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1.
Epilepsia ; 60(8): 1602-1609, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31268555

RESUMO

OBJECTIVE: Treatment options for seizure clusters are limited; the need for easy-to-administer treatments remains. The Staccato system delivers drug deep into the lung via inhalation. In this phase 2a study, we investigated the ability of three different doses of Staccato alprazolam to suppress the electroencephalographic (EEG) photoparoxysmal response (PPR) compared with placebo in participants with photosensitive seizures. METHODS: Adults (18-60 years) with a diagnosis and history of PPR on EEG with or without an epilepsy diagnosis were eligible to participate. Participants received Staccato alprazolam 0.5, 1.0, and 2.0 mg, and Staccato placebo (twice) in random order. Intermittent photic stimulation and clinical assessments were performed at one predose and seven postdose time points. The primary endpoint of the study was the change in standardized photosensitivity range (SPR) in participants receiving each dose of Staccato alprazolam. RESULTS: Fifteen participants with a prior epilepsy diagnosis were screened; five were enrolled, randomized, and completed the study. All participants were white females with a mean (SD) age of 27.2 (6.8) years. All doses of Staccato alprazolam reduced the SPR at 2 minutes; the effect was sustained through 4 hours for the 0.5-mg dose and 6 hours for the 1.0- and 2.0-mg doses. The magnitude and duration of sedation and sleepiness were dose-related. Four participants (80%) experienced ≥1 adverse event (AE); none was severe or serious. Cough, diarrhea, dysgeusia, oral dysesthesia, sedation, and somnolence were experienced by two participants (40%) each. SIGNIFICANCE: This proof-of-concept study demonstrated that Staccato alprazolam 0.5, 1.0, and 2.0 mg rapidly suppressed epileptiform activity in photosensitive participants with epilepsy. The AE profile of Staccato alprazolam was similar to what has been reported for alprazolam for other indications. The results support further development of Staccato alprazolam as a rescue medication for the acute treatment of seizures.

2.
Neurology ; 93(6): e559-e567, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31292226

RESUMO

OBJECTIVE: To evaluate the effect of cenobamate in patients with photoparoxysmal-EEG response (PPR) to intermittent photic stimulation (IPS) as proof of principle of efficacy in patients with epilepsy. METHODS: In this multicenter, single-blind study, adults with photosensitive epilepsy, with/without concomitant antiepileptic drug therapy, underwent IPS under 3 eye conditions after a single dose of placebo (day -1, day 2) or cenobamate (day 1; 100, 250, or 400 mg). Complete suppression was a standardized photosensitivity range reduction to 0 over ≥1 time points for all eye conditions. Partial suppression was a ≥3-point reduction over ≥3 testing times vs the same time points on day -1 in ≥1 eye condition. Pharmacokinetics and safety were assessed. RESULTS: Of 6 evaluable patients, 5 reentered to receive higher doses. Cenobamate 100 mg produced partial suppression in 1 of 3 patients; 250 mg produced complete suppression in 1 of 4 and partial suppression in 4 of 4 patients; and 400 mg produced complete suppression in 1 of 4 and partial suppression in 2 of 4 patients. PPR was consistently reduced on days 1 and 2 (>24 hours after cenobamate) vs day -1 (placebo) with the 250- and 400-mg doses. Area under the plasma concentration-time curve (before dose to last measurable concentration) values between 201 and 400 µg/h/mL resulted in partial suppression in 4 of 6 (66%) patients. Most common adverse events were dizziness and somnolence. CONCLUSIONS: This proof-of-principle study demonstrated that cenobamate is a potentially effective product for epilepsy. CLINICALTRIALSGOV IDENTIFIER: NCT00616148. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that, for patients with photosensitive epilepsy, cenobamate suppresses IPS-induced PPR.


Assuntos
Anticonvulsivantes/uso terapêutico , Carbamatos/uso terapêutico , Clorofenóis/uso terapêutico , Epilepsia Reflexa/tratamento farmacológico , Tetrazóis/uso terapêutico , Adolescente , Adulto , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/farmacocinética , Área Sob a Curva , Carbamatos/efeitos adversos , Carbamatos/farmacocinética , Clorofenóis/efeitos adversos , Clorofenóis/farmacocinética , Relação Dose-Resposta a Droga , Eletroencefalografia , Feminino , Humanos , Masculino , Estimulação Luminosa , Método Simples-Cego , Tetrazóis/efeitos adversos , Tetrazóis/farmacocinética , Adulto Jovem
3.
Cancers (Basel) ; 10(8)2018 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-30127241

RESUMO

Ataxia telangiectasia mutated and Rad3 related kinase (ATR) signals replication stress and DNA damage to S and G2 arrest and promotes DNA repair. Mutations in p53, critical for G1 checkpoint control, are common in cancer and predicted to confer vulnerability to ATR inhibitors. Reported data on the impact of p53 status are variable possibly because of the use of unmatched cells and surrogate endpoints of survival. The cytotoxicity of VE-821 alone and its ability to potentiate radiation and gemcitabine cytotoxicity was determined in isogenic and unmatched p53 wild-type (wt) and null/mutant cells, as well as immortalised nonmalignant MCF10 (immortalised non-neoplastic) cells, by colony-forming assay. The effect on cell cycle checkpoints was determined by flow cytometry. The isogenic p53 defective cells were not more sensitive to VE-821 alone. Defective p53 consistently conferred greater chemo- and radiosensitisation, particularly at high dose levels in isogenic cells but not unmatched cells. VE-821 did not sensitise MCF10 cells. We conclude that p53 status is just one factor contributing to chemo- and radiosensitisation by ATR inhibition, the lack of chemo- or radiosensitisation in the noncancerous cells suggests an element of tumour-specificity that warrants further investigation. The greater sensitisation at high-dose irradiation suggests that ATR inhibitors may be most effective with hypofractionated radiotherapy.

4.
Epilepsia ; 58(11): 1861-1869, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28980702

RESUMO

OBJECTIVE: A prospective multicenter phase III trial was undertaken to evaluate the performance and tolerability in the epilepsy monitoring unit (EMU) of an investigational wearable surface electromyographic (sEMG) monitoring system for the detection of generalized tonic-clonic seizures (GTCSs). METHODS: One hundred ninety-nine patients with a history of GTCSs who were admitted to the EMU in 11 level IV epilepsy centers for clinically indicated video-electroencephalographic monitoring also received sEMG monitoring with a wearable device that was worn on the arm over the biceps muscle. All recorded sEMG data were processed at a central site using a previously developed detection algorithm. Detected GTCSs were compared to events verified by a majority of three expert reviewers. RESULTS: For all subjects, the detection algorithm detected 35 of 46 (76%, 95% confidence interval [CI] = 0.61-0.87) of the GTCSs, with a positive predictive value (PPV) of 0.03 and a mean false alarm rate (FAR) of 2.52 per 24 h. For data recorded while the device was placed over the midline of the biceps muscle, the system detected 29 of 29 GTCSs (100%, 95% CI = 0.88-1.00), with a detection delay averaging 7.70 s, a PPV of 6.2%, and a mean FAR of 1.44 per 24 h. Mild to moderate adverse events were reported in 28% (55 of 199) of subjects and led to study withdrawal in 9% (17 of 199). These adverse events consisted mostly of skin irritation caused by the electrode patch that resolved without treatment. No serious adverse events were reported. SIGNIFICANCE: Detection of GTCSs using an sEMG monitoring device on the biceps is feasible. Proper positioning of this device is important for accuracy, and for some patients, minimizing the number of false positives may be challenging.


Assuntos
Eletromiografia/métodos , Epilepsia Tônico-Clônica/diagnóstico , Epilepsia Tônico-Clônica/fisiopatologia , Monitorização Ambulatorial/métodos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
5.
JAMA Neurol ; 74(8): 919-926, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28654954

RESUMO

Importance: Switching between generic antiepileptic drugs is a highly debated issue that affects both clinical care and overall health care costs. Objective: To evaluate the single-dose pharmacokinetic bioequivalence of 3 (1 branded and 2 generic drugs) on-market, immediate-release lamotrigine drug products. Design, Setting, and Participants: The Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy (EQUIGEN) single-dose study is a crossover, prospective, sequence-randomized, replicate pharmacokinetic study conducted at 5 US academic epilepsy centers. Fifty adults (≥18 years) with epilepsy who were taking concomitant antiepileptic drugs and not currently receiving lamotrigine were enrolled between July 18, 2013, and January 19, 2015. Every participant was randomly assigned to 1 of 3 equivalent sequences, each comprising 6 study periods, during which they had blood draws before and after medication administration. Forty-nine participants were included in intention-to-treat analyses. Interventions: Participants received a single 25-mg dose of immediate-release lamotrigine at the start of each period, with the branded and the 2 most disparate generic products each studied twice. Lamotrigine was selected as the antiepileptic drug of interest because of its wide use, publications indicating problems with generic switches, and complaints to the US Food and Drug Administration regarding generic products. Both participants and study personnel were blinded to the specific generic products selected. Main Outcomes and Measures: The primary outcome was bioequivalence between products. Maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) were compared, and average bioequivalence (ABE) was established if the 90% CIs of the ratios of the 2 products were within equivalence limits (80%-125%). Results: Of the 50 randomized participants, 49 (98%) received all 3 lamotrigine products and completed at least 3 pharmacokinetic assessments and 46 (92%) completed all 6 pharmacokinetic assessments. Among the 49 participants, 28 (57%) were men and 21 (43%) were women, 42 (86%) self-identified as white, and 46 (16) years was the mean (SD) age. The 3 drug products were considered bioequivalent because the 90% CIs were within equivalence limits (lowest and highest CI limits for Cmax, 92.6% and 110.4%; for AUC0-96, 96.9% and 101.9%). Replicate testing demonstrated no significant differences in within-subject variability across the 3 products (likelihood ratios, χ22 for log-transformed variables: AUC0-96, 2.58; Cmax, 0.64; and AUC0-∞, 4.05; P ≥ .13) and that the 3 products were also bioequivalent according to scaled ABE and individual bioequivalence criteria with no subject × formulation interaction (Cmax, 0.00; AUC0-96, 0.54; and AUC0-∞, 0.36; P ≥ .76). Conclusions and Relevance: This study provides evidence that the disparate lamotrigine products studied are bioequivalent when tested in people with epilepsy taking concomitant antiepileptic drugs. Trial Registration: clinicaltrials.gov Identifier: NCT01733394.


Assuntos
Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Triazinas/farmacocinética , Triazinas/uso terapêutico , Adulto , Anticonvulsivantes/sangue , Anticonvulsivantes/economia , Área Sob a Curva , Medicamentos Genéricos/farmacocinética , Medicamentos Genéricos/uso terapêutico , Epilepsia/sangue , Epilepsia/economia , Feminino , Humanos , Lamotrigina , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Equivalência Terapêutica , Fatores de Tempo , Triazinas/sangue , Triazinas/economia , Estados Unidos
6.
Nat Commun ; 7: 13837, 2016 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-27958275

RESUMO

Identifying genetic biomarkers of synthetic lethal drug sensitivity effects provides one approach to the development of targeted cancer therapies. Mutations in ARID1A represent one of the most common molecular alterations in human cancer, but therapeutic approaches that target these defects are not yet clinically available. We demonstrate that defects in ARID1A sensitize tumour cells to clinical inhibitors of the DNA damage checkpoint kinase, ATR, both in vitro and in vivo. Mechanistically, ARID1A deficiency results in topoisomerase 2A and cell cycle defects, which cause an increased reliance on ATR checkpoint activity. In ARID1A mutant tumour cells, inhibition of ATR triggers premature mitotic entry, genomic instability and apoptosis. The data presented here provide the pre-clinical and mechanistic rationale for assessing ARID1A defects as a biomarker of single-agent ATR inhibitor response and represents a novel synthetic lethal approach to targeting tumour cells.


Assuntos
Pontos de Checagem do Ciclo Celular/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Antineoplásicos/farmacologia , Apoptose , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Interferência de RNA
8.
Nat Rev Clin Oncol ; 13(10): 627-42, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27245279

RESUMO

In countries with the best cancer outcomes, approximately 60% of patients receive radiotherapy as part of their treatment, which is one of the most cost-effective cancer treatments. Notably, around 40% of cancer cures include the use of radiotherapy, either as a single modality or combined with other treatments. Radiotherapy can provide enormous benefit to patients with cancer. In the past decade, significant technical advances, such as image-guided radiotherapy, intensity-modulated radiotherapy, stereotactic radiotherapy, and proton therapy enable higher doses of radiotherapy to be delivered to the tumour with significantly lower doses to normal surrounding tissues. However, apart from the combination of traditional cytotoxic chemotherapy with radiotherapy, little progress has been made in identifying and defining optimal targeted therapy and radiotherapy combinations to improve the efficacy of cancer treatment. The National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group (CTRad) formed a Joint Working Group with representatives from academia, industry, patient groups and regulatory bodies to address this lack of progress and to publish recommendations for future clinical research. Herein, we highlight the Working Group's consensus recommendations to increase the number of novel drugs being successfully registered in combination with radiotherapy to improve clinical outcomes for patients with cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/radioterapia , Hipóxia Celular/efeitos da radiação , Ensaios Clínicos como Assunto/métodos , Terapia Combinada , Aprovação de Drogas , Humanos , Neoplasias/tratamento farmacológico , Educação de Pacientes como Assunto , Participação do Paciente , Garantia da Qualidade dos Cuidados de Saúde , Qualidade da Assistência à Saúde , Doses de Radiação , Tolerância a Radiação/efeitos da radiação , Resultado do Tratamento
9.
Lancet Neurol ; 15(4): 365-72, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26875743

RESUMO

BACKGROUND: Patients and clinicians share concerns that generic drug substitution might lead to loss of efficacy or emergence of adverse events. In this trial, we assessed US Food and Drug Administration (FDA) bioequivalence standards by studying the effects of switching between two disparate generic immediate-release lamotrigine products in patients with epilepsy. METHODS: The Equivalence among Generic Antiepileptic Drugs (EQUIGEN) chronic-dose study was a randomised, double-blind, crossover study that enrolled adults (aged ≥18 years) with epilepsy from six epilepsy centres at academic institutions across the USA who were receiving immediate-release lamotrigine dosed at 100 mg, 200 mg, 300 mg, or 400 mg twice daily. Eligible patients were randomly allocated (1:1) to one of two treatment sequences (sequence 1 or sequence 2), comprising four study periods of 14 days each. During each 14-day treatment period, patients received balanced doses of an oral generic lamotrigine product every 12 h (200-800 mg total, identical to lamotrigine dose prior to study enrolment); after each 14-day period, patients were crossed over to receive the other generic product. Computer-based randomisation was done using random permuted blocks of size two or four for each site to prevent sequence predictability. Both patients and study personnel were masked to the generic products selected, their predicted exposure (ie, "high" vs "low"), and their group allocation. The primary outcome of this trial was bioequivalence between the generic products, which was assessed at the end of the study through a comparison of maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) for each product in the analysis population (all patients who completed all four treatment periods). Bioequivalence was established if the 90% CIs of the ratios of these two parameters for the two products were within equivalence limits (80-125%) in the analysis population. This study is registered with ClinicalTrials.gov\, number NCT01713777. FINDINGS: Between April 25, 2013, and Aug 12, 2014, 35 eligible patients were enrolled and randomly assigned to treatment sequence 1 (n=15) or treatment sequence 2 (n=20). 33 patients completed all four treatment periods and were included in the primary outcome analysis. The 90% CIs of the ratios of both Cmax and AUC were within equivalence limits (AUC 90% CI 98-103, Cmax 90% CI 99-105), showing that lamotrigine exposures were equivalent between the generic products. No significant changes in seizure frequency or adverse events were recorded. No deaths, study-related serious adverse events, or changes in clinical laboratory values or vital signs occurred during this study. INTERPRETATION: Disparate generic lamotrigine products in patients with epilepsy showed bioequivalence with no detectable difference in clinical effects, confirming that US Food and Drug Administration bioequivalence standards are appropriate. FUNDING: American Epilepsy Society, Epilepsy Foundation, and US Food and Drug Administration.


Assuntos
Anticonvulsivantes/farmacologia , Substituição de Medicamentos/normas , Medicamentos Genéricos/farmacologia , Epilepsia/tratamento farmacológico , Equivalência Terapêutica , Triazinas/farmacologia , United States Food and Drug Administration/normas , Adulto , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/farmacocinética , Estudos Cross-Over , Método Duplo-Cego , Substituição de Medicamentos/efeitos adversos , Medicamentos Genéricos/administração & dosagem , Medicamentos Genéricos/efeitos adversos , Medicamentos Genéricos/farmacocinética , Feminino , Humanos , Lamotrigina , Masculino , Pessoa de Meia-Idade , Triazinas/administração & dosagem , Triazinas/efeitos adversos , Triazinas/farmacocinética , Estados Unidos
11.
Cell Rep ; 14(2): 298-309, 2016 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-26748709

RESUMO

ATR and CHK1 maintain cancer cell survival under replication stress and inhibitors of both kinases are currently undergoing clinical trials. As ATR activity is increased after CHK1 inhibition, we hypothesized that this may indicate an increased reliance on ATR for survival. Indeed, we observe that replication stress induced by the CHK1 inhibitor AZD7762 results in replication catastrophe and apoptosis, when combined with the ATR inhibitor VE-821 specifically in cancer cells. Combined treatment with ATR and CHK1 inhibitors leads to replication fork arrest, ssDNA accumulation, replication collapse, and synergistic cell death in cancer cells in vitro and in vivo. Inhibition of CDK reversed replication stress and synthetic lethality, demonstrating that regulation of origin firing by ATR and CHK1 explains the synthetic lethality. In conclusion, this study exemplifies cancer-specific synthetic lethality between two proteins in the same pathway and raises the prospect of combining ATR and CHK1 inhibitors as promising cancer therapy.


Assuntos
Proteínas Quinases/genética , Apoptose , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem , Dano ao DNA , Humanos , Proteínas Quinases/metabolismo
12.
Oncotarget ; 6(32): 32396-409, 2015 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-26486089

RESUMO

ATR is an attractive target in cancer therapy because it signals replication stress and DNA lesions for repair and to S/G2 checkpoints. Cancer-specific defects in the DNA damage response (DDR) may render cancer cells vulnerable to ATR inhibition alone. We determined the cytotoxicity of the ATR inhibitor VE-821 in isogenically matched cells with DDR imbalance. Cell cycle arrest, DNA damage accumulation and repair were determined following VE-821 exposure.Defects in homologous recombination repair (HRR: ATM, BRCA2 and XRCC3) and base excision repair (BER: XRCC1) conferred sensitivity to VE-821. Surprisingly, the loss of different components of the trimeric non-homologous end-joining (NHEJ) protein DNA-PK had opposing effects. Loss of the DNA-binding component, Ku80, caused hypersensitivity to VE-821, but loss of its partner catalytic subunit, DNA-PKcs, did not. Unexpectedly, VE-821 was particularly cytotoxic to human and hamster cells expressing high levels of DNA-PKcs. High DNA-PKcs was associated with replicative stress and activation of the DDR. VE-821 suppressed HRR, determined by RAD51 focus formation, to a greater extent in cells with high DNA-PKcs.Defects in HRR and BER and high DNA-PKcs expression, that are common in cancer, confer sensitivity to ATR inhibitor monotherapy and may be developed as predictive biomarkers for personalised medicine.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Dano ao DNA , Reparo do DNA , Glioblastoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Sulfonas/farmacologia , Animais , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Células CHO , Linhagem Celular Tumoral , Biologia Computacional , Cricetinae , Cricetulus , Reparo do DNA/genética , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Proteína Quinase Ativada por DNA/genética , Proteína Quinase Ativada por DNA/metabolismo , Bases de Dados Genéticas , Relação Dose-Resposta a Droga , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Perfilação da Expressão Gênica/métodos , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glioblastoma/enzimologia , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Terapia de Alvo Molecular , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Transfecção
13.
Sci Transl Med ; 7(309): 309ra161, 2015 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-26468323

RESUMO

When neuroimaging reveals a brain lesion, drug-resistant epilepsy patients show better outcomes after resective surgery than do the one-third of drug-resistant epilepsy patients who have normal brain magnetic resonance imaging (MRI). We applied a glutamate imaging method, GluCEST (glutamate chemical exchange saturation transfer), to patients with nonlesional temporal lobe epilepsy based on conventional MRI. GluCEST correctly lateralized the temporal lobe seizure focus on visual and quantitative analyses in all patients. MR spectra, available for a subset of patients and controls, corroborated the GluCEST findings. Hippocampal volumes were not significantly different between hemispheres. GluCEST allowed high-resolution functional imaging of brain glutamate and has potential to identify the epileptic focus in patients previously deemed nonlesional. This method may lead to improved clinical outcomes for temporal lobe epilepsy as well as other localization-related epilepsies.


Assuntos
Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/cirurgia , Neuroimagem/métodos , Adulto , Epilepsias Parciais/diagnóstico , Epilepsias Parciais/cirurgia , Epilepsia do Lobo Temporal/diagnóstico , Epilepsia do Lobo Temporal/cirurgia , Feminino , Ácido Glutâmico , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade
14.
Artigo em Inglês | MEDLINE | ID: mdl-26418017

RESUMO

BACKGROUND/AIMS: Transorbital approaches traditionally have focused on skull base and cavernous sinus lesions medial to the globe. Lateral orbital approaches to the temporal lobe have not been widely explored despite several theoretical advantages compared to open craniotomy. Recently, we demonstrated the feasibility of the lateral transorbital technique in cadaveric specimens with endoscopic visualization. We describe our initial clinical experience with the endoscope-assisted lateral transorbital approach to lesions in the temporal lobe. METHODS: Two patients with mesial temporal lobe pathology presenting with seizures underwent surgery. The use of a transpalpebral or Stallard-Wright eyebrow incision enabled access to the intraorbital compartment, and a lateral orbital wall 'keyhole' opening permitted visualization of the anterior temporal pole. RESULTS: This approach afforded adequate access to the surgical target and surrounding structures and was well tolerated by the patients. To the best of our knowledge, this report constitutes the first case series describing the endoscope-assisted lateral transorbital approach to the temporal lobe. We discuss the limits of exposure, the nuances of opening and closing, and comparisons to open craniotomy. CONCLUSION: Further prospective investigation of this approach is warranted for comparison to traditional approaches to the mesial temporal lobe.


Assuntos
Tonsila do Cerebelo/cirurgia , Neoplasias Encefálicas/cirurgia , Endoscopia/métodos , Córtex Entorrinal/cirurgia , Hipocampo/cirurgia , Procedimentos Neurocirúrgicos/métodos , Convulsões/cirurgia , Adulto , Tonsila do Cerebelo/patologia , Biópsia , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/diagnóstico , Craniotomia/métodos , Córtex Entorrinal/patologia , Feminino , Hipocampo/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Órbita , Convulsões/diagnóstico , Convulsões/etiologia
15.
Neurology ; 84(10): 1017-25, 2015 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-25663221

RESUMO

OBJECTIVE: To report long-term efficacy and safety results of the SANTE trial investigating deep brain stimulation of the anterior nucleus of the thalamus (ANT) for treatment of localization-related epilepsy. METHODS: This long-term follow-up is a continuation of a previously reported trial of 5- vs 0-V ANT stimulation. Long-term follow-up began 13 months after device implantation with stimulation parameters adjusted at the investigators' discretion. Seizure frequency was determined using daily seizure diaries. RESULTS: The median percent seizure reduction from baseline at 1 year was 41%, and 69% at 5 years. The responder rate (≥50% reduction in seizure frequency) at 1 year was 43%, and 68% at 5 years. In the 5 years of follow-up, 16% of subjects were seizure-free for at least 6 months. There were no reported unanticipated adverse device effects or symptomatic intracranial hemorrhages. The Liverpool Seizure Severity Scale and 31-item Quality of Life in Epilepsy measure showed statistically significant improvement over baseline by 1 year and at 5 years (p < 0.001). CONCLUSION: Long-term follow-up of ANT deep brain stimulation showed sustained efficacy and safety in a treatment-resistant population. CLASSIFICATION OF EVIDENCE: This long-term follow-up provides Class IV evidence that for patients with drug-resistant partial epilepsy, anterior thalamic stimulation is associated with a 69% reduction in seizure frequency and a 34% serious device-related adverse event rate at 5 years.


Assuntos
Núcleos Anteriores do Tálamo/fisiopatologia , Estimulação Encefálica Profunda/efeitos adversos , Epilepsias Parciais/terapia , Adolescente , Adulto , Idoso , Núcleos Anteriores do Tálamo/cirurgia , Estimulação Encefálica Profunda/métodos , Epilepsias Parciais/fisiopatologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
16.
Mol Oncol ; 9(2): 463-72, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25459351

RESUMO

BACKGROUND: ATR, which signals DNA damage to S/G2 cell cycle checkpoints and for repair, is an attractive target in cancer therapy. ATR inhibitors are being developed and a pharmacodynamic assay is needed to support clinical studies. METHODS: Phosphorylation of ATR targets, Chk1 and H2AX, was evaluated in MCF7 and K562 cells, human volunteer PBMCs and whole blood by Western blot, immunofluorescence microscopy and flow cytometry after DNA damage. The effect of cell cycle phase, ATR knockdown and inhibition on these phosphorylation events was determined. RESULTS: Hydroxyurea, UV and 4NQO induced Chk1 and H2AX phosphorylation in MCF7 and K562 cells. UV/4NQO activation of ATR was detectable in non-cycling cells. Chk1 phosphorylation was reduced by ATR knockdown and reflects ATR activity for 3 h, H2AX phosphorylation after UV/4NQO is ATR-dependent for 1 h but increasingly ATM and DNA-PK-dependent at later time points. In isolated PBMCs both phospho-targets were detectable after UV/4NQO but in PBMCs from whole blood treated with 4NQO only H2AX was detectable. CONCLUSION: PhosphoChk1 and H2AX are useful biomarkers for ATR inhibition using a variety of immuno-detection methods, but timing may be critical. Importantly, ATR activity is detectable in non-cycling PBMCs allowing them to be used as a surrogate tissue for biomarker measurement. In PBMCs from whole blood treated with 4NQO phosphoH2AX was the most useful biomarker of ATR activity and a clinically viable pharmacodynamic assay for ATR inhibitors has been developed.


Assuntos
Antineoplásicos , Biomarcadores Tumorais/metabolismo , Histonas/metabolismo , Proteínas de Neoplasias/metabolismo , Inibidores de Proteínas Quinases , Proteínas Quinases/metabolismo , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Biomarcadores Tumorais/antagonistas & inibidores , Quinase 1 do Ponto de Checagem , Feminino , Humanos , Células K562 , Masculino , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia
17.
Cancer Res ; 74(23): 6968-79, 2014 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-25269479

RESUMO

Camptothecin and its derivatives, topotecan and irinotecan, are specific topoisomerase I (Top1) inhibitors and potent anticancer drugs killing cancer cells by producing replication-associated DNA double-strand breaks, and the indenoisoquinoline LMP-400 (indotecan) is a novel Top1 inhibitor in clinical trial. To develop novel drug combinations, we conducted a synthetic lethal siRNA screen using a library that targets nearly 7,000 human genes. Depletion of ATR, the main transducer of replication stress, came as a top candidate gene for camptothecin synthetic lethality. Validation studies using ATR siRNA and the ATR inhibitor VE-821 confirmed marked antiproliferative synergy with camptothecin and even greater synergy with LMP-400. Single-cell analyses and DNA fiber combing assays showed that VE-821 abrogates the S-phase replication elongation checkpoint and the replication origin-firing checkpoint induced by camptothecin and LMP-400. As expected, the combination of Top1 inhibitors with VE-821 inhibited the phosphorylation of ATR and Chk1; however, it strongly induced γH2AX. In cells treated with the combination, the γH2AX pattern changed over time from the well-defined Top1-induced damage foci to an intense peripheral and diffuse nuclear staining, which could be used as response biomarker. Finally, the clinical derivative of VE-821, VX-970, enhanced the in vivo tumor response to irinotecan without additional toxicity. A key implication of our work is the mechanistic rationale and proof of principle it provides to evaluate the combination of Top1 inhibitors with ATR inhibitors in clinical trials.


Assuntos
Replicação do DNA/efeitos dos fármacos , DNA Topoisomerases Tipo I/metabolismo , Compostos Organotiofosforados/farmacologia , Pirazinas/farmacologia , Origem de Replicação/efeitos dos fármacos , Sulfonas/farmacologia , Inibidores da Topoisomerase I/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem , Dano ao DNA , Células HT29 , Histonas/genética , Histonas/metabolismo , Humanos , Irinotecano , Fosforilação/efeitos dos fármacos , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Análise de Célula Única/métodos , Topotecan/farmacologia
18.
Oncotarget ; 5(14): 5674-85, 2014 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-25010037

RESUMO

Platinum-based DNA-damaging chemotherapy is standard-of-care for most patients with lung cancer but outcomes remain poor. This has been attributed, in part, to the highly effective repair network known as the DNA-damage response (DDR). ATR kinase is a critical regulator of this pathway, and its inhibition has been shown to sensitize some cancer, but not normal, cells in vitro to DNA damaging agents. However, there are limited in vivo proof-of-concept data for ATR inhibition. To address this we profiled VX-970, the first clinical ATR inhibitor, in a series of in vitro and in vivo lung cancer models and compared it with an inhibitor of the downstream kinase Chk1. VX-970 markedly sensitized a large proportion of a lung cancer cell line and primary tumor panel in vitro to multiple DNA damaging drugs with clear differences to Chk1 inhibition observed. In vivo VX-970 blocked ATR activity in tumors and dramatically enhanced the efficacy of cisplatin across a panel of patient derived primary lung xenografts. The combination led to complete tumor growth inhibition in three cisplatin-insensitive models and durable tumor regression in a cisplatin-sensitive model. These data provide a strong rationale for the clinical evaluation of VX-970 in lung cancer patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cisplatino/farmacologia , Dano ao DNA , Isoxazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Animais , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , DNA/efeitos dos fármacos , DNA/genética , Sinergismo Farmacológico , Feminino , Humanos , Camundongos , Camundongos SCID , Fosforilação , Inibidores de Proteínas Quinases/administração & dosagem , Distribuição Aleatória , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Acta Crystallogr D Biol Crystallogr ; 70(Pt 5): 1465-75, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24816114

RESUMO

Bloom's syndrome is an autosomal recessive genome-instability disorder associated with a predisposition to cancer, premature aging and developmental abnormalities. It is caused by mutations that inactivate the DNA helicase activity of the BLM protein or nullify protein expression. The BLM helicase has been implicated in the alternative lengthening of telomeres (ALT) pathway, which is essential for the limitless replication of some cancer cells. This pathway is used by 10-15% of cancers, where inhibitors of BLM are expected to facilitate telomere shortening, leading to apoptosis or senescence. Here, the crystal structure of the human BLM helicase in complex with ADP and a 3'-overhang DNA duplex is reported. In addition to the helicase core, the BLM construct used for crystallization (residues 640-1298) includes the RecQ C-terminal (RQC) and the helicase and ribonuclease D C-terminal (HRDC) domains. Analysis of the structure provides detailed information on the interactions of the protein with DNA and helps to explain the mechanism coupling ATP hydrolysis and DNA unwinding. In addition, mapping of the missense mutations onto the structure provides insights into the molecular basis of Bloom's syndrome.


Assuntos
Difosfato de Adenosina/metabolismo , RecQ Helicases/química , RecQ Helicases/metabolismo , Síndrome de Bloom/genética , Domínio Catalítico , Cristalografia por Raios X , Humanos , Hidrólise , Modelos Moleculares , Mutação , Ácidos Nucleicos Heteroduplexes , Conformação Proteica , RecQ Helicases/genética
20.
Clin Nucl Med ; 39(7): e365-6, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24152618

RESUMO

A 55-year-old woman with known relapsing-remitting multiple sclerosis (RRMS) on natalizumab (Tysabri®) for 3 years was admitted to the hospital with worsening word-finding difficulties and gait instability. Neurologic examination revealed right hemianopia, right arm hemiplegia, right-sided sensory loss, and global aphasia. The patient underwent MRI and PET imaging with concurrent electroencephalogram. She was subsequently diagnosed with natalizumab-induced progressive multifocal leukoencephalopathy (PML) and treated with plasmapheresis, intravenous immunoglobulin, and high-dose intravenous steroids. Steroids were continued over a 3-month hospital course and tapered upon discharge. Speech, arm strength, and ambulation have since improved.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Leucoencefalopatia Multifocal Progressiva/induzido quimicamente , Feminino , Humanos , Leucoencefalopatia Multifocal Progressiva/diagnóstico por imagem , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Natalizumab , Tomografia por Emissão de Pósitrons
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