Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Nonclinical Profile of PF-06952229 (MDV6058), a Novel TGFβRI/Activin Like Kinase 5 (ALK-5) Inhibitor Supports Clinical Evaluation in Cancer","authors":"Mausumee Guha, Stephane Thibault, Son Pham, Sebastian Bernales, Rama Pai, Francisco J. Herrera, Theodore R. Johnson, Allison Vitsky, Tina Fernando, Martin Finkelstein","doi":"10.1124/jpet.124.002193","DOIUrl":"https://doi.org/10.1124/jpet.124.002193","url":null,"abstract":"The development of TGFβR inhibitors (TGFβRi) as new medicines have been affected by cardiac valvulopathy and arteriopathy toxicity findings in nonclinical toxicology studies. PF-06952229 (MDV6058) selected using rational drug design is a potent and selective TGFβRI inhibitor (TGFβRIi) with a relatively clean off-target selectivity profile and good pharmacokinetic properties across species. PF-06952229 inhibited clinically translatable phospho-SMAD2 biomarker ({greater than or equal to}60%) in human and cynomolgus monkey peripheral blood mononuclear cells, as well as in mouse and rat splenocytes. Using an optimized, intermittent dosing schedule (7 day-on, 7-off/cycle; five cycles), PF-06952229 demonstrated efficacy in a 63-day syngeneic MC38 colon carcinoma mouse model. In the pivotal repeat dose toxicity studies (rat and cynomolgus monkey), PF-06952229 on an intermittent dosing schedule (5 day-on, 5-off/cycle; five cycles, 28 doses) showed no cardiac-related adverse findings. However, new toxicity findings related to PF-06952229 included reversible hepatocellular (hepatocyte necrosis with corresponding clinically monitorable transaminase increases) and lung (hemorrhage with mixed cell inflammation) findings at {greater than or equal to} targeted projected clinical efficacious exposures. Furthermore, partially reversible cartilage hypertrophy (trachea and femur in rat; femur in monkey), and partially to fully reversible, clinically monitorable decreases in serum phosphorus and urinary phosphate, at {greater than or equal to} projected clinically efficacious exposures were observed. Given the integral role of TGFβ in endochondral bone formation, cartilage findings in toxicity studies have been observed with other TGFβRi class of compounds. The favorable cumulative profile of PF-06952229 in biochemical, pharmacodynamic, pharmacokinetic and nonclinical studies, allowed for its evaluation in cancer patients using the intermittent dosing schedule (7-on/7-off) and careful protocol-defined monitoring.","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142255558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sensory-motor neuropathy in Mfn2 T105M knock-in mice and its reversal by a novel piperine-derived mitofusin activator","authors":"Jochen Weigele, Lihong Zhang, Antonietta Franco, Etienne Cartier, Gerald W. Dorn","doi":"10.1124/jpet.124.002258","DOIUrl":"https://doi.org/10.1124/jpet.124.002258","url":null,"abstract":"Mitochondrial dysfunction is a hallmark of many genetic neurodegenerative diseases, but therapeutic options to reverse mitochondrial dysfunction are limited. While recent studies support the possibility of improving mitochondrial fusion/fission dynamics and motility to correct mitochondrial dysfunction and resulting neurodegeneration in Charcot-Marie-Tooth disease (CMT) and other neuropathies, the clinical utility of reported compounds and relevance of pre-clinical models are uncertain. Here, we describe motor and sensory neuron dysfunction characteristic of clinical CMT type 2A in a CRISPR/Casp-engineered Mfn2 Thr105Met (T105M) mutant knock-in mouse. We further demonstrate that daily oral treatment with a novel mitofusin activator derived from the natural product piperine can reverse these neurological phenotypes. Piperine derivative 8015 promoted mitochondrial fusion and motility in Mfn2-deficient cells in a mitofusin-dependent manner, and reversed mitochondrial dysfunction in cultured fibroblasts and reprogrammed motor neurons from a human CMT2A patient carrying the MFN2 T105M mutation. Like previous mitofusin activators, 8015 exhibited stereospecific functionality, but the more active stereoisomer, 8015-P2, is unique in that it has sub-nanomolar potency and undergoes entero-hepatic recirculation which extends its in vivo half-life. Daily administration of 8015-P2 to Mfn2 T105M knock-in mice for 6 weeks normalized neuromuscular and sensory dysfunction and corrected histological/ultrastructural neurodegeneration and neurogenic myoatrophy. These studies describe a more clinically relevant mouse model of CMT2A and an improved mitofusin activator derived from piperine. We posit that 8015-P2 and other piperine derivatives may benefit CMT2A or other neurodegenerative conditions wherein mitochondrial dysdynamism plays a contributory role.","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142255557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First-in-Class Mitogen-Activated Protein Kinase p38α: MAPK-Activated Protein Kinase-2 (MK2) Dual Signal Modulator with Anti-inflammatory and Endothelial-stabilizing Properties","authors":"Mohan E Tulapurkar, Kari Ann Shirey, Katerina N. Lugkey, Wendy Luo, Ritu Lal, Adam Galan, Omar Mahmoud, Nathaniel McClean, Kiruphagaran Thangaraju, Daniel Cericola, Daniel Lewis, William A. Murphy, Steven Fletcher, Alexander D. MacKerell, Stefanie N. Vogel, Paul Shapiro, Jeffrey D Hasday","doi":"10.1124/jpet.124.002281","DOIUrl":"https://doi.org/10.1124/jpet.124.002281","url":null,"abstract":"We previously identified a small molecule, UM101, predicted to bind to the substrate-binding groove of p38aMitogen-activated Protein Kinase (MAPK) near the binding site of its proinflammatory substrate, MAPK-activated protein kinase (MK2). UM101 exhibited anti-inflammatory, endothelial-stabilizing, and lung-protective effects. To overcome its limited aqueous solubility and p38a binding affinity, we designed an analog of UM101, GEn-1124, with improved aqueous solubility, stability, and p38a binding affinity. Compared with UM101, GEn-1124 has 18-fold greater p38a-binding affinity as measured by Surface Plasmon Resonance (SPR), 11-fold greater aqueous solubility, enhanced barrier-stabilizing activity in thrombin-stimulated human pulmonary artery endothelial cells (hPAEC) <em>in vitro,</em> and greater lung protection <em>in vivo</em>. GEn-1124 improved survival from 10% to 40% in murine acute lung injury (ALI) induced by combined exposure to intratracheal bacterial endotoxin lipopolysaccharide (LPS) instillation and febrile-range hyperthermia (FRH) and from 0% to 50% in a mouse influenza pneumonia model. Gene expression analysis by RNASeq in TNFa-treated hPAEC showed that the gene-modifying effects of GEn-1124 were much more restricted to TNFa-inducible genes than the catalytic site p38 inhibitor, SB203580. Gene expression pathway analysis, confocal immunofluorescence analysis of p38aand MK2 subcellular trafficking, and SPR analysis of phosphorylated p38a:MK2 binding affinity supports a novel mechanism of action. GEn-1124 destabilizes the activated p38a:MK2 complex, dissociates nuclear export of MK2 and p38a, thereby promoting intranuclear retention and enhanced intranuclear signaling by phosphorylated p38a retention, and accelerated inactivation of p38-free cytosolic MK2 by unopposed phosphatases.","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142255556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Factors influencing the Central Nervous System (CNS) distribution of the ATR inhibitor elimusertib (BAY1895344): Implications for the treatment of CNS tumors","authors":"Sneha Rathi, Ann C Mladek, Ju-Hee Oh, Sonja Dragojevic, Danielle M. Burgenske, Wenjuan Zhang, Surabhi Talele, Wenqiu Zhang, Katrina K Bakken, Brett L Carlson, Margaret A Connors, Lihong He, Zeng Hu, Jann N. Sarkaria, William F. Elmquist","doi":"10.1124/jpet.123.002002","DOIUrl":"https://doi.org/10.1124/jpet.123.002002","url":null,"abstract":"Glioblastoma (GBM) is a disease of the whole brain, with infiltrative tumor cells protected by an intact BBB. GBM has a poor prognosis despite aggressive treatment, in part due to lack of adequate drug permeability at the BBB. Standard of care GBM therapies include radiation and cytotoxic chemotherapy that lead to DNA damage. Subsequent activation of DNA damage response (DDR) pathways can induce resistance. Various DDR inhibitors, targeting the key regulators of these pathways such as ataxia telangiectasia mutated and Rad3-related (ATR), are being explored as radio- and chemo-sensitizers. Elimusertib, a novel ATR kinase inhibitor, can prevent repair of damaged DNA, increasing efficacy of DNA damaging cytotoxic therapies. Robust synergy was observed <em>in vitro </em>when elimusertib was combined with the DNA-damaging agent, temozolomide, however, we did not observe improvement with this combination in <em>in vivo </em>efficacy studies in GBM orthotopic tumor-bearing mice. This <em>in vitro - in vivo</em> disconnect was explored to understand factors influencing CNS distribution of elimusertib and reasons for lack of efficacy. We observed that elimusertib is rapidly cleared from systemic circulation in mice and would not maintain adequate exposure in the CNS for efficacious combination therapy with temozolomide. CNS distribution of elimusertib is partially limited by P-gp efflux at the BBB, and high binding to CNS tissues leads to low levels of pharmacologically active (unbound) drug in the brain. Acknowledging the potential for inter-species differences in pharmacokinetics, these data suggest that clinical translation of elimusertib in combination with temozolomide for treatment of GBM may be limited.","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142255553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<b>Significance of Nitric Oxide Derived from the</b> <b>Nitric Oxide Synthases System in Cardiovascular</b> <b>Inter-Organ Cross-Talk</b>.","authors":"Masato Tsutsui, Kazuhiro Yatera","doi":"10.1124/jpet.124.002222","DOIUrl":"https://doi.org/10.1124/jpet.124.002222","url":null,"abstract":"<p><p>Inter-organ cross-talk contributes to the pathogenesis of various disorders, and drug development based on inter-organ cross-talk is attracting attention. The roles of nitric oxide (NO) derived from the NO synthases system (NOSs) in inter-organ cross-talk remain unclear. We have investigated this issue by using our mice deficient in all three NOSs (triple n/i/eNOSs^-/- mice). We reported that 2/3 nephrectomized triple n/i/eNOSs^-/- mice die suddenly because of early onset of myocardial infarction, suggesting the protective role of NO derived from NOSs in the cross-talk between the kidney and the heart. We studied the role of NO derived from NOSs expressed in the bone marrow in vascular lesion formation. Constrictive arterial remodeling and neointimal formation following unilateral carotid artery ligation were prominently aggravated in wild-type mice transplanted with triple n/i/eNOSs^-/- bone marrow cells as compared with those with wild-type bone marrow cells, suggesting the protective role of NO derived from NOSs in the cross-talk between the bone marrow and the blood vessel. We further investigated the role of NO derived from NOSs expressed in the bone marrow in pulmonary hypertension. The extent of pulmonary hypertension after chronic hypoxic exposure was markedly exacerbated in wild-type mice underwent triple n/i/eNOSs^-/- bone marrow transplantation as compared with those underwent wild-type bone marrow transplantation, suggesting the protective role of NO derived from NOSs in the cross-talk between the bone marrow and the lung. These lines of evidence demonstrate that systemic and myelocytic NOSs could be novel therapeutic targets for myocardial infarction, vascular disease, and pulmonary hypertension. <b>Significance Statement</b> We demonstrated in studies with triple n/i/eNOSs^-/- mice that partial nephrectomy accelerates the occurrence of myocardial infarction induced by systemic NOSs deficiency, that myelocytic NOSs deficiency aggravates vascular lesion formation after unilateral carotid artery ligation, and that myelocytic NOSs deficiency exacerbates chronic hypoxia-induced pulmonary hypertension. These results suggest that NO derived from NOSs plays a protective role in cardiovascular inter-organ cross-talk, indicating that systemic and myelocytic NOSs could be important therapeutic targets for myocardial infarction, vascular disease, and pulmonary hypertension.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KVX-053, a Protein Tyrosine Phosphatase 4A3 inhibitor, ameliorates SARS-CoV-2 Spike protein subunit 1 - induced acute lung injury in mice.","authors":"Pavel A Solopov, Ruben Manuel Luciano Colunga Biancatelli, Tierney Day, Betsy Gregory, Elizabeth R Sharlow, John S Lazo, John D Catravas","doi":"10.1124/jpet.124.002154","DOIUrl":"10.1124/jpet.124.002154","url":null,"abstract":"<p><p>The Acute Respiratory Distress Syndrome (ARDS), often preceded by acute lung injury (ALI), is characterized by the accumulation of inflammatory fluid in the lung alveoli, leaky alveolar epithelium and endothelium, and overexpression of pro-inflammatory cytokines. This progression from ALI to ARDS is a major contributor to the high mortality observed in COVID-19 patients. The Spike protein of SARS-CoV-2 binds to lung ACE2 and, in addition to facilitating viral cell entry, it plays an important role in the development of ALI and ARDS, especially in the later phases of COVID-19 as well as long COVID. Protein tyrosine phosphatase (PTP) 4A3 is a key mediator of ARDS pathology. This study tested the hypothesis that targeting PTP4A3 would prevent COVID-19 associated ALI. Intratracheal administration of SARS-CoV-2 Spike protein Subunit 1 to K18-hACE2 transgenic mice expressing human ACE2 elicited pulmonary and systemic inflammation, leaky alveoli, overexpression of cytokines, structural lung injury and lung dysfunction; all these symptoms were ameliorated by the selective, allosteric inhibitor of PTP4A3, KVX-053. These findings provide the first evidence supporting a role for PTP4A3 in the development of SARS-CoV-2- mediated ALI. <b>Significance Statement</b> This study tested the hypothesis that targeting PTP4A3 would prevent COVID-19 associated ALI/ARDS. Intratracheal administration of SARS-CoV-2 Spike protein Subunit 1 to K18-hACE2 transgenic mice expressing human ACE2 elicited pulmonary and systemic inflammation, leaky alveoli, overexpression of cytokines and chemokines, structural lung injury and lung dysfunction; all these symptoms were ameliorated by the selective, allosteric inhibitor of PTP4A3, KVX-053. These findings suggest that this novel PTP4A3 inhibitor may be useful against COVID-19 and potentially other viral-induced ARDS.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of TTX-S Na⁺ currents by a novel blocker QLS-278 for antinociception.","authors":"Min Su, Xiang-Shuo Ou-Yang, Ping Zhou, Li-Ying Dong, Li-Ming Shao, Ke-Wei Wang, Ya-Ni Liu","doi":"10.1124/jpet.124.002273","DOIUrl":"https://doi.org/10.1124/jpet.124.002273","url":null,"abstract":"<p><p>Genetic loss-of-function mutations of Nav1.7 channel, abundantly expressed in peripheral nociceptive neurons, cause congenital insensitivity to pain (CIP) in humans, indicating that selective inhibition of the channel may lead to potential therapy of pain disorders. In this study, we investigated a novel compound, 5-chloro-N-(cyclopropylsulfonyl)-2-fluoro-4-(2-(8-(furan-2-ylmethyl)-8-azaspiro [4.5] decan-2-yl) ethoxy) benzamide (QLS-278) that inhibits Nav1.7 channel and exhibits anti-nociceptive activity. Compound QLS-278 exhibits inactivation- and concentration-dependent inhibition of macroscopic currents of Nav1.7 channels stably expressed in HEK293 cells with an IC₅₀ of 1.2 {plus minus} 0.2 μM. QLS-278 causes a hyperpolarization shift of the channel inactivation and delays recovery from inactivation, without an obvious effect on voltage-dependent activation. In mouse DRG neurons, QLS-278 suppresses native TTX-sensitive Nav currents and also reduces neuronal firing. Moreover, QLS-278 dose-dependently relieves neuropathic pain induced by spared nerve injury and inflammatory pain induced by formalin without significant alteration of spontaneous locomotor activity in mice. Altogether, our identification of the novel compound QLS-278 may hold developmental potential for the treatment of chronic pain. <b>Significance Statement</b> QLS-278, a novel voltage-gated sodium Nav1.7 channel blocker, inhibits native TTX-S Na⁺ current and reduces action potential firings in DRG sensory neurons. QLS-278 also exhibits antinociceptive activity in mouse models of pain, thus demonstrating potential for the development of a treatment for chronic pain.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<b>Mitigation of cisplatin-induced acute kidney injury through oral administration of FAAH Inhibitor PF-04457845</b>.","authors":"Chaoling Chen, Weili Wang, Justin L Poklis, Pin-Lan Li, Aron H Lichtman, David A Gewirtz, Ningjun Li","doi":"10.1124/jpet.124.002282","DOIUrl":"https://doi.org/10.1124/jpet.124.002282","url":null,"abstract":"<p><p>Fatty acid amide hydrolase (FAAH) serves as the primary enzyme responsible for degrading the endocannabinoid anandamide (AEA). Inhibition of FAAH, either through pharmacological means or genetic manipulation, can effectively reduce inflammation in various organs, including the brain, colon, heart, and kidneys. Infusion of a FAAH inhibitor into the kidney medulla has been shown to induce diuretic and natriuretic effects. FAAH knockout mice have shown protection against both post-ischemia reperfusion injury and cisplatin-induced acute kidney injury (AKI), although through distinct mechanisms. The present study was based on the hypothesis that pharmacological inhibition of FAAH activity could mitigate cisplatin-induced AKI, exploring potential renoprotective mechanism. Male wild type C57BL/6 were administered an oral gavage of a FAAH inhibitor (PF-04457845, 5mg/kg) or vehicle (10% PEG200+5% Tween80+normal saline) at 72, 48, 24, and 2 hours before and 24 and 48 hours after a single intraperitoneal injection of cisplatin (Cis, 25 mg/kg). Mice were euthanatized 72 hours after cisplatin treatment. Compared to vehicle-treated mice, PF-04457845-treated mice showed a decrease of cisplatin-induced plasma creatinine, blood urea nitrogen levels, kidney injury biomarkers (NGAL and KIM-1) and renal tubular damage. The renal protection from oral gavage of PF-04457845 against cisplatin-induced nephrotoxicity was associated with an enhanced AEA tone and reduced levels of DNA damage response biomarkers p53 and p21. Our work demonstrates that PF-04457845 effectively alleviates cisplatin-induced nephrotoxicity in mice, underscoring the potential of orally targeting FAAH as a novel strategy to prevent cisplatin nephrotoxicity. <b>Significance Statement</b> Oral administration of FAAH inhibitor, can reduce cisplatin-induced DNA damage response, tubular damages, and kidney dysfunction. Inactivation of FAAH could be a potential strategy to prevent cisplatin-induced nephrotoxicity.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug-induced long QT syndrome: Concept and non-clinical models for predicting the onset of drug-induced torsade de pointes in patients in compliance with ICH E14/S7B guidance.","authors":"Atsushi Sugiyama, Ai Goto, Hiroko Izumi-Nakaseko, Yoshinori Takei, Akira Takahara, Ryuichi Kambayashi","doi":"10.1124/jpet.124.002184","DOIUrl":"https://doi.org/10.1124/jpet.124.002184","url":null,"abstract":"<p><p>ICH established S7B and E14 guidelines in 2005 to prevent drug-induced torsade de pointes (TdP), effectively preventing the development of high-risk drugs. However, those guidelines unfortunately hampered the development of some potentially valuable drug candidates despite not being proven to be proarrhythmic. In response, Comprehensive In Vitro Proarrhythmia Assay (CiPA) and Exposure-Response Modeling were proposed in 2013 to reinforce proarrhythmic risk assessment. In 2022, ICH released E14/S7B Q&As (Stage 1), emphasizing a \"double negative\" nonclinical scenario for low-risk compounds. For \"non-double negative\" compounds, new Q&As are expected to be enacted as Stage 2 shortly, in which more detailed recommendations for proarrhythmia models and proarrhythmic surrogate markers will be provided. This review details the onset mechanisms of drug-induced TdP, including I_Kr inhibition, pharmacokinetic factors, autonomic regulation and reduced repolarization reserve. It also explores the utility of proarrhythmic surrogate markers (J-T_peak, T_peak-T_end and terminal repolarization period) besides QT interval. Finally, it presents various in silico, in vitro, ex vivo and in vivo models for proarrhythmic risk prediction, such as CiPA in silico model, iPS cell-derived cardiomyocyte sheet, Langendorff perfused heart preparation, chronic atrioventricular block animals (dogs, monkeys, pigs and rabbits), acute atrioventricular block rabbits, methoxamine-sensitized rabbits, and genetically engineered rabbits for specific long QT syndromes. Those models along with the surrogate markers can play important roles in quantifying TdP risk of new compounds, impacting late-phase clinical design and regulatory decision-making, and preventing adverse events on post-marketing clinical use. <b>Significance Statement</b> Since ICH S7B/E14 guidelines unfortunately hampered the development of some potentially valuable compounds with unproven proarrhythmic risk, Comprehensive In Vitro Proarrhythmia Assay and Exposure-Response Modeling were proposed in 2013 to reinforce proarrhythmic risk assessment of new compounds. In 2022, ICH released Q&As (Stage 1) emphasizing \"double negative\" nonclinical scenario for low-risk compounds, and new Q&As (Stage 2) for \"non-double negative\" compounds are expected. This review delves into proarrhythmic mechanisms with surrogate markers, and explores various models for proarrhythmic risk prediction.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Seeing through the Haze: Monoacylglycerol Lipase Inhibitors As Analgesics.","authors":"Jenny L Wilkerson","doi":"10.1124/jpet.124.002132","DOIUrl":"https://doi.org/10.1124/jpet.124.002132","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142004412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}