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[Medicaments and oral healthcare. Proliferation of the gingiva].
de Baat, C, Zweers, PGMA, Vissink, A
Nederlands tijdschrift voor tandheelkunde. 2018;(7-8):397-402
Abstract
Adverse effects of medications and self care products on the gingiva can be divided into inflammation, intrinsic discolouration, irritation, trauma, cytotoxicity, lichenoid reaction, and proliferation. This article deals with the last-mentioned type of adverse effects; the other 6 have been discussed in a previous article. Proliferation of the gingiva as an adverse effect of medications has been reported for anticonvulsants, calcineurin inhibitors, calcium channel blockers and isotretinoin. With regard to the anticonvulsants that have been registered in the Netherlands, proliferation of the gingiva is predominantly induced by phenytoin, but also by carbamazepine, ethosuximide, phenobarbital, gabapentin, levetiracetam, primidone and valproic acid. All calcineurin inhibitors registered in the Netherlands may induce the adverse effect. This is also the case for nearly all calcium channel blockers, but particularly for dihydropyridines. Presumably, proliferation of the gingiva may be prevented or reduced in a number of ways. The most important one is good oral hygiene. Furthermore, proteins and cells that play an important role [in the process of gingival proliferation] have been discovered and there are medications that have the potential to eliminate these proteins and cells.
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Current and up-and-coming pharmacotherapy for obsessive-compulsive disorder in adults.
Grassi, G, Pallanti, S
Expert opinion on pharmacotherapy. 2018;(14):1541-1550
Abstract
INTRODUCTION Only 40-60% of obsessive-compulsive patients respond to first line treatments, such as selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioral therapy. Several second-line treatments have been investigated in the last two decades, and most of them seem to work, at least in a subset of patients. However, since there is still a lack of treatment predictors, the treatment of obsessive-compulsive disorder (OCD) is still empirical and non-evidence based. AREAS COVERED In this paper, we review current and up-and-coming pharmacotherapy for OCD in adults, focusing on two emerging fields of research, inflammation and glutamate systems, since they have attracted the greatest attention in recent years in OCD pharmacological research. EXPERT OPINION Most of the investigated second-line agents seem to work at least in a subset of patients with OCD. These results raise an open question: what works for who? In our opinion, this question should be answered in a precision medicine perspective or, in other words, individualizing diagnostic processes and treatment approaches. In a precision medicine approach, OCD treatment should be sub-type specific, phase specific, multimodal and sequential, and, more importantly, dimensional.
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Pyridoxine-dependent epilepsies: an observational study on clinical, diagnostic, therapeutic and prognostic features in a pediatric cohort.
Falsaperla, R, Vari, MS, Toldo, I, Murgia, A, Sartori, S, Vecchi, M, Suppiej, A, Burlina, A, Mastrangelo, M, Leuzzi, V, et al
Metabolic brain disease. 2018;(1):261-269
Abstract
The aim of our study was to describe the clinical, electroencephalogram, molecular findings and the diagnostic and therapeutic flow-chart of children with pyridoxine-dependent epilepsies (PDEs). We performed a retrospective observational study on children with PDEs, diagnosed and followed-up in Italian Pediatric Departments. In each centre, the authors collected data from a cohort of children admitted for intractable seizures, responsive to pyridoxine administration and resistant to other anticonvulsant therapies. Data were retrospectively analysed from January 2016 to January 2017. Sixteen patients (13 males, and 3 females) were included. We found that 93.75% of patients underwent conventional anticonvulsant therapy before starting pyridoxine administration and 62.5% had ex-juvantibus diagnosis, as specific serum diagnostic tests had been performed in only 37.5% of patients by alpha-AASA and pipecolic acid blood and urine dosage. The most common type of seizure was generalized tonic-clonic in 7 patients and the most common EEG pattern was characterized by a "burst suppression" pattern. Before pyridoxine administration, other anticonvulsant drugs were used in 93.75% of patients, with consequent onset of drug-resistance. Phenobarbital was the most frequently used drug as first-line treatment. The importance of our study relies on the need of a deeper knowledge of PDEs in terms of early diagnosis, avoiding incorrect treatment and related adverse events, clinical and EEG pathognomonic features, and genetic aspects of the disease.
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The Lack of Effect of Food on the Pharmacokinetics of ZX008 (Fenfluramine Oral Solution): Results of a Single-dose, Two-period Crossover Study.
Gammaitoni, A, Smith, S, Boyd, B
Clinical therapeutics. 2018;(8):1338-1346
Abstract
PURPOSE Fenfluramine is being developed as a low-dose adjunctive treatment for seizures in patients with Dravet syndrome and other epileptic encephalopathies, including Lennox-Gastaut syndrome. Most patients with Dravet syndrome receive multiple antiepileptic drugs, making it challenging for caregivers to track correct administration times. The present Phase I study was conducted to determine the effect of food on the pharmacokinetic properties of fenfluramine. METHODS Healthy nonsmoking subjects aged 18 to 50 years were enrolled in an open-label, crossover, Phase I pharmacokinetic and safety profile study and received 2 single 0.8-mg/kg doses of ZX008 (fenfluramine hydrochloride oral solution), 1 after a 10-hour overnight fast and the other 30 minutes after the start of consumption of a high-fat breakfast, in a randomly assigned order. A washout period of at least 9 days separated the 2 treatment periods. Venous blood samples were taken before each dose and periodically for 72 hours after each dose for determination of concentrations of fenfluramine and its active metabolite norfenfluramine. Plasma pharmacokinetic parameters were estimated for each subject by noncompartmental analysis. FINDINGS In the 13 subjects completing both treatment periods, food had no effect on the rate or extent of absorption and bioavailability of fenfluramine as assessed by fed vs fasted adjusted geometric mean observed plasma Cmax (59.1 vs 56.7 ng/mL; NS) and AUC0-∞ (1640 vs 1600 ng · h/mL; NS). Additionally, there was no impact of food on systemic exposure of norfenfluramine. Seven subjects reported at least 1 treatment-emergent adverse event; all treatment-emergent adverse events were mild in severity. IMPLICATIONS The bioequivalence and tolerability of single 0.8-mg/kg oral doses of ZX008 in the fed and fasted states support ZX008 administration without regard to meals.
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[Diagnosis and management of de novo epilepsy].
Louise, T
Presse medicale (Paris, France : 1983). 2018;(3):227-233
Abstract
The diagnosis of de novo epilepsy is complex. An accurate diagnostic approach has to be followed based on specific key steps. Epileptic seizure or non-epileptic malaise: risk of diagnosis error around 20%. Facing a first unprovoked seizure, the practitioner has to know the risk factors specifically linked to an increase risk of seizure recurrence. In presence of these factors, an antiepileptic drug would be indicated. The first antiepileptic drug has to be highly selected according to the epilepsy type and causes but also to the patient characteristics (sex, age, comorbidities, associated drugs, profession, and way of life…) An exhaustive patient Education needs to support the first antiepileptic drug prescription: (sleep and nutritional advices, benefit of observance, antiepileptic drugs features and side effects, follow-up, prognosis…) A regular follow-up is essential to control the observance, tolerability and efficacy of the antiepileptic drug, and to control also the good acceptance of the disease. A systematic research of common comorbidities may be also performed. Electroencephalogram and antiepileptic drugs levels are unnecessary in the classical follow up of known epileptic patients (except specific cases).
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Stiripentol efficacy and safety in Dravet syndrome: a 12-year observational study.
Myers, KA, Lightfoot, P, Patil, SG, Cross, JH, Scheffer, IE
Developmental medicine and child neurology. 2018;(6):574-578
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Abstract
AIM: To assess long-term safety and efficacy of stiripentol as an antiepileptic medication for people with Dravet syndrome. METHOD A prospective, observational open-label study (2003-2015) of the efficacy and long-term safety of stiripentol in patients with Dravet syndrome and ongoing seizures. Frequency of generalized tonic-clonic seizures, focal seizures, status epilepticus, and adverse events were recorded. RESULTS Forty-one patients started stiripentol, with median age at enrolment 5 years 7 months (range 11mo-22y) and median duration of treatment 37 months (range 2-141mo). Twenty out of 41 patients had greater than or equal to 50% long-term reduction in frequency of generalized tonic-clonic seizures. Frequency of focal seizures was decreased by greater than or equal to 50% in 11 out of 23 patients over the long-term. Frequency of status epilepticus was decreased by 50% or more in 11 out of 26 patients. The most common adverse events were anorexia, weight loss, sedation, and behavioural changes. One patient had worsening of absence and myoclonic seizures. Another developed recurrent pancreatitis on concurrent valproate. INTERPRETATION Stiripentol improves long-term seizure frequency in approximately 50% of patients with Dravet syndrome, when used as part of unrestricted polytherapy. Long-term use appears safe. In more than 40% of patients, episodes of status epilepticus markedly decrease after stiripentol initiation. What this paper adds Frequency of status epilepticus is reduced in 40% of patients with Dravet syndrome after stiripentol initiation. Stiripentol is effective for generalized tonic-clonic and focal seizures. Stiripentol can be safely used with a range of antiepileptic drugs.
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Sodium Valproate, a Histone Deacetylase Inhibitor, Is Associated With Reduced Stroke Risk After Previous Ischemic Stroke or Transient Ischemic Attack.
Brookes, RL, Crichton, S, Wolfe, CDA, Yi, Q, Li, L, Hankey, GJ, Rothwell, PM, Markus, HS
Stroke. 2018;(1):54-61
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Abstract
BACKGROUND AND PURPOSE A variant in the histone deacetylase 9 (HDAC9) gene is associated with large artery stroke. Therefore, inhibiting HDAC9 might offer a novel secondary preventative treatment for ischemic stroke. The antiepileptic drug sodium valproate (SVA) is a nonspecific inhibitor of HDAC9. We tested whether SVA therapy given after ischemic stroke was associated with reduced recurrent stroke rate. METHODS Data were pooled from 3 prospective studies recruiting patients with previous stroke or transient ischemic attack and long-term follow-up: the South London Stroke Register, The Vitamins to Prevent Stroke Study, and the Oxford Vascular Study. Patients receiving SVA were compared with patients who received antiepileptic drugs other than SVA using survival analysis and Cox Regression. RESULTS A total of 11 949 patients with confirmed ischemic event were included. Recurrent stroke rate was lower in patient taking SVA (17 of 168) than other antiepileptic drugs (105 of 530; log-rank survival analysis P=0.002). On Cox regression, controlling for potential cofounders, SVA remained associated with reduced stroke (hazard ratio=0.44; 95% confidence interval: 0.3-0.7; P=0.002). A similar result was obtained when patients taking SVA were compared with all cases not taking SVA (Cox regression, hazard ratio=0.47; 95% confidence interval: 0.29-0.77; P=0.003). CONCLUSIONS These results suggest that exposure to SVA, an inhibitor of HDAC, may be associated with a lower recurrent stroke risk although we cannot exclude residual confounding in this study design. This supports the hypothesis that HDAC9 is important in the ischemic stroke pathogenesis and that its inhibition, by SVA or a more specific HDAC9 inhibitor, is worthy of evaluation as a treatment to prevent recurrent ischemic stroke.
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Neonatal epilepsies: Clinical management.
Cornet, MC, Sands, TT, Cilio, MR
Seminars in fetal & neonatal medicine. 2018;(3):204-212
Abstract
Whereas the majority of seizures in neonates are related to acute brain injury, a substantial minority are the first symptom of a neonatal-onset epilepsy, often linked to a pathogenic genetic variant. This defect may disrupt cortical development (e.g., lissencephaly, focal cortical dysplasia), lead to metabolic changes (e.g., pyridoxine-dependent epilepsy, sulfite oxidase deficiency) or lead to cortical dysfunction without metabolic or macroscopic structural changes (e.g., channelopathies, STXBP1). Historically, studies on treatment response and long-term consequences of neonatal seizures have lumped all etiologies together. However, etiology has been consistently shown to be the most important determinant of outcome. Here, we address the elements differentiating neonatal-onset epilepsies from acute symptomatic seizures. We review some common neonatal-onset epilepsies and emphasize how pathognomonic electro-clinical phenotypes such as the ones associated with KCNQ2 or KCNT1 gene mutation, when recognized early, can lead to targeted diagnostic testing and precision medicine treatment, enabling the possibility of improved outcome.
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Valproate and childbearing potential: new regulations.
Sisodiya, SM, ,
Practical neurology. 2018;(3):176-178
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Tolerability of adjunctive eslicarbazepine acetate according to concomitant lamotrigine or carbamazepine use: A subgroup analysis of three phase III trials in adults with focal (partial-onset) seizures.
Abou-Khalil, B, Klein, P, Shah, A, Ryvlin, P, Specchio, LM, Gama, H, Rocha, F, Blum, D, Grinnell, T, Cheng, H, et al
Epilepsy research. 2018;:80-86
Abstract
OBJECTIVE To evaluate and compare the effects of concomitant lamotrigine (LTG) or carbamazepine (CBZ) on the incidence of treatment-emergent adverse events (TEAEs) in patients taking adjunctive eslicarbazepine acetate (ESL) for focal (partial-onset) seizures (FS). METHODS These post-hoc analyses of data pooled from three randomized, double-blind, placebo-controlled studies of adjunctive ESL (BIA-2093-301, -302 and -304) included adults (≥16 years) with FS refractory to 1-3 antiepileptic drugs (AEDs). Patients were randomized equally to placebo, ESL 400 mg (Studies 301 and 302 only), 800 mg, or 1200 mg once daily (8-week baseline, 2-week titration, and 12-week maintenance periods). TEAEs, TEAEs leading to discontinuation, and serious AEs (SAEs) were evaluated in patients taking, or not taking, LTG (excluding those taking CBZ or phenytoin [PHT]; i.e., the +LTG and -LTG/-CBZ subgroups), or CBZ (excluding those taking LTG or PHT; i.e., the +CBZ and -LTG/-CBZ subgroups) at baseline. RESULTS LTG was used concomitantly by 248 patients (+LTG; placebo, n = 81; ESL, n = 167) and CBZ by 613 patients (+CBZ; placebo, n = 172; ESL, n = 441); 361 patients were taking neither LTG nor CBZ (-LTG/-CBZ; placebo, n = 109; ESL, n = 252). The overall incidence of TEAEs with ESL (any dose) was numerically higher for +CBZ (77%) than for +LTG (73%) or -LTG/-CBZ (68%; statistical significance not tested). Among patients taking ESL, dizziness, diplopia, and vomiting were reported more frequently in the +CBZ subgroup (30%, 14%, and 10%, respectively) than in the +LTG (16%, 8%, 5%) or -LTG/-CBZ (11%, 3%, 5%) subgroups. The overall incidence of TEAEs leading to discontinuation with ESL was higher for +CBZ (21%) than for +LTG (13%) or -LTG/-CBZ (15%). Dizziness leading to discontinuation with ESL was reported more frequently in the +CBZ subgroup than in the +LTG or -LTG/-CBZ subgroups (9%, 3%, and 3%, respectively). The overall incidence of SAEs in patients taking ESL was comparable across subgroups (+LTG, 5%; +CBZ, 6%; -LTG/-CBZ, 5%). The results were similar when evaluating placebo-adjusted incidences. CONCLUSION There was a potential pharmacodynamic interaction between AEDs with a putatively similar mechanism of action, with a seemingly lesser interaction between ESL and LTG versus ESL and CBZ. If combining ESL with LTG or CBZ, clinicians should be aware of the potential risk for an increased incidence of TEAEs typically associated with voltage-gated sodium channel inhibitors (e.g., dizziness, blurred vision, vertigo, diplopia, headache, or vomiting).