AUTHOR=Cao Wei-Yi , Liu Jun-Yu , Sun Min , Wang Jing-Kun , Lu Fang , Yang Qiao-Ning , Zhang Wan-Tong , Zi Ming-Jie , Zhang Bai-E , Liu Hong-Bin , Wang Shu-Ge , Wu Yi , Wu Rong-Zu , Wu Wen-Di , Li Rui , Zhu Zhao-Yun , Gao Rui 

TITLE=Pharmacokinetics, safety, and efficacy of Fuqi Guben Gao in the treatment of kidney-yang deficiency syndrome: a randomized, double-blind phase I trial

JOURNAL=Frontiers in Pharmacology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1351871

DOI=10.3389/fphar.2024.1351871

ISSN=1663-9812

ABSTRACT=<p><bold>Introduction:</bold> Fuqi Guben Gao (FQGBG) is a botanical drug formulation composed of FuZi (FZ; <italic>Aconitum carmichaelii</italic> Debeaux [Ranunculaceae; Aconiti radix cocta]), Wolfberry (<italic>Lycium barbarum</italic> L. [Solanaceae; Lycii fructus]), and Cinnamon (<italic>Neolitsea cassia</italic> (L.) Kosterm. [Lauraceae; Cinnamomi cortex]). It has been used to clinically treat nocturia caused by kidney-yang deficiency syndrome (KYDS) for over 30 years and warms kidney yang. However, the pharmacological mechanism and the safety of FQGBG in humans require further exploration and evaluation.</p><p><bold>Methods:</bold> We investigated the efficacy of FQGBG in reducing urination and improving immune organ damage in two kinds of KYDS model rats (hydrocortisone-induced model and natural aging model), and evaluated the safety of different oral FQGBG doses through pharmacokinetic (PK) parameters, metabonomics, and occurrence of adverse reactions in healthy Chinese participants in a randomized, double-blind, placebo-controlled, single ascending dose clinical trial. Forty-two participants were allocated to six cohorts with FQGBG doses of 12.5, 25, 50, 75, 100, and 125 g. The PKs of FQGBG in plasma were determined using a fully validated LC-MS/MS method.</p><p><bold>Results:</bold> FQGBG significantly and rapidly improved the symptoms of increased urination in both two KYDS model rats and significantly resisted the adrenal atrophy in hydrocortisone-induced KYDS model rats. No apparent increase in adverse events was observed with dose escalation. Major adverse drug reactions included toothache, thirst, heat sensation, gum pain, diarrhea, abdominal distension, T-wave changes, and elevated creatinine levels. The PK results showed a higher exposure level of benzoylhypaconine (BHA) than benzoylmesaconine (BMA) and a shorter half-life of BMA than BHA. Toxic diester alkaloids, aconitine, mesaconitine, and hypaconitine were below the lower quantitative limit. Drug-induced metabolite markers primarily included lysophosphatidylcholines, fatty acids, phenylalanine, and arginine metabolites; no safety-related metabolite changes were observed.</p><p><bold>Conclusion:</bold> Under the investigated dosing regimen, FQGBG was safe. The efficacy mechanism of FQGBG in treating nocturia caused by KYDS may be related to the improvement of the hypothalamus-pituitary-adrenal axis function and increased energy metabolism.</p><p><bold>Clinical Trial Registration:</bold><ext-link ext-link-type="uri" xlink:href="https://www.chictr.org.cn/showproj.html?proj=26934" xmlns:xlink="http://www.w3.org/1999/xlink">https://www.chictr.org.cn/showproj.html?proj=26934</ext-link>, identifier ChiCTR1800015840.</p>