Towards “CO in a pill”: Pharmacokinetic studies of carbon monoxide prodrugs in mice

Adapting decarbonylation chemistry for the development of prodrugs capable of in vivo delivery of carbon monoxide utilizing sweeteners as carrier molecules

“…In comparison, this COHb elevation is within the limits established by human clinical trials to be safe 42,43 and comparable to the efficacy levels established in preclinical animal studies. 44,45 Consistent with the in vitro kinetic properties of BW-CO-306 and BW-CO-103 (another CO prodrug which has been shown to be efficacious in various animal models such as colitis), 46 with half-lives of 1.3 min and 1.2 h, respectively, BW-CO-103 gave a more sustained elevation of COHb 17 with a t max of 60 min while BW-CO-306 gave a burst of CO resulting in a spike of COHb elevation with a t max of 10 min that only lasted for around 30 min ( Fig. 5D ).…”

“… 16 There are several reviews discussing in detail the various existing delivery forms of CO. 1,10,11 We are interested in developing organic CO prodrugs as donors for developing CO-based therapeutics as “CO in a pill” for eventual clinical applications. 17 Along this line, we 18 and Larsen's lab 19 developed cheletropic extrusion-based CO prodrugs with tunable release rates, triggered release, and the ability to target the mitochondria. 20 Fig.…”

Multi-Modal Regulation of Circadian Physiology by Interactive Features of Biological Clocks

“…The crucial role of CO in circadian rhythms was further confirmed by a later study showing that selective removal of endogenous CO by administration of hemoCD1, a highly selective CO scavenger, considerably disrupts CLOCK/NPAS2:BMAL1-dependent rhythmic expression of clock genes in mice [ 175 ]. Notably, against the common notion of CO as a metabolic waste product or toxic poison, this circadian gasotransmitter is becoming an emerging therapeutic target for neuroprotection as well as for treating inflammation, cancer, and sickle cell disease [ 176 , 177 ]. In line with this notion, recent studies have shown that CO exerts a protective effect on neuronal or ischemic injuries by preserving or enhancing circadian rhythms [ 178 , 179 ].…”

Role of Carbon Monoxide in Host–Gut Microbiome Communication

“…On average, the human body produces CO at the rate of 16.4 μmol h –1 and up to 160 μmol h –1 under stress, which primarily undergoes pulmonary excretion. , The half-life of CO bound hemoglobin under room air is around 300 min . Under different circumstances, the t 1/2 may and should vary depending on various factors such as the form of CO delivery, duration of exposure, and atmospheric oxygen conditions. − Endogenous presence of CO in blood was demonstrated in 1933 by Gettler and Mattice who first suggested the gut microbiome is a conceivable source . The average nonsmoker has a carbonylhemoglobin (COHb, also commonly referred to as carboxyhemoglobin) level under 2% COHb .…”