Phase I clinical trial to evaluate the safety and pharmacokinetics of capsule formulation of the standardized extract of Atractylodes lancea

10.1016/j.jtcme.2021.02.002

Kesara Na-Bangchang；Inthuorn Kulma；Tullayakorn Plengsuriyakarn；Thipaporn Tharavanij；Kanawut Kotawng；Anurak Chemung；Nadda Muhamad；Juntra Karbwang

Safety ； Pharmacokinetics ； Atractylodin ； Atractylodes lancea ； Phase I clinical trial

Journal of Traditional and Complementary Medicine

11卷4期（2021 / 07 / 01）

343 - 355

英文

Background and aim: Atractylodes lancea (AL) has been demonstrated in a series of studies to be a potential candidate for the treatment of cholangiocarcinoma. The aim of the current study was to evaluate the safety and pharmacokinetics of the capsule formulation of the standardized AL extract in healthy Thai participants. Experimental procedure: Forty-eight healthy Thai participants who fulfilled the inclusion and had none of the exclusion criteria were allocated to two study groups. The group 1 participants were randomized to receive a single oral dose of 1,000 mg of AL or placebo (20:4 participants). The group 2 participants were randomized to receive daily oral doses of 1,000 mg AL or placebo daily for 21 days (20:4 participants). Safety and tolerability of the two AL regimens were monitored. Blood samples were collected for measurement of atractylodin concentrations by HPLC and pharmacokinetic analysis was performed using model-dependent and model-independent analysis. Results and conclusion: The AL extract was well tolerated in both groups. Atractylodin was rapidly absorbed but with low systemic exposure and residence time. There was no difference in the pharmacokinetic parameters of atractylodin following a single or multiple dosing, suggesting the absence of accumulation and dose-dependency in human plasma after continuous dosing for 21 days. The information on human pharmacokinetics of AL, when given as capsule formulation of the standardized extract, would assist in further dose optimization in cholangiocarcinoma patients with the defined pharmacokinetic-pharmacodynamic relationship.

1. Thongchot, S,Thanee, M,Loilome, W(2019).Curative effect of xanthohumol supplementation during liver fluke-associated cholangiocarcinogenesis: potential involvement of autophagy.J Tradit Complement Med,10(3),230-235.
   連結：
2. Chang, WX,Xu, CX,Liu, YQ,Qian, C(2016).Determination and pharmacokinetic comparisons of atractylodin after oral administration of crude and processed Atractyldon rhizome.Phcog Mag,12(45),80-83.
3. Chiou, LC,Chang, CC(1992).Antagonism by beta-eudesmol of neostigmine-induced neuromuscular failure in mouse diaphragms.Eur J Pharmacol,216(2),199-206.
4. Doherty, B,Nambudiri, VE,Palmer, WC(2017).Update on the diagnosis and treatment of cholangiocarcinoma.Curr Gastroenterol Rep,19(1),2-10.
5. Gibaldi, M(1991).Biopharmaceutics and Clinical Pharmacokinetics.UK:Lea and Febiger.
6. Itthipanichpong, R,Lupreechaset, A,Chotewuttakorn, S(2010).Effect of Ayurved Siriraj herbal recipe Chantaleela on platelet aggregation.J Med Assoc Thai,93(1),115-122.
7. Jiang, L,Zhang, C,Li, H(2017).Quantification of b-eudesmol in rat plasma using LC-MS/MS and its application to a pharmacokinetic study.Biomed Chromatogr,31,e4023.
8. Jun, X,Fu, P,Lei, Y,Cheng, P(2018).Pharmacological efects of medicinal components of Atractylodes lancea (Thunb) DC.Chin Med,13,59.
9. Kamiyama, H,Takano, S,Ishikawa, E,Tsuboi, K,Matsumura, A(2005).Anti-angiogenic and immunomodulatory effect of the herbal medicine “Juzen-taiho-to” on malignant glioma.Biol Pharm Bull,28(11),2111-2116.
10. Kamsa-ard, S,Luvira, V,Suwanrungruang, K(2019).Cholangiocarcinoma trends, incidence, and relative survival in Khon Kaen, Thailand from 1989 through 2013: a population-based cancer registry study.J Epidemiol,29(5),197-204.
11. Khan, SA,Tavolari, S,Brandi, G(2019).Cholangiocarcinoma: epidemiology and risk factors.Liver Int,39(1),19-31.
12. Kimura, M,Diwan, PV,Yanagi, S,Kon-no, Y,Kimura, I(1995).Potentiating effects of beta-eudesmol-related cyclohexylidene derivatives on succinylcholine-induced neuromuscular block in isolated phrenic nerve-diaphragm muscles of normal and alloxan-diabetic mice.Biol Pharm Bull,18(3),407-410.
13. Kitagawa, H,Munekage, M,Ichikawa, K(2015).Pharmacokinetics of active components of Yokukansan, a Traditional Japanese herbal medicine after a single oral administration to healthy Japanese volunteers: a cross over, randomized study.PloS One
14. Koonrungsesomboon, N,Na-Bangchang, K,Karbwang, J(2014).Therapeutic potential and pharmacological activities of Atractylodes lancea (Thunb) DC.Asian Pac J Trop Med,7(6),421-428.
15. Liu, Y,Jia, Z,Dong, L,Wang, R,Qiu, G(2008).A randomized pilot study of atractylenolide I on gastric cancer cachexia patients.Evid Based Complement Alternat Med,5(3),337-344.
16. Martviset, P,Chaijaroenkul, W,Muhamad, P,Na-Bangchang, K(2018).Bioactive constituents isolated from Atractylodes lancea (Thunb.) DC. rhizome exhibit synergistic effect against cholangiocarcinoma cell.J Exp Pharmacol,10,59-64.
17. Muroi, M,Tanaka, K,Kimura, I,Kimura, M(1989).beta-eudesmol (a main component of Atractylodes lancea)-induced potentiation of depolarizing neuromuscular blockade in diaphragm muscles of normal and diabetic mice.Jpn J Pharmacol,50(1),69-71.
18. Na-Bangchang, K,Plengsuriyakarn, T,Karbwang, J(2017).Research and development of Atractylodes lancea (Thunb) DC. as a promising candidate for cholangiocarcinoma chemotherapeutics.Evid Based Complement Alternat Med
19. Naranjo, CA,Busto, U,Sellers, EM(1981).A method for estimating the probability of adverse drug reactions.Clin Pharmacol Ther,30(2),239-245.
20. Nasu, Y,Iwashita, M,Saito, M,Fushiya, S,Nakahata, N(2009).Inhibitory effects of Atractylodis lanceae rhizoma and Poria on collagen- or thromboxane A2-induced aggregation in rabbit platelets.Biol Pharm Bull,32(5),856-860.
21. Nojima, H,Kimura, I,Kimura, M(1992).Blocking action of succinylcholine with beta-eudesmol on acetylcholine-activated channel activity at endplates of single muscle cells of adult mice.Brain Res,575(2),337-340.
22. Perez-Montoyo, H.(2020).Therapeutic potential of autophagy modulation in chol-angiocarcinoma.Cells,9(3),614-633.
23. Plengsuriyakarn, T,Karbwang, J,Na-Bangchang, K(2015).Anticancer activity using positron emission tomography-computed tomography and pharmacokinetics of b-eudesmol in human cholangiocarcinoma xenografted nude mouse model.Clin Exp Pharmacol Physiol,42(3),293-304.
24. Plengsuriyakarn, T,Viyanant, V,Eursitthichai, V(2012).Anticancer activities against cholangiocarcinoma, toxicity and pharmacological activities of Thai medicinal plants in animal models.BMC Compl Alternative Med,12
25. Rattanathada, T,Cheoymang, A,Asasujarit, R,Plengsuriyakarn, T,Na-Bangchang, K(2020).Development of oral pharmaceutical formulation of standardized crude ethanolic extract of Atractylodes lancea (Thunb) DC.J Chin Pharmaceut Sci.,29(4),280-293.
26. Resch, M,Steigel, A,Chen, Z,Bauer, R(1998).5-Lipoxygenase and cyclooxygenase-1 inhibitory active compounds from Atractylodes lancea.J Nat Prod,61(3),347-350.
27. Sripa, B,Bethony, JM,Sithithaworn, P(2011).Opisthorchiasis and Opisthorchis-associated cholangiocarcinoma in Thailand and Laos.Acta Trop,120(1),S158-S168.
28. Thongchot, S,Ferraresi, A,Vidoni, C(2018).Resveratrol interrupts the pro-invasive communication between cancer associated fibroblasts and cholangiocarcinoma cells.Canc Lett,430,160-171.
29. Thongchot, S,Utaijaratrasmi, P,Jamjantra, P(2020).Interleukin-6 and hepatocyte growth factor produce from chromosomal abberant cholangiocarcinoma-associated fibroblasts.Genom Gen,13(2&3),33-43.
30. U.S. Department of Health and Human Services F, and Drug Administration aCfDEa, (CDER) R(2005).U.S. Department of Health and Human Services F, and Drug Administration aCfDEa, (CDER) R. Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteer. Guidance for Industry. 2005..
31. US National Cancer Institute(2003).US National Cancer Institute. Cancer Therapy Evaluation Program. Common toxicity criteria, version 4. 2003..
32. Wang, CC,Lin, SY,Cheng, HC,Hou, WC(2006).Pro-oxidant and cytotoxic activities of atractylenolide I in human promyeloleukemic HL-60 cells.Food Chem Toxicol,44(8),1308-1315.
33. Wang, GT(1990).Treatment of operated late gastric carcinoma with prescription of strengthening the patient’s resistance and dispelling the invading evil in combination with chemotherapy: follow-up study of 158 patients and experimental study in animals.Zhong Xi Yi Jie He Za Zhi,10(12),712-716.
34. Xiao-Wen, C,Chen-Xi, X,Yu-Qiang, L,Cai, Q(2016).Determination and pharmacokinetic comparisons of atractylodin after oral administration of crude and processed Atractylodis rhizome.Phcog Mag,12(45),80-83.
35. Zhang, Y,Zhimin, W,Jingjing, Z,Bo, C(2012).Determination of atractylodin in rat plasma by HPLC-UV method and its application to a pharmacokinetic Study.J Liq Chromatogr Relat Technol,35(6),778-787.