Cardiovascular safety of low-dose fenfluramine in Dravet syndrome: a review of its benefit-risk profile in a new patient population

Objective: Dravet syndrome (DS) is a rare, treatment-resistant epilepsy syndrome for which current treatment regimens are often ineffective. Fenfluramine is currently in development for treatment of DS, based on reports in the 1980s and 1990s of its anti-epileptic activity in pediatric patients with intractable epilepsy. However, fenfluramine was withdrawn from global markets in 1997 following reports of its association with pulmonary hypertension and heart valve disease in adult patients treated for obesity. This review was conducted to assess cardiac safety of fenfluramine when used at lower doses for treatment of DS.

Methods: Pubmed was searched for clinical studies of fenfluramine in obese adults who reported incidence of heart valve disease. These data were reviewed against published results from Belgian patients with DS who have been treated with low-dose fenfluramine for up to 28 years.

Results: Nine controlled studies of fenfluramine and related compounds (dexfenfluramine and/or phentermine) which assessed incidence and severity of cardiac valve disease in 3,268 treated patients and 2,017 control subjects have been reported. Mild or greater aortic valve regurgitation was found in 9.6% of treated patients compared with 3.9% of control subjects, and moderate or greater mitral valve regurgitation was found in 3.1% of treated patients and 2.5% of control subjects. Nineteen DS patients have been treated for up to 28 years with 10–20?mg/day fenfluramine, with no clinical signs or symptoms of cardiac valve disease or pulmonary hypertension. Slight and clinically unimportant changes in valve structure have been seen on echocardiography in five patients at some time during the observation period.

Conclusions: A different benefit-risk relationship appears to be emerging when fenfluramine is used at low doses for extended periods in young patients with DS. Continued cardiac assessments during ongoing Phase 3 clinical trials will provide additional safety information for this potential new and effective treatment.     

More daytime sleepiness and worse quality of sleep in patients with Dravet Syndrome compared to other epilepsy patients

Aim

Sleep problems are often reported in patients with a Dravet Syndrome (DS). In this study we explored the sleep behavior in DS and compared the prevalence of sleep problems with other epilepsy patients.

Rare copy number variants in neuropsychiatric disorders: Specific phenotype or not?

From a number of genome-wide association studies it was shown that de novo and/or rare copy number variants (CNVs) are found at an increased frequency in neuropsychiatric diseases. In this study we examined the prevalence of CNVs in six genomic regions (1q21.1, 2p16.3, 3q29, 15q11.2, 15q13.3, and 16p11.2) previously implicated in neuropsychiatric diseases. Hereto, a cohort of four neuropsychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder, and intellectual disability) and control individuals from three different populations was used in combination with Multilpex Amplicon Quantifiaction (MAQ) assays, capable of high resolution (kb range) and custom-tailored CNV detection. Our results confirm the etiological candidacy of the six selected CNV regions for neuropsychiatric diseases. It is possible that CNVs in these regions can result in disturbed brain development and in this way lead to an increased susceptibility for different neuropsychiatric disorders, dependent on additional genetic and environmental factors. Our results also suggest that the neurodevelopmental component is larger in the etiology of schizophrenia and intellectual disability than in mood disorders. Finally, our data suggest that deletions are in general more pathogenic than duplications. Given the high frequency of the examined CNVs (1-2%) in patients of different neuropsychiatric disorders, screening of large cohorts with an affordable and feasible method like the MAQ assays used in this study is likely to result in important progress in unraveling the genetic factors leading to an increased susceptibility for several psychiatric disorders. ? 2012 Wiley Periodicals, Inc.     

Lack of association of an insertion/deletion polymorphism in the G protein-coupled receptor 50 with bipolar disorder in a Northern Swedish population

GPR50 is a G protein-coupled receptor, located on Xq28 and related to the melatonin receptor family. It is suggested as a functional and positional candidate gene for bipolar disorder (BP). Recently an insertion/deletion polymorphism in GPR50, Delta502-505, was found to be associated with BP in a Scottish association sample (P=0.007). When the analysis was restricted to female subjects, the association increased in significance (P=0.00023). We attempted to replicate this finding in a Northern Swedish association sample, but no significant association was detected (P=0.7, women only: P=0.65).     

Mesothelin Levels in Urine are Affected by Glomerular Leakage and Tubular Reabsorption

BackgroundMesothelin is a soluble biomarker of malignant mesothelioma. Levels in serum, however, are also influenced by other factors, including age and glomerular filtration rate (GFR). The measurement of mesothelin in urine has recently gained interest, but the renal handling of this protein has not been sufficiently examined.Patients and MethodsA total of 75 patients with benign kidney disease were prospectively included in the study. Mesothelin levels were measured in the serum and in the urine of all the participants by using enzyme-linked immunosorbent assay. Urinary albumin and alpha 1-microglobulin (A1M) levels, which are markers of glomerular leakage and of decreased tubular reabsorption, respectively, and the estimated GFR (eGFR) of each participant were obtained. All urine analyte levels were standardized (std) against urinary creatinine levels.ResultsAbsolute mesothelin levels in urine (median, 0.58 nmol/L; interquartile range [IQR], 0.25-1.03 nmol/L) were significantly lower than those in serum (median, 1.74 nmol/L; IQR, 1.35-2.43 nmol/L; P < .001). Urinary mesothelin_std levels positively correlated with serum mesothelin (r = 0.35, P < .01), albumin_std (r = 0.51, P < .001), and A1M_std levels (r = 0.71, P < .001). Neither age nor eGFR were associated with urinary mesothelin_std levels. Similarly, multiple linear regression analysis indicated that only albumin_std and A1M_std levels were significantly positively associated with the urinary mesothelin_std levels (adjusted R² = 0.49).ConclusionMesothelin levels in urine are affected by impaired glomerular and tubular function, which can influence the interpretation of mesothelin measurements and might cause false-positive results. These effects need to be accounted for to improve the further validation and possible clinical use of urinary mesothelin.     

Evaluation of a new set of automated chemiluminescense assays for anticardiolipin and anti-beta2-glycoprotein I antibodies in the laboratory diagnosis of the antiphospholipid syndrome

Introduction

The laboratory diagnosis of antiphospholipid syndrome (APS) requires the demonstration of antiphospholipid antibodies (aPL): lupus anticoagulant (LAC) measured through coagulation assays, anticardiolipin IgG or IgM antibodies (aCL) and/or anti-β2glycoprotein I IgG or IgM antibodies (aβ2GPI), usually detected by ELISA

Materials and methods

We evaluated the diagnostic value of aCL and aβ2GPI measured by a new automated system using the chemiluminescence principle, the immunoanalyzer Zenit RA (Menarini).

Results

Results of aCL and aβ2GPI were correlated with the clinical background of the patients and with results of ELISA (n = 314). Correlated to the clinical background sensitivity/specificity ranged for aCL IgG between 7.5-45.2% / 54.2-98.8%, for aCL IgM 3.4-5.5% / 89.9-94%, for aβ2GPI IgG 5.5-25.3% / 75.6-100% and aβ2GPI IgM 3.4-4.8% / 89.9-92.3%, depending on the cut-off used. Sensitivity with manufacturer's cut-offs was comparable to ELISA, except for aβ2GPI IgG with a significantly lower sensitivity compared to ELISA (5.5% vs 11.6%).In the APS patient population (n = 30) sensitivity of aCL IgG and aβ2GPI IgG was higher measured by ELISA compared to Zenit RA (46.7% vs 30.0%, and 46.7% vs 26.7%, respectively).Agreement between Zenit RA results and ELISA results for the four parameters was moderate (Kappa-values ranging 0.509-0.565). Sensitivity was 38.5%, 53.3%, 40% and 69.2% for aCL IgG, aCL IgM, aβ2GPI IgG and aβ2GPI IgM, respectively, applying the highest cut-off value for Zenit RA, raising towards 64.3%, 100%, 57.1%, for aCL IgG, aCL IgM, aβ2GPI IgG, respectively, in a APS patient population.

Conclusions

The new technology of chemiluminescense for measuring aPL showed good performance characteristics. Interpretation of results with a cut-off value associated with a good discrimination for disease, resulted in a lower sensitivity for the diagnosis of APS for aβ2GPI IgG measured by Zenit RA assays compared to ELISA; sensitivity for aCL IgG was comparable to ELISA. Specificity for all parameters was high and comparable for aCL and aβ2GPI.     

High-dose salvage intensity-modulated radiotherapy with or without androgen deprivation after radical prostatectomy for rising or persisting prostate-specific antigen: 5-year results

Background

Long-term results with salvage radiotherapy (SRT) for a biochemical recurrence after radical prostatectomy (RP) are poor. It has been suggested that radiotherapy doses >70 Gy might result in improved outcome.

Objective

To report on the late toxicity profile and outcome of patients treated with high-dose salvage intensity-modulated radiotherapy (HD-SIMRT) with or without androgen deprivation (AD).

Design, setting, and participants

Between 1999 and 2008, 136 patients were referred for HD-SIMRT with or without AD. The median follow-up was 5 yr. Indications for HD-SIMRT were persisting prostate-specific antigen (PSA) or a rising PSA following RP. All patients were irradiated at a single, tertiary, academic centre. AD was initiated on the basis of seminal vesicle invasion, preprostatectomy PSA >20 ng/ml, Gleason score ≥4 + 3 (n = 43), or personal preference of the referring urologist (n = 54).

Intervention

A median 76-Gy dose was prescribed to the RP bed using intensity-modulated radiotherapy (IMRT) in all patients. AD consisted of a luteinising hormone-releasing hormone analogue for 6 mo.

Measurements

Univariate and multivariate analyses were used to examine the influence of patient- and treatment-related factors on late toxicity, biochemical relapse-free survival (bRFS), and clinical relapse-free survival (cRFS).

Results and limitations

The 5-yr actuarial bRFS and cRFS were 56% and 86%, respectively. On multivariate analysis, the presence of perineural invasion at RP (hazard ratio [HR]: 6.19, p = 0.001) and an increasing pre-SRT PSA (PSA 0.5 ng/ml: HR: 1; PSA 1-1.5 ng/ml: HR: 1.60, p = 0.30; and PSA >1 ng/ml: HR: 2.70, p = 0.02) were independent factors for a decreased bRFS. The addition of AD improved bRFS (HR: 0.33, p = 0.005). On multivariate analysis, none of the variables was a predictor of cRFS. The 5-yr risk of grade 2-3 toxicity was 22% and 8% for genitourinary and gastrointestinal symptoms, respectively.

Conclusions

IMRT allows for safe dose escalation to 76 Gy with good bRFS.