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

Introduction: Fuqi Guben Gao (FQGBG) is a botanical drug formulation composed of FuZi (FZ; Aconitum carmichaelii Debeaux [Ranunculaceae; Aconiti radix cocta]), Wolfberry (Lycium barbarum L. [Solanaceae; Lycii fructus]), and Cinnamon (Neolitsea cassia (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. Methods: 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. Results: 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. Conclusion: 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. Clinical Trial Registration: https://www.chictr.org.cn/showproj.html?proj=26934, identifier ChiCTR1800015840.

Predictive factors and clinical efficacy of Chinese medicine Shengji ointment in the treatment of diabetic foot ulcers in the elderly: a prospective study.

Objective: This study aims to investigate the predictive factors and efficacy of traditional Chinese medicine Shengji Ointment in the treatment of diabetic foot ulcers in the elderly population, with the intent of formulating an effective predictive model for deep diabetic foot ulcer healing. The importance of this research lies in its provision of new perspectives and tools for addressing the severe health impact of diabetic foot ulcers in the elderly population, considering the complexity and diversity of its treatment methods. Methods: The study includes 180 elderly patients with Wagner grade 3-4 diabetic foot ulcers that involve the tendon or fascia. The dependent variable is the initiation time of granulation tissue development. Independent variables encompass demographic information, a treatment strategy including Shengji Ointment, pre-treatment trauma assessment data, routine blood count, and biochemical index test results. Lasso regression is employed for variable selection, and Cox regression is utilized for the construction of a prediction model. A nomogram is generated to authenticate the model. Results: The Chinese Medicine treatment approach, ulcer location, creatinine levels, BMI, and haemoglobin levels are identified as independent predictors of granulation tissue development in diabetic foot ulcers. The combined treatment of Chinese herbal Shengji ointment and bromelain positively influenced granulation tissue development. The location of plantar ulcers, impaired renal functionality, obesity, and anaemia are established as independent risk factors that might influence the speed and probability of ulcer healing. The area under the time-dependent ROC curve fluctuates between 0.7 and 0.8, demonstrating substantial discrimination and calibration of the model. Conclusion: The study ascertains that a combined treatment strategy incorporating Shengji Ointment demonstrates greater effectiveness than the use of cleansing gel debridement alone in facilitating the healing of Wagner grade 3 or higher diabetic foot ulcers. Furthermore, the predictive model developed in this research serves as a valuable tool in evaluating the efficacy of Chinese Medicine treatments like Shengji Ointment for diabetic foot ulcers in the elderly. It aids clinicians in effectively assessing and adjusting treatment strategies, thereby proving its significant application value in clinical practice. Clinical Trial Registration: (https://www.chictr.org.cn/hvshowproject.html?id=73862&v=1.5&u_atoken=b403af53-d3b9-41ae-a7e2-db5498609b0c&u_asession=01tNh69p235bMUO4CmHIXcv8Hxirl5-557Duue9QB5lGfl3mf8IvPlcs2kN2zC30voX0KNBwm7Lovlpxjd_P_q4JsKWYrT3W_NKPr8w6oU7K_AyPrQhedMUWBMR2-ZDL_KO0uwDPR9XlF566xraDvT9mBkFo3NEHBv0PZUm6pbxQU&u_asig=05Kd_Q8fjv-24MVbZpOS9ef3xuCCN-tSVH5eUoJKgNLM7E0-n0zMpW6xLq9gh9aUhkKEEA15rdDoCydncF99APBwVSaTPgEG_V_B1iT4wimdCTxV_4ZVbTlDewxyQtE4YgU4-Oza7KPi94RJ64Utel0yZfqg3Tlm-bVxFNOY-zXFP9JS7q8ZD7Xtz2Ly-b0kmuyAKRFSVJkkdwVUnyHAIJzSYJ6SfhFl0WMTCCasZ7zV2I2qfyrp5m-SELPVeREKgX_6yRmLu26qT8kGfcS-Yaeu3h9VXwMyh6PgyDIVSG1W-7D_Sko5YQtpDbs3uvezYkZcUUY4o9-zDPaoYelmMDs8u7I4TPvtCXaPp44YUJcQ9bHr-_RmKA5V8nji3daArhmWspDxyAEEo4kbsryBKb9Q&u_aref=NNH1nHSUCE6pNvCilV%2F1MD0aERs%3D), identifier (ChiCTR2000039327).

The clinical population pharmacokinetics, metabolomics and therapeutic analysis of alkaloids from Alstonia scholaris leaves in acute bronchitis patients.

BACKGROUND: Capsule of alkaloids from leaf of Alstonia scholaris (CALAS) is a new investigational botanical drug (No. 2011L01436) for respiratory disease. Clinical population pharmacokinetics (PK), metabolomics and therapeutic data are essential to guide dosing in patients. Previous research has demonstrated the potential therapeutic effect of CALAS on acute bronchitis. Further clinical trial data are needed to verify its clinical efficacy, pharmacokinetics behavior, and influence of dosage and other factors. PURPOSE: To verify the clinical efficacy and explore the potential biomarkers related to CALAS treatment for acute bronchitis. MATERIALS AND METHODS: Oral CALAS was assessed in a randomized, double-blind, placebo-controlled trial. Fifty-five eligible patients were randomly assigned to four cohorts to receive 20, 40 or 80 mg, of CALAS three times daily for seven days, or placebo. Each CALAS cohort included 15 subjects, and the placebo group included 10 subjects. A population PK model of CALAS was developed using plasma with four major alkaloid components. Metabolomics analysis was performed to identify biomarkers correlated with the therapeutic effect of CALAS, and efficacy and safety were assessed based on clinical symptoms and adverse events. RESULTS: The symptoms of acute bronchitis were alleviated by CALAS treatment without serious adverse events or clinically significant changes in vital signs, electrocardiography or upper abdominal Doppler ultrasonography. Moreover, one compartment model with first-order absorption showed that an increase in aspartate transaminase will reduce the clearance (CL) of scholaricine, and picrinine CL was inversely proportional to body mass index, while 19-epischolaricine and vallesamine CL increased with aging. The serum samples from acute bronchitis patients at different time points were analyzed using UPLC-QTOF in combination with the orthogonal projection to latent structures-discriminant analysis, which indicated higher levels of lysophosphatidylcholines, lysophosphatidylethanolamines and amino acids with CALAS treatment than with placebo. CONCLUSION: This is the first study to evaluate the clinical efficacy and explored the potential biomarkers related to CALAS therapeutic mechanism of acute bronchitis by means of clinical trial combined the metabolomics study. This exploratory study provides a basis for further research on clinical efficacy and optimal dosing regimens based on pharmacokinetics behavior. Additional acute bronchitis patients and CALAS PK samples collected in future studies may be used to improve model performance and maximize its clinical value.

Pharmacokinetics and safety evaluation in healthy Chinese volunteers of alkaloids from leaf of Alstonia scholaris: A multiple doses phase I clinical trial.

BACKGROUND: Alstonia scholaris (Apocynaceae) was reported to be a rich source of indole alkaloids, which exhibited remarkably bioactivities. The leaf of A. scholaris has been used in 'dai' ethno-medicine for treatment of respiratory diseases, and the defined indole alkaloids from leaf of A. scholaris has been registered as investigational new botanical drug (No. 2011L01436) and was approved for phase I/II clinical trials by China Food and Drug Administration (CFDA). PURPOSE: The aim of the trial is to evaluate the safety and explore the relationship of dosing frequency and pharmacokinetics after oral administration of capsule of alkaloids from leaf of A. scholaris (CALAS) at different doses. METHODS: In this randomized, open-labelled, single-center clinical trial, the safety and pharmacokinetics of CALAS were assessed in eligible healthy Chinese volunteers after oral administration of different doses. Each volunteer (n = 10 per group) received single dose of CALAS from 20 mg, 40 mg, 80 mg to 120 mg orally. The pharmacokinetics of CALAS was investigated in healthy Chinese subjects' plasma by a fully-validated LC-MS/MS method. Safety was assessed biochemically and clinically throughout the study, and drug re-excitation research was conducted to verify the correlation between investigational product and minor adverse events. The trial was registered on August 26, 2015 (http://www.chictr.org.cn/showproj.aspx?proj=11736), number ChiCTR-IPR-15006976. RESULTS: 40 subjects completed the study, and as a result, vallesamine had the highest concentration in plasma of healthy volunteers, and the AUC exposure level in each compounds in turn is vallesamine > scholaricine > 19-epischolaricine > picrinine. For the safety evaluation of CALAS, two cases of minor adverse events were observed during the trial, but the drug re-excitation research indicated that these two adverse events were related to the individual's physiological variation. CONCLUSION: Pharmacokinetic characteristics of each ingredient showed different patterns. 19-epischolaricine, vallesamine and picrinine were match to the linear pharmacokinetic characteristics, but scholaricine conformed to the characteristics of nonlinear pharmacokinetics. The CALAS was safe in healthy subjects under the current dose regimen.