To seek a novel and potent antitussive drug based on Shedan—Chuanbei powder, a complex of traditional Chinese medicine preparation for cough therapy.
Verticinone—cholic acid (Ver—CA) salt, a novel, salifying derivative of verticinone and cholic acid, both of which are the major bioactive components in Shedan—Chuanbei powder, was synthesized. We then evaluated the antitussive activity and the acute toxicity of the salt.
The new compound, with good solubility in water, has much more potent antitussive activity in comparison with the same dose of single verticinone and single cholic acid. The administration 3 mg/kg of Ver—CA could result in over 50% reduction of a citric acid-induced cough. Pretreatment with naloxone (0.8 mg/kg, ip) can only partially antagonize its anti-tussive effect. On the other hand, glybenclamide (3 mg/kg, ip), an ATP-sensitive K+ channel blocker, can also significantly reduce the antitussive effect of Ver—CA. A further acute toxicity study showed that the LD50 values of Ver—CA were 3 times that of verticinone.
Based on the studies of pharmacology and acute toxicity, the salt has a synergic and attenuated toxicity compared with single verticinone and cholic acid. Moreover, the present study also suggests that Ver—CA, a potential novel antitussive agent, may exert its antitussive effect via both the peripheral (modulated by ATP-sensitive K+ channels) and central mechanisms (modulated by the opioid receptor).
Schappert SM . Ambulatory care visits to physician offices, hospital outpatient departments, and emergency departments: United States, 1995. Vital Health Stat 13. 1997; 129: 1–38.
Dicpinigaitis PV . Potential new cough therapies. Pulm Pharmacol Ther 2004; 17: 459–62.
Yuan R, Lin Y . Traditional Chinese medicine: an approach to scientific proof and clinical validation. Pharmacol Ther 2000; 86: 191–8.
Jia W, Gao WY, Yan YQ, Wang J, Xu ZH, Zheng WJ, et al. The rediscovery of ancient Chinese herbal formulas. Phytothe Res 2004; 18: 681–6.
Lin G, Li P, Li SL, Chan SW . Chromatographic analysis of Fritillaria isosteroidal alkaloids, the active ingredients of Beimu, the antitussive traditional Chinese medicinal herb. J Chromatogr A 2001; 935: 321–38.
Qian BC, Xu HJ . Studies on the antitussive and sedative activities of peimine and peiminine. Acta Pharm Sin 1985; 20: 306–8. Chinese.
Yeh YH, Wang DY, Liau MY, Wu ML, Deng JF, Noguchi T, et al. Bile acid composition in snake bile juice and toxicity of snake bile acids to rats. Comp Biochem Phys C 2003; 136: 277–84.
Wei XC . Determination of the contents of verticinone in Shedan–Chuanbei powder. J Chin Med Meter 1999; 22: 420–1. Chinese.
Wu WY . Determination of the contents of taurocholate in Shedan-Chuanbei powder. J Chin Med Meter 1998; 21: 419–20. Chinese.
Forsberg K, Karlsson JA, Theodorsson E, Lundberg JM, Persson CGA . Cough and bronchoconstriction mediated by capsaicin-sensitive sensory neurons in the guinea-pig. Pulm Pharmacol 1988; 1: 33–9.
Bliss CI . The calculation of the dosage-mortality curve. Ann Appl Biol 1935; 22: 134–67.
Adcock JJ, Schneider C, Smith TW . Effects of codeine, morphine and a novel opioid pentapeptide BW443C, on cough, nociception and ventilation in the unanaesthetized guinea pig. Br J Pharmacol 1988; 93: 93–100.
Hu XM, Shi CZ . A preliminary pharmacodynamic study on the preparation of artificial Fel Serpentis and Bulbus Fritiliariae Cirrhosae. Tradit Chin Drug Res Clin Pharmacol 2001; 12: 95–7. Chinese.
Zhao RY, Fan CF, Fan XD . Experimental pharmacodynamic study of Bear Gall and bulbs of Fritillariae Ussuriensis oral liquid. Chin J Tradit Med Sci Tech 1999; 6: 151–3. Chinese.
Zhang P . A preclinical pharmaceutical research of the total alkaloids from bulbs of Fritillaria hupehensis and its preparation [PhD Dissertation]. Wuhan: Tongji Medical College, Huazhong University of Science and Technology; 2006. Chinese.
Gallico L, Borghi PJ, Dalla RC, Ceserani R, Tognella S . Moguisteine: a novel peripheral non–narcotic antitussive drug. Br J Pharmacol 1994; 112: 795–800.
Morikawa T, Gallico L, Widdicombe JG . Actions of moguisteine on cough and pulmonary rapidly adapting receptor activity in the guinea pig. Pharmacol Res 1997; 35: 113–8.
Morita K, Kamei J . Involvement of ATP-sensitive K+ channels in the antitussive effect of moguisteine. Eur J Pharmacol 2000; 395: 161–4.
Gordon R, Gordon RJ, Sofia D . Antitussive activity of some naturally occurring cannabinoids in anesthetized cats. Eur J Pharmcol 1976; 35: 309–13.
Baekey DM, Morris K, Gestreau C, Li Z, Lindsey B, Shannon R . Medullary respiratory neurones and control of laryngeal motoneurones during fictive eupnoe and cough in the cat. J Physiol 2001; 534: 565–81.
Project supported by the Fund of the Key Project of the Education Ministry, China, 2006 and the Fund of the International Cooperation Project of Science and Technology, the Ministry of Science and Technology, China (China and Korea, No 2006DFA33210). The present study has been applied for patent in China (application No 200610019027.0).
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Xu, Fz., Chen, C., Zhang, Yh. et al. Synthesis and antitussive evaluation of verticinone-cholic acid salt, a novel and potential cough therapeutic agent. Acta Pharmacol Sin 28, 1591–1596 (2007). https://doi.org/10.1111/j.1745-7254.2007.00179.x
- verticinone-cholic acid salt
- Shedan-Chuanbei powder
- cholic acid
- antitussive effect
- ATP-sensitive K+ channels