A Novel Hydrogen Sulfide Prodrug, SG1002, Promotes Hydrogen Sulfide and Nitric Oxide Bioavailability in Heart Failure Patients

Abstract

SummaryRecent studies demonstrate robust molecular cross talk and signaling between hydrogen sulfide (H2S) and nitric oxide (NO). Heart failure (HF) patients are deficient in both H2S and NO, two molecules that are critical for cardiovascular homeostasis. A phase I clinical trial of a novel H2S prodrug (SG1002) was designed to assess safety and changes in H2S and NO bioavailability in healthy and HF subjects. Healthy subjects (n = 7) and heart failure patients (n = 8) received oral SG1002 treatment in escalating dosages of 200, 400, and 800 mg twice daily for 7 days for each dose. Safety and tolerability were assessed by physical examination, vital signs, and ECG analysis. Plasma samples were collected during a 24‐h period each week for H2S and NO analysis. BNP and glutathione levels were analyzed as markers of cardiac health and redox status. Administration of SG1002 resulted in increased H2S levels in healthy subjects. We also observed increased H2S levels in HF subjects following 400 mg SG1002. Nitrite, a metabolite of NO, was increased in both healthy and HF patients receiving 400 mg and 800 mg SG1002. HF subjects treated with SG1002 displayed stable drug levels over the course of the trial. SG1002 was safe and well tolerated at all doses in both healthy and HF subjects. These data suggest that SG1002 increases blood H2S levels and circulating NO bioavailability. The finding that SG1002 attenuates increases in BNP in HF patients suggests that this novel agent warrants further study in a larger clinical study.

Emerging role of hydrogen sulfide-microRNA crosstalk in cardiovascular diseases

“…Clinical trials with SG1002 will be exciting to follow and to see if the increase in H 2 S levels translate into significant benefits in treating or preventing heart failure. Results from the initial clinical trial with SG1002 have recently been reported, demonstrating that SG1002 increases H 2 S and nitrite levels with few, mild adverse events (118). Furthermore, sulfur donors are being attached to current drug treatments, such as naproxen, improving their anti-inflammatory effectiveness and decreasing gastrointestinal and cardiovascular side effects (13,19,35,42,105).…”

“…that act as H 2 S donors and have antioxidant, anti-inflammatory, and vasorelaxant properties (14,94,116,132). Slow release sulfide donors such as GYY4137 (88), SG1002 (9,78,118), AP39 (138), and S-propargyl-cysteine (58,149) (118). Because of the volatile nature and short half-life of H 2 S, a continuous, low-level H 2 S release may provide an extended therapeutic potential than a single bolus using high levels as used in many NaHS and Na 2 S studies (19).…”

“…H 2 S reduces hypertension (2, 3), improves glucose uptake and metabolism (9, 89), protects against ischemia-reperfusion (I/R) injury (70,81,141,161), and decreases cardiac hypertrophy (9,73,93,97). Further evidence shows that free H 2 S levels are reduced in patients with CVD (64,79,118), suggesting H 2 S supplementation may be a potential therapy for mitigating CVD. However, the underlying molecular mechanisms for H 2 S-mediated improvement in cardiac function, or amelioration of cardiac dysfunction in CVD, are not completely understood.…”

Regulation of vascular tone homeostasis by NO and H2S: Implications in hypertension

“…For example, it has been reported that the major beneficial effects of garlic rich diets are mediated by H 2 S production [57]. According to experimental, preclinical, and clinical studies [19, 303, 304], elevation of H 2 S by using dietary sources or donors could be a hopeful therapeutic strategy in addressing/managing hypertension [19]. Many antihypertensive drugs exert their protective effects at least in part by increasing NO bioavailability [15].…”

Вплив Тиреоїдних Гормонів На Процеси Реметилування Та Транссульфування Сірковмісних Амінокислот В Органах Щурів

“…З десульфуразним шля-хом обміну цистеїну асоціюється продукція важ-ливої регуляторної газової молекули гідроген сульфіду (H 2 S). На сьогодні встановлено, що H 2 S відіграє важливу роль в агрегації тромбоцитів та регуляції судинного тонусу, скоротливості міокар-да, нейротрансмісії, секреції інсуліну [4,9,13,14].…”