Cipa

BACKGROUND: Congenital insensitivity to pain (CIP) is a rare autosomal recessive disorder characterized primarily by an inability to perceive physical pain from birth, resulting in the accumulation of bruising, inflammation, and fractures that affect patient's life expectancy. CIP has different forms including CIP and CIPA. CIP with Anhidrosis (CIPA) is the most common type of CIP, which is caused mainly by mutations in NTRK1 and NGF genes, and is characterized by mental retardation and the inability to sweat (Anhidrosis)...

Cardiac cytochrome P450 2J2 (CYP2J2) metabolizes endogenous polyunsaturated fatty acid, arachidonic acid (AA), to bioactive regioisomeric epoxyeicosatrienoic acid (EET) metabolites. This endogenous metabolic pathway has been postulated to play a homeostatic role in cardiac electrophysiology. However, it is unknown if drugs that cause intermediate to high risk torsades de pointes (TdP) exhibit inhibitory effects against CYP2J2 metabolism of AA to EETs. In this study, we demonstrated that 11 out of 16 drugs screened with intermediate to high risk of TdP as defined by the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative are concurrently reversible inhibitors of CYP2J2 metabolism of AA, with unbound inhibitory constant (Ki,AA,u ) values ranging widely from 0...

Guidelines for preclinical drug development reduce the occurrence of arrhythmia-related side effects. Besides ample evidence for the presence of arrhythmogenic substances in plants, there is no consensus on a research strategy for the evaluation of proarrhythmic effects of herbal products. Here, we propose a cardiac safety assay for the detection of proarrhythmic effects of plant extracts based on the experimental approaches described in the Comprehensive In vitro Proarrhythmia Assay (CiPA). Microelectrode array studies (MEAs) and voltage sensing optical technique on human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were combined with ionic current measurements in mammalian cell lines , In-silico simulations of cardiac action potentials (APs) and statistic regression analysis...

Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) are currently used following the Comprehensive in vitro Proarrhythmic Assay (CiPA) initiative and subsequent recommendations in the International Council for Harmonization (ICH) guidelines S7B and E14 Q&A, to detect drug-induced cardiotoxicity. Monocultures of hiPSC-CMs are immature compared to adult ventricular cardiomyocytes and might lack the native heterogeneous nature. We investigated whether hiPSC-CMs, treated to enhance structural maturity, are superior in detecting drug-induced changes in electrophysiology and contraction...

BACKGROUND: Congenital insensitivity to pain with anhidrosis (CIPA) with Charcot arthropathy is a rare combination in orthopaedic clinical practice. The experience dealing with such patients is limited. Here with this case of approximately 10 years follow-up, we wish to shed light on the choices of strategies of surgeries and alerting clinicians with post-surgery complications. The possible underlying reasons for the recurrent Charcot arthropathies as well as strategies for peri-operative management for such surgical cases are also discussed...

3'-Phosphoadenosine-5'-phosphosulfate (PAPS) is the bioactive form of sulfate and is involved in all biological sulfation reactions. The enzymatic transformation method for PAPS is promising, but the low efficiency and high cost of enzyme purification and storage restrict its practical applications. Here, we reported PAPS biosynthesis with a protein crystalline inclusion (PCI)-based enzyme immobilization system. First, the in vivo crystalline inclusion protein CipA was identified as an efficient auto-assembly tag for immobilizing the bifunctional PAPS synthase (ASAK)...

This study proposes a convolutional neural network (CNN) model using action potential (AP) shapes as input for proarrhythmic risk assessment, considering the hypothesis that machine-learning features automatically extracted from AP shapes contain more meaningful information than do manually extracted indicators. We used 28 drugs listed in the comprehensive in vitro proarrhythmia assay (CiPA), consisting of eight high-risk, eleven intermediate-risk, and nine low-risk torsadogenic drugs. We performed drug simulations to generate AP shapes using experimental drug data, obtaining 2000 AP shapes per drug...

The hERG channel is one of the essential ion channels composing the cardiac action potential and the toxicity assay for new drug. Recently, the comprehensive in vitro proarrhythmia assay (CiPA) was adopted for cardiac toxicity evaluation. One of the hurdles for this protocol is identifying the kinetic effect of the new drug on the hERG channel. This procedure included the model-based parameter identification from the experiments. There are many mathematical methods to infer the parameters; however, there are two main difficulties in fitting parameters...

Researchers have recently proposed the Comprehensive In-vitro Proarrhythmia Assay (CiPA) to analyze medicines' TdP risks. Using the TdP metric known as qNet, numerous single-drug effects have been studied to classify the medications as low, intermediate, and high-risk. Furthermore, multiple medication therapies are recognized as a potential method for curing patients, mainly when limited drugs are available. This work expands the TdP risk assessment of drugs by introducing a CiPA-based in silico analysis of the TdP risk of combined drugs...

Levetiracetam (LEV), a well-established anti-seizure medication (ASM), was launched before the original ICH S7B nonclinical guidance assessing QT prolongation potential and the introduction of the Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm. No information was available on its effects on cardiac channels. The goal of this work was to "pressure test" the CiPA approach with LEV and check the concordance of nonclinical core and follow-up S7B assays with clinical and post-marketing data. The following experiments were conducted with LEV (0...

BACKGROUND: Sophoridine (SR) has shown the potential to be an antiarrhythmic agent. However, SR's electrophysiological properties and druggability research are relatively inadequate, which limits the development of SR as an antiarrhythmic candidate. PURPOSE: To facilitate the development process of SR as an antiarrhythmic candidate, we performed integrated studies on the electrophysiological properties of SR in vitro and ex vivo to gain more comprehensive insights into the multi-ion channel blocking effects of SR, which provided the foundation for the further drugability studies in antiarrhythmic and safety studies...

BACKGROUND AND OBJECTIVE: In silico prediction of drug-induced ventricular arrhythmia often requires computationally intensive simulations, making its application tedious and non-interactive. This inconvenience can be mitigated using matrices of precomputed simulation results, allowing instantaneous computation of biomarkers such as action potential duration at 90% of the repolarisation (APD90 ). However, preparing such matrices can be computationally intensive for the method developers, limiting the range of simulated conditions...

Drug-induced cardiotoxicity is one of the main causes of drug failure, which leads to subsequent withdrawal from pharmaceutical development. Therefore, identifying the potential toxic candidate in the early stages of drug development is important. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a useful tool for assessing candidate compounds for arrhythmias. However, a suitable model using hiPSC-CMs to predict the risk of torsade de pointes (TdP) has not been fully established. The present study aimed to establish a predictive TdP model based on hiPSC-CMs...

Drug safety initiatives have endorsed human iPSC-derived cardiomyocytes (hiPSC-CMs) as an in vitro model for predicting drug-induced cardiac arrhythmia. However, the extent to which human-defined features of in vitro arrhythmia predict actual clinical risk has been much debated. Here, we trained a convolutional neural network classifier (CNN) to learn features of in vitro action potential recordings of hiPSC-CMs that are associated with lethal Torsade de Pointes arrhythmia. The CNN classifier accurately predicted the risk of drug-induced arrhythmia in people...

BACKGROUND: Congenital insensitivity to pain with anhidrosis (CIPA) is a very rare inherited autosomal recessive disease that has multiple clinical manifestations. Since its symptoms are related to different systems, this disorder has been investigated on a variety of topics. To better understand publications about CIPA, we conducted a bibliometric study to evaluate research publications on CIPA from 2000 to 2021, and delineate the key contributions in terms of countries, authors and sources...

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare disorder with an absence of pain perception, anhidrosis, heat intolerance, and varying degrees of mental retardation. Though cases of CIPA have innate analgesia, they have been known to have tactile hyperesthesia, thus making anesthesia necessary in case of any surgery. Perioperative complications due to abnormal autonomic functions like bradycardia, hypotension, and hyperthermia are major challenges in the anesthetic management of these cases...

BACKGROUND: Novel coronavirus disease (COVID-19) outbreaks have dramatically changed lifestyles, with various effects on the physical and mental health of families and children with various childhood-onset neurological diseases. A questionnaire survey was conducted to identify family-specific issues and needs of patients with congenital insensitivity to pain with anhidrosis (CIPA) during major changes in their daily lives due to the COVID-19 outbreaks. METHODS: An anonymous questionnaire was sent to 56 families that were members of the Association of Patients and Families of CIPA in Japan between October and November 2020, the first 2 months of the third outbreak...

Clozapine is an atypical neuroleptic used to manage treatment-resistant schizophrenia which is known to inhibit cardiac hERG/KV 11.1 potassium channels, a pharmacological property associated with increased risk of potentially fatal Torsades de Pointes (TdP) and sudden cardiac death (SCD). Yet, the long-standing clinical practice of clozapine does not show a consistent association with increased incidence of TdP, although SCD is considerably higher among schizophrenic patients than in the general population...

Since the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiation, many studies have suggested various in silico features based on ionic charges, action potentials (AP), or intracellular calcium (Ca) to assess proarrhythmic risk. These in silico features are computed through electrophysiological simulations using in vitro experimental datasets as input, therefore changing with the quality of in vitro experimental data; however, research to validate the robustness of in silico features for proarrhythmic risk assessment of drugs depending on in vitro datasets has not been conducted...

In-cell protein crystallization (ICPC) has been investigated as a technique to support the advancement of structural biology because it does not require protein purification and a complicated crystallization process. However, only a few protein structures have been reported because these crystals formed incidentally in living cells and are insufficient in size and quality for structure analysis. Here, we have developed a cell-free protein crystallization (CFPC) method, which involves direct protein crystallization using cell-free protein synthesis...