Guanylate Cyclase Stimulator Research Articles

Expert Opinion on the Identification and Pharmacological Management of Worsening Heart Failure

Worsening heart failure (WHF) is a distinct under-diagnosed and under-treated condition, independent of location of care. Heart failure (HF) progression is punctuated by repeated WHF events, each resulting in reduced cardiac function. One-third of the patients with HF with reduced ejection fraction experience a decompensation event. These decompensation events often result in the emergency department visits and HF hospitalization. Despite its inclusion in recent guidelines, there is no precise definition of WHF or its various forms. It is worth noting that WHF signals a need for treatment optimization as per guideline-directed medical therapy and the addition of novel drugs like a stimulator of soluble guanylate cyclase that benefit this high-risk patient population. This practical document is based on the expert opinion of cardiologists, cardiothoracic surgeons, and physicians that discussed the definition, assessment, pharmacological management, and monitoring of WHF patients in a hospitalized setting. In addition, there is also a need for an expert opinion for the management of WHF in an outpatient setting.

Efficacy, safety, and pharmacokinetics of inhaled treprostinil in Japanese patients with pulmonary arterial hypertension.

Treprostinil is a chemically stable analog of prostacyclin, and inhaled treprostinil was developed to deliver the effects directly to the pulmonary vasculature while minimizing systemic side effects. The objective of the study was to evaluate the efficacy on hemodynamics and exercise capacity, safety, and pharmacokinetics (PK) of inhaled treprostinil in Japanese patients with pulmonary arterial hypertension (PAH). Inhaled treprostinil was administered at three breaths (18 μg)/session four times daily, and the dose was gradually increased to a maximum of nine breaths (54 μg)/session. Endpoints included change in pulmonary vascular resistance index (PVRI) as primary, other efficacy parameters, safety, and PK. SeventeenPAH patients, the majority of whom (76.5%) had been receiving both an endothelin receptor antagonist (ERA) and a phosphodiesterase type-5 (PDE5) inhibitor/soluble guanylate cyclase (sGC) stimulator, received inhaled treprostinil. At Week 12, PVRI statistically decreased by -39.4 ± 25.5% (95% confidence interval: -52.6 to -26.3). The most frequently reported adverse events related to treprostinil were headache, cough, throat irritation, and hot flush. Regarding PK, there were no notable differences in the geometric mean C max and AUClast between Japanese and non-Japanese patients. Treatment with inhaled treprostinil using the dosing regimen approved in the United States resulted in significant improvement in hemodynamics, exercise capacity, and symptoms with a favorable tolerability and safety profile in Japanese patients. Inhaled treprostinil could be a valuable therapeutic option for Japanese patients with PAH, including those receiving a combination therapy with an ERA and a PDE5 inhibitor/sGC stimulator. Trial registration: JAPIC Clinical Trials Information [JapicCTI-194651].

Worsening heart failure and current management strategies with a focus on soluble guanylate cyclase stimulators

Worsening heart failure and current management strategies with a focus on soluble guanylate cyclase stimulators

Possibilities of long-term effective treatment of idiopathic pulmonary arterial hypertension by replacing sildenafil with riociguat and using sequential combination therapy: case report

Modern pathogenetic therapy of idiopathic pulmonary arterial hypertension (IPAH), a severe life-threatening cardiovascular disease of unknown etiology, leads to a positive clinical effect due to reverse remodeling of the vessels of the microvasculature of the lungs. Highly effective drugs of specific therapy that act on the main targets of pathogenesis have now been introduced into clinical practice.The presented clinical case of a patient with diagnosed in 2014 IPAH with an initial functional class III according to the WHO classification demonstrates high long-term efficacy and safety of specific therapy based on the use of the soluble guanylate cyclase stimulator riociguat for 5 years after replacing previous therapy with sildenafil with further implementation of the strategy of sequential combination therapy due to the addition of ambrisentan and selexipag.

Vericiguat: A New Hope for Heart Failure Patients.

Heart failure with reduced ejection fraction (HFrEF) is the inability of the heart to adequately contract or eject blood. This heart is unable to produce adequate cardiac output to perfuse vital tissues. At a fundamental level, it is known that the cardioprotective pathway of nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate is impaired in heart failure patients. Vericiguat is a novel, orally used, small molecule, and direct stimulator of the soluble guanylate cyclase, and thus, it enhances the production of cyclic guanosine monophosphate. Vericiguat was approved by the FDA in January of 2021 to reduce the risk of cardiovascular death and heart failure hospitalization following a hospitalization for heart failure or need for outpatient IV diuretics, in adults with symptomatic chronic heart failure and ejection fraction less than 45%. In this review, we describe the chemical and mechanistic aspects, pharmacokinetics, adverse effects, and contraindications of vericiguat so as to facilitate its optimal therapeutic use.

The Soluble Guanylate Cyclase Stimulator BAY 41-2272 Attenuates Transforming Growth Factor β1-Induced Myofibroblast Differentiation of Human Corneal Keratocytes

Corneal transparency, necessary for vision and depending on the high organization of stromal extracellular matrix, is maintained by keratocytes. Severe or continuous corneal injuries determine exaggerated healing responses resulting in the formation of irreversible fibrotic scars and vision impairment. Soluble guanylate cyclase (sGC) stimulation demonstrated antifibrotic effects in both experimental fibrosis and human lung and skin fibroblasts. Here, we assessed whether sGC stimulation with BAY 41-2272 could attenuate transforming growth factor β1 (TGFβ1)-induced myofibroblast differentiation of human corneal keratocytes. Cells were challenged with TGFβ1, with/without BAY 41-2272 preincubation, and subsequently assessed for viability, proliferation, migration, chemoinvasion, as well for the expression of myofibroblast/fibroblast activation markers and contractile abilities. Treatment with BAY 41-2272 did not affect keratocyte viability, while preincubation of cells with the sGC stimulator was able to inhibit TGFβ1-induced proliferation, wound healing capacity, and invasiveness. BAY 41-2272 was also able to attenuate TGFβ1-induced myofibroblast-like profibrotic phenotype of keratocytes, as demonstrated by the significant decrease in ACTA2, COL1A1, COL1A2, FN1 and PDPN gene expression, as well as in α-smooth muscle actin, α-1 chain of type I collagen, podoplanin, vimentin and N-cadherin protein expression. Finally, BAY 41-2272 significantly counteracted the TGFβ1-induced myofibroblast-like ability of keratocytes to contract collagen gels, reduced phosphorylated Smad3 protein levels, and attenuated gene expression of proinflammatory cytokines. Collectively, our data show for the first time that BAY 41-2272 is effective in counteracting keratocyte-to-myofibroblast transition, thus providing the rationale for the development of sGC stimulators as novel promising modulators of corneal scarring and fibrosis.

Praliciguat Promotes Ischemic Leg Reperfusion in Leptin Receptor-Deficient Mice.

Lower-limb peripheral artery disease is one of the major complications of diabetes. Peripheral artery disease is associated with poor limb and cardiovascular prognoses, along with a dramatic decrease in life expectancy. Despite major medical advances in the treatment of diabetes, a substantial therapeutic gap remains in the peripheral artery disease population. Praliciguat is an orally available sGC (soluble guanylate cyclase) stimulator that has been reported both preclinically and in early stage clinical trials to have favorable effects in metabolic and hemodynamic outcomes, suggesting that it may have a potential beneficial effect in peripheral artery disease. We evaluated the effect of praliciguat on hind limb ischemia recovery in a mouse model of type 2 diabetes. Hind limb ischemia was induced in leptin receptor-deficient (Leprdb/db) mice by ligation and excision of the left femoral artery. Praliciguat (10 mg/kg/day) was administered in the diet starting 3 days before surgery. Twenty-eight days after surgery, ischemic foot perfusion and function parameters were better in praliciguat-treated mice than in vehicle controls. Improved ischemic foot perfusion was not associated with either improved traditional cardiovascular risk factors (ie, weight, glycemia) or increased angiogenesis. However, treatment with praliciguat significantly increased arteriole diameter, decreased ICAM1 (intercellular adhesion molecule 1) expression, and prevented the accumulation of oxidative proangiogenic and proinflammatory muscle fibers. While investigating the mechanism underlying the beneficial effects of praliciguat therapy, we found that praliciguat significantly downregulated Myh2 and Cxcl12 mRNA expression in cultured myoblasts and that conditioned medium form praliciguat-treated myoblast decreased ICAM1 mRNA expression in endothelial cells. These results suggest that praliciguat therapy may decrease ICAM1 expression in endothelial cells by downregulating Cxcl12 in myocytes. Our results demonstrated that praliciguat promotes blood flow recovery in the ischemic muscle of mice with type 2 diabetes, at least in part by increasing arteriole diameter and by downregulating ICAM1 expression.

Effects of an inhaled soluble guanylate cyclase (sGC) stimulator MK-5475 in pulmonary arterial hypertension (PAH)

BackgroundNovel therapeutics for pulmonary arterial hypertension (PAH) with improved safety/tolerability profiles are needed to address continued high rates of morbidity/mortality. MethodsThis Phase 1 study evaluated efficacy/safety of inhaled single-dose MK-5475, an investigational, small-molecule stimulator of soluble guanylate cyclase designed for inhaled delivery via a dry-powder inhaler device, in participants with PAH (Clinicaltrials.gov: NCT03744637). Eligible participants were 18–70 years of age; body mass index ≤35 kg/m2; diagnosis of PAH (Group 1 pulmonary hypertension). In Part 1, participants received double-blind MK-5475 or placebo for safety assessment (primary outcome). In Part 2, 4 panels participated in ≤3 open-label periods. Part 2/Period 1 assessed safety/tolerability. Part 2/Periods 2 and 3, respectively, involved functional respiratory imaging for measuring pulmonary blood volume (secondary outcome) and right heart catheterization for measuring pulmonary vascular resistance (primary outcome). ResultsMK-5475 was generally well tolerated without systemic side effects on blood pressure or heart rate up to 24 h post dose. With respect to the primary pharmacodynamic outcome, mean reductions in pulmonary vascular resistance ranged from 21% to 30% across 120 μg and 360 μg doses. ConclusionsTreatment with inhaled single-dose MK-5475 showed rapid and sustained reductions in pulmonary vascular resistance and increases in pulmonary blood volume. MK-5475 was generally well tolerated versus placebo without vasodilatory systemic side effects. The promising pulmonary selectivity and favorable safety/tolerability profile of MK-5475 seen in this study of adult participants with PAH lays the foundation for further clinical development.

Association Between Copayment and Adherence to Medications for Pulmonary Arterial Hypertension.

Background Pharmacologic treatment for pulmonary arterial hypertension (PAH) improves exercise capacity, functional class, and hemodynamic indexes. However, monthly prescription costs often exceed $4000. We examined associations between (1) medication copayment and (2) annual household income with adherence to pulmonary vasodilator therapy among individuals with PAH. Methods and Results We used administrative claims data from an insured population in the United States to identify individuals diagnosed with PAH between 2015 and 2020. All individuals had ≥1 medication claim for endothelin receptor antagonists, phosphodiesterase type-5 inhibitors, prostanoids or prostacyclin receptor agonists, or the soluble guanylate cyclase stimulator riociguat. We defined copayments as low, medium, or high, as determined by their distributions for each medication class. Annual household income was categorized as <$40 000, $40 000 to $74 999, and ≥$75 000. The primary outcome was medication adherence, defined by proportion of days covered ≥80%. We studied 4025 adults (aged 65.9±13.3 years; 71.2% women). Compared with those with annual household income ≥$75 000, individuals in the <$40 000 and $40 000 to $74 999 categories had no significant differences in medication adherence. Compared with those with low copayments, individuals with high copayments had decreased adherence to prostanoids (odds ratio [OR], 0.36 [95% CI, 0.20-0.65]; P<0.001) and combination therapy with endothelin receptor antagonist and phosphodiesterase type-5 inhibitor (OR, 0.61 [95% CI, 0.38-0.97]; P=0.03). Conclusions We identified associations between copayment and adherence to prostanoids and combination therapy among individuals with PAH. Copayment may be a structural barrier to medication adherence and merits inclusion in studies examining access to pharmacotherapy among individuals with PAH.

Soluble guanylate cyclase stimulators in patients with heart failure with reduced ejection fraction across the risk spectrum.

Patients with heart failure with reduced ejection fraction (HFrEF) have a high residual risk of adverse outcomes, even when treated with optimal guideline-directed medical therapy and in a clinically stable state. Soluble guanylate cyclase (sGC) stimulators have the potential to lower this risk by modifying the nitric oxide-sGC-cyclic guanosine monophosphate cascade-a pathophysiological pathway that has been targeted with limited success in HFrEF previously. Vericiguat, an sGC stimulator, was shown to improve outcomes in patients with HFrEF in the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial. However, this trial included patients with recently worsening disease. In this brief review, we discuss the rationale of evaluating sGC stimulators in lower-risk HFrEF patients. First, all key HFrEF medications have been evaluated in both higher- and lower-risk populations, and the treatment effect is not always consistent across the risk spectrum. Second, pre-clinical studies and post-hoc studies of the VICTORIA trial have suggested that sGC stimulators may have cardioprotective effects-these effects may be more apparent when the medication is initiated earlier in the disease process. Third, the effect of vericiguat on cardiovascular mortality remains uncertain and a trial with a longer follow-up in a lower-risk population may allow better assessment of its effect on cardiovascular mortality. Therefore, there is a pertinent need to investigate the effects of vericiguat in optimally treated, low-risk HFrEF patients (i.e. those without recently worsening heart failure).

Antihypertensive Effects of a Soluble Guanylate Cyclase Stimulator.

We studied antihypertensive activity of an indolinone derivative (compound GRS), a soluble guanylate cyclase stimulator and a drug with previously proven antiaggregant effects. Contraction activity of isolated aorta segments of Wistar-Kyoto (WKY) rats was assessed in vitro using a mechanographic method. Addition of GRS (0.1-100 μМ) resulted in dose-dependent relaxation of endothelium-denuded aorta segments. Pretreatment of aorta smooth muscle segments with a specific inhibitor of soluble guanylate cyclase (ODQ, 1 μM) weakened the vasodilatory effect of GRS. Antihypertensive activity of the indolinone derivative GRS was studied in spontaneously hypertensive SHR rats. Single oral administration of 5 and 10 mg/kg GRS was followed by a significant dose-dependent reduction of systolic and diastolic BP in SHR rats. Antihypertensive effect of GRS in a dose of 5 mg/kg was more potent than that of the reference drug isosorbide dinitrate. GRS in a dose of 10 mg/kg did not affect systolic and diastolic BP in normotensive WKY rats.

Targeting soluble guanylate cyclase with Riociguat has potency to alleviate testicular ischaemia reperfusion injury via regulating various cellular pathways.

Testicular ischaemia reperfusion (I/R) injury results with serious dysfunctions in testis. This study aims to explore effects of soluble guanylate cyclase (sGC) stimulator Riociguat on experimental testicular I/R injury in rats. Twenty-one male rats were divided into three groups (Control, IR and IRR). The control group was not exposed to any application. Bilateral testis from IR and IRR animals were rotated 720° in opposite directions for 3 h to induce experimental testicular ischaemia. Animals in IR and IRR groups were subjected to 3 h of reperfusion. Isotonic and Riociguat were administered to the animals 30 min prior reperfusion by oral gavage. At the end of experiment, animals were sacrificed and tissue samples were used for analyses. Riociguat treatment significantly decreased tissue malondialdehyde and Luminol levels compared to the IR group (p < 0.05). The pathological changes, pro-apoptotic proteins (Bax, Caspase 3, and Caspase 9) and apoptotic index in the IR group were down regulated in Riociguat treated animals (p < 0.05). Riociguat treatment was also significantly increased anti-apoptotic Bcl-2 expression, but alleviated tissue injury via modulating pro-inflammatory cytokine IL-1β levels and significantly (p < 0.05) down-regulating NF-κB activity. Moreover, mTOR and ERK phosphorylation increased in IR group (p < 0.05), but Riociguat treatment reduced protein phosphorylation. Our experiment indicated that targeting sGC might support surgical interventions in testicular I/R injury by modulating oxidative stress, inflammation, and apoptotic protein expression levels, but more detailed studies are required to explore the protective activity of Riociguat and underlying mechanisms in testicular I/R injury.

Riociguat and the right ventricle in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are progressive diseases that can lead to right heart failure and death. Right ventricular dysfunction, hypertrophy and maladaptive remodelling are consequences of increased right ventricular (RV) afterload in PAH and CTEPH and are indicative of long-term outcomes. Because RV failure is the main cause of morbidity and mortality in PAH and CTEPH, successful treatments should lead to improvements in RV parameters. Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of PAH and inoperable or persistent/recurrent CTEPH after pulmonary endarterectomy. This review examines the current evidence showing the effect of riociguat on the right ventricle, with particular focus on remodelling, function and structural parameters in preclinical models and patients with PAH or CTEPH.

Change in REVEAL Lite 2 and COMPERA 2.0 risk status in patients with pulmonary arterial hypertension initiating oral treprostinil on dual background therapy: a retrospective chart review

Abstract Background Post-hoc analyses of the FREEDOM-EV study demonstrated that addition of oral treprostinil (ORE) to background monotherapy improves risk in patients with pulmonary arterial hypertension (PAH). Evidence is needed to understand the incremental effect of ORE added to dual background therapy with an endothelin receptor antagonist (ERA) and phosphodiesterase-5 inhibitor (PDE5)/soluble guanylate cyclase stimulator (sGC). Purpose To describe longitudinal changes in REVEAL Lite 2 and COMPERA 2.0 risk status in patients initiating ORE on dual background therapy. Methods A multisite, double-blind retrospective chart review of PAH patients was conducted by US PAH-treating physicians and included patients meeting prior diagnostic PAH criteria (mPAP ≥25 mmHg/PAWP ≤15 mmHg/PVR &amp;gt;3 WU), age ≥18 at diagnosis, began a PAH treatment 01/2014–03/2017, and had NT-proBNP/BNP, WHO functional class (FC), and 6-minute walk distance (6MWD) at baseline visit. Baseline was most recent assessment prior to ORE initiation. This analysis included a subset of patients on dual background therapy at time of ORE initiation without prior prostacyclin use. Follow-up was evaluated in 0–6 and 6–12 months after ORE initiation. Results 30 (61.2%) of 49 ORE patients were on dual background therapy at time of ORE start; 23 had baseline assessments while on dual background therapy and were included in this analysis. At baseline, mean (SD) 6MWD was 140.9 (49.8) m and 21 (91.3%) patients were FC III. Prior to ORE, median (IQR) time on ERA was 6.6 (5.5–7.6) months and PDE5/sGC was 3.7 (3.3–5.7) months. After ORE start, median (IQR) time to follow-up was 4.3 (3.4–5.6) months in 0–6 months and 10.9 (9.6–11.6) months in 6–12 months. Using REVEAL Lite 2, baseline mean (SD) REVEAL Lite 2 risk score was 7.9 (0.8); 1 (4.4%), 2 (8.7%), and 20 (87%) patients were in the low, intermediate, and high risk strata, respectively. In 0–6 months (n=22), 13 (59.1%) patients improved and 9 (40.9%) stabilized REVEAL Lite 2 risk strata from baseline. In 6–12 months (n=22), mean (SD) REVEAL Lite 2 risk score was 6.5 (1.1); 15 patients (68.2%) improved, 6 (27.3%) stabilized, and 1 (4.6%) worsened REVEAL Lite 2 risk strata from baseline. Using COMPERA 2.0, at baseline, 1 (4.4%) patient was in the intermediate-low and 22 (95.7%) patients were in the intermediate-high risk strata. In 0–6 months (n=15), 10 (66.7%) patients improved and 5 (33.3%) patients stabilized COMPERA 2.0 risk strata from baseline. In 6–12 months (n=17), 15 (88.2%) patients improved and 2 (11.8%) stabilized COMPERA 2.0 risk strata from baseline. Conclusion Of patients initiating oral treprostinil in this study, most were on dual background therapy and at high risk by REVEAL Lite 2 or intermediate-high risk by COMPERA 2.0. This analysis suggests adding ORE to dual background therapy can improve risk status in patients, with clinical benefit attained within 6 months and continued incremental improvement through first year of therapy. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): United Therapeutics Corporation

Evaluating Riociguat in the Treatment of Pulmonary Arterial Hypertension: A Real-World Perspective.

Pulmonary hypertension (PH) is a broad term describing the mean pulmonary artery pressure, as measured by right heart catheterization, exceeds 20mmHg. Pulmonary arterial hypertension (PAH) exists when PH is accompanied by a normal wedge pressure and elevated pulmonary vascular resistance. PAH is typified by dysmorphic and dysfunctional pulmonary arterial vasculature. Attempting to restore the functionality of the pulmonary artery is a hallmark of care to the PAH patient. Riociguat is a powerful stimulator of soluble guanylate cyclase and increases blood flow through the pulmonary arteries by dilating vascular smooth muscle cells. This review examines the pharmacology of riociguat, the fundamental clinical trials applying it to PAH patients, practical aspects when selecting its use, and future directions for its utilization.

Riociguat inhibits ultra-large VWF string formation on pulmonary artery endothelial cells from chronic thromboembolic pulmonary hypertension patients.

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.

INITIAL TREATMENT STRATEGY IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION USING TWO LARGE US ADMINISTRATIVE CLAIMS DATABASES

INITIAL TREATMENT STRATEGY IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION USING TWO LARGE US ADMINISTRATIVE CLAIMS DATABASES

Emerging Treatment Approaches to Improve Outcomes in Patients with Heart Failure

Heart failure (HF) is a major public health problem around the world. Although currently available therapies have improved outcomes, morbidity and mortality in patients with HF remain unacceptably high. Most guideline-recommended therapies for HF are indicated for patients with a reduced left ventricular ejection fraction (HFrEF). Until recently, treatment options that improved outcomes in patients with HF and preserved left ventricular ejection fraction or mildly reduced ejection fraction were limited. Over the past several years, however, several new drugs including angiotensin receptor neprilysin inhibitors (ARNIs), sodium glucose cotransporter 2 inhibitors (SGLT2 inhibitors), soluble guanylate cyclase stimulators, and a cardiac myotrope, omecamtiv mecarbil have all reported positive results in pivotal phase III clinical trials. Moreover, the results of these studies have provided evidence that both ARNIs and SGLT2 inhibitors can improve clinical outcomes in patients with HF across a broad spectrum of LVEF, not just in HFrEF. This article presents the rationale for the use of each of these 4 new classes of drugs, reviews the results from pivotal clinical trials showing their safety and efficacy, and provides a framework for how each drug has begun to be integrated into new HF management guidelines. Collectively, these new drugs provide hope for the millions of patients around the world who suffer from HF.

Antithrombotic Activity of an Indolinone Derivative – a Soluble Guanylate Cyclase Stimulator

Introduction . The article presents the results of studying the antithrombotic activity of a novel drug, a soluble guanylate cyclase stimulator (codename – GRS), in experimental models of arterial and venous thrombosis and thromboembolism. Aim . Study the antithrombotic action of GRS compound in comparison with clopidogrel and rivaroxaban in the following models: arterial thrombosis induced by iron chloride application to carotid artery wall in rats; thromboembolism induced by intravenous administration of thrombin solution in mice; venous thrombosis induced by the ligature of inferior vena cava in rats. Materials and methods . Arterial thrombosis was modelled in rats by applying a pad soaked in iron chloride (FeCl 3 ) to the carotid artery, GRS compound was administered orally in median effective dose of 10 mg/kg once 3 hours before pad application. Blood flow in carotid arteries and blood clot mass were registered. Thromboembolism was induced in mice by intravenous administration of thrombin solution, GRS in dose 10 mg/kg or the reference drug clopidogrel were administered once orally daily for 3 days. Animal mortality, survival time and blood clot size were registered. Venous thrombosis was induced in rats by the ligature of inferior vena cava below renal veins, GRS in dose 10 mg/kg, reference drug rivaroxaban in 5 mg/kg dose or their combination in these doses were administered once orally 1 hour before vein ligature. The mass of dry and wet blood clots was registered. Results and discussion . In arterial thrombosis model GRS compound in 10 mg/kg, administered 3 hours before iron chloride application, increased the time to blood flow cessation in the carotid artery by 35 % and reduced the frequency of complete artery occlusion by 2 times compared to the control group ( р &lt; 0.05). 60 min after arterial thrombosis modelling complete occlusion was observed in 28 % of animals in GRS group and in 75 % of control animals, while after 24 hours the occlusion was observed in 14 % of animals in GRS group and in 50 % of control group animals ( p &lt; 0.05). In thrombin-induced thromboembolism model in mice GRS did not reduce the size of blood clots in pulmonary vessels, while clopidogrel reduced it by 48 %. In GRS group 80 % of animals died of thrombosis, compared to 30 % in clopidogrel group and 90 % in the control group. In ligature-induced venous thrombosis in rats GRS after single oral administration reduced the mass of dry blood clot, being as potent as rivaroxaban. Combined administration of GRS and rivaroxaban did not enhance their antithrombotic action. Conclusion . GRS after single oral administration in 10 mg/kg dose had potent antithrombotic action in models of arterial and venous thrombosis in rats, while not preventing pulmonary vessel thrombosis in mice after thrombin administration. Therapeutic action of GRS in experimental venous thrombosis was as potent as that of rivaroxaban. Antithrombotic action of GRS compound results not only from its antiplatelet action, but also from the alleviation of endothelial dysfunction in arteries and veins.

2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension.

2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension.