作者: Shinohara, Keisuke ; Hashimoto, Toru ; Fujino, Takeo ; Abe, Kohtaro ; Suenaga, Tomoyasu ; Ide, Tomomi ; Matsushima, Shouji ; Kinugawa, Shintaro ; Yoshitake, Tomoaki ; Yamamoto, Shoei

BACKGROUNDSA soluble guanylyl cyclase stimulator vericiguat has been shown to reduce cardiovascular mortality or hospitalization for heart failure in patients with worsening heart failure in the VICTORIA study. However, little is known about the effects of vericiguat on biventricular structure and function.METHODS AND RESULTSA retrospective analysis of 63 consecutive patients with heart failure with reduced ejection fraction (HFrEF) who were treated with vericiguat was performed. Clinical data and echocardiographic parameters were compared between baseline and follow-up after the initiation of vericiguat. The median follow-up duration was 266 days. Treatment with vericiguat significantly reduced the plasma BNP levels (log-transformed) compared to baseline (2.46 ± 0.51 vs. 2.14 ± 0.58, p < 0.0001). Left ventricular end-diastolic volume index and left ventricular end-systolic volume index were significantly reduced (LVEDVI, 113.5 ± 46.3 vs. 103.6 ± 51.0, p = 0.0056; LVESVI, 82.0 ± 41.9 vs. 72.8 ± 44.7, p = 0.0077; respectively). The tricuspid annular plane systolic excursion to pulmonary artery systolic pressure (TAPSE/PASP) ratio, an indicator of right ventricle-pulmonary artery (RV-PA) coupling, increased significantly after the treatment (0.56 ± 0.29 vs. 0.92 ± 1.09, p < 0.0001). Univariate and multivariate analyses showed that the treatment effects of vericiguat on BNP levels, LV reverse remodeling, and RV-PA coupling were not correlated with the achievement of the quadruple therapy with beta-blockers, renin-angiotensin system inhibitors, mineralocorticoid inhibitors, and sodium-glucose cotransporter-2 inhibitors, nor with worsening heart failure (WHF).CONCLUSIONTreatment with vericiguat improved adverse LV remodeling and RV-PA uncoupling in HFrEF patients. These effects were independent of WHF and achieving the quadruple therapy. Patients with HFrEF may benefit from early initiation of vericiguat to prevent biventricular adverse remodeling.

2024-10-11·ACS Infectious Diseases

Identification of Chemical Scaffolds That Inhibit the Mycobacterium tuberculosis Respiratory Complex Succinate Dehydrogenase

Article

作者: Cheung, Chen-Yi ; Steyn, Adrie J.C. ; Hards, Kiel ; Kita, Kiyoshi ; Yan, Ming ; Jowsey, William J. ; Mackenzie, Jared S. ; Hickey, Anthony J.R. ; Brimble, Margaret A. ; Ding, Xiaobo ; Li, Zhengqiu ; Furkert, Daniel P. ; Williams, Zoe C. ; Cook, Gregory M. ; Adolph, Cara ; McNeil, Matthew B. ; Zhang, Tianyu ; Keighley, Laura M. ; Inaoka, Daniel Ken ; Kyte, Matson ; Tian, Guo-Bao

Drug-resistant Mycobacterium tuberculosis is a significant cause of infectious disease morbidity and mortality for which new antimicrobials are urgently needed. Inhibitors of mycobacterial respiratory energy metabolism have emerged as promising next-generation antimicrobials, but a number of targets remain unexplored. Succinate dehydrogenase (SDH), a focal point in mycobacterial central carbon metabolism and respiratory energy production, is required for growth and survival in M. tuberculosis under a number of conditions, highlighting the potential of inhibitors targeting mycobacterial SDH enzymes. To advance SDH as a novel drug target in M. tuberculosis, we utilized a combination of biochemical screening and in-silico deep learning technologies to identify multiple chemical scaffolds capable of inhibiting mycobacterial SDH activity. Antimicrobial susceptibility assays show that lead inhibitors are bacteriostatic agents with activity against wild-type and drug-resistant strains of M. tuberculosis. Mode of action studies on lead compounds demonstrate that the specific inhibition of SDH activity dysregulates mycobacterial metabolism and respiration and results in the secretion of intracellular succinate. Interaction assays demonstrate that the chemical inhibition of SDH activity potentiates the activity of other bioenergetic inhibitors and prevents the emergence of resistance to a variety of drugs. Overall, this study shows that SDH inhibitors are promising next-generation antimicrobials against M. tuberculosis.

2024-08-28·Journal of Agricultural and Food Chemistry

Discovery of Novel (5-Mercapto-4-phenyl-4H-1,2,4-triazol-3-yl)methyl Phenyl Carbamate as a Potent Phytoene Desaturase Inhibitor through Scaffold Hopping and Linker Modification

Article

作者: Zhang, Di ; Jia, Ding ; Ma, Dejun ; Wang, Chunxue ; Xi, Zhen ; Yu, Zhilei ; Zhang, Yichi ; Hong, Zeyu ; Xu, Han ; Gu, Yucheng

Phytoene desaturase (PDS) is a key rate-limiting enzyme in the carotenoid biosynthesis pathway. Although commercial PDS inhibitors have been developed for decades, it remains necessary to develop novel PDS inhibitors with higher bioactivity. In this work, we used the scaffold hopping and linker modification approaches to design and synthesize a series of compounds (7a-7o, 8a-8l, and 14a-14d). The postemergence application assay demonstrated that 8e and 7e separately showed the best herbicidal activity at 750 g a.i./ha and lower doses (187.5 g, 375g a.i./ha) without no significant toxicity to maize and wheat. The surface plasmon resonance revealed strong binding affinity between 7e and Synechococcus PDS (SynPDS). The HPLC analysis confirmed that 8e at 750 g a.i./ha caused significant phytoene accumulation in Arabidopsis seedlings. This work demonstrates the efficacy of structure-guided optimization through scaffold hopping and linker modification to design potent PDS inhibitors with enhanced bioactivity and crop safety.

项与 Biofilm inhibitors(Naval Medical University) 相关的新闻（医药）

2024-09-04

·PRNewswire

Astellas to Present VEOZAH™ (fezolinetant) Data at 2024 Annual Meeting of The Menopause Society

- Pooled analyses from two SKYLIGHT™ studies highlight impact on sleep disturbance and impairment, relationship between improvements in the frequency or severity of hot flashes and mood - Pooled data from three SKYLIGHT™ studies assess safety and tolerability in Hispanic/Latina women - Responder analysis from DAYLIGHT™study evaluates reduction in VMS frequency in women unwilling or unable to take hormone therapy TOKYO, Sept. 4, 2024 /PRNewswire/ -- Astellas Pharma Inc. (TSE: 4503, President and CEO: Naoki Okamura, "Astellas") announced that VEOZAH™ (fezolinetant), its first-in-class treatment for moderate to severe vasomotor symptoms (VMS) due to menopause, will be featured in four oral presentations during the 2024 Annual Meeting of The Menopause Society (TMS) September 10-14 in Chicago. VMS, also known as hot flashes and/or night sweats, are common symptoms of menopause.1,2 Marci English, Vice President, Head of BioPharma Development, Astellas "We are thrilled to share multiple presentations at this year's Annual Meeting of The Menopause Society that continue to add to our extensive body of evidence for VEOZAH as a first in class nonhormonal treatment for moderate to severe VMS due to menopause. We are looking forward to highlighting patient-reported sleep data from our SKYLIGHT studies, as well as a new responder analysis from our DAYLIGHT study that included women who are unwilling or unable to take hormone therapy." Fezolinetant data to be presented during the 2024 Annual Meeting of The Menopause Society include: Two separate pooled analyses from SKYLIGHT 1 and SKYLIGHT 2 examining improvements in patient-reported sleep disturbance and impairment (Session 1; Thursday, Sept. 12, 4:30-4:45 p.m.; Marla Shapiro, C.M.), as well as the relationship between improvements in the frequency or severity of hot flashes and mood (Top Scoring Abstract Session; Friday, Sept. 13, 1-1:15 p.m.; Genevieve Neal-Perry, M.D.). Data from DAYLIGHT evaluating percent reduction (≥50%, ≥75% and 100%) in frequency of moderate to severe VMS in women considered unsuitable for hormone therapy (Session 2; Thursday, Sept. 12, 5:45-6 p.m.; Marla Shapiro, C.M.). Pooled data from SKYLIGHT 1, SKYLIGHT 2 and SKYLIGHT 4 assessing the safety and efficacy of fezolinetant in Hispanic and Latina participants (Session 1; Thursday, Sept. 12, 4:45-5 p.m.; Genevieve Neal-Perry, M.D.). An additional poster presentation will highlight results of a qualitative analysis designed to identify concepts and perspectives related to VMS experience among Black or African American women (Thursday, Sept. 12, 6:15-7:15 p.m.; Makeba Williams, M.D.). About the BRIGHT SKY™ Phase 3 Program The BRIGHT SKY pivotal trials, SKYLIGHT 1™ (NCT04003155) and SKYLIGHT 2™ (NCT04003142), enrolled over 1,000 women with moderate to severe VMS. The trials are double-blinded, placebo-controlled for the first 12 weeks followed by a 40-week treatment extension period. Women were enrolled at over 180 sites within the U.S., Canada and Europe. SKYLIGHT 4™ (NCT04003389) is a 52-week double-blinded, placebo-controlled study designed to investigate the long-term safety of fezolinetant. For SKYLIGHT 4, over 1,800 women with VMS were enrolled at over 180 sites within the U.S., Canada and Europe. About DAYLIGHT DAYLIGHT (NCT05033886) is a Phase 3b, randomized, double-blind, placebo-controlled, 24-week study to assess the efficacy and safety of fezolinetant in menopausal women aged 40-65 suffering from moderate to severe VMS and considered unsuitable for hormone therapy. A total of 453 women were enrolled at 69 sites in Canada, Europe and Turkey. About VEOZAH (fezolinetant) VEOZAH (fezolinetant) is a neurokinin 3 (NK3) receptor antagonist approved in the U.S. for the treatment of moderate to severe vasomotor symptoms (VMS) due to menopause. VEOZAH is not a hormone. VMS are the feelings of warmth in the face, neck, and chest, or sudden intense feelings of heat and sweating ("hot flashes" or "hot flushes"). VEOZAH works by blocking neurokinin B (NKB) binding on the kisspeptin/neurokinin B/dynorphin (KNDy) neuron to modulate neuronal activity in the thermoregulatory center of the brain (the hypothalamus) to reduce the frequency and severity of moderate to severe VMS due to menopause. U.S. Important Safety Information Do not use VEOZAH if you: have cirrhosis. have severe kidney problems or kidney failure. are taking certain medicines called CYP1A2 inhibitors. Ask your healthcare provider if you are not sure. Before you use VEOZAH, tell your healthcare provider about all of your medical conditions, including if you: have liver disease or problems. have kidney problems. have any medical conditions that may become worse while you are using VEOZAH. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VEOZAH may affect the way other medicines work, and other medicines may affect how VEOZAH works. VEOZAH can cause serious side effects, including: increased liver blood test values and liver problems. Your healthcare provider will do a blood test to check your liver before you start taking VEOZAH. Your healthcare provider will also do this blood test monthly for the first 3 months, at month 6, and month 9 after you start taking VEOZAH or if you have signs or symptoms that suggest liver problems. If your liver blood test values are elevated, your healthcare provider may advise you to stop treatment or request additional liver blood tests. Stop VEOZAH and call your healthcare provider right away if you have the following signs or symptoms of liver problems: feeling more tired than you do usually nausea vomiting itching yellowing of the eyes or skin (jaundice) pale feces dark urine pain in the right upper stomach (abdomen) The most common side effects of VEOZAH include: stomach (abdominal) pain diarrhea difficulty sleeping (insomnia) back pain hot flashes or hot flushes These are not all the possible side effects of VEOZAH. Tell your healthcare provider if you have any side effect that bothers you or does not go away. Call your healthcare provider for medical advice about side effects. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit or call 1-800- FDA-1088. For more information, please see the full Prescribing Information and Patient Product Information for VEOZAH (fezolinetant). About Astellas Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. We are promoting the Focus Area Approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on Biology and Modality. Furthermore, we are also looking beyond our foundational Rx focus to create Rx+® healthcare solutions that combine our expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of healthcare change to turn innovative science into VALUE for patients. For more information, please visit our website at . Cautionary Notes In this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on management's current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas' intellectual property rights by third parties. Information about pharmaceutical products (including products currently in development) which is included in this press release is not intended to constitute an advertisement or medical advice. References 1 Utian WH. Psychosocial and socioeconomic burden of vasomotor symptoms in menopause: a comprehensive review. Health Qual Life Outcomes. 2005;3:47. 2 Jones RE, Lopez KH, eds. Human Reproductive Biology. 4th ed. Waltham, MA: Elsevier, 2014:120. SOURCE Astellas Pharma Inc.

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100 项与 Biofilm inhibitors(Naval Medical University) 相关的药物交易

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