21 results on '"Stefan Spinty"'
Search Results
2. A Phase 1b Trial to Assess the Pharmacokinetics of Ezutromid in Pediatric Duchenne Muscular Dystrophy Patients on a Balanced Diet
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Francesco Muntoni, Stefan Spinty, Gary Layton, Imelda Hughes, Kay E. Davies, Bina Tejura, Jonathon M. Tinsley, Helen Roper, and Shawn Harriman
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Male ,Drug ,medicine.medical_specialty ,Adolescent ,Utrophin ,media_common.quotation_subject ,Duchenne muscular dystrophy ,Administration, Oral ,Pharmaceutical Science ,Placebo ,Drug Administration Schedule ,Food group ,Double-Blind Method ,Suspensions ,Pharmacokinetics ,Internal medicine ,Humans ,Medicine ,Pharmacology (medical) ,Child ,Adverse effect ,media_common ,Benzoxazoles ,business.industry ,medicine.disease ,Diet ,Muscular Dystrophy, Duchenne ,Clinical trial ,business - Abstract
Ezutromid (SMT C1100) is a small-molecule utrophin modulator that was developed to treat Duchenne muscular dystrophy (DMD). Previous clinical trials of this agent revealed lower exposure in DMD patients compared with healthy volunteers, which may reflect differences in diet. This study evaluated the pharmacokinetics of ezutromid in patients with DMD who followed a balanced diet. This was a multicenter, double-blind, placebo-controlled, ascending single and multiple oral dose study. Twelve pediatric patients were randomly allocated to 1 of 3 treatment sequences within which were 3 treatment periods of 2 weeks each. Each patient received, in a dose-escalating fashion, 1250 mg and 2500 mg twice daily (BID) of ezutromid administered orally as a microfluidized suspension (F3) with placebo in the other treatment period. Throughout the study, patients followed a balanced diet including recommended proportions of major food groups and administration of drug accompanied with 100 mL of full-fat milk. This approach improved the absorption of ezutromid, resulting in higher systemic exposure, with considerable variability in exposure between patients at each dose level. Single and multiple oral doses of 1250 mg and 2500 mg BID were considered safe and well tolerated. No severe or serious adverse events and no study discontinuations due to adverse events were reported. This study provides assurance that, with the formulation tested (F3) and instructions regarding food (balanced diet and whole-fat milk), 2500 mg BID of ezutromid achieves plasma concentrations that, based on preclinical studies, should be able to modulate utrophin expression in future clinical trials.
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- 2019
3. Utility and safety of plasma exchange in paediatric neuroimmune disorders
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Michael Absoud, Jonathan Gadian, Ming K. Lim, Stefan Spinty, Rachel Kneen, Rajat Gupta, Michael Eyre, Shakti Agrawal, Kate Lamb, Cheryl Hemingway, Katie Rose, Martin Smith, Evangeline Wassmer, Sunny Philip, Yael Hacohen, and David V. Milford
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Male ,030506 rehabilitation ,Pediatrics ,medicine.medical_specialty ,Adolescent ,MEDLINE ,Diagnostic Techniques, Neurological ,Patient characteristics ,Severity of Illness Index ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Developmental Neuroscience ,Modified Rankin Scale ,Intensive care ,Severity of illness ,medicine ,Humans ,Immunologic Factors ,Child ,Prospective cohort study ,Plasma Exchange ,business.industry ,Medical record ,Immunoglobulins, Intravenous ,Infant ,Treatment Outcome ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Female ,Neurology (clinical) ,Nervous System Diseases ,0305 other medical science ,business ,030217 neurology & neurosurgery ,Cohort study - Abstract
Our aim was to ascertain the indications, side effects, and outcomes in children receiving therapeutic plasma exchange (TPE) for neurological disorders.Medical records were retrospectively reviewed for 58 consecutive children (age ≤16y) undergoing 67 courses of TPE across four tertiary centres. Patient characteristics, treatment schedules, complications, and outcomes were analysed.Median age at initiation of TPE was 9 years (range 1-15y). Indications included peripheral nervous system (PNS; n=18) and central nervous system (CNS; n=40) disorders. Courses comprised a median six exchanges (range 2-179) over 8 days (range 3-466). Forty-two out of 58 (73%) children were severely disabled (bedridden) at initiation and 24 out of 58 (41%) were admitted to intensive care units. Treating clinicians' impression of response was positive in 16 out of 18 of those with PNS disorders versus 22 out of 40 with CNS disorders (p=0.016). Improvements in disability (modified Rankin Scale) occurred in 13 out of 58 (22%) children by completion of TPE (p=0.003). Complications occurred in 40 out of 67 (60%) courses, of which 16 out of 67 (24%) were line related. Potentially life-threatening complications occurred in 2 out of 67 (3%) courses.This cohort study provides safety and efficacy information for clinicians and families and a basis for future prospective studies.Disability scores for severe neuroimmune disorders remained stable or improved during therapeutic plasma exchange treatment. Complications occurred frequently but were typically mild and correctable.UTILIDAD Y SEGURIDAD DEL INTERCAMBIO DE PLASMA EN TRASTORNOS NEUROINMUNES PEDIÁTRICOS: OBJETIVO: Nuestro objetivo fue determinar las indicaciones, los efectos secundarios y los resultados en niños que recibieron intercambio terapéutico de plasma (TPE) para trastornos neurológicos. MÉTODO: Se revisaron retrospectivamente los registros médicos de 58 niños consecutivos (≤16 años) que se sometieron a 67 cursos de TPE en cuatro centros terciarios. Se analizaron las características de los pacientes, los esquemas de tratamiento, las complicaciones y los resultados. RESULTADOS: La edad mediana al inicio de la TPE fue de 9 años (rango 1-15 años). Las indicaciones incluían trastornos del sistema nervioso periférico (SNP; n = 18) y del sistema nervioso central (SNC; n = 40). Los cursos comprendieron una mediana de 6 intercambios (rango 2-179) durante 8 días (rango 3-466). Cuarenta y dos de 58 (73%) niños presentaban un grado de discapacidad severa (postrados en cama) al inicio y 24 de 58 (41%) fueron ingresados en unidades de cuidados intensivos. El tratamiento de la impresión de respuesta de los médicos fue positivo en 16 de 18 de las personas con trastornos de SNP versus 22 de 40 en trastornos del SNC (p = 0,016). Las mejoras en la discapacidad (escala de Rankin modificada) se produjeron en 13 de los 58 (22%) niños al completar el TPE (p = 0,003). Las complicaciones ocurrieron en 40 de 67 cursos (60%), de los cuales 16 de 67 (24%) estaban relacionados con la línea. Complicaciones potencialmente peligrosas para la vida ocurrieron en 2 de 67 (3%) cursos. INTERPRETACIÓN: Este estudio de cohorte proporciona información de seguridad y eficacia para profesionales y familiares y una base para futuros estudios prospectivos.UTILIDADE E SEGURANÇA DA TRANSFERÊNCIA DE PLASMA EM TRANSTORNOS NEUROIMUNES PEDIÁTRICOS: OBJETIVO: Nosso objetivo foi verificar as indicações, efeitos colaterais, e resultados em crianças recebendo transferência terapêutica de plasma (TTP) para transtornos neurológicos. MÉTODO: Registros médicos foram retrospectivamente revisados para 58 crianças (idade ≤16a) passando por 67 cursos de TTP em quatro centros terciários. Características dos pacientes, rotina de tratamento, complicações e resultados foram analisados. RESULTADOS: A idade mediana ao início da TTP foi 9 anos (variação 1-15 anos). Indicações incluíram transtornos do sistema nervoso periférico (SNP; n = 18) e sistema nervoso central (SNC; n = 40) disorders. Os cursos compreenderam uma mediana de seis transferências (variação 2-179) em 8 dias (variação 3-466). Quarenta e duas em 58 (73%) crianças estavam severamente incapacidadas (acamadas) no início e 24 em 58 (41%) foram admitidas em unidades de cuidado intensivo. A impressão de resposta dos clínicos que as tratavam foi positiva em 16 de 18 daquelas com transtornos do SNP versus 22 de 40 daquelas com desordens do SNC (p = 0,016). Melhoras na incapacidade (Escala de Rankin modificada) ocorreram em 13 de 58 (22%) crianças ao final da TTP (p = 0,003). Complicações ocorreram em 40 de 67 (60%) cursos, dos quais 16 em 67 (24%) eram relacionados à linha. Complicações com potencial risco de vida ocorreram em 2 de 67 (3%) cursos. INTERPRETAÇÃO: Este estudo de coorte fornece informação sobre a segurança e eficácia para clínicos e famílias, e uma base para futuros estudos prospectivos.
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- 2019
4. Health related quality of life in young, steroid-naïve boys with Duchenne muscular dystrophy
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Giuseppe Vita, Helen Roper, Tiziana Mongini, Leslie Morrison, Nancy L. Kuntz, Russell J. Butterfield, Perry B. Shieh, Hugh J. McMillan, Erik K Henricson, Adnan Y. Manzur, Elaine McColl, Federica Ricci, Ulrike Schara-Schmidt, Anne-Marie Childs, Mathula Thangarajh, Gian Luca Vita, Peter B. Kang, Imelda Hughes, Jean K. Mah, Iain Horrocks, Michela Guglieri, Richard S. Finkel, William B. Martens, James F. Howard, Luca Bello, Taeun Chang, Elena Pegoraro, Kevin M. Flanigan, W. Bryan Burnette, Matthew Wicklund, Maja von der Hagen, Craig M. McDonald, Richard J. Barohn, Giovanni Baranello, Robert C. Griggs, Jeffrey Statland, Michael P. McDermott, Stefan Spinty, Ekkehard Wilichowski, Lorenzo Maggi, Emma Ciafaloni, Ashutosh Kumar, Janbernd Kirschner, Volker Straub, Monika Krzesniak-Swinarska, Craig Campbell, and Basil T. Darras
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Male ,Parents ,0301 basic medicine ,Duchenne muscular dystrophy ,Neuromuscular disease ,Psychometrics ,Intraclass correlation ,Patient demographics ,Medizin ,Disease ,03 medical and health sciences ,Health related quality of life ,Psychosocial ,0302 clinical medicine ,Disease severity ,Surveys and Questionnaires ,medicine ,Humans ,Child ,Genetics (clinical) ,business.industry ,medicine.disease ,humanities ,Muscular Dystrophy, Duchenne ,Cross-Sectional Studies ,030104 developmental biology ,Caregivers ,Neurology ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Quality of Life ,Self Report ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Clinical psychology - Abstract
Knowledge of health related quality of life (HRQOL) in the immediate phase following DMD diagnosis has not been well-characterized. It is important to understand HRQOL early in disease for both clinical care and studies of treatment. The relationship between parent-proxy and child self-report HRQOL and their associations with medical, psycho-social and behavioral symptoms deserve study. In this study HRQOL was measured using the PedsQL inventory in parent/caregiver and corticosteroid-naïve boys (ages 4 to 7 years) participating in the FOR-DMD study. Agreement between the parent-proxy report and the boys' self-report HRQOL was measured using intraclass correlation coefficients (ICCs). Factors associated with HRQOL, including standardized psychosocial and behavioral measures in this cross-sectional sample, were explored using correlations. The results showed that the level of agreement between 70 dyads of child self-report and parent-proxy ratings of HRQOL was poor for the generic PedsQL total score (ICC=0.48, 95% CI (0.23, 0.66)) and its subscale scores, and was similarly low for the neuromuscular disease module (ICC=0.24, 95% CI (0.00, 0.45)). Parents rated their child's HRQOL as poorer than the children rated themselves in all scales. Psychosocial outcome measures were more highly associated with HRQOL measures than disease severity or patient demographic variables. In the early phases of DMD, child and parent-proxy HRQOL ratings were discordant. In early DMD, psychosocial and behavioral aspects appear to be more relevant to HRQOL than disease severity factors.
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- 2021
5. Preventing Cardiomyopathy in DMD: A Randomized Placebo-Controlled Drug Trial
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Stefan Spinty, Thomas Chadwick, Michela Guglieri, Ruth Wood, Kate Bushby, Gillian Watson, Francesco Muntoni, Andrew Bryant, Elaine McColl, John P. Bourke, and Helen Roper
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medicine.medical_specialty ,Ejection fraction ,Combination therapy ,business.industry ,Duchenne muscular dystrophy ,Research ,Cardiomyopathy ,medicine.disease ,Placebo ,Bisoprolol ,Internal medicine ,Perindopril ,medicine ,Neurology (clinical) ,business ,Adverse effect ,medicine.drug - Abstract
ObjectiveTo determine whether a combination of 2 heart medications would be tolerated and could prevent/delay the onset of cardiomyopathy in boys with Duchenne muscular dystrophy (DMD) compared with placebo.MethodsThis multicenter, parallel group, 1:1 patient randomized, placebo-controlled study of prophylactic perindopril and bisoprolol recruited boys with DMD aged 5–13 years, with normal ventricular function. Repeat assessments of left ventricular (LV) function, electrocardiogram, and adverse event reporting were performed 6 monthly. The primary outcome was change in ejection fraction between arms after 36 months. The study was approved by the National Research Ethics Service Committee East Midlands—Derby.ResultsEighty-five boys were recruited (76% on steroid therapy) and randomized to combination heart drugs or matched placebo. Group change in left ventricular ejection fraction (LVEF%) at 36 months from baseline was −2.2% ± 6.0% and −2.9% ± 6.1% in active and placebo arms (adjusted mean difference: −2.1, 95% CI −5.2 to 1.1). There was no difference between treatment arms over repeated assessments (analysis of variance) up to 36 months (trial arms p = 0.53); arm-over-time (p = 0.44). Four participants on placebo but none on active therapy were withdrawn due to deteriorations in LV function. Secondary outcomes did not differ between arms either. Thirty-six serious adverse events occurred none due to cardiac events or trial medication.ConclusionsCombination therapy was well tolerated. Consistent with the previous prophylactic perindopril heart study, there was no evidence of group benefit after 36-month treatment.Classification of EvidenceThis study provides Class I evidence that combination perindopril-bisoprolol therapy was well tolerated but did not change decline in LVEF significantly in boys with DMD.
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- 2020
6. Rhabdomyolysis and myoglobinuria following bisphosphonate infusion in patients with Duchenne muscular dystrophy
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Poonam Dharmaraj, Stefan Spinty, Jennifer Lemon, and Lucy Turner
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medicine.medical_specialty ,medicine.medical_treatment ,Duchenne muscular dystrophy ,Zoledronic Acid ,Rhabdomyolysis ,Internal medicine ,medicine ,Humans ,In patient ,Muscular dystrophy ,Genetics (clinical) ,Diphosphonates ,business.industry ,Myoglobinuria ,Bisphosphonate ,medicine.disease ,Muscular Dystrophy, Duchenne ,Zoledronic acid ,Neurology ,Pediatrics, Perinatology and Child Health ,Neurology (clinical) ,business ,medicine.drug - Published
- 2019
7. Vigabatrin with hormonal treatment versus hormonal treatment alone (ICISS) for infantile spasms: 18-month outcomes of an open-label, randomised controlled trial
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Finbar J K O'Callaghan, Stuart W Edwards, Fabienne Dietrich Alber, Mario Cortina Borja, Eleanor Hancock, Anthony L Johnson, Colin R Kennedy, Marcus Likeman, Andrew L Lux, Mark T Mackay, Andrew A Mallick, Richard W Newton, Melinda Nolan, Ronit Pressler, Dietz Rating, Bernhard Schmitt, Christopher M Verity, John P Osborne, Maysara Abdel Aziz, Triloknath Acharya, Carolyn Adcock, Robert Jones, Rachel Howells, Ben Marsh, Kemi Adejare, Rashmi Adiga, Mary Wheater, Mansoor Ahmed, Mohammad Sawal, Chhavi Goel, MAS Ahmed, Michael Alber, Markus Wolff, Susanne Ruf, Asya Al-Kharusi, Hassan Al-Moasseb, Ruchi Arora, Richard Beach, Patricia Atkinson, Kunle Ayonrinde, Pronab Bala, Nicola Bamford, Nagi Barakat, Nigel Basheer, Peter Baxter, Santosh Mordekar, Chris Rittey, Ingo Borggraefe, Peter Borusiak, Sabine Cagnoli, Richard Brown, Sophie Calvert, Duncan Cameron, Ramesh Chaniyil, Ravi Chinthapalli, Gabriel Chow, William Whitehouse, Vinodhini Clarke, Chris Cooper, Alexane Datta, Selwyn D'Costa, Christian de Goede, Helen Basu, David Deekollu, Adela Della Marina, Penelope Dison, Colin Dunkley, Megan Eaton, Julie Ellison, Robert Pugh, Penny Fallon, Hani Faza, Imti Choonara, Richard Morton, Mal Ratnayaka, Colin Ferrie, Amanda Freeman, Stephen Warriner, Maria Garcia, Malihe Ghazavi, Frances Gibbon, John Gibbs, Des Ginbey, Iolanda Guarino, Rajesh Gupta, Mary Hanlon, Siân Harris, Paul Munyard, Cheryl Hemingway, Christin Eltze, Marios Kaliakatsos, Velayutham Murugan, Robert Robinson, Jeen Tan, Daniel Hindley, Adrian Hughes, Akmal Hussain, Greg Boden, Munir Hussain, Nahin Hussain, Lyvia Dabydeen, Kate Irwin, Julia Jacobs, Praveen Jauhari, Philip Minchom, Simon Jones, Michael Karenfort, Reinhard Keimer, Colin Kennedy, Fenella Kirkham, Andrea Whitney, Martin Kirkpatrick, Alice Jollands, Rachel Kneen, Anand Iyer, Amy McTague, Stefan Spinty, Ramesh Kumar, Gerhard Kurlemann, Matthew Lee, Eman Jurges, Robert Levy, Helen Lewis, Hilary Lewis, Andrew Lloyd Evans, Ne-Ron Loh, John Osborne, Finbar O'Callaghan, Hilary Maddicks, Thomas Luecke, Andrew Lux, Anirban Majumdar, Kayal Vijayakumar, Mark MacKay, Jeremy Freeman, Michael Hayman, Andrew Kornberg, Rick Leventer, Monique Ryan, Tyson Ware, Penny Mancais, Katina Marinaki, Albert Massarano, Satheesh Mathew, Ailsa McLellan, Colin Melville, Leena Mewasingh, Hiltrud Muhle, Eisawi Nagmeldin, Jeyashree Natarajan, Suresh Nelapatla, Jailosi Gondwe, Richard Newton, Imelda Hughes, Tim Martland, Gary McCullagh, Grace Vassallo, Stephen Nirmal, Suzanne Davis, Rakesh Patel, Cynthia Sharpe, Anas Olabi, Kevin O'Neill, Jim Gould, Axel Panzer, Manuela Theophil, Srinivas Parepalli, Frank Hinde, Martin Smith, Alasdair Parker, Manali Chitre, Sunny Philip, Rajat Gupta, Evangeline Wassmer, Mike Pike, Tony McShane, Nandhini Prakash, Beena Padmakumar, Clair Pridmore, Viola Prietsch, Peter Krieg, Ros Quinlivan, Michael Quinn, Andrew Collinson, Usha Rajalingam, Karl Rakshi, Tekki Rao, Asha Ravi, Rob Rifkin, Helen Roper, Piers Rowlandson, Lynette Sadleir, Sanjay Sahi, Arun Saraswatula, Siobhan O'Sullivan, Kethar Saravanan, Alastair Scammell, Sudhakar Rao, Susanne Schubert-Bast, David J Scott, Fraser Scott, Matthew Pye, Ayaz Shah, Elma Stephen, Shambhu Shah, Andrew Butterfill, Pauline Shute, Rajeeva Singh, Brigid Allogoa, Ravinder Singh, Gyanranjan Sinha, Puthuval Sivakumar, Robert Smith, Sivaranjini Sriskandan, Martin Steinert, Michael Strassburg, Susi Strozzi, Geeta Subramanian, Andrew Tandy, University of Zurich, and O'Callaghan, Finbar J K
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Pediatrics ,medicine.medical_specialty ,Combination therapy ,610 Medicine & health ,Vigabatrin ,law.invention ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,Pharmacotherapy ,Randomized controlled trial ,law ,030225 pediatrics ,medicine ,Developmental and Educational Psychology ,Pediatrics, Perinatology, and Child Health ,2735 Pediatrics, Perinatology and Child Health ,3204 Developmental and Educational Psychology ,Intention-to-treat analysis ,business.industry ,medicine.disease ,10036 Medical Clinic ,Pediatrics, Perinatology and Child Health ,Prednisolone ,Hormonal therapy ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
BACKGROUND: Infantile spasms constitute a severe form of epileptic encephalopathy. In the International Collaborative Infantile Spasms Study (ICISS), we showed that combining vigabatrin with hormonal therapy was more effective than hormonal therapy alone at stopping spasms between days 14 and 42 of treatment. In this planned follow-up, we aimed to assess whether combination therapy was associated with improved developmental and epilepsy outcomes at 18 months of age.METHODS: In ICISS, a multicentre, open-label, randomised controlled trial, infants were enrolled from 102 hospitals (three in Australia, 11 in Germany, two in New Zealand, three in Switzerland, and 83 in the UK). Eligible infants had a clinical diagnosis of infantile spasms and a hypsarrhythmic (or similar) electroencephalogram (EEG) no more than 7 days before enrolment. Participants were randomly assigned (1:1) by a secure website to receive hormonal therapy with vigabatrin or hormonal therapy alone. If parents consented, there was an additional randomisation (1:1) of type of hormonal therapy used (prednisolone or tetracosactide depot). Block randomisation was stratified for hormonal treatment and risk of developmental impairment. Parents and clinicians were not masked to therapy, but investigators assessing epilepsy and developmental outcomes at 18 months were masked to treatment allocation. Minimum doses were oral prednisolone 10 mg four times a day or intramuscular tetracosactide depot 0·5 mg (40 IU) on alternate days with or without oral vigabatrin 100 mg/kg per day. The primary outcome at 18 months was development as assessed by the Vineland Adaptive Behaviour Scales (VABS) composite score. Secondary outcomes were the presence or absence of epileptic seizures or infantile spasms in the previous 28 days, as recorded by parents and carers, and the use of any anti-epileptic treatment (including ketogenic diet) in the previous 28 days. Analysis was by intention to treat. The trial is registered with the ISRCTN registry, number 54363174, and EudraCT, number 2006-000788-27.FINDINGS: Between March 7, 2007, and May 22, 2014, 766 infants were screened and, of those, 377 were randomly assigned to hormonal therapy with vigabatrin (n=186) or hormonal therapy alone (n=191). 362 infants were assessed for developmental and epilepsy outcomes at 18 months, 181 in each treatment group. Mean VABS scores did not differ significantly between the combination therapy group and the hormonal therapy alone group (73·9 [SE 1·3] vs 72·7 [1·4], difference -1·2 [95% CI -4·9 to 2·6], p=0·55). Presence of epilepsy at the assessment at age 18 months was similar in both treatment groups (54 [30·0%] of 180 infants who received combination therapy vs 52 [29·2%] of 178 who received hormonal therapy alone; difference 0·8% [95% CI -8·8 to 10·4], p=0·90). Presence of spasms was also similar in both treatment groups (27 [15·0%] of 180 infants on combination therapy vs 28 [15·7%] of 178 on hormonal therapy alone; difference 0·7% [95% CI -6·9 to 8·3], p=0·85). At the 18-month assessment, 158 (44·1%) of 358 infants were on some form of anti-epileptic treatment. Initial control of spasms between days 14 and 42 of treatment was associated with higher mean VABS scores at 18 months (79·1 [SE 1·2] vs 63·2 [1·1], difference 15·9 [95% CI 12·4 to 19·5], pINTERPRETATION: Combination therapy did not result in improved developmental or epilepsy outcomes at 18 months. However, early clinical response to treatment was associated with improved developmental and epilepsy outcomes at 18 months. Longer lead-time to treatment was associated with poorer outcomes. Rapid diagnosis and effective treatment of infantile spasms could therefore improve outcomes.FUNDING: The Castang Foundation, Bath Unit for Research in Paediatrics, National Institute of Health Research, the Royal United Hospitals Bath NHS Foundation Trust, BRONNER-BENDER Stiftung/Gernsbach, University Children's Hospital Zurich.
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- 2018
8. A checklist for clinical trials in rare disease: obstacles and anticipatory actions—lessons learned from the FOR-DMD trial
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Ulrike Schara, Deborah Hirtz, Mary W. Brown, James F. Howard, W. Bryan Burnette, Nancy L. Kuntz, Maja von der Hagen, Lucia Morandi, Tiziana Mongini, Janbernd Kirschner, Emma Ciafaloni, Basil T. Darras, Richard J. Barohn, Giuseppe Vita, Michela Guglieri, Robert C. Griggs, Hanns Lochmüller, Elaine McColl, Kimberly A. Hart, Adnan Y. Manzur, Anne Marie Childs, Kate Bushby, William B. Martens, Craig Campbell, Elena Pegoraro, Kevin M. Flanigan, Barbara E. Herr, Rabi Tawil, Imelda Hughes, Russell J. Butterfield, Jennifer Wilkinson, Matthew Wicklund, Richard S. Finkel, Iain Horrocks, Helen Roper, Rebecca A. Crow, Perry B. Shieh, Hugh J. McMillan, Wendy King, Michael P. McDermott, Stefan Spinty, Mathula Thangarajh, Leslie Morrison, Ekkehard Wilichowski, Volker Straub, Craig M. McDonald, Jean K. Mah, and M. Eagle
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Budgets ,Duchenne muscular dystrophy ,Research design ,Time Factors ,International Cooperation ,Medizin ,Medicine (miscellaneous) ,Review ,Contracts ,Indemnity ,Clinical trial regulations ,03 medical and health sciences ,Rare Diseases ,0302 clinical medicine ,Procurement ,Research Support as Topic ,Interim ,Humans ,Multicenter Studies as Topic ,Medicine ,Pharmacology (medical) ,Operations management ,Academic-led clinical trial ,Clinical trial ,Rare disease ,Clinical Trials as Topic ,Muscular Dystrophy, Duchenne ,Patient Selection ,Steroids ,Treatment Outcome ,Checklist ,Research Design ,Muscular Dystrophy ,030212 general & internal medicine ,lcsh:R5-920 ,business.industry ,Timeline ,Duchenne ,3. Good health ,lcsh:Medicine (General) ,business ,030217 neurology & neurosurgery ,Diversity (business) - Abstract
Background Trials in rare diseases have many challenges, among which are the need to set up multiple sites in different countries to achieve recruitment targets and the divergent landscape of clinical trial regulations in those countries. Over the past years, there have been initiatives to facilitate the process of international study set-up, but the fruits of these deliberations require time to be operationally in place. FOR-DMD (Finding the Optimum Steroid Regimen for Duchenne Muscular Dystrophy) is an academic-led clinical trial which aims to find the optimum steroid regimen for Duchenne muscular dystrophy, funded by the National Institutes of Health (NIH) for 5 years (July 2010 to June 2015), anticipating that all sites (40 across the USA, Canada, the UK, Germany and Italy) would be open to recruitment from July 2011. However, study start-up was significantly delayed and recruitment did not start until January 2013. Method The FOR-DMD study is used as an example to identify systematic problems in the set-up of international, multi-centre clinical trials. The full timeline of the FOR-DMD study, from funding approval to site activation, was collated and reviewed. Systematic issues were identified and grouped into (1) study set-up, e.g. drug procurement; (2) country set-up, e.g. competent authority applications; and (3) site set-up, e.g. contracts, to identify the main causes of delay and suggest areas where anticipatory action could overcome these obstacles in future studies. Results Time from the first contact to site activation across countries ranged from 6 to 24 months. Reasons of delay were universal (sponsor agreement, drug procurement, budgetary constraints), country specific (complexity and diversity of regulatory processes, indemnity requirements) and site specific (contracting and approvals). The main identified obstacles included (1) issues related to drug supply, (2) NIH requirements regarding contracting with non-US sites, (3) differing regulatory requirements in the five participating countries, (4) lack of national harmonisation with contracting and the requirement to negotiate terms and contract individually with each site and (5) diversity of languages needed for study materials. Additionally, as with many academic-led studies, the FOR-DMD study did not have access to the infrastructure and expertise that a contracted research organisation could provide, organisations often employed in pharmaceutical-sponsored studies. This delay impacted recruitment, challenged the clinical relevance of the study outcomes and potentially delayed the delivery of the best treatment to patients. Conclusion Based on the FOR-DMD experience, and as an interim solution, we have devised a checklist of steps to not only anticipate and minimise delays in academic international trial initiation but also identify obstacles that will require a concerted effort on the part of many stakeholders to mitigate.
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- 2018
9. Developing Standardized Corticosteroid Treatment for Duchenne Muscular Dystrophy
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Adnan Y. Manzur, Wendy King, William B. Martens, Matthew Wicklund, Mary W. Brown, Elena Pegoraro, Tiziana Mongini, Maja von der Hagen, James F. Howard, Emma Ciafaloni, Barbara E. Herr, Tracey Willis, Kimberly A. Hart, Craig Campbell, Rabi Tawil, Imelda Hughes, Richard J. Barohn, Ulrike Schara, Helen Roper, Kevin M. Flanigan, Iain Horrocks, Elaine McColl, Nancy L. Kuntz, Leslie Morrison, Robert C. Griggs, Michael P. McDermott, Stefan Spinty, Russell J. Butterfield, Giovanni Baranello, Deborah Hirtz, Giuseppe Vita, W. Bryan Burnette, Mathula Thangarajh, Basil T. Darras, Ekkehard Wilichowski, Kate Bushby, Anne-Marie Childs, Richard S. Finkel, Craig M. McDonald, Perry B. Shieh, Hugh J. McMillan, Michela Guglieri, Volker Straub, Janbernd Kirschner, Jean K. Mah, M. Eagle, and Jennifer Wilkinson
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0301 basic medicine ,Male ,Pediatrics ,Duchenne muscular dystrophy ,Vital Capacity ,Medizin ,Disability Evaluation ,0302 clinical medicine ,Prednisone ,Pregnenediones ,Pharmacology (medical) ,Muscular Dystrophy ,Range of Motion, Articular ,Child ,Deflazacort ,Medicine (all) ,General Medicine ,3. Good health ,Prednisolone ,Randomized ,Standards of care ,Patient Satisfaction ,Research Design ,Child, Preschool ,Heart Function Tests ,Corticosteroid ,hormones, hormone substitutes, and hormone antagonists ,Immunosuppressive Agents ,medicine.drug ,Range of Motion ,medicine.medical_specialty ,medicine.drug_class ,Article ,Drug Administration Schedule ,03 medical and health sciences ,Double-Blind Method ,medicine ,Humans ,Muscle Strength ,Adverse effect ,Preschool ,business.industry ,medicine.disease ,Duchenne ,Clinical trial ,Muscular Dystrophy, Duchenne ,Regimen ,030104 developmental biology ,Physical therapy ,business ,030217 neurology & neurosurgery ,Articular - Abstract
Despite corticosteroids being the only treatment documented to improve strength and function in boys with Duchenne muscular dystrophy (DMD) corticosteroid prescription is inconsistent and in some countries, corticosteroids are not prescribed. We are conducting a clinical trial that (1) compares the 3 most frequently prescribed corticosteroid regimes; (2) standardizes treatment of DMD complications; and (3) standardizes prevention of corticosteroid side effects. Investigators at 38 sites in 5 countries plan to recruit 300 boys aged 4-7 who are randomly assigned to one of three regimens: daily prednisone; daily deflazacort; or intermittent prednisone (10days on/10days off). Boys are followed for a minimum of 3years to assess the relative effectiveness and adverse event profiles of the different regimens. The primary outcome is a 3-dimensional variable consisting of log-transformed time to rise from the floor, forced vital capacity, and subject/parent satisfaction with treatment, each averaged over all post-baseline visits. The study protocol includes evidence- and consensus-based treatment of DMD complications and of corticosteroid side effects. This study seeks to establish a standard corticosteroid regimen for DMD. Since all new interventions for DMD are being developed as add-on therapies to corticosteroids, defining the optimum regimen is of importance for all new treatments.
- Published
- 2017
10. Randomised placebo-controlled trial of combination ACE inhibitor and beta-blocker therapy to prevent cardiomyopathy in children with Duchenne muscular dystrophy? (DMD Heart Protection Study): a protocol study
- Author
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Gillian Watson, Stefan Spinty, Jennifer Wilkinson, Francesco Muntoni, Tracey Willis, Thomas Chadwick, Michela Guglieri, Ruth Wood, Andrew Bryant, Helen Roper, Satish Adwani, Chris Speed, Kate Bushby, Elaine McColl, Sandeep Jayawant, John P. Bourke, and Ashish Chikermane
- Subjects
Male ,medicine.medical_specialty ,Adolescent ,Combination therapy ,medicine.drug_class ,Heart Ventricles ,Adrenergic beta-Antagonists ,Vital Capacity ,Cardiomyopathy ,Placebo-controlled study ,Angiotensin-Converting Enzyme Inhibitors ,Cardiovascular Medicine ,030204 cardiovascular system & hematology ,ace-inhibitor ,Electrocardiography ,03 medical and health sciences ,0302 clinical medicine ,Quality of life ,Forced Expiratory Volume ,Protocol ,medicine ,Humans ,Multicenter Studies as Topic ,Child ,Intensive care medicine ,Adverse effect ,Beta blocker ,duchenne muscular dystrophy ,Randomized Controlled Trials as Topic ,business.industry ,General Medicine ,medicine.disease ,prophylactic therapy ,Muscular Dystrophy, Duchenne ,Echocardiography ,Bisoprolol ,Child, Preschool ,beta-blocker ,cardiac dystrophinopathy ,Drug Therapy, Combination ,Cardiomyopathies ,business ,Heart Protection Study ,030217 neurology & neurosurgery ,medicine.drug - Abstract
IntroductionAlthough cardiologists were ‘late-comers’ to the multidisciplinary team—contributing to the complex care of patients with Duchenne muscular dystrophy (DMD), they now recognise the importance of systematic cardiac surveillance and timely therapy to prolonged survival in patients with DMD. Empirical deployment of cardioactive medications has already improved outcomes, but the evidence base for clinical decision making is weak. Fundamental questions remain as to whether prophylactic therapy is justified and convincingly superior to prompt deployment of the same therapies once left ventricular (LV) dysfunction is detected. Even if it were, at what age should therapy be introduced and with what specific drugs?Methods and analysisWe are conducting a multicentre, parallel group, randomised, placebo-controlled study of combination therapy with an ACE inhibitor (perindopril) and a beta-blocker (bisoprolol) in boys with DMD aged 5–13 years, with normal LV function by echocardiographic criteria at the time of recruitment. Boys are being followed-up for a minimum of 3 years and a maximum of 5 years and undergo repeat assessments of LV function, heart rate and ECG, forced expiratory volume in the 1 s and forced vital capacity, adverse event reporting and quality of life at 6 monthly intervals.The primary outcome is change in LV function between active and placebo-treated participants over the course of the study.Ethics and disseminationThe study was approved by ‘NRES Committee East Midlands – Derby’. The results will be disseminated through manuscript publications, an international workshop and presentations to scientific meetings and parent forums.Translational aspectsThe study seeks to establish the evidence for prophylactic heart therapies for children with DMD, define the optimum age for their introduction and identify any safety concerns.Article summaryThe protocol describes the design of an ongoing multicentre, double-blind, randomised placebo-controlled study to establish the evidence for the use of prophylactic heart therapies in children with DMD, define the optimum age for their introduction and identify any safety concerns.Trial registration numbersEudraCT2007-005932-10 andISRCTN50395346; Pre-results.
- Published
- 2018
11. Migrating partial seizures of infancy: expansion of the electroclinical, radiological and pathological disease spectrum
- Author
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Karine Lascelles, Manju A. Kurian, Sanjay Bhate, Anthony Cronin, J. Helen Cross, Amy McTague, Elaine Hughes, Andrew Curran, Esther Meyer, Rachel Kneen, Ailsa McLellan, Thomas S. Jacques, John H. Livingston, Archana Desurkar, Rosalind J. Jefferson, Ingrid E. Scheffer, Richard Appleton, Annapurna Poduri, Michael A. Farrell, Stefan Spinty, Mary D. King, and Shivaram Avula
- Subjects
Male ,PLCB1 ,Pathology ,medicine.medical_specialty ,Movement disorders ,Cohort Studies ,Epilepsy ,Atrophy ,Neuroimaging ,medicine ,Humans ,Comparative Genomic Hybridization ,medicine.diagnostic_test ,business.industry ,Infant ,Electroencephalography ,Magnetic resonance imaging ,Original Articles ,medicine.disease ,Magnetic Resonance Imaging ,Hypsarrhythmia ,Radiography ,Population Surveillance ,Mutation ,Female ,Epilepsies, Partial ,Neurology (clinical) ,Levetiracetam ,medicine.symptom ,business ,medicine.drug - Abstract
Migrating partial seizures of infancy, also known as epilepsy of infancy with migrating focal seizures, is a rare early infantile epileptic encephalopathy with poor prognosis, presenting with focal seizures in the first year of life. A national surveillance study was undertaken in conjunction with the British Paediatric Neurology Surveillance Unit to further define the clinical, pathological and molecular genetic features of this disorder. Fourteen children with migrating partial seizures of infancy were reported during the 2 year study period (estimated prevalence 0.11 per 100 000 children). The study has revealed that migrating partial seizures of infancy is associated with an expanded spectrum of clinical features (including severe gut dysmotility and a movement disorder) and electrographic features including hypsarrhythmia (associated with infantile spasms) and burst suppression. We also report novel brain imaging findings including delayed myelination with white matter hyperintensity on brain magnetic resonance imaging in one-third of the cohort, and decreased N-acetyl aspartate on magnetic resonance spectroscopy. Putaminal atrophy (on both magnetic resonance imaging and at post-mortem) was evident in one patient. Additional neuropathological findings included bilateral hippocampal gliosis and neuronal loss in two patients who had post-mortem examinations. Within this cohort, we identified two patients with mutations in the newly discovered KCNT1 gene. Comparative genomic hybridization array, SCN1A testing and genetic testing for other currently known early infantile epileptic encephalopathy genes (including PLCB1 and SLC25A22) was non-informative for the rest of the cohort.
- Published
- 2013
12. Safety, Tolerability, and Pharmacokinetics of SMT C1100, a 2-Arylbenzoxazole Utrophin Modulator, following Single- and Multiple-Dose Administration to Pediatric Patients with Duchenne Muscular Dystrophy
- Author
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Imelda Hughes, Bina Tejura, Jonathon M. Tinsley, Valeria Ricotti, Kay E. Davies, Gary Layton, Helen Roper, Neil Robinson, Francesco Muntoni, and Stefan Spinty
- Subjects
0301 basic medicine ,Male ,Heredity ,Utrophin ,Genetic Linkage ,Duchenne muscular dystrophy ,Duchenne Muscular Dystrophy ,Pharmacokinetic Analysis ,Biochemistry ,Pediatrics ,Muscular Dystrophies ,0302 clinical medicine ,Drug Metabolism ,Elimination Half-Life Calculation ,Medicine and Health Sciences ,Metabolites ,Muscular dystrophy ,Child ,Benzoxazoles ,Multidisciplinary ,biology ,Pharmaceutics ,Adjustment of Dosage at Steady State ,Tolerability ,Neurology ,X-Linked Traits ,Sex Linkage ,Anesthesia ,Child, Preschool ,Medicine ,Research Article ,medicine.medical_specialty ,Science ,03 medical and health sciences ,Dose Prediction Methods ,Pharmacokinetics ,medicine ,Genetics ,Humans ,Dosing ,Adverse effect ,Pharmacology ,Clinical Genetics ,business.industry ,Biology and Life Sciences ,Proteins ,medicine.disease ,Surgery ,Clinical trial ,Muscular Dystrophy, Duchenne ,Cytoskeletal Proteins ,030104 developmental biology ,Metabolism ,Pharmacologic Analysis ,biology.protein ,Creatine kinase ,business ,030217 neurology & neurosurgery ,Biomarkers - Abstract
PurposeSMT C1100 is a utrophin modulator being evaluated as a treatment for Duchenne muscular dystrophy (DMD). This study, the first in pediatric DMD patients, reports the safety, tolerability and PK parameters of single and multiple doses of SMT C1100, as well as analyze potential biomarkers of muscle damage.MethodsThis multicenter, Phase 1 study enrolled 12 patients, divided equally into three groups (A-C). Group A were given 50 mg/kg on Days 1 and 11, and 50 mg/kg bid on Days 2 to 10. Group B and C received 100 mg/kg on Days 1 and 11; Group B and Group C were given 100 mg/kg bid and 100 mg/kg tid, respectively, on Days 2 to 10. A safety review was performed on all patients following the single dose and there was at least 2 weeks between each dose escalation, for safety and PK review. Adverse events (AEs) were monitored throughout the study.ResultsMost patients experienced mild AEs and there were no serious AEs. Two patients required analgesia for pain (headache, ear pain and toothache). One patient experienced moderate psychiatric AEs (abnormal behaviour and mood swings). Plasma concentrations of SMT C1100 at Days 1 and 11 indicated a high degree of patient variability regardless of dose. Unexpectedly the SMT C1100 levels were significantly lower than similar doses administered to healthy volunteers in an earlier clinical study. In general, individual baseline changes of creatine phosphokinase, alanine aminotransferase, aspartate aminotransferase levels fell with SMT C1100 dosing.ConclusionsSMT C1100 was well tolerated in pediatric DMD patients.Trial registrationClinicalTrials.gov NCT02383511.
- Published
- 2016
13. Dopa-Responsive Dystonia and Chorea as a Presenting Feature in Ataxia-Telangiectasia
- Author
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Malcolm Taylor, Stefan Spinty, Philip J. Byrd, Sarah Thompson, and Anand Iyer
- Subjects
Dopa-Responsive Dystonia ,Levodopa ,business.industry ,Chorea ,Case Reports ,medicine.disease ,Neurology ,Feature (computer vision) ,Ataxia-telangiectasia ,Medicine ,Neurology (clinical) ,medicine.symptom ,business ,Neuroscience ,medicine.drug - Published
- 2014
14. The use of nusinersen in the 'real world': the UK and Ireland experience with the expanded access program (EAP)
- Author
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S Brown, Pinki Munot, M. Illingworth, R. Tillmann, Andreas Brunklaus, Sithara Ramdas, Imelda Hughes, A. Mayhew, Iain Horrocks, Stefan Spinty, R. Kulshrestha, Kayal Vijayakumar, Tracey Willis, I. Douglas, V. Gowda, D. Krishnakumar, S. Macauley, V. Straub, M. Di Marco, Adnan Y. Manzur, Elizabeth Wraige, Anne-Marie Childs, Louise Hartley, V. Selby, Peter Baxter, R. Muni-Lofra, Marion Main, S. Gregson, Gary McCullagh, R. Madhu, R. Mochrie, Francesco Muntoni, Mariacristina Scoto, Jennifer Dunne, Karen L. White, Sandya Tirupathi, M. Douglas, Declan O'Rourke, Martin Kirkpatrick, and C. Marini Bettolo
- Subjects
business.industry ,Public relations ,030227 psychiatry ,03 medical and health sciences ,0302 clinical medicine ,Neurology ,Political science ,Expanded access ,Pediatrics, Perinatology and Child Health ,Nusinersen ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Genetics (clinical) - Published
- 2018
15. Overcoming pharmacokinetic challenges to drug administration in Duchenne muscular dystrophy: Lessons from Phase 1 development of ezutromid
- Author
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S. Harriman, Stefan Spinty, Bina Tejura, K. Davies, I. Hughes, H. Roper, Francesco Muntoni, and Anirban Majumdar
- Subjects
medicine.medical_specialty ,Pharmacokinetics ,business.industry ,Duchenne muscular dystrophy ,Pediatrics, Perinatology and Child Health ,medicine ,Physical therapy ,Drug administration ,Neurology (clinical) ,General Medicine ,Intensive care medicine ,medicine.disease ,business - Published
- 2017
16. G335(P) Phenytoin dosing and serum concentrations in paediatric patients requiring 20 mg/kg intravenous loading dose
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Stefan Spinty, GK Verghese, Richard Appleton, Daniel B Hawcutt, Joe D Piper, and Paul Newland
- Subjects
Phenytoin ,RM ,business.industry ,RJ ,RJ101 ,Status epilepticus ,Loading dose ,Refractory ,Pharmacokinetics ,Anesthesia ,Pediatrics, Perinatology and Child Health ,Toxicity ,Medicine ,Dosing ,medicine.symptom ,business ,Adverse effect ,medicine.drug - Abstract
Aim Phenytoin’s loading dose for refractory tonic-clonic seizures in children was changed from 18 mg/kg to 20 mg/kg in January 2011 to reduce the theoretical risk of miscalculation. Phenytoin has complex pharmacokinetics and there is no data on the effectiveness and safety of the new dose. Therefore we aimed to measure the intravenous levels of phenytoin in children to assess the effectiveness, safety and toxicity of this new dosing regimen. Methods The use of intravenous loading doses of phenytoin was audited over 27 months to evaluate the pharmacokinetic, clinical and toxic effects of the new dose in clinical practice. Current clinical practice at our institution is to measure the total serum phenytoin concentrations 1–3 h post loading dose, aiming for a level 10–20 µg/ml. Serum phenytoin concentrations were compared with both dose (weight adjusted) and time. Results Serum phenytoin concentrations were measured on 46 occasions from 41 children (38 retrospective and 8 prospective), of which 24 were within 60–180 (median 105) minutes following completion of infusion of the loading dose. Use of estimated weights meant patients received between 15.5 and 27.5 mg/kg (78–138% expected dose). Supra-therapeutic serum concentrations (>20 µg/ml were present in 5/24 (20.1%) (three using actual weight, two using estimated). Three adverse effects consistent with phenytoin toxicity were noted in children with supra-therapeutic concentrations. Two errors in dose prescriptions were found. Conclusion The new intravenous 20 mg/kg loading dose has similar percentage of therapeutic and supra-therapeutic serum phenytoin concentrations to previously published estimates for the 18 mg/kg dose. However, there are a greater number of potentially associated toxicities than in previous studies at the lower dose. A wide range of doses continue to be applied due to errors in estimated weight, giving up to 138% of the expected dose in this cohort. The new regime is also not immune to prescribing errors. Despite its efficacy, the variable pharmacokinetic and toxicity profiles strengthens the case for finding alternative anti-epileptics in status epilepticus.
- Published
- 2014
17. Phenytoin dosing and serum concentrations in paediatric patients requiring 20 mg/kg intravenous loading
- Author
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George K Verghese, Stefan Spinty, Richard Appleton, Joe D Piper, Paul Newland, and Daniel B Hawcutt
- Subjects
Phenytoin ,Male ,Adolescent ,Status epilepticus ,Loading dose ,Young Adult ,Therapeutic index ,Status Epilepticus ,Pharmacokinetics ,medicine ,Humans ,Drug Dosage Calculations ,Dosing ,Prospective Studies ,Adverse effect ,Child ,Retrospective Studies ,business.industry ,Infant, Newborn ,Infant ,Anesthesia ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Cohort ,Administration, Intravenous ,Anticonvulsants ,Female ,medicine.symptom ,business ,medicine.drug - Abstract
Introduction Phenytoin has complex pharmacokinetics. The intravenous loading dose of phenytoin for children in status epilepticus has recently been increased from 18 to 20 mg/kg. There are no data on the clinical effectiveness and safety of this new dose. Methods The use of intravenous loading doses of phenytoin was audited over 27 months to evaluate the pharmacokinetic, clinical and toxic effects of the new dose in clinical practice. Serum phenytoin concentrations were compared with dose (weight-adjusted) and time. Results Serum phenytoin concentrations were measured on 48 occasions from 41 children (39 retrospective and 9 prospective), of which 24 were within 60–180 (median 105) minutes following completion of infusion of the loading dose. Use of estimated weights meant patients received between 15.5 and 27.5 mg/kg (78% to 138% expected dose). Supra-therapeutic serum concentrations >20 µg/mL were present in 5/24 (20.1%) (after doses based on actual weight in three and estimated weight in two patients). Three adverse effects consistent with phenytoin toxicity were noted in children with supra-therapeutic concentrations. Two errors in dose prescriptions were found. Conclusions The majority of serum phenytoin concentrations were in the therapeutic range. Estimating weight in children for the 20 mg/kg intravenous loading dose of phenytoin is often clinically necessary but inaccurate, resulting in up to 138% of the expected and recommended dose in this cohort.
- Published
- 2014
18. Percutaneous correction of scoliosis in Duchenne muscular dystrophy: a new technique
- Author
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Stefan Spinty, Jai Trivedi, Neil Davidson, Andrew James Bowey, and Colin E. Bruce
- Subjects
medicine.medical_specialty ,Percutaneous ,business.industry ,Duchenne muscular dystrophy ,medicine ,Surgery ,Orthopedics and Sports Medicine ,Neurology (clinical) ,Scoliosis ,medicine.disease ,business - Published
- 2016
19. Clinical reasoning: a case of acute onset bilateral ptosis in a young child
- Author
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Darshan Das, Ram Kumar, and Stefan Spinty
- Subjects
medicine.medical_specialty ,genetic structures ,Photophobia ,Cranial nerve examination ,Diagnosis, Differential ,Pharyngeal reflex ,Ptosis ,Esophoria ,medicine ,Oculomotor Nerve Diseases ,Blepharoptosis ,Humans ,Unilateral ptosis ,Diplopia ,Miller Fisher Syndrome ,business.industry ,medicine.disease ,eye diseases ,Surgery ,Child, Preschool ,Acute Disease ,Female ,sense organs ,Neurology (clinical) ,medicine.symptom ,business ,Esotropia - Abstract
A 5-year-old boy presented with acute onset bilateral ptosis. An initial unilateral ptosis had evolved over the preceding 3 days, following a resolved pyrexial upper respiratory tract illness (URI) treated with oral penicillin. His mother reported that recently he was unable to walk half a mile to school, but had no difficulty with stairs. There was no history of ocular pain, vomiting, headaches, weight loss, dysphagia, constipation, or urinary disturbance. The ptosis was reported not to fluctuate, with no reported tearing, photophobia, or visual disturbance. His prior development was normal, and there was no family history of relevant neuromuscular or autoimmune disorders. On examination he was alert and apyrexial, without rash or lymphadenopathy. His systemic examination was unremarkable aside from enlarged noninflamed tonsils. He had bilateral ptosis obscuring the visual axis: marginal reflex distances were −3 mm and −2 mm on the left and right, respectively. There was no conjunctival injection or tearing. Pupil sizes were 4 mm, equal, and reacted briskly to light and accommodation without relative afferent pupillary defect. Fundus examination was normal. There was full range and no fatigability of extraocular movements. Cover test findings were equivocal: a subtle left esophoria at near, and small (8 D) esotropia with horizontal diplopia at distance. Forced eye closure was normal without eyelid myotonia. Other cranial nerve examination was normal including facial sensation, bulbar strength, and gag reflex. He had normal muscle bulk, tone, and active muscle …
- Published
- 2012
20. G.P.102
- Author
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Valeria Ricotti, Francesco Muntoni, Stefan Spinty, Jonathon M. Tinsley, A. Bracchi, Imelda Hughes, G. Horne, and Helen Roper
- Subjects
musculoskeletal diseases ,congenital, hereditary, and neonatal diseases and abnormalities ,mdx mouse ,medicine.medical_specialty ,biology ,business.industry ,Duchenne muscular dystrophy ,Pharmacology ,musculoskeletal system ,medicine.disease ,Surgery ,Clinical trial ,Neurology ,Pharmacokinetics ,In vivo ,Pediatrics, Perinatology and Child Health ,Utrophin ,medicine ,biology.protein ,Neurology (clinical) ,Muscular dystrophy ,business ,Dystrophin ,Genetics (clinical) - Abstract
The continual expression of utrophin protein by pharmacological maintenance of utrophin transcription in dystrophin deficient muscle fibres is a potential disease modifying treatment for Duchenne muscular dystrophy (DMD). SMT C1100 is a small molecule utrophin modulator demonstrating significant benefit on the muscular dystrophy in the dystrophin deficient mdx mouse. Assessment of the in vitro and in vivo pharmacology plus the clean toxicology and safety data from the pre-clinical work led to the nomination of SMT C1100 as the first candidate for evaluation in DMD clinical trials. We previously reported that SMT C1100 successfully completed a Phase 1 healthy volunteer trial in which an oral paediatric formulation was deemed safe and well tolerated with plasma levels above those determined to be effective to modulate utrophin levels ex-vivo in DMD myoblasts and dystrophin deficient mdx mice. The first DMD paediatric patient trials of SMT C1100 started with an open-label, single and multiple oral dose finding Phase 1b study in DMD boys earlier this year. The purpose of the study was to determine whether increasing doses of SMT C1100 were safe, well tolerated and to understand the pharmacokinetic properties in patients with DMD. The boys were studied in 3 groups (Groups A to C), with each group consisting of 4 patients aged between 5 to 11 years. The doses for Groups A to C were administered in an escalating manner after safety review for each dose group. We will present the summary data from this trial.
- Published
- 2014
21. Utrophin modulators to treat Duchenne muscular dystrophy (DMD): Results from a Phase 1b Clinical Trial of SMT C1100
- Author
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Kay E. Davies, Bina Tejura, Jonathon M. Tinsley, Helen Roper, Imelda Hughes, R. Ricotti, Gary Layton, Stefan Spinty, and Francesco Muntoni
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Duchenne muscular dystrophy ,medicine.disease ,Clinical trial ,Neurology ,Internal medicine ,Pediatrics, Perinatology and Child Health ,Utrophin ,Medicine ,Neurology (clinical) ,business ,Genetics (clinical) - Published
- 2015
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