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Kunicki PK, Grymm MT, Pawiński T, Szulczyk D, Waligóra M, Kopeć G. A simple HPLC-UV method for monitoring therapeutic adherence in pulmonary arterial hypertension. J Chromatogr B Analyt Technol Biomed Life Sci 2025; 1252:124443. [PMID: 39787725 DOI: 10.1016/j.jchromb.2024.124443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 12/23/2024] [Accepted: 12/24/2024] [Indexed: 01/12/2025]
Abstract
A considerable percentage of ineffective treatment in pulmonary arterial hypertension (PAH) may be related to subtherapeutic dosage or non-adherence. The aim of the study was to develop a simple analytical method suitable for plasma determination of selected drugs: riociguat (RIO), bosentan (BOS) and macitentan (MAC) administered to PAH patients. An isocratic HPLC-UV system (Spectra Physics - Shimadzu) with a manual injector (50 μL loop) was applied. Chromatographic analysis was performed using a Suplecosil LC-CN column (150 × 4.6 mm, 5 μm) protected with a Supelguard precolumn at room temperature. The separation was carried out using the mobile phase: CH3CN:H2O:0.5 M KH2PO4:85 % H3PO4 (172:324.2:3.7:0.1, v/v) at a flow rate of 1.8 mL/min. Ethyl acetate (4 mL) was used for 10-min liquid-liquid extraction from 0.4 mL alkalized plasma sample. Detection was performed at λ = 245 nm chosen as a compromise between signal intensity and matrix interference. The analytes were eluted at retention times of 4.4 min (RIO), 5.4 min (BOS), 8.9 min (MAC) and 7.8 min for gallopamil (internal standard, GAL). The method was found linear and calibrated in the ranges: 5-1000 ng/mL for RIO, 10-2000 ng/mL for BOS and 20-2000 ng/mL for MAC, with r2 of 0.9991 for RIO, 0.9983 for BOS, and 0.9949 for MAC, respectively. Within the given ranges, the method ensured reliable results with the required precision and accuracy: ≤15 % (≤20 % for LLOQ). There was no significant carryover effect. The method has been successfully used in pilot study on adherence in patients treated for PAH, enabling monitoring of RIO, BOS and MAC. Drug concentrations were assessed in samples taken before (C0) and 3 h after drug administration (C3). For RIO, BOS and MAC, the developed method was suitable for both C0 and C3 samples, allowing steady-state drug determination if used. The presented method can be recommended to laboratories equipped with basic HPLC apparatus as an attractive analytical tool for both TDM and adherence studies.
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Affiliation(s)
- Paweł K Kunicki
- Department of Drug Chemistry, Pharmaceutical and Biomedical Analysis, Medical University of Warsaw, Warsaw, Poland.
| | - Maciej T Grymm
- Department of Drug Chemistry, Pharmaceutical and Biomedical Analysis, Medical University of Warsaw, Warsaw, Poland
| | - Tomasz Pawiński
- Department of Drug Chemistry, Pharmaceutical and Biomedical Analysis, Medical University of Warsaw, Warsaw, Poland
| | - Daniel Szulczyk
- Chair and Department of Biochemistry, Medical University of Warsaw, Warsaw, Poland
| | - Marcin Waligóra
- Pulmonary Circulation Centre, Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, Krakow, Poland; Department of Cardiac and Vascular Diseases, St. John Paul II Hospital, Krakow, Poland; Center for Innovative Medical Education, Department of Medical Education, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland
| | - Grzegorz Kopeć
- Pulmonary Circulation Centre, Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, Krakow, Poland; Department of Cardiac and Vascular Diseases, St. John Paul II Hospital, Krakow, Poland
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Sandner P, Follmann M, Becker-Pelster E, Hahn MG, Meier C, Freitas C, Roessig L, Stasch JP. Soluble GC stimulators and activators: Past, present and future. Br J Pharmacol 2024; 181:4130-4151. [PMID: 34600441 DOI: 10.1111/bph.15698] [Citation(s) in RCA: 49] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 08/30/2021] [Indexed: 12/20/2022] Open
Abstract
The discovery of soluble GC (sGC) stimulators and sGC activators provided valuable tools to elucidate NO-sGC signalling and opened novel pharmacological opportunities for cardiovascular indications and beyond. The first-in-class sGC stimulator riociguat was approved for pulmonary hypertension in 2013 and vericiguat very recently for heart failure. sGC stimulators enhance sGC activity independent of NO and also act synergistically with endogenous NO. The sGC activators specifically bind to, and activate, the oxidised haem-free form of sGC. Substantial research efforts improved on the first-generation sGC activators such as cinaciguat, culminating in the discovery of runcaciguat, currently in clinical Phase II trials for chronic kidney disease and diabetic retinopathy. Here, we highlight the discovery and development of sGC stimulators and sGC activators, their unique modes of action, their preclinical characteristics and the clinical studies. In the future, we expect to see more sGC agonists in new indications, reflecting their unique therapeutic potential.
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Affiliation(s)
- Peter Sandner
- Pharmaceuticals Research & Development, Bayer AG, Wuppertal, Germany
- Institute of Pharmacology, Hannover Medical School, Hanover, Germany
| | - Markus Follmann
- Pharmaceuticals Research & Development, Bayer AG, Wuppertal, Germany
| | | | - Michael G Hahn
- Pharmaceuticals Research & Development, Bayer AG, Wuppertal, Germany
| | - Christian Meier
- Pharmaceuticals Medical Affairs and Pharmacovigilance, Bayer AG, Berlin, Germany
| | - Cecilia Freitas
- Pharmaceuticals Research & Development, Bayer AG, Wuppertal, Germany
| | - Lothar Roessig
- Pharmaceuticals Research & Development, Bayer AG, Wuppertal, Germany
| | - Johannes-Peter Stasch
- Pharmaceuticals Research & Development, Bayer AG, Wuppertal, Germany
- Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Halle, Germany
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3
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Wong D, Seitz F, Bauer V, Giessmann T, Schulze F. Safety, tolerability, pharmacokinetics, and pharmacodynamics of BI 685509, a soluble guanylyl cyclase activator, in healthy volunteers: Results from two randomized controlled trials. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:8101-8116. [PMID: 38789635 PMCID: PMC11449976 DOI: 10.1007/s00210-024-03165-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 05/13/2024] [Indexed: 05/26/2024]
Abstract
This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of BI 685509 after oral single rising doses (SRDs) or multiple rising doses (MRDs) in healthy volunteers. In the SRD trial (NCT02694354; February 29, 2016), within each of the three dose groups (DGs), six subjects received BI 685509 (1.0, 2.5, or 5.0 mg) and two received placebo (N = 24). In the MRD trial (NCT03116906; April 17, 2017), within each of the five DGs, nine subjects received BI 685509 (uptitrated to 1 mg once daily [qd; DG1], 2.5 mg twice daily [DG2], 5.0 mg qd [DG3]; 3.0 mg three times daily [tid; DG4] or 4.0 mg tid [DG5]) and three received placebo, for 14-17 days (N = 60). In the SRD trial, 7/24 subjects (29.2%) had ≥ 1 adverse event (AE), most frequently orthostatic dysregulation (n = 4). In the MRD trial, 26/45 subjects (57.8%) receiving BI 685509 had ≥ 1 AE, most frequently orthostatic dysregulation and fatigue (each n = 12). Tolerance development led to a marked decrease in orthostatic dysregulation events (DG3). BI 685509 was rapidly absorbed after oral administration, and exposure increased in a dose-proportional manner after single doses. Multiple dosing resulted in near-dose-proportional increase in exposure and limited accumulation. BI 685509 pharmacokinetics appeared linear with time; steady state occurred 3-5 days after each multiple-dosing period. Increased plasma cyclic guanosine monophosphate and decreased blood pressure followed by a compensatory increase in heart rate indicated target engagement. BI 685509 was generally well tolerated; orthostatic dysregulation may be appropriately countered by careful uptitration.
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Affiliation(s)
- Diane Wong
- Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, 06877, USA.
| | | | - Verena Bauer
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an Der Riss, Germany
| | - Thomas Giessmann
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an Der Riss, Germany
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4
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Li Q, Chen X, Zhang S, Li W, Lin H. Analysis of riociguat and desmethyl riociguat by UPLC-MS/MS and its interaction with quercetin. Front Pharmacol 2024; 15:1470377. [PMID: 39359248 PMCID: PMC11444992 DOI: 10.3389/fphar.2024.1470377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 09/05/2024] [Indexed: 10/04/2024] Open
Abstract
Riociguat, an orally soluble guanylate cyclase (sGC)-promoting drug, is mainly used in the clinical treatment of pulmonary hypertension (PH). In this study, a novel ultra-performance liquid chromatography-tandem mass spectrometry method was developed to quantify the concentrations of riociguat and its metabolite (M1) in plasma. The precision, stability, accuracy, matrix effect, and recovery of the methodology were satisfactory. Quercetin, a well-recognized compound, functions as a novel anticancer agent with the potential to alleviate symptoms of PH. Therefore, the potential interaction between quercetin and riociguat was investigated in this study. The levels of riociguat and M1 in rat plasma were measured using the method developed in this study to evaluate the interactions between riociguat and quercetin in rats. The results revealed that quercetin significantly inhibited riociguat and M1 metabolism with increased systemic exposure.
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Affiliation(s)
- Qingqing Li
- Department of Pharmacy, Ningbo Municipal Hospital of Traditional Chinese Medicine (TCM), Affiliated Hospital of Zhejiang Chinese Medical University, Ningbo, China
| | - Xiaohai Chen
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Siping Zhang
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wanshu Li
- Department of Pharmacy, Ningbo Municipal Hospital of Traditional Chinese Medicine (TCM), Affiliated Hospital of Zhejiang Chinese Medical University, Ningbo, China
| | - Hangjuan Lin
- Department of Pharmacy, Ningbo Municipal Hospital of Traditional Chinese Medicine (TCM), Affiliated Hospital of Zhejiang Chinese Medical University, Ningbo, China
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Lou J, Li N, Jiang X, Cai X, Wang L, Wu X, Zhang W, Jin C, Zhuang X. Inhibition of P-Glycoprotein Asymmetrically Alters the In Vivo Exposure Profile of SGC003F: A Novel Guanylate Cyclase Stimulator. Pharmaceuticals (Basel) 2024; 17:1140. [PMID: 39338304 PMCID: PMC11435065 DOI: 10.3390/ph17091140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 08/22/2024] [Accepted: 08/26/2024] [Indexed: 09/30/2024] Open
Abstract
As a novel guanylate cyclase stimulator, SGC003F is being developed for the treatment of heart failure with a reduced ejection fraction (HFrEF). This study aimed to assess the effect of P-glycoprotein (P-gp) inhibition on SGC003F exposure in vivo, comparing plasma and tissue levels, and evaluating the role of P-gp in the small intestine, blood-brain barrier (BBB), and kidney in impacting the tissue exposure. Tariquidar, a P-gp inhibitor, was added to monolayer transport assays to observe the changes in the transmembrane characteristics of SGC003F. Rats were given SGC003F with tariquidar via various routes to measure plasma, tissue, urine, and fecal concentrations. The inclusion of tariquidar significantly altered the pharmacokinetics of SGC003F. In LLC-PK1-MDR1 cells, tariquidar reduced the efflux ratio of SGC003F from 6.56 to 1.28. In rats, it enhanced the plasma AUC by 3.05 or 1.61 times, increased the Cmax by 2.13 or 1.07 times, and notably improved bioavailability from 46.4% to 95%. Additionally, co-administration with tariquidar led to a decrease in fecal excretion and an increase in tissue exposure, with only a moderate effect on the partition ratios in the small intestine and brain. P-gp inhibition impacts SGC003F exposure, with plasma levels not fully reflecting tissue levels. P-gp in the small intestine and BBB affects SGC003F's pharmacokinetics, warranting further clinical drug-drug interaction (DDI) studies.
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Affiliation(s)
- Jinle Lou
- Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
- College of Pharmay, Yanbian University, Yanji 133000, China
| | - Nan Li
- Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
- College of Pharmay, Yanbian University, Yanji 133000, China
| | - Xue Jiang
- Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Xu Cai
- Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Lingchao Wang
- Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Xia Wu
- Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Wenpeng Zhang
- Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Chunmei Jin
- College of Pharmay, Yanbian University, Yanji 133000, China
| | - Xiaomei Zhuang
- Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
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Mas-Roselló J, Tenor H, Szabo T, Naef R, Sieber S, Gademann K. Bifunctional Sildenafil Diazeniumdiolates Acting as Phosphodiesterase 5 Inhibitors and Nitric Oxide Donors- Towards Wound Healing. Chembiochem 2024; 25:e202300801. [PMID: 38430555 DOI: 10.1002/cbic.202300801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 02/29/2024] [Accepted: 02/29/2024] [Indexed: 03/04/2024]
Abstract
Inefficient wound healing poses a global health challenge with a lack of efficient treatments. Wound healing issues often correlate with low endogenous nitric oxide (NO) levels. While exogenous delivery with NO-releasing compounds represents a promising therapeutic strategy, controlling the release of the highly reactive NO remains challenging. Phosphodiesterase 5 (PDE5) inhibitors, like sildenafil, have also been shown to promote wound healing. This study explores hybrid compounds, combining NO-releasing diazeniumdiolates with a sildenafil-derived PDE5 inhibitor. One compound demonstrated a favorable NO-release profile, triggered by an esterase (prodrug), and displayed in vitro nanomolar inhibition potency against PDE5 and thrombin-induced platelet aggregation. Both factors are known to promote blood flow and oxygenation. Thus, our findings unveil promising prospects for effective wound healing treatments.
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Affiliation(s)
- Josep Mas-Roselló
- Department of Chemistry, University of Zurich, 8057, Zurich, Switzerland
| | - Hermann Tenor
- Topadur Pharma AG, Grabenstrasse 11A, 8952, Schlieren, Switzerland
| | - Timea Szabo
- Department of Chemistry, University of Zurich, 8057, Zurich, Switzerland
| | - Reto Naef
- Topadur Pharma AG, Grabenstrasse 11A, 8952, Schlieren, Switzerland
| | - Simon Sieber
- Department of Chemistry, University of Zurich, 8057, Zurich, Switzerland
| | - Karl Gademann
- Department of Chemistry, University of Zurich, 8057, Zurich, Switzerland
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7
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Santos RT, de Sá Freire Onofre ME, de Assis Fernandes Caldeira D, Klein AB, Rocco PRM, Cruz FF, Silva PL. Pharmacological Agents and Potential New Therapies in Pulmonary Arterial Hypertension. Curr Vasc Pharmacol 2024; 22:155-170. [PMID: 38115617 DOI: 10.2174/0115701611266576231211045731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Revised: 10/09/2023] [Accepted: 11/15/2023] [Indexed: 12/21/2023]
Abstract
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by an imbalance between vasoactive mediators, which causes vascular remodeling, increased pulmonary vascular resistance, and right ventricular overload, ultimately leading to heart failure and death. A metabolic theory has been suggested to explain the pathophysiology of PAH whereby abnormalities in mitochondrial biogenesis can trigger a hyperproliferative and apoptosis-resistant phenotype in cardiopulmonary and malignant cells, leading to mitochondrial dysfunction, which in turn causes the Warburg effect. This can culminate in the mitophagy of pulmonary vessels and cardiomyocytes. The present narrative review focuses on the pathophysiology of PAH, the pharmacological agents currently available for its treatment, and promising and challenging areas of therapeutic investigation.
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Affiliation(s)
- Renata Trabach Santos
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Maria Eduarda de Sá Freire Onofre
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Dayene de Assis Fernandes Caldeira
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Adriane Bello Klein
- Laboratory of Cardiovascular Physiology and Reactive Oxygen Species, Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Patricia Rieken Macedo Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fernanda Ferreira Cruz
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Pedro Leme Silva
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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Yin Q, Zheng X, Song Y, Wu L, Li L, Tong R, Han L, Bian Y. Decoding signaling mechanisms: unraveling the targets of guanylate cyclase agonists in cardiovascular and digestive diseases. Front Pharmacol 2023; 14:1272073. [PMID: 38186653 PMCID: PMC10771398 DOI: 10.3389/fphar.2023.1272073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 12/08/2023] [Indexed: 01/09/2024] Open
Abstract
Soluble guanylate cyclase agonists and guanylate cyclase C agonists are two popular drugs for diseases of the cardiovascular system and digestive systems. The common denominator in these conditions is the potential therapeutic target of guanylate cyclase. Thanks to in-depth explorations of their underlying signaling mechanisms, the targets of these drugs are becoming clearer. This review explains the recent research progress regarding potential drugs in this class by introducing representative drugs and current findings on them.
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Affiliation(s)
- Qinan Yin
- Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xingyue Zheng
- Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yujie Song
- Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Liuyun Wu
- Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Lian Li
- Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Rongsheng Tong
- Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Lizhu Han
- Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yuan Bian
- Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
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9
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Delcroix M, Belge C, Maleux G, Godinas L. Monographic Issue on Pulmonary Hypertension: Medical and Interventional Treatment for Chronic Thromboembolic Pulmonary Hypertension. Semin Respir Crit Care Med 2023; 44:840-850. [PMID: 37567250 DOI: 10.1055/s-0043-1770122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/13/2023]
Abstract
Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism. The reasons why clots do not resorb are incompletely understood, but the result is partial or complete fibrothrombotic obstruction of pulmonary arteries. A secondary microvasculopathy aggravates the pulmonary hypertension (PH) as a consequence of high flow and shear stress in the nonoccluded arteries. The treatment of CTEPH has long been purely surgical, but many patients were inoperable because of inaccessible lesions or severe comorbidities. Alternatives were developed, including medical therapy and more recently balloon pulmonary angioplasty (BPA). Depending on the generation of the obstructed vessels, the treatment will be surgical, up to the (sub)segmental level, or by BPA for more distal vessels. PH drugs are used to treat the microvasculopathy. The current paper describes the therapeutic management of inoperable patients: the medical approach with PH drugs used in mono- or combination therapy; the proper use of anticoagulants in CTEPH; the technique, indications, and results at short- and long-term of BPA; the multimodal approach for inoperable patients combining PH drugs and BPA; and the effects of rehabilitation. It shows the importance of a multidisciplinary approach to the disease.
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Affiliation(s)
- Marion Delcroix
- Clinical Department of Respiratory Diseases, Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven-University of Leuven, University Hospitals of Leuven, Leuven, Belgium
- European Reference Network on Rare Pulmonary Diseases (ERN-LUNG), Belgium
| | - Catharina Belge
- Clinical Department of Respiratory Diseases, Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven-University of Leuven, University Hospitals of Leuven, Leuven, Belgium
- European Reference Network on Rare Pulmonary Diseases (ERN-LUNG), Belgium
| | - Geert Maleux
- Clinical Department of Radiology, University Hospitals of Leuven, Leuven, Belgium
| | - Laurent Godinas
- Clinical Department of Respiratory Diseases, Department of Chronic Diseases and Metabolism (CHROMETA), Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven-University of Leuven, University Hospitals of Leuven, Leuven, Belgium
- European Reference Network on Rare Pulmonary Diseases (ERN-LUNG), Belgium
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10
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Miller E, Sampson CU, Desai AA, Karnes JH. Differential drug response in pulmonary arterial hypertension: The potential for precision medicine. Pulm Circ 2023; 13:e12304. [PMID: 37927610 PMCID: PMC10621006 DOI: 10.1002/pul2.12304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 10/05/2023] [Accepted: 10/11/2023] [Indexed: 11/07/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) is a rare, complex, and deadly cardiopulmonary disease. It is characterized by changes in endothelial cell function and smooth muscle cell proliferation in the pulmonary arteries, causing persistent vasoconstriction, resulting in right heart hypertrophy and failure. There are multiple drug classes specific to PAH treatment, but variation between patients may impact treatment response. A small subset of patients is responsive to pulmonary vasodilators and can be treated with calcium channel blockers, which would be deleterious if prescribed to a typical PAH patient. Little is known about the underlying cause of this important difference in vasoresponsive PAH patients. Sex, race/ethnicity, and pharmacogenomics may also factor into efficacy and safety of PAH-specific drugs. Research has indicated that endothelin receptor antagonists may be more effective in women and there have been some minor differences found in certain races and ethnicities, but these findings are muddled by the impact of socioeconomic factors and a lack of representation of non-White patients in clinical trials. Genetic variants in genes such as CYP3A5, CYP2C9, PTGIS, PTGIR, GNG2, CHST3, and CHST13 may influence the efficacy and safety of certain PAH-specific drugs. PAH research faces many challenges, but there is potential for new methodologies to glean new insights into PAH development and treatment.
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Affiliation(s)
- Elise Miller
- Department of Pharmacy Practice and ScienceUniversity of Arizona R. Ken Coit College of PharmacyTucsonArizonaUSA
| | - Chinwuwanuju Ugo‐Obi Sampson
- Department of Pharmacy Practice and ScienceUniversity of Arizona R. Ken Coit College of PharmacyTucsonArizonaUSA
| | - Ankit A. Desai
- Department of MedicineIndiana University School of MedicineIndianapolisIndianaUSA
| | - Jason H. Karnes
- Department of Pharmacy Practice and ScienceUniversity of Arizona R. Ken Coit College of PharmacyTucsonArizonaUSA
- Department of Biomedical InformaticsVanderbilt University School of MedicineNashvilleTennesseeUSA
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11
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Willmann S, Keller AK, Meyer M, van der Mey D, Wirsching G, Zhang Y, Drenth HJ, Keunecke A, Vendel E, Saleh S. Population pharmacokinetics of riociguat in a pediatric population (aged ≥ 6 years) with pulmonary arterial hypertension. Pediatr Pulmonol 2023; 58:908-917. [PMID: 36507572 DOI: 10.1002/ppul.26277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 10/26/2022] [Accepted: 12/08/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND The PATENT-CHILD study investigated riociguat in children aged ≥ 6 to <18 years with pulmonary arterial hypertension (PAH) treated with tablets or an oral pediatric suspension based on bodyweight-adjusted dosing of up to 2.5 mg three times daily. PATENT-CHILD demonstrated an acceptable riociguat safety profile and individual plasma concentrations in pediatric patients were consistent with those in adult patients. METHODS Using the data set from PATENT-CHILD and building on existing population pharmacokinetic (PK) models for riociguat and its major metabolite (M1) in adults with PAH, a coupled riociguat-M1 PK model was developed. The final model developed incorporated a one-compartment model for riociguat, coupled to a one-compartment model for M1, allowing for presystemic formation of M1. It included allometric scaling exponents for bodyweight. RESULTS Apparent clearance of riociguat was similar in children and adult patients with PAH (median [interquartile range] 2.20 [1.75-3.44] and 2.08 L/h [1.55-2.97]). Factors contributing to lower PK exposure were lower riociguat maintenance dose in PATENT-CHILD, and a higher riociguat clearance in some adolescent patients, compared with adult patients. No effects of formulation, sex, or age on riociguat PK were observed. An exploratory PK/pharmacodynamics analysis found the increase in 6-min walking distance in pediatric patients treated with riociguat was not related to riociguat PK. CONCLUSIONS Body size is the main determinant of PK in growing children, and the model supports clinical data that, for children weighing < 50 kg, a bodyweight-adjusted dose of riociguat should be used to achieve a similar exposure to that observed in adults with PAH.
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Affiliation(s)
| | | | | | | | | | - Yang Zhang
- Clinical Pharmacometrics, Bayer AG, Wuppertal, Germany
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12
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Kameshima S, Nakamura Y, Uehara K, Kodama T, Yamawaki H, Nishi K, Okano S, Niijima R, Kimura Y, Itoh N. Effects of a Soluble Guanylate Cyclase Stimulator Riociguat on Contractility of Isolated Pulmonary Artery and Hemodynamics of U46619-Induced Pulmonary Hypertension in Dogs. Vet Sci 2023; 10:vetsci10020159. [PMID: 36851463 PMCID: PMC9960282 DOI: 10.3390/vetsci10020159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/13/2023] [Accepted: 02/14/2023] [Indexed: 02/18/2023] Open
Abstract
Soluble guanylate cyclase (sGC) stimulator riociguat is a relatively novel therapeutic agent for pulmonary hypertension (PH) in human medicine. Riociguat induces endothelium-independent pulmonary artery (PA) relaxation by directly activating the sGC-cyclic guanosine-3',5'-monophosphate (cGMP) pathway in muscle cells. Although riociguat may be effective in the treatment of dogs with refractory PH, basic studies on its clinical application in veterinary medicine are lacking. The present study aimed to explore the effects of riociguat on the contractility of an isolated canine PA and the hemodynamics of dogs with acute PH. In an isolated endothelium-denuded canine PA, the effects of riociguat on endothelin (ET)-1-induced contraction and cGMP levels were investigated using the Magnus method and ELISA, respectively. The effect of riociguat on the hemodynamics of the thromboxane A2 analog U46619-induced PH model dog was examined by invasive catheterization. Riociguat increased cGMP levels and reduced ET-1-induced contraction of the isolated PA. Riociguat inhibited the U46619-induced elevation of PA pressure and pulmonary vascular resistance and increased cardiac output, but it had no effect on basal systemic blood pressure. These results demonstrate for the first time that riociguat can inhibit the elevation of PA pressure through PA relaxation via an endothelium-independent increase in cGMP in dogs with PH.
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Affiliation(s)
- Satoshi Kameshima
- Laboratory of Small Animal Internal Medicine 1, School of Veterinary Medicine, Kitasato University, Higashi 23 Bancho 35-1, Towada 034-8628, Aomori, Japan
- Correspondence: ; Tel.: +81-176-23-4371
| | - Yuki Nakamura
- Laboratory of Small Animal Internal Medicine 1, School of Veterinary Medicine, Kitasato University, Higashi 23 Bancho 35-1, Towada 034-8628, Aomori, Japan
| | - Kenji Uehara
- Laboratory of Small Animal Internal Medicine 1, School of Veterinary Medicine, Kitasato University, Higashi 23 Bancho 35-1, Towada 034-8628, Aomori, Japan
| | - Tomoko Kodama
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi 23 Bancho 35-1, Towada 034-8628, Aomori, Japan
| | - Hideyuki Yamawaki
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Higashi 23 Bancho 35-1, Towada 034-8628, Aomori, Japan
| | - Kotaro Nishi
- Laboratory of Small Animal Surgery 2, School of Veterinary Medicine, Kitasato University, Higashi 23 Bancho 35-1, Towada 034-8628, Aomori, Japan
| | - Shozo Okano
- Laboratory of Small Animal Surgery 2, School of Veterinary Medicine, Kitasato University, Higashi 23 Bancho 35-1, Towada 034-8628, Aomori, Japan
| | - Ryo Niijima
- Small Animal Teaching Hospital, School of Veterinary Medicine, Kitasato University, Higashi 23 Bancho 35-1, Towada 034-8628, Aomori, Japan
| | - Yuya Kimura
- Laboratory of Small Animal Internal Medicine 1, School of Veterinary Medicine, Kitasato University, Higashi 23 Bancho 35-1, Towada 034-8628, Aomori, Japan
| | - Naoyuki Itoh
- Laboratory of Small Animal Internal Medicine 1, School of Veterinary Medicine, Kitasato University, Higashi 23 Bancho 35-1, Towada 034-8628, Aomori, Japan
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13
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Jujo Sanada T, Manz XD, Symersky P, Pan X, Yoshida K, Aman J, Bogaard HJ. Riociguat inhibits ultra-large VWF string formation on pulmonary artery endothelial cells from chronic thromboembolic pulmonary hypertension patients. Pulm Circ 2022; 12:e12146. [PMID: 36568694 PMCID: PMC9768460 DOI: 10.1002/pul2.12146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 10/03/2022] [Indexed: 12/27/2022] Open
Abstract
Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by elevated pulmonary arterial pressure and organized thrombi within pulmonary arteries. Riociguat is a soluble guanylate cyclase stimulator and is approved for patients with inoperable CTEPH or residual pulmonary hypertension after pulmonary endarterectomy (PEA). Previous work suggested that riociguat treatment is associated with an increased risk of bleeding, although the mechanism is unclear. The aim of this study is to assess how riociguat affects primary hemostasis by studying its effect on the interaction between platelets and endothelial cells derived from CTEPH patients. Pulmonary artery endothelial cells (PAECs) were isolated from thrombus-free regions of PEA material. Purified PAECs were cultured in flow chambers and were stimulated with 0.1 and 1 µM riociguat for 24 h before flow experiments. After stimulation with histamine, PAECs were exposed to platelets under shear stress. Platelet adhesion and expression of von Willebrand Factor (VWF) were evaluated to assess the role of riociguat in hemostasis. Under dynamic conditions, 0.1 and 1.0 µM of riociguat suppressed platelet adhesion on the surface of PAECs. Although riociguat did not affect intracellular expression and secretion of VWF, PAECs stimulated with riociguat produced fewer VWF strings than unstimulated PAECs. Flow cytometry suggested that decreased VWF string formation upon riociguat treatment may be associated with suppressed cell surface expression of P-selectin, a protein that stabilizes VWF anchoring on the endothelial surface. In conclusion, Riociguat inhibits VWF string elongation and platelet adhesion on the surface of CTEPH-PAECs, possibly by reduced P-selectin cell surface expression.
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Affiliation(s)
- Takayuki Jujo Sanada
- Department of Pulmonary Medicine, Amsterdam UMCVU University Medical CenterAmsterdamThe Netherlands
- Department of Respirology, Graduate School of MedicineChiba UniversityChibaJapan
| | - Xue D. Manz
- Department of Pulmonary Medicine, Amsterdam UMCVU University Medical CenterAmsterdamThe Netherlands
| | - Petr Symersky
- Department of Cardio‐Thoracic SurgeryAmsterdam UMC, VU University Medical CenterAmsterdamThe Netherlands
- Department of Cardio‐thoracic SurgeryOLVG HospitalAmsterdamThe Netherlands
| | - Xiaoke Pan
- Department of Pulmonary Medicine, Amsterdam UMCVU University Medical CenterAmsterdamThe Netherlands
| | - Keimei Yoshida
- Department of Pulmonary Medicine, Amsterdam UMCVU University Medical CenterAmsterdamThe Netherlands
- Kyushu University Faculty of Medicine Graduate School of Medical Sciences School of MedicineFukuokaJapan
| | - Jurjan Aman
- Department of Pulmonary Medicine, Amsterdam UMCVU University Medical CenterAmsterdamThe Netherlands
| | - Harm Jan Bogaard
- Department of Pulmonary Medicine, Amsterdam UMCVU University Medical CenterAmsterdamThe Netherlands
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14
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Kocak OF, Albayrak M, Yaman ME, Atila A, Kadioglu Y, Araz O. Determination and pharmacokinetic study of riociguat by UPLC-MS/MS in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2022; 1210:123454. [PMID: 36095936 DOI: 10.1016/j.jchromb.2022.123454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 09/01/2022] [Accepted: 09/04/2022] [Indexed: 10/31/2022]
Abstract
Pulmonary hypertension (PH) is frequent in the general population and is linked to an increased risk of death. Riociguat is a kind of endothelin receptor antagonist that is often used to treat PH. For pharmacokinetic studies and the determination of riociguat in PH patients, a new, quick, easy, and sensitive UPLC-MS/MS approach was designed and validated. Riociguat and irbesartan (IS) were detected using ESI in positive ion and multiple reaction monitoring mode, respectively, by monitoring the mass transitions m/z 423.0 → 391.0 and 429.1 → 206.9. A reverse-phase C18 column (5 μm, 4.6 × 150 mm) was used with an isocratic mobile phase of water containing 0.1 % formic acid-acetonitrile (25:75, v/v) at a flow rate of 1 ml/min for chromatographic separation. In the range of 5-400 ng/ml, the calibration curve was linear and had a good correlation coefficient (0.9972). This is the first UPLC-MS/MS technique that has been developed and validated for determining riociguat from human plasma. The developed analytical method was extensively validated for linearity, selectivity, specificity, accuracy, precision, sensitivity, stability, matrix effect and recovery, according to FDA criteria. The devised approach was successfully used for a pharmacokinetic research and riociguat determination in PH patients.
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Affiliation(s)
- Omer Faruk Kocak
- Omer Faruk Kocak, Atatürk University, Vocational School of Technical Sciences, Department of Chemical Technology, Erzurum, Turkey
| | - Mevlut Albayrak
- Mevlut Albayrak, Ataturk University, Health Services Vocational Training School, Department of Medical Laboratory Techniques, Erzurum, Turkey.
| | - Mehmet Emrah Yaman
- Mehmet Emrah Yaman, Atatürk University, Faculty of Pharmacy, Department of Analytical Chemistry, Erzurum, Turkey
| | - Alptug Atila
- Alptug Atila, Atatürk University, Faculty of Pharmacy, Department of Analytical Chemistry, Erzurum, Turkey
| | - Yucel Kadioglu
- Yucel Kadioglu, Atatürk University, Faculty of Pharmacy, Department of Analytical Chemistry, Erzurum, Turkey
| | - Omer Araz
- Omer Araz, Atatürk University, Faculty of Medicine, Department of Pulmonary Diseases, Erzurum, Turkey
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15
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Dachs TM, Duca F, Rettl R, Binder-Rodriguez C, Dalos D, Ligios LC, Kammerlander A, Grünig E, Pretsch I, Steringer-Mascherbauer R, Ablasser K, Wargenau M, Mascherbauer J, Lang IM, Hengstenberg C, Badr-Eslam R, Kastner J, Bonderman D. Riociguat in pulmonary hypertension and heart failure with preserved ejection fraction: the haemoDYNAMIC trial. Eur Heart J 2022; 43:3402-3413. [PMID: 35909264 PMCID: PMC9492239 DOI: 10.1093/eurheartj/ehac389] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 06/12/2022] [Accepted: 07/06/2022] [Indexed: 12/16/2022] Open
Abstract
AIMS The presence of pulmonary hypertension (PH) severely aggravates the clinical course of heart failure with preserved ejection fraction (HFpEF). To date, neither established heart failure therapies nor pulmonary vasodilators proved beneficial. This study investigated the efficacy of chronic treatment with the oral soluble guanylate cyclase stimulator riociguat in patients with PH-HFpEF. METHODS AND RESULTS The phase IIb, randomized, double-blind, placebo-controlled, parallel-group, multicentre DYNAMIC trial assessed riociguat in PH-HFpEF. Patients were recruited at five hospitals across Austria and Germany. Key eligibility criteria were mean pulmonary artery pressure ≥25 mmHg, pulmonary arterial wedge pressure >15 mmHg, and left ventricular ejection fraction ≥50%. Patients were randomized to oral treatment with riociguat or placebo (1:1). Patients started at 0.5 mg three times daily (TID) and were up-titrated to 1.5 mg TID. The primary efficacy endpoint was change from baseline to week 26 in cardiac output (CO) at rest, measured by right heart catheterization. Primary efficacy analyses were performed on the full analysis set. Fifty-eight patients received riociguat and 56 patients placebo. After 26 weeks, CO increased by 0.37 ± 1.263 L/min in the riociguat group and decreased by -0.11 ± 0.921 L/min in the placebo group (least-squares mean difference: 0.54 L/min, 95% confidence interval 0.112, 0.971; P = 0.0142). Five patients dropped out due to riociguat-related adverse events but no riociguat-related serious adverse event or death occurred. CONCLUSION The vasodilator riociguat improved haemodynamics in PH-HFpEF. Riociguat was safe in most patients but led to more dropouts as compared to placebo and did not change clinical symptoms within the study period.
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Affiliation(s)
- Theresa-Marie Dachs
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Franz Duca
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - René Rettl
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Christina Binder-Rodriguez
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Daniel Dalos
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Luciana Camuz Ligios
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Andreas Kammerlander
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Ekkehard Grünig
- Centre for Pulmonary Hypertension, Thoraxklinik at Heidelberg University Hospital, Translational Lung Research Centre Heidelberg (TLRC), German Centre for Lung Research (DZL), 69126 Heidelberg, Germany
| | - Ingrid Pretsch
- Division of Cardiology and Intensive Care, Department of Internal Medicine II, Paracelsus Medical University of Salzburg, Muellner Hauptstraße 48, 5020 Salzburg, Austria
| | - Regina Steringer-Mascherbauer
- Division of Cardiology, Angiology and Intensive Care, Department of Internal Medicine II, Public Hospital Elisabethinen Linz, Fadingerstraße 1, 4020 Linz, Austria
| | - Klemens Ablasser
- Division of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria
| | - Manfred Wargenau
- M.A.R.C.O. GmbH & Co. KG, Institute for Clinical Research and Statistics, Schirmerstraße 71, 40211 Duesseldorf, Germany
| | - Julia Mascherbauer
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.,Division of Cardiology, Department of Internal Medicine III, University Hospital of St. Poelten, Dunant-Platz 1, 3100 St. Poelten, Austria
| | - Irene M Lang
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Christian Hengstenberg
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Roza Badr-Eslam
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Johannes Kastner
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Diana Bonderman
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.,Division of Cardiology, Department of Internal Medicine V, Favoriten Clinic, Kundratstraße 3, 1100 Vienna, Austria
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16
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García Aguilar H, Gorenflo M, Ivy DD, Moledina S, Castaldi B, Ishida H, Cześniewicz P, Kusa J, Miera O, Pattathu J, Weng K, Ablonczy L, Apitz C, Katona M, Kurosaki K, Pulido T, Yamagishi H, Yasuda K, Cisternas G, Goth M, Lippert S, Radomskyj A, Saleh S, Willmann S, Wirsching G, Bonnet D, Beghetti M. Riociguat in children with pulmonary arterial hypertension: The PATENT-CHILD study. Pulm Circ 2022; 12:e12133. [PMID: 36186721 PMCID: PMC9485817 DOI: 10.1002/pul2.12133] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 07/29/2022] [Accepted: 08/25/2022] [Indexed: 11/07/2022] Open
Abstract
Riociguat, a soluble guanylate cyclase stimulator, is approved for treatment of adults with pulmonary arterial hypertension (PAH). The safety, tolerability, and pharmacokinetics (PK) of oral riociguat in a pediatric population with PAH was assessed in PATENT-CHILD (NCT02562235), a multicenter, single-arm, 24-week, open-label, Phase 3 study. Patients aged 6-17 years in World Health Organization functional class (WHO-FC) I-III treated with stable endothelin receptor antagonists and/or prostacyclin analogs received riociguat equivalent to 0.5-2.5 mg three times daily in adults, as either oral pediatric suspension or tablets, based on bodyweight. Primary outcomes were safety, tolerability, and PK of riociguat. Twenty-four patients (mean age 12.8 years), 18 of whom were in WHO-FC II, were enrolled. Adverse events (AEs), mostly mild or moderate, were reported in 20 patients (83%). Four patients (17%) experienced a serious AE; all resolved by study end and two (8%) were considered study-drug related. Hypotension was reported in three patients and hemoptysis in one (all mild/moderate intensity). Riociguat plasma concentrations in pediatric patients were consistent with those published in adult patients. From baseline to Week 24, mean ± standard deviation increase in 6-minute walking distance was 23 ± 69 m (n = 19), and mean decrease in NT-proBNP was -66 ± 585 pg/ml (n = 14). There was no change in WHO-FC. Two patients experienced clinical worsening events of hospitalization for right heart failure. PK results confirmed a suitable riociguat dosing strategy for pediatric patients with PAH. The data suggest an acceptable safety profile with potential efficacy signals.
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Affiliation(s)
| | - Matthias Gorenflo
- Department of Pediatric Cardiology and Congenital CardiologyHeidelberg University Medical CentreHeidelbergGermany
| | - D. Dunbar Ivy
- Division of Cardiology, Department of Pediatrics, University of Colorado School of MedicineChildren's Hospital ColoradoAuroraColoradoUSA
| | - Shahin Moledina
- Cardiology DepartmentGreat Ormond Street Hospital for Children NHS Foundation TrustLondonUK
| | - Biagio Castaldi
- Dipartimento di PediatriaAzienda Ospedaliera di PadovaPadovaItaly
| | - Hidekazu Ishida
- Department of PediatricsOsaka University Graduate School of MedicineOsakaJapan
| | - Paweł Cześniewicz
- Department of Pediatric Cardiology, Regional Specialist HospitalResearch and Development CenterWroclawPoland
| | - Jacek Kusa
- Department of Pediatric Cardiology, Regional Specialist HospitalResearch and Development CenterWroclawPoland
| | - Oliver Miera
- Department of Congenital Heart Disease/Pediatric CardiologyGerman Heart CenterBerlinGermany
| | - Joseph Pattathu
- Department of Pediatric Cardiology and Congenital CardiologyHeidelberg University Medical CentreHeidelbergGermany
- Present address:
University of MunichMunichGermany
| | - Ken‐Pen Weng
- Department of Pediatrics, Congenital Structural Heart Disease CenterKaohsiung Veterans General HospitalKaohsiungTaiwan
| | - Laszlo Ablonczy
- Pediatric Cardiac CenterHungarian Institute of CardiologyBudapestHungary
| | - Christian Apitz
- Division of Pediatric CardiologyUniversity Children's Hospital UlmUlmGermany
| | - Marta Katona
- Department of Pediatrics, Albert Szent‐Györgyi Medical CenterUniversity of SzegedSzegedHungary
| | - Kenichi Kurosaki
- Department of Pediatric CardiologyNational Cerebral and Cardiovascular CenterOsakaJapan
| | - Tomas Pulido
- Clinical Research DepartmentIgnacio Chavez National Heart InstituteMexico CityMexico
| | | | - Kazushi Yasuda
- Department of Pediatric CardiologyAichi Children's Health and Medical CenterAichiJapan
| | | | | | | | | | | | | | | | - Damien Bonnet
- M3C‐Necker, Hôpital Necker Enfants maladesAPHP Université de ParisParisFrance
| | - Maurice Beghetti
- Paediatric Cardiology UnitUniversity Hospitals of GenevaGenevaSwitzerland
- Centre Universitaire Romand De Cardiologie Et Chirurgie Cardiaque Pédiatrique, Children's University HospitalUniversity of Geneva and LausanneGenevaSwitzerland
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17
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Xia J, Hui N, Tian L, Liang C, Zhang J, Liu J, Wang J, Ren X, Xie X, Wang K. Development of vericiguat: The first soluble guanylate cyclase (sGC) stimulator launched for heart failure with reduced ejection fraction (HFrEF). Biomed Pharmacother 2022; 149:112894. [PMID: 35367763 DOI: 10.1016/j.biopha.2022.112894] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 03/23/2022] [Accepted: 03/25/2022] [Indexed: 11/02/2022] Open
Abstract
In recent years, with improvements in treatments for heart failure (HF), the survival period of patients has been extended. However, the emergence of some patients with repeated hospitalizations due to their worsening conditions and low survival rates followed. Currently, few drugs are available for such patients. Vericiguat was first drug approved for the treatment of symptomatic patients with chronic HF with reduced ejection fraction (HFrEF) to reduce the occurrence of worsening HF. This article provides comprehensive information about vericiguat in terms of drug design and development, structure-activity relationship (SAR), synthesis, pharmacological efficacy, and clinical practice. In addition, insights into the current vericiguat trials and treatments of HF are also discussed.
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Affiliation(s)
- Juan Xia
- Laboratory of Hematologic Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, PR China.
| | - Nan Hui
- Faculty of Pharmacy, Shaanxi University of Science & Technology, Xi'an 710021, PR China.
| | - Lei Tian
- Faculty of Pharmacy, Shaanxi University of Science & Technology, Xi'an 710021, PR China.
| | - Chengyuan Liang
- Faculty of Pharmacy, Shaanxi University of Science & Technology, Xi'an 710021, PR China.
| | - Jie Zhang
- Faculty of Pharmacy, Shaanxi University of Science & Technology, Xi'an 710021, PR China.
| | - Jifang Liu
- Faculty of Pharmacy, Shaanxi University of Science & Technology, Xi'an 710021, PR China.
| | - Jun Wang
- Faculty of Pharmacy, Shaanxi University of Science & Technology, Xi'an 710021, PR China; Key Laboratory of Traditional Chinese and Tibetan Medicine of Qinghai Province, Qinghai Provincial Drug Inspection and Testing Institute, Xining 810000, PR China.
| | - Xiaodong Ren
- Medical College, Guizhou University, Guiyang 550025, PR China.
| | - Xiaolin Xie
- Shaanxi Panlong Pharmaceutical Group Co., Ltd. Xi'an, 710025, PR China.
| | - Kun Wang
- Children's Center, the Affiliated Taian City Centeral Hospital of Qingdao University, Taian, Shandong, 271000, PR China.
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Nascimento DZD, Marques GM, Schuelter-Trevisol F. Potential interactions between psychotropic drugs and alcohol and tobacco dependence. BRAZ J PHARM SCI 2022. [DOI: 10.1590/s2175-97902022e20401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
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19
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Kobalava ZD, Lazarev PV. Nitric oxide — soluble guanylate cyclase — cyclic guanosine monophosphate signaling pathway in the pathogenesis of heart failure and search for novel therapeutic targets. КАРДИОВАСКУЛЯРНАЯ ТЕРАПИЯ И ПРОФИЛАКТИКА 2021. [DOI: 10.15829/1728-8800-2021-3035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Heart failure is a severe disease with an unfavorable prognosis, which requires intensification of therapy and the search for novel approaches to treatment. In this review, the physiological significance of soluble guanylate cyclase-related signaling pathway, reasons for decrease in its activity in heart failure and possible consequences are discussed. Pharmacological methods of stimulating the production of cyclic guanosine monophosphate using drugs with different mechanisms of action are considered. Data from clinical studies regarding their effectiveness and safety are presented. A promising approach is stimulation of soluble guanylate cyclase, which showed beneficial effects in preclinical studies, as well as in the recently completed phase III VICTORIA study.
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20
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Ying M, Song J, Gu S, Zhao R, Li M. Efficacy and safety of riociguat in the treatment of chronic thromboembolic pulmonary arterial hypertension: A meta-analysis. Medicine (Baltimore) 2021; 100:e26211. [PMID: 34087896 PMCID: PMC8183702 DOI: 10.1097/md.0000000000026211] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 04/16/2021] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Riociguat is a novel soluble guanylate cyclase stimulator, and has been widely used for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (CTEPH). Some studies found that riociguat had better effects on CTEPH and proved to be safe, but the results were not utterly consistent. Therefore, the purpose of this study was to comprehensively evaluate the efficacy and safety of riociguat in the treatment of CTEPH. METHODS Randomized controlled trials on riociguat for the treatment of CTEPH were searched through such electronic databases as PubMed, Embase, Cochrane Library, Web of Science, China national knowledge internet, and Wanfang. The outcomes included exercise capacity, pulmonary hemodynamics, and side effects. The fixed-effects or random-effects models were used to analyze the pooled data, and heterogeneity was assessed by the I2 test. RESULTS Four studies involving 520 patients were included in this meta-analysis. Compared with the placebo group, riociguat significantly improved the hemodynamic indexes and increased 6-min walking distance (P < .0001, standardized mean difference (SMD) = -0.24, 95%CI -0.35 to -0.12; P < .00001, SMD = 0.52, 95%CI 0.33 to 0.71), and decreased the Borg dyspnea score (P = .002, SMD = -0.31, 95%CI -0.51 to -0.12). In addition, riociguat could also significantly reduce the living with pulmonary hypertension scores and increase the EQ-5D scores (P = .01, SMD=-0.23, 95%CI -0.42 to -0.05; P < .00001, SMD = 0.47, 95%CI 0.27 to 0.66), but there was no significant difference in the change level of N-terminal pro-hormone B-type natriuretic peptide in patients with riociguat (P = .20, SMD = -0.24, 95%CI -0.61 to -0.13). The common adverse events of riociguat were dyspepsia and peripheral edema, and no other serious adverse reactions were observed. CONCLUSIONS We confirmed that riociguat had better therapeutic effects in improving the hemodynamic parameters and exercise capacity in patients with CTEPH without inducing serious adverse events. This will provide a reasonable medication regimen for the treatment of CTEPH.
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Oldenburger A, Birk G, Schlepütz M, Broermann A, Stierstorfer B, Pullen SS, Rippmann JF. Modulation of vascular contraction via soluble guanylate cyclase signaling in a novel ex vivo method using rat precision-cut liver slices. Pharmacol Res Perspect 2021; 9:e00768. [PMID: 34014044 PMCID: PMC8135082 DOI: 10.1002/prp2.768] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 03/09/2021] [Accepted: 03/10/2021] [Indexed: 01/05/2023] Open
Abstract
Fibrotic processes in the liver of non-alcoholic steatohepatitis (NASH) patients cause microcirculatory dysfunction in the organ which increases blood vessel resistance and causes portal hypertension. Assessing blood vessel function in the liver is challenging, necessitating the development of novel methods in normal and fibrotic tissue that allow for drug screening and translation toward pre-clinical settings. Cultures of precision cut liver slices (PCLS) from normal and fibrotic rat livers were used for blood vessel function analysis. Live recording of vessel diameter was used to assess the response to endothelin-1, serotonin and soluble guanylate cyclase (sGC) activation. A cascade of contraction and relaxation events in response to serotonin, endothelin-1, Ketanserin and sGC activity could be established using vessel diameter analysis of rat PCLS. Both the sGC activator BI 703704 and the sGC stimulator Riociguat prevented serotonin-induced contraction in PCLS from naive rats. By contrast, PCLS cultures from the rat CCl4 NASH model were only responsive to the sGC activator, thus establishing that the sGC enzyme is rendered non-responsive to nitric oxide under oxidative stress found in fibrotic livers. The role of the sGC pathway for vessel relaxation of fibrotic liver tissue was identified in our model. The obtained data shows that the inhibitory capacities on vessel contraction of sGC compounds can be translated to published preclinical data. Altogether, this novel ex vivo PCLS method allows for the differentiation of drug candidates and the translation of therapeutic approaches towards the clinical use.
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Affiliation(s)
- Anouk Oldenburger
- CardioMetabolic Diseases ResearchBoehringer Ingelheim Pharma GmbH & Co. KGBiberach a.d. RissGermany
| | - Gerald Birk
- Target Discovery SciencesBoehringer Ingelheim Pharma GmbH & Co. KGBiberach an der RissGermany
| | - Marco Schlepütz
- Immunology and Respiratory Diseases ResearchBoehringer Ingelheim Pharma GmbH & Co. KGBiberach an der RissGermany
| | - Andre Broermann
- CardioMetabolic Diseases ResearchBoehringer Ingelheim Pharma GmbH & Co. KGBiberach a.d. RissGermany
| | - Birgit Stierstorfer
- Target Discovery SciencesBoehringer Ingelheim Pharma GmbH & Co. KGBiberach an der RissGermany
| | - Steven S. Pullen
- CardioMetabolic Diseases ResearchBoehringer Ingelheim Pharmaceuticals, IncRidgefieldCTUSA
| | - Jörg F. Rippmann
- Cancer Immunology+Immune ModulationBoehringer Ingelheim Pharma GmbH & Co. KGBiberach a.d. RissGermany
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Al-Qadi M, LeVarge B, Ford HJ. Epidemiology, Pathogenesis, and Clinical Approach in Group 5 Pulmonary Hypertension. Front Med (Lausanne) 2021; 7:616720. [PMID: 33842491 PMCID: PMC8026868 DOI: 10.3389/fmed.2020.616720] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 12/17/2020] [Indexed: 01/19/2023] Open
Abstract
Pulmonary hypertension (PH) is recognized to be associated with a number of comorbid conditions. Based on these associations, PH is classified into 5 groups, considering common pathophysiologic drivers of disease, histopathologic features, clinical manifestations and course, and response to PH therapy. However, in some of these associated conditions, these characteristics are less well-understood. These include, among others, conditions commonly encountered in clinical practice such as sarcoidosis, sickle cell disease, myeloproliferative disorders, and chronic kidney disease/end stage renal disease. PH in these contexts presents a significant challenge to clinicians with respect to disease management. The most recent updated clinical classification schemata from the 6th World Symposium on PH classifies such entities in Group 5, highlighting the often unclear and/or multifactorial nature of PH. An in-depth review of the state of the science of Group 5 PH with respect to epidemiology, pathogenesis, and management is provided. Where applicable, future directions with respect to research needed to enhance understanding of the clinical course of these entities is also discussed.
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Affiliation(s)
- Mazen Al-Qadi
- Division of Pulmonary and Critical Care Medicine, Pulmonary Hypertension Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Barbara LeVarge
- Division of Pulmonary and Critical Care Medicine, Pulmonary Hypertension Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - H James Ford
- Division of Pulmonary and Critical Care Medicine, Pulmonary Hypertension Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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Boettcher M, Loewen S, Gerrits M, Becker C. Pharmacodynamic and Pharmacokinetic Interaction Profile of Vericiguat: Results from Three Randomized Phase I Studies in Healthy Volunteers. Clin Pharmacokinet 2021; 60:337-351. [PMID: 33030703 PMCID: PMC7932970 DOI: 10.1007/s40262-020-00935-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
BACKGROUND Vericiguat, a direct stimulator of soluble guanylate cyclase, has been developed as a first-in-class therapy for symptomatic chronic heart failure (HF) and ejection fraction < 45%. METHODS Safety, pharmacodynamic (PD), and pharmacokinetic (PK) interactions between vericiguat and drugs used in HF (sacubitril/valsartan [SV] and aspirin [acetylsalicylic acid]) or with a narrow therapeutic index (warfarin) were evaluated in three phase I studies. RESULTS Vericiguat 15 mg (single dose [SD]) had no effect on bleeding time or platelet aggregation when coadministered with aspirin 1000 mg versus aspirin alone: estimated differences in least squares means 2.7% (95% confidence interval [CI] - 90.4 to 95.8) and 2.4% (95% CI - 7.0 to 11.8) turbidimetry, respectively. Vericiguat 10 mg (once daily) had no effect on coagulation inhibition elicited by warfarin 25 mg (SD; mean ratios of area under the concentration-time curve from time zero to 96 h for clotting parameter treatment comparisons approximated 100.0%). There were no clinically relevant PD changes whether SV 97/103 mg was administered with single or multiple doses of vericiguat 2.5 mg or placebo (differences in systolic blood pressure [BP] - 1.66 mmHg [90% CI - 4.22 to 0.90]; diastolic BP - 1.80 mmHg [90% CI - 3.24 to - 0.36]; heart rate - 0.33 beats/min [90% CI - 2.25 to 1.60]). Vericiguat demonstrated no PK interactions when coadministered with aspirin, warfarin, or SV at steady state. Treatments were well tolerated. CONCLUSIONS Coadministration of vericiguat with SV, aspirin, or warfarin was well tolerated. No clinically relevant PD or PK interactions were observed, supporting concomitant use of these drugs, commonly used by patients with HF, with vericiguat and no dose adjustment. EUDRACT NUMBER 2014-000765-52; 2014-004880-19; 2015-004809-16.
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Affiliation(s)
- Michael Boettcher
- Clinical Pharmacology, Bayer AG, Research and Development, Pharmaceuticals, Aprather Weg 18a, 42113, Wuppertal, Germany
| | | | - Mireille Gerrits
- Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA
| | - Corina Becker
- Clinical Pharmacology, Bayer AG, Research and Development, Pharmaceuticals, Aprather Weg 18a, 42113, Wuppertal, Germany.
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24
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Sandner P, Zimmer DP, Milne GT, Follmann M, Hobbs A, Stasch JP. Soluble Guanylate Cyclase Stimulators and Activators. Handb Exp Pharmacol 2021; 264:355-394. [PMID: 30689085 DOI: 10.1007/164_2018_197] [Citation(s) in RCA: 98] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
When Furchgott, Murad, and Ignarro were honored with the Nobel prize for the identification of nitric oxide (NO) in 1998, the therapeutic implications of this discovery could not be fully anticipated. This was due to the fact that available therapeutics like NO donors did not allow a constant and long-lasting cyclic guanylyl monophosphate (cGMP) stimulation and had a narrow therapeutic window. Now, 20 years later, the stimulator of soluble guanylate cyclase (sGC), riociguat, is on the market and is the only drug approved for the treatment of two forms of pulmonary hypertension (PAH/CTEPH), and a variety of other sGC stimulators and sGC activators are in preclinical and clinical development for additional indications. The discovery of sGC stimulators and sGC activators is a milestone in the field of NO/sGC/cGMP pharmacology. The sGC stimulators and sGC activators bind directly to reduced, heme-containing and oxidized, heme-free sGC, respectively, which results in an increase in cGMP production. The action of sGC stimulators at the heme-containing enzyme is independent of NO but is enhanced in the presence of NO whereas the sGC activators interact with the heme-free form of sGC. These highly innovative pharmacological principles of sGC stimulation and activation seem to have a very broad therapeutic potential. Therefore, in both academia and industry, intensive research and development efforts have been undertaken to fully exploit the therapeutic benefit of these new compound classes. Here we summarize the discovery of sGC stimulators and sGC activators and the current developments in both compound classes, including the mode of action, the chemical structures, and the genesis of the terminology and nomenclature. In addition, preclinical studies exploring multiple aspects of their in vitro, ex vivo, and in vivo pharmacology are reviewed, providing an overview of multiple potential applications. Finally, the clinical developments, investigating the treatment potential of these compounds in various diseases like heart failure, diabetic kidney disease, fibrotic diseases, and hypertension, are reported. In summary, sGC stimulators and sGC activators have a unique mode of action with a broad treatment potential in cardiovascular diseases and beyond.
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Affiliation(s)
- Peter Sandner
- Bayer AG, Pharmaceuticals R&D, Pharma Research Center, Wuppertal, Germany. .,Department of Pharmacology, Hannover Medical School, Hannover, Germany.
| | | | | | - Markus Follmann
- Bayer AG, Pharmaceuticals R&D, Pharma Research Center, Wuppertal, Germany
| | - Adrian Hobbs
- Barts and the London School of Medicine and Dentistry QMUL, London, UK
| | - Johannes-Peter Stasch
- Bayer AG, Pharmaceuticals R&D, Pharma Research Center, Wuppertal, Germany.,Institute of Pharmacy, University Halle-Wittenberg, Halle, Germany
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25
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Ghofrani HA, D'Armini AM, Kim NH, Mayer E, Simonneau G. Interventional and pharmacological management of chronic thromboembolic pulmonary hypertension. Respir Med 2021; 177:106293. [PMID: 33465538 DOI: 10.1016/j.rmed.2020.106293] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 12/11/2020] [Accepted: 12/27/2020] [Indexed: 11/24/2022]
Abstract
Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by obstruction of the pulmonary vasculature, leading to increased pulmonary vascular resistance and ultimately right ventricular failure, the leading cause of death in non-operated patients. This article reviews the current management of CTEPH. The standard of care in CTEPH is pulmonary endarterectomy (PEA). However, up to 40% of patients with CTEPH are ineligible for PEA, and up to 51% develop persistent/recurrent PH after PEA. Riociguat is currently the only medical therapy licensed for treatment of inoperable or persistent/recurrent CTEPH after PEA based on the results of the Phase III CHEST-1 study. Studies of balloon pulmonary angioplasty (BPA) have shown benefits in patients with inoperable or persistent/recurrent CTEPH after PEA; however, data are lacking from large, prospective, controlled studies. Studies of macitentan in patients with inoperable CTEPH and treprostinil in patients with inoperable or persistent/recurrent CTEPH showed positive results. Combination therapy is under evaluation in CTEPH, and long-term data are not available. In the future, CTEPH may be managed by PEA, medical therapy or BPA - alone or in combination, according to individual patient needs. Patients should be referred to experienced centers capable of assessing and delivering all options.
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Affiliation(s)
- Hossein-Ardeschir Ghofrani
- Department of Internal Medicine, University of Giessen and Marburg Lung Center, Giessen, Germany; Department of Pneumology, Kerckhoff-Klinik, Bad Nauheim, Germany; Department of Medicine, Imperial College London, London, UK.
| | - Andrea M D'Armini
- Department of Cardio-Thoracic and Vascular Surgery, Heart and Lung Transplantation and Pulmonary Hypertension Unit, Foundation IRCCS Policlinico San Matteo, University of Pavia School of Medicine, Pavia, Italy
| | - Nick H Kim
- Division of Pulmonary and Critical Care Medicine, University of California, San Diego, USA
| | - Eckhard Mayer
- Department of Thoracic Surgery, Kerckhoff Clinic, Bad Nauheim, Germany; Member of the German Center for Lung Research (DZL), Germany
| | - Gérald Simonneau
- Assistance Publique-Hôpitaux de Paris, Service de Pneumologie, Hôpital Bicêtre, Université Paris-Saclay, Laboratoire d'Excellence en Recherche sur le Médicament et Innovation Thérapeutique, Le Kremlin, Bicêtre, France
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26
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Paulo M, Costa DEFR, Bonaventura D, Lunardi CN, Bendhack LM. Nitric Oxide Donors as Potential Drugs for the Treatment of Vascular Diseases Due to Endothelium Dysfunction. Curr Pharm Des 2021; 26:3748-3759. [PMID: 32427079 DOI: 10.2174/1381612826666200519114442] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 04/07/2020] [Indexed: 11/22/2022]
Abstract
Endothelial dysfunction and consequent vasoconstriction are a common condition in patients with hypertension and other cardiovascular diseases. Endothelial cells produce and release vasodilator substances that play a pivotal role in normal vascular tone. The mechanisms underlying endothelial dysfunction are multifactorial. However, enhanced reactive oxygen species (ROS) production and consequent vasoconstriction instead of endothelium-derived relaxant generation and consequent vasodilatation contribute to this dysfunction considerably. The main targets of the drugs that are currently used to treat vascular diseases concerning enzyme activities and protein functions that are impaired by endothelial nitric oxide synthase (eNOS) uncoupling and ROS production. Nitric oxide (NO) bioavailability can decrease due to deficient NO production by eNOS and/or NO release to vascular smooth muscle cells, which impairs endothelial function. Considering the NO cellular mechanisms, tackling the issue of eNOS uncoupling could avoid endothelial dysfunction: provision of the enzyme cofactor tetrahydrobiopterin (BH4) should elicit NO release from NO donors, to activate soluble guanylyl cyclase. This should increase cyclic guanosine-monophosphate (cGMP) generation and inhibit phosphodiesterases (especially PDE5) that selectively degrade cGMP. Consequently, protein kinase-G should be activated, and K+ channels should be phosphorylated and activated, which is crucial for cell membrane hyperpolarization and vasodilation and/or inhibition of ROS production. The present review summarizes the current concepts about the vascular cellular mechanisms that underlie endothelial dysfunction and which could be the target of drugs for the treatment of patients with cardiovascular disease.
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Affiliation(s)
- Michele Paulo
- Department Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirao Preto- University of Sao Paulo Av. Do Cafe SN, Brazil
| | - Daniela E F R Costa
- Department of Pharmacology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Daniella Bonaventura
- Department of Pharmacology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Claure N Lunardi
- Laboratory of Photochemistry and Nanobiotechnology, University of Brasilia, Brasilia, Brazil
| | - Lusiane M Bendhack
- Department Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirao Preto- University of Sao Paulo Av. Do Cafe SN, Brazil
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27
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Shah J, Kotadiya R. A Critical Review on Analytical Methods for Recently Approved FDC Drugs: Pregabalin and Etoricoxib. Crit Rev Anal Chem 2020; 52:1048-1068. [PMID: 33307732 DOI: 10.1080/10408347.2020.1855411] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Fixed-dose combinations (FDCs) refer to products containing two or more active ingredients combined in a single dosage form. The FDCs are justified because of several advantages. These are a) potentiating therapeutic efficacy, b) reducing the incidences of adverse drug effects, c) having pharmacokinetic advantages, d) reducing pills burden, e) reducing the dose of individual drugs and f) decreasing the drug resistance development. A recently approved FDC of Pregabalin IP (75 mg) and Etoricoxib (60 mg) recommended to control neuropathic chronic back pain. Analytical methods are available for individual quantitation of pregabalin (PGB) and etoricoxib (ETC), but an effective and reliable analytical method has not been reported for their combination. Thus, the objective of this literature survey was to gather information on various analytical instrumental methods used so far for the individual quantitation of PGB and ETC in various matrices. Such data would be useful to the scientific community to develop a novel analytical method for the analysis of recently approved FDC of PGB and ETC. Various scientific databases were explored to meet the objectives, and the information is synchronized. The reported methods are high-performance liquid chromatography (48% & 53%), hyphenated techniques (54% & 21%), spectroscopy (50% & 34%), and high-performance thin-layer chromatography, or thin-layer chromatography (6% & 13%) for pregabalin and etoricoxib, respectively. All these methods were specific and selective for the analysis of individual drugs.
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Affiliation(s)
- Janvi Shah
- Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology, Changa, Gujarat, India
| | - Rajendra Kotadiya
- Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology, Changa, Gujarat, India
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Rüdebusch J, Benkner A, Nath N, Fleuch L, Kaderali L, Grube K, Klingel K, Eckstein G, Meitinger T, Fielitz J, Felix SB. Stimulation of soluble guanylyl cyclase (sGC) by riociguat attenuates heart failure and pathological cardiac remodelling. Br J Pharmacol 2020; 179:2430-2442. [PMID: 33247945 DOI: 10.1111/bph.15333] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 10/16/2020] [Accepted: 11/17/2020] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND AND PURPOSE Heart failure is associated with an impaired NO-soluble guanylyl cyclase (sGC)-cGMP pathway and its augmentation is thought to be beneficial for its therapy. We hypothesized that stimulation of sGC by the sGC stimulator riociguat prevents pathological cardiac remodelling and heart failure in response to chronic pressure overload. EXPERIMENTAL APPROACH Transverse aortic constriction or sham surgery was performed in C57BL/6N mice. After 3 weeks of transverse aortic constriction when heart failure was established, animals receive either riociguat or its vehicle for 5 additional weeks. Cardiac function was evaluated weekly by echocardiography. Eight weeks after surgery, histological analyses were performed to evaluate remodelling and the transcriptome of the left ventricles (LVs) was analysed by RNA sequencing. Cell culture experiments were used for mechanistically studies. KEY RESULTS Transverse aortic constriction resulted in a continuous decrease of LV ejection fraction and an increase in LV mass until week 3. Five weeks of riociguat treatment resulted in an improved LV ejection fraction and a decrease in the ratio of left ventricular mass to total body weight (LVM/BW), myocardial fibrosis and myocyte cross-sectional area. RNA sequencing revealed that riociguat reduced the expression of myocardial stress and remodelling genes (e.g. Nppa, Nppb, Myh7 and collagen) and attenuated the activation of biological pathways associated with cardiac hypertrophy and heart failure. Riociguat reversed pathological stress response in cultivated myocytes and fibroblasts. CONCLUSION AND IMPLICATIONS Stimulation of the sGC reverses transverse aortic constriction-induced heart failure and remodelling, which is associated with improved myocardial gene expression.
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Affiliation(s)
- Julia Rüdebusch
- Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.,DZHK (German Centre for Cardiovascular Research, partner site Greifswald), Greifswald, Germany
| | - Alexander Benkner
- Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.,DZHK (German Centre for Cardiovascular Research, partner site Greifswald), Greifswald, Germany
| | - Neetika Nath
- Institute of Bioinformatics, University Medicine Greifswald, Greifswald, Germany
| | - Lina Fleuch
- Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.,DZHK (German Centre for Cardiovascular Research, partner site Greifswald), Greifswald, Germany
| | - Lars Kaderali
- DZHK (German Centre for Cardiovascular Research, partner site Greifswald), Greifswald, Germany.,Institute of Bioinformatics, University Medicine Greifswald, Greifswald, Germany
| | - Karina Grube
- Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.,DZHK (German Centre for Cardiovascular Research, partner site Greifswald), Greifswald, Germany
| | - Karin Klingel
- Cardiopathology, Institute for Pathology, University Hospital Tübingen, Tübingen, Germany
| | - Gertrud Eckstein
- Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
| | - Thomas Meitinger
- Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
| | - Jens Fielitz
- Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.,DZHK (German Centre for Cardiovascular Research, partner site Greifswald), Greifswald, Germany
| | - Stephan B Felix
- Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.,DZHK (German Centre for Cardiovascular Research, partner site Greifswald), Greifswald, Germany
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Boettcher M, Gerisch M, Lobmeyer M, Besche N, Thomas D, Gerrits M, Lemmen J, Mueck W, Radtke M, Becker C. Metabolism and Pharmacokinetic Drug-Drug Interaction Profile of Vericiguat, A Soluble Guanylate Cyclase Stimulator: Results From Preclinical and Phase I Healthy Volunteer Studies. Clin Pharmacokinet 2020; 59:1407-1418. [PMID: 32458378 PMCID: PMC7658073 DOI: 10.1007/s40262-020-00895-x] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Vericiguat is a stimulator of soluble guanylate cyclase currently under investigation as a first-in-class therapy for worsening chronic heart failure (NCT02861534). Patients with heart failure often require polypharmacy because of comorbidities. Hence, understanding the clearance mechanisms, elimination, and potential for pharmacokinetic drug-drug interactions of vericiguat is important for dose recommendations in this patient population. METHODS Biotransformation and perpetrator properties of vericiguat were characterized in vitro using human hepatocytes, liver microsomes, and recombinant enzymes. This was complemented by a human mass balance study and ten drug-drug interaction studies in healthy volunteers wherein vericiguat was co-administered orally with omeprazole, magnesium/aluminum hydroxide, ketoconazole, rifampicin, mefenamic acid, midazolam, warfarin, digoxin, sacubitril/valsartan, aspirin, or sildenafil. RESULTS In the human mass balance study, mean total radioactivity recovered was 98.3% of the dose administered (53.1% and 45.2% excreted via urine and feces, respectively). The main metabolic pathway of vericiguat is glucuronidation via uridine diphosphate-glucuronosyltransferase 1A9 and 1A1. In vitro studies revealed a low risk of vericiguat acting as a perpetrator by inhibiting cytochrome P450s, uridine diphosphate-glucuronosyltransferase isoforms, or major transport proteins, or by inducing cytochrome P450s. These observations were supported by phase I drug-drug interaction studies. Phase I studies that assessed the propensity of vericiguat as a victim drug showed changes in the range that did not warrant recommendations for dose adjustment in phase III. CONCLUSIONS A low pharmacokinetic interaction potential of vericiguat was estimated from in vitro data and confirmed in vivo. Thus, vericiguat is suitable for a patient population with multiple comorbidities requiring polypharmacy.
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Affiliation(s)
- Michael Boettcher
- Clinical Pharmacology, Bayer AG, Aprather Weg 18a, 41113, Wuppertal, Germany
| | | | - Maximilian Lobmeyer
- Clinical Pharmacology, Bayer AG, Aprather Weg 18a, 41113, Wuppertal, Germany
| | - Nina Besche
- Chrestos Concept GmbH & Co. KG, Girardetstr. 1-5, 45131, Essen, Germany
| | - Dirk Thomas
- Experimental Medicine, Bayer AG, Aprather Weg 18a, 41113, Wuppertal, Germany
| | - Mireille Gerrits
- Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA
| | - Julia Lemmen
- DMPK, Bayer AG, Aprather Weg 18a, 41113, Wuppertal, Germany
| | - Wolfgang Mueck
- Clinical Pharmacology, Bayer AG, Aprather Weg 18a, 41113, Wuppertal, Germany
| | - Martin Radtke
- DMPK, Bayer AG, Aprather Weg 18a, 41113, Wuppertal, Germany
| | - Corina Becker
- Clinical Pharmacology, Bayer AG, Aprather Weg 18a, 41113, Wuppertal, Germany.
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30
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BAY 41-2272 Attenuates CTGF Expression via sGC/cGMP-Independent Pathway in TGFβ1-Activated Hepatic Stellate Cells. Biomedicines 2020; 8:biomedicines8090330. [PMID: 32899801 DOI: 10.3390/biomedicines8090330] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 09/02/2020] [Accepted: 09/03/2020] [Indexed: 12/12/2022] Open
Abstract
Activation of hepatic stellate cells (HSCs) is a critical pathogenic feature of liver fibrosis and cirrhosis. BAY 41-2272 is a canonical non-nitric oxide (NO)-based soluble guanylyl cyclase (sGC) stimulator that triggers cyclic guanosine monophosphate (cGMP) signaling for attenuation of fibrotic disorders; however, the impact of BAY 41-2272 on HSC activation remains ill-defined. Transforming growth factor (TGF)β and its downstream connective tissue growth factor (CTGF or cellular communication network factor 2, CCN2) are critical fibrogenic cytokines for accelerating HSC activation. Here, we identified that BAY 41-2272 significantly inhibited the TGFβ1-induced mRNA and protein expression of CTGF in mouse primary HSCs. Indeed, BAY 41-2272 increased the sGC activity and cGMP levels that were potentiated by two NO donors and inhibited by a specific sGC inhibitor, ODQ. Surprisingly, the inhibitory effects of BAY 41-2272 on CTGF expression were independent of the sGC/cGMP pathway in TGFβ1-activated primary HSCs. BAY 41-2272 selectively restricted the TGFβ1-induced phosphorylation of Akt but not canonical Smad2/3 in primary HSCs. Together, we illustrate a unique framework of BAY 41-2272 for inhibiting TGFβ1-induced CTGF upregulation and HSC activation via a noncanonical Akt-dependent but sGC/cGMP-independent pathway.
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Kreisel W, Schaffner D, Lazaro A, Trebicka J, Merfort I, Schmitt-Graeff A, Deibert P. Phosphodiesterases in the Liver as Potential Therapeutic Targets of Cirrhotic Portal Hypertension. Int J Mol Sci 2020; 21:6223. [PMID: 32872119 PMCID: PMC7503357 DOI: 10.3390/ijms21176223] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 08/23/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis is a frequent condition with high impact on patients' life expectancy and health care systems. Cirrhotic portal hypertension (PH) gradually develops with deteriorating liver function and can lead to life-threatening complications. Other than an increase in intrahepatic flow resistance due to morphological remodeling of the organ, a functional dysregulation of the sinusoids, the smallest functional units of liver vasculature, plays a pivotal role. Vascular tone is primarily regulated by the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, wherein soluble guanylate cyclase (sGC) and phosphodiesterase-5 (PDE-5) are key enzymes. Recent data showed characteristic alterations in the expression of these regulatory enzymes or metabolite levels in liver cirrhosis. Additionally, a disturbed zonation of the components of this pathway along the sinusoids was detected. This review describes current knowledge of the pathophysiology of PH with focus on the enzymes regulating cGMP availability, i.e., sGC and PDE-5. The results have primarily been obtained in animal models of liver cirrhosis. However, clinical and histochemical data suggest that the new biochemical model we propose can be applied to human liver cirrhosis. The role of PDE-5 as potential target for medical therapy of PH is discussed.
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Affiliation(s)
- Wolfgang Kreisel
- Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Denise Schaffner
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (D.S.); (A.L.); (P.D.)
- Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, 79104 Freiburg, Germany;
- Department of Radiology–Medical Physics, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Adhara Lazaro
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (D.S.); (A.L.); (P.D.)
| | - Jonel Trebicka
- Translational Hepatology, Department of Internal Medicine I, Goethe University Clinic Frankfurt, 60590 Frankfurt, Germany;
| | - Irmgard Merfort
- Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, 79104 Freiburg, Germany;
| | | | - Peter Deibert
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (D.S.); (A.L.); (P.D.)
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Donaldson S, Ogunti R, Kibreab A, Mehari A. Riociguat in the Treatment of Chronic Thromboembolic Pulmonary Hypertension: An Evidence-Based Review of Its Place in Therapy. CORE EVIDENCE 2020; 15:31-40. [PMID: 32904692 PMCID: PMC7457580 DOI: 10.2147/ce.s172791] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 08/08/2020] [Indexed: 11/29/2022]
Abstract
Chronic thromboembolic pulmonary hypertension (CTEPH) is classified as group-4 pulmonary hypertension caused by organized thrombi in pulmonary arteries and vasculopathy in nonoccluded areas leading to right heart failure and death. In addition to chronic anticoagulation therapy, each patient with CTEPH should receive treatment assessment starting with evaluation for pulmonary endarterectomy (PEA), which is the guideline recommended treatment. There is increasing experience with balloon pulmonary angioplasty (BPA) for inoperable patients; this option, like PEA, is reserved for specialized centers with expertise in this treatment method. Inoperable patients are candidates for targeted drug therapy. Riociguat remains the only approved medical therapy for CTEPH patients deemed inoperable or with persistent pulmonary hypertension after PEA. The role of riociguat therapy preoperatively or in tandem with BPA is currently under investigation. The purpose of this review is to evaluate the safety and efficacy of riociguat in the treatment of CTEPH.
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Affiliation(s)
- Sahai Donaldson
- Howard University College of Medicine, Washington, DC, USA.,Division of Pulmonary and Critical Care, Washington, DC, USA
| | - Richard Ogunti
- Howard University College of Medicine, Washington, DC, USA
| | - Angesom Kibreab
- Howard University College of Medicine, Washington, DC, USA.,Division of Gastroenterology and Hepatology, Washington, DC, USA
| | - Alem Mehari
- Howard University College of Medicine, Washington, DC, USA.,Division of Pulmonary and Critical Care, Washington, DC, USA
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Hložek T, Štícha M, Bursová M, Jelínek I, Tůma P, Čabala R. Sensitive CE-MS method for monitoring of riociguat and desmethylriociguat levels in human serum. Electrophoresis 2020; 41:1564-1567. [PMID: 32640044 DOI: 10.1002/elps.202000135] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/29/2020] [Accepted: 06/30/2020] [Indexed: 11/10/2022]
Abstract
Riociguat is novel antihypertensive drug for treatment of pulmonary hypertension. As such, it is still being tested in many clinical and pharmacokinetic trials. Existing methods that determine serum riociguat and desmethylriociguat (DMR) are based solely on liquid chromatography with mass spectrometry. Therefore, we present a novel capillary electrophoresis with mass spectrometry method (CE-MS) for their determination in human serum as alternative method for ongoing trials. Complete resolution of both analytes was achieved by means of pH optimization of ammonium formate background electrolytes that are fully compatible with ESI/MS detection. Simple liquid-liquid extraction was used as sample pretreatment. The calibration dependence of the method was linear (in the range of 10-1000 ng/mL), with adequate accuracy (90.1-114.9%) and precision (13.4%). LOD and LOQ were arbitrarily set at 10 ng/mL for both analytes. Clinical applicability was validated using serum samples from patients treated with riociguat in pharmacokinetic study and the results corresponded with reference HPLC-MS/MS values. Capillary electrophoresis proved to be sensitive and selective tool for the analysis of riociguat and DMR.
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Affiliation(s)
- Tomáš Hložek
- Department of Analytical Chemistry, Faculty of Science, Charles University, Prague, Czech Republic.,Institute of Forensic Medicine and Toxicology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.,Department of Hygiene, Third Faculty of Medicine, Charles University, Prague, Czech Republic.,Department of Analytical Chemistry, Faculty of Chemical Technology, University of Pardubice, Pardubice, Czech Republic
| | - Martin Štícha
- Department of Analytical Chemistry, Faculty of Science, Charles University, Prague, Czech Republic
| | - Miroslava Bursová
- Institute of Forensic Medicine and Toxicology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Ivan Jelínek
- Department of Analytical Chemistry, Faculty of Science, Charles University, Prague, Czech Republic
| | - Petr Tůma
- Department of Hygiene, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Radomír Čabala
- Department of Analytical Chemistry, Faculty of Science, Charles University, Prague, Czech Republic.,Institute of Forensic Medicine and Toxicology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
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Michaličková D, Jansa P, Bursová M, Hložek T, Čabala R, Hartinger JM, Ambrož D, Aschermann M, Lindner J, Linhart A, Slanař O, Krekels EHJ. Population pharmacokinetics of riociguat and its metabolite in patients with chronic thromboembolic pulmonary hypertension from routine clinical practice. Pulm Circ 2020; 10:2045894019898031. [PMID: 32095231 PMCID: PMC7011339 DOI: 10.1177/2045894019898031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 12/09/2019] [Indexed: 12/20/2022] Open
Abstract
Pharmacokinetic data for riociguat in patients with chronic thromboembolic
pulmonary hypertension (CTEPH) have previously been reported from randomized
clinical trials, which may not fully reflect the population encountered in
routine practice. The aim of the current study was to characterize the
pharmacokinetic of riociguat and its metabolite M1 in the patients from routine
clinical practice. A population pharmacokinetic model was developed in NONMEM
7.3, based on riociguat and its metabolite plasma concentrations from 49
patients with CTEPH. One sample with riociguat and M1 concentrations was
available from each patient obtained at different time points after last dose.
Age, bodyweight, sex, smoking status, concomitant medications, kidney and liver
function markers were tested as potential covariates of pharmacokinetic of
riociguat and its metabolite. Riociguat and M1 disposition was best described
with one-compartment models. Apparent volume of distribution (Vd/F) for
riociguat and M1 were assumed to be the same. Total bilirubin and creatinine
clearance were the most predictive covariates for apparent riociguat metabolic
clearance to M1 (CLf,M1/F) and for apparent riociguat clearance
through remaining pathways (CLe,r/F), respectively.
CLf,M1/F, CLe,r/F, Vd/F of riociguat and M1, and clearance
of M1 (CLe,M1/F) for a typical individual with 70 mL/min creatinine
clearance and 0.69 mg/dL total bilirubin were 0.665 L/h (relative standard
error = 17%)), 0.66 (18%) L/h, 3.63 (15%) L and 1.47 (19%) L/h, respectively.
Upon visual identification of six outlying individuals, an absorption lag-time
of 2.95 (6%) h was estimated for these patients. In conclusion, the only
clinical characteristics related to riociguat exposure in patients with CTEPH
from routine clinical practice are total bilirubin and creatinine clearance.
This confirms the findings of the previous population pharmacokinetic studies
based on data from randomized clinical trials.
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Affiliation(s)
- Danica Michaličková
- Institute of Pharmacology, First Faculty of Medicine & General University Hospital, Charles University, Prague, Czech Republic
| | - Pavel Jansa
- 2nd Department of Medicine - Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Miroslava Bursová
- Institute of Forensic Medicine and Toxicology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Tomáš Hložek
- Institute of Forensic Medicine and Toxicology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.,Department of Analytical Chemistry, Faculty of Science, Charles University, Prague, Czech Republic
| | - Radomír Čabala
- Institute of Forensic Medicine and Toxicology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.,Department of Analytical Chemistry, Faculty of Science, Charles University, Prague, Czech Republic
| | - Jan Miroslav Hartinger
- Institute of Pharmacology, First Faculty of Medicine & General University Hospital, Charles University, Prague, Czech Republic
| | - David Ambrož
- 2nd Department of Medicine - Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Michael Aschermann
- 2nd Department of Medicine - Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Jaroslav Lindner
- 2nd Department of Surgery - Department of Cardiovascular Surgery, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Aleš Linhart
- 2nd Department of Medicine - Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Ondřej Slanař
- Institute of Pharmacology, First Faculty of Medicine & General University Hospital, Charles University, Prague, Czech Republic
| | - Elke H J Krekels
- Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
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Effect of Macitentan on the Pharmacokinetics of the Breast Cancer Resistance Protein Substrates, Rosuvastatin and Riociguat, in Healthy Male Subjects. Clin Drug Investig 2020; 39:1223-1232. [PMID: 31552642 PMCID: PMC6842351 DOI: 10.1007/s40261-019-00857-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Background Macitentan is a clinically approved endothelin receptor antagonist for the treatment of pulmonary arterial hypertension (PAH). Increasing use of combination drug therapy in PAH means that it is important to recognize potential drug–drug interactions (DDIs) that could affect the efficacy and safety of macitentan in patients with PAH. Objective Two Phase 1 studies were conducted to investigate the effect of macitentan at steady-state on the pharmacokinetics of the breast cancer resistance protein (BCRP) substrates, rosuvastatin and riociguat in healthy male subjects. Another objective was to determine the safety and tolerability of concomitant administration of rosuvastatin or riociguat with macitentan. Methods Healthy male subjects received a single oral dose of rosuvastatin 10 mg (n = 20) or riociguat 1 mg (n = 20) on Day 1 (reference treatment). A loading oral dose of macitentan 30 mg was administered on Day 5 followed by macitentan 10 mg once-daily from Day 6 to Day 15 (riociguat study) or Day 6 to Day 16 (rosuvastatin study). A concomitant oral dose of rosuvastatin 10 mg or riociguat 1 mg was administered on Day 10 (test treatment). Pharmacokinetics were evaluated for 96 h after treatment on Day 1 and for 144 h (riociguat study) or 168 h (rosuvastatin study) after treatment on Day 10. To compare the reference and test treatments, the geometric mean ratio was calculated for the maximum plasma concentration (Cmax), the area under the plasma concentration-time curve (AUC) from zero (pre-dose) to time of the last measured concentration above the limit of quantification (AUC0–t), the AUC from zero to infinity (AUC0–∞) and the terminal elimination half-life (t½) of rosuvastatin, riociguat and riociguat’s metabolite, M1. The difference in the time to reach maximum plasma concentration (tmax) was determined by the Wilcoxon test. Trough levels of macitentan and its metabolite, ACT-132577, were measured and safety was monitored throughout. Results Ninety percent confidence intervals of the geometric mean ratios were within the bioequivalence criteria of 0.80–1.25. There was no significant difference between test and reference tmax. Rosuvastatin or riociguat did not affect the steady-state concentrations of macitentan and ACT-132577. The adverse event profile was consistent with the known safety profiles of the drugs. Conclusions Macitentan 10 mg did not affect the pharmacokinetics of BCRP substrates, rosuvastatin or riociguat in healthy male subjects. EudraCT numbers: 2017–003095–31 and 2017–003502–41.
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Ranka S, Mohananey D, Agarwal N, Verma BR, Villablanca P, Mewhort HE, Ramakrishna H. Chronic Thromboembolic Pulmonary Hypertension-Management Strategies and Outcomes. J Cardiothorac Vasc Anesth 2019; 34:2513-2523. [PMID: 31883688 DOI: 10.1053/j.jvca.2019.11.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 11/14/2019] [Indexed: 11/11/2022]
Abstract
Chronic thromboembolic pulmonary hypertension (CTEPH) is rare but complex pathophysiological disease with hallmark features of chronic thrombotic mechanical obstruction, right ventricular dysfunction, and secondary pulmonary arteriopathy. It increasingly is being understood that chronic infection/inflammation, abnormal fibrinolysis, and cytokines play an important role in pathogenesis such that only a subset of patients with pulmonary embolism develop CTEPH. Diagnosis remains challenging given the lack of early clinical signs and overlap with other cardiopulmonary conditions. Pulmonary endarterectomy is the surgical procedure of choice with good postoperative survival and functional outcomes, especially when done at high-volume centers with a multidisciplinary approach. There has been a resurgence of balloon pulmonary angioplasty (BPA) as salvage therapy for inoperable CTEPH or in its newfound hybrid role for persistent postoperative pulmonary hypertension with excellent 1-year and 3-year survival. Use of riociguat has shown promising improvements in functional outcomes up to 2 years after initiation. Endothelin receptor antagonists serve a supplemental role postoperatively or in inoperable CTEPH. The role of drug therapy preoperatively or in tandem with BPA is currently under investigation.
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Affiliation(s)
- Sagar Ranka
- Department of Cardiovascular Medicine, Kansas University Medical Center, Kansas City, KS
| | - Divyanshu Mohananey
- Department of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, WI
| | - Nikhil Agarwal
- Division of Cardiovascular Medicine, University of Buffalo, Buffalo, NY
| | - Beni Rai Verma
- Department of Cardiology, Cleveland Clinic, Cleveland, OH
| | | | | | - Harish Ramakrishna
- Division of Cardiovascular and Thoracic Anesthesiology, Department of Anesthesia and Perioperative Medicine, Mayo Clinic, Rochester, MN.
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Azizi M, Rossignol P, Hulot JS. Emerging Drug Classes and Their Potential Use in Hypertension. Hypertension 2019; 74:1075-1083. [DOI: 10.1161/hypertensionaha.119.12676] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Despite the availability of multiple antihypertensive drugs targeting the different pathways implicated in its pathophysiology, hypertension remains poorly controlled worldwide, and its prevalence is increasing because of the aging of the population and the obesity epidemic. Although nonadherence to treatment contributes to uncontrolled hypertension, it is likely that not all the pathophysiological mechanisms are neutralized by the various classes of antihypertensive treatment currently available, and, the counter-regulatory mechanisms triggered by these treatments may decrease their blood pressure–lowering effect. The development of new antihypertensive drugs acting on new targets, with different modes of action, therefore, remains essential, to improve blood pressure control and reduce the residual burden of cardiovascular risks further. However, the difficulties encountered in the conception, development, costs, and delivery to the market of new classes of antihypertensive agents highlights the hurdles that must be overcome to release and to evaluate their long-term safety and efficacy for hypertension only, especially because of the market pressure of cheap generic drugs. New chemical entities with blood pressure–lowering efficacy are thus being developed more for heart failure or diabetic kidney disease, 2 diseases pathophysiologically associated with hypertension. These include dual angiotensin II receptor-neprilysin inhibitors, soluble guanylate cyclase stimulators, nonsteroidal dihydropyridine-based mineralocorticoid receptor antagonists, as well as sodium-glucose cotransporter 2 inhibitors. However, centrally acting aminopeptidase A inhibitors and endothelin receptor antagonists have a dedicated program of development for hypertension. All these emergent drug classes and their potential use in hypertension are reviewed here.
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Affiliation(s)
- Michel Azizi
- From the Université de Paris, CIC1418, INSERM, F-75015 Paris, France (M.A., J.-S.H.)
- Hypertension unit and DMU CARTE, AP-HP, Hôpital Européen Georges-Pompidou, Paris, France (M.A.)
- F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Paris, France (M.A., J.-S.H.)
| | - Patrick Rossignol
- Université de Lorraine, Inserm, Centre d’Investigations Cliniques-Plurithématique 1433, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France (P.R.)
| | - Jean-Sébastien Hulot
- From the Université de Paris, CIC1418, INSERM, F-75015 Paris, France (M.A., J.-S.H.)
- F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Paris, France (M.A., J.-S.H.)
- Université de Paris, PARCC, INSERM, F-75015 Paris, France (J.-S.H.)
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Jungmann NA, Lang D, Saleh S, Van Der Mey D, Gerisch M. In vitro- in vivo correlation of the drug-drug interaction potential of antiretroviral HIV treatment regimens on CYP1A1 substrate riociguat. Expert Opin Drug Metab Toxicol 2019; 15:975-984. [PMID: 31619082 DOI: 10.1080/17425255.2019.1681968] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Objectives: Riociguat is a soluble guanylate cyclase stimulator licensed for the treatment of pulmonary arterial hypertension (PAH), a potentially fatal complication of human immunodeficiency virus infection. This study investigated the inhibitory potency of selected antiretroviral regimens on the metabolic clearance of riociguat.Methods: The inhibitory potential of the components of six antiretroviral combinations (ATRIPLA® (efavirenz/emtricitabine/tenofovir disoproxil), COMPLERA® (rilpivirine/emtricitabine/tenofovir disoproxil), STRIBILD® (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil), TRIUMEQ® (abacavir/dolutegravir/lamivudine), and two ritonavir-boosted regimens) on riociguat metabolism were evaluated in recombinant human CYP1A1 and CYP3A4 as well as in human hepatocytes exhibiting both CYP1A1 and CYP3A4 activity. In vitro-in vivo correlation was performed between calculated and observed increases in riociguat exposure in vivo.Results: Using both in vitro systems, the predicted increase in exposure of riociguat was highest with components of TRIUMEQ® followed by COMPLERA®, ATRIPLA®, STRIBILD®, and the ritonavir-boosted regimens. Further experiments in human hepatocytes confirmed CYP1A1 to be the predominant enzyme in the metabolic clearance of riociguat.Conclusion: Antiretroviral treatment containing the potent CYP1A1 inhibitor abacavir had the greatest impact on riociguat metabolic clearance. The impact of comedications containing only strong CYP3A4 inhibitors e.g. ritonavir was less pronounced, suggesting a benefit of riociguat over PAH-targeting medications with contraindications for use with strong CYP3A4 inhibitors.
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Affiliation(s)
| | - Dieter Lang
- Drug Metabolism and Pharmacokinetics, Bayer AG, Wuppertal, Germany
| | | | | | - Michael Gerisch
- Drug Metabolism and Pharmacokinetics, Bayer AG, Wuppertal, Germany
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Štícha M, Hložek T, Bursová M, Čabala R, Jelínek I. Development of a CE-MS method for the study of riociguat and metabolite M1 in pharmaceutical analysis. Electrophoresis 2019; 40:2936-2945. [PMID: 31520473 DOI: 10.1002/elps.201900181] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 08/21/2019] [Accepted: 08/31/2019] [Indexed: 11/11/2022]
Abstract
Riociguat is a novel antihypertensive drug for the treatment of pulmonary hypertension. We present electrophoretic characterization, i.e. migration behavior of riociguat and metabolite M1 as support for optimized CZE/MS assay. Fundamental separation parameters, such as peak width, symmetry, and resolution are studied in a series of ammonium formate buffers within pH range 2.60-5.61. The narrow region of peak symmetry lies close to pH 4.0 for both analytes. Accordingly, the value of resolution maximizes in a background electrolyte adjusted to pH 4.10. Basic calibration parameters estimated from CZE experiments with absorption photometric and mass spectrometric detection of riociguat and metabolite M1 were evaluated. More than three orders lower LOD was achieved with high resolution mass spectrometric detection. The observed difference in the sensitivity of both detection techniques gives priority to the utilization of CZE/MS in practice. The values of dissociation constants of riociguat and metabolite M1, pKBH , were determined from CZE measurements in lithium formate and lithium acetate background electrolytes with constant ionic strength. The value of pKBH = 4.30 ± 0.02 for riociguat corresponds well to the value already presented in the literature. According to our observation, metabolite M1 behaves like a slightly stronger base with estimated pKBH = 4.40 ± 0.02.
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Affiliation(s)
- Martin Štícha
- Department of Analytical Chemistry, Faculty of Science, Charles University, Prague 2, Czech Republic
| | - Tomáš Hložek
- Department of Analytical Chemistry, Faculty of Science, Charles University, Prague 2, Czech Republic.,Institute of Forensic Medicine and Toxicology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague 2, Czech Republic
| | - Miroslava Bursová
- Department of Analytical Chemistry, Faculty of Science, Charles University, Prague 2, Czech Republic.,Institute of Forensic Medicine and Toxicology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague 2, Czech Republic
| | - Radomír Čabala
- Department of Analytical Chemistry, Faculty of Science, Charles University, Prague 2, Czech Republic.,Institute of Forensic Medicine and Toxicology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague 2, Czech Republic
| | - Ivan Jelínek
- Department of Analytical Chemistry, Faculty of Science, Charles University, Prague 2, Czech Republic
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40
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Toxvig AK, Wehland M, Grimm D, Infanger M, Krüger M. A focus on riociguat in the treatment of pulmonary arterial hypertension. Basic Clin Pharmacol Toxicol 2019; 125:202-214. [PMID: 31206240 DOI: 10.1111/bcpt.13272] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 06/03/2019] [Indexed: 01/24/2023]
Abstract
Current treatment of pulmonary arterial hypertension (PAH) targets three signalling pathways: the nitric oxide (NO) pathway, the endothelin pathway and the prostacyclin pathway. Riociguat is a soluble guanylate cyclase stimulator, acting via the NO pathway in a new way: unlike other common drugs targeting this pathway (eg tadalafil and sildenafil), riociguat acts independently of endogenous NO. This MiniReview focuses on PAH treatment with riociguat and on its advantages and disadvantages compared with other drugs targeting the NO pathway. In the PATENT-1 trial (NCT00810693), riociguat improved significantly the 6-minute walking distance in patients suffering from PAH, with a mean difference (MD) of 36 m compared with a placebo group. The results are comparable to those found for its competitors tadalafil (MD of 33 m) and sildenafil (MD of 50 m) in the PHIRST-1 trial (NCT00125918) and the SUPER-1 trial (NCT00644605). No obvious advantages were found regarding pharmacokinetic features and adverse events. In the RESPITE study (NCT02007629), patients with PAH with insufficient response to treatment with tadalafil or sildenafil were switched to riociguat. These results indicate that riociguat might be superior regarding efficacy to PDE-5 inhibitors in a patient group, where endogenous NO production might be insufficient. This finding was further examined in the REPLACE study (NCT02891850). Moreover, riociguat has shown promising anti-proliferative, anti-inflammatory and anti-fibrotic effects in animal models. Further investigations are needed to determine whether this applies also to human beings. Taken together, riociguat induces vasodilation of the pulmonary arteries and leads to an improvement in the ability to carry out physical activity.
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Affiliation(s)
| | - Markus Wehland
- Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University Magdeburg, Magdeburg, Germany
| | - Daniela Grimm
- Department of Biomedicine, Pharmacology, Aarhus University, Aarhus C, Denmark.,Department of Microgravity and Translational Regenerative Medicine, Faculty of Medicine and Mechanical Engineering, Otto von Guericke University Magdeburg, Magdeburg, Germany
| | - Manfred Infanger
- Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University Magdeburg, Magdeburg, Germany
| | - Marcus Krüger
- Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University Magdeburg, Magdeburg, Germany
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41
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Kwapiszewska G, Johansen AKZ, Gomez-Arroyo J, Voelkel NF. Role of the Aryl Hydrocarbon Receptor/ARNT/Cytochrome P450 System in Pulmonary Vascular Diseases. Circ Res 2019; 125:356-366. [PMID: 31242807 DOI: 10.1161/circresaha.119.315054] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
RATIONALE CYPs (cytochrome p450) are critically involved in the metabolism of xenobiotics and toxins. Given that pulmonary hypertension is strongly associated with environmental exposure, we hypothesize that CYPs play a role in the development and maintenance of pathological vascular remodeling. OBJECTIVE We sought to identify key CYPs that could link drug or hormone metabolism to the development of pulmonary hypertension. METHODS AND RESULTS We searched in Medline (PubMed) database, as well as http://www.clinicaltrials.gov, for CYPs associated with many key aspects of pulmonary arterial hypertension including, but not limited to, severe pulmonary hypertension, estrogen metabolism, inflammation mechanisms, quasi-malignant cell growth, drug susceptibility, and metabolism of the pulmonary arterial hypertension-specific drugs. CONCLUSIONS We postulate a hypothesis where the AhR (aryl hydrocarbon receptor) mediates aberrant cell growth via expression of different CYPs associated with estrogen metabolism and inflammation.
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Affiliation(s)
- Grazyna Kwapiszewska
- From the Ludwig Boltzmann Institute for Lung Vascular Research, Medical University of Graz, Austria (G.K.)
| | - Anne Katrine Z Johansen
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (A.K.Z.J.)
| | - Jose Gomez-Arroyo
- Division of Pulmonary and Critical Care Medicine, University of Cincinnati College of Medicine, OH (J.G.-A.)
- Division of Pulmonary Biology, Perinatal Institute of Cincinnati Children's Hospital Research Foundation, OH (J.G.-A.)
| | - Norbert F Voelkel
- Department of Pulmonary Medicine, Amsterdam University Medical Centers, the Netherlands (N.F.V.)
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42
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Pectol DC, Khan S, Chupik RB, Elsabahy M, Wooley KL, Darensbourg MY, Lim SM. Toward the Optimization of Dinitrosyl Iron Complexes as Therapeutics for Smooth Muscle Cells. Mol Pharm 2019; 16:3178-3187. [PMID: 31244220 DOI: 10.1021/acs.molpharmaceut.9b00389] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
In this study, dinitrosyl iron complexes (DNICs) are shown to deliver nitric oxide (NO) into the cytosol of vascular smooth muscle cells (SMCs), which play a major role in vascular relaxation and contraction. Malfunction of SMCs can lead to hypertension, asthma, and erectile dysfunction, among other disorders. For comparison of the five DNIC derivatives, the following protocols were examined: (a) the Griess assay to detect nitrite (derived from NO conversion) in the absence and presence of SMCs; (b) the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2 H-tetrazolium (MTS) assay for cell viability; (c) an immunotoxicity assay to establish if DNICs stimulate immune response; and (d) a fluorometric assay to detect intracellular NO from treatment with DNICs. Dimeric Roussin's red ester (RRE)-type {Fe(NO)2}9 complexes containing phenylthiolate bridges, [(μ-SPh)Fe(NO)2]2 or SPhRRE, were found to deliver NO with the lowest effect on cell toxicity (i.e., highest IC50). In contrast, the RRE-DNIC with the biocompatible thioglucose moiety, [(μ-SGlu)Fe(NO)2]2 (SGlu = 1-thio-β-d-glucose tetraacetate) or SGluRRE, delivered a higher concentration of NO to the cytosol of SMCs with a 10-fold decrease in IC50. Additionally, monomeric DNICs stabilized by a bulky N-heterocyclic carbene (NHC), namely, 1,3-bis(2,4,6-trimethylphenyl)imidazolidene (IMes), were synthesized and yielded the DNIC complexes SGluNHC, [IMes(SGlu)Fe(NO)2], and SPhNHC, [IMes(SPh)Fe(NO)2]. These oxidized {Fe(NO)2}9 NHC DNICs have an IC50 of ∼7 μM; however, the NHC-based complexes did not transfer NO into the SMC. Per contra, the reduced, mononuclear {Fe(NO)2}10 neocuproine-based DNIC, neoDNIC, depressed the viability of the SMCs, as well as generated an increase of intracellular NO. Regardless of the coordination environment or oxidation state, all DNICs showed a dinitrosyl iron unit (DNIU)-dependent increase in viability. This study demonstrates a structure-function relationship between the DNIU coordination environment and the efficacy of the DNIC treatments.
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43
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DeJesus E, Saleh S, Cheng S, van der Mey D, Becker C, Frey R, Unger S, Mueck W. Pharmacokinetic interaction of riociguat and antiretroviral combination regimens in HIV-1-infected adults. Pulm Circ 2019; 9:2045894019848644. [PMID: 30997864 PMCID: PMC6540510 DOI: 10.1177/2045894019848644] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Riociguat, a first-in-class soluble guanylate cyclase stimulator, is approved for
the treatment of pulmonary arterial hypertension (PAH), a serious potential
complication of human immunodeficiency virus (HIV) infection. This open-label
study investigated the pharmacokinetic drug–drug interaction potential of
antiretroviral therapies on riociguat exposure in HIV-infected adults.
HIV-infected adults without PAH on stable antiretroviral regimens
(efavirenz/emtricitabine/tenofovir disoproxil,
emtricitabine/rilpivirine/tenofovir disoproxil,
elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil,
abacavir/dolutegravir/lamivudine, or a ritonavir-boosted triple regimen) for ≥ 6
weeks received a single riociguat dose (0.5 mg). Riociguat pharmacokinetics and
safety were assessed; pharmacokinetics was compared with historical healthy
volunteer data. Of 41 participants treated (n = 8 in each arm, except n = 9 in
the ritonavir-boosted triple regimen arm), 40 were included in the
pharmacokinetic analyses. Riociguat median tmax was 1.00–1.27 h, with
comparable maximum concentration (Cmax) across the five background
antiretroviral groups. Riociguat exposure was highest with
abacavir/dolutegravir/lamivudine, followed by
elvitegravir/cobicistat/emtricitabine/tenofovir
disoproxil > emtricitabine/rilpivirine/tenofovir
disoproxil > ritonavir-boosted triple
regimen > efavirenz/emtricitabine/tenofovir disoproxil; riociguat area under
the plasma concentration versus time curve (AUC) was approximately threefold
higher with abacavir/dolutegravir/lamivudine than
efavirenz/emtricitabine/tenofovir disoproxil. Compared with historical data,
riociguat exposure in HIV-infected adults was similar when co-administered with
efavirenz/emtricitabine/tenofovir disoproxil, slightly increased when
administered with ritonavir-boosted triple regimen and increased by
approximately threefold when administered with abacavir/dolutegravir/lamivudine.
Riociguat was well tolerated, with no new safety findings. Riociguat was well
tolerated in adults with HIV on stable background antiretroviral therapy
although an apparent increase in AUC of riociguat was observed in patients
receiving abacavir/dolutegravir/lamivudine. Patients should be monitored closely
during riociguat initiation and dose adjustment for signs and symptoms of
hypotension.
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Affiliation(s)
| | - Soundos Saleh
- 2 Clinical Pharmacology, Bayer AG, Wuppertal, Germany
| | - Sue Cheng
- 3 Celgene Corporation, Summit, NJ, USA
| | | | - Corina Becker
- 2 Clinical Pharmacology, Bayer AG, Wuppertal, Germany
| | - Reiner Frey
- 2 Clinical Pharmacology, Bayer AG, Wuppertal, Germany
| | - Sigrun Unger
- 4 Global Biostatistics, Bayer AG, Wuppertal, Germany
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44
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Sandner P. From molecules to patients: exploring the therapeutic role of soluble guanylate cyclase stimulators. Biol Chem 2019; 399:679-690. [PMID: 29604206 DOI: 10.1515/hsz-2018-0155] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 03/23/2018] [Indexed: 12/22/2022]
Abstract
Nitric oxide (NO) signaling represents one of the major regulatory pathways for cardiovascular function. After the discovery of NO, awarded with the Nobel Prize in 1998, this signaling cascade was stepwise clarified. We now have a good understanding of NO production and NO downstream targets such as the soluble guanylyl cyclases (sGCs) which catalyze cGMP production. Based on the important role of NO-signaling in the cardiovascular system, intense research and development efforts are currently ongoing to fully exploit the therapeutic potential of cGMP increase. Recently, NO-independent stimulators of sGC (sGC stimulators) were discovered and characterized. This new compound class has a unique mode of action, directly binding to sGC and triggering cGMP production. The first sGC stimulator made available to patients is riociguat, which was approved in 2013 for the treatment of different forms of pulmonary hypertension (PH). Besides riociguat, other sGC stimulators are in clinical development, with vericiguat in phase 3 clinical development for the treatment of chronic heart failure (HF). Based on the broad impact of NO/cGMP signaling, sGC stimulators could have an even broader therapeutic potential beyond PH and HF. Within this review, the NO/sGC/cGMP/PKG/PDE-signaling cascade and the major pharmacological intervention sites are described. In addition, the discovery and mode of action of sGC stimulators and the clinical development in PH and HF is covered. Finally, the preclinical and clinical evidence and treatment approaches for sGC stimulators beyond these indications and the cardiovascular disease space, like in fibrotic diseases as in systemic sclerosis (SSc), are reviewed.
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Affiliation(s)
- Peter Sandner
- Bayer AG, Drug-Discovery, Pharma Research Center Wuppertal, Aprather Weg 18a, D-42069 Wuppertal, Germany.,Hannover Medical School, Department of Pharmacology, Hannover, Germany
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45
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Maideen NMP. Tobacco smoking and its drug interactions with comedications involving CYP and UGT enzymes and nicotine. World J Pharmacol 2019; 8:14-25. [DOI: 10.5497/wjp.v8.i2.14] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 01/20/2019] [Accepted: 01/28/2019] [Indexed: 02/06/2023] Open
Abstract
Tobacco smoking is a global public health threat causing several illnesses including cardiovascular disease (Myocardial infarction), cerebrovascular disease (Stroke), peripheral vascular disease (Claudication), chronic obstructive pulmonary disease, asthma, reduced female infertility, sexual dysfunction in men, different types of cancer and many other diseases. It has been estimated in 2015 that approximately 1.3 billion people smoke, around the globe. Use of medications among smokers is more common, nowadays. This review is aimed to identify the medications affected by smoking, involving Cytochrome P450 (CYP) and uridine diphosphate-glucuronosyltransferases (UGTs) enzymes and Nicotine. Polycyclic aromatic hydrocarbons (PAHs) of tobacco smoke have been associated with the induction of CYP enzymes such as CYP1A1, CYP1A2 and possibly CYP2E1 and UGT enzymes. The drugs metabolized by CYP1A1, CYP1A2, CYP2E1 and UGT enzymes might be affected by tobacco smoking and the smokers taking medications metabolized by those enzymes, may need higher doses due to decreased plasma concentrations through enhanced induction by PAHs of tobacco smoke. The prescribers and the pharmacists are required to be aware of medications affected by tobacco smoking to prevent the toxicity-associated complications during smoking cessation.
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Halank M, Tausche K, Grünig E, Ewert R, Preston IR. Practical management of riociguat in patients with pulmonary arterial hypertension. Ther Adv Respir Dis 2019; 13:1753466619868938. [PMID: 31438774 PMCID: PMC6710674 DOI: 10.1177/1753466619868938] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 06/21/2019] [Indexed: 12/15/2022] Open
Abstract
Riociguat is one of several approved therapies available for patients with pulmonary arterial hypertension (PAH). Treatment should be initiated and monitored at an expert center by a physician experienced in treating PAH, and the dose adjusted in the absence of signs and symptoms of hypotension. In certain populations, including patients with hepatic or renal impairment, the elderly, and smokers, riociguat exposure may differ, and dose adjustments should therefore be made with caution according to the established scheme. Common adverse events are often easily managed, particularly if they are discussed before starting therapy. Combination therapy with riociguat and other PAH-targeted agents is feasible and generally well tolerated, although the coadministration of phosphodiesterase type 5 inhibitors (PDE5i) and riociguat is contraindicated. An open-label, randomized study is currently ongoing to assess whether patients who do not achieve treatment goals while receiving PDE5i may benefit from switching to riociguat. In this review, we provide a clinical view on the practical management of patients with PAH receiving riociguat, with a focus on the opinions and personal experience of the authors. The reviews of this paper are available via the supplemental material section.
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Affiliation(s)
- Michael Halank
- Internal Clinical I, University Hospital Carl Gustav Carus, Fetscherstrasse 74, Dresden, 01307, Germany
| | - Kristin Tausche
- Medical Clinic 1/Pneumology, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Ekkehard Grünig
- Center for Pulmonary Hypertension, Thorax Clinic at University Hospital, Heidelberg, Germany
| | - Ralf Ewert
- Clinic for Internal Medicine B, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany
| | - Ioana R. Preston
- Pulmonary, Critical Care and Sleep Division, Tufts University Medical Center, Boston, Massachusetts, USA
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Hanrahan JP, Wakefield JD, Wilson PJ, Mihova M, Chickering JG, Ruff D, Hall M, Milne GT, Currie MG, Profy AT. A Randomized, Placebo-Controlled, Multiple-Ascending-Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Soluble Guanylate Cyclase Stimulator Praliciguat in Healthy Subjects. Clin Pharmacol Drug Dev 2018; 8:564-575. [PMID: 30422390 DOI: 10.1002/cpdd.627] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 10/08/2018] [Indexed: 12/14/2022]
Abstract
Nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling is central to the regulation of several physiological processes, including blood flow and inflammation. Deficient NO signaling is implicated in multiple diseases. sGC stimulators are small molecules that enhance sGC activity, particularly in combination with NO. In a randomized, placebo-controlled phase 1 study, the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple ascending doses of the sGC stimulator praliciguat were assessed in 44 healthy adults. Four cohorts of 11 subjects (8 praliciguat, 3 placebo) received once-daily praliciguat for 14 days before up-titrating for 7 days (treatment sequences: 15/30 mg, 20/40 mg, 30/40 mg, and weight-based). All doses were tolerated. No serious or severe adverse events (AEs) were reported. The most common AEs in praliciguat recipients were headache and symptoms consistent with blood pressure (BP) lowering/vasodilation. There were no laboratory, vital sign, electrocardiographic, or platelet function findings indicative of a safety concern. Pharmacokinetics were dose proportional, with an effective half-life of 24-37 hours, supporting once-daily dosing. Praliciguat produced dose-related increases in plasma cGMP consistent with stimulation of sGC. Repeated once-daily dosing showed sustained decreases in BP. Results support evaluation of praliciguat for the treatment of conditions associated with deficient NO signaling.
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Affiliation(s)
| | | | | | | | | | - Dennis Ruff
- ICON Early Phase Services LLC, San Antonio, TX, USA
| | - Michael Hall
- Ironwood Pharmaceuticals Inc., Cambridge, MA, USA
| | - G Todd Milne
- Ironwood Pharmaceuticals Inc., Cambridge, MA, USA
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