Introduction: Multiple sclerosis (MS) is a chronic immune-mediated inflammatory disorder of the brain and spinal cord characterized by inflammation, demyelination, and axonal degeneration.
Area ...covered: Even though the pharmacological armamentarium for MS treatment is considerably improved in the last 20 years, safety data especially for the second-line and innovative treatments are lacking. In order to analyze the safety profile of drugs used for the treatment of MS, a literature review of pre-marketing, post-marketing studies and case reports was performed.
Expert opinion: Nowadays, the numerous drugs approved in the last years for the treatment of MS allow a better control of the disease and a better patient compliance. The main advantages of the new disease-modifying agents for MS (DMTs), in fact, derive from the new oral administration and the prolonged half-life with consequent improvement in compliance compared to first-line therapy which required subcutaneous administrations. However, DMTs can cause serious, sometimes life-threatening or fatal, drug adverse reactions.
Due to the lack of safety data and given the recent marketing approval of the last DMTs for MS, observational studies and post-marketing surveillance activities will be necessary in order to improve the knowledge about the safety profile of these drugs and the improvement of their use in clinical practice.
The practical effectiveness of second-generation antipsychotics in children and adolescents is an understudied issue. It is a crucial area of study, though, because such patients are often treated ...for long-lasting disorders.
We carried out a 24-month (March 2012-March 2014) observational study on an unselected population of pediatric outpatients treated with risperidone, aripiprazole, olanzapine, or quetiapine aiming to (1) describe drug use, (2) compare post hoc the discontinuation rates due to specific causes and dose adjustments by Kaplan-Meier analyses between drugs, and (3) analyze predictors influencing these outcomes by Cox multivariate models.
Among 184 pediatric patients, 77% patients were prescribed risperidone, and 18% were prescribed aripiprazole. Olanzapine or quetiapine were scantly used; therefore, they were excluded from analyses. Risperidone was prevalent in younger, male patients with disruptive behavioral disorders; aripiprazole, in patients with tic disorders. Overall, discontinuations occurred mostly in the first 6 months, and, at 24 months, the discontinuation numbers were similar between users of risperidone and aripiprazole (41.5% vs 39.4%). In univariate analyses, dose reduction was higher for aripiprazole (P = .033). Multivariate analyses yielded the following predictors: for all-cause discontinuation, baseline severity (hazard ratio HR = 1.48, P = .001) and dose increase (HR = 3.55, P = .001); for patient-decided discontinuation, dose change (increase: HR = 6.43, P = .004; reduction: HR = 7.89, P = .049) and the presence of concomitant drugs (HR = 4.03, P = .034), while autistic patients discontinued less (HR = 0.23, P = .050); for clinician-decided discontinuation due to adverse drug reactions, baseline severity (HR = 1.96, P = .005) and dose increase (HR = 5.09, P = .016); for clinician-decided discontinuation due to inefficacy, baseline severity (HR = 2.88, P = .014) and the use of aripiprazole (HR = 5.55, P = .013); for dose increase, none; for dose reduction, the occurrence of adverse drug reactions (HR = 4.74, P = .046), while dose reduction was less probable in autistic patients (HR = 0.22, P = .042).
The findings of this study show a similarity between the overall effectiveness of risperidone and aripiprazole in a real-life pediatric outpatient setting.
Purpose
Available guidelines on therapeutic drug monitoring of second-generation antipsychotics were designed for adults; therefore, they cannot be transferred as such in pediatric patients, who may ...have different drug absorption, distribution, metabolism, and elimination. Moreover, available tools that guide dosing in neuropsychiatric pediatric patients are scant, leading to the possibility of reduced efficacy and/or increased risks of toxicity. Here we describe the results of observational therapeutic drug monitoring conducted in three pediatric neuropsychiatry units across Italy in 2012–2014, with the following aims: (1) to describe the distribution of plasma concentrations of second-generation antipsychotics in our pediatric patients and (2) to identify clinical covariates associated with plasma drug levels.
Methods
Five hundred fifty-six plasma trough concentrations of the second-generation antipsychotics risperidone (plus 9-hydroxy-risperidone), aripiprazole, olanzapine, and quetiapine were measured from 172 pediatric outpatients overall. The distribution of drug concentrations was described and correlated with drug doses and clinical variables.
Results
Risperidone plasma levels were lower than in adults (median 13.6 ng/ml), with a high inter-patient (78.9 %) but lower intra-patient (34.2 %) variability. In multiple regression analyses, risperidone plasma levels depended only on drug dose (
p
< 0.001). Aripiprazole plasma levels were similar to those described in adults (median 165.8 ng/ml) and were widely distributed, with an inter-patient variability of 81.1 %, while the intra-patient variability was much lower (29.3 %). Multiple regression analyses indicated that aripiprazole plasma levels were influenced by the daily doses (
p
< 0.001) and by the number of concomitant drugs (
p
< 0.01).
Conclusion
Our study described the distribution of plasma levels of SGAs in a real-life setting involving pediatric patients, significantly increasing the amount of available data for this fragile population. If confirmed in larger dataset, these data may contribute to the definition of optimal therapeutic window for risperidone and aripiprazole plasma levels in pediatric patients.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Abstract only
TPS789
Background: Treatment of metastatic colorectal cancer (mCRC) has improved due to the introduction of more active chemotherapies (CT) and novel targeted agents that have ...significantly increased response rate (RR), progression free survival (PFS) and overall survival (OS). Recently, CORRECT and CONCUR trials have demonstrated both activity and efficacy of regorafenib, a small multi-kinase inhibitor, as monotherapy in pretreated mCRC. The wide range of action of regorafenib makes it an ideal candidate for monotherapy in earlier disease treatment lines in which different pathways could be involved in the acquisition of resistance. To improve long term efficacy of first line therapy several therapeutic approaches of maintenance treatment have been explored in mCRC. Methods: RAVELLO is an academic randomized, double-blind, placebo-controlled, multi-center, phase III study designed to evaluate efficacy and safety of regorafenib as maintenance treatment after first line therapy. Eligible patients: pathologically confirmed mCRC RAS wild type (KRAS and NRAS genes) treated with a first line fluoropyrimidine-based CT in combination with an anti-EGFR (epidermal growth factor receptor) monoclonal antibody for a minimum of 4 to a maximum of 8 months, with a stratification by response to the first line treatment (complete response/partial response or stable disease). 480 patients will be enrolled and randomly assigned in a 1:1 ratio to receive 160 mg regorafenib or placebo per os, every day for 3 weeks of every 4 weeks cycle, until disease progression or unacceptable toxicity. Primary endpoint is PFS. With a two-tailed alpha error of 0.05, the study will have 90% power to detect a 3-month prolongation of median PFS from randomization (corresponding to a hazard ratio of progression of 0.67 with 6-month median PFS expected in the control arm). Secondary endopoint are OS, safety, and biomarker correlative studies. Currently, one patient has been enrolled and is on treatment. EudraCT number: 2013-005428-41. Clinical trial information: 2013-005428-41.
Stevens-Johnson Syndrome (SJS) is one of the most severe muco-cutaneous diseases and its occurrence is often attributed to drug use. The aim of the present study is to quantify the risk of SJS in ...association with drug and vaccine use in children.
A multicenter surveillance of children hospitalized through the emergency departments for acute conditions of interest is currently ongoing in Italy. Cases with a diagnosis of SJS were retrieved from all admissions. Parents were interviewed on child's use of drugs and vaccines preceding the onset of symptoms that led to the hospitalization. We compared the use of drugs and vaccines in cases with the corresponding use in a control group of children hospitalized for acute neurological conditions.
Twenty-nine children with a diagnosis of SJS and 1,362 with neurological disorders were hospitalized between 1(st) November 1999 and 31(st) October 2012. Cases were more frequently exposed to drugs (79% vs 58% in the control group; adjusted OR 2.4; 95% CI 1.0-6.1). Anticonvulsants presented the highest adjusted OR: 26.8 (95% CI 8.4-86.0). Significantly elevated risks were also estimated for antibiotics use (adjusted OR 3.3; 95% CI 1.5-7.2), corticosteroids (adjusted OR 4.2; 95% CI 1.8-9.9) and paracetamol (adjusted OR 3.2; 95% CI 1.5-6.9). No increased risk was estimated for vaccines (adjusted OR: 0.9; 95% CI 0.3-2.8).
Our study provides additional evidence on the etiologic role of drugs and vaccines in the occurrence of SJS in children.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Highlights • Vaccine effectiveness in children visiting an Emergency Department for influenza. • Test negative case-control study in 11 paediatric centres in two influenza seasons. • Vaccine ...effectiveness in preventing ED visits: 38% (95% CI −52% to 75%). • Add information for recommendation for vaccination in children.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
It has been hypothesized that gluten-dependent production of anti-tissue-transglutaminase 2 (anti-TG2) antibodies may occur only at an intestinal level. We have investigated intestinal production of ...anti-TG2 antibodies in 136 patients with normal serum levels of anti-TG2 antibodies and normal duodenal mucosa. Intestinal deposits of anti-TG2 antibodies were evaluated by immunofluorescence and anti-TG2 antibodies released in organ culture supernatants measured by ELISA. Intestinal antibody libraries were obtained from 10 subjects. Immunohistochemistry for CD25⁺, CD3⁺, and TCR-γδ⁺ was assessed in subjects with positive (
= 32) and negative (
= 31) intestinal anti-TG2 antibodies. Globally 33/136 (24%) seronegative patients produced anti-TG2 autoantibodies at an intestinal level. Antibody libraries analysis confirmed the anti-TG2 antibodies mucosal production in all (
= 8) positive subjects. Lamina propria CD25⁺ cell count was significantly (
< 0.05) higher in patients with intestinal anti-TG2. Moreover, 13/32 (41%) of them showed high TCR-γδ⁺/CD3⁺ ratios. Intestinal anti-TG2 antibody production does not show absolute specificity for CD. It is seen more often in association with inflamed mucosa. Further investigations are necessary to prove the possible role of dietary gluten.
Gene therapy of Usher syndrome type 1B (USH1B) due to mutations in the large Myosin VIIA (MYO7A) gene is limited by the packaging capacity of adeno-associated viral (AAV) vectors. To overcome this, ...we have previously developed dual AAV8 vectors which encode human MYO7A (dual AAV8.MYO7A). Here we show that subretinal administration of 1.37E+9 to 1.37E+10 genome copies of a good-manufacturing-practice-like lot of dual AAV8.MYO7A improves the retinal defects of a mouse model of USH1B. The same lot was used in non-human primates at doses 1.6× and 4.3× the highest dose proposed for the clinical trial which was based on mouse efficacy data. Long-lasting alterations in retinal function and morphology were observed following subretinal administration of dual AAV8.MYO7A at the high dose. These findings were modest and improved over time in the low-dose group, as also observed in other studies involving the use of AAV8 in non-human primates and humans. Biodistribution and shedding studies confirmed the presence of vector DNA mainly in the visual pathway. Accordingly, we detected human MYO7A mRNA expression predominantly in the retina. Overall, these studies pave the way for the clinical translation of subretinal administration of dual AAV vectors in USH1B subjects.
Display omitted
Ferla, Dell’Aquila et al. provide evidence in mice and non-human primates of the efficacy and safety of subretinal administration of dual hybrid adeno-associated viral vectors to treat retinitis pigmentosa associated with Usher syndrome type 1B.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract The gold standard for the study of the macro-anatomy of the aortic root are multi-detector computed tomography (MDCT) and magnetic resonance (MR) imaging. Both technologies have major ...advantages and limitations. Although 4D echo is entering the study of the aortic root, 2D echo is the most commonly used diagnostic tool in daily practice. We designed and developed an algorithm for 3D modeling of the aortic root based on measures taken routinely at 2D echocardiography from 20 healthy individuals with normal aortic root. The tool was then translated in 12 patients who underwent both echo and MDCT. The results obtained with the 3D modeling program were quantitatively and qualitatively compared with 3D reconstruction from MDCT. Ad hoc ratios describing the morphology of the aortic root in MDCT and in the 3D model were used for comparison. In 12 patients with aortic root dilatation, the ratios obtained with our model are in good agreement with those from MDCT. Linear correlation for both long axis and short axis ratios was strong. The 3D modeling software can be easily adopted by cardiologists routinely involved in clinical evaluation of the pathology of the aortic root. The tool is easy to apply, does not require additional costs, and may be used to generate a set of data images for monitoring the evolution of the morphology and dimension of the aortic root, flanking the 3D MDCT and MR that remain the gold standard tools.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
PDF
