A novel hydrogen sulfide prodrug, SG1002, promotes hydrogen sulfide and nitric oxide bioavailability in heart failure patients

Abstract

Recent studies demonstrate robust molecular cross talk and signaling between hydrogen sulfide (H2 S) and nitric oxide (NO). Heart failure (HF) patients are deficient in both H2 S and NO, two molecules that are critical for cardiovascular homeostasis. A phase I clinical trial of a novel H2 S prodrug (SG1002) was designed to assess safety and changes in H2 S 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 H2 S and NO analysis. BNP and glutathione levels were analyzed as markers of cardiac health and redox status. Administration of SG1002 resulted in increased H2 S levels in healthy subjects. We also observed increased H2 S 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 H2 S 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.

Trial registration: ClinicalTrials.gov NCT01989208.

Keywords: Nitrite; Oxidative stress; Phase 1 clinical trial; Sulfide.

Figure 1

SG1002 phase I clinical trial in heart failure patients. Subjects received 200 mg oral capsules SG1002 or placebo twice daily (BID) for 7 days (visit 1, days 0–6); then increased to 400 mg SG1002 or placebo BID for 7 days (visit 2, days 7–13); then increased to 800 mg SG1002 or placebo BID for 7 days (visit 3, days 14–21). Blood was collected for pharmacokinetic analysis at 0, 0.5, 1, 2, and 4 h immediately following the administration of SG1002 or placebo at visits 1 and 2 and at 0, 0.5, 1, 2, 4, 6, 12, and 24 h during visit 3. Samples for the analysis of brain natriuretic peptide (BNP) and oxidative stress (glutathione) were taken on days 0, 7, 14, and 21 prior to the administration of SG1002. Parameters for safety, including physical examination, vital sign measurements, and electrocardiogram (ECG), were measured at baseline, 1, 2 and 3 weeks time points.

Figure 2

Peak sulfide levels for healthy and heart failure subjects following 1st dose of 200, 400 and 800 mg SG1002 (individual maximum concentrations reached 0.5–4 h post administration). (A) Peak free H₂S levels following 200, 400 and 800 mg BID in healthy subjects. (B) Peak free H₂S levels following 200, 400 and 800 mg BID in heart failure subjects. (C) Peak sulfane sulfur levels following 200, 400 and 800 mg BID in healthy subjects. (D) Peak sulfane sulfur levels following 200, 400 and 800 mg BID in heart failure subjects. *P < 0.05, **P < 0.01 compared to baseline (pretreatment values) using a 1‐way ANOVA with a Bonferroni multiple comparison correction test. Values are expressed as mean ± SEM.

Figure 3

Pharmacokinetic analysis of free H₂S and sulfane sulfur in healthy subjects. (A) Free H₂S levels following 200 mg SG1002 BID, (B) 400 mg BID, and (C) 800 mg BID. (D) Free sulfane sulfur levels following 200 mg SG1002 BID, (E) 400 mg BID, and (F) 800 mg BID. Values are expressed as mean ± SEM. n = 5.

Figure 4

Pharmacokinetic analysis of free H₂S and sulfane sulfur in heart failure subjects. (A) Free H₂S levels following 200 mg SG1002 BID, (B) 400 mg BID, and (C) 800 mg BID. (D) Free sulfane sulfur levels following 200 mg SG1002 BID, (E) 400 mg BID, and (F) 800 mg BID. Values are expressed as mean ± SEM. n = 6.

Figure 5

Pharmacokinetic analysis of nitrite in healthy and heart failure subjects. (A) Nitrite levels following 200 mg SG1002 BID, (B) 400 mg BID, and (C) 800 mg BID in healthy subjects (n = 5). (D) Plasma nitrite levels following 200 mg SG1002 BID, (E) 400 mg BID, and (F) 800 mg BID in HF subjects (n = 6). Values are expressed as mean ± SEM.

Figure 6

Peak nitrite levels for healthy and heart failure subjects following 1st dose of 200, 400, and 800 mg SG1002 (individual maximum concentrations reached 0.5–4 h post administration). (A) Peak nitrite levels following 200, 400, and 800 mg BID in healthy subjects (n = 5). (B) Peak nitrite levels following 200, 400, and 800 mg BID in heart failure subjects (n = 6). *P < 0.05, ***P < 0.001 compared to baseline (pretreatment values) using a 1‐way ANOVA with a Bonferroni multiple comparison correction test. Values are expressed as mean ± SEM.

Figure 7

Markers of cardiac health following SG1002 treatment in heart failure subjects. (A) Fold change in the stress responsive polypeptide, BNP. Circulating BNP concentrations were measure at baseline, day 7 (completion of 200 mg BID), day 14 (400 mg BID), and day 21 (800 mg BID). (B) Relative reduced (GSH) and oxidized (GSSG) glutathione levels in RBCs at baseline, after 7 days of 200 mg BID (day 7), after 7 days of 400 mg BID (day 14), and after 7 days of 800 mg BID (day 21). Values are expressed as mean ± SEM.