Summary Background Clopidogrel and low-dose aspirin have become the mainstay oral antiplatelet regimen to prevent recurrent ischaemic events after acute coronary syndromes or stent placement. The ...frequent genetic functional variant 681 G>A (*2) of cytochrome P450 2C19 ( CYP2C19 ) is an important contributor to the wide variability between individuals of the antiplatelet effect of clopidogrel. We assessed whether the CYP2C19*2 polymorphism affected long-term prognosis of patients who were chronically treated with clopidogrel. Methods Between April 1, 1996, and April 1, 2008, 259 young patients (aged <45 years) who survived a first myocardial infarction and were exposed to clopidogrel treatment for at least a month, were enrolled in a multicentre registry and underwent CYP2C19*2 determination. The primary endpoint was a composite of death, myocardial infarction, and urgent coronary revascularisation occurring during exposure to clopidogrel. Follow-up was every 6 months. The key secondary endpoint was stent thrombosis proven by angiography. Findings Median clopidogrel exposure time was 1·07 years (IQR 0·28–3·0). Baseline characteristics were balanced between carriers (heterozygous *1/*2, n=64; homozygous *2/*2, n=9) and non-carriers (n=186) of CYP2C19*2 variant. The primary endpoint occurred more frequently in carriers than in non-carriers (15 vs 11 events; hazard ratio HR 3·69 95% CI 1·69–8·05, p=0·0005), as did stent thrombosis (eight vs four events; HR 6·02 1·81–20·04, p=0·0009). The detrimental effect of the CYP2C19*2 genetic variant persisted from 6 months after clopidogrel initiation up to the end of follow-up (HR 3·00 1·27–7·10, p=0·009). After multivariable analysis, the CYP2C19*2 genetic variant was the only independent predictor of cardiovascular events (HR 4·04 1·81–9·02, p=0·0006). Interpretation The CYP2C19*2 genetic variant is a major determinant of prognosis in young patients who are receiving clopidogrel treatment after myocardial infarction. Funding Délégation à la Recherche Clinique, Assistance Publique-Hôpitaux de Paris.
An improper balance of regulatory/effector T (Treg/Teff) cells is central to the development of autoimmune diseases, including type 1 diabetes. We previously showed that low-dose interleukin 2 (IL2) ...induced Treg cell expansion and activation and clinical improvement in patients with hepatitis-C-virus-induced vasculitis. We aimed to establish which low doses of IL2 would be safe and induce Treg cells in patients with type 1 diabetes, considering that: (1) type 1 diabetes might be linked to alteration of the IL2/IL2R activation pathway; (2) activation of pathogenic Teff cells by IL2 could exacerbate disease; and (3) the safety of low-dose IL2 is not known in type 1 diabetes.
This was a single-centre phase 1/2 study. 24 adult patients (18-55 years) with established insulin-dependent type 1 diabetes and at least one diabetes-related autoantibody were enrolled and randomly assigned (in a 1:1:1:1 ratio, by computer-generated randomisation list, with block size four) to placebo or IL2 at 0.33 MIU/day, 1 MIU/day, or 3 MIU/day for a 5-day course and were followed up for 60 days. All investigators and participants were masked to assignment. The primary outcome was change in Treg cells, measured by flow cytometry, and expressed as a percentage of CD4+ T cells, from day 1 to day 60. This trial is registered with ClinicalTrials.gov, number NCT01353833.
Six patients were assigned to each group between June 1, 2011, and Feb 3, 2012. IL2 was well tolerated at all doses, with no serious adverse events. However, there was a dose-response association for non-serious adverse events during the treatment phase (days 1-6); one patient in the placebo group, three patients in the 0.33 MIU group, five patients in the 1 MIU group, and six patients in the 3 MIU group had non-serious adverse events. The most common adverse events in the treatment phase were injection-site reaction (no patients with placebo vs three patients with 0.33 MIU and 1 MIU vs two patients with 3 MIU) and influenza-like syndrome (no patients with placebo vs one patient with 0.33 MIU and 1 MIU vs four patients with 3 MIU). After the treatment phase, adverse events did not differ between groups. IL2 did not induce deleterious changes in glucose-metabolism variables. IL2 induced a dose-dependent increase in the proportion of Treg cells, significant at all doses compared with placebo (placebo mean increase 0.5% SD 0.4; 0.33 MIU 2.8% 1.2, p=0.0039; 1 MIU 3.9% 1.8, p=0.0039; 3 MIU 4.8% 1.9 p=0.0039).
We have defined a well-tolerated and immunologically effective dose range of IL2 for application to type 1 diabetes therapy and prevention, which could be relevant to other disorders in which a Treg cell increase would be desirable.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder caused by the loss of motor neurons. Its etiology remains unknown, but several hypothesis have been raised to explain motor neuron ...death, including oxidative stress. Dysregulation of cellular iron metabolism can lead to increased oxidative stress, and existing data argue for a role of iron metabolism in ALS pathophysiology.
We performed a retrospective analysis of iron metabolism (IM) variables (serum levels of iron, transferrin, ferritin, and TSC for Transferrin Saturation Coefficient) in a cohort of 694 ALS patients and 297 healthy controls.
Serum ferritin levels and TSC were higher, whereas serum transferrin levels were lower in ALS patients than controls. In addition, patients with a high level serum ferritin had a shorter survival time compared to those with low level serum ferritin (618 days versus 921 days for men subgroup; p = .007). Site of onset and ALS-FRS score were not associated with IM variables.
This study suggests that ALS patients may have increased iron storage, as measured by increased serum ferritin and TSC. Elevated serum ferritin may also have a deleterious impact on survival in ALS.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease for which the genetic contribution is incompletely understood.
We conducted a joint analysis of 5,523,934 imputed SNPs in two ...newly-genotyped progressive supranuclear palsy cohorts, primarily derived from two clinical trials (Allon davunetide and NNIPPS riluzole trials in PSP) and a previously published genome-wide association study (GWAS), in total comprising 1646 cases and 10,662 controls of European ancestry.
We identified 5 associated loci at a genome-wide significance threshold P < 5 × 10
, including replication of 3 loci from previous studies and 2 novel loci at 6p21.1 and 12p12.1 (near RUNX2 and SLCO1A2, respectively). At the 17q21.31 locus, stepwise regression analysis confirmed the presence of multiple independent loci (localized near MAPT and KANSL1). An additional 4 loci were highly suggestive of association (P < 1 × 10
). We analyzed the genetic correlation with multiple neurodegenerative diseases, and found that PSP had shared polygenic heritability with Parkinson's disease and amyotrophic lateral sclerosis.
In total, we identified 6 additional significant or suggestive SNP associations with PSP, and discovered genetic overlap with other neurodegenerative diseases. These findings clarify the pathogenesis and genetic architecture of PSP.
Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and autonomic dysfunction. Pathogenic mechanisms remain obscure but the ...neuropathological hallmark is the presence of alpha-synuclein-immunoreactive glial cytoplasmic inclusions. Genetic variants of the alpha-synuclein gene, SNCA, are thus strong candidates for genetic association with MSA. One follow-up to a genome-wide association of Parkinson's disease has identified association of a SNP in SNCA with MSA.
We evaluated 32 SNPs in the SNCA gene in a European population of 239 cases and 617 controls recruited as part of the Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS) study. We used 161 independently collected samples for replication. Two SNCA SNPs showed association with MSA: rs3822086 (P = 0.0044), and rs3775444 (P = 0.012), although only the first survived correction for multiple testing. In the MSA-C subgroup the association strengthened despite more than halving the number of cases: rs3822086 P = 0.0024, OR 2.153, (95% CI 1.3-3.6); rs3775444 P = 0.0017, OR 4.386 (95% CI 1.6-11.7). A 7-SNP haplotype incorporating three SNPs either side of rs3822086 strengthened the association with MSA-C further (best haplotype, P = 8.7 x 10(-4)). The association with rs3822086 was replicated in the independent samples (P = 0.035).
We report a genetic association between MSA and alpha-synuclein which has replicated in independent samples. The strongest association is with the cerebellar subtype of MSA.
ClinicalTrials.gov NCT00211224.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Natural History and Neuroprotection in Parkinson Plus Syndromes (NNIPPS) study was a large phase III randomized placebo-controlled trial of riluzole in Progressive Supranuclear Palsy (PSP, n = ...362) and Multiple System Atrophy (MSA, n = 398). To assess disease severity and progression, we constructed and validated a new clinical rating scale as an ancillary study.
Patients were assessed at entry and 6-montly for up to 3 years. Evaluation of the scale's psychometric properties included reliability (n = 116), validity (n = 760), and responsiveness (n = 642). Among the 85 items of the initial scale, factor analysis revealed 83 items contributing to 15 clinically relevant dimensions, including Activity of daily Living/Mobility, Axial bradykinesia, Limb bradykinesia, Rigidity, Oculomotor, Cerebellar, Bulbar/Pseudo-bulbar, Mental, Orthostatic, Urinary, Limb dystonia, Axial dystonia, Pyramidal, Myoclonus and Tremor. All but the Pyramidal dimension demonstrated good internal consistency (Cronbach α ≥ 0.70). Inter-rater reliability was high for the total score (Intra-class coefficient = 0.94) and 9 dimensions (Intra-class coefficient = 0.80-0.93), and moderate (Intra-class coefficient = 0.54-0.77) for 6. Correlations of the total score with other clinical measures of severity were good (rho ≥ 0.70). The total score was significantly and linearly related to survival (p<0.0001). Responsiveness expressed as the Standardized Response Mean was high for the total score slope of change (SRM = 1.10), though higher in PSP (SRM = 1.25) than in MSA (SRM = 1.0), indicating a more rapid progression of PSP. The slope of change was constant with increasing disease severity demonstrating good linearity of the scale throughout disease stages. Although MSA and PSP differed quantitatively on the total score at entry and on rate of progression, the relative contribution of clinical dimensions to overall severity and progression was similar.
The NNIPPS-PPS has suitable validity, is reliable and sensitive, and therefore is appropriate for use in clinical studies with PSP or MSA.
ClinicalTrials.gov NCT00211224.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The efflux pumps located at the blood–brain barrier (BBB) prevent drugs entering the brain. As such, efflux pumps are a major obstacle to drug brain distribution. Amyotrophic lateral sclerosis (ALS) ...is a fatal neurodegenerative disease with little therapeutics available: riluzole is the only drug approved in its treatment. The lack of response to treatment in ALS may be, at least in part, due to increased activities of efflux pumps in relation to disease, leading to subtherapeutic brain concentrations of drugs. In the present study, we used a transgenic mouse model of ALS (G86R mSOD1 mice) to test this hypothesis. Expression and functionality of P-glycoprotein (ABCB1, P-gp) and Breast Cancer Resistance Protein (ABCG2, BCRP), two major efflux pumps, were studied. We observed an increased P-gp expression (1.5-fold) in presymptomatic mSOD1 mice compared to wild-type controls. Consistent with this, P-gp function was also increased by 1.5-fold and riluzole brain disposition was decreased by 1.7-fold in mSOD1 mice. Contrasting with this, BCRP expression and function were unaltered by the pathology. These results demonstrate that BBB transport proteins are modified in G86R mSOD1 mice ALS model. Such findings underline potential problems in extrapolating the results of animal studies to humans and developing clinical trials, especially for drugs transported by P-gp.
Amyotrophic lateral sclerosis (ALS) is a life-threatening neurodegenerative disease involving upper and lower motor neurons loss. Clinical features are highly variable among patients and there are ...currently few known disease-modifying factors underlying this heterogeneity. Serotonin is involved in a range of functions altered in ALS, including motor neuron excitability and energy metabolism. However, whether serotoninergic activity represents a disease modifier of ALS natural history remains unknown.
Platelet and plasma unconjugated concentrations of serotonin and plasma 5-HIAA, the major serotonin metabolite, levels were measured using HPLC with coulometric detection in a cohort of 85 patients with ALS all followed-up until death and compared to a control group of 29 subjects.
Platelet serotonin levels were significantly decreased in ALS patients. Platelet serotonin levels did not correlate with disease duration but were positively correlated with survival of the patients. Univariate Cox model analysis showed a 57% decreased risk of death for patients with platelet serotonin levels in the normal range relative to patients with abnormally low platelet serotonin (p = 0.0195). This protective effect remained significant after adjustment with age, gender or site of onset in multivariate analysis. Plasma unconjugated serotonin and 5-HIAA levels were unchanged in ALS patients compared to controls and did not correlate with clinical parameters.
The positive correlation between platelet serotonin levels and survival strongly suggests that serotonin influences the course of ALS disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative fatal disease. Drugs used in this disease need to cross the blood–brain barrier (BBB). Only riluzole is approved for ALS treatment. We have ...investigated riluzole as a breast cancer resistance protein (BCRP) substrate by studying its brain transport in CF1 mdr1a (−/−) mice and its intracellular uptake on BeWo cells (human placental choriocarcinoma cell line). We have also investigated the effect of riluzole on BCRP expression level and on its activity using the prazocin as a test probe for brain transport and intracellular uptake. Assays on mdr1a (−/−) mice and BeWo cells showed a higher uptake of riluzole when pretreated with a BCRP inhibitor. After repeated doses of riluzole, BCRP activity was increased in CF1 mdr1a (−/−) mice, riluzole uptake was decrease and both BCRP expression and activity were increased in BeWo cells. In conclusion, we report in this study that riluzole is transported by BCRP at the BBB level and can enhance its function. These results taken with our previous studies on riluzole and P-glycoprotein show that drug–drug interactions between riluzole and efflux transporters substrates may occur at the BBB level and should be taken into account in future clinical trial design in ALS.
amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by the loss of motorneurons. The only drug approved is riluzole. Minocycline is an antibiotic with numerous ...neuroprotective properties. riluzole and minocycline were given to an animal model of ALS and had beneficial effect on the disease. The combination was then tested in humans in phase II and phase III studies with less beneficial effects and a faster decline of the disease in the group treated with minocycline. In a previous study, we showed that riluzole is transported out of the brain by the P-glycoprotein at the blood-brain barrier level.
in this work, we studied in CF1 mice, the plasmatic and cerebral pharmacokinetics of riluzole combined or not with minocycline.
our results showed that the kinetics of riluzole are not linear with dose, but that cerebral AUC0-infinity increase proportionally with plasmatic AUC0-infinity. At the dose of 10 mg/kg, the cerebral AUC0-infinity /plasmatic AUC0-infinity ratio was 4.6 in mdr1a (-/-) mice and 2.4 in mdr1a (+/+) mice. The combination of minocycline (170 mg/kg) and riluzole (10 mg/kg) induced a 2 fold increase in the cerebral AUC0-infinity of riluzole and induced a neuromuscular toxicity in mice. This effect of minocycline was not found at low concentration (10 mg/kg of minocycline).
if our results are confirmed in humans, riluzole cerebral concentrations could be predicted by plasmatic concentrations. Furthermore, the combination of high doses of minocycline with riluzole could induce neurological toxicity that lead to deceiving results in ALS clinical studies.
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