Posted by Sin1A is an unstable NO releasing metabolite of Molsidomine. Molsidomine is a prodrug that undergoes first-pass metabolism in the liver, and thus, linsidomine (SIN-1) is formed. SIN-1 is further decomposed nonenzymatically to SIN-1A, then to SIN-1•+, which spontaneously releases NO. An early patent (US5698535A) described the catalytic and stabilizing effect of CDs.
Covid-19 shed light again on this old discovery as this disease often leads to hypoxia-induced pulmonary vasoconstriction related to acute respiratory distress syndrome. For that reason, inhalative therapeutic options (e.g. NO gas inhalation) have been the subject of several clinical trials. In a recently published experimental study, it was aimed to examine the hemodynamic impact of the inhalation of the SIN-1 (3-morpholinosydnonimine) formulation transforming to NO-releasing Sin1A (N-nitroso-N-morpholino-amino-acetonitrile stabilized by a HPBCD) in a porcine model of acute pulmonary hypertension.
Landrace pigs were divided into the following experimental groups: iNO (inhaled nitric oxide, n = 3), SIN-1A-5 (5 mg, n = 3), and SIN-1A-10 (10 mg, n = 3). Parallel insertion of a PiCCO system and a pulmonary artery catheter (Swan-Ganz) was performed for continuous hemodynamic monitoring. The impact of iNO (15 min) and SIN-1A inhalation (30 min) was investigated under physiologic conditions and U46619-induced acute pulmonary hypertension. Mean pulmonary arterial pressure (PAP) was reduced transiently by both substances. SIN-1A-10 had a comparable impact compared to iNO after U46619-induced pulmonary hypertension. PAP and pulmonary vascular resistance (PVR) decreased significantly (changes in PAP: −30.1% iNO, −22.1% SIN-1A-5, −31.2% SIN-1A-10). While iNO therapy did not alter the mean arterial pressure (MAP) and systemic vascular resistance (SVR), SIN-1A administration resulted in decreased MAP and SVR values. Consequently, the PVR/SVR ratio was markedly reduced in the iNO group, while SIN-1A did not alter this parameter. The pulmonary vasodilatory impact of inhaled SIN-1A was shown to be dose-dependent. A larger dose of SIN-1A (10 mg) resulted in decreased PAP and PVR in a similar manner to the gold standard iNO therapy. Inhalation of the nebulized solution of the new SIN-1A formulation (stabilized by a cyclodextrin derivative) might be a valuable, effective option where iNO therapy is not available due to dosing difficulties or availability.
Oláh, A.; Barta, B.A.; Ruppert, M.; Sayour, A.A.; Nagy, D.; Bálint, T.; Nagy, G.V.; Puskás, I.; Szente, L.; Szőcs, L.; et al. A Comparative Investigation of the Pulmonary Vasodilating Effects of Inhaled NO Gas Therapy and Inhalation of a New Drug Formulation Containing a NO Donor Metabolite (SIN-1A). Int. J. Mol. Sci. 2024, 25, 7981. https://doi.org/10.3390/ijms25147981