A hydrogen-sulfide derivative of mesalamine reduces the severity of intestinal and lung injury in necrotizing enterocolitis through endothelial nitric oxide synthase

Article

作者: Li, Hongge ; Markel, Troy A. ; Hosfield, Brian D. ; Pecoraro, Anthony R. ; Shelley, W. Christopher ; Drucker, Natalie A. ; Hunter, Chelsea E. ; Manohar, Krishna

Necrotizing enterocolitis (NEC) remains a devastating disease that affects preterm infants. Hydrogen sulfide (H2S) donors have been shown to reduce the severity of NEC, but the optimal compound has yet to be identified. We hypothesized that oral H2S-Mesalamine (ATB-429) would improve outcomes in experimental NEC, and its benefits would be dependent on endothelial nitric oxide synthase (eNOS) pathways. NEC was induced in 5-day-old wild-type (WT) and eNOS knockout (eNOSKO) pups by formula feeding and stress. Four groups were studied in both WT and eNOSKO mice: 1) breastfed controls, 2) NEC, 3) NEC + 50 mg/kg mesalamine, and 4) NEC + 130 mg/kg ATB-429. Mesalamine and ATB-429 doses were equimolar. Pups were monitored for sickness scores and perfusion to the gut was measured by Laser Doppler Imaging (LDI). After euthanasia of the pups, intestine and lung were hematoxylin and eosin-stained and scored for injury in a blind fashion. TLR4 expression was quantified by Western blot and IL-6 expression by ELISA. P < 0.05 was significant. Both WT and eNOSKO breastfed controls underwent normal development and demonstrated milder intestinal and pulmonary injury compared with NEC groups. For the WT groups, ATB-429 significantly improved weight gain, reduced clinical sickness score, and improved perfusion compared with the NEC group. In addition, WT ATB-429 pups had a significantly milder intestinal and pulmonary histologic injury when compared with NEC. ATB-429 attenuated the increase in TLR4 and IL-6 expression in the intestine. When the experiment was repeated in eNOSKO pups, ATB-429 offered no benefit in weight gain, sickness scores, perfusion, intestinal injury, pulmonary injury, or decreasing intestinal inflammatory markers. An H2S derivative of mesalamine improves outcomes in experimental NEC. Protective effects appear to be mediated through eNOS. Further research is warranted to explore whether ATB-429 may be an effective oral therapy to combat NEC.

2022-02-01·Antioxidants & Redox Signaling2区 · 生物学

Microbiome Profile and Molecular Pathways Alterations in Gastrointestinal Tract by Hydrogen Sulfide-Releasing Nonsteroidal Anti-Inflammatory Drug (ATB-352): Insight into Possible Safer Polypharmacy

2区 · 生物学

Article

作者: Magierowska, Katarzyna ; Wójcik, Dagmara ; Korbut, Edyta ; Hankus, Jerzy ; Głowacka, Urszula ; Szetela, Małgorzata ; Surmiak, Marcin ; Chmura, Anna ; Magierowski, Marcin ; Cieszkowski, Jakub ; Wallace, John L. ; Danielak, Aleksandra

Aims: Nonsteroidal anti-inflammatory drugs, including ketoprofen, induce adverse effects within the gastrointestinal (GI)-tract. Hydrogen sulfide (H₂S) is an antioxidative gaseous mediator contributing to GI-protection. We aimed to evaluate the GI safety of a novel H₂S-releasing derivative of ketoprofen (ATB-352) versus classic ketoprofen and the molecular mechanisms of their activity after chronic treatment in experimental animal models. Results: Ketoprofen (10 mg/kg/day) administered intragastrically for 7 days in contrast with ATB-352 (14 mg/kg/day) reduced mucosal H₂S content inducing GI damage with significantly increased injury score, altered intestinal microbiome profile, and modulation of more than 50% of 36 investigated molecular sensors (e.g., mammalian target of rapamycin or suppressor of cytokine signaling 3 [SOCS3]). Polypharmacy with aspirin (10 mg/kg/day) enhanced ketoprofen toxicity not affecting GI safety of ATB-352. Omeprazole (20 mg/kg/day) decreased ketoprofen-induced injury to the level of ATB-352 alone. Both compounds combined or not with aspirin or omeprazole maintained the ability to inhibit cyclooxygenase (COX) activity manifested by decreased prostaglandin production. Innovation and Conclusions: Ketoprofen-induced H₂S-production decrease and intestinal microbiome profile alterations lead to GI toxicity observed on macro-/microscopic and molecular levels. Ketoprofen but not ATB-352 requires concomitant treatment with omeprazole to eliminate GI adverse effects. ATB-352 applied alone or in a polypharmacy setting with aspirin effectively inhibited COX and maintained GI safety due to H₂S-release. Neither compound affected DNA oxidation in the GI mucosa, but ATB-352 had lower impact on molecular oxidative/inflammatory response pathways and intestinal microbiome. The GI safety of ATB-352 could be due to the involvement of heme oxygenase 1 and SOCS3 pathway activation. Antioxid. Redox Signal. 36, 189-210.

2021-07-01·Biomedicine & Pharmacotherapy2区 · 医学

Future prospects of ketoprofen in improving the safety of the gastric mucosa

2区 · 医学

Review

作者: Nieradko-Iwanicka, Barbara ; Kuczyńska, Joanna

INTRODUCTIONKetoprofen (K) was synthesized in 1968. K belongs to nonsteroidal anti-inflammatory drugs (NSAIDs) and has analgesic, anti-inflammatory and antipyretic properties. K is commonly used due to rapid absorption, simple metabolism, high antinociceptive activity and fast blood brain barrier crossing. However, this substance causes various side effects which are the major factors affecting its' popularity. Many researchers have modified this drug to discover an improved and safe NSAID.AIMThe aim of the review was to find in recent publications data bout future prospects of K of improved safety for the gastric mucosa after oral administration.METHODSystematic literature review was conducted in March 2021 (2015 onwards). We selected 22 articles from PubMed, Google Scholar, Medline Complete databases.RESULTS AND DISCUSSIONMany studies aimed at obtaining K with lower ulcerogenic properties. This article describes K with lysine, new K delivery systems, K in form of hydrogels, prodrugs and codrugs of K, K as ATB-352, K with zinc, K encapsulated as proliposomal powders and several substances that reduce the gastric side effects of K described after 2015.CONCLUSIONOur review confirms that modifications of K maintain its' desirable actions and decrease ulcer producing side effect. Some new forms of K were also found to have better activity profile compared to the parent drug.

项与 ATB-352 相关的新闻（医药）

2024-04-19

·BioSpace

Antibe Provides Update on CCAA Proceedings

TORONTO--(BUSINESS WIRE)-- Antibe Therapeutics Inc. (“Antibe” or the “Company”) (TSX: ATE) announced that the Company sought an extension of its previously announced stay of proceedings (“Stay”) under the Companies’ Creditors Arrangement Act (the “CCAA”) at a hearing before the Ontario Superior Court of Justice (Commercial List) (the “Court”) on April 18, 2024. The Court has reserved its decision and extended the Stay pending release of the decision. The Company is requesting to extend the Stay until May 24, 2024 in order to be able to continue engaging with the U.S. Food and Drug Administration with respect to the previously announced hold on the Company’s planned Phase II trial and to determine appropriate next steps. About Antibe Therapeutics Inc. Antibe is a clinical-stage biotechnology company leveraging its proprietary hydrogen sulfide platform to develop next-generation therapies to target pain and inflammation arising from a wide range of medical conditions. The Company’s current pipeline includes assets that seek to overcome the gastrointestinal ulcers and bleeding associated with nonsteroidal anti-inflammatory drugs (“NSAIDs”). Antibe’s lead drug, otenaproxesul, is intended as a safer alternative to opioids and today’s NSAIDs for acute pain. Antibe’s second pipeline drug, ATB-352, is being developed for a specialized pain indication. The Company’s next target is inflammatory bowel disease (“IBD”), a condition long in need of safer, more effective therapies. Learn more at antibethera.com. Forward Looking Statements This news release includes certain forward-looking statements under applicable securities laws, which may include, but are not limited to, statements concerning the extension of the Stay, payment of amounts due to Nuance under the arbitral award, anticipated engagement with the U.S. Food and Drug Administration concerning the clinical hold on otenaproxesul. Any statements contained herein that are not statements of historical facts may be deemed to be forward-looking, including those identified by the expressions “will”, “anticipate”, “believe”, “plan”, “estimate”, “expect”, “intend”, “propose” and similar wording. Forward-looking statements involve known and unknown risks and uncertainties that could cause actual results, performance, or achievements to differ materially from those expressed or implied in this news release. Factors that could cause actual results to differ materially from those anticipated in this news release include, but are not limited to, the decision of the Court with respect to the extension of the Stay and any subsequent determinations made by the Court, the Company’s inability to timely execute on its business strategy and timely and successfully complete its clinical trials and studies, the Company’s inability to obtain the necessary regulatory approvals related to its activities, risks associated with drug development generally and those risk factors set forth in the Company’s public filings made in Canada and available on sedarplus.com. The Company assumes no obligation to update the forward-looking statements or to update the reasons why actual results could differ from those reflected in the forward-looking statements except as required by applicable law.

临床2期

2024-04-16

·BioSpace

Antibe Announces TSX Delisting Review

TORONTO--(BUSINESS WIRE)-- Antibe Therapeutics Inc. (“Antibe” or the “Company”) (TSX: ATE) announced that the Toronto Stock Exchange (“TSX”) is reviewing the eligibility for continued listing on the TSX of the securities of the Company. The TSX has identified the Company’s financial condition as a criterion for delisting applicable to the Company. Antibe has been invited to make submissions to TSX and a hearing has been scheduled for the afternoon of April 23, 2024. Further updates will be provided as appropriate. The Company also confirms that it is no longer quoted on the OTCQX. About Antibe Therapeutics Inc. Antibe is a clinical-stage biotechnology company leveraging its proprietary hydrogen sulfide platform to develop next-generation therapies to target pain and inflammation arising from a wide range of medical conditions. The Company’s current pipeline includes assets that seek to overcome the gastrointestinal ulcers and bleeding associated with nonsteroidal anti-inflammatory drugs (“NSAIDs”). Antibe’s lead drug, otenaproxesul, is intended as a safer alternative to opioids and today’s NSAIDs for acute pain. Antibe’s second pipeline drug, ATB-352, is being developed for a specialized pain indication. The Company’s next target is inflammatory bowel disease (“IBD”), a condition long in need of safer, more effective therapies. Learn more at antibethera.com. Forward Looking Statements This news release includes certain forward-looking statements under applicable securities laws, which may include, but are not limited to, statements concerning the TSX delisting review. Any statements contained herein that are not statements of historical facts may be deemed to be forward-looking, including those identified by the expressions “will”, “anticipate”, “believe”, “plan”, “estimate”, “expect”, “intend”, “propose” and similar wording. Forward-looking statements involve known and unknown risks and uncertainties that could cause actual results, performance, or achievements to differ materially from those expressed or implied in this news release. Factors that could cause actual results to differ materially from those anticipated in this news release include, but are not limited to, the decision of the TSX with respect to the delisting , the Company’s inability to timely execute on its business strategy and timely and successfully complete its clinical trials and studies, the Company’s inability to obtain the necessary regulatory approvals related to its activities, risks associated with drug development generally and those risk factors set forth in the Company’s public filings made in Canada and available on sedarplus.com. The Company assumes no obligation to update the forward-looking statements or to update the reasons why actual results could differ from those reflected in the forward-looking statements except as required by applicable law. View source version on businesswire.com: Contacts Antibe Therapeutics Inc. Christina Cameron VP Investor Relations +1 416-577-1443 christina@antibethera.com Source: Antibe Therapeutics Inc. View this news release online at:

2024-04-09

·BioSpace

Antibe to File an Application for an Initial Order Under Companies' Creditors Arrangement Act

TORONTO--(BUSINESS WIRE)-- Antibe Therapeutics Inc. (“Antibe” or the “Company”) (TSX: ATE, OTCQX: ATBPF) announced that it intends to application today with the Ontario Superior Court of Justice (Commercial List) (the "Court") for an Initial Order under the Companies' Creditors Arrangement Act (the "CCAA"). The application seeks an order that would, amongst other things, stay any action by Nuance Pharma to enforce the previously announced confidential ruling from the Singapore International Arbitration Centre requiring Antibe to pay approximately US$24 million to Nuance and would also enable the Company to continue engaging with the U.S. Food and Drug Administration with respect to the previously announced hold on the Company’s planned Phase II trial. In addition, the Company announced that Amal Khouri and Jennifer McNealey have resigned from its Board of Directors effective April 8, 2024. The Company thanks both Ms. Khouri and Ms. McNealey for their valuable contributions and wishes them well in their future endeavors. Additional Information Further updates will be provided as appropriate. About Antibe Therapeutics Inc. Antibe is a clinical-stage biotechnology company leveraging its proprietary hydrogen sulfide platform to develop next-generation therapies to target pain and inflammation arising from a wide range of medical conditions. The Company’s current pipeline includes assets that seek to overcome the gastrointestinal ulcers and bleeding associated with nonsteroidal anti-inflammatory drugs (“NSAIDs”). Antibe’s lead drug, otenaproxesul, is intended as a safer alternative to opioids and today’s NSAIDs for acute pain. Antibe’s second pipeline drug, ATB-352, is being developed for a specialized pain indication. The Company’s next target is inflammatory bowel disease (“IBD”), a condition long in need of safer, more effective therapies. Learn more at antibethera.com. Forward Looking Statements This news release includes certain forward-looking statements under applicable securities laws, which may include, but are not limited to, statements concerning the application to the Court and the proposed terms of the Initial Order, payment of amounts due to Nuance under the arbitral award, anticipated engagement with the U.S. Food and Drug Administration concerning the clinical hold on otenaproxesul. Any statements contained herein that are not statements of historical facts may be deemed to be forward-looking, including those identified by the expressions “will”, “anticipate”, “believe”, “plan”, “estimate”, “expect”, “intend”, “propose” and similar wording. Forward-looking statements involve known and unknown risks and uncertainties that could cause actual results, performance, or achievements to differ materially from those expressed or implied in this news release. Factors that could cause actual results to differ materially from those anticipated in this news release include, but are not limited to, the decision of the Court with respect to the Initial Order and any subsequent determinations made by the Court, the Company’s inability to timely execute on its business strategy and timely and successfully complete its clinical trials and studies, the Company’s inability to obtain the necessary regulatory approvals related to its activities, risks associated with drug development generally and those risk factors set forth in the Company’s public filings made in Canada and available on sedarplus.com. The Company assumes no obligation to update the forward-looking statements or to update the reasons why actual results could differ from those reflected in the forward-looking statements except as required by applicable law.

临床2期高管变更

100 项与 ATB-352 相关的药物交易

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