A Double‐Blind,Randomized, Placebo and Active‐Controlled Study of Nebicapone for the Treatment of Motor Fluctuations in Parkinson's Disease

To determine the efficacy, safety and tolerability of nebicapone, a new catechol‐O‐methyltransferase inhibitor for the treatment of motor fluctuations in Parkinson's disease (PD), we conducted a multicenter, randomized, 8‐week double‐blind, placebo‐ and active‐controlled, parallel‐group study comparing nebicapone 50 mg, 100 mg, or 150 mg, entacapone 200 mg (active control) or placebo administered concomitantly with levodopa/carbidopa or levodopa/benserazide. Two hundred and fifty‐two PD patients with motor fluctuations treated with levodopa/carbidopa or levodopa/benserazide (4–8 daily doses) were enrolled and 250 patients were eligible for intention‐to‐treat (ITT) analysis on the basis of having at least one efficacy assessment. The primary endpoint was 8‐week change from baseline in absolute “Off” time duration noted in self‐scoring diaries. At 8 weeks of treatment the mean daily “Off” time decreased significantly compared to placebo for nebicapone 150 mg (?106 min; 95%CI: ?192; ?21) and entacapone 200 mg (?81 min; 95%CI: ?142; ?19). The decrease in “Off” time with nebicapone 50 mg or 100 mg did not reach statistical significance. Treatment‐emergent adverse events were reported by 32% to 49% of patients in any treatment group, with no observed dose relationship in the nebicapone groups. Clinically relevant elevations in aspartate transaminase (AST) and/or alanine transaminase (ALT) were observed in 4 of 46 patients with the nebicapone 150 mg dose. The results of this study show that nebicapone 150 mg is efficacious for the treatment of motor fluctuations in PD patients. However, the risk of increasing liver transaminases and its clinically relevance deserves further evaluation.     

Neuroanatomical abnormalities in schizophrenia: a multimodal voxelwise meta-analysis and meta-regression analysis

Despite an increasing number of published voxel based morphometry studies of schizophrenia, there has been no adequate attempt to examine gray (GM) and white matter (WM) abnormalities and the heterogeneity of published findings. In the current article, we used a coordinate based meta-analysis technique to simultaneously examine GM and WM abnormalities in schizophrenia and to assess the effects of gender, chronicity, negative symptoms and other clinical variables. 79 studies meeting our inclusion criteria were included in the meta-analysis. Schizophrenia was associated with GM reductions in the bilateral insula/inferior frontal cortex, superior temporal gyrus, anterior cingulate gyrus/medial frontal cortex, thalamus and left amygdala. In WM analyses of volumetric and diffusion-weighted images, schizophrenia was associated with decreased FA and/or WM in interhemispheric fibers, anterior thalamic radiation, inferior longitudinal fasciculi, inferior frontal occipital fasciculi, cingulum and fornix. Male gender, chronic illness and negative symptoms were associated with more severe GM abnormalities and illness chronicity was associated with more severe WM deficits. The meta-analyses revealed overlapping GM and WM structural findings in schizophrenia, characterized by bilateral anterior cortical, limbic and subcortical GM abnormalities, and WM changes in regions including tracts that connect these structures within and between hemispheres. However, the available findings are biased towards characteristics of schizophrenia samples with poor prognosis.     

Prodromal Parkinson disease in patients with idiopathic hyposmia

Journal of Neurology - Idiopathic hyposmia (IH) is a prodromal marker of Parkinson disease (PD). However, IH is common in the general population and only a minority will develop PD. Identification...     

Determination of [11C]PBR28 binding potential in vivo: a first human TSPO blocking study

Positron emission tomography (PET) targeting the 18 kDa translocator protein (TSPO) is used to quantify neuroinflammation. Translocator protein is expressed throughout the brain, and therefore a classical reference region approach cannot be used to estimate binding potential (BP_ND). Here, we used blockade of the TSPO radioligand [¹¹C]PBR28 with the TSPO ligand XBD173, to determine the non-displaceable volume of distribution (V_ND), and hence estimate the BP_ND. A total of 26 healthy volunteers, 16 high-affinity binders (HABs) and 10 mixed affinity binders (MABs) underwent a [¹¹C]PBR28 PET scan with arterial sampling. Six of the HABs received oral XBD173 (10 to 90 mg), 2 hours before a repeat scan. In XBD173-dosed subjects, V_ND was estimated via the occupancy plot. Values of BP_ND for all subjects were calculated using this V_ND estimate. Total volume of distribution (V_T) of MABs (2.94±0.31) was lower than V_T of HABs (4.33±0.29) (P<0.005). There was dose-dependent occupancy of TSPO by XBD173 (ED50=0.34±0.13 mg/kg). The occupancy plot provided a V_ND estimate of 1.98 (1.69, 2.26). Based on these V_ND estimates, BP_ND for HABs is approximately twice that of MABs, consistent with predictions from in vitro data. Our estimates of [¹¹C]PBR28 V_ND and hence BP_ND in the healthy human brain are consistent with in vitro predictions. XBD173 blockade provides a practical means of estimating V_ND for TSPO targeting radioligands.     

Are prediction equations for glomerular filtration rate useful for the long-term monitoring of type 2 diabetic patients?

Background. The aim of this study was to compare the accuracyof prediction equations [modification of diet in renal disease(MDRD), simplified MDRD, Cockcroft–Gault (CG), reciprocalof creatinine and creatinine clearance] in a cohort of patientswith type 2 diabetes. Methods. A total of 525 glomerular filtration rates (GFRs) using¹²⁵I-iothalamate were carried out over 10 years in 87 type 2diabetic patients. Accuracy was evaluated at three levels ofrenal function according to the baseline values obtained withthe isotopic method: hyperfiltration (GFR: >140 ml/min/1.73m²; 140 isotopic determinations in 27 patients), normal renalfunction (GFR: 140–90 ml/min/1.73 m²; 294 isotopic determinationsin 47 patients) and chronic kidney disease (CKD) stages 2–3(GFR: 30–89 ml/min/1.73 m²; 87 isotopic determinationsin 13 patients). The annual slope for GFR (change in GFR expressedas ml/min/year) was considered to ascertain the variabilityin the equations compared with the isotopic method during follow-up.Student's t-test was used to determine the existence of significantdifferences between prediction equations and the isotopic method(P < 0.05 with Bonferroni adjusted for five contrast tests). Results. In the subgroup of patients with hyperfiltration, aGFR slope calculated with ¹²⁵I-iothalamate –4.8 ±4.7 ml/min/year was obtained. GFR slope in patients with normalrenal function was –3.0 ± 2.3 ml/min/year. In bothsituations, all equations presented a significant underestimationcompared with the isotopic GFR (P < 0.01; P < 0.05). Inthe subgroup of CKD stages 2–3, the slope for GFR with¹²⁵I-iothalamate was –1.4 ± 1.8 ml/min/year. Thebest prediction equation compared with the isotopic method provedto be MDRD with a slope for GFR of –1.4 ± 1.3 ml/min/year(P: NS) compared with the CG formula –1.0 ± 0.9ml/min/year (P: NS). Creatinine clearance presented the greatestvariability in estimation (P < 0.001). Conclusions. In the normal renal function and hyperfiltrationgroups, none of the prediction equations demonstrated acceptableaccuracy owing to excessive underestimation of renal function.In CKD stages 2–3, with mean serum creatinine 133 µmol/l(1.5 mg/dl), the MDRD equation can be used to estimate GFR duringthe monitoring and follow-up of patients with type 2 diabetesreceiving insulin, anti-diabetic drugs or both.     

Asthma,Rhinitis, and Nasal Polyp Multimorbidities

The aim of this review is to assist pulmonologists in the management of diseases involving both the upper and lower respiratory tract that are linked by a common, interrelated epidemiology, clinical signs and symptoms, and inflammatory mechanism , asthma, in particular.The document discusses the definitions of the various sinonasal phenotypes associated with asthma: allergic and non-allergic rhinitis and chronic rhinosinusitis with or without nasal polyps. Diagnostic criteria and severity levels are also listed.Particular attention has been given to the 2 main syndromes associated with asthma: (i) allergic rhinitis, the most common, and (ii) chronic rhinosinusitis with nasal polyps, the disease most closely associated with severe asthma.To summarize, the upper respiratory tract should always be evaluated in order to achieve a single diagnosis and comprehensive treatment of the “united airway”.     

A Systematic Review and Meta-analysis of Adjuvant and Neoadjuvant Chemotherapy for Upper Tract Urothelial Carcinoma

Context

The role of adjuvant chemotherapy (AC) or neoadjuvant chemotherapy (NC) remains poorly defined for the management of upper tract urothelial carcinoma (UTUC), although some studies suggest a benefit.

Objective

To update the current evidence on the role of NC and AC for UTUC patients.

Evidence acquisition

We searched for all studies investigating NC or AC for UTUC in Medline, Embase, the Cochrane Central Register of Controlled Trials, and abstracts from the American Society of Clinical Oncology meetings prior to February 2014. A systematic review and meta-analysis were performed.

Evidence synthesis

No randomized trials investigated the role of AC for UTUC. There was one prospective study (n = 36) investigating adjuvant carboplatin–paclitaxel and nine retrospective studies, with a total of 482 patients receiving cisplatin-based or non-cisplatin–based AC after nephroureterectomy (NU) and 1300 patients receiving NU alone. Across three cisplatin-based studies, the pooled hazard ratio (HR) for overall survival (OS) was 0.43 (95% confidence interval [CI], 0.21–0.89; p = 0.023) compared with those who received surgery alone. For disease-free survival (DFS), the pooled HR across two studies was 0.49 (95% CI, 0.24–0.99; p = 0.048). Benefit was not seen for non-cisplatin–based regimens. For NC, two phase 2 trials demonstrated favorable pathologic downstaging rates, with 3-yr OS and disease-specific survival (DSS) ≤93%. Across two retrospective studies investigating NC, there was a DSS benefit, with a pooled HR of 0.41 (95% CI, 0.22–0.76; p = 0.005).

Conclusions

There appears to be an OS and DFS benefit for cisplatin-based AC in UTUC. This evidence is limited by the retrospective nature of studies and their relatively small sample size. NC appears to be promising, but more trials are needed to confirm its utility.

Patient summary

After a comprehensive search of studies examining the role of chemotherapy for upper tract urothelial cancer, the pooled evidence shows that cisplatin-based adjuvant chemotherapy was beneficial for prolonging survival.