Safety and efficacy of soluble guanylate cyclase stimulators in patients with heart failure: A systematic review and meta-analysis

BACKGROUND The utility of novel oral soluble guanylate cyclase(sGC)stimulators(vericiguat and riociguat),in patients with reduced or preserved ejection fraction heart failure(HFrEF/HFpEF)is currently unclear.AIM To determine the efficacy and safety of sGC stimulators in HF patients.METHODS Multiple databases were searched to identify relevant randomized controlled trials(RCTs).Data on the safety and efficacy of sGC stimulators were compared using relative risk ratio(RR)on a random effect model.RESULTS Six RCTs,comprising 5604 patients(2801 in sGC stimulator group and 2803 placebo group)were included.The primary endpoint(a composite of cardiovascular mortality and first HF-related hospitalization)was significantly reduced in patients receiving sGC stimulators compared to placebo[RR 0.92,95%confidence interval(CI):0.85-0.99,P=0.02].The incidence of total HF-related hospitalizations were also lower in sGC group(RR 0.91,95%CI:0.86-0.96,P=0.0009),however,sGC stimulators had no impact on all-cause mortality(RR 0.96,95%CI:0.86-1.07,P=0.45)or cardiovascular mortality(RR 0.94,95%CI:0.83-1.06,P=0.29).The overall safety endpoint(a composite of hypotension and syncope)was also similar between the two groups(RR 1.50,95%CI:0.93-2.42,P=0.10).By contrast,a stratified subgroup analysis adjusted by type of sGC stimulator and HF(vericiguat vs riociguat and HFrEF vs HFpEF)showed near identical rates for all safety and efficacy endpoints between the two groups at a mean follow-up of 19 wk.For the primary composite endpoint,the number needed to treat was 35,the number needed to harm was 44.CONCLUSION The use of vericiguat and riociguat in conjunction with standard HF therapy,shows no benefit in terms of decreasing HF-related hospitalizations or mortality.

Plecanatide-mediated activation of guanylate cyclase-C suppresses inflammation-induced colorectal carcinogenesis in Apc+/Min-FCCC mice

AIM To evaluate the effect of orally administered plecanatide on colorectal dysplasia in Apc^(+/Min-FCCC) mice with dextran sodium sulfate(DSS)-induced inflammation. METHODS Inflammation driven colorectal carcinogenesis was induced in Apc^(+/Min-FCCC) mice by administering DSS in their drinking water. Mice were fed a diet supplemented with plecanatide(0-20 ppm) and its effect on the multiplicity of histopathologically confirmed polypoid,flat and indeterminate dysplasia was evaluated. Plecanatide-mediated activation of guanylate cyclase-C(GC-C) signaling was assessed in colon tissues by measuring cyclic guanosine monophosphate(cG MP) by ELISA, protein kinase G-II and vasodilator stimulated phosphoprotein by immunoblotting. Ki-67, c-myc and cyclin D1 were used as markers of proliferation. Cellular levels and localization of b-catenin in colon tissues were assessed by immunoblotting and immunohistochemistry, respectively. Uroguanylin(UG) and GC-C transcript levels were measured by quantitative reverse transcription polymerase chain reaction(RT-PCR). A mouse cytokine array panel was used to detect cytokines in the supernatant of colon explant cultures. RESULTS Oral treatment of Apc^(+/Min-FCCC) mice with plecanatide produced a statistically significant reduction in the formation of inflammation-driven polypoid, flat and indeterminate dysplasias. This anti-carcinogenic activity of plecanatide was accompanied by activation of cG MP/GC-C signaling mediated inhibition of Wnt/b-catenin signaling and reduced proliferation. Plecanatide also decreased secretion of pro-inflammatory cytokines(IL-6, IL-1 TNF), chemokines(MIP-1, IP-10) and growth factors(GCSF and GMCSF) from colon explants derived from mice with acute DSS-induced inflammation. The effect of plecanatidemediated inhibition of inflammation/dysplasia on endogenous expression of UG and GC-C transcripts was measured in intestinal tissues. Although GC-C expression was not altered appreciably, a statistically significant increase in the level of UG transcripts was detected in the proximal small intestine and colon, potentially due to a reduction in intestinal inflammation and/or neoplasia. Taken together, these results suggest that reductions in endogenous UG, accompanied by dysregulation in GC-C signaling, may be an early event in inflammation-promoted colorectal neoplasia; an event that can potentially be ameliorated by prophylactic intervention with plecanatide.CONCLUSION This study provides the first evidence that orally administered plecanatide reduces the multiplicity of inflammation-driven colonic dysplasia in mice, demonstrating the utility for developing GC-C agonists as chemopreventive agents.

Plecanatide and dolcanatide, novel guanylate cyclase-C agonists, ameliorate gastrointestinal inflammation in experimental models of murine colitis

AIM: To evaluate the effect of orally administeredplecanatide or dolcanatide, analogs of uroguanylin, on amelioration of colitis in murine models.METHODS: The cyclic guanosine monophosphate(cG MP) stimulatory potency of plecanatide and dolcanatide was measured using a human colon carcinoma T84 cellbased assay. For animal studies all test agents were formulated in phosphate buffered saline. Sulfasalazine or 5-amino salicylic acid(5-ASA) served as positive controls. Effect of oral treatment with test agents on amelioration of acute colitis induced either by dextran sulfate sodium(DSS) in drinking water or by rectal instillation of trinitrobenzene sulfonic(TNBS) acid, was examined in BALB/c and/or BDF1 mice. Additionally, the effect of orally administered plecanatide on the spontaneous colitis in T-cell receptor alpha knockout(TCRα-/-) mice was also examined. Amelioration of colitis was assessed by monitoring severity of colitis, disease activity index and by histopathology. Frozen colon tissues were used to measure myeloperoxidase activity.RESULTS: Plecanatide and dolcanatide are structurally related analogs of uroguanylin, which is an endogenous ligand of guanylate cyclase-C(GC-C). As expected from the agonists of GC-C, both plecanatide and dolcanatide exhibited potent cG MP-stimulatory activity in T84 cells. Once-daily treatment by oral gavage with either of these analogs(0.05-0.5 mg/kg) ameliorated colitis in both DSS and TNBS-induced models of acute colitis, as assessed by body weight, reduction in colitis severity(P < 0.05) and disease activity index(P < 0.05). Amelioration of colitis by either of the drug candidates was comparable to that achieved by orally administered sulfasalazine or 5-ASA. Plecanatide also effectively ameliorated colitis in TCRα-/- mice, a model of spontaneous colitis. As dolcanatide exhibited higher resistance to proteolysis in simulated gastric and intestinal juices, it was selected for further studies. CONCLUSION: This is the first-ever study reporting the therapeutic utility of GC-C agonists as a new class of orally delivered and mucosally active drug candidates for the treatment of inflammatory bowel diseases.

Isolation,Purification and Spectral Characteristics of Soluble Guanylate Cyclase from Bovine Lung

We isolated and purified high purity and high activity soluble Guanylate cyclase(sGC)from bovine lung.The electronic absorption and resonance Raman spectra of the ferrous and ferric forms of sGC were recorded.In the ferrous state of sGC,the electronic absorption spectra showed a sharp peak at 431 nm and a single broad peak in the T/U region at 559 nm.The resonance Raman spectra of sGC(ferrous)showed a stronger band at 1357 cm^(-1)and a single peak at 1473 cm^(-1).For the ferric form of sGC,the Soret band was at 390 nm and resonance Raman peak was at 1375 cm^(-1).These spectra show that the heme iron of the ferrous and ferric sGC are all 5 coordination and high spin.

Expression of nitric oxide synthase and guanylate cyclase in the human ciliary body and trabecular meshwork

Background The role played by the nitric oxide （NO） signaling pathway in the aqueous humor dynamics is still unclear.This study was designed to investigate the expression and distribution of NO synthase （NOS） isoforms and guanylate cyclase （GC） in human ciliary body,trabecular meshwork and the Schlemm＇s canal.Methods Twelve eyes after corneal transplantation were used.Expression of three NOS isoforms （i.e.neuronal NOS （nNOS）,inducible NOS （iNOS） and endothelial NOS （eNOS）） and GC were assessed in 10 eyes by immunohistochemical staining using monoclonal or polyclonal antibody of NOS and GC.Ciliary bodies were dissected free and the total proteins were extracted.Western blotting was performed to confirm the protein expression of 3 NOS isoforms and GC.Results Expression of 3 NOS isoforms and GC were observed in the ciliary epithelium,ciliary muscle,trabecular meshwork and the endothelium of the Schlemm＇s canal.Immunoreactivity of nNOS was detected mainly along the apical cytoplasmic junction of the non-pigmented epithelium （NPE） and pigmented epithelial （PE） cells.Protein expressions of 3 NOS isoforms and GC were confirmed in isolated human ciliary body by Western blotting.Conclusions The expression of NOS isoforms and GC in human ciliary body suggest the possible involvement of NO and cyclic guanosine monophosphate （cyclic GMP,cGMP） signaling pathway in the ciliary body,and may play a role in both processes of aqueous humor formation and drainage.

The roles of cysteines in the heme domain of human soluble guanylate cyclase

Soluble guanylate cyclase（sGC） is a critical heme-containing enzyme involved in NO signaling.The dimerization of sGC subunits is necessary for its bioactivity and its mechanism is a striking and an indistinct issue.The roles of heme domain cysteines of the sGC on the dimerization and heme binding were investigated herein.The site-directed mutations of three conserved cysteines（C78A,C122A and C174S） were studied systematically and the three mutants were characterized by gel filtration analysis,UV-vis spectroscopy and heme transfer examination.Cys78 was involved in heme binding but not referred to the dimerization,while Cys174 was demonstrated to be involved in the homodimerization.These results provide new insights into the cysteine-related dimerization regulation of sGC.

Changes of Adenylate Cyclase and Guanylate Cyclase in the Frontal Cortex,Lenticula,Corpus Amygdaloideum,and Hippocampus in Morphine‑dependent Rats

To detect the changes of adenylate cyclase(AC)and guanylate cyclase(GC)in the four cerebral regions that are concerned with psychogenic dependence of morphine in rats,including the frontal cortex,lenticula,corpus amygdaloideum,and hippocampus.To discuss the relation between the expressions of AC and GC with the psychogenic dependence on morphine.Different periods of morphine‑dependent rat models were established,and enzyme histochemistry was used to detect the variations of AC and GC in four cerebral regions.Compared with the control group,AC and GC in all the morphine‑dependent groups increased.The data indicated that the amounts of AC and GC were significantly different between the morphine‑dependent groups and the control group when tested at periods of 1 week,2 weeks,4 weeks,and 8 weeks(P<0.05 or P<0.01).There were significant differences when comparing the 1‑week group with the 2‑week,4‑week,and 8‑week groups(P<0.05 or P<0.01).There were significant differences when comparing the 2‑week dependent group with the 4‑week dependent group or the 8‑week dependent group(P<0.05 or P<0.01).The activities of AC and GC increased in four cerebral regions of morphine‑dependent rats.The psychogenic dependence on morphine appears to be closely linked to the upgrade of AC and GC.

Impact of vericiguat on heart failure with reduced ejection fraction:a review

Introduction:Heart failure is a major public health issue with a prevalence of about 26 million people worldwide.Reduced nitric oxide availability,lower soluble guanylate cyclase(sGC)activity,and decreased cyclic guanosine monophosphate(cGMP)production are the causes of HF's development.Vericiguat prescribed under the brand name Verquvo was approved by U.S.Food and Drug Administration(FDA)in January 2021.It is a novel agent and the first sGC stimulator which helps to treat patients suffering from heart failure with reduced ejection fraction(HFrEF).Objective:The mechanism of action(cGMP pathway)of vericiguat,its clinical trials,its use in the treatment of heart failure,and its possible future aspects in therapeutic recommendations are all covered in this review.It will also raise awareness amongst healthcare professionals about the pharmacokinetic and pharmacodynamic parameters,dosing,administration,and drug-related problems of this new drug.Methods:Various databases for drug review were used in this review like PubMed,Medline,Google scholar,Drug bank,U.s.FDA,Medscape,and European society of cardiology guidelines.A total of 58 articles were screened out of which 39 articles were included in this review.Results:This review discusses vericiguat's mechanism of action(cGMP pathway),clinical studies,application in the treatment of heart failure,and potential future considerations in therapeutic recommendations.It will also educate healthcare professionals about the new drug's pharmacokinetics and pharmacodynamics,dose,administration,and drug-related problems.Conclusion:After hospitalization for HFrEF,the 5-year survival rate is just 25%,and disease morbidity and death are stil significant.As adjunctive therapy for individuals with heart failure and a low ejection fraction,vericiguat has a moderate level of effectiveness.Vericiguat's efficacy as an adjunct therapy to different drugs used to cure HF has to be further investigated.Vericiguat's safety and dosage in patients who have severe renal or hepatic illness need to be studied further.

Pharmacological evaluation of NSAID-induced gastropathy as a “Translatable” model of referred visceral sensitivity

AIM To evaluate whether non-steroidal anti-inflammatory drugs(NSAIDs)-induced gastropathy is a clinically predictive model of referred visceral hypersensitivity.METHODS Gastric ulcer pain was induced by the oral administration of indomethacin to male,CD1 mice(n = 10/group) and then assessed by measuring referred abdominal hypersensitivity to tactile application. A diverse range of pharmacological mechanisms contributing to the pain were subsequently investigated. These mechanisms included: transient receptor potential(TRP),sodium and acid-sensing ion channels(ASICs) as well as opioid receptors and guanylate cyclase C(GC-C). RESULTS Results showed that two opioids and a GC-C agonist,morphine,asimadoline and linaclotide,respectively,the TRP antagonists,AMG9810 and HC-030031 and the sodium channel blocker,carbamazepine,elicited a dose-and/or time-dependent attenuation of referred visceral hypersensitivity,while the ASIC blocker,amiloride,was ineffective at all doses tested. CONCLUSION Together,these findings implicate opioid receptors,GC-C,and sodium and TRP channel activation as possible mechanisms associated with visceral hypersensitivity. More importantly,these findings also validate NSAID-induced gastropathy as a sensitive and clinically predictive mouse model suitable for assessing novel molecules with potential pain-attenuating properties.

Synthesis, Crystal Structure and Catalytic Activity of a Dinuclear Aluminum Alkyl Complex

Treatment of indolyl-3-aldimines（3-~tBuN=CH）C8H5NH with AlMe3 afforded the deprotonated indolyl aluminum complex cis-[（μ-η~1：η~1-3-~tBuN=CH）C8H5NAlMe2]2,and its crystal structure was determined by X-ray single-crystal diffraction.The crystal belongs to the orthorhombic system,space group P21212 with a = 14.590（9）,b = 15.860（2）,c = 13.266（8） A,μ=0.118 mm^（-1）,Mr = 512.64,V= 3069.5（3） A^3,Z = 4,Dc= 1.109 g/cm^3,F（000） = 1104,R= 0.0451 and wR = 0.0937 for 4978 observed reflections with I 2σ（I）.In addition,the title compound exhibited a high catalytic activity toward the addition of amines to carbodiimide to form guanidines.

Synthesis of Guanidines from Amines and Carbodiimides Catalyzed by Mono-lndenyI-Ligated Rare Earth Metal Bis（silylamide） Complexes

Nucleophilic addition of primary aromatic amines to carbodiimides in the presence of catalytic amount of the mono-indenyl-ligated rare earth metal bis（silylamide） complexes （C9H6CMe2CHzCsH4N-a）Ln[N（SiHMe2）2]2 at room temperature afforded efficiently a series of guanidines with a wide spectrum of substituents on the nitrogen atoms.

Synthesis, structure and catalytic behavior of ytterbium complexes bearing a phenoxy(quinolinyl)amide ligand

Two ytterbium complexes stabilized by phenoxy（quinolinyl）amide ligand 3,5-But2-2-OC6H2CH2N-8-C9H6N （L） were synthesized and characterized. Reaction of anhydrous YbC13 with 1 equiv, of LLi2 in THF gave the ytterbium chloride [LYbCI（THF）]2 （1） in 73% yield. A further reaction of complex 1 with equimolar of NaN（SiMe3）2 in THF afforded the unexpected heterobimetallic ＂ate＂-complex L2YbNa（THF）2 （2） via a ligand redistribution reaction. Complex 2 could also be prepared in high isolated yield by the reaction of anhydrous YbC13 with 2 equiv, of LNa2 generated in situ. Both complexes 1 and 2 were characterized by IR spectroscopy, elemental analysis, and sin- gle-crystal X-ray diffraction analysis. It was found that complex 2 was an effective catalyst for the addition reaction of aromatic amines to carbodiimides.