Initiating stiripentol before 2 years of age in patients with Dravet syndrome is safe and beneficial against status epilepticus.

AIM: To evaluate the safety and efficacy of stiripentol initiated before 2 years of age in patients with Dravet syndrome. METHOD: This was a 30-year, real-world retrospective study. We extracted the data of the 131 patients (59 females, 72 males) who initiated stiripentol before 2 years of age between 1991 and 2021 from the four longitudinal databases of Dravet syndrome available in France. RESULTS: Stiripentol was added to valproate and clobazam (93%) at 13 months and a median dose of 50 mg/kg/day. With short-term therapy (<6 months on stiripentol, median 4 months, median age 16 months), the frequency of tonic-clonic seizures (TCS) lasting longer than 5 minutes decreased (p < 0.01) and status epilepticus (>30 minutes) disappeared in 55% of patients. With long-term therapy (last visit on stiripentol <7 years of age, median stiripentol 28 months, median age 41 months), the frequency of long-lasting TCS continued to decline (p = 0.03). Emergency hospitalizations dropped from 91% to 43% and 12% with short- and long-term therapies respectively (p < 0.001). Three patients died, all from sudden unexpected death in epilepsy. Three patients discontinued stiripentol for adverse events; 55% reported at least one adverse event, mostly loss of appetite/weight (21%) and somnolence (11%). Stiripentol was used earlier, at lower doses, and was better tolerated by patients in the newest database than in the oldest (p < 0.01). INTERPRETATION: Initiating stiripentol in infants with Dravet syndrome is safe and beneficial, significantly reducing long-lasting seizures including status epilepticus, hospitalizations, and mortality in the critical first years of life.

Additional Results from Two Randomized, Placebo-Controlled Trials of Stiripentol in Dravet Syndrome Highlight a Rapid Antiseizure Efficacy with Longer Seizure-Free Periods.

INTRODUCTION: The efficacy of stiripentol in Dravet syndrome children was evidenced in two randomized, double-blind, placebo-controlled, phase 3 studies, namely STICLO France (October 1996-August 1998) and STICLO Italy (April 1999-October 2000), but data were not fully exploited at the time. METHODS: This post-hoc analysis used additional information, notably collected during the open-label extension (OLE) month, or reported by caregivers in individual diaries, to evaluate new outcomes. RESULTS: Overall, 64 patients were included (31 in the placebo group, 33 in the stiripentol group) of whom 34 (53.1%) were female. Patients' mean and median (25%; 75%) age were 9.2 years (range 3.0-20.7 years) and 8.7 years (6.0; 12.1) respectively. At the end of the double-blind treatment period, 72% of the patients in the stiripentol group had a ≥ 50% decrease in generalized tonic-clonic seizure (GTCS) frequency, versus 7% in the placebo group (P < 0.001), 56% had a profound (≥ 75%) decrease versus 3% in the placebo group (P < 0.001), and 38% were free of GTCS, but none in the placebo group (P < 0.001). The onset of stiripentol efficacy was rapid, significant from the fourth day of treatment onwards. The median longest period of consecutive days with no GTCS was 32 days in the stiripentol group compared to 8.5 days in the placebo group (P < 0.001). Further to the switch to the third month OLE, an 80.2% decrease in seizure frequency from baseline was observed in patients previously receiving placebo, while no change in efficacy was observed in those already on stiripentol. Adverse events were more frequent in the stiripentol group, with significantly more episodes of somnolence, anorexia, and weight decrease than in the placebo group. CONCLUSION: Altogether these new analyses of the STICLO data reinforce the evidence for a remarkable efficacy of stiripentol in Dravet syndrome, with a demonstrated rapid onset of action and sustained response, as also evidenced in further post-randomized trials.

Stiripentol in Dravet syndrome: results of a retrospective U.S. study.

PURPOSE: To review the efficacy and tolerability of stiripentol in the treatment of U.S. children with Dravet syndrome. METHODS: U.S. clinicians who had prescribed stiripentol for two or more children with Dravet syndrome between March 2005 and 2012 were contacted to request participation in this retrospective study. Data collected included overall seizure frequency, frequency of prolonged seizures, and use of rescue medications and emergency room (ER)/hospital visits in the year preceding stiripentol initiation, and with stiripentol therapy. We separately assessed efficacy in the following treatment groups: group A, stiripentol without clobazam or valproate; group B, stiripentol with clobazam but without valproate; group C, stiripentol with valproate but without clobazam; and group D, stiripentol with clobazam and valproate. In addition, adverse effects were recorded. KEY FINDINGS: Thirteen of 16 clinicians contacted for study participated and provided data on 82 children. Stiripentol was initiated a median of 6.0 years after seizure onset and 1.2 years after diagnosis of Dravet syndrome. Compared to baseline, overall seizure frequency was reduced in 2/6 in group A, 28/35 in group B, 8/14 in group C, and 30/48 in group D. All children with prolonged seizure frequency greater than quarterly during the baseline period experienced a reduction in this frequency on the various treatment arms with stiripentol. Similarly, 2/4 patients in group A, 25/25 in group B, 5/10 in group C, and 26/33 in group D experienced reduction in frequency of rescue medication use and 1/1 in group A, 12/12 in group B, 3/5 in group C, and 18/19 in group D had reduction in frequency of ER/hospital visits. Adverse effects were reported in 38, most commonly sedation and reduced appetite. Four patients (5%) discontinued stiripentol for adverse effects and two (2%) for lack of efficacy. SIGNIFICANCE: Stiripentol is an effective and well-tolerated therapy that markedly reduced frequency of prolonged seizures in Dravet syndrome.

Mildly oxidized LDL particle subspecies are distinct in their capacity to induce apoptosis in endothelial cells: role of lipid hydroperoxides.

The risk of atherosclerosis is intimately related to the heterogeneity of low-density lipoprotein (LDL) particles. The potential relationship between oxidative modification of distinct LDL subspecies and induction of apoptosis in arterial wall cells is indeterminate. The capacity of light LDL3 versus dense LDL5 to induce cytotoxicity in endothelial cells as a function of the degree of copper-mediated oxidation was compared. Mildly oxidized LDL3 (oxLDL3) exerted potent cytotoxicity, which was intimately related to both the degree of oxidation and the oxLDL3 concentration based on either cholesterol content or particle number. In contrast, dense LDL5 particles exerted a minor effect on cell viability. Cells incubated with oxLDL3 exhibited apoptotic features, with cytoplasmic condensation, cell or nuclear fragmentation, and accumulation of DNA fragments. OxLDL3-induced apoptosis involved cytoplasmic release of cytochrome c, with a concomitant increase in caspase-3-like protease activity. OxLDL3 particles were uniquely distinct from oxLDL5 particles in their elevated content of lipid hydroperoxides. Hydroperoxide removal by NaBH4 markedly reduced oxLDL3-induced cytotoxicity, leading to an increase in cell viability. Lipid hydroperoxide content of oxidatively modified LDL subclasses is therefore a major determinant of the induction of apoptosis in endothelial cells. These data are highly relevant to atherogenic hypercholesterolemia, in which the LDL phenotype is dominated by elevated concentrations of light LDL3.

Involvement of the TP receptor in TNF-α-induced endothelial tissue factor expression.

BACKGROUND: Thromboxane (TX) A2, prostaglandin endoperoxides and F2-isoprostanes exert their effects through a TX-prostanoid (TP) receptor, also expressed in endothelial cells. We investigated a role of the TP receptor in the endothelial expression of tissue factor (TF), a key trigger to thrombosis. METHODS AND RESULTS: Human umbilical vein endothelial cells (HUVEC) exposed to the TP receptor agonist U46619 featured a concentration-dependent increase in TF surface exposure and procoagulant activity. HUVEC pre-incubation with the TP receptor antagonist S18886, followed by stimulation with either U46619 or tumor necrosis factor-α (TNF-α), attenuated TF surface exposure and activity compared with stimulated control. Aspirin or indomethacin, while inhibiting cyclooxygenase (COX)-1 and -2 activities, did not mimic this effect. Probing of underlying mechanisms by selective pharmacological and gene silencing experiments showed that S18886 reduced U46619- or TNF-α-induced TF expression inhibiting ROS production, NAD(P)H oxidase and PKC activation. In addition, S18886 also inhibited ERK activation in the presence of both U46619 and TNF-α alone, while inhibition of JNK activation only occurred in the presence of U46619. CONCLUSION: The endothelial TP receptor contributes to TF surface exposure and activity induced not only by known TP receptor agonists, but also by TNF-α. Such findings expand the therapeutic potential of TP receptor inhibition.

LDL particle subclasses in hypercholesterolemia. Molecular determinants of reduced lipid hydroperoxide stability.

Hypercholesterolemia is characterized by elevated plasma levels of LDL in which the cholesteryl ester (CE)-rich LDL subclasses of light and intermediate density (LDL1+2 and LDL3, respectively) typically predominate. The molecular mechanisms implicated in oxidation of LDL particle subclasses in hypercholesterolemia are indeterminate. Lipid hydroperoxides (LOOH), primary oxidation products in LDL, are implicated in atherogenesis. LOOH formation was evaluated in light (LDL1+2), intermediate (LDL3), and dense (LDL4+5) LDL subclasses from hypercholesterolemic (HC) subjects (n = 7) during copper-mediated oxidative stress, and compared with that in corresponding subclasses from normolipidemic subjects (n = 7). HC LDL subclasses were distinguished by lower polyunsaturated phospholipid-alpha-tocopherol ratios (P < 0.02), lower contents of phosphatidyl choline (PC)16:0-18:0/18:2 and PC16:0-18:0/20:4+22:6 (P < 0.002), and higher surface phospholipid-free cholesterol ratios (P < 0.04). The LDL3, LDL4, and LDL5 subclasses in HC subjects displayed low-core polyunsaturated CE-alpha-tocopherol ratios (P < 0.05), despite similar PUFA CE content. These physicochemical differences did not modify the oxidative susceptibility of HC LDL but underlie the marked instability of cholesterol linoleate hydroperoxides in HC LDL1+2, LDL3, and LDL4 subclasses. Elevated concentrations of large, CE-rich, light, and intermediate LDL subclasses (LDL1+2, LDL3) in hypercholesterolemia may therefore act as an abundant proatherogenic source of highly unstable LOOH in the arterial wall.