Multi target therapy instead of mono receptor approach: Motility modulation beyond MCP

Abstract

Motility-modulating drugs are important in functional GI diseases, formely with a mono receptor approach as a gold standard. Important examples were cisaprid, which stimulates 5-HT4-receptors, and metoclopramide (MCP), a dopamine D2 antagonist and additionally an 5-HT3-antagonist and 5-HT4-agonist, enhancing gastrointestinal motility. This changed by the withdrawal of cisapride due to cardiac, and recently the referral for metoclopramide (MCP) due to neurological side effects, with omission of functional dyspepsia from its therapeutic indications. It is therefore important to identify other options with proven clinical efficacy but more favorable safety. Herbal medicinal products like the multi drug combination STW 5 have shown to be a safe and effective treatment option in these indications, which raises the question for the – obviously different – underlying mechanisms of action. For identifying effects on GI motility, a systematic database search was conducted in accordance to the PRISMA statement. Studies on STW 5 in small intestinal preparations [1] showed spasmolysis in spastic, tonicising effects in the relaxed state. This was confirmed in inflamed intestinal tissue in vitro and in vivo [2]. In the stomach, a region specific action was described in vitro, based on an inhibition of Ca influx via SOC channels in the gastric fundus and on a stimulation of Ca influx via L type Ca channels in the antrum and was confirmed in a clinical pharmacological study in vivo [3]. A tonicising effect on the lower esophageal sphincter is based on the same mechanisms of action[1]. Components of STW 5 have been shown to act synergistically [4]. While MCP or cisaprid, despite acting via only few specific targets, have been shown to have serious side effects, STW 5 has, in contrast, multiple targets, which potentially contribute to its clinical effects, and an excellent safety profile [1], documented by its use for more than 50 years and in more than 25 mio patients.