Clinical research on concurrent use of Chinese herbal formulas and chemotherapy is rapidly evolving. With increasing efforts to improve the biomedical understanding and clinical utility of herbal medicine in cancer therapies, some prospective clinical trials have been published, with more currently underway in both human and veterinary medicine. There are many other published research articles which are epidemiological studies or retrospective evaluations and meta-analyses.
We often hear a lot of the negatives or limiting comments about what we don't know yet. It is equally, if not more, important to also make an effort to be informed about what we do know. As, from there, we are empowered to expand our current understanding and ask the important, intelligent and informed questions which are necessary for the continued positive growth in our patient care options and improved patient outcomes.
In this blog post I have included a list of some of the more recent studies of these types for your information and in the interest of assisting pet parents and the veterinary profession in becoming aware of some of the many research articles that currently are available on Chinese Herbal Medicine and cancer-related topics.
In this Blog you will find:
40 articles with abstracts or article summaries and links to the articles
some clinical perspectives on interpreting research
an outline of how I generally tend to recommend integrating herbs in my patient care
introductory considerations regarding potential herb-drug interactions
Perspectives on Integrative Medicine from the Scientific Literature
Diehl V. Hematology Am Soc Hematol Educ Program. 2009:320-5.
Integrative medicine (IM) has become a major challenge for doctors and nurses, as well as psychologists and many other disciplines involved in the endeavor to help patients to better tolerate the burden of toxic therapies and give patients tools so they can actively participate in their "salutogenesis." IM encompasses psycho-oncology, acupuncture, and physical and mental exercises to restore vital capacities lost due to toxic therapies; furthermore, it aims to replenish nutritional and metabolic deficits during and after cancer treatment. IM gains an ever increasing importance in the face of the rapidly growing number of cancer survivors demanding more than just evidence-based diagnostic and therapeutic strategies. IM has to prove its value and justification by filling the gap between unproven methods of alternative medicine, still used by many cancer patients, and academic conventional medicine, which often does not satisfy the emotional and spiritual needs of cancer patients.
Chen HY, Feng Y, Lao L. J Integr Med. 2014 May;12(3):187-90.
To meet community demands with optimal Chinese and conventional medical treatment, the University of Hong Kong is promoting integrative medicine by developing Chinese medicine programmes that train students of both Western and Chinese medicine. The programmes emphasize multi-disciplinary training and interaction between the two therapeutic approaches, enabling students to establish reliable, consistent, and respectful mutual cooperation in their future careers.
Yun H, Sun L, Mao JJ. J Natl Cancer Inst Monogr. 2017 Nov 1;2017(52).
Integrative Medicine is being offered in an expanding number of leading human cancer centers. This 2017 study reported that, of 45 National Cancer Institute (NCI)–designated comprehensive cancer center websites, 67% offered consultation on herbal therapies and 91% offered consultations about nutrition. Among the most common integrative medicine therapies offered were exercise (98%), acupuncture (89%), and meditation (89%).
Review Articles
A number of review article have recently been published on the potential role of herbal therapies for mitigation of chemotherapy side effects and possible mechanisms for these effects.
A Review on the Effect of Traditional Chinese Medicine Against Anthracycline-Induced Cardiac Toxicity.
Xinyu Yang, Nian Liu, Xinye Li, et al. Front Pharmacol. 2018; 9: 444.
Anthracyclines are effective agents generally used to treat solid-tumor and hematologic malignancies. The use of anthracyclines for over 40 years has improved cancer survival statistics. Nevertheless, the clinical utility of anthracyclines is limited by its dose-dependent cardiotoxicity that adversely affects 10–30% of patients. Anthracycline-induced cardiotoxicity may be classified as acute/subacute or chronic/late toxicity and leads to devastating adverse effects resulting in poor quality of life, morbidity, and premature mortality. Traditional Chinese medicine has a history of over 2,000 years, involving both unique theories and substantial experience. Several studies have investigated the potential of natural products to decrease the cardiotoxic effects of chemotherapeutic agents on healthy cells, without negatively affecting their antineoplastic activity. This article discusses the mechanism of anthracycline-induced cardiotoxicity, and summarizes traditional Chinese medicine treatment for anthracycline-induced heart failure (HF), cardiac arrhythmia, cardiomyopathy, and myocardial ischemia in recent years, in order to provide a reference for the clinical prevention and treatment of cardiac toxicity.
Qing-Yu Zhang, Fei-Xuan Wang, Ke-Ke Jia, et al. Front Pharmacol. 2018; 9: 1253.
Cancer is the second leading cause of death in the world. Chemotherapy and radiotherapy are the common cancer treatments. However, the development of adverse effects resulting from chemotherapy and radiotherapy hinders the clinical use, and negatively reduces the quality of life in cancer patients. Natural products including crude extracts, bioactive components-enriched fractions and pure compounds prepared from herbs as well as herbal formulas have been proved to prevent and treat cancer. Of significant interest, some natural products can reduce chemotherapy and radiotherapy-induced oral mucositis, gastrointestinal toxicity, hepatotoxicity, nephrotoxicity, hematopoietic system injury, cardiotoxicity, and neurotoxicity. This review focuses in detail on the effectiveness of these natural products, and describes the possible mechanisms of the actions in reducing chemotherapy and radiotherapy-induced side effects. Recent advances in the efficacy of natural dietary supplements to counteract these side effects are highlighted. In addition, we draw particular attention to gut microbiotan in the context of prebiotic potential of natural products for the protection against cancer therapy-induced toxicities. We conclude that some natural products are potential therapeutic perspective for the prevention and treatment of chemotherapy and radiotherapy-induced side effects. Further studies are required to validate the efficacy of natural products in cancer patients, and elucidate potential underlying mechanisms.
Multi-Component Herbal Products in the Prevention and Treatment of Chemotherapy-Associated Toxicity and Side Effects: A Review on Experimental and Clinical Evidences.
Fu B, Wang N, Tan HY, et al. Front Pharmacol. 2018 Nov 29;9:1394.
Chemotherapy is nowadays the main treatment of human cancers. Chemotherapeutic agents target rapidly dividing cancer cells to suppress tumor progression, however, their non-specific cytotoxicity often leads to significant side effects that might be intolerable to cancer patients. Multi-component herbal products have been used for thousands of years for the treatment of multiple human diseases. This study aims to systematically summarize and evaluate the experimental and clinical evidences of the efficacy of multi-component herbal products in improving chemotherapy-induced side effect. Literature was retrieved from PubMed database and evaluated based on the side effects described. Multi-component herbal products were found to be effective in ameliorating the neurotoxicity, gastrointestinal toxicity, hematological toxicity, cardiotoxicity, hepatotoxicity and nephrotoxicity. Both experimental and clinical evidences were found, indicating the potential of applying multicomponent herbal products in the clinical treatment of chemotherapy-induced side effects. However, the lack of mechanistic and pharmacokinetic studies, inconsistency in product quality, as well as insufficient clinical evidence suggested that more investigations are urgently necessary. In all, our review shed light on the potential of using multi-component herbal products in the clinical management of chemotherapy-induced toxicity and side effects. We also discussed the potential threats of natural products for cancer treatment and compared the advantages of using herbs to conventional chemical drugs.
Wang Z, Qi F, Cui Y, et al. Biosci Trends. 2018;12(3):220-239.
Numerous studies have indicated that in cancer treatment Chinese herbal medicines in combination with chemo-, radio-, or targeted-therapy can be used to enhance the efficacy of and diminish the side effects and complications caused by these therapies. Therefore, an understanding of Chinese herbal medicines is needed by physicians and other health care providers. This review provides an update on Chinese herbal medicines as adjuvant treatment of anticancer therapeutics. First, some Chinese herbal medicines (e.g. Astragalus, Ginseng, Scutellaria barbata, TJ-41, TJ-48, PHY906, Huachansu injection, and Kanglaite injection) that are commonly used for treating the cancer and/or reducing the toxicity induced by chemo-, radio-, or targeted-therapy are discussed. These Chinese herbal medicines have been shown to possess great advantages in terms of suppressing tumor progression, increasing the sensitivity of chemo-, radio-, or targeted-therapeutics, improving an organism's immune system function, and lessening the damage caused by these therapeutics. Second, some clinical trials using Chinese herbal medicines as adjuvant improving cancer treatment related side effects and complications are reviewed. Some Chinese herbal medicines have a significant effect on reducing cancer-related fatigue and pain, improving peripheral neuropathy and gastrointestinal side effects including diarrhea, nausea, and vomiting, decrease the incidence of bone marrow suppression, protecting anthracycline-induced cardiotoxicity and radiation-induced pneumonitis, and relieving EGFR-TKIs related acneiform eruptions and other side effects. This review of those medicines should contribute to an understanding of Chinese herbal medicines as adjuvant treatment for cancer and provide useful information for the development of more effective anti-cancer drugs. However, rigorously designed trials on potential Chinese herbal medicine must be further examined involving cancer treatment especially molecular targeted-therapy in the future.
Some Recent Meta-analysis on use of Chinese Herbal Medicine with Conventional Therapies
Zhang S, Shi L, Mao D, et al. Evid Based Complement Alternat Med. 2018 Jan 29;2018:6180810.
This review comprised 12 randomized clinical studies of 701 patients. Conclusion: JPJD herbs can improve quality of life, relieve symptoms, and reduce adverse events of advanced CRC patients receiving chemotherapy. However, the results showed no significant effect on tumor response.
Yang XB, Chai XS, Wu WY, et al. Chin J Integr Med. 2018 Oct;24(10):734-740.
A randomized controlled trial was conducted from 2009 to 2012 in South China. Seventy chemotherapy naive patients diagnosed with stage IIIB/IV non-small cell lung cancer with EGFR mutations were randomly assigned to GF group [gefitinib (250 mg/day orally) plus FZKA (250 mL, twice per day, orally); 35 cases] or G group (gefitinib 250 mg/day orally; 35 cases). GF group had significantly longer Progression Free Survival (PFS) and Median Survival Time (MST) compared with the G group, with median PFS of 12.5 months vs. 8.4 months, MST of 21.5 months vs. 18.3 months. The most common toxic effects in the GF group and G group were rash or acne (42.8% vs. 57.1%, P>0.05), diarrhea (11.5% vs. 31.4%, P<0.05), and stomatitis (2.9% vs. 8.7%, P>0.05). Conclusion: Patients with advanced non-small cell lung cancer selected by EGFR mutations have longer PFS, MST with less toxicity treated with gefitinib plus FZKA than gefitinib alone.
Oral Chinese Herbal Medicine as an Adjuvant Treatment for Chemotherapy, or Radiotherapy, Induced Myelosuppression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Hou B, Liu R, Qin Z, et al. Evid Based Complement Alternat Med. 2017;2017:3432750.
1021 articles from the date of databases inception to October 7, 2016 were searched. 14 articles were selected for the final analysis. Pooled data showed that CHM significantly decreased the suppression rate of leukocytes, neutrophils, hemoglobin, and platelets compared with the control group, particularly in grade III-IV toxicity. Conclusion: CHM as an adjuvant can alleviate myelosuppression induced by chemotherapy or radiotherapy, reduce grade III-IV toxicity, and maintain therapeutic dose and treatment cycle. However, due to heterogeneity and publication bias, the results should be interpreted with caution and validated by conducting strictly designed multicenter RCTs of high quality and large scale.
Chinese Herbal Medicine as an Adjunctive Therapy for Breast Cancer: A Systematic Review and Meta-Analysis.
Zhu L, Li L, Li Y, et al. Evid Based Complement Alternat Med. 2016; 2016:9469276.
The study results showed that Chinese Herbal Medicine (CHM) combined with chemotherapy significantly increased tumor response and KPS as compared to using chemotherapy alone. Besides, CHM as an adjunctive therapy significantly reduced the nausea and vomiting at toxicity grade of III-IV. Moreover, the combined therapy significantly prevented the decline of WBC in patients under chemotherapy at toxicity grade of III-IV and prevented the decline of platelet at toxicity grade of III-IV or I-IV. Conclusion: This study suggests that CHM combined with chemotherapy in comparison with chemotherapy alone can significantly enhance tumor response, improve KPS, and alleviate toxicity induced by chemotherapy in breast cancer patients. However, a firm conclusion could not be reached due to the lack of high quality trials and large-scale RCTs, so further trials with higher quality and larger scale are needed.
Chinese Herbal Medicine and Fluorouracil-Based Chemotherapy for Colorectal Cancer: A Quality-Adjusted Meta-Analysis of Randomized Controlled Trials.
McCulloch M, Ly H, Broffman M, et al. Integr Cancer Ther. 2016 Sep;15(3):285-307.
Conclusion: Not accounting for Cochrane Risk of Bias (ROB) would have exaggerated evidence of benefit and failed to detect nonsignificance of results. In the present analysis, involving 36 studies, 2593 patients, 20 outcomes, 36 medical institutions, and 271 named research authors, 92% of the data points were from studies at high ROB. Given the poor quality of the data in studies identified, it cannot be concluded whether combining Chinese herbs with chemotherapy reduces toxicity of chemotherapy.
Chinese herbal medicine for myelosuppression induced by chemotherapy or radiotherapy: a systematic review of randomized controlled trials.
Jia Y, Du H, Yao M, et al. Evid Based Complement Alternat Med. 2015;2015:690976.
Eight RCTs were included (818 patients). Pooled data showed that increase of white blood cells (WBCs) is higher with CHM plus chemotherapy/radiotherapy than with chemotherapy/radiotherapy only. Both CHM compared to placebo and CHM combined with chemotherapy/radiotherapy compared to chemotherapy/radiotherapy lacked significant differences in the peripheral platelets, red blood cells (RBCs), and hemoglobin changes. Conclusion: Our results demonstrated that CHM significantly protected peripheral blood WBCs from a decrease caused by chemotherapy or radiotherapy. There were no significant protective effects on peripheral RBCs, hemoglobin, or platelets, which may be related to low quality and small sample of included studies.
Yang XB, Wu WY, Long SQ, et al. Complement Ther Med. 2014 Dec;22(6):1010-8.
159 non-small-cell lung cancer patients were retrospectively evaluated. Among the 159 patients, 100 patients treated with gefitinib (250mg/day orally) plus CHM ("Fuzheng Kang'ai" decoction, a Chinese herbal medicine, 250ml/bid/day orally), 59 patients treated with gefitinib (250mg/day orally) only. 58 pairs were matched successfully. 1 patient (treated with gefitinib) with the age of 27 years failed to be matched. Progression-free survival was significantly longer in patients treated with gefitinib plus CHM than with gefitinib: median PFS was 13.1 months with gefitinib plus CHM versus 11.43 months with gefitinib. Median overall survival was longer with gefitinib plus CHM than with gefitinib: median MST was 22.83 months with gefitinib plus CHM versus 18.7 months with gefitinib. The most common adverse event was rash, the incidence in the gefitinib plus CHM group was 41.38% while in the gefitinib group was 24.14%. Conclusion: This case-control analysis suggested that treatment with gefitinib plus CHM prolonged PFS and MST compared with gefitinib in patients with NSCLC, and it is worthy of further study.
Liu ZL, Zhu WR, Zhou WC, et al. J Integr Med. 2014 Jul;12(4):346-58.
TCMH plus EGFR-TKI treatment group was compared with an EGFR-TKI control group in patients with advanced NSCLC.
In this review, 19 studies were included based on the selection criteria. Of them, 13 studies were of high quality and 6 studies were of low quality. Meta-analysis demonstrated a statistically significant higher ORR, DCR, one-year survival rate, 2-year survival rate and improved or stable KPS. Severe toxicity for rash was decreased, as were nausea, vomiting and diarrhea. Sensitivity analysis indicated that findings of the meta-analysis were robust to study quality. Conclusion: TCMH intervention can increase efficacy and reduce toxicity when combined with EGFR-TKI for advanced NSCLC, although this result requires further verification by more well designed studies.
Shi Guang Li, Hai Yong Chen, Chen Sheng Ou-Yang, et al. PLoS One. 2013; 8(2): e57604.
Publications in 11 electronic databases were extensively searched, and 24 trials were included for analysis. A sum of 2,109 patients was enrolled in these studies, at which 1,064 patients participated in CT combined CHM and 1,039 in CT (six patients dropped out and were not reported the group enrolled). Compared to using CT alone, CHM combined with CT significantly increase one-year survival rate. Besides, the combined therapy significantly increased immediate tumor response and improved Karnofsky performance score (KPS). Combined therapy remarkably reduced the nausea and vomiting at toxicity grade of III–IV and prevented the decline of hemoglobin and platelet in patients under CT at toxicity grade of I–IV. Moreover, the herbs that are frequently used in NSCLC patients were identified. Conclusion: This systematic review suggests that CHM as an adjuvant therapy can reduce CT toxicity, prolong survival rate, enhance immediate tumor response, and improve KPS in advanced NSCLC patients. However, due to the lack of large-scale randomized clinical trials in the included studies, further larger scale trials are needed.
Zhong LL, Chen HY, Cho WC, et al. Complement Ther Med. 2012 Aug;20(4):240-52.
Randomized controlled trials with CHM to treat colorectal cancer were extensively searched in seven databases. Two researchers independently assessed the quality and validity of included trials and extracted outcome data for synthesis. 20 trials were included for analysis. Compared to using chemotherapy alone, CHM combined with chemotherapy significantly increased 1- and 3-year survival rate. The combined therapy significantly slowed colorectal cancer progression and improved quality of life. It had positive effects in immunoregulation. CHM as an adjunctive therapy also had significant advantages in reducing the adverse effects of chemotherapy. Conclusion: This systematic review suggests that CHM as an adjunctive therapy with chemotherapy versus chemotherapy alone has significant efficacy in terms of prolonging survival, enhancement of tumor response, improvement of quality of life, immunoregulation, and alleviation of acute adverse effects. However, a firm conclusion could not be reached because of the poor quality of the included trials. Further trials with higher quality are required and the efficacy in other forms of advantages remains to be further determined.
Dong J, Su SY, Wang MY, et al. J. Exp. Clin. Cancer Res. 2010;29:137.
Twenty-nine studies were included in this review based on our selection criteria. Of them, ten studies were of high quality and the rest were of low quality. The meta-analysis showed there was a statistically significant higher tumor response and performance status but lower severe toxicity for WBC, PLT, HB, and nausea and vomiting, when the SFI plus platinum-based chemotherapy treatment group was compared with the platinum-based chemotherapy control group. Sensitivity analysis was restricted to studies with the high quality, and the result was similar when the studies with low quality were excluded. Asymmetry was observed in a funnel plot analysis, and Egger's test also indicated an evidence of publication bias (P = 0.016). Conclusions: SFI intervention appears to be useful to increase efficacy and reduce toxicity when combined with platinum-based chemotherapy for advanced NSCLC, although this result needs to be further verified by more high-quality trials.
Cho WC, Chen HY. Expert Opin Investig Drugs. 2009 May;18(5):617-35.
Conclusion: Chinese herbal therapy was associated with a significant rise in the number of patients with survival > 1-year, 2-year and 3-year, as well as a significant rise in the number of patients who reported complete or partial response and non-deterioration performance status. Chinese herbal therapy also showed significant efficacies in the increase of T cells and natural killer cells, whereas a significant lower blood alpha-fetoprotein concentration was reported. There were a significant increase in white blood cell count, a significant lower risk in patients with nausea and vomiting, and a significant rise in patients with increased body weight when Chinese herbal therapy was given. The evidence from this review supports the use of Chinese herbal therapy to enhance the efficacy of TACE in HCC patients. However, owing to limited data and heterogeneity of the included studies, further trials are required.
Cho WC, Chen HY. Cancer Invest. 2009 Mar;27(3):334-44.
A meta-analysis was conducted covering English- and Chinese-language studies published from 1966 to November 2007. Extensive searches were performed with the AMED, CINAHL, Cochrane Library, EMBASE, MEDLINE, Ovid EBM Review, and CNKI databases. Controlled trials comparing NPC patients treating by TCM combined with conventional cancer therapy (treatment group) versus patients using conventional cancer therapy alone (control group) were analyzed. Of the 178 potentially relevant publications, 18 controlled trials met the inclusion criteria. There were 18 studies (n = 1732) reported significant increase in the number of patients with survival more than 1, 3, or 5 years in the treatment group. Six studies (n = 464) reported enhancement of complete or partial immediate tumor responses with TCM combination treatment. Two studies (n = 135) reported stabilized or improved Karnofsky performance status with TCM combination treatment. Five studies (n = 439) significantly reduced the risk of adverse effects in the treatment group. Three studies (n = 182) reported significant immuno-stimulation in the treatment group. There were 16 Chinese herbs found to be commonly used across the studies. Conclusion: Published studies suggest that TCM is efficacious as a concomitant therapy for NPC patients. These results require confirmation with rigorously controlled trials.
Dai Z, Wan X, Kang H, et al. J. Tradit. Chin. Med. 2008;28(1):34–38.
During the period from 2000 to 2005, 126 patients with local advanced breast cancer were treated with the neoadjuvant chemotherapy and randomly divided into the following two groups: a control group of 61 cases treated by chemotherapy alone and a study group of 65 cases treated by chemotherapy plus shenqi fuzheng injection. All the cases of both groups were given the CEF regimen. The clinical effects, the effects on T-lymphocyte subgroup and NK cells, and the toxic side effects were observed. For the primary tumor in the breast, the total effective rate was 69.2% (45/65) in the study group and 49.2% (30/61) in the control group with a statistically significant difference in the intergroup comparison. There was no progression of the disease in both the groups, and there were no grade IV toxic side effects in the two groups. The major toxic responses were myelosuppression and gastrointestinal reaction, which were milder in the study group than the control group, and with a shorter recovery course in the former than the latter. Besides, an obvious rise of the T-lymphocyte subgroup and NK cells was found in the study group after the neoadjuvant chemotherapy, with a very significant difference from the controls (P < 0.01). Conclusions: Shenqi fuzheng Injection can improve and regulate immune function of the patients with local advanced breast cancer given the neoadjuvant chemotherapy, and therefore it can enhance the curative effect and reduce the side effect as well.
McCulloch M, See C, Shu XJ, et al. J Clin Oncol. 2006 Jan 20;24(3):419-30.
Evidence from randomized trials was evaluated to assess whether Astragalus-based Chinese herbal medicine combined with platinum-based chemotherapy (versus platinum-based chemotherapy alone) improves survival, increases tumor response, improves performance status, or reduces chemotherapy toxicity. Of 1,305 potentially relevant publications, 34 randomized studies representing 2,815 patients met inclusion criteria. Conclusion: Astragalus-based Chinese herbal medicine may increase effectiveness of platinum-based chemotherapy when combined with chemotherapy. These results require confirmation with rigorously controlled trials.
Shu X, McCulloch M, Xiao H, et al. Integr Cancer Ther. 2005 Sep;4(3):219-29.
Conclusion: These findings provide promising evidence that combining Chinese herbal medicine with chemotherapy may benefit patients with HCC. Because of the low quality of these studies, these findings should be confirmed through conducting high-quality, rigorously controlled trials.
Individual Human Studies
Wang, Q. Front Pharmacol, 2018.
Seventy-one patients were enrolled from 8 medical centers in China, and were randomly assigned to a maintenance chemotherapy plus CHMF group (n = 35) or a maintenance chemotherapy plus placebo group (n = 36). Patients in the CHMF group showed significant improvements in median PFS, KPS scores, fatigue, interference with daily activities and dyspnea compared with patients in the placebo group. Compared with the placebo group, the incidence of AEs decreased in the CHMF group, including loss of appetite and dry mouth. Conclusion: The essential finding of our study is that maintenance chemotherapy combined with CHMF may prolong PFS, relieve symptoms, improve QoL and alleviate the side effects.
Kuo, YT. Integr Cancer Ther, 2018
Patients with pancreatic cancer registered in the Taiwanese Registry for Catastrophic Illness Patients Database between 1997 and 2010 were evaluated. CHM users had a lower hazard ratio of mortality risk. Those who received CHM therapy for more than 90 days had significantly lower hazard ratios of mortality risk than non-CHM users. The survival probability was higher for patients in the CHM group. Bai-hua-she-she-cao (Herba Oldenlandiae; Hedyotis diffusaSpreng) and Xiang-sha-liu-jun-zi-tang (Costus and Chinese Amomum Combination) were the most commonly used single herb and Chinese herbal formula, respectively. Conclusions: Complementary Chinese herbal therapy might be associated with reduced mortality among patients with pancreatic cancer. Further prospective clinical trial is warranted.
Li, TM. J Ethnopharmacol, 2018
The Chinese Herbal Medicine (CHM) group was characterized by a longer follow up time and more cases of hyperlipidemia and liver cirrhosis. This group exhibited a lower mortality hazard ratio, after adjusting for comorbidities. The trend was also observed that the cumulative survival probability was higher in CHM than in non-CHM users. Analysis of their CHM prescription pattern revealed that Bu-Zhong-Yi-Qi-Tang (BZYQT), Xiang-Sha-Liu-Jun-Zi-Tang (XSLJZT), and Bai-He-Gu-Jin-Tang (BHGJT); and Bei-Mu (BM), Xing-Ren (XR) and Ge-Gen (GG) were found to be the top three formulas and herbs, respectively. Among them, BM was the core CHM of the major cluster, and Jie-Geng (JG) and Mai-Men-Dong-Tang (MMDT) were important CHMs by CHM network analysis. Conclusion: The use of CHM as an adjunctive therapy may reduce the mortality hazard ratio of lung cancer patients. The investigation of their comprehensive CHM prescription patterns might be useful in future large-scale, randomized clinical investigations of agent effectiveness, safety, and potential interactions with conventional treatments for lung cancer patients.
Ohnishi, S. J Gynecol Oncol, 2017
Patients with uterine cervical or corpus cancer who were to receive cisplatin (50 mg/m² day 1) and paclitaxel (135 mg/m² day 0) as first-line chemotherapy were randomly assigned to the rikkunshito (Liu Jun Zi Tang) group receiving oral administration on days 0-13 with standard antiemetics, or the control group receiving antiemetics only. The CC rate in the overall phase was significantly higher in the rikkunshito group than in the control group, as were the secondary endpoints: the CC rate in the delayed phase (24-120 hours), and the complete response (CR) rates (no emesis and no rescue medication) in the overall and delayed, and time to treatment failure. Appetite assessed by visual analogue scale (VAS) appeared to be superior in the rikkunshito group from day 2 through day 6. Conclusion: Rikkunshito (Liu Jun Zi Tang) provided additive effect for the prevention of CINV and anorexia.
Hung, KF. J Ethnopharmacol, 2017. Mar 6;199:168-174
From the Registry for Catastrophic Illness Patients Database, we included all patients with gastric cancer whose age at diagnosis was ≥18 from 1997 to 2010 in Taiwan. There was a total of 1333 patients in the CHM-cohort and 44786 patients in the non-CHM cohort. After matching, we compared 962 newly diagnosed CHM users and 962 non-CHM users. CHM users had a lower HR of mortality risk. Compared to the non-CHM users, the aHR among CHM-users is 0.37 for those who used CHM more than 180 days annually. The Kaplan-Meier curve revealed that the survival probability was higher for complementary CHM-users. Bai-Hua-She-She-Cao (Herba Hedyotidis Diffusae) was the most commonly used single herb and Xiang-Sha-Liu-Jun-Zi-Tang was the most commonly used herbal formula among CHM prescriptions. Conclusion: Complementary CHM improves the overall survival among patients with gastric cancer in Taiwan. Further ethnopharmacological investigations and clinical trials are required to validate the efficacy and safety.
Fleischer T, Chang TT, Chiang JH, et al. Integr Cancer Ther. 2017 Jun;16(2):156-164.
Using the Taiwanese National Health Insurance Research Database, we performed a nationwide population-based cohort study among AML patients from 1997 to 2010. 498 patients were included into the study. The HR of the CHM group was 0.41 (95% CI = 0.26-0.65; P = .0001) compared with the non-CHM group. This decrease in HR was also shown to be dose dependent ( P < .001). The 3 single-herbs most commonly prescribed were Salvia miltiorrhiza (Dan Shen), Astragalus membranaceus (Huang Qi), and Spatholobus suberectus (Ji Xue Teng). The 3 mutli-herb products most commonly prescribed were Jia Wei Xiao Yao San, Gui Pi Tang, and Qi Ju Di Huang Wan. Conclusion: Prospective controlled clinical data is still needed, however, this study provides real-world data regarding the benefit AML patients may have from CHM. This study suggests that all AML patients, regardless of age or other prognostic factors, may achieve longer survival times when receiving CHM in addition to standard therapy.
Yu Mao, Jian Hao, Zi-Qi Jin, et al. Oncotarget. 2017 Apr 18; 8(16): 27007–27021.
Chinese Herbal Medicine (CHM) plays a significant role in breast cancer treatment. We conduct the study to ascertain the relative molecular targets of effective Chinese herbs in treating stage IV breast cancer. Patients in the CHM group had a median survival time of 55 months, which was longer than the 23 months of patients in the non-CHM group. Cox regression analysis indicated that CHM was an independent protective factor. Correlation analysis showed that 10 herbs were strongly correlated with favorable survival outcomes (P<0.01). Bioinformatics analyses suggested that the 10 herbs might achieve anti-breast cancer activity primarily through inhibiting HSP90, ERα and TOP-II related pathways.
Note:
Among a number of active compounds, Quercitin was found in all of these herbs. The authors state, "Quercetin, a kind of flavonoids found in various plants, can inhibit the proliferation of a broad scope of malignancies." Among these ten herbs were: San Qi: Panax Notoginseng (Radix Pseudoginseng), Gan Cao: Licorice root (Radix Glycyrrhizae), Qing Pi: Tangerine peel (Citri Reticulatae Pericarpium viride), Shang Lu: Poke Root (Phytolaccae Radix), Tian Hua Fen: Trichosanthes (Trichosanthes Kirilowii Maxim), Zhe Bei Mu: Fritillaria bulb (Fritillariae Thunbergii Bulbus), Yin Yang Huo: Epimedium (Herba Epimedii). It is important to realize that these herbs were not taken alone but as part of appropriately prescribed Chinese Herbal Medicine Formulas. Herbal medicines contain many compounds that often work synergistically to assist in disease control. This is one of the reasons I recommend Traditional Chinese Herbal Medicines over single compound supplements which are often given with a pharmacological mechanism in mind and may require different doses to achieve a meaningful result. Results of studies like these should be interpreted with the understanding that efficacy when taken as part of a patient specific herbal formula prescription does not necessarily prove efficacy if taken alone.
Fleischer T, Chang TT, Chiang JH, et al. Medicine (Baltimore). 2016 May;95(21):e3788.
An NHI Research Database-based cohort study was performed; the timeframe of the study was January 2000 to December 2010. A total of 808 patients were diagnosed with CLL in Taiwan within the defined study period. After randomly matching for age and sex and excluding patients younger than 18 years of age, data from 616 patients were analyzed. The 2 study groups both received standard of care treatment. In addition, 1 group also received CHM. Patients who were registered as receiving other forms of CM, such as acupuncture, were excluded. We found that the HR associated with the adjunctive use of CHM was less than half when compared to the non-CHM group (0.43, 95% CI 0.33-0.55, P < 0.0001) and that treatment-naive patients who used CHM had the lowest HR. We also established that this association between reduction in HR and CHM was dose-dependent, and the longer CHM users received prescriptions, the lower the HR (P < 0.001). Conclusion: Our data suggests that the treatment of CLL with adjunctive CHM may have a substantial positive impact on mortality, especially for treatment-naive patients. Further research is needed to confirm whether there is a direct causal relationship between CHM and the outcomes displayed.
Guo L, Bai SP, Zhao L, et al. Med. Oncol. 2012;29(3):1656–1662.
One hundred thirty-six patients with NSCLC were enrolled in this study from May 2008 to March 2010. Patients were randomized to receive either VC (VC arm) or VC combined with APS (VC-APS arm). The objective response rate of was 42.64% in the VC-APS arm and 36.76% in the VC arm. The difference was not statistically significant. Median survival time was 10.7 and 10.2 months in VC-APS arm and VC arm, with 1-year survival rates of 35.3 and 32.4%, respectively. After 3 cycles of treatment, there were significant differences in the overall patient QOL, physical function, fatigue, nausea and vomiting, pain, and loss of appetite between the two study groups. Conclusion: the treatment of APS integrated with VC had significantly improved QOL in patients with advanced NSCLC compared with VC alone.
Ghalaut VS, Sangwan L, Dahiya K, et al. J Oncol Pharm Pract. 2012 Jun;18(2):186-90.
Nitric oxide (NO) is involved in different stages of malignancies. Increased levels of NO have been reported in different leukemias. Imatinib is the preferred drug for the treatment of chronic myeloid leukemia (CML). Turmeric powder contains curcumin which has anti-leukemic property and also decreases NO synthesis. This study was conducted on fifty patients of CML divided into two groups, group A receiving imatinib alone and group B receiving turmeric powder along with imatinib for six weeks. Nitric oxide levels were estimated in these patients before and after receiving therapy and were analyzed statistically. Nitric oxide levels were found to be significantly decreased in both the groups, but more significantly in group B after receiving the respective treatments. Thus, curcumin acts as an adjuvant to imatinib in decreasing the NO levels and may help in the treatment of CML patients.
Chan KK, Yao TJ, Jones B, et al. Ann Oncol. 2011 Oct;22(10):2241-9.
Patients with ovarian cancer were randomized to receive either TCM or placebo in addition to standard chemotherapy. The primary outcome was global health status (GHS) score, assessed by European Organization for Research and Treatment of Cancer questionnaire, while the secondary outcomes were other QOL items, chemotoxicity according to World Health Organization criteria and alterations in immune function as measured by immune cells count and the numbers of cytokines-secreting cells. There was no significant difference in the GHS between the two groups. With adjustment for stage, chemotherapy type, disease status, age and baseline value, emotional function, cognitive function and nausea and vomiting were found to be worse or less improved in the TCM group compared with placebo group after six cycles of chemotherapy. The TCM group had less neutropenia after three cycles (0% grade 4 neutropenia versus 28.6%). There were no other significant differences in terms of chemotoxicity. Lymphocyte counts and cytokine activities decreased less in the TCM group. Conclusions:TCM did not improve QOL but did have some effects in terms of maintaining immune function.
Liu ML, Chien LY, Tai CJ, et al. Evid Based Complement Alternat Med. 2011.
A case-control design was used to examine the medical records of patients with cancer who received chemotherapy in a teaching hospital in Taipei in 2004. A total of 184 courses of chemotherapy among 89 patients were studied. Of the 184 courses, 42 used TCM jointly with chemotherapy served as cases, while the remaining 142 courses served as controls. Outcome variables included counts of cancelled or delayed chemotherapies and liver function (aspartate aminotransferase, AST and alanine aminotransferase, ALT) 1 week before, during and 2 weeks after chemotherapy. Generalized estimating equations were used to analyze the data. Patients who had concomitant TCM with chemotherapy had lower serum ALT and AST during chemotherapy than the controls. There was no significant difference between the case and control groups for odds of completing one course of chemotherapy. Conclusion: Use of TCM with chemotherapy resulted in protection of the liver during chemotherapy, as manifested by lower serum AST and ALT levels.
Lee J.J., Lee J.J. Integr. Cancer Ther. 2010;9(1):24–31.
All patients with histologic evidence of an incurable malignancy had a weight loss of at least 5% during the preceding 6 months and a patient-estimated severe anorexia. The herbal decoction was administered 30 minutes after meals, three times a day for 3 weeks. Eleven patients were recruited from January, 2007 to January, 2009. The mean age was 59.8 years old. The change in anorexia from baseline with the herbal decoction was significantly different and anorexia was improved. The mean value of the maximal body weight was 55.6 kg and differed significantly from the 54.6 kg at baseline. Changes in cytokine levels and anthropometric measurements from baseline to the 3rd week were not significant. All toxicities were manageable. Conclusion: Appetite and body weight were improved with the herbal decoction. This herbal decoction shows some potential for management of cancer-related anorexia.
Yen Y, So S, Rose M, et al. Anticancer Res. 2009;29(10):4083–4092.
PHY906 is a Chinese medicine formula consisting of a mixture of four herbs (Scutellaria baicalensis Georgi, Glycyrrhiza uralensis Fisch., Paeonia lactiflora Pall., and the fruit of Ziziphus jujube Mill.) with claims for the treatment of severe gastrointestinal distress. PHY906 enhanced the therapeutic index of various chemotherapeutic agents in human hepatocellular carcinoma xenografts. Accordingly, here a phase I/II clinical study was conducted with the combination of capecitabine in patients with advanced, unresectable hepatocellular carcinoma. More than 60% of patients had either stable disease or better after two treatment cycles. Median overall survival was 9.2 months. Asian patients had a higher median overall survival (16.5 months) than non-Asian patients (6.2 months, p=0.03). Patients' quality of life did not deteriorate significantly during treatment. Conclusion: This finding supported further investigation of PHY906 as an adjuvant therapy of capecitabine in a larger hepatocellular cancer population.
In Vivo Animal Studies
Traditional Chinese medicine Gegen Qinlian decoction ameliorates irinotecan chemotherapy-induced gut toxicity in mice.
Wu Y, Wang D, Yang X, et al. Biomed Pharmacother. 2019 Jan;109:2252-2261
Gegen Qinlian decoction (GQT), is a classic traditional Chinese medicine formula chronicled in Shang Han Lun, and is widely used to treat diarrhea and inflammation symptoms in various gastrointestinal disorders. The protective effect of GQT extract towards alleviating diarrhea in mice following irinotecan administration was investigated. The synergistic effect of GQT extract combined with irinotecan against tumor growth in a colorectal tumor mouse model, induced by HT-29 colon cancer cells xenograft subcutaneously, was investigated. The obtained GQT extract profoundly ameliorated the gut toxicity induced by irinotecan. After 5 days of administration of GQT extract to mice with diarrhea induced by irinotecan, aberrantly elevated levels of pro-inflammatory cytokines, including IL-1β, COX-2, ICAM-1, and TNF-α, were significantly decreased. Meanwhile, GQT extract also exhibited a remarkable anti-oxidative stress effect. Moreover, GQT extract was shown to improve inhibition of the colonic tumor growth synergistically with irinotecan. Conclusion: The present study indicates that GQT extract can ameliorate irinotecan induced gut toxicity in mice and improve irinotecan efficacy in colorectal cancer treatment.
Sin TK, Tam BT, Yung BY, et al. J. Physiol. 2015;593(8):1887–1899.
Animals were randomized to receive saline, doxorubicin, and doxorubicin in combination with resveratrol, in the presence or absence of SIRT1 inhibitors, sirtinol or EX527. Resveratrol alone, but not in combination with either of the SIRT1 inhibitors, suppressed the doxorubicin-induced impairment of cardiac systolic function in aged animals. Conclusion: These data demonstrate that resveratrol ameliorates doxorubicin-induced cardiotoxicity in aged hearts through the restoration of SIRT1 activity to attenuate USP7-related catabolic/pro-apoptotic signaling.
Takeda H, Sadakane C, Hattori T, et al. Gastroenterology. 2008 Jun;134(7):2004-13.
This study investigated the decreases of plasma acylated-ghrelin level and food intake caused by cisplatin, serotonin (5-HT), 5-HT agonists, and vagotomy as well as the decrease-suppressing effects of rikkunshito (Liu Jun Zi Tang) and 5-HT antagonists. In addition, binding affinities of rikkunshito (Liu Jun Zi Tang) components were determined in receptor-binding assays using 5-HT2B and 5-HT2C receptors. Administration of rat ghrelin improved the cisplatin-induced decrease in food intake. Vagotomy decreased the plasma acylated-ghrelin level, which was decreased further by cisplatin. Rikkunshito (Liu Jun Zi Tang) suppressed such cisplatin-induced decreases of plasma acylated-ghrelin level and food intake. The suppressive effect of rikkunshito (Liu Jun Zi Tang) was blocked by a ghrelin antagonist. Oral administration of rikkunshito (Liu Jun Zi Tang) suppressed the cisplatin-induced decrease in the plasma acylated-ghrelin level. Conclusion: The cisplatin-induced decreases of the plasma acylated-ghrelin level and food intake are mediated by 5-HT2B/2C receptors and suppressed by flavonoids in rikkunshito.
In addition to the more clinically-focused studies like the ones above, there are thousands of in vitro studies published regarding the mechanisms of action of individual herbs in various cancer-related topics. (In vitro means that the studies take place outside of a living organism, such as in a test tube or petri dish. In vivo means a study which take place in an actual living organism.)
While all these types of studies carry their own limitations related to various research designs, these studies provide invaluable information for the continued progress in our understanding of how best to utilize herbal therapies in patient care. They are an important part of the systematic process of the scientific method in gathering information to determine which types of treatment interventions are worthy of more extensive (and costly) investigation with randomized, placebo controlled clinical trials.
A Clinical Approach to Herbal Therapies and Chemotherapy
With careful patient selection and client education, I have used a number of herbal formulas, from specific herbal companies that I trust, simultaneously with Adriamycin, Cytoxan, Leukeran, Vincristine, Vinblastine, Mitoxantrone, Actinomycin D, Carboplatin, CCNU and Palladia with no anecdotally observed increase in clinically relevant chemotherapy toxicity in my practice over the past 12 years. Based on these years of clinical experience directly and carefully managing patients with Chinese Herbal Medicine and chemotherapy, this is how I generally tend to incorporate herbal therapies into my Integrative Medicine approach to patient care:
Before starting herbal formulas, I first document tumor response/behavior when gross disease is present. This allows for more objective assessment about how herbal treatments are affecting tumor response. In my practice, herbal prescriptions are always made on a patient specific basis using Traditional Chinese Herbal Medicine prescribing principles and cross referenced with what is known from available western biomedicine research.
In patients receiving combination treatment with chemotherapy and herbs, I usually recommend introducing herbal therapies after the first cycle of chemotherapy is administered in order to determine baseline responses and toxicities in individual patients. Individual patient metabolism and sensitivities to chemotherapy and other drugs can vary. This allows for ease in clinical management and better determination of cause of any observed side effects. Physical exams and reassessment are performed typically every 3-4 weeks, more or less depending on the patient. Bloodwork is monitored regularly.
Another more conservative approach would be to stop herbal therapies 48 hours before chemotherapy and start again 48 hours after. Alternatively, some clinicians or clients may choose to wait until completion of chemotherapy and implement herbal therapies as a type of maintenance therapy or supportive care. Unless herbs are being used specifically with the goal of mitigating side effect of chemotherapy, such as myelosuppression, these are good options for those who are uncomfortable combining herbal therapies concurrent with chemotherapy administration.
Herbal therapies, like any other prescribed treatment, should always be used with informed consent regarding what is and is not known about efficacy, toxicity and combination therapies. Based on the published prospective and retrospective evaluation of human cases, integration seems to be well-tolerated. There is no overt evidence that "Chinese herbal therapies", in general, decrease survival or increase toxicity when administered with the chemotherapy drugs we typically use in veterinary medicine in most of these retrospective populations. This also fits with my personal clinical experience. In fact, many of these studies suggest the potential for improving disease control and/or decreasing toxicities, motivating development of prospective clinical trials.
There does exist, however, the reality of potential herb-drug interactions. It is always recommended to work closely with a veterinarian trained in herbal medicine when using these therapies in your pet, especially if they are receiving other medications. For example, hormone responsive cancers require special consideration as some herbs display estrogenic activity. Additionally, there is some evidence that toxicity may occur with specific herb/chemotherapy combinations, such as a case report of liver toxicity with concomitant use of Temozolamide and Bu Zhong Yi Qi Tang, a Chinese Herbal formula commonly prescribed to support quality of life in patients receiving chemotherapy.
A Note on Interpreting the Research
A majority of published research on potential anti-neoplastic action of herbs and their compounds exists as in vitro and in vivo studies, many of which evaluate individual compounds found in single herbs with the goal of identifying compounds which can be developed into pharmaceutical drugs. This information provides scientific proof of principle and aides in our understanding of the mechanisms by which these herbs may be exerting their clinical effects. However conclusions derived from these types of studies must be interpreted with the understanding that effects in vitro, or in vivo studies using injectable forms of the herbs, do not necessarily predict biological or clinically relevant activity in a patient receiving oral treatment. Chinese herbal medicine is prescribed as complex multi-herb formulas which contain numerous compounds and herbs. Studies have shown herb combining results in synergistic activity and also modulates absorption, metabolism and potential side effects of sister herbs within the formula. Additionally, herbal formulas are ingested orally so are also impacted by the gut microbiome, which may alter the compounds which are ultimately absorbed into the living system.
Perspectives on Drug-Herb Interactions
Complicating determination of clinically relevant herb-drug interactions based on published literature is the fact that in vitro evidence of interaction does not necessarily correlate with clinically relevant toxicities or in vivo interactions in a living biological system orally ingesting whole herbs (rather than specific isolated compounds) or complex formulas. For example, milk thistle and Panax ginseng show CYP3A4 inhibition in vitro, raising theoretical concern for risk of increasing toxicity of drugs metabolized through this pathway. However, in clinical studies these herbal supplements did not cause significant pharmacokinetic interactions with midazolam, irinotecan, docetaxel and imatinib. Additionally, the brand and dosing of herbal products as well as timing of oral administration with chemotherapy may affect these potential interactions.
Similarly, there is in vitro evidence of CYP3A4 inhibition by single herbs which contradicts the in vivo information. This illustrates that in vitro data may not correlate with metabolism in a living organism or with clinically relevant herb-drug interactions. There is also evidence that certain herbs, like Angelica Root/Dang Gui, inhibit CYP3A4 in vivo although the formulas they are contained in do not. Based on this information, then, individual herbs may have different effects on the P450 system than the multi-herb formulas in which they are contained. It may be that the amount of single herb within a larger formula is not sufficient to cause inhibition seen with the individual herb or that the complex interaction of the herbs within the whole formula alters the pharmacodynamics seen with individual herbs.
Additionally, pharmacodynamics related to P450 effects from herbal therapies are complex. Some plants and compounds which inhibit P450 enzymes in vitro have shown tissue specific effects. The importance of this is that inhibition of P450 enzymes by these compounds may, for example, positively impact drug absorption from the intestines via these routes and/or positively impact tumor response in tumor tissue without impacting pharmacokinetics of drug clearance effects on liver P450. Quercitin and Tetradine (derived from Stephania/Hang Fang Ji) are two examples of this.
References (click on article title for links)
Saruwatari J, Nakagawa K, Shindo J, et al. The in-vivo effects of sho-saiko-to, a traditional Chinese herbal medicine, on two cytochrome P450enzymes (1A2 and 3A) and xanthine oxidase in man. J Pharm Pharmacol. 2003 Nov;55(11):1553-9.
Fan XH, Shi WZ, Cheng YX, Zou KJ, Yang XF. [Effects of xuefu zhuyu decoction on antioxidant and drug-metabolizing enzymes in liver of rats]. [Article in Chinese] Zhongguo Zhong Yao Za Zhi. 2014 Nov;39(22):4453-8
Fan XH, Shi WZ, Cheng YX, Yang XF. Effects of Buyang Huanwu Decoction on antioxidant and drug-metabolizing enzymes in rat liver. Chin J Nat Med. 2014 Jun;12(6):449-54.
Goey AK, Mooiman KD, Beijnen JH, et al. Relevance of in vitro and clinical data for predicting CYP3A4-mediated herb-drug interactions in cancer patients. Cancer Treat Rev. 2013 Nov;39(7):773-83.
Hu XQ, Sun Y, Lau E, Zhao M, Su SB. Advances in Synergistic Combinations of Chinese Herbal Medicine for the Treatment of Cancer. Current Cancer Drug Targets. 2016 May; 16(4): 346-356.
Choi JS, Piao YJ, Kang KW. Effects of quercetin on the bioavailability of doxorubicin in rats: role of CYP3A4 and P-gp inhibition by quercetin. Arch Pharm Res. 2011 Apr;34(4):607-13.
Dai CL, Xiong HY, Tang LF, et al. Tetrandrine achieved plasma concentrations capable of reversing MDR in vitro and had no apparent effect on doxorubicin pharmacokinetics in mice. Cancer Chemother Pharmacol. 2007 Oct;60(5):741-50.
A Clinical Perspective on Potential or Theoretical Herb-Drug Interactions
Risk of metabolic P450 (CYP3A4) interaction with chemotherapy for the formulas Xiao Chai Hu Tang, Xue Fu Zhu Yu Tang and Bu Yang Huang Wu Tang should be low based on evidence that these formulas did not inhibit CYP34A in human and rat studies in vivo.
Patients receiving other P450 substrate medications, medications with a narrow therapeutic index, or medications in which small changes in blood levels may significantly impact patient wellness (such as cardiac medications or anti-seizure medications), should be managed carefully with thoughtful consideration given to risk versus benefit of concurrent administration of herbal formulas. One practical consideration may be to separate administration of medications and herbs.
Notice that many drugs which are known to affect P450 enzymes are routinely given concurrently with chemotherapy without commonly recognized clinically relevant increase in toxicities. This is also true for many herbal medicines used in veterinary Chinese Herbal Medicine. Increased risk for alterations in drug clearance or efficacy are expected to be more likely when multiple drugs, whether they are pharmaceutical or herbal, are used simultaneously and may be affected by dose intensity.
Medications which may affect P450 drug metabolism for drugs commonly used in veterinary oncology: on-line resource
CYP3A4 substrates:
Adriamycin, Vinca Alkyloids, Tyrosine Kinase Inhibitors,
dexamethasone/prednisone, tramadol, fentanyl, etoposide
CYP3A4 inhibitors:
erythromycin, ketoconazole, ciprofloxacin, diltiazem, enrofloxacin
CYP3A4 inducers:
phenobarbital
CPY2C19 substrates:
Cytoxan, Plavix, diazepam
CPY2C19 inhibitors:
cimetidine, omeprazole, fluoxetine, fluconazole, ketoconazole