Safety and tolerability of an antiasthma herbal Formula (ASHMI) in adult subjects with asthma: a randomized, double-blinded, placebo-controlled, dose-escalation phase I study

Abstract

Background: Complementary and alternative medicines are increasingly used for the treatment of asthma in Western countries. A novel three-herb antiasthma herbal medicine intervention (ASHMI; Sino-Lion Pharmaceutical Company; Shan Dong China) was demonstrated to be effective and safe in a murine model of asthma and in a preliminary clinical study in China.

Objective: The objective of this study was to evaluate the safety and tolerability of ASHMI in adult subjects with allergic asthma.

Design: Randomized, double-blind, placebo-controlled, dose escalation, phase I trial aimed at developing a botanical drug under the United States Food and Drug Administration Investigational New Drug title.

Interventions: Subjects received one of three doses of ASHMI or placebo: 600 mg (2 capsules); 1200 mg (4 capsules); or 1800 mg (6 capsules) twice daily for 1 week. Four (4) ASHMI and 2 placebo subjects were treated at each dose level. Subjects continued to use their conventional asthma medications for the duration of the study.

Outcome measures: Vital signs, physical examination, laboratory data, and electrocardiogram data were monitored throughout the study to assess occurrence of adverse events (AEs). Immunomodulatory studies were performed to evaluate the effect of ASHMI on cytokine, chemokine, and growth factor levels.

Results: Twenty (20) nonsmoking, allergic subjects with asthma were included in the study. Eight (8) subjects (4 ASHMI and 4 placebo) reported mild gastrointestinal symptoms. No grade 3 AEs were observed during the study period. Vital signs, electrocardiogram findings, and laboratory results obtained at pre- and post-treatment visits remained within normal range. No abnormal immunologic alterations were detected.

Conclusion: In this phase I study, ASHMI appeared to be safe and well tolerated by subjects with asthma. These findings allowed initiation of a larger phase II study to assess the efficacy of ASHMI.

FIG. 1.

Samples of raw herb materials used in ASHMI^™ (Sino-Lion Pharmaceutical Company, Shan Dong, China).

FIG. 2.

High-pressure liquid chromatography (HPLC) chromatogram of individual herbs and ASHMI^™ (Sino-Lion Pharmaceutical Company, Shan Dong, China) product: A–C: HPLC fingerprints of individual herbs. D: The HPLC fingerprint of ASHMI. HPLC conditions: column, Agilent Zorbax SB-C₁₈ column (150×4.6 mm i.d.; 5 μm particle size); flow rate, 1mL/minute; wavelength, 254 nm; column temperature, 27°C; mobile phase A, 0.15% H₃PO₄, mobile phase B, acetonitrile. Data were processed using Waters Empower software.

FIG. 3.

Levels of various cytokines, chemokines, growth factors, adhesions molecules, and receptors in serum samples pre- and post-treatment with ASHMI^™ (Sino-Lion Pharmaceutical Company, Shan Dong, China) (N = 4) or placebo (N = 3). Peripheral blood samples for immunologic studies were obtained from some participants and evaluated using 23- and 27- Plex Bio-Plex human cytokine assays. Of the 50 analytes tested, 41 were within the detectable range, and these are divided into cytokines (A), chemokines (B), growth factors (C), and adhesion molecules and receptors (D). IL-1a, 1b, 4, 5, 7, 10, 12 (p70), 17, and TNF-β levels were below the detection range and hence not shown in the graphs. IL, interleukin; r, receptor; G, growth; CSF, colony-stimulating factor; GM, granulocyte macrophage; IFN, interferon; LIF, leukemia inhibitory factor; M, macrophage; MIF, macrophage migration inhibitory factor; TNF, tumor necrosis factor; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; CTACK, cutaneous T-cell attracting chemokine; GRO, growth-regulated protein; IP, interferon-γ inducible protein; MCP, macrophage chemoattractant protein; MCAF, monocyte chemotactic and activating factor; MIG, monokine-induced interferon gamma; MIP, macrophage inflammatory protein; RANTES, regulated on activation, normal T expressed and secreted; SDF, stromal cell derived factor; NGF, nerve growth factor; FGF, fibroblast growth factor; HGF, hepatocyte growth factor; PDGF platelet derived growth factor; SCF, stem cell factor; SCGF, stem cell growth factor; VEGF, vascular endothelial growth factor; ICAM, intercellular adhesion molecule; VCAM, vascular cell adhesion molecule.