[Translation] A randomized, double-blind, placebo-controlled, multicenter clinical study to evaluate the efficacy and safety of polycresol sulfonaldehyde suppositories in the treatment of anal symptoms after hemorrhoid surgery

以复方聚甲酚磺醛栓模拟剂为对照，评价复方聚甲酚磺醛栓治疗痔术后肛门症状的有效性和安全性

[Translation]

To evaluate the efficacy and safety of polycresol sulfonaldehyde suppositories in the treatment of anal symptoms after hemorrhoid surgery, using polycresol sulfonaldehyde suppositories as a control.

Start Date02 Nov 2018

Sponsor / Collaborator

Shenyang Yaolian Technology Innovation Co., Ltd.

CTR20192652 / Active, not recruiting

评价复方聚甲酚磺醛栓治疗内痔或混合痔有效性和安全性的随机、双盲、安慰剂平行对照、多中心临床研究

[Translation] A randomized, double-blind, placebo-controlled, multicenter clinical study to evaluate the efficacy and safety of polycresol sulfonate suppositories in the treatment of internal or mixed hemorrhoids

以复方聚甲酚磺醛栓模拟剂为对照，评价复方聚甲酚磺醛栓治疗内痔或混合痔的有效性和安全性

[Translation]

To evaluate the efficacy and safety of polycresol sulfonaldehyde suppositories in the treatment of internal or mixed hemorrhoids, using polycresol sulfonaldehyde suppositories as a control.

Start Date15 Oct 2018

Sponsor / Collaborator

Shenyang Yaolian Technology Innovation Co., Ltd.

CTR20130055 / CompletedPhase 3

复方聚甲酚磺醛栓与复方角菜酸酯栓平行对照治疗内痔随机、双盲、多中心临床试验

[Translation] A randomized, double-blind, multicenter clinical trial comparing compound polycresol sulfonate suppositories and compound carraghenate suppositories in the treatment of internal hemorrhoids

评价复方聚甲酚磺醛栓治疗内痔的有效性和安全性

[Translation]

To evaluate the effectiveness and safety of compound polycresol sulfonaldehyde suppositories in the treatment of internal hemorrhoids

Start Date29 Jul 2011

Sponsor / Collaborator

Shandong Chengchuang Pharmaceutical R&D Co., Ltd.

100 Clinical Results associated with Nav1.8 x Nav1.5

100 Translational Medicine associated with Nav1.8 x Nav1.5

0 Patents (Medical) associated with Nav1.8 x Nav1.5

Literatures (Medical) associated with Nav1.8 x Nav1.5

01 Oct 2024·Toxicological Sciences

Deconvoluting and derisking QRS complex widening to improve cardiac safety profile of novel plasmepsin X antimalarials

Article

Author: de Haro, Teresa ; Gerets, Helga H J ; Laleu, Benoit ; Hebeisen, Simon ; Lowe, Martin A ; Cardenas, Alvaro ; Valentin, Jean-Pierre ; Gryshkova, Vitalina ; Korlowski, Chloé ; Delaunois, Annie

AbstractQuinoline-related antimalarial drugs have been associated with cardiotoxicity risk, in particular QT prolongation and QRS complex widening. In collaboration with Medicines for Malaria Venture, we discovered novel plasmepsin X (PMX) inhibitors for malaria treatment. The first lead compounds tested in anesthetized guinea pigs (GPs) induced profound QRS widening, although exhibiting weak inhibition of NaV1.5-mediated currents in standard patch clamp assays. To understand the mechanism(s) underlying QRS widening to identify further compounds devoid of such liability, we established a set of in vitro models including CaV1.2, NaV1.5 rate-dependence, and NaV1.8 patch clamp assays, human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), and Langendorff-perfused isolated GP hearts. Six compounds were tested in all models including anesthetized GP, and 8 additional compounds were tested in vitro only. All compounds tested in anesthetized GP and isolated hearts showed a similar cardiovascular profile, consisting of QRS widening, bradycardia, negative inotropy, hypotension, and for some, QT prolongation. However, a left shift of the concentration–response curves was noted from in vitro to in vivo GP data. When comparing in vitro models, there was a good consistency between decrease in sodium spike amplitude in hiPSC-CM and QRS widening in isolated hearts. Patch clamp assay results showed that the QRS widening observed with PMX inhibitors is likely multifactorial, primarily due to NaV1.8 and NaV1.5 rate-dependent sodium blockade and/or calcium channel-mediated mechanisms. In conclusion, early de-risking of QRS widening using a set of different in vitro assays allowed to identify novel PMX inhibitors with improved cardiac safety profile.

01 Aug 2024·Biochemical and Biophysical Research Communications

Unique electrophysiological property of a novel Nav1.7, Nav1.8, and Nav1.9 sodium channel blocker, ANP-230

Article

Author: Takada, Yoshinori ; Kudo, Takehiro ; Ishibashi, Fumiaki ; Oyamada, Yoshihiro ; Maezawa, Yasuyo ; Ikeda, Kazuhito ; Honda, Shigeyuki ; Kamei, Tatsuya ; Yamane, Hana

Voltage-gated sodium channel subtypes, Nav1.7, Nav1.8, and Nav1.9 are predominantly expressed in peripheral sensory neurons. Recent genetic studies have revealed that they are involved in pathological pain processing and that the blockade of Nav1.7, Nav1.8, or Nav1.9 will become a promising pharmacotherapy especially for neuropathic pain. A growing number of drug discovery programs have targeted either of the subtypes to obtain a selective inhibitor which can provide pain relief without affecting the cardiovascular and central nervous systems, though none of them has been approved yet. Here we describe the in vitro characteristics of ANP-230, a novel sodium channel blocker under clinical development. Surprisingly, ANP-230 was shown to block three pain-related subtypes, human Nav1.7, Nav1.8, and Nav1.9 with similar potency, but had only low inhibitory activity to human cardiac Nav1.5 channel and rat central Nav channels. The voltage clamp experiments using different step pulse protocols revealed that ANP-230 had a "tonic block" mode of action without state- and use-dependency. In addition, ANP-230 caused a depolarizing shift of the activation curve and decelerated gating kinetics in human Nav1.7-stably expressing cells. The depolarizing shift of activation curve was commonly observed in human Nav1.8-stably expressing cells as well as rat dorsal root ganglion neurons. These data suggested a quite unique mechanism of Nav channel inhibition by ANP-230. Finally, ANP-230 reduced excitability of rat dorsal root ganglion neurons in a concentration dependent manner. Collectively, these promising results indicate that ANP-230 could be a potent drug for neuropathic pain.

01 Jun 2024·Circulation: Genomic and Precision Medicine

Meta-Analysis of Genome-Wide Association Studies Reveals Genetic Mechanisms of Supraventricular Arrhythmias

Article

Author: Rader, Daniel J ; Weng, Lu-Chen ; Gaziano, J Michael ; Choi, Seung Hoan ; May, Heidi T ; Svendsen, Jesper H ; Lubitz, Steven A ; Kane, John P ; Khan, Habib R ; Dubé, Marie-Pierre ; Nafissi, Navid A ; Roden, Dan M ; Ellinor, Patrick T ; Nauffal, Victor ; Roselli, Carolina ; Orland, Kate M ; Marcus, Gregory M ; Cho, Kelly ; Friedman, Daniel J ; Leong-Sit, Peter ; Pullinger, Clive R ; Yoneda, Zachary T ; Khurshid, Shaan ; Hartmann, Jacob P ; Olesen, Morten S ; Jordà, Paloma ; Sun, Yan V ; Andreasen, Laura ; Palotie, Aarno ; Subbiah, Rajesh ; Eckhardt, Lee L ; Walker, Bruce ; Skanes, Allan C ; Nadkarni, Girish ; Treu, Timothy M ; Johnson, Renee ; Lee, Simon ; Damrauer, Scott M ; Cutler, Michael J ; Shah, Svati H ; Roberts, Jason D ; Karlsson Linnér, Richard ; Oetjens, Matthew T ; Loos, Ruth J F ; Shoemaker, M Benjamin ; Hall, Amelia Weber ; Knight, Stacey ; Wilson, Peter W F ; Tadros, Rafik ; Beer, Dominik ; Morrill, Valerie N ; Fatkin, Diane ; Haggerty, Christopher M ; Tardif, Jean-Claude ; Issa, Tariq Z ; Clayton, Anne ; Judy, Renae L ; Hyman, Matthew C ; Rämö, Joel T

BACKGROUND:Substantial data support a heritable basis for supraventricular tachycardias, but the genetic determinants and molecular mechanisms of these arrhythmias are poorly understood. We sought to identify genetic loci associated with atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular accessory pathways or atrioventricular reciprocating tachycardia (AVAPs/AVRT).METHODS:We performed multiancestry meta-analyses of genome-wide association studies to identify genetic loci for AVNRT (4 studies) and AVAP/AVRT (7 studies). We assessed evidence supporting the potential causal effects of candidate genes by analyzing relations between associated variants and cardiac gene expression, performing transcriptome-wide analyses, and examining prior genome-wide association studies.RESULTS: Analyses comprised 2384 AVNRT cases and 106 489 referents, and 2811 AVAP/AVRT cases and 1,483 093 referents. We identified 2 significant loci for AVNRT, which implicate NKX2-5 and TTN as disease susceptibility genes. A transcriptome-wide association analysis supported an association between reduced predicted cardiac expression of NKX2-5 and AVNRT. We identified 3 significant loci for AVAP/AVRT, which implicate SCN5A , SCN10A , and TTN/CCDC141 . Variant associations at several loci have been previously reported for cardiac phenotypes, including atrial fibrillation, stroke, Brugada syndrome, and electrocardiographic intervals. CONCLUSIONS:Our findings highlight gene regions associated with ion channel function (AVAP/AVRT), as well as cardiac development and the sarcomere (AVAP/AVRT and AVNRT) as important potential effectors of supraventricular tachycardia susceptibility.

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