Natalizumab treatment shows low cumulative probabilities of confirmed disability worsening to EDSS milestones in the long-term setting.

Abstract Background Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. Methods TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. Results Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0–2.0 to ≥3.0, 2.0–3.0 to ≥4.0, and 4.0–5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). Conclusions In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0–9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0–5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance

Pharmacokinetics of atorvastatin and its metabolites after single and multiple dosing in hypercholesterolaemic haemodialysis patients

Background. Patients with chronic renal failure commonly suffer from a secondary form of complex dyslipidaemia, and may benefit from lipid-lowering treatment. Atorvastatin has been shown to reduce efficiently the levels of atherogenic lipoproteins also in patients with renal failure, but pharmacokinetic data in haemodialysis patients are lacking. Methods. In this study, hypercholesterolaemic haemodialysis patients received 40 mg (n = 12) or 80 mg (n = 11) atorvastatin once daily, first as a single dose and then continuously for 2 weeks. Plasma levels of atorvastatin and its active and inactive metabolites were measured by LC/MS/MS, and pharmacokinetic parameters (Cmax, tmax, AUC, t1/2) compared between single and multiple dosing, and between the different doses. Results. The pharmacokinetic parameters of the parent drug atorvastatin acid were not significantly different after single and 2-week multiple dosing; they showed dose-proportionality between the 40 and 80 mg dose, and were comparable to findings in healthy volunteers. Dose-proportionality and absence of accumulation was also observed for the major active metabolite orthohydroxy-atorvastatin and the inactive metabolites atorvastatin lactone and ortho-hydroxy-atorvastatin lactone, but the levels of the active metabolite were relatively lower, and the inactive metabolites higher, compared with healthy volunteers. The para-hydroxymetabolites constituted only a minor pathway in atorvastatin's metabolic elimination. Haemodialysis did not cause enhanced clearance of atorvastatin or its metabolites, the drug was well tolerated and there were no serious adverse events. Conclusion. While subtle differences may exist in the metabolic processing of atorvastatin in haemodialysis patients, active drug did not accumulate nor did it show enhanced elimination, and levels were comparable to those measured in healthy volunteers. Therefore there is no need to adapt atorvastatin dosage in this particular patient population.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Pharmacokinetics of atorvastatin and its metabolites after single and multiple dosing in hypercholesterolaemic haemodialysis patients

Background. Patients with chronic renal failure commonly suffer from a secondary form of complex dyslipidaemia, and may benefit from lipid-lowering treatment. Atorvastatin has been shown to reduce efficiently the levels of atherogenic lipoproteins also in patients with renal failure, but pharmacokinetic data in haemodialysis patients are lacking. Methods. In this study, hypercholesterolaemic haemodialysis patients received 40 mg (n = 12) or 80 mg (n = 11) atorvastatin once daily, first as a single dose and then continuously for 2 weeks. Plasma levels of atorvastatin and its active and inactive metabolites were measured by LC/MS/MS, and pharmacokinetic parameters (Cmax, tmax, AUC, t1/2) compared between single and multiple dosing, and between the different doses. Results. The pharmacokinetic parameters of the parent drug atorvastatin acid were not significantly different after single and 2-week multiple dosing; they showed dose-proportionality between the 40 and 80 mg dose, and were comparable to findings in healthy volunteers. Dose-proportionality and absence of accumulation was also observed for the major active metabolite orthohydroxy-atorvastatin and the inactive metabolites atorvastatin lactone and ortho-hydroxy-atorvastatin lactone, but the levels of the active metabolite were relatively lower, and the inactive metabolites higher, compared with healthy volunteers. The para-hydroxymetabolites constituted only a minor pathway in atorvastatin's metabolic elimination. Haemodialysis did not cause enhanced clearance of atorvastatin or its metabolites, the drug was well tolerated and there were no serious adverse events. Conclusion. While subtle differences may exist in the metabolic processing of atorvastatin in haemodialysis patients, active drug did not accumulate nor did it show enhanced elimination, and levels were comparable to those measured in healthy volunteers. Therefore there is no need to adapt atorvastatin dosage in this particular patient population.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Epilepsy as part of the phenotype associated with ATP1A2 mutations

PURPOSE: Mutations in the ATP1A2 gene have been described in families with familial hemiplegic migraine (FHM). FHM is a variant of migraine with aura characterized by the occurrence of hemiplegia during the aura. Within several FHM families, some patients also had epileptic seizures. In this study we tested the hypothesis that mutations in ATP1A2 may be common in patients presenting with epilepsy and migraine. METHODS: We selected 20 families with epilepsy and migraine and performed mutation analysis of ATP1A2 in the probands by direct sequencing of all exons and splice-site junctions. RESULTS: Novel ATP1A2 mutations were found in two of the 20 families (10%). The p.Gly900Arg mutation was present in a family with epilepsy and FHM, and the p.Cys702Tyr mutation occurred in a family with occipitotemporal epilepsy and migraine with and without visual aura. In the two families together, six mutation carriers had the combination of epilepsy and migraine, two had only epilepsy, and six had only migraine. DISCUSSION: This study shows that a history of migraine and a family history of both epilepsy and migraine should be obtained in all patients presenting with epilepsy in the epilepsy clinic. It may be worthwhile to screen patients with a combination of epilepsy and migraine and a positive family history of either migraine or epilepsy for mutations in the ATP1A2 gene.status: publishe

Lipid and apoprotein changes during atorvastatin up-titration in hemodialysis patients with hypercholesterolemia: A placebo-controlled study

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Perinatal follow-up of children born after preimplantation genetic diagnosis between 1995 and 2014

Purpose We aim to evaluate the safety of PGD. We focus on the congenital malformation rate and additionally report on adverse perinatal outcome. Methods We collated data from a large group of singletons and multiples born after PGD between 1995 and 2014. Data on congenital malformation rates in live born children and terminated pregnancies, misdiagnosis rate, birth parameters, perinatal mortality, and hospital admissions were prospectively collected by questionnaires. Results Four hundred thirty-nine pregnancies in 381 women resulted in 364 live born children. Nine children (2.5%) had major malformations. This percentage is consistent with other PGD cohorts and comparable to the prevalence reported by the European Surveillance of Congenital Anomalies (EUROCAT). We reported one misdiagnosis resulting in a spontaneous abortion of a fetus with an unbalanced chromosome pattern. 20% of the children were born premature (<37 weeks) and less than 15% had a low birth weight. The incidence of hospital admissions is in line with prematurity and low birth weight rate. One child from a twin, one child from a triplet, and one singleton died at 23, 32, and 37 weeks of gestation respectively. Conclusions We found no evidence that PGD treatment increases the risk on congenital malformations or adverse perinatal outcome

Involvement of 5-HT(1B) receptors in collar-induced hypersensitivity to 5-hydroxytryptamine of the rabbit carotid artery

1. In humans intimal thickening is a prerequisite of atherosclerosis. Application of a silicone collar around the rabbit carotid artery induces an intimal thickening but in addition it increases the sensitivity to the vasoconstrictor action of serotonin (5-hydroxytryptamine, 5-HT). The 5-HT receptors involved in collar-induced hypersensitivity to 5-HT were investigated using several agonists and antagonists. 2. One week after placement of collars around both carotid arteries of anaesthetized rabbits, rings (2 mm width) from inside (=collar) and outside (=sham) the collars were mounted in organ baths (10 ml) for isometric force measurements at 6 g loading tension. 3. Collared rings were more sensitive to the contractile effect of 5-HT (7.6 fold) and 5-carboxamidotryptamine (31 fold, 5-CT, 5-HT(1) agonist) in cumulative concentration response curves. Sumatriptan (5-HT(1B/1D) agonist) caused concentration-dependent constrictions in collared rings only. 4. Collar placement did not significantly alter pA(2) values (Schild regression) or apparent pK(b) values (non-linear regression) of spiperone and methysergide (mixed 5-HT(2A)/5-HT(1) antagonists) or ketanserin and ritanserin (5-HT(2A) antagonists), indicating unchanged binding characteristics of the 5-HT(2A) receptor. However, the reduced slope of the Schild regression pointed to a heterogeneous receptor population in collared rings. 5. In contrast, the apparent pK(b) value of methiothepin (5-HT(1B) antagonist) was significantly reduced by collar placement, and its antagonism shifted from non-surmountable in sham rings to surmountable in collared segments. 6. Taken together, this study demonstrates that the serotonergic receptor involved in the hypersensitivity to 5-HT of rabbit collared carotid artery is a 5-HT(1B) receptor subtype

Safety and efficacy of natalizumab in Belgian multiple sclerosis patients: subgroup analysis of the natalizumab observational program

Natalizumab (Tysabri(®)) is highly efficacious in controlling disease activity in relapsing multiple sclerosis (MS) patients. As it is one of the more recent therapies for MS, there remains a need for long-term safety and efficacy data of natalizumab in a clinical practice setting. The Tysabri observational program (TOP) is an open-label, multicenter, multinational, prospective observational study, aiming to recruit up to 6,000 patients with relapsing-remitting MS from Europe, Canada and Australia. The objectives of this study are to collect long-term safety and efficacy data on disease activity and disability progression. We report here the interim results of the 563 patients included in TOP between December 2007 and 2012 from Belgium. This patient cohort was older at baseline, had longer disease duration, higher neurological impairment, and a higher baseline annualized relapse rate, when compared to patients included in the pivotal phase III AFFIRM trial. Nevertheless, the efficacy of natalizumab was comparable. The annualized relapse rate on treatment was reduced by 90.70 % (p < 0.0001) with a cumulative probability of relapse of 26.87 % at 24 months. The cumulative probabilities of sustained disability improvement and progression at 24 months were 25.68 and 9.01 %, respectively. There were no new safety concerns over the follow-up period. Two cases of progressive multifocal leukoencephalopathy were diagnosed. Our results are consistent with other observational studies in the post-marketing setting