Oral Administration of Soluble Guanylate Cyclase Agonists to Rats Results in Osteoclastic Bone Resorption and Remodeling with New Bone Formation in the Appendicular and Axial Skeleton

Homer, Bruce L.; Morton, Daniel G.; Bagi, Cedo M.; Warneke, James; Andresen, Catharine J.; Whiteley, Laurence O.; Morris, Dale L.; Tones, Michael A.

doi:10.1177/0192623314546559

Cited by 13 publications

(13 citation statements)

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“…The NO-sGC-cGMP pathway is also an important regulator of the metabolism and function of osteoblasts and osteoclasts and regulates bone formation, resorption and remodeling [ 64 , 65 ]. Although, the initial animal studies of riociguat activity in adolescent rats and mice showed various degrees of bone resorption and remodeling in the femur and tibia [ 17 ], clinical studies in adults did not show any adverse effect on bones. In addition, we have reported normal bone densities in mice lacking GC1 demonstrating that GC1 does not play an important role in specifying bone density [ 66 ].…”

Section: Discussionmentioning

confidence: 99%

“…Regardless, the FDA has raised a concern for a future reference for use of riociguat in pediatric patients, even when conducting clinical trials [ 67 ]. However, Homer et al, in their recent study using 7 to 9 weeks old Sprague Dawley rats, demonstrated that while riociguat initially caused adverse bone changes, they found these bone changes reversible, with partial recovery after 2 weeks and no bony changes at all after 5 weeks of recovery [ 17 ]. Similarly, in our study, we found that daily IP injection of riociguat for 9 days did not affect trabeculae, bone length and bone volume in secondary spongiosa of femur.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, by stimulating sGC, riociguat could be very beneficial in the setting of BPD with PH in that oxidative stress is a key inducer. However, riociguat is not approved by the FDA for use in neonates or pediatric patients, given the concern that sGC agonists may cause abnormal bone growth [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

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Riociguat prevents hyperoxia-induced lung injury and pulmonary hypertension in neonatal rats without effects on long bone growth

et al. 2018

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Bronchopulmonary dysplasia (BPD) remains the most common and serious chronic lung disease of premature infants. Severe BPD complicated with pulmonary hypertension (PH) increases the mortality of these infants. Riociguat is an allosteric soluble guanylate cyclase stimulator and is approved by the FDA for treating PH in adults. However, it has not been approved for use in neonates due to concern for adverse effects on long bone growth. To address this concern we investigated if administration of riociguat is beneficial in preventing hyperoxia-induced lung injury and PH without side effects on long bone growth in newborn rats. Newborn rats were randomized to normoxia (21% O2) or hyperoxia (85% O2) exposure groups within 24 hours of birth, and received riociguat or placebo by once daily intraperitoneal injections during continuous normoxia or hyperoxia exposure for 9 days. In the hyperoxia control group, radial alveolar count, mean linear intercept and vascular density were significantly decreased, the pathological hallmarks of BPD, and these were accompanied by an increased inflammatory response. There was also significantly elevated vascular muscularization of peripheral pulmonary vessels, right ventricular systolic pressure and right ventricular hypertrophy indicating PH. However, administration of riociguat significantly decreased lung inflammation, improved alveolar and vascular development, and decreased PH during hyperoxia by inducing cGMP production. Additionally, riociguat did not affect long bone growth or structure. These data indicate that riociguat is beneficial in preventing hyperoxia-induced lung injury and PH without affecting long bone growth and structure and hence, suggests riociguat may be a potential novel agent for preventing BPD and PH in neonates.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Riociguat prevents hyperoxia-induced lung injury and pulmonary hypertension in neonatal rats without effects on long bone growth

et al. 2018

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“…It has been documented through internal and published studies that high concentrations of sGCa cause DIVI in the mesenteric arteries of rats. 28 Thus, we used a proprietary sGCa that in internal studies caused highly reproducible vascular injury in the mesenteric arteries, in the optical imaging studies.…”

Section: Discussionmentioning

confidence: 99%

“…It has been documented through internal and published studies that high concentrations of sGCas cause DIVI in the mesenteric arteries of rats. 28 The optical agents were used to quantitatively measure DIVI in rat mesenteric arteries after oral dosing of the sGCa, and concordance was assessed with histopathology and immunohistochemistry.…”

Section: -25mentioning

confidence: 99%

Optical Imaging Biomarkers of Drug-Induced Vascular Injury

Lin¹,

Suresch²,

Connolly³

et al. 2015

Mol Imaging

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Drug-induced vascular injury (DIVI), defined as arterial medial degeneration/necrosis usually associated with perivascular inflammation, is frequently observed in the mesenteric arteries of rats but the relevance to humans remains a hurdle for drug development. Here, we describe the evaluation of commercially available optical imaging biomarkers using a rat DIVI model. Male Sprague Dawley rats were administered 10 mg/kg/day of a proprietary soluble guanylate cyclase activator (sGCa). Optical agents, AngioSense for the detection of vessel permeability, MMPSense for the detection of activated matrix metalloproteinases (MMPs), and IntegriSense for the detection of αvβ3 integrin, were injected via tail vein 24 hours before fluorescence (FL) ex vivo imaging. Imaging found a statistically significant difference in FL from all optical agents between treated and vehicle groups (p < .05). Mesenteric arteries were further analyzed by histopathology, flow cytometry, and immunohistochemistry. Histopathology confirmed perivascular inflammation and/or arterial medial degeneration in the sGCa-treated animals. Flow cytometry of digested arteries revealed myeloid cells as a main source of MMPSense signal. Immunohistochemical analysis further identified elevated MMP-9 expression within arterial walls and surrounding tissue of treated animals. Together, these data demonstrate that MMPSense and AngioSense are sensitive optical imaging biomarkers for the quantification of DIVI in rat mesenteric arteries.

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Riociguat in children with pulmonary arterial hypertension: The PATENT–CHILD study

et al. 2022

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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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Oral Administration of Soluble Guanylate Cyclase Agonists to Rats Results in Osteoclastic Bone Resorption and Remodeling with New Bone Formation in the Appendicular and Axial Skeleton

Cited by 13 publications

References 45 publications

Riociguat prevents hyperoxia-induced lung injury and pulmonary hypertension in neonatal rats without effects on long bone growth

Riociguat prevents hyperoxia-induced lung injury and pulmonary hypertension in neonatal rats without effects on long bone growth

Optical Imaging Biomarkers of Drug-Induced Vascular Injury

Riociguat in children with pulmonary arterial hypertension: The PATENT–CHILD study

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