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Berenson F.,Child Neurology Associates | Vasconcellos E.,Neuro Network Partners | Pakalnis A.,Nationwide Childrens Research Institute | Mao L.,Ortho McNeil Janssen Scientific Affairs | And 2 more authors.
Headache | Year: 2010

Objectives. - This study evaluated the long-term safety of oral almotriptan 12.5 mg for the treatment of multiple migraine episodes in adolescents over a 12-month period. Efficacy outcomes were assessed as a secondary objective. Methods. - Adolescent migraineurs aged 12-17 years were enrolled in this 12-month, open-label study (Study ID CR002827). Patients were instructed to record their assessments on paper headache records whenever they experienced a migraine headache that they treated with study medication. Safety was assessed descriptively and assessments included adverse event (AE) recording, change in laboratory values, vital signs, and electrocardiogram parameters. Efficacy outcomes were assessed descriptively and outcomes included rates for 2- and 24-hour pain relief and sustained pain relief, 2- and 24-hour pain-free and sustained pain-free, and presence of migraine-associated symptoms of photophobia, phonophobia, nausea and vomiting. Results. - Overall, 67.1% of patients reported ≥1 AE over the course of the trial, 7.6% had an AE judged by the study investigator to be related to treatment with almotriptan, 2.4% discontinued because of an AE, and 1.9% reported serious AEs. The most commonly reported treatment-related AEs (occurring in ≥1% of patients) were nausea (1.4%) and somnolence (1.4%). Pain relief responses for treated migraines of moderate or severe intensity at baseline were 61.7% and 68.6%, at 2 and 24 hours, respectively; the sustained pain relief rate was 55.5%. Pain-free responses were reported for 40.5% of all treated migraines at 2 hours and 65.9% of treated migraines at 24 hours; the sustained pain-free rate was 38.4%. The proportion of migraines that achieved the pain relief, sustained pain relief, pain-free and sustained pain-free endpoints were similar in the 12- to 14-year and 15- to 17-year age groups. Treating with almotriptan 12.5 mg when headache pain was mild was associated with higher rates of pain relief and pain-free at 2 and 24 hours, and sustained pain relief and sustained pain-free, compared with treatment initiated when pain was severe. Conclusions. - Almotriptan 12.5 mg was well tolerated in this adolescent population over a 12-month period. No unexpected safety or tolerability concerns were revealed over the course of this study. The results are consistent with almotriptan 12.5 mg being effective for the acute treatment of pain and symptoms associated with migraine in both younger and older adolescents. © 2010 the Authors. Journal compilation.


Hettmer S.,University Hospital Berlin | Li Z.,Genomics Institute of the Novartis Research Foundation | Billin A.N.,Glaxosmithkline | Barr F.G.,U.S. National Cancer Institute | And 19 more authors.
Cold Spring Harbor Perspectives in Biology | Year: 2014

Rhabdomyosarcoma (RMS) represents a rare, heterogeneous group of mesodermal malignancies with skeletal muscle differentiation. One major subgroup of RMS tumors (so-called “fusion-positive” tumors) carries exclusive chromosomal translocations that join the DNAbinding domain of the PAX3 or PAX7 gene to the transactivation domain of the FOXO1 (previously known as FKHR) gene. Fusion-negative RMS represents a heterogeneous spectrum of tumors with frequent RAS pathway activation. Overtly metastatic disease at diagnosis is more frequently found in individuals with fusion-positive than in those with fusion-negative tumors. RMS is the most common pediatric soft-tissue sarcoma, and approximately 60% of all children and adolescents diagnosed with RMS are cured by currently available multimodal therapies. However, a curative outcome is achieved in ,30% of high-risk individuals with RMS, including all those diagnosed as adults, those diagnosed with fusionpositive tumors during childhood (including metastatic and nonmetastatic tumors), and those diagnosed with metastatic disease during childhood (including fusion-positive and fusion-negative tumors). This white paper outlines current challenges in RMS research and their implications for developing more effective therapies. Urgent clinical problems include local control, systemic disease, need for improved risk stratification, and characterization of differences in disease course in children and adults. Biological challenges include definition of the cellular functions of PAX-FOXO1 fusion proteins, clarification of disease heterogeneity, elucidation of the cellular origins of RMS, delineation of the tumor microenvironment, and identification of means for rational selection and testing of new combination therapies. To streamline future therapeutic developments, it will be critical to improve access to fresh tumor tissue for research purposes, consider alternative trial designs to optimize early clinical testing of candidate drugs, coalesce advocacy efforts to garner public and industry support, and facilitate collaborative efforts between academia and industry. © 2014 Cold Spring Harbor Laboratory Press. All rights reserved.


Fischer A.J.,Ohio State University | Bosse J.L.,Ohio State University | El-Hodiri H.M.,Ohio State University | El-Hodiri H.M.,Nationwide Childrens Research Institute
Experimental Eye Research | Year: 2013

The ciliary marginal zone (CMZ) is a circumferential ring of cells found at the extreme periphery of the maturing and mature neural retina that consists of retinal stem and progenitor cells. It functions to add retinal neurons to the periphery of the neural retina in larval and adult fish, larval frogs, and birds. Additionally, the CMZ may contribute to regeneration of the damaged retina in frogs and fish. In mammals, cells from the ciliary epithelium can be induced to express retinal stem cell-like characteristics in culture but may not comprise a classically defined CMZ. © 2013.


Hong S.-H.,Georgetown University | Youbi S.E.,Georgetown University | Peter Hong S.,Battelle | Kallakury B.,Georgetown University | And 6 more authors.
Oncotarget | Year: 2014

Transcription factors have long been deemed 'undruggable' targets for therapeutics. Enhanced recognition of protein biochemistry as well as the need to have more targeted approaches to treat cancer has rendered transcription factors approachable for therapeutic development. Since transcription factors lack enzymatic domains, the specific targeting of these proteins has unique challenges. One challenge is the hydrophobic microenvironment that affects small molecules gaining access to block protein interactions. The most attractive transcription factors to target are those formed from tumor specific chromosomal translocations that are validated oncogenic driver proteins. EWS-FLI1 is a fusion protein that results from the pathognomonic translocation of Ewing sarcoma (ES). Our past work created the small molecule YK-4-279 that blocks EWS-FLI1 from interacting with RNA Helicase A (RHA). To fulfill long-standing promise in the field by creating a clinically useful drug, steps are required to allow for in vivo administration. These investigations identify the need for continuous presence of the small molecule protein-protein inhibitor for a period of days. We describe the pharmacokinetics of YK-4-279 and its individual enantiomers. In vivo studies confirm prior in vitro experiments showing (S)-YK-4-279 as the EWSFLI1 specific enantiomer demonstrating both induction of apoptosis and reduction of EWS-FLI1 regulated caveolin-1 protein. We have created the first rat xenograft model of ES, treated with (S)-YK-4-279 dosing based upon PK modeling leading to a sustained complete response in 2 of 6 ES tumors. Combining laboratory studies, pharmacokinetic measurements, and modeling has allowed us to create a paradigm that can be optimized for in vivo systems using both in vitro data and pharmacokinetic simulations. Thus, (S)-YK-4-279 as a small molecule drug is ready for continued development towards a first-in-human, first-in-class, clinical trial.


Fischer A.J.,Ohio State University | Bosse J.L.,Ohio State University | El-Hodiri H.M.,Ohio State University | El-Hodiri H.M.,Nationwide Childrens Research Institute
Experimental Eye Research | Year: 2014

The ciliary marginal zone (CMZ) is a circumferential ring of cells found at the extreme periphery of the maturing and mature neural retina that consists of retinal stem and progenitor cells. It functions to add retinal neurons to the periphery of the neural retina in larval and adult fish, larval frogs, and birds. Additionally, the CMZ may contribute to regeneration of the damaged retina in frogs and fish. In mammals, cells from the ciliary epithelium can be induced to express retinal stem cell-like characteristics in culture but may not comprise a classically defined CMZ. © 2014.

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