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PURPOSE: To evaluate the safety and tolerability of adjunctive perampanel in a Japanese subpopulation of Study 311 (NCT02849626), which was a global, multicenter, open-label, single-arm study of children (aged 4 to <12 years) with inadequately controlled focal-onset seizures (FOS), with or without focal to bilateral tonic-clonic seizures (FBTCS) or generalized tonic-clonic seizures (GTCS). METHODS: Study 311 comprised a Core Study, Extension A, and Extension B; this report focuses on the Japanese patient subgroup in the Core Study only. In the Core Study, Japanese patients (FOS only) received adjunctive perampanel ≤12 mg/day in a 23-week Treatment Phase. Endpoints included safety/tolerability (primary) and median percent change in seizure frequency per 28 days from baseline. Patients were stratified by age and concomitant enzyme-inducing anti-seizure medication (EIASM) use. RESULTS: Of 65 enrolled Japanese patients, 56 completed the Core Study and nine withdrew. The most common reason for discontinuation was adverse events (AEs) (n = 4 [6.2%]). The mean (standard deviation) daily dose of perampanel in Japanese FOS patients was 5.8 (2.2) mg/day. During the Core Study, treatment-emergent AEs (TEAEs) were reported by 89% of Japanese patients, most commonly nasopharyngitis (28%) and somnolence (28%). The median percent reduction in seizure frequency per 28 days from baseline was 37% and the lower limit of the 95% CI was greater than 10.5%, satisfying the pre-defined efficacy criteria. Perampanel was effective regardless of age or concomitant EIASM use. CONCLUSION: Perampanel as adjunctive therapy is generally safe, well-tolerated, and efficacious in Japanese children aged 4 to <12 years with FOS (with/without FBTCS).
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Anticonvulsivantes , Piridonas , Convulsões , Criança , Humanos , Anticonvulsivantes/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada , População do Leste Asiático , Piridonas/uso terapêutico , Convulsões/tratamento farmacológico , Resultado do Tratamento , Pré-EscolarRESUMO
Lysophosphatidic acid (LPA) is a bioactive lipid mediator that elicits a number of biological functions, including smooth muscle contraction, cell motility, proliferation, and morphological change. LPA is endogenously produced by autotaxin (ATX) from extracellular lysophosphatidylcholine (LPC) in plasma. Herein, we report our medicinal chemistry effort to identify a novel and highly potent ATX inhibitor, ONO-8430506 (20), with good oral availability. To enhance the enzymatic ATX inhibitory activity, we designed several compounds by structurally comparing our hit compound with the endogenous ligand LPC. Further optimization to improve the pharmacokinetic profile and enhance the ATX inhibitory activity in human plasma resulted in the identification of ONO-8430506 (20), which enhanced the antitumor effect of paclitaxel in a breast cancer model.
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The modification of the novel G protein-biased EP2 agonist 1 has been investigated to improve its G protein activity and develop a better understanding of its structure-functional selectivity relationship (SFSR). The optimization of the substituents on the phenyl ring of 1, followed by the inversion of the hydroxyl group on the cyclopentane moiety led to compound 9, which showed a 100-fold increase in its G protein activity compared with 1 without any increase in ß-arrestin recruitment. Furthermore, SFSR studies revealed that the combination of meta and para substituents on the phenyl moiety was crucial to the functional selectivity.
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Receptores de Prostaglandina E Subtipo EP2/agonistas , Relação Estrutura-Atividade , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Proteínas de Ligação ao GTP/química , Humanos , Oligopeptídeos/química , Oligopeptídeos/farmacologiaRESUMO
To identify G protein-biased and highly subtype-selective EP2 receptor agonists, a series of bicyclic prostaglandin analogues were designed and synthesized. Structural hybridization of EP2/4 dual agonist 5 and prostacyclin analogue 6, followed by simplification of the ω chain enabled us to discover novel EP2 agonists with a unique prostacyclin-like scaffold. Further optimization of the ω chain was performed to improve EP2 agonist activity and subtype selectivity. Phenoxy derivative 18a showed potent agonist activity and excellent subtype selectivity. Furthermore, a series of compounds were identified as G protein-biased EP2 receptor agonists. These are the first examples of biased ligands of prostanoid receptors.
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Objective: We examined the short-term efficacy and safety of rufinamide (RFN) in patients with Lennox-Gastaut syndrome (LGS). Methods: We performed a retrospective review of clinical records of patients with LGS who started RFN treatment between July 2013 and June 2014 at the Hokkaido Medical Center for Child Health and Rehabilitation and Midorigaoka Ryo-iku-en. Efficacy and safety were evaluated when the patients had completed three months of treatment. Patients were classified into four categories according to percent seizure reduction : remission (seizure-free), response (seizure reduction≥50%), no change (seizure reduction<50% or increase) and aggravation (seizure increase≥50%). Responder rate (RR) was the percentage of patients with≥50% decrease in seizure frequency. Results: Thirteen LGS patients (8 males, 5 females) were studied. The efficacy for tonic seizures (13 patients) was remission 1 patient, response 3 patients, no change 8 patients and aggravation 1 patient, with RR of 30.8%. Two patients discontinued LGS due to seizure aggravation. Four patients experienced transient remission. For generalized tonic clonic seizures (2 patients), 1 patient achieved remission and 1 patient showed no change. Two patients of atonic seizures showed no change. Of 2 patients of atypical absence, 1 patient showed response and 1 patient no change. Eight patients had adverse effects such as somnolence (6 patients), sleep disturbance (1 patient), and appetite loss (4 patients) including weight loss in 2 patients. There were no severe adverse effects and no discontinuation due to adverse effects. Conclusions: Short-term effectiveness for tonic seizures was observed when patients with LGS were treated with RFN, with transient remission in some patients. We consider that RFN is worth trying in patients with LGS due to its efficacy for tonic seizures and absence of severe adverse effects.
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Anticonvulsivantes/uso terapêutico , Síndrome de Lennox-Gastaut/tratamento farmacológico , Triazóis/uso terapêutico , Criança , Feminino , Humanos , Masculino , LinhagemRESUMO
INTRODUCTION: We report the case of a 2-year-old boy who showed a huge midline mass in the brain at prenatal assessment. CASE REPORT: After birth, magnetic resonance imaging (MRI) revealed a conglomerate mass with an infolded microgyrus at the midline, which was suspected as a midline brain-in-brain malformation. MRI also showed incomplete cleavage of his frontal cortex and thalamus, consistent with lobar holoprosencephaly. The patient underwent an incisional biopsy of the mass on the second day of life. The mass consisted of normal central nervous tissue with gray and white matter, representing a heterotopic brain. The malformation was considered to be a subcortical heterotopia. With maturity, focal signal changes and decreased cerebral perfusion became clear on brain imaging, suggesting secondary glial degeneration. Coincident with these MRI abnormalities, the child developed psychomotor retardation and severe epilepsy focused on the side of the intracranial mass.
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Encéfalo/fisiopatologia , Coristoma/fisiopatologia , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/fisiopatologia , Epilepsia/fisiopatologia , Holoprosencefalia/fisiopatologia , Encéfalo/patologia , Pré-Escolar , Coristoma/complicações , Coristoma/patologia , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/complicações , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/patologia , Eletroencefalografia , Epilepsia/etiologia , Feminino , Holoprosencefalia/complicações , Holoprosencefalia/patologia , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Gravidez , Transtornos Psicomotores/etiologia , Ultrassonografia Pré-NatalRESUMO
Defects in the mitochondrial translation apparatus can impair energy production in affected tissues and organs. Most components of this apparatus are encoded by nuclear genes, including GFM2, which encodes a mitochondrial ribosome recycling factor. A few patients with mutations in some of these genes have been reported to date. Here, we present two female siblings with arthrogryposis multiplex congenita, optic atrophy and severe mental retardation. The younger sister had a progressive cerebellar atrophy and bilateral neuropathological findings in the brainstem. Although her cerebrospinal fluid (CSF) levels of lactate and pyruvate were not increased, brain magnetic resonance spectroscopy showed a lactate peak. Additionally, her CSF lactate/pyruvate and serum beta-hydroxybutyrate/acetoacetate ratios were high, and levels of oxidative phosphorylation in skin fibroblasts were reduced. We therefore diagnosed Leigh syndrome. Genomic investigation confirmed the presence of compound heterozygous GFM2 mutations (c.206+4A>G and c.2029-1G>A) in both siblings, causing aberrant splicing with premature stop codons (p.Gly50Glufs*4 and p.Ala677Leufs*2, respectively). These findings suggest that GFM2 mutations could be causative of a phenotype of Leigh syndrome with arthrogryposis multiplex congenita.
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Artrogripose/genética , Doença de Leigh/genética , Proteínas Mitocondriais/genética , Fator G para Elongação de Peptídeos/genética , Artrogripose/complicações , Sequência de Bases , Criança , Evolução Fatal , Feminino , Heterozigoto , Humanos , Lactente , Doença de Leigh/complicações , Linhagem , IrmãosRESUMO
BACKGROUND: Paroxysmal tonic upward gaze is a childhood oculomotor syndrome characterized by episodes of conjugate upward deviation of the eyes. Its pathogenesis is unknown, and the etiology is heterogeneous. PATIENT DESCRIPTION: We describe a 2-year-old girl with Angelman syndrome who developed paroxysmal tonic upward gaze at 9 months of age. She presented with developmental delay, blond hair, jerky movements, ataxia, and epilepsy. Genetic testing revealed a maternal deletion of 15q11-13, confirming Angelman syndrome. CONCLUSIONS: This is the first report of Angelman syndrome complicated by paroxysmal tonic upward gaze. Both transient paroxysmal tonic upward gaze and Angelman syndrome have been associated with dopaminergic neurons. We speculate that the dopaminergic abnormalities present in Angelman syndrome may cause paroxysmal tonic upward gaze.
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Síndrome de Angelman/complicações , Transtornos da Motilidade Ocular/complicações , Síndrome de Angelman/genética , Síndrome de Angelman/fisiopatologia , Encéfalo/fisiopatologia , Pré-Escolar , Eletroencefalografia , Feminino , Humanos , Transtornos da Motilidade Ocular/genética , Transtornos da Motilidade Ocular/fisiopatologiaRESUMO
Subependymal giant cell astrocytomas are benign tumors often observed with tuberous sclerosis complex. These tumors are rarely diagnosed during fetal life or early infancy. Until recently, the only available treatment has been surgical resection. Current clinical research has demonstrated that everolimus can induce these tumors' regression. We report a 19-month-old boy with tuberous sclerosis complex. At 2 months of age, he presented with congenital subependymal giant cell astrocytoma that was complicated by refractory epilepsy and severe mental retardation. Treatment with everolimus was started when he was 10 months old. Three months after initiating everolimus, the tumor was significantly reduced in size, and the reduction was subsequently maintained. His seizures decreased and he showed cognitive and developmental improvement. No severe adverse events have been observed to date. Everolimus has promise as an effective alternative to surgery for subependymal giant cell astrocytomas during early infancy.
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Antineoplásicos/uso terapêutico , Astrocitoma/tratamento farmacológico , Neoplasias Encefálicas/tratamento farmacológico , Everolimo/uso terapêutico , Esclerose Tuberosa/tratamento farmacológico , Astrocitoma/complicações , Neoplasias Encefálicas/complicações , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Esclerose Tuberosa/complicaçõesRESUMO
OBJECTIVE: It is sometime difficult to achieve effective blood levels of lamotrigine (LTG) by the methods of administration presented in the product labeling (PL). We highlighted the importance of measuring LTG blood levels, and proposed a method of adjusting the optimum dosage of LTG based on the pharmacokinetic interaction. METHOD: Four types of maintenance dose of LTG were determined whether LTG was administrated in combination with valproate sodium and/or enzyme-inducing antiepileptic drugs or with agents except for them. This method is compared with the method presented in the PL. We exhibited the clinical course of three patients who took LTG according to our method since the blood levels were not elevated enough by the method shown in the PL. RESULTS: The maintenance dosage described in the PL was lower than that in our methods. The blood levels in these three patients were increased enough to be effective after the therapy by our method. CONCLUSIONS: Measuring the LTG blood level is important to create an optimum dosing schedule. Since the maintenance doses of LTG presented in PL may be inappropriate, they should be adequately adjusted by reference to the LTG blood level.
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Anticonvulsivantes/sangue , Epilepsia/tratamento farmacológico , Triazinas/sangue , Adolescente , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/uso terapêutico , Pré-Escolar , Cálculos da Dosagem de Medicamento , Feminino , Humanos , Lamotrigina , Masculino , Triazinas/administração & dosagem , Triazinas/uso terapêutico , Adulto JovemRESUMO
OBJECTIVE: The purpose of this study was to assess the characteristics of women with epilepsy who developed polycystic ovary syndrome (PCOS) owing to therapy with valproate sodium (VPA). METHODS: Our study comprised 77 patients on therapy with VPA--20 patients with PCOS and 57 without PCOS (control group). We assessed their epilepsy type, status of seizure control, and mental and physical statuses as well as the starting age, administration period, total dosage, and the highest value of blood concentration of VPA. RESULTS: As compared with the control group, the PCOS group showed significantly high rates of association with mental retardation, severe physical disabilities, and poor seizure control, and symptomatic generalized epilepsy. However, the starting age, administration period, total dosage, and the highest value of blood concentration of VPA were not significantly different between the 2 groups. Nineteen of the 20 patients with PCOS had characteristically high androstenedione levels. CONCLUSIONS: Our study demonstrated that refractory symptomatic generalized epilepsy, polypharmacy including VPA and severe motor and intellectual disabilities are risk factors of developing PCOS.
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Epilepsia/tratamento farmacológico , Síndrome do Ovário Policístico/diagnóstico , Ácido Valproico/efeitos adversos , Adolescente , Adulto , Androstenodiona/sangue , Epilepsia/metabolismo , Feminino , Humanos , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/metabolismo , Guias de Prática Clínica como Assunto , Fatores de Risco , Ácido Valproico/metabolismo , Ácido Valproico/uso terapêutico , Adulto JovemRESUMO
Topiramate (TPM) was administered to 25 children with intractable generalized epilepsy. A > or =50% decrease in seizure frequency was observed in 56% and 45% of children at two months and one year after initiation of TPM therapy, respectively. However, efficacy of TPM for Lennox-Gastaut syndrome was low. TPM therapy was discontinued in five of 25 children at 3-5.5 months due to lack of efficacy or aggravation of seizures. No serious adverse effects were observed during TPM therapy. The present study revealed that TPM has clinical efficacy in the treatment of children with intractable generalized epilepsy.
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Anticonvulsivantes/uso terapêutico , Epilepsia Generalizada/tratamento farmacológico , Frutose/análogos & derivados , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Frutose/uso terapêutico , Humanos , Lactente , Masculino , Topiramato , Resultado do TratamentoRESUMO
PURPOSE: De novo STXBP1 mutations have been found in individuals with early infantile epileptic encephalopathy with suppression-burst pattern (EIEE). Our aim was to delineate the clinical spectrum of subjects with STXBP1 mutations, and to examine their biologic aspects. METHODS: STXBP1 was analyzed in 29 and 54 cases of cryptogenic EIEE and West syndrome, respectively, as a second cohort. RNA splicing was analyzed in lymphoblastoid cells from a subject harboring a c.663 + 5G>A mutation. Expression of STXBP1 protein with missense mutations was examined in neuroblastoma2A cells. RESULTS: A total of seven novel STXBP1 mutations were found in nine EIEE cases, but not in West syndrome. The mutations include two frameshift mutations, three nonsense mutations, a splicing mutation, and a recurrent missense mutation in three unrelated cases. Including our previous data, 10 of 14 individuals (71%) with STXBP1 aberrations had the onset of spasms after 1 month, suggesting relatively later onset of epileptic spasms. Nonsense-mediated mRNA decay associated with abnormal splicing was demonstrated. Transient expression revealed that STXBP1 proteins with missense mutations resulted in degradation in neuroblastoma2A cells. DISCUSSION: Collectively, STXBP1 aberrations can account for about one-third individuals with EIEE (14 of 43). These genetic and biologic data clearly showed that haploinsufficiency of STXBP1 is the important cause for cryptogenic EIEE.
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Eletroencefalografia/estatística & dados numéricos , Epilepsia Generalizada/genética , Haploinsuficiência/genética , Proteínas Munc18/genética , Mutação de Sentido Incorreto/genética , Espasmos Infantis/genética , Encéfalo/fisiopatologia , Epilepsia Generalizada/diagnóstico , Epilepsia Generalizada/fisiopatologia , Feminino , Haploinsuficiência/fisiologia , Humanos , Lactente , Recém-Nascido , Masculino , Mutação de Sentido Incorreto/fisiologia , Espasmos Infantis/diagnóstico , Espasmos Infantis/fisiopatologiaRESUMO
Eighty-two episodes of status epilepticus or clusters of seizures in 45 children were treated with intravenous midazolam. Twenty-two children had epilepsy and 23 had acute symptomatic seizures. Midazolam was administered as an intravenous bolus dose at 0.06-0.4 mg/kg (mean 0.173 mg/kg), followed by continuous intravenous infusion at 0.05-0.4 mg/kg/hr (mean 0.191 mg/kg/hr). The mean duration of the treatment was 132.7 hours. Complete arrest of seizures was achieved in 62 episodes, and decrease by more than 50% in seizure frequency in 8 clusters of seizures. In these 70 successfully treated cases (85.4%), the effect appeared within 45 minutes after the initiation of therapy. No severe adverse effects were noted except stridor and mild respiratory suppression in 2 cases. Midazolam is an effective and safe drug to be used in a first-line or second-line therapy for status epilepticus and clusters of seizures in children.
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Midazolam/administração & dosagem , Convulsões/tratamento farmacológico , Estado Epiléptico/tratamento farmacológico , Adolescente , Adulto , Criança , Pré-Escolar , Humanos , Lactente , Infusões Intravenosas , Injeções Intravenosas , Fatores de Tempo , Resultado do TratamentoRESUMO
The relationship between oral health and general health in the elderly has been much studied. However, further studies focussing on the influence of oral health on the quality of life (QOL) among the elderly are required. The goal of this study was to evaluate the relationship between oral health and physical or cultural activities. Subjects were 101 community-dwelling elderly persons who were functionally independent (mean age 70.3). Oral health status was evaluated according to the number of remaining teeth and the number of functional teeth. Physical and cultural activities were evaluated from self-reported information. The relationship between oral health and physical or cultural activities was examined by logistic regression analysis. About 60% of subjects took part in cultural activities, and less than half actively exercised (leisure sports, 33.6%; travel, 42.6%). Persons with 20 or more remaining teeth were more active in leisure sports (Odds ratio (OR)=4.86, 95% confidence interval (CI)=1.34, 17.38) and travel (OR=5.42, 95% CI=1.63, 18.08) than those with fewer than 20 remaining teeth. These results suggest that the number of remaining teeth is associated with physical activity in elderly persons.
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Exercício Físico , Arcada Parcialmente Edêntula/patologia , Atividades de Lazer , Saúde Bucal , Viagem , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Japão , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Análise de RegressãoRESUMO
Expression of common gamma chain (gammac) on monocytes was studied in five carriers of X-linked severe combined immunodeficiency (X-SCID) and two X-SCID patients who underwent cord blood stem cell transplantation (CBSCT). Flow cytometric analysis revealed that both gammac-negative and positive monocytes co-existed in X-SCID carriers, whereas no gammac-negative T, B or NK cells were observed in them. Clonal analysis and reverse transcription polymerase chain reaction studies revealed that 13.2-45.0% of monocytes from these carriers expressed the mutant gammac message. X-SCID patients who received CBSCT persistently possessed the majority of gammac-negative monocytes with a good clinical course. These results, together, may indicate that gammac is not essential for monocyte development/function in vivo.
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Transplante de Células-Tronco Hematopoéticas , Monócitos/metabolismo , Receptores de Interleucina-7/genética , Imunodeficiência Combinada Severa/genética , Feminino , Sangue Fetal , Citometria de Fluxo , Ligação Genética , Heterozigoto , Humanos , Subunidade gama Comum de Receptores de Interleucina , Masculino , Mutação , RNA Mensageiro/genética , Receptores de Interleucina-7/sangue , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Imunodeficiência Combinada Severa/sangue , Cromossomo XRESUMO
Recently a tumor suppressor gene, a deleted in malignant brain tumor gene (DMBT1), was detected on chromosome 10. In some types of tumors, the frequent deletion of DMBT1 locus have been reported as well as loss of heterozygosity (LOH) on chromosome 10. However, little is known relating to human oral squamous cell carcinoma (OSCC). To study the genetic aberrations on chromosome 10 in OSCC, we performed polymerase chain reaction (PCR) analysis of microsatellite polymorphisms corresponding to 16 loci, containing 2 DMBT1 loci. We examined 38 oral primary squamous cell carcinoma (SCC) tissues and corresponding normal tissues. Microsatellite instability (MI) was detected at least on 1 of the 16 loci in 15 (39.5%) of 38 cases, and loss of heterozygosity (LOH) at least 1 of the 16 loci was also observed in 28 (73.7%) of 38 cases. LOH was accumulated at D10S202 (34.6%) and D10S217 (28.6%), suggesting the presence of two putative tumor suppressor genes associated with OSCC. The 2 DMBT1 loci, D10S209 and D10S587, had comparatively high frequent LOH (20.0 and 22.7%, respectively), maybe indicating the important role of DMBT1 in OSCC. No significant correlation between histological differentiation and LOH was found. These results suggest that genetic aberrations on chromosome 10 play important roles in the oncogenesis of OSCC.
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Carcinoma de Células Escamosas/genética , Cromossomos Humanos Par 10 , Neoplasias Bucais/genética , Aberrações Cromossômicas , DNA Complementar/metabolismo , Humanos , Perda de Heterozigosidade , Repetições de Microssatélites , Polimorfismo Genético , Células Tumorais CultivadasRESUMO
Obesity and craniofacial abnormalities may contribute to the pathogenesis of obstructive sleep apnea. The purpose of this study was to evaluate the influence of body habitus and craniofacial characteristics on types of pharyngeal closure. The types of pharyngeal closure were determined by endoscopic evaluations of closing pressures of the passive pharynx in 54 paralyzed and anesthetized patients with sleep-disordered breathing (SDB). Assessment of craniofacial characteristics of the SDB patients and 24 normal subjects were made by lateral cephalometry. As compared with normal subjects, SDB patients demonstrated receded mandibles and long lower faces with downward mandible development. SDB patients with positive closing pressures at both the velopharynx and oropharynx (VP + OP group) demonstrated smaller maxillas and mandibles than those with positive closing pressures at the velopharynx only (VP-only group). Obesity was more prominent in the VP-only group than in the VP + OP group. Our results suggest that obesity and craniofacial abnormalities contribute synergistically to increases in collapsibility of the passive pharyngeal airway in patients with SDB. Furthermore, the relative contribution of obesity and craniofacial anomaly appears to determine the type of pharyngeal closure in SDB.