Is Ramosetron Really Useful to Treat Diabetic Diarrhea With Rapid Small Bowel Transit?: Author's Reply

Abstract

TO THE EDITOR: I appreciate for Dr. Lee's comments.1 The 5-hydroxytryptamine (5-HT) receptors (the original 5-HT M receptor) are distributed widely in both the gastrointestinal (GI) tract and the central nerve system, and result in increased intestinal secretion and alteration of peristaltic activity. The action of 5-HT3 receptor antagonists (5-HT3RAs) to modify contraction-relaxation responses would be dependent on the relative balance of excitatory-inhibitory tone. Therefore, 5-HT3RAs might reduce motor activity in the presence of an abnormally increased basal activity. Ramosetron, a selective 5-HT3 receptor antagonist, has been confirmed to have an inhibitory effect on lower GI transit. This drug has been known to be effective for diarrhea predominant irritable bowel syndrome in both animal and clinical studies. But its effects and mechanisms on the upper GI tract (stomach and small intestine) have not been verified. Classic sympathetic, parasympathetic autonomous nervous system, and the enteric nervous system (ENS) are important for the regulation of enteric function. Diabetes results in abnormalities of the ENS, such as loss of neurons containing nitric oxide synthase, which mediates GI tract relaxation, and an increase in the serotonin contents, which regulate GI tract contraction. An imbalance between the inhibitory and excitatory ENS could be one of the causes of diabetic diarrhea. The 5-HT3 receptor antagonist inhibits the excitatory neurons of ENS thus plays a role in regulating a balance of the ENS components in diabetic patients.2,3 Based on these mechanisms, Murao and Hosokawa2 reported the effect of ramosetron, which was developed as an antiemetic drug for cancer chemotherapy and for the treatment of diabetic diarrhea. In our study, the effect was well demonstrated by its inhibitory effects on accelerated GI transit caused by 5-HT, thyrotropin-releasing hormone and mustard oil.3 However, Hirata et al4 showed recently that ramosetron significantly inhibited the delayed gastric emptying in a corticotrophin releasing factor and soybean oil-induced rat model, in comparison with anti-diarrheal agent and spasmolytics. We should consider the differences in the dose of ramosetron and the action mechanism of the substance that caused changes in altered GI transit. There were conflicting results from animal experiments on the same drug.3,4 This could be an evidence presenting the different treatment effects of ramosetron in patients with autonomic neuropathy, diabetic diarrhea and gastroparesis.