Pharmacokinetic Analysis of Prognostic Factors in Patients With Advanced-Stage Intrahepatic Cholangiocarcinoma Following the Administration of Capsule Formulation of the Standardized Extract of Atractylodes lancea (Thunb) DC.

BACKGROUND: A statistical model is essential in determining the appropriate predictive indicators for therapies in many types of cancers. Predictors have been compared favorably to the traditional systems for many cancers. Thus, this study has been proposed as a new standard approach. A recent study on the clinical efficacy of Atractylodes lancea (Thunb) DC. (AL) revealed the higher clinical benefits in patients with advanced-stage intrahepatic cholangiocarcinoma (ICC) treated with AL compared with standard supportive care. We investigated the relationships between clinical efficacy and pharmacokinetic parameters of serum bioactivity of AL and its active constituent atractylodin and determined therapeutic ranges. METHODS: Group 1 of advanced-stage ICC patients received daily doses of 1000 mg of standardized extract of the capsule formulation of AL (CMC-AL) for 90 days. Group 2 received daily doses of 1000 mg of CMC-AL for 14 days, followed by 1500 mg for 14 days, and 2000 mg for 62 days. Group 3 (control group) received palliative care. Cox proportional hazard model and Receiver Operating Characteristic (ROC) were applied to determine the cut-off values of AUC0-inf, Cmax, and Cavg associated with therapeutic outcomes. Number needed to treat (NNT) and relative risk (RR) were also applied to determine potential predictors. RESULTS: The AUC0-inf of total AL bioactivity of >96.71 µg hour/ml was identified as a promising predictor of disease prognosis, that is, progression-free survival (PFS) and disease control rate (DCR). Cmax of total AL bioactivity of >21.42 was identified as a predictor of the prognosis of survival. The therapeutic range of total AL bioactivity for PFS and DCR is 14.48 to 65.8 µg/ml, and for overall survival is 10.97 to 65.8 µg/ml. Conclusions: The predictors of ICC disease prognosis were established based on the pharmacokinetics of total AL bioactivity. The information could be exploited to improve the clinical efficacy of AL in patients with advanced-stage ICC. These predictors will be validated in a phase 2B clinical study. TRIAL REGISTRATION: TCTR20210129007 (TCTR: www.clinicaltrials.in.th).

Preclinical studies of toxicity and anti-cholangiocarcinoma activity of the standardized capsule formulation of Atractylodes lancea (Thunb.) DC.

BACKGROUND: Cholangiocarcinoma (CCA), the adenocarcinoma of the biliary duct, is commonly reported in Asia, with the highest incidence in northeastern Thailand. Chemotherapy of CCA has been limited by the lack of effective chemotherapeutic drugs. A series of previous in vitro and in vivo studies support further research and development of Atractylodes lancea (Thunb.) DC. (AL) as a potential candidate for treating CCA as a crude ethanolic extract. In the present study, we evaluated the toxicity and anti-CCA activity of the CMC (Chemistry, Manufacturing, and Control) capsule formulation of the ethanolic rhizome extract of AL (CMC-AL) in animals. METHODS: Major steps included acute, subchronic and chronic toxicity testing in Wistar rats and anti-CCA activity in a CCA-xenografted nude mouse model. The safety of CMC-AL was determined based on the maximum tolerated dose (MTD) and no-observed-adverse-effect level (NOAEL) according to the OECD guideline. The anti-CCA activity of CMC-AL in nude mice was evaluated after transplantation of CL-6 cells to evaluate inhibitory effects on tumor size progression and metastasis and survival time prolongation. Safety assessments included hematology, biochemistry parameters and histopathological examination. Lung metastasis was investigated using VEGF ELISA kit. RESULTS: All evaluations confirmed satisfactory pharmaceutical properties of oral formulation and safety profile of the CMC-AL with no overt toxicity up to the MTD and NOAEL of 5,000 and 3,000 mg/kg body weight, respectively. CMC-AL exhibited potent anti-CCA efficacy with regard to inhibitory activity on tumor progression and lung metastasis. CONCLUSIONS: CMC-AL is safe and should be further investigated in a clinical trial as a potential therapy for CCA patients.

The Role of Herbal Medicine in Cholangiocarcinoma Control: A Systematic Review.

The growing incidence of cholangiocarcinoma (bile duct cancer) and limited treatment options stimulate a pressing demand for research and the development of new chemotherapeutics against cholangiocarcinoma. This study aimed to systematically review herbs and herb-derived compounds or herbal formulations that have been investigated for their anti-cholangiocarcinoma potential. Systematic literature searches were conducted in three electronic databases: PubMed, ScienceDirect, and Scopus. One hundred and twenty-three research articles fulfilled the eligibility critera and were included in the analysis (68 herbs, isolated compounds and/or synthetic analogs, 9 herbal formulations, and 119 compounds that are commonly found in several plant species). The most investigated herbs were Atractylodes lancea (Thunb.) DC. (Compositae) and Curcuma longa L. (Zingiberaceae). Only A. lancea (Thunb.) DC. (Compositae) has undergone the full process of nonclinical and clinical development to deliver the final product for clinical use. The extracts of A. lancea (Thunb.) DC. (Compositae), Garcinia hanburyi Hook.f. (Clusiaceae), and Piper nigrum L. (Piperaceae) exhibit antiproliferative activities against human cholangiocarcinoma cells (IC50 < 15 µg/mL). Cucurbitacin B and triptolide are herbal isolated compounds that exhibit the most promising activities (IC50 < 1 µM). A series of experimental studies (in vitro, in vivo, and humans) confirmed the anti-cholangiocarcinoma potential and safety profile of A. lancea (Thunb.) DC. (Compositae) and its active compounds atractylodin and ß-eudesmol, including the capsule pharmaceutical of the standardized A. lancea (Thunb.) DC. (Compositae) extract. Future research should be focused on the full development of the candidate herbs to deliver products that are safe and effective for cholangiocarcinoma control.

In Silico Prediction of Andrographolide Dosage Regimens for COVID-19 Treatment.

Andrographolide (APE) has been used for COVID-19 treatment in various clinical settings in South-East Asia due to its benefits on reduction of viral clearance and prevention of disease progression. However, the limitation of APE clinical use is the high incidence of adverse events. The objective of this study was to find the optimal dosage regimens of APE for COVID-19 treatment. The whole-body physiologically-based pharmacokinetic (PBPK) models were constructed using data from the published articles and validated against clinical observations. The inhibitory effect of APE was determined for the potency of drug efficacy. For prevention of pneumonia, multiple oral doses such as 120[Formula: see text]mg for three doses, followed by 60[Formula: see text]mg three times daily for 4 consecutive days, or 200[Formula: see text]mg intravenous infusion at the rate of 20 mg/h once daily is advised in patients with mild COVID-19. For prevention of pneumonia and reduction of viral clearance time, the recommended dosage regimen is 500[Formula: see text]mg intravenous infusion at the rate of 25[Formula: see text]mg/h once daily in patients with mild-to-moderate COVID-19. One hundred virtual populations (50 males and 50 females) were simulated for oral and intravenous infusion formulations of APE. The eligible PBPK/PD models successfully predicted optimal dosage regimens and formulations of APE for prevention of disease progression and/or reduction of viral clearance time. Additionally, APE should be co-administered with other antiviral drugs to enhance therapeutic efficacy for COVID-19 treatment.

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

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.

Ethical considerations and challenges in herbal drug trials with the focus on scientific validity and risk assessment.

Scientific validity and risk assessment are two main ethical issues which raise specific challenges and are unique to clinical trials investigating crude extracts/fractions from herbal materials. There are considerable challenges for both clinical investigators and ethics committee members in dealing with such issues, many of them remain unresolved, resulting in a large variation in ethical requirements, justification, and decisions. Despite a remarkable surge in herbal medicine research globally, a number of clinical investigators or even ethics committee members have limited confidence in dealing with related ethical issues. In this article, we extensively review and discuss the two main ethical issues (i.e., scientific validity and risk assessment) and highlight key considerations that are important for ethical review and justification for the conduct of herbal drug trials.

Anti-malarial activity of traditional Kampo medicine Coptis rhizome extract and its major active compounds.

BACKGROUND: Herbal medicine has been a rich source of new drugs exemplified by quinine and artemisinin. In this study, a variety of Japanese traditional herbal medicine ('Kampo') were examined for their potential anti-malarial activities. METHODS: A comprehensive screening methods were designed to identify novel anti-malarial drugs from a library of Kampo herbal extracts (n = 120) and related compounds (n = 96). The anti-malarial activity was initially evaluated in vitro against chloroquine/mefloquine-sensitive (3D7) and-resistant (Dd2) strains of Plasmodium falciparum. The cytotoxicity was also evaluated using primary adult mouse brain cells. After being selected through the first in vitro assay, positive extracts and compounds were examined for possible in vivo anti-malarial activity. RESULTS: Out of 120 herbal extracts, Coptis rhizome showed the highest anti-malarial activity (IC50 1.9 µg/mL of 3D7 and 4.85 µg/mL of Dd2) with a high selectivity index (SI) > 263 (3D7) and > 103 (Dd2). Three major chlorinated compounds (coptisine, berberine, and palmatine) related to Coptis rhizome also showed anti-malarial activities with IC50 1.1, 2.6, and 6.0 µM (against 3D7) and 3.1, 6.3, and 11.8 µM (against Dd2), respectively. Among them, coptisine chloride exhibited the highest anti-malarial activity (IC50 1.1 µM against 3D7 and 3.1 µM against Dd2) with SI of 37.8 and 13.2, respectively. Finally, the herbal extract of Coptis rhizome and its major active compound coptisine chloride exhibited significant anti-malarial activity in mice infected with Plasmodium yoelii 17X strain with respect to its activity on parasite suppression consistently from day 3 to day 7 post-challenge. The effect ranged from 50.38 to 72.13% (P < 0.05) for Coptis rhizome and from 81 to 89% (P < 0.01) for coptisine chloride. CONCLUSION: Coptis rhizome and its major active compound coptisine chloride showed promising anti-malarial activity against chloroquine-sensitive (3D7) and -resistant (Dd2) strains in vitro as well as in vivo mouse malaria model. Thus, Kampo herbal medicine is a potential natural resource for novel anti-malarial agents.

Medicinal plants for in vitro antiplasmodial activities: A systematic review of literature.

The increasing resistance of malaria to drugs raise the need to new antimalarial agents. Antiplasmodial herbs and their active compounds are the most promising source the new antimalarial agents. This study aimed to identify the medicinal plants with very good in vitro antiplasmodial activities, with half-maximal inhibitory concentration (IC50)≤1µg/ml, and to determine trends in the process of screening their antiplasmodial activities. A total of 58 reports published in the English language were retrieved from the bibliographical databases. Screening and data extraction were performed by two independent reviewers. The herbs were categorized as very good, good, moderate and inactive if the IC50 values were <0.1µg/ml, 0.1-1µg/ml, >1-5µg/ml and >5µg/ml respectively. We documented 752 medicinal plants belonging to 254 genera. The majority of the plants were reported from Africa followed by Asia. The traditional use for malaria treatment was the most common reason for the selection of the plants for investigation. About 80% of the plants experimented were reported to be inactive. Among plants identified as having very good to good antiplasmodial crude extracts are Harungana madagascariensis, Quassia africana, and Brucea javanica, while Picrolemma spruce, Aspidosperma vargasi, Aspidosperma desmanthum, and Artemisia annua were reported to have individual compound isolates with very good antiplasmodial activities. In conclusion, the number of plant species assessed so far is still small compared with the stock in nature's plant library. A mechanism of systematically approaching and exploring the untouched plant genera needs to be designed.

Research and Development of Atractylodes lancea (Thunb) DC. as a Promising Candidate for Cholangiocarcinoma Chemotherapeutics.

Treatment and control of cholangiocarcinoma (CCA): the bile duct cancer is limited by the lack of effective chemotherapeutic drugs and alternative drugs are needed, particularly those from natural sources. This article reviews steps of research and development of Atractylodes lancea (Thunb) DC. (AL) as potential candidate for CCA chemotherapy, with adoption of the reverse pharmacology approach. Major steps include (1) reviewing of existing information on its phytochemistry and pharmacological properties, (2) screening of its activities against CCA, (3) standardization of AL, (4) nonclinical studies to evaluate anti-CCA activities, (5) phytochemistry and standardization of AL extract, (6) development of oral pharmaceutical formulation of standardized AL extract, and (7) toxicity testing of oral pharmaceutical formulation of standardized AL extract. Results from a series of our study confirm anti-CCA potential and safety profiles of both the crude extract and the finished product (oral pharmaceutical formulation of the standardized AL extract). Phases I and II clinical trials of the product to confirm tolerability and efficacy in healthy subjects and patients with advanced stage CCA will be carried out soon.

Exploratory, Phase II Controlled Trial of Shiunko Ointment Local Application Twice a Day for 4 Weeks in Ethiopian Patients with Localized Cutaneous Leishmaniasis.

The clinical efficacy and safety of Shiunko ointment (phase II clinical trial) was investigated in 40 Ethiopian patients with cutaneous leishmaniasis. Patients were randomized to receive treatment with Shiunko ointment or placebo (n = 20, each), applied on the lesion twice a day for 4 weeks. Clinicoparasitological assessments were performed before treatment, weekly for 4 weeks, and then 4, 8, and 12 weeks after the end of treatment. A marked reduction in lesion size was observed on week 16 of treatment in the Shiunko compared with placebo group (69% and 22% reduction, resp.). The overall rate of lesion reduction during the four weeks of treatment was significantly faster in the Shiunko group. Shiunko provided significant effect on wound closure in patients with ulcerated lesion. The clinical efficacy and tolerability of Shiunko were comparable to placebo with regard to its clinicoparasitological response (cure rate and parasitological clearance). Results of this preliminary study may suggest that Shiunko could be useful as adjuvant or as complementary treatment, not as alternatives to current treatment. Its attractive action includes fast lesion healing with a significantly smaller lesion at week 16 of treatment compared with placebo. In addition, its action was promoted in ulcerative lesions.

Ethical considerations in clinical research on herbal medicine for prevention of cardiovascular disease in the ageing.

BACKGROUND: Cardiovascular disease (CVD) in the ageing is a major public health problem worldwide. The nature of most CVD is subclinical with pathological processes that can span over years. Use of preventive measures could be an appropriate approach to prevailing over CVD in the ageing, and herbal medicine is one of the promising preventive approaches and is currently of interest among medical societies. In the evidence-based era, herbal medicine is, however, often underestimated and approached with skepticism, mainly due to the paucity of scientific evidence. Properly designed clinical trials on herbal medicine for prevention of CVD in a geriatric population are thus of importance and of clinical value. PURPOSE: To review ethical issues and discuss considerations when such research is proposed. CHAPTERS/SECTIONS: Four ethical issues, including the scientific validity of research, risk-benefit assessments, subject selection and vulnerability, and informed consent, are structured and extensively discussed in this article. CONCLUSIONS: Ethical core considerations of prevention research of CVD on herbal medicine involve particular attention on the scientific validity of research, risk-benefit assessments, subject selection and vulnerability, and informed consent. These issues and considerations are keys, although they must be adapted to an individual research setting in which a clinical study is proposed.

Anticancer Activity of Atractylodes lancea (Thunb.) DC in a Hamster Model and Application of PET-CT for Early Detection and Monitoring Progression of Cholangiocarcinoma.

Opisthorchis viverrini (OV)-induced cholangiocarcinoma (CCA) is an important cancer in the Great Mekong region, particularly in Thailand. Limitations of treatment options and the lack of an effective diagnostic tool for early detection of CCA are major concerns for the control of this type of cancer. The aim of the study was to investigate anti-CCA activity of the ethanolic extract of Atractylodes lancea (Thunb.) DC., and the applicability of positron emission tomography-computed tomography (PET-CT) as a tool for detection and monitoring the progression of CCA in Opisthorchis viverrini (OV)/dimethylnitrosamine (DMN)-induced CCA hamsters. Male Syrian hamsters were used for toxicity tests and anti-CCA activity evaluation. Development of CCA was induced by initial feeding of 50 metacercariae of OV, followed by drinking water containing 12.5 ppm of DMN in hamsters. The ethanolic extract of A. lancea (Thunb.) DC. was administered orally for 30 days. PET-CT was performed every 4 weeks after initiation of CCA using 18F-fluorodeoxyglucose (18F-FDG). Results from the present study suggest that the ethanolic extract of A. lancea (Thunb.) DC. rhizome exhibited promising anti-CCA activity and safety profile in the OV/DMN-induced hamster model. To successfully apply PET-CT as a tool for early detection of tumor development and progression, modification of radiolabeling approach is required to improve its specificity for CCA cells.

Traditional herbal medicine for the control of tropical diseases.

Throughout history, traditional herbal medicine has afforded a rich repository of remedies with diverse chemical structures and bioactivities against several health disorders. A common issue of herbal medicine is the limitation of information on their pharmacological activities and their active constituents. Traditionally, the use of herbal medicine has been based on empirical treatment and passed on from generation to generation with information available only in local journals. This prevents several herbal medicines from being developed to their full potential. The presentation will focus on research and development of Atractylodes lancea (Thunb) DC. (AL: family Compositae) as a potential chemotherapeutic for cholangiocarcinoma (CCA), the bile duct cancer commonly found in Southeast Asia. The dried rhizome of AL is a medicinal plant used in Chinese ("Cang Zhu"), Japan ("So-jutsu") and Thai ("Khod-Kha-Mao") traditional medicine for its various pharmacological properties including anticancer, anti-inflammation and antimicrobial activities, activities on central nervous, cardiovascular, and gastrointestinal systems. The major constituents in the essential oils from AL rhizome are ß-eudesmol, hinesol and atractylon. Preliminary investigation has demonstrated its promising anti-CCA activity both in vitro and animal (Opisthorchis viverrini/dimethylnitrosamine-induced CCA in hamsters and CCA-xenografted nude mice) models with high selectivity index comparing with the standard drug, 5-fluorouracil. It also showed virtually no toxicity with only minimal CNS effects on locomotor activity at the maximum dose of 5,000 mg/kg body weight. Studies are underway to identify active constituent(s) which contribute to anti-CCA activity as well as its pharmacokinetic and pharmacodynamic properties. The main research interest of my research group is the discovery and development of traditional herbal medicine for the treatment of two important tropical diseases, cholangiocarcinoma and malaria. As the time is quite limited, I am going to give you the summary of the conceptual framework and highlight some important findings which will illustrate how different approaches have been used or applied for the discovery of the promising candidates for these two diseases.

Therapeutic potential and pharmacological activities of Atractylodes lancea (Thunb.) DC.

The rhizome of Atractylodes lancea (A. lancea) (Thunb.) DC. (AL) is extensively used in Chinese, Thai, and Japanese traditional medicines as crude extracts/decoctions or a component in various herbal formulations. Various pharmacological activities of AL and its major constituents have been demonstrated in vitro, ex vivo, and in animal models. Results from the toxicity studies in animal models suggest safety profile of AL and its active constituents. Despite extensive use with positive impression in many diseases, there has not been a clinical study that can conclusively support its efficacy and safety profile in human. This review comprehensively summarizes current information on the pharmacological activities of AL and their active constituents including anticancer, anti-inflammatory, antimicrobial and antipyretic activities, as well as activities on central nervous, cardiovascular, and gastrointestinal systems.

Antimalarial activity of plumbagin in vitro and in animal models.

BACKGROUND: Plumbagin is the major active constituent in several plants including Plumbago indica Linn. (root). This compound has been shown to exhibit a wide spectrum of biological and pharmacological activities. The present study aimed to evaluate the in vitro and in vivo antimalarial activity of plumbagin including its acute and subacute toxicity in mice. METHODS: In vitro antimalarial activity of plumbagin against K1 and 3D7 Plasmodium falciparum clones were assessed using SYBR Green I based assay. In vivo antimalarial activity was investigated in Plasmodium berghei-infected mouse model (a 4-day suppressive test). RESULTS: Plumbagin exhibited promising antimalarial activity with in vitro IC50 (concentration that inhibits parasite growth to 50%) against 3D7 chloroquine-sensitive P. falciparum and K1 chloroquine-resistant P. falciparum clones of 580 (270-640) and 370 (270-490) nM, respectively. Toxicity testing indicated relatively low toxicity at the dose levels up to 100 (single oral dose) and 25 (daily doses for 14 days) mg/kg body weight for acute and subacute toxicity, respectively. Chloroquine exhibited the most potent antimalarial activity in mice infected with P. berghei ANKA strain with respect to its activity on the reduction of parasitaemia on day 4 and the prolongation of survival time. CONCLUSIONS: Plumbagin at the dose of 25 mg/kg body weight given for 4 days was safe and produced weak antimalarial activity. Chemical derivatization of the parent compound or preparation of modified formulation is required to improve its systemic bioavailability.

Immunostimulating effect of a well-known Thai folkloric remedy in breast cancer patients.

The study aimed to evaluate immune-stimulating effects of a well-known Thai folkloric remedy when used for adjuvant therapy with conventional chemotherapeutics for treatment of breast cancer. Immunostimulating influence of the remedy (215 mg/kg body weight per day) on NK cell activity and TNF-α release from the monocytes/macrophages were investigated in a total of 15 healthy women and 13 female patients with breast cancer (Group 1). The effect of breast tumor surgery on NK cell activity was further investigated in 18 female patients with breast cancer (Group 2). NK cell cytotoxic activity was determined by chromium release cytotoxic assay using K562, an erythroleukemic cell line. TNF-α release from monocytes/macrophages separated from blood samples was determined through a biological assay using actinomycin D-treated L929 mouse fibroblast cells in the presence and absence of LPS. Baseline NK cell activity of the monocytes/macrophages separated from Group 2 patients expressed as %cytotoxicity was significantly lower than in the healthy subjects at E:T ratios of 100:1 and 25:1. In healthy subjects, there was no change in NK cell cytotoxic activity (%cytotoxicity or LU) following 1 and 2 weeks of treatment with the remedy compared with the baseline at various E:T ratios but the binding activity (%binding) was significantly increased after 2 weeks of treatment. The addition of one or two conventional chemotherapeutic regimens did not significantly reduce the NK cytotoxic activity but did affect release of TNF-α in both unstimulated and LPS-stimulated samples. Surgery produced a significant suppressive effect on NK cell activity. The use of the remedy as an adjunct therapy may improve therapeutic efficacy and safety profiles of conventional chemotherapeutic regimens through stimulation of the immune system in cancer patients.