus, dorsal posterior cingulate cortex (PCC), and the central precuneus in AD patients compared to CN participants. Functional abnormalities in the dorsal PCC and central precuneus were also related to amyloid burden and volumetric hippocampal loss. Across the entire AD spectrum, functional connectivity of the central precuneus was associated with disease severity and specific deficits in memory and executive function. These findings provide new evidence showing that the PMC is selectively impacted in AD, with prominent network failures of the dorsal PCC and central precuneus underpinning the neurodegenerative and cognitive dysfunctions associated with the disease.     

Risperidone monotherapy for post-traumatic stress disorder related to sexual assault and domestic abuse in women

Post-traumatic stress disorder is a common, chronic, and often disabling mental illness. Selective serotonin reuptake inhibitors are the usual first-line treatment for post-traumatic stress disorder, but many patients fail to respond adequately. Thus, other treatment options, including the atypical antipsychotics such as risperidone, need to be tested. Women between the ages of 19 and 64 years with post-traumatic stress disorder were enrolled. Symptom severity was rated at baseline using the Treatment Outcomes Post-traumatic Stress Disorder Scale-8, Hamilton Rating Scale for Anxiety, Hamilton Rating Scale for Depression, and Clinician Administered Post-traumatic Stress Disorder Scale. After washout from other psychotropic medications, 20 participants were randomized to either risperidone or placebo. Total score on the Treatment Outcomes Post-traumatic Stress Disorder Scale-8 served as the primary outcome measure. Repeated-measures analysis of variance was followed by Newman-Keuls tests. A significant main effect exists for visits using the Treatment Outcomes Post-traumatic Stress Disorder Scale-8 raw score. For the treatment group, the difference between baseline Treatment Outcomes Post-traumatic Stress Disorder Scale-8 scores and treatment visit scores was significant beginning at visit 6 and continued through visit 11. No significant difference observed between baseline and any treatment visit for the placebo group. The Clinician Administered Post-traumatic Stress Disorder Scale, Hamilton Rating Scale for Anxiety, and Hamilton Rating Scale for Depression data revealed a similar pattern. In this small pilot study, risperidone monotherapy was more effective than placebo in the treatment of post-traumatic stress disorder.     

Gender-related associations between psychiatric disorders and alcohol use disorder: Findings from the french “Mental health in the general population” survey

Archives of Women's Mental Health - Women with alcohol use disorder (AUD) might be particularly vulnerable to psychiatric comorbidities. However, population surveys have yielded disparate...     

Loss of ARID1A/BAF250a expression in ovarian endometriosis and clear cell carcinoma

Ovarian endometriosis has been associated with increased risk for ovarian clear cell carcinoma (CCC). Atypical endometriosis shares common molecular alterations with CCC and therefore, has been proposed as a precursor lesion of CCC, although it is unclear if benign endometriosis is pre-neoplastic. In this study, we examined some molecular alterations in ovarian benign endometriosis, atypical endometriosis, and CCC in comparison to papillary serous carcinoma (PSC). These included BAF250a (encoded by ARID1A), a recently identified major tumor suppressor in ovarian CCC, as well as hepatocyte nuclear factor (HNF)-1b, estrogen receptor (ER), progesterone receptor (PR), and P53. We confirmed that CCC but not PSC had loss of BAF250a expression, HNF-1b up-regulation, loss of ER expression and P53 expression. We further showed that both atypical endometriosis and adjacent CCC had loss of BAF250a expression (38.5% vs. 57.7%), HNF-1b up-regulation (53.8% vs. 92.3%), and loss of ER (84.6% vs. 92.3%) and PR (76.9% vs. 84.6%) expression. Importantly, about 20% of benign ovarian endometriosis had loss of BAF250a expression, 33% with HNF-1b up-regulation, 23% loss of ER expression and 50% loss of PR expression, respectively. The concurrent rate of loss of BAF250a expression, HNF-1b up-regulation, and loss of ER expression was not observed in any benign endometriosis, and was increased to 23.1% in atypical endometriosis, and was further increased to 42.3% in CCC. Therefore, the molecular alterations accumulate in a stepwise manner along the transformation process from benign endometriosis through atypical endometriosis to CCC. These data suggest that a portion of benign ovarian endometriosis has already undergone genetic alterations that lead to aberrant protein expression, possibly conferring a higher risk for malignant transformation.