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Pediatric Drug Development

Heng Xu, Yang Shu
Treatment outcomes for acute lymphoblastic leukemia (ALL), especially pediatric ALL, have greatly improved due to the risk-adapted therapy. Combination of drug development, clinical practice, as well as basic genetic researches has brought the survival rate of ALL from less than 10% to more than 90% today, not only increasing the treatment efficacy but also limiting adverse drug reactions (ADRs). In this review, we summarized the landscape identification of ALL genetic alterations, which provided the opportunity to increase the survival rate and especially minimize the relapse risk of ALL, and highlighted the importance of the development of new technologies of genomic investigation for translational medicine...
2018: Methods in Molecular Biology
Xavier Tchetnya, Calypse Asangbe Ngwasiri, Tiayah Munge, Leopold Ndemnge Aminde
BACKGROUND: Toxic epidermal necrolysis (TEN) is a rare life threatening dermatological disorder characterized by extensive epidermal detachment and erosion of mucous membranes. It is typically a side effect of some medications. Nevirapine, a nonnucleoside reverse transcriptase inhibitor (NNRTI) is one of the frequently used components of highly active antiretroviral therapy (HAART). Skin rash is its common adverse reaction, usually mild and rarely progressing to TEN. Ophthalmic involvement is common as well but rarely progresses to blindness especially in the pediatric population...
March 13, 2018: BMC Pediatrics
Ana Marin Navarro, Evelyn Susanto, Anna Falk, Margareta Wilhelm
In vitro modeling of complex diseases is now a possibility with the use of patient-derived induced pluripotent stem (iPS) cells. Their stem cell properties, including self-renewal and their potential to virtually differentiate into any cell type, emphasize their importance as a translational tool for modeling disorders that so far have been limited by the unavailability of primary cell lines, animal models, or inaccessible human materials. Around 100 genes with germline mutations have been described to be responsible for cancer predisposition...
December 2018: Cell Death Discovery
Diana Bellavia, Rocco Palermo, Maria Pia Felli, Isabella Screpanti, Saula Checquolo
Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Although the therapy of ALL has significantly improved, the heterogeneous genetic landscape of the disease often causes relapse, which is difficult to treat. Achieving a positive outcome for patients with relapsed or refractory ALL remains a challenging issue. The high prevalence of NOTCH-activating mutations in T-cell acute lymphoblastic leukemia (T-ALL) and the central role of NOTCH signaling in regulating cell survival and growth of ALL provide a rationale for the development of Notch signaling-targeted strategies in this disease...
March 12, 2018: Expert Opinion on Therapeutic Targets
J J Garcia-Penas
INTRODUCTION: Most individuals with epilepsy will respond to pharmacologic treatment; however, approximately 20-30% will develop medically refractory epilepsy. Cognitive side effects of antiepileptic drugs are common and can negatively affect tolerability, compliance, and long-term retention of the treatment. Ketogenic diet is an effective and well-tolerated treatment for these children with refractory epilepsy without any negative effect on cognition or behavior. AIM: To review the current state of experimental and clinical data concerning the neuroprotective and cognitive effects of the ketogenic diet in both humans and animals...
March 1, 2018: Revista de Neurologia
Jean-François Ghersi-Egea, Elodie Saudrais, Nathalie Strazielle
Drug bioavailability to the developing brain is a major concern in the treatment of neonates and infants as well as pregnant and breast-feeding women. Central adverse drug reactions can have dramatic consequences for brain development, leading to major neurological impairment. Factors setting the cerebral bioavailability of drugs include protein-unbound drug concentration in plasma, local cerebral blood flow, permeability across blood-brain interfaces, binding to neural cells, volume of cerebral fluid compartments, and cerebrospinal fluid secretion rate...
March 7, 2018: Pharmaceutical Research
Karoly Toth, Jacqueline F Spencer, Baoling Ying, Ann E Tollefson, Caroll B Hartline, Eric T Richard, Jiajun Fan, Jinglei Lyu, Boris A Kashemirov, Cheryl Harteg, Dawn Reyna, Elke Lipka, Mark N Prichard, Charles E McKenna, William S M Wold
Human adenoviruses (AdV) cause generally mild infections of the respiratory and GI tracts as well as some other tissues. However, AdV can cause serious infection in severely immunosuppressed individuals, especially pediatric patients undergoing allogeneic hematopoietic stem cell transplantation, where mortality rates are up to 80% with disseminated disease. Despite the seriousness of AdV disease, there are no drugs approved specifically to treat AdV infections. We report here that USC-087, an N-alkyl tyrosinamide phosphonate ester prodrug of HPMPA, the adenine analog of cidofovir, is highly effective against multiple AdV types in cell culture...
March 3, 2018: Antiviral Research
Joanna Y Huang, Paul Monagle, M Patricia Massicotte, Christina J VanderPluym
INTRODUCTION: Ventricular Assist Devices (VADs) are increasingly utilised in children with end-stage heart failure, and experience high bleeding and clotting rates. In particular, pediatric VAD patients are more challenging than adults to anticoagulate due to developmental hemostasis, lack of suitable drug preparations, and difficult anticoagulation monitoring often due to poor vascular access; in addition to difficulties of VAD design in smaller children. This review aims to summarize the current evidence related to antithrombotic therapy in pediatric VAD patients...
February 28, 2018: Thrombosis Research
Xiangxiang Shi, Jun Zheng, Tingting Yan
Human respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants and young children. Here, the RSV fusion (F) glycoprotein epitope FFL was redesigned based on its complex crystal structure with motavizumab, an mAb drug in development for the prevention of RSV infections, aiming to obtain therapeutic peptide vaccines with high affinity to induce RSV-specific neutralizing antibodies. Computational modeling and analysis found that only a small region covering the helix-turn-helix (HTH) motif of FFL can directly interact with motavizumab and confer stability and specificity to the complex system, while the rest of the epitope primarily serves as a structural scaffold that stabilizes the HTH conformation of motavizumab-binding site...
March 2, 2018: Journal of Molecular Modeling
Million A Tegenge, Iftekhar Mahmood, Zhen Jiang, Richard Forshee
Allometric approaches are widely used for interspecies scaling for the prediction of pharmacokinetic (PK) parameters during drug development. The concept of allometry can also be extended to predict PK parameters from adults to children. Three methods for extrapolating pediatric clearance were developed and evaluated using the clearance values of 4 drugs. The first method was established using a simple allometric (SA) model with estimated coefficient and exponent based on data ranging from children older than 2 years to adult...
February 28, 2018: Journal of Clinical Pharmacology
Timothy McKinnon, Rosemarie Venier, Marielle Yohe, Sivasish Sindiri, Berkley E Gryder, Jack F Shern, Leah Kabaroff, Brendan Dickson, Krista Schleicher, Guillaume Chouinard-Pelletier, Serena Menezes, Abha Gupta, Xiaohu Zhang, Rajarashi Guha, Marc Ferrer, Craig J Thomas, Yuhong Wei, Dariush Davani, Cynthia J Guidos, Javed Khan, Rebecca A Gladdy
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and outcomes have stagnated, highlighting a need for novel therapies. Genomic analysis of RMS has revealed that alterations in the receptor tyrosine kinase (RTK)/RAS/PI3K axis are common and that FGFR4 is frequently mutated or overexpressed. Although FGFR4 is a potentially druggable receptor tyrosine kinase, its functions in RMS are undefined. This study tested FGFR4-activating mutations and overexpression for the ability to generate RMS in mice...
February 28, 2018: Oncogene
Zachary N Warnken, Hugh D C Smyth, Daniel A Davis, Steve Weitman, John G Kuhn, Robert O Williams
Effective targeting of nasal spray deposition could improve local, systemic, and CNS drug delivery, however, this has proven to be difficult due anatomical features of the nasal cavity including the nasal valve and turbinate structures. Furthermore, nasal cavity geometries and dimensions vary between individuals based on differences in their age, gender and ethnicity. The effect of patient-specific administration parameters was evaluated for their ability to overcome the barriers to targeted nasal drug delivery...
February 27, 2018: Molecular Pharmaceutics
Serkan Kırık, Olcay Güngör, Sedat Işıkay, Can Acıpayam, Yasemin Çoban, Emre Çelik
Decreased height of the eyelid or the narrowing of the lid is called ptosis. Ptosis has several causes. Malignancy-related conditions such as Horner's syndrome, which causes unilateral ptosis in the pediatric age group, and patients with malignancy receiving chemotherapeutic treatment, are often secondary to these drugs and ptosis is a clue of underlying diseases. Underlying pathologies can lead to different clinical conditions such as cognitive impairment from coma, the presence of ptosis should be cautionary...
December 2017: Türk Pediatri Arşivi
Hermine I Brunner, Nikolay Tzaribachev, Gabriel Vega-Cornejo, Ingrid Louw, Alberto Berman, Inmaculada Calvo Penadés, Jordi Antón, Francisco Ávila-Zapata, Rubén Cuttica, Gerd Horneff, Ivan Foeldvari, Vladimir Keltsev, Daniel J Kingsbury, Diego Oscar Viola, Rik Joos, Bernard Lauwerys, Maria Eliana Paz Gastañaga, Maria Elena Rama, Carine Wouters, John Bohnsack, Johannes Breedt, Michel Fischbach, Thomas Lutz, Kirsten Minden, Tatiana Miraval, Mahmood Mtm Ally, Nadina Rubio-Pérez, Elisabeth Solau Gervais, Riana van Zyl, Xiaohui Li, Marleen Nys, Robert Wong, Subhashis Banerjee, Daniel J Lovell, Alberto Martini, Nicolino Ruperto
OBJECTIVE: To investigate pharmacokinetics, effectiveness, and safety of subcutaneous (SC) abatacept over 24 months (M) in patients with polyarticular-course juvenile idiopathic arthritis (pJIA). METHODS: In this phase III, open-label, international, multicenter, single-arm study, patients with pJIA (cohort 1: 6-17 years; cohort 2: 2-5 years) who failed ≥1 disease-modifying antirheumatic drug received weight-tiered SC abatacept weekly: 10-<25 kg (50 mg); 25-<50 kg (87...
February 26, 2018: Arthritis & Rheumatology
Paul Harmatz, Chester B Whitley, Raymond Y Wang, Mislen Bauer, Wenjie Song, Christine Haller, Emil Kakkis
BACKGROUND: Drug development for ultra-rare diseases is challenging because small sample sizes and heterogeneous study populations hamper the ability of randomized, placebo-controlled trials with a single primary endpoint to demonstrate valid treatment effects. METHODS: To overcome these challenges, a novel Blind Start design was utilized in a study of vestronidase alfa in mucopolysaccharidosis VII (Sly syndrome), an ultra-rare lysosomal disease, that demonstrates the strengths of this approach in a challenging drug-development setting...
February 12, 2018: Molecular Genetics and Metabolism
Holly L Peay, Barbara B Biesecker, Benjamin S Wilfond, Jill Jarecki, Kendall L Umstead, Diana M Escolar, Aad Tibben
BACKGROUND/AIMS: Pediatric rare disease presents a challenging situation of high unmet need and a limited pool of potential clinical trial participants. Understanding perspectives of parents of children who have not participated in trials may facilitate approaches to optimize participation rates. The objective of this study was to explore factors associated with parental interest in enrolling children with pediatric neuromuscular disorders in clinical trials. METHODS: Parents of individuals with Duchenne or Becker muscular dystrophy and spinal muscular atrophy were recruited through advocacy organizations, a registry, and clinics...
January 1, 2018: Clinical Trials: Journal of the Society for Clinical Trials
Susanne Thümmler, Emmanuelle Dor, Renaud David, Graziella Leali, Michele Battista, Alexia David, Florence Askenazy, Céline Verstuyft
Background: Severe mental health disorders in children and adolescents represent a major public health problem. Despite adequate drug treatment, some patients develop pharmacoresistant disease. As a consequence, physicians are confronted with prescribing challenges, prolonged hospitalization and increased risk of adverse events, thus aggravating short-, medium-, and long-term prognosis. The majority of psychotropic treatments, particularly antipsychotics and antidepressants, are metabolized at hepatic level by cytochrome P450 (CYP), particularly by CYP3A4 and CYP2D6...
2018: Frontiers in Psychiatry
Seetha Chandran, K S Dinesh, B J Patgiri, Prasanth Dharmarajan
Childhood is considered as the most important phase in life, which determines the quality of health, well being, learning and behaviour across the lifespan. This may be the reason for giving the foremost position for Balacikitsa among Ashtangas (8 branches) of Ayurveda. The regional growth of indigenous medicine gave significant contribution for the development of primary health care. Kerala has major contribution of many authentic textbooks of Balacikitsa like Arogyakalpadruma, Vaidya Tarakam etc. These are more practically oriented and it can be considered as a physician's quick reference hand book...
February 19, 2018: Journal of Ayurveda and Integrative Medicine
Michael J Mello, Sara J Becker, Julie Bromberg, Janette Baird, Mark R Zonfrillo, Anthony Spirito
BACKGROUND: The American College of Surgeons mandates universal screening for alcohol misuse and delivery of an intervention for those screening positive as a requirement for certification as a level 1 trauma center. Though this requirement has been mandated for over a decade, its implementation has been challenging. Our research team completed an implementation study supporting seven pediatric trauma centers' compliance with the requirement by developing and implementing an institutional alcohol Screening, Brief Intervention and Referral to Treatment (SBIRT) policy for adolescent trauma patients...
February 22, 2018: Implementation Science: IS
Amy S Paller, Rakesh Singh, Martin Cloutier, Marjolaine Gauthier-Loiselle, Bruno Emond, Annie Guérin, Arijit Ganguli
IMPORTANCE: While psoriasis (Ps) is mainly characterized as an adult disease, it can also develop during childhood. However, prevalence estimates of pediatric psoriasis in the United States (US) are lacking. OBJECTIVE: To assess the 2015 annual prevalence of Ps and moderate-to-severe Ps in pediatric individuals in the US. DESIGN: This is a retrospective study based on a large administrative insurance claims database in the US. SETTING: Data were extracted from the Truven Health Analytics MarketScan® Commercial Claims and Encounters database, which covers over 60 million individuals with employer-provided health insurance across the US...
February 1, 2018: Journal of Drugs in Dermatology: JDD
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