Dobupride

Dobupride--what exactly is its degradation behavior?

Degradation profile and identification of the major degradation products of dobupride under several conditions by GC/MS and HPLC-particle beam/MS

The effect of pH, light, temperature and oxygen on the stability of dobupride (1), a novel gastroprokinetic drug, has been studied, storing the sample in the solid state and as a solution in methanol-water. The main forced degradation products have been identified by means of techniques such as GC/MS and HPLC-particle beam/MS, and two major degradation pathways have been characterized. One degradation route involves the loss of chlorine, yielding 4-amino-2-butoxy-N-[1-(1,3-dioxolan-2-ylmethyl)piperid -4-yl]benzamide (4) as the major degradation product. The second pathway results from cleavage of the piperidine-amide bond, producing 4-amino-2-butoxy-5-chlorobenzamide (2) as the major degradation product. Under the studied conditions, except when exposed to direct light in solution, dobupride has been shown to be very stable: after 5 months storage, the benzamide 2 (second pathway) was the only product identified (less than 0.5%). However, when dobupride in solution is exposed to natural or artificial sunlight, degradation is very fast, and after 7 days only 5% of the unchanged product remains. Under these circumstances, the main degradation route is the first one, with compound 4 being the most abundant degradation product, and compound 2 only being detectable in small amounts.

Repetitive supply-demand ischemia with dobutamine increases glucose uptake in postischemic and remote myocardium

The goal of this study was to determine whether myocardial glucose uptake after repetitive ischemia differs in response to coronary occlusion-reperfusion versus supply-demand ischemia induced by dobutamine. Although glucose metabolism is increased after myocardial ischemia, the metabolic effect of supply-demand ischemia induced by dobutamine may increase glucose metabolism within remote myocardium. This would make it difficult to discriminate postischemic from remote myocardium with glucose tracers.
Methods: Eighteen swine with a hydraulic occluder and flow probe on the circumflex artery underwent repetitive ischemia. In group 1 (n = 9), the circumflex artery was occluded, whereas in group 2 (n = 9), circumflex flow was decreased by 30% before dobutamine (40 micro g/kg/min intravenously). Each pig underwent 15 min of ischemia, twice per day for 5 d. Echocardiography and PET to determine myocardial glucose ((18)F-FDG) uptake were performed after final ischemia, and tissue was later analyzed for activation of Akt, p38 mitogen-activated protein, and adenosine monophosphate (AMP) kinase.
Results: Wall thickening in the circumflex region was lower than in remote regions in both groups. (18)F-FDG uptake in the circumflex region was similar in groups 1 and 2 (0.22 +/- 0.03 and 0.23 +/- 0.04 micro mol/min/g, respectively; not statistically significant). In the remote region, (18)F-FDG uptake was lower than in the circumflex region in group 1 (0.14 +/- 0.03 micro mol/min/g; P < 0.05) but was similar to that in the circumflex region in group 2 (0.20 +/- 0.03 micro mol/min/g; not statistically significant). AMP kinase activity in the remote region was significantly lower than in the circumflex region in group 1 but was similar to that in the circumflex region in group 2.
Conclusion: Unlike repetitive coronary artery occlusion-reperfusion, repetitive supply-demand ischemia with dobutamine alters glucose uptake within the remote myocardium, possibly as a result of AMP kinase activation. Clinically, these data suggest that (18)F-FDG studies have a limited role in discriminating postischemic from remote myocardium after dobutamine stress.