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Robert M Lester, Joy Olbertz
hERG assays and thorough ECG trials have been mandated since 2005 to evaluate the QT interval and potential proarrhythmic risk of new chemical entities. The high cost of these studies and the shortcomings inherent in these binary and limited approaches to drug evaluation have prompted regulators to search for more cost effective and mechanistic paradigms to assess drug liability as exemplified by the CiPA initiative and the exposure response ICH E14(R3) guidance document. Areas Covered: This review profiles the changing regulatory landscape as it pertains to early drug development and outlines the analyses that can be performed to characterize preclinical and early clinical cardiovascular risk...
October 10, 2016: Expert Review of Clinical Pharmacology
Ksenia Blinova, Jayna Stohlman, Jose Vicente, Dulciana Chan, Lars Johannesen, Maria P Hortigon-Vinagre, Victor Zamora, Godfrey Smith, William J Crumb, Li Pang, Beverly Lyn-Cook, James Ross, Mathew Brock, Stacie Chvatal, Daniel Millard, Loriano Galeotti, Norman Stockbridge, David G Strauss
BACKGROUND: Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) hold promise for assessment of drug-induced arrhythmias and are being considered for use under the Comprehensive in Vitro Proarrhythmia Assay (CiPA). METHODS AND RESULTS: We studied the effects of 26 drugs and 3 drug combinations on two commercially available iPSC-CM types using high-throughput voltage-sensitive dye (VSD) and microelectrode-array (MEA) assays being studied for the Comprehensive in Vitro Proarrhythmia Assessment (CiPA) initiative and compared the results to clinical QT prolongation and torsade de pointes (TdP) risk...
October 3, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
Luca Sala, Milena Bellin, Christine L Mummery
Cardiotoxicity is a severe side effect of drugs that induce structural or electrophysiological changes in heart muscle cells. As a result, the heart undergoes failure and potentially lethal arrhythmias. It is still a major reason for drug failure in preclinical and clinical phases of drug discovery. Current methods for predicting cardiotoxicity are based on guidelines which combine electrophysiological analysis of cell lines expressing ion channels ectopically in vitro with animal models and clinical trials...
September 19, 2016: British Journal of Pharmacology
Babar Kayani, Mathew David Sewell, Johnson Platinum, Andre Olivier, Timothy W R Briggs, Deborah M Eastwood
BACKGROUND: Congenital indifference to pain with anhidrosis (CIPA) is a rare hereditary neuropathy, which is associated with defective sensation to noxious stimuli and autonomic dysfunction. The objective of the study was to report on the orthopaedic manifestations of this condition and provide an evidence-based approach for management. METHODS: Retrospective review of 14 consecutive patients with CIPA referred to a single tertiary centre. Mean age of diagnosis was 2...
September 6, 2016: European Journal of Paediatric Neurology: EJPN
María Luisa Franco, Cristina Melero, Esther Sarasola, Paloma Acebo, Alfonso Luque, Isabel Calatayud-Baselga, María García-Barcina, Marçal Vilar
Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disorder characterized by insensitivity to noxious stimuli and variable intellectual disability (ID) due to mutations in the NTRK1 gene encoding the NGF receptor TrkA. To get an insight in the effect of NTRK1 mutations in the cognitive phenotype we biochemically characterized three TrkA mutations identified in children diagnosed of CIPA with variable ID. These mutations are located in different domains of the protein; L213P in the extracellular domain, Δ736 in the kinase domain and C300stop in the extracellular domain, a new mutation causing CIPA diagnosed in a Spanish teenager...
August 22, 2016: Journal of Biological Chemistry
Jose Vicente, Norman Stockbridge, David G Strauss
Fourteen drugs were removed from the market worldwide because their potential to cause torsade de pointes (torsade), a potentially fatal ventricular arrhythmia. The observation that most drugs that cause torsade block the potassium channel encoded by the human ether-à-go-go related gene (hERG) and prolong the heart rate corrected QT interval (QTc) on the ECG, led to a focus on screening new drugs for their potential to block the hERG potassium channel and prolong QTc. This has been a successful strategy keeping torsadogenic drugs off the market, but has resulted in drugs being dropped from development, sometimes inappropriately...
July 28, 2016: Journal of Electrocardiology
Thomas Colatsky, Bernard Fermini, Gary Gintant, Jennifer B Pierson, Philip Sager, Yuko Sekino, David G Strauss, Norman Stockbridge
The implementation of the ICH S7B and E14 guidelines has been successful in preventing the introduction of potentially torsadogenic drugs to the market, but it has also unduly constrained drug development by focusing on hERG block and QT prolongation as essential determinants of proarrhythmia risk. The Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative was established to develop a new paradigm for assessing proarrhythmic risk, building on the emergence of new technologies and an expanded understanding of torsadogenic mechanisms beyond hERG block...
September 2016: Journal of Pharmacological and Toxicological Methods
Xiaoyu Zhang, Liang Guo, Haoyu Zeng, Stephen L White, Michael Furniss, Bharathi Balasubramanian, Edward Lis, Armando Lagrutta, Frederick Sannajust, Li Leyna Zhao, Biao Xi, Xiaobo Wang, Myrtle Davis, Yama A Abassi
INTRODUCTION: The ICH S7B guidelines recommend that all new chemical entities should be subjected to hERG repolarization screening due to its association with life-threatening "Torsades de Pointes" (TdP) arrhythmia. However, it has become evident that not all hERG channel inhibitors result in TdP and not all compounds that induce QT prolongation and TdP necessarily inhibit hERG. In order to address the limitations of the S7B/E14 guidelines, the FDA through a public/private partnership initiated the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative to examine the possible modification and refinement of the ICH E14/S7B guidelines...
September 2016: Journal of Pharmacological and Toxicological Methods
Guy Page, Phachareeya Ratchada, Yannick Miron, Guido Steiner, Andre Ghetti, Paul E Miller, Jack A Reynolds, Ken Wang, Andrea Greiter-Wilke, Liudmila Polonchuk, Martin Traebert, Gary A Gintant, Najah Abi-Gerges
While current S7B/E14 guidelines have succeeded in protecting patients from QT-prolonging drugs, the absence of a predictive paradigm identifying pro-arrhythmic risks has limited the development of valuable drug programs. We investigated if a human ex-vivo action potential (AP)-based model could provide a more predictive approach for assessing pro-arrhythmic risk in man. Human ventricular trabeculae from ethically consented organ donors were used to evaluate the effects of dofetilide, d,l-sotalol, quinidine, paracetamol and verapamil on AP duration (APD) and recognized pro-arrhythmia predictors (short-term variability of APD at 90% repolarization (STV(APD90)), triangulation (ADP90-APD30) and incidence of early afterdepolarizations at 1 and 2Hz to quantitatively identify the pro-arrhythmic risk...
September 2016: Journal of Pharmacological and Toxicological Methods
Icilio Cavero, Jean-Michel Guillon, Veronique Ballet, Mike Clements, Jean-Frédéric Gerbeau, Henry Holzgrefe
INTRODUCTION: The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a nonclinical Safety Pharmacology paradigm for discovering electrophysiological mechanisms that are likely to confer proarrhythmic liability to drug candidates intended for human use. TOPICS COVERED: Key talks delivered at the 'CiPA on my mind' session, held during the 2015 Annual Meeting of the Safety Pharmacology Society (SPS), are summarized. Issues and potential solutions relating to crucial constituents [e...
September 2016: Journal of Pharmacological and Toxicological Methods
Graham T Dempsey, Khuram W Chaudhary, Nicholas Atwater, Cuong Nguyen, Barry S Brown, John D McNeish, Adam E Cohen, Joel M Kralj
INTRODUCTION: The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative seeks an in vitro test to accurately predict clinical Torsades de Pointes (TdP). We developed a cardiotoxicity assay incorporating simultaneous measurement of the action potential (AP) waveform and Ca(2+) transient (CT) in human iPSC-derived cardiomyocytes (CMs). Concurrent optogenetic pacing provided a well-controlled electrophysiological background. METHODS: We used the Optopatch platform for all-optical electrophysiology (Hochbaum et al...
September 2016: Journal of Pharmacological and Toxicological Methods
Ingo Kurth, Manuela Baumgartner, Maria Schabhüttl, Cecilia Tomni, Reinhard Windhager, Tim M Strom, Thomas Wieland, Kurt Gremel, Michaela Auer-Grumbach
Congenital insensitivity to pain and anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV), is characterized by recurrent episodes of unexplained high fever, loss of pain perception and temperature sensation, absent sweating, repeated traumatic and thermal injuries, and mild mental retardation. After exclusion of obviously pathogenic mutations in NTRK1, the most common cause of CIPA, whole exome sequencing (WES) was carried out in a CIPA patient with unrelated parents...
September 2016: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
Zhihua Li, Sara Dutta, Jiansong Sheng, Phu N Tran, Wendy Wu, Thomas Colatsky
INTRODUCTION: Current regulatory guidelines for assessing the risk of QT prolongation include in vitro assays assessing drug effects on the human ether-à-go-go-related (hERG; also known as Kv11.1) channel expressed in cell lines. These assays are typically conducted at room temperature to promote the ease and stability of recording hERG currents. However, the new Comprehensive in vitro Proarrhythmia Assay (CiPA) paradigm proposes to use an in silico model of the human ventricular myocyte to assess risk, requiring as input hERG channel pharmacology data obtained at physiological temperatures...
September 2016: Journal of Pharmacological and Toxicological Methods
Alison Obergrussberger, Krisztina Juhasz, Ulrich Thomas, Sonja Stölzle-Feix, Nadine Becker, Leo Dörr, Matthias Beckler, Corina Bot, Michael George, Niels Fertig
INTRODUCTION: While extracellular field potential (EFP) recordings using multi-electrode arrays (MEAs) are a well-established technique for monitoring changes in cardiac and neuronal function, impedance is a relatively unexploited technology. The combination of EFP, impedance and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has important implications for safety pharmacology as functional information about contraction and field potentials can be gleaned from human cardiomyocytes in a beating monolayer...
September 2016: Journal of Pharmacological and Toxicological Methods
William J Crumb, Jose Vicente, Lars Johannesen, David G Strauss
INTRODUCTION: The Comprehensive in vitro Proarrhythmia Assay (CiPA) is intended to address the misidentification of drug-associated torsade de pointes risk based solely on hERG and QT data. This new paradigm will consist of four interrelated components, one of which is a panel consisting of six ion channels whose currents are important in both depolarization and repolarization of the cardiac action potential. This study examined the effects of 30 clinical drugs on these ion channels. METHODS: Ion currents were evaluated in expression systems using the manual whole cell patch clamp technique...
September 2016: Journal of Pharmacological and Toxicological Methods
Vugar Nabiyev, Ateş Kara, M Cemalettin Aksoy
BACKGROUND: Congenital insensitivity to pain and anhidrosis (CIPA) is a rare clinical condition characterized by the absence of normal subjective and objective responses to noxious stimuli in patients with intact central and peripheral nervous systems. CASE PRESENTATIONS: Two patients with CIPA are reported. The first patient was a 13-year-old girl who presented to our hospital with multiple joint destructions secondary to osteomyelitis. The second patient was a 10-year-old boy who presented with multiple hand lesions and right leg osteomyelitis...
September 2016: Child's Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery
Ziga Ude, Isolda Romero-Canelón, Brendan Twamley, Deirdre Fitzgerald Hughes, Peter J Sadler, Celine J Marmion
7-(4-(Decanoyl)piperazin-1-yl)-ciprofloxacin, CipA, (1) which is an analogue of the antibiotic ciprofloxacin, and its ruthenium(II) complex [Ru(η(6)-p-cymene)(CipA-H)Cl], (2) have been synthesised and the x-ray crystal structures of 1·1.3H2O·0.6CH3OH and 2·CH3OH·0.5H2O determined. The complex adopts a typical pseudo-octahedral 'piano-stool' geometry, with Ru(II) π-bonded to the p-cymene ring and σ-bonded to a chloride and two oxygen atoms of the chelated fluoroquinolone ligand. The complex is highly cytotoxic in the low μM range and is as potent as the clinical drug cisplatin against the human cancer cell lines A2780, A549, HCT116, and PC3...
July 2016: Journal of Inorganic Biochemistry
Qi Xu, Michael G Resch, Kara Podkaminer, Shihui Yang, John O Baker, Bryon S Donohoe, Charlotte Wilson, Dawn M Klingeman, Daniel G Olson, Stephen R Decker, Richard J Giannone, Robert L Hettich, Steven D Brown, Lee R Lynd, Edward A Bayer, Michael E Himmel, Yannick J Bomble
Clostridium thermocellum is the most efficient microorganism for solubilizing lignocellulosic biomass known to date. Its high cellulose digestion capability is attributed to efficient cellulases consisting of both a free-enzyme system and a tethered cellulosomal system wherein carbohydrate active enzymes (CAZymes) are organized by primary and secondary scaffoldin proteins to generate large protein complexes attached to the bacterial cell wall. This study demonstrates that C. thermocellum also uses a type of cellulosomal system not bound to the bacterial cell wall, called the "cell-free" cellulosomal system...
February 2016: Science Advances
J Gordon Millichap
Investigators from New York University, NY, studied 14 patients with congenital insensitivity to pain with anhidrosis (CIPA), compared to 10 patients with chronically deficient sympathetic activity (pure autonomic failure), and 15 normal age-matched controls.
April 2015: Pediatric neurology briefs
Icilio Cavero, Henry Holzgrefe, Mike Clements
INTRODUCTION: Early clinical Phase I ECG investigations designed to replace the currently applied thorough QT (TQT) study are reviewed to examine how they could complement and verify the conclusions of nonclinical investigations and, in particular, the Comprehensive in vitro Proarrhythmia Assay (CiPA). TOPICS: The IQ-CSRC trial is a prospective ascending multiple-dose first in human (FIH) type investigation performed as a possible replacement for the thorough QT study (TQT)...
July 2016: Journal of Pharmacological and Toxicological Methods
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