DA-9701, also known as Motilitone, is a botanical drug primarily used for the treatment of functional dyspepsia (FD). This medication originates from traditional Korean medicine and comprises two main herbal ingredients, Yan Hu Suo (Corydalis Rhizoma) and Qian Niu Zi (Pharbitidis Semen). The ratio is Yan Hu Suo(5):Qian Niu Zi(1). Yan Hu Suo and Qian Niu Zi has been used as a analgesics and blood-invigorating herbs in TCM.
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| Qian Niu Zi flower |
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| Yan Hu Suo flower |
Yan Hu Suo(Corydalis Rhizoma) is warm, acrid, and bitter, primarily associated with the heart, liver, and spleen. It's used in doses ranging from 3-9 grams. This herb invigorates blood, dispels blood stasis, regulates qi, and relieves pain. It should be used with caution during pregnancy. High doses of 60-120 grams can cause toxicity, including dizziness, spasms, low blood pressure, and dyspnea.
Qian Niu Zi(Pharbitidis Semen), also known as Morning glory seeds, is cold, bitter, and acrid, associated with the lungs, kidneys, and large intestine. It's used in doses between 3-10 grams. The herb drains water, promotes urination, dispels phlegm, kills parasites, and purges constipation. Like Yan Hu Suo, Qian Niu Zi is also contraindicated during pregnancy and should be used with caution in weak patients. Overdosing can lead to headaches, vomiting, and diarrhea.
Mechanism of Action
Motilitone stimulates the 5-HT4 receptor, increasing gastric contractility and propulsion pressure, which promotes gastrointestinal motility. It also inhibits the D2 receptor, enhancing the secretion of acetylcholine and triggering smooth muscle contraction. This dual action helps reduce the sensitivity to gastric wall stimulation, increasing the stomach's adaptive response, and thus alleviating symptoms of dyspepsia that appear after eating.
Efficacy and Safety
FD is a complex condition that can cause various symptoms of indigestion, despite the lack of any organic lesions. The disease often shows complex etiology, with symptoms fluctuating due to factors like food and stress. In this context, Motilitone, a multi-target drug composed of natural ingredients, can act on both 5-HT and D2 receptors simultaneously, offering an effective treatment for FD with multifaceted symptoms.
Motilitone, the sixth natural drug developed in Korea, has been approved by the Korean FDA, although it is yet to receive approval from the US FDA.
Research has shown that Motilitone exhibits several mechanisms of action, such as prokinetic effects, fundus relaxation, and visceral analgesia, mediated by dopamine D₂ and several serotonin receptors involved in gastrointestinal functions. Clinical studies indicate that Motilitone helps improve FD symptoms and gastrointestinal functions, while offering better safety compared to conventional medicines.
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| Jin, Mirim & Son, Miwon. (2018). DA-9701 (Motilitone): A Multi-Targeting Botanical Drug for the Treatment of Functional Dyspepsia. International Journal of Molecular Sciences. 19. |
One RCT conducted in Korea assess the effects and safety of Motilitone on patients with constipation-type irritable bowel syndrome (IBS-C) concurrent with functional dyspepsia. The study diagnosed Functional dyspepsia and IBS-C based on the Rome III criteria and administered either 30 mg of DA-9701 or a placebo three times daily to randomized subjects for a period of 4 weeks. The primary outcomes were evaluated based on the percentage of responders in the overall symptom evaluation of IBS-C and functional dyspepsia. Thirty patients each were enrolled in the IBS-C and placebo groups. The DA-9701 group had a responder rate of 53.33%, while the placebo group had a rate of 40.00% (P = 0.301). The DA-9701 group had a significantly higher decrease in abdominal pain score at week 3 compared to the placebo group (0.96 ± 0.77 vs 0.55 ± 0.79, P = 0.042), but this difference was not significant at week 4. Motilitone showed a trend of treatment efficacy in patients with both IBS-C and FD, including overall improvement and safety compared to the placebo.[1]
One review study about motilitone and Functional Dyspepsia states it effectively improves Functional dyspepsia symptoms. Functional dyspepsiais a common gastrointestinal disorder marked by symptoms like postprandial fullness, early satiety, and epigastric pain or burning sensations. Given the complexity and varied nature of Functional dyspepsiapa thophysiology, it presents significant challenges in terms of treatment and the development of new drugs. Current medications that target a single pathway have shown unsatisfactory efficacy and safety. Motilitone presents a promising alternative. Since its launch in Korea in 2011, it has been prescribed for FD. It operates on multiple mechanisms, including prokinetic effects, fundus relaxation, and visceral analgesia, mediated by dopamine D₂ and several serotonin receptors involved in gastrointestinal functions.[2]
Another RCT compared the effectiveness of Motilitone, a new prokinetic agent, with pantoprazole, a conventional proton pump inhibitor, in treating functional dyspepsia involving 389 patients. Patients were divided into three groups: one received 30-mg Motilitone three times a day, another received 40-mg pantoprazole, and the third group received a combination of both. The primary measure of efficacy was the patient's global assessment of their symptoms after 4 weeks. Results showed similar rates of symptom improvement across all three groups: 60.5% for the Motilitone group, 65.6% for the pantoprazole group, and 63.5% for the combination therapy group. These results did not significantly differ among the groups. All treatment groups reported substantial improvements in response rate and symptoms across functional dyspepsia subtypes, and in dyspepsia-related quality of life.[3]
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Side Effects and Drug Interactions
Side effects of Motilitone can include dizziness (0.4%), constipation (2.2%), diarrhea, elevated amylase levels, tachycardia (0.4%), increased prolactin levels (1.7%), and various skin reactions like itching, rash, hives, and skin pain.
When used concurrently with anticholinergic drugs, Motilitone's effect may be diminished, as these drugs can suppress gastrointestinal motility.
Precautions
Given its mechanism of action, which can enhance the effects of acetylcholine, Motilitone should be used with caution. Moreover, clinical trials have typically administered the drug for up to 4 weeks for functional dyspepsia. If there's no improvement in symptoms after 4 weeks of use, it's advisable to discontinue the drug and consider alternative treatment options.
Use in Pregnancy and Breastfeeding
In TCM, both herbs are contraindicated to pregnancy. The safety of Motilitone in pregnant and breastfeeding women is yet to be established. Therefore, it should only be administered in these populations if the potential therapeutic benefits are considered to outweigh potential risks.
Case Reports with dog
Interestingly, there have been reports of Motilitone use in non-human subjects, like dogs. One such case involved a three-month-old Maltese dog that presented with lethargy after consuming Motilitone. The dog developed symptoms of a cholinergic crisis, which were successfully managed with intravenous administration of atropine and supportive fluid therapy.[4]
Conclusion
Motilitone is a unique drug primarily used for the treatment of functional dyspepsia. Originating from traditional Asian medicine, it combines two potent herbs and targets multiple pathways to alleviate gastrointestinal symptoms. "Biomedicine from Traditional Chinese Medicine" presents a new attempt in pharmaceutical development. These drugs have been developed for purposes different from those in traditional medicine. In traditional Chinese medicine, Yan Hu Suo and Qian Niu Zi are used as blood invigorating herbs, but the main target of this newly developed drug is functional dyspepsia. Ironically, while these herbs have analgesic effects in traditional medicine, they are not used to aid digestion. Through such research and attempts, a reinterpretation of traditional medicine is possible, which will be beneficial for the development of new drugs.
1. Lee JY, Kim N, Yoon H, Shin CM, Park YS, Lee DH. A Randomized, Double-blinded, Placebo-controlled Study to Evaluate the Efficacy and Safety of DA-9701 (Motilitone) in Patients With Constipation-type Irritable Bowel Syndrome and Functional Dyspepsia Overlap: A Pilot Study. J Neurogastroenterol Motil. 2022 Apr 30;28(2):265-275
2. Jin M, Son M. DA-9701 (Motilitone): A Multi-Targeting Botanical Drug for the Treatment of Functional Dyspepsia. Int J Mol Sci. 2018 Dec 13;19(12):4035. doi: 10.3390/ijms19124035.
3. Jung, H., et al. (2016). Efficacy of DA-9701 (Motilitone) in Functional Dyspepsia Compared to Pantoprazole: A Multicenter, Randomized, Double-blind, Non-inferiority Study. Journal of Neurogastroenterology and Motility, 22, 254 - 263.
4. Yoon-Hwan Kim, Motilitone toxicity in a dog, Korean Journal of Veterinary Research . Jun2021, Vol. 61 Issue 2, p1-5. 5p.