The safety and tolerability of alkaloids from Alstonia scholaris leaves in healthy Chinese volunteers: a single-centre, randomized, double-blind, placebo-controlled phase I clinical trial

References

• China Food and Drug Administration. 2003. The guideline for good clinical practice. Beijing (China): National Medical Products Administration.
   Google Scholar
• China Food and Drug Administration. 2015. Guidelines for the clinical research of Chinese medicine new drugs. Beijing (Chian): National Medical Products Administration. Chinese
   Google Scholar
• International Conference on Harmonization. 2002. E1-E10 International Conference on Harmaonisation of technical requirements for registration of pharmaceuticals for human use ICH harmonised tripartite guideline. Washington DC: The European Medicines Agency; p. 69–72.
   Google Scholar
• Cai XH, Bao MF, Zhang Y, Zeng CX, Liu YP, Luo XD. 2011. A new type of monoterpenoid indole alkaloid precursor from Alstonia rostrata. Org Lett. 13(14):3568–3571.
   PubMed Web of Science ®Google Scholar
• Cai XH, Du ZZ, Luo XD. 2007. Unique monoterpenoid indole alkaloids from Alstonia scholaris. Org Lett. 9(9):1817–1820.
   PubMed Web of Science ®Google Scholar
• Cai XH, Liu YP, Feng T, Luo XD. 2008. Picrinine-type alkaloids from the leaves of Alstonia scholaris. Chin J Nat Med. 6(1):20–22.
   Google Scholar
• Cai XH, Shang JH, Feng T, Luo XD. 2010. Novel alkaloids from Alstonia scholaris. Z Naturforsch B. 65(9):1164–1168.
   Google Scholar
• Cai XH, Tan QG, Liu YP, Feng T, Du ZZ, Li WQ, Luo XD. 2008. A cage-monoterpene indole alkaloid from Alstonia scholaris. Org Lett. 10(4):577–580.
   PubMed Web of Science ®Google Scholar
• Cao J, Shen HM, Wang Q, Qian Y, Guo HC, Li K, Qiao X, Guo DA, Luo XD, Ye M. 2016. Characterization of chemical constituents and rats metabolites of an alkaloidal extract of Alstonia scholaris leaves by liquid chromatography coupled with mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 1026:43–55.
   PubMed Web of Science ®Google Scholar
• Chen YY, Yang J, Yang XW, Khan A, Liu L, Wang B, Zhao YL, Liu YP, Ding ZT, Luo XD. 2016. Alstorisine A, a nor-monoterpenoid indole alkaloid from cecidogenous leaves of Alstonia scholaris. Tetrahedron Lett. 57(16):1754–1757.
   Web of Science ®Google Scholar
• Du GS, Cai XH, Shang JH, Luo XD. 2007. Non-alkaline constituents from leaf of Alstonia scholaris. Chin J Nat Med. 5:259–262.
   Google Scholar
• Du GS, Shang JH, Cai XH, Luo XD. 2007. Antitussive constituents from roots of Alstonia scholaris (Apocynaceae). Acta Bot Yunnanica. 29:365–366.
   Google Scholar
• Feng T, Cai XH, Du ZZ, Luo XD. 2008. Iridoids from the bark of Alstonia scholaris. HCA. 91(12):2247–2251.
   Web of Science ®Google Scholar
• Feng T, Cai XH, Zhao PJ, Du ZZ, Li WQ, Luo XD. 2009. Monoterpenoid indole alkaloids from the bark of Alstonia scholaris. Planta Med. 75(14):1537–1541.
   PubMed Web of Science ®Google Scholar
• Hill RA, Sutherland A. 2007. Hot off the press. Nat Prod Rep. 24(3):500–503.
   Google Scholar
• Hill RA, Sutherland A. 2008. Hot off the press. Nat Prod Rep. 25:220–226.
   PubMed Web of Science ®Google Scholar
• Hill RA, Sutherland A. 2011. Hot off the press. Nat Prod Rep. 28(10):1621–1625.
   Google Scholar
• Hill RA, Sutherland A. 2014. Hot off the press. Nat Prod Rep. 31(10):1242–1246.
   Google Scholar
• Hill RA, Sutherland A. 2015. Hot off the press. Nat Prod Rep. 32(2):111–115.
   Google Scholar
• Hill RA, Sutherland A. 2016a. Hot off the press. Nat Prod Rep. 33(4):530–534.
   Google Scholar
• Hill RA, Sutherland A. 2016b. Hot off the press. Nat Prod Rep. 33(2):122–126.
   Google Scholar
• Hou YY, Cao XL, Dong LY, Wang LQ, Cheng BF, Shi Q, Luo XD, Bai G. 2012. Bioactivity-based liquid chromatography-coupled electrospray ionization tandem ion trap/time of flight mass spectrometry for β2AR agonist identification in alkaloidal extract of Alstonia scholaris. J Chromatogr A. 1227:203–209.
   PubMed Web of Science ®Google Scholar
• Hou YY, Cao XL, Wang LQ, Cheng BF, Dong LY, Luo XD, Bai G, Gao WY. 2012. Microfractionation bioactivity-based ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry for the identification of nuclear factor-κB inhibitors and β2 adrenergic receptor agonists in an alkaloidal extract of the folk herb Alstonia scholaris. J Chromatogr B Analyt Technol Biomed Life Sci. 908:98–104.
   PubMed Web of Science ®Google Scholar
• Li PT, Leeuwenberg AJM, Middleton DJ. 1996. Apocynaceae. Flora of China. 16:143–163.
   Google Scholar
• Li R, Zi MJ, Gou ZP, Zhao YL, Zhang WT, Lu F, Cao WY, Zhao YP, Li QN, Zhao Y, et al. 2019. Pharmacokinetics and safety evaluation in healthy Chinese volunteers of alkaloids from leaf of Alstonia scholaris, a multiple doses phase I clinical trial. Phytomedicine. 61:152813–152828.
   PubMed Web of Science ®Google Scholar
• Liu L, Chen YY, Qin XJ, Wang B, Jin Q, Liu YP, Luo XD. 2015. Antibacterial monoterpenoid indole alkaloids from Alstonia scholaris cultivated in temperate zone. Fitoterapia. 105:160–164.
   PubMed Web of Science ®Google Scholar
• Liu YP, Lai R, Yao YG, Zhang ZK, Pu ET, Cai XH, Luo XD. 2013. Induced furoeudesmanes: a defense mechanism against stress in Laggera pterodonta, a Chinese herbal plant. Org Lett. 15(19):4940–4943.
   PubMed Web of Science ®Google Scholar
• Pan ZQ, Qin XJ, Liu YP, Wu T, Luo XD, Xia CF. 2016. Alstoscholarisines H-J, indole alkaloids from Alstonia scholaris: structural evaluation and bioinspired synthesis of alstoscholarisine H. Org Lett. 18(4):654–657.
   PubMed Web of Science ®Google Scholar
• Penel N, Kramar A. 2012. What does a modified-Fibonacci dose-escalation actually correspond to? BMC Med Res Methodol. 12:103–107.
   PubMed Web of Science ®Google Scholar
• Qin XJ, Zhao YL, Lunga PK, Yang XW, Song CW, Cheng GG, Liu L, Chen YY, Liu YP, Luo XD. 2015. Indole alkaloids with antibacterial activity from aqueous fraction of Alstonia scholaris. Tetrahedron. 71(25):4372–4378.
   Web of Science ®Google Scholar
• Qin XJ, Zhao YL, Song CW, Wang B, Chen YY, Liu L, Li Q, Li D, Liu YP, Luo XD. 2015. Monoterpenoid indole alkaloids from inadequately dried leaves of Alstonia scholaris. Nat Prod Bioprospect. 5(4):185–193.
   PubMed Web of Science ®Google Scholar
• Shang JH, Cai XH, Feng T, Zhao YL, Wang JK, Zhang LY, Yan M, Luo XD. 2010. Pharmacological evaluation of Alstonia scholaris: anti-inflammatory and analgesic effects. J Ethnopharmacol. 129(2):174–181.
   PubMed Web of Science ®Google Scholar
• Shang JH, Cai XH, Zhao YL, Feng T, Luo XD. 2010. Pharmacological evaluation of Alstonia scholaris: anti-tussive, anti-asthmatic and expectorant activities. J Ethnopharmacol. 129(3):293–298.
   PubMed Web of Science ®Google Scholar
• World Medical Association Declaration of Helsinki. 2013. Recommendations guiding medical doctors in biomedical research involving human subjects. Fortaleza (Brazil): World Medical Association.
   Google Scholar
• Xu Y, Feng T, Cai XH, Luo XD. 2009. A new C13-norisoprenoid from leaves of Alstonia scholaris. Chin J Nat Med. 7(1):21–23.
   Google Scholar
• Yamauchi T, Abe F, Chen RF, Nonaka GI, Santisuk T, Padolina WG. 1990. Alkaloids from the leaves of Alstonia scholaris in Taiwan, Thailand, Indonesia and the Philippines. Phytochemistry. 29(11):3547–3552.
   Web of Science ®Google Scholar
• Yang KF, Zhao YL. 2013. [Study on the lowest effective dose of Alstonia scholaris (L.) R. Br. for anti-tussive and anti-asthmatic effects in guinea pigs]. Yunnan J of Trad Chinese Med Materia Med. 34:58–59. Chinese
   Google Scholar
• Yang XW, Luo XD, Lunga PK, Zhao YL, Qin XJ, Chen YY, Liu L, Li XN, Liu YP. 2014. Scholarisines H-O, novel indole alkaloid derivatives from long-term stored Alstonia scholaris. Tetrahedron. 71(22):3694–3698.
   Web of Science ®Google Scholar
• Yang XW, Qin XJ, Zhao YL, Lunga PK, Li XN, Jiang SZ, Cheng GG, Liu YP, Luo XD. 2014. Alstolactines A-C, novel monoterpenoid indole alkaloids from Alstonia scholaris. Tetrahedron Lett. 55(33):4593–4596.
   Web of Science ®Google Scholar
• Yang XW, Song CW, Zhang Y, Khan A, Jiang LP, Chen YB, Liu YP, Luo XD. 2015. Alstoscholarisines F and G, two unusual monoterpenoid indole alkaloids from the leaves of Alstonia scholaris. Tetrahedron Lett. 56(48):6715–6718.
   Web of Science ®Google Scholar
• Yang XW, Yang CP, Jiang LP, Qin XJ, Liu YP, Shen QS, Chen YB, Luo XD. 2014. Indole alkaloids with new skeleton activating neural stem cells. Org Lett. 16(21):5808–5811.
   PubMed Web of Science ®Google Scholar
• Zhang ZY, Luo XD, Li S. 2014. Comparative genetic and chemical profiling performed on Alstonia scholaris in China and its implications to standardization of traditional Chinese medicine. J Med Plants Res. 8:301–306.
   Google Scholar
• Zhao YL, Cao J, Shang JH, Liu YP, Khan A, Wang HS, Qian Y, Liu L, Ye M, Luo XD. 2017. Airways antiallergic effect and pharmacokinetics of alkaloids from Alstonia scholaris. Phytomedicine. 27:63–72.
   PubMed Web of Science ®Google Scholar
• Zhao YL, Gou ZP, Shang JH, Li WY, Kuang Y, Li MY, Luo XD. 2021. Anti-microbial effects in vitro and in vivo of Alstonia scholaris. Nat Prod Bioprospect. DOI:10.1007/s13659-020-00294-6.
   Web of Science ®Google Scholar
• Zhao YL, Pu SB, Qi Y, Wu BF, Shang JH, Liu YP, Hu D, Luo XD. 2021. Pharmacological effects of indole alkaloids from Alstonia scholaris (L.) R. Br. on pulmonary fibrosis in vivo. J Ethnopharmacol. 267:113506..
   PubMed Web of Science ®Google Scholar
• Zhao YL, Shang JH, Pu SB, Wang HS, Wang B, Liu L, Liu YP, Mei SH, Luo XD. 2016. Effect of total alkaloids from Alstonia scholaris on airway inflammation in rats. J Ethnopharmacol. 178:258–265.
   PubMed Web of Science ®Google Scholar
• Zhao YL, Su M, Shang JH, Wang X, Bao GL, Ma J, Sun QD, Yuan F, Wang JK, Luo XD. 2020a. Genotoxicity and safety pharmacology studies of indole alkaloids extract from leaves of Alstonia scholaris (L.) R. Br. Nat Prod Bioprospect. 10(3):119–129.
   PubMed Web of Science ®Google Scholar
• Zhao YL, Su M, Shang JH, Wang X, Bao GL, Ma J, Sun QD, Yuan F, Wang JK, Luo XD. 2020b. Acute and sub-chronic toxicity of indole alkaloids extract from leaves of Alstonia scholaris (L.) R. Br. in beagle dogs. Nat Prod Bioprospect. 10(4):209–220.
   PubMed Web of Science ®Google Scholar
• Zhao YL, Su M, Shang JH, Wang X, Njateng GSS, Bao GL, Ma J, Sun QD, Yuan F, Wang JK, et al. 2020. Acute and chronic toxicity of indole alkaloids from leaves of Alstonia scholaris (L.) R. Br. in mice and rats. Nat Prod Bioprospect. 10(2):77–88.
   PubMed Web of Science ®Google Scholar
• Zhao YL, Yang ZF, Shang JH, Huang WY, Wang B, Wei X, Khan A, Yuan ZW, Liu YP, Wang YF, et al. 2018. Effects of indole alkaloids from leaf of Alstonia scholaris on post-infectious cough in mice. J Ethnopharmacol. 218:69–75.
   PubMed Web of Science ®Google Scholar
• Zhao YL, Yang ZF, Wu BF, Shang JH, Liu YP, Wang XH, Luo XD. 2020. Indole alkaloids from leaves of Alstonia scholaris (L.) R. Br. protect against emphysema in mice. J Ethnopharmacol. 259:112949.
   PubMed Web of Science ®Google Scholar
• Zhou H, He HP, Luo XD, Wang YH, Yang XW, Di YT, Hao XJ. 2005. Three new indole alkaloids from the leaves of Alstonia scholaris. HCA. 88(9):2508–2512.
   Web of Science ®Google Scholar