Fecal SN-38 Content as a Surrogate Predictor of Intestinal SN-38 Exposure and Associated Irinotecan-induced Severe Delayed-Onset Diarrhea by a Novel Use of the Spectrofluorimetric Method.

BACKGROUND: Irinotecan administration can lead to severe delayed-onset diarrhea (SDOD) in clinical practice. Currently, there is no reliable surrogate predictor of intestinal exposure to SN-38 and subsequent diarrhea incidence. METHODS: The relationship between fecal 7-ethyl-10-hydroxycamptothecin (SN-38) content and SDOD was investigated in Fisher 344 rats using a novel spectrofluorimetric method. Additionally, a pharmacokinetic study of irinotecan was performed to evaluate the biodistribution of SN-38 to establish the relationship between tissue and fecal SN-38 exposure. RESULTS: The spectrofluorimetric method was successfully employed to measure fecal SN-38 and CPT-11 content from Day 3 to Day 6 post-irinotecan administration. Only fecal SN-38 content on Day 3 exhibited a significantly positive correlation with SDOD incidence on Days 4 and 5. A cutoff value of SN-38 ≥ 0.066 mg/g in feces was identified, predicting severe diarrhea incidence with 81% accuracy and 80% specificity. The positive correlation between fecal SN-38 content and SN-38 exposure in the ileum on Day 3 was also reflected in the changes of indicators during intestinal injury, such as prostaglandin E2 level and antioxidant activity. CONCLUSION: Fecal SN-38 content proves to be representative of intestinal exposure to SN-38, indicative of intestinal injury, and predictive of SDOD incidence in rats, while the spectrofluorimetric method demonstrates the translational potential.

Herbal Medicines as Adjuvants for the Treatment of Chemotherapy-Induced Diarrhea.

BACKGROUND: Chemotherapeutic drugs used in cancer treatment often result in gastrointestinal toxicity, notably diarrhea, impacting patients' quality of life. Complementary and Alternative Medicine (CAM) has garnered increasing interest as an alternative to conventional approaches as a potential solution for managing chemotherapyinduced diarrhea (CID). OBJECTIVE: To summarize current research focusing on herbal medicines as adjuvant therapy to prevent or treat chemotherapy-induced diarrhea, including clinical assessments, mechanism of actions, active components, and potential pharmacokinetic interactions between herbal medicines and chemotherapeutic drugs. METHODS: We performed the literature review from PubMed, CNKI, Google Scholar, Web of Science, and Scopus using "Chemotherapy", "Diarrhea," and "Complementary and Alternative Medicine" as the search keywords. RESULTS: Using herbal medicines as adjuvants provides an effective approach to treating or preventing CID with improved or unaffected antitumor activity of chemotherapeutic drugs. Among these herbal formulations, scutellaria, ginger, and ginseng are the most frequently used herbs in the prescriptions for CID. The main antidiarrheal components in herbs include wogonin, baicalin, chrysin, quercetin, gingerol, and ginsenosides. These herbs, formulations, and bioactive components relieved CID through different mechanisms, including directly decreasing local drug exposure, anti-inflammation, inhibiting epithelial apoptosis, or promoting epithelium stem cell regeneration. The application of herbal medicines as adjunctive therapies showed efficacy in preventing or treating CID in multiple clinical trials. However, more well-designed clinical studies are expected to validate the results further. Despite some clinical studies demonstrating that certain herbal medicines could potentially attenuate CID and improve efficacy, it remains necessary to evaluate herbal safety. The interactions between herbs and drugs are also potential concerns, but few clinical trials have focused on investigating this aspect. CONCLUSION: In clinical practise, herbal medications show potential as adjuvant treatments for gastrointestinal toxicities induced by chemotherapy, particularly diarrhoea. Further well-designed clinical studies are needed to validate their efficacy, ensure safety, and explore potential drug-herb interactions.

[Bletilla striata polysaccharide improves toxic and side effects induced by 5-FU: an untargeted metabolomics study].

This study aimed to analyze the effect of Bletilla striata polysaccharide(BSP) on endogenous metabolites in serum of tumor-bearing mice treated with 5-fluorouracil(5-FU) by untargeted metabolomics techniques and explore the mechanism of BSP in alleviating the toxic and side effects induced by 5-FU. Male BALB/C mice were randomly divided into a normal group, a model group, a 5-FU group, and a 5-FU + BSP group, with eight mice in each group. Mouse colon cancer cells(CT26) were transplanted into the mice except for those in the normal group to construct the tumor-bearing mouse model by subcutaneous injection, and 5-FU chemotherapy and BSP treatment were carried out from the second day of modeling. The changes in body weight, diarrhea, and white blood cell count in the peripheral blood were recorded. The mice were sacrificed and sampled when the tumor weight of mice in the model group reached approximately 1 g. TUNEL staining was used to detect the cell apoptosis in the small intestine of each group. The proportions of hematopoietic stem cells and myeloid progenitor cells in bone marrow were measured by flow cytometry. Five serum samples were selected randomly from each group for untargeted metabolomics analysis. The results showed that BSP was not effective in inhibiting colon cancer in mice, but diarrhea, leukopenia, and weight loss caused by 5-FU chemotherapy were significantly improved after BSP intervention. In addition, apoptotic cells decreased in the small intestinal tissues and the percentages of hematopoietic stem cells and myeloid progenitor cells in bone marrow were significantly higher after BSP treatment. Metabolomics results showed that the toxic and side effects of 5-FU resulted in significant decrease in 29 metabolites and significant increase in 22 metabolites in mouse serum. Among them, 19 disordered metabolites showed a return to normal levels in the 5-FU+BSP group. The results of pathway enrichment indicated that metabolic pathways mainly involved pyrimidine metabolism, arachidonic acid metabolism, and steroid hormone biosynthesis. Therefore, BSP may ameliorate the toxic and side effects of 5-FU in the intestinal tract and bone marrow presumably by regulating nucleotide synthesis, inflammatory damage, and hormone production.

Collagenous Colitis in a Patient With Gastric Cancer Who Underwent Chemotherapy.

Herein, we present a case of collagenous colitis in a patient who underwent chemotherapy for gastric cancer, comprising five cycles of S-1 plus oxaliplatin and trastuzumab, followed by five cycles of paclitaxel and ramucirumab and seven cycles of nivolumab. The subsequent initiation of trastuzumab deruxtecan chemotherapy led to the development of grade 3 diarrhea after the second cycle of treatment. Collagenous colitis was diagnosed via colonoscopy and biopsy. The patient's diarrhea improved following the cessation of lansoprazole. This case highlights the importance of considering collagenous colitis as a differential diagnosis, in addition to chemotherapy-induced colitis and immune-related adverse event (irAE) colitis, in patients with similar clinical presentations.

(-)-Epigallocatechin-3-Gallate Attenuates the Adverse Reactions Triggered by Selenium Nanoparticles without Compromising Their Suppressing Effect on Peritoneal Carcinomatosis in Mice Bearing Hepatocarcinoma 22 Cells.

Increasing evidence shows that selenium and polyphenols are two types of the most reported compounds in tumor chemoprevention due to their remarkable antitumor activity and high safety profile. The cross-talk between polyphenols and selenium is a hot research topic, and the combination of polyphenols and selenium is a valuable strategy for fighting cancer. The current work investigated the combination anti-peritoneal carcinomatosis (PC) effect of selenium nanoparticles (SeNPs) and green tea (Camellia sinensis) polyphenol (-)-epigallocatechin-3-gallate (EGCG) in mice bearing murine hepatocarcinoma 22 (H22) cells. Results showed that SeNPs alone significantly inhibited cancer cell proliferation and extended the survival time of mice bearing H22 cells. Still, the potential therapeutic efficacy is accompanied by an approximately eighty percent diarrhea rate. When EGCG was combined with SeNPs, EGCG did not affect the tumor proliferation inhibition effect but eliminated diarrhea triggered by SeNPs. In addition, both the intracellular selectively accumulated EGCG without killing effect on cancer cells and the enhanced antioxidant enzyme levels in ascites after EGCG was delivered alone by intraperitoneal injection indicated that H22 cells were insensitive to EGCG. Moreover, EGCG could prevent SeNP-caused systemic oxidative damage by enhancing serum superoxide dismutase, glutathione, and glutathione peroxidase levels in healthy mice. Overall, we found that H22 cells are insensitive to EGCG, but combining EGCG with SeNPs could protect against SeNP-triggered diarrhea without compromising the suppressing efficacy of SeNPs on PC in mice bearing H22 cells and attenuate SeNP-caused systemic toxicity in healthy mice. These results suggest that EGCG could be employed as a promising candidate for preventing the adverse reactions of chemotherapy including chemotherapy-induced diarrhea and systemic toxicity in cancer individuals.

CDK4/6 inhibitor modulating active and quiescent intestinal stem cells for prevention of chemotherapy-induced diarrhea.

Chemotherapy-induced diarrhea causes dehydration, debilitation, infection, and even death, but there are currently no Food and Drug Administration (FDA)-approved drugs for treatment of chemotherapy-induced diarrhea. It is generally believed that the timely regulation of intestinal stem cell (ISC) fate may provide a meaningful solution for intestinal injuries. However, the lineage plasticity of ISCs during and after chemotherapy remains poorly understood. Here, we demonstrated that palbociclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, regulated the fate of active or quiescent ISCs, provided multilineage protection from the toxicity of several different chemotherapeutics, and accelerated gastrointestinal epithelium recovery. Consistent with in vivo results, we determined that palbociclib enhanced intestinal organoid and ex vivo tissue survival after chemotherapy. Lineage tracing studies have shown that palbociclib protects active ISCs marked by Lgr5 and Olfm4 during chemotherapy and unexpectedly activates quiescent ISCs marked by Bmi1 to immediately participate in crypt regeneration after chemotherapy. Furthermore, palbociclib does not decrease the efficacy of cytotoxic chemotherapy in tumor grafts. The experimental evidence suggests that the combination of CDK4/6 inhibitors with chemotherapy could reduce damage to the gastrointestinal epithelium in patients. © 2023 The Pathological Society of Great Britain and Ireland.

Bletilla striata polysaccharide improves toxic and side effects induced by 5-FU: an untargeted metabolomics study / 中国中药杂志

This study aimed to analyze the effect of Bletilla striata polysaccharide(BSP) on endogenous metabolites in serum of tumor-bearing mice treated with 5-fluorouracil(5-FU) by untargeted metabolomics techniques and explore the mechanism of BSP in alleviating the toxic and side effects induced by 5-FU. Male BALB/C mice were randomly divided into a normal group, a model group, a 5-FU group, and a 5-FU + BSP group, with eight mice in each group. Mouse colon cancer cells(CT26) were transplanted into the mice except for those in the normal group to construct the tumor-bearing mouse model by subcutaneous injection, and 5-FU chemotherapy and BSP treatment were carried out from the second day of modeling. The changes in body weight, diarrhea, and white blood cell count in the peripheral blood were recorded. The mice were sacrificed and sampled when the tumor weight of mice in the model group reached approximately 1 g. TUNEL staining was used to detect the cell apoptosis in the small intestine of each group. The proportions of hematopoietic stem cells and myeloid progenitor cells in bone marrow were measured by flow cytometry. Five serum samples were selected randomly from each group for untargeted metabolomics analysis. The results showed that BSP was not effective in inhibiting colon cancer in mice, but diarrhea, leukopenia, and weight loss caused by 5-FU chemotherapy were significantly improved after BSP intervention. In addition, apoptotic cells decreased in the small intestinal tissues and the percentages of hematopoietic stem cells and myeloid progenitor cells in bone marrow were significantly higher after BSP treatment. Metabolomics results showed that the toxic and side effects of 5-FU resulted in significant decrease in 29 metabolites and significant increase in 22 metabolites in mouse serum. Among them, 19 disordered metabolites showed a return to normal levels in the 5-FU+BSP group. The results of pathway enrichment indicated that metabolic pathways mainly involved pyrimidine metabolism, arachidonic acid metabolism, and steroid hormone biosynthesis. Therefore, BSP may ameliorate the toxic and side effects of 5-FU in the intestinal tract and bone marrow presumably by regulating nucleotide synthesis, inflammatory damage, and hormone production.

Effects of Liujun Anwei Prescription on NF-κB and iNOS protein in small intestine of mice with chemotherapy-related diarrhea based on mass spectrometry and network pharmacology / 国际中医中药杂志

Objective:To investigate the potential key targets of Liujun Anwei Prescription and its effects on NF-κB/iNOS-NO in small intestine of mice with chemotherapy- associated diarrhea; To reveal the anti-inflammatory components and molecular mechanism.Methods:UPLC-Q/TOF MS combined with UNIFI software was used to analyze the chemical components of Liujun Anwei Prescription. PubChem database was searched to obtain the active components of Liujun Anwei Prescription, and the Swiss Target Prediction was used to predict the targets. The database of DisGeNET, OMIM and GeneCards were searched to obtain the targets of chemotherapy-related diarrhea. The potential targets of Liujun Anwei Prescription in the treatment of chemotherapy-related diarrhea diseases were obtained by crossing the targets of active components of Liujun Anwei Prescription and those related to diarrhea diseases. The PPI network and component-target-pathway network were constructed by Cytoscape 3.7.1 software, and the intersecting targets were analyzed by GO and KEGG based on David Database. The potential active components and potential targets predicted in the network were verified by using Autodock software. 60 C57BL/6J male mice were divided into normal control group, model group, positive control group and Liujun Anwei Prescription high-, medium- and low-dosage groups according to random number table method, with 10 mice in each group. In addition to the normal control group, the other groups of mice were intraperitoneally injected with 5-fluorouracil injection 50 mg/kg preparation to construct CID mouse model. After 14 days, the expressions of NF-κB and iNOS in jejunum were detected by Western blot.Results:A total of 197 compounds were identified, and 156 key compounds of Liujun Anwei Prescription were screened, involving 82 potential targets, mainly through NOS2 and other key targets, playing a role through cancer pathway, PI3K-Akt, NF-κB signal pathway. The experimental results showed that Liujun Anwei Prescription could significantly down-regulate the protein expressions of NF-κB and iNOS.Conclusion:This study reveals the pharmacodynamic material basis of Liujun Anwei Prescription, which can be achieved by decreaseing the levels of NF-κB and iNOS to affect the inflammatory response of intestinal tissue, improve intestinal mucosal barrier function, and thus improve chemotherapy related diarrhea.

Clinical Efficacy of Bifid Triple Viable Capsules for Chemotherapy-induced Diarrhea: A Meta-analysis / 胃肠病学

Background: Chemotherapy-induced diarrhea (CID) is a major challenge during chemotherapy, which not only affects the quality of life, but also reduces the effectiveness of chemotherapy. Aims: To evaluate the clinical efficacy of Bifid triple viable capsules in the treatment of CID in malignant tumors by using meta - analysis. Methods: Randomized controlled trials (RCTs) on Bifid triple viable capsules for the treatment of CID were retrieved from CNKI, Wanfang, VIP, China Biology Medicine disc, Chinese Clinical Trial Registry, PubMed, Embase, Cochrane Library, Web of Science and ClinicalTrails databases from the date of database establishment to December 2022. According to the inclusion and exclusion criteria, literatures were screened, extracted, and the quality of literature was evaluated. Meta - analysis was performed by using Stata/MP 14.0 software. Results: A total of 10 RCTs including 790 patients were enrolled. Meta - analysis results showed that efficacy of Bifid triple viable capsules in the treatment of CID was significantly increased than that of controls (OR=2.22, 95% CI: 1.69 - 2.92, P<0.000 1), and serum endotoxin, tumor necrosis factor - α, D - lactic acid, diamine oxidase were significantly decreased in Bifid triple viable capsules group than in controls (P<0.05). Conclusions: The addition of Bifid triple viable capsules adjuvant to the original symptomatic treatment of CID can optimize the treatment efficacy.

Efficacy of Hangeshashinto in the Prevention of Chemotherapy-Induced Diarrhea: A Systematic Review and Meta-Analysis.

Hangeshashinto has attracted attention owing to its potential to prevent chemotherapy-induced diarrhea. However, studies on the efficacy of Hangeshashinto have had conflicting results. Evaluating the efficacy of Hangeshashinto may contribute to reducing the use and adverse events caused by drug therapy for chemotherapy-induced diarrhea. Medical Literature Analysis and Retrieval System Online (MEDLINE), PubMed, Ichushi, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov were searched to retrieve all the relevant studies. Randomized controlled trials (RCTs) comparing the administration of Hangeshashinto with that of other treatments in patients with cancer receiving chemotherapy were included. The primary outcome was severe (grade 3-4) diarrhea assessed using the Common Terminology Criteria for Adverse Events. The secondary outcome was mild (grade 0-2) diarrhea. Out of 324 records identified, three studies were selected for the meta-analysis. Irinotecan was used for chemotherapy in all these studies. Hangeshashinto did not reduce the incidence of severe diarrhea compared with other treatments (risk ratio (RR) 0.40, 95% confidence interval (CI) 0.11-1.41, P = 0.15; low-quality evidence). Moreover, Hangeshashinto did not reduce the incidence of mild diarrhea (RR 1.35, 95% CI 0.87-2.09, P = 0.18; low-quality evidence). However, in the subgroup analysis compared with no treatment, the Hangeshashinto group had a significantly lower incidence of severe diarrhea (RR 0.17, 95% CI 0.03-0.88, P = 0.03; low-quality evidence). At present, insufficient evidence exists to support the claim that Hangeshashinto prevents diarrhea caused by irinotecan-based chemotherapy.

HALT-D: a randomized open-label phase II study of crofelemer for the prevention of chemotherapy-induced diarrhea in patients with HER2-positive breast cancer receiving trastuzumab, pertuzumab, and a taxane.

PURPOSE: To assess whether crofelemer would prevent chemotherapy-induced diarrhea (CID) diarrhea in patients with HER2-positive, any-stage breast cancer receiving trastuzumab (H), pertuzumab (P), and a taxane (T; docetaxel or paclitaxel), with/without carboplatin (C; always combined with docetaxel rather than paclitaxel). METHODS: Patients scheduled to receive ≥ 3 consecutive TCHP/THP cycles were randomized to crofelemer 125 mg orally twice daily during chemotherapy cycles 1 and 2 or no scheduled prophylactic medication (control). All received standard breakthrough antidiarrheal medication (BTAD) as needed. The primary endpoint was incidence of any-grade CID for ≥ 2 consecutive days. Secondary endpoints were incidence of all-grade and grade 3/4 CID by cycle/stratum; time to onset and duration of CID; stool consistency; use of BTAD; and quality of life (Functional Assessment of Chronic Illness Therapy for Patients With Diarrhea [FACIT-D] score). RESULTS: Fifty-one patients were randomized to crofelemer (n = 26) or control (n = 25). There was no statistically significant difference between arms for the primary endpoint; however, incidence of grade ≥ 2 CID was reduced with crofelemer vs control (19.2% vs 24.0% in cycle 1; 8.0% vs 39.1%, in cycle 2). Patients receiving crofelemer were 1.8 times more likely to see their diarrhea resolved and had less frequent watery diarrhea. CONCLUSION: Despite the choice of primary endpoint being insensitive, crofelemer reduced the incidence and severity of CID in patients with HER2-positive breast cancer receiving P-based therapy. These data are supportive of further testing of crofelemer in CID. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02910219, prospectively registered September 21, 2016.

A Review of Potential Role of Capsule Endoscopy in the Work-Up for Chemotherapy-Induced Diarrhea.

Chemotherapy-induced diarrhea (CID) is a common, severe side effect of chemotherapy, immunotherapy, and targeted therapy. Because patients are more prone to continuing chemotherapy if they do not suffer from CID, appropriate diagnosis and monitoring of this disease are essential. However, suitable monitoring methods are yet to be developed. To date, several studies have shown that small-bowel capsule endoscopy (SBCE) is useful in visualizing the entire small intestinal mucosa and detecting small intestinal abnormalities, including bleeding, malignant tumors, and mucosal injury, associated with the use of nonsteroidal anti-inflammatory drugs and low-dose aspirin. Currently, limited studies have evaluated the small intestinal mucosa using SBCE in patients receiving fluoropyrimidine-based chemotherapy or immune checkpoint inhibitors. These studies have reported that small intestinal mucosal injury is common in patients with severe fluoropyrimidine-induced diarrhea. SBCE might be a useful screening method for the early detection of enterocolitis induced by immune checkpoint inhibitors. SBCE may be a powerful tool for the diagnosis and monitoring of CID, and understanding its indication, contraindication, and capsule-retention risk for each patient is important for clinicians.

Efficacy of Herbal Medicines Intervention for Colorectal Cancer Patients With Chemotherapy-Induced Gastrointestinal Toxicity - a Systematic Review and Meta-Analysis.

Purpose: Chemotherapy-induced gastrointestinal (CIGI) toxicity affects the quality of life of patients with colorectal cancer (CRC) and the clinical application of treatment drugs. This review aims to evaluate the efficacy of traditional herbal medicines (HMs) in alleviating symptoms of CIGI toxicity (including nausea and vomiting, anorexia, diarrhea, constipation, oral mucositis, abdominal pain, and abdominal distension), and to explore further individual herb or herbal combinations in alleviating the CIGI toxicity. Methods: Nine electronic databases were screened from 2010 to 2020. Twenty-two randomized controlled trials with a total of 1,995 patients evaluating the complementary efficacy of HMs with chemotherapy compared with chemotherapy-alone were included. Further, sensitivity analyses of orally administered multi-ingredient HM interventions were explored based on the composition of HM interventions. Results: The meta-analysis showed that HM treatment combined with chemotherapy significantly alleviated the overall CIGI toxicity (RR = 0.78 [0.72, 0.84], p < 0.001, I 2 = 44%), nausea and vomiting (RR = 0.74 [0.66, 0.82], p < 0.001, I 2 = 35%), diarrhea (P = 0.02, RR = 0.64, 95% CI = 0.44-0.93, I 2 = 50%), oral mucositis (RR = 0.65 [0.48, 0.88], P = 0.005, I 2 = 24%), and abdominal distension (RR = 0.36 [0.18, 0.73], P = 0.004, I 2 = 0%). However, no statistically significant effects of HMs were shown in studies with a double-blind design for CIGI toxicity. Based on the ingredients of the HMs, further sensitivity analyses identified five herbs [Glycyrrhiza uralensis Fisch., Atractylodes macrocephala Koidz., Astragalus membranaceus (Fisch.) Bge., Codonopsis pilosula (Franch.) Nannf., and the pericarp of Citrus reticulata Blanco.] that were associated with significant reductions in CIGI toxicity. Conclusion: A statistically significant effect of HMs combined with chemotherapy on alleviating the overall CIGI toxicity, nausea and vomiting, diarrhea, oral mucositis, or abdominal distension is only shown in studies without a double-blind design. Further well-designed, double-blinded, large-scaled randomized controlled trials (RCTs) are warranted to comprehensively evaluate the treatment efficacy. Further clinical research that includes the five herbs with chemotherapy for patients, the safety of the combinations of these herbs, and the potential synergistic effects of these combinations of herbs should be conducted.

Effect of electroacupuncture on chemotherapy-induced diarrhea: study protocol for a randomized controlled trial.

BACKGROUND: Chemotherapy-induced diarrhea (CID) is one of the side effects of chemotherapy. Diarrhea not only affects the overall treatment effectiveness but also reduces patients' quality of life. Severe diarrhea can lead to electrolyte imbalance and even be life-threatening. Although acupuncture has been widely used in clinical practice and its effectiveness for managing functional diarrhea has been recognized, there is no sound evidence of its efficacy in managing CID. Therefore, the aim of the proposed randomized controlled trial is to examine the effectiveness and potential risks of using acupuncture for the management of CID and to describe its protocol herein. METHODS: This trial will be conducted in a double-blinded manner and comprise two arms that will be investigated across multiple centers in parallel. The study cohort will comprise 168 outpatients who have CID from six Chinese hospitals. The patients will be randomly and equally divided between an intervention group (electroacupuncture) and a control group (micro-electroacupuncture). In the former, acupuncture will be performed with the conventional method to induce the de qi sensation, and in the latter group, acupuncture will be performed with a sham procedure that does not involve the insertion of needles. The acupoints ST25, SP14, SP6, and ST37 will be applied in the two methods. These procedures will be performed three times a week for four consecutive weeks. The number of days on which CID occurred, the incidence of CID, and fecal characteristics are considered as the primary outcomes, and the Functional Assessment of Chronic Illness Therapy for Patients with Diarrhea subscale score and the World Health Organization Quality of Life assessment are considered as secondary outcomes. The patients will be closely observed for complications and fluctuations in vital signs. DISCUSSION: If the findings from the trial demonstrate the effectiveness and safety of using acupuncture to treat CID, they could serve as evidence for the clinical application of acupuncture as a complementary treatment for cancer patients during chemotherapy. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000035715, registered on August 16, 2020.

Chemical Constituent of ß-Glucuronidase Inhibitors from the Root of Neolitsea acuminatissima.

Neolitsea acuminatissima (Lauraceae) is an endemic plant in Taiwan. One new carboline alkaloid, demethoxydaibucarboline A (1), two new eudesmanolide-type sesquiterpenes, methyl-neolitacumone A (2), neolitacumone E (3), and twelve known compounds (4-15) were isolated from the root of Neolitsea acuminatissima. Their structures were elucidated by spectroscopic analysis. Glucuronidation represents a major metabolism process of detoxification for carcinogens in the liver. However, intestinal bacterial ß-Glucuronidase (ßG) has been considered pivotal to colorectal carcinogenesis. To develop specific bacterial-ßG inhibitors with no effect on human ßG, methanolic extract of roots of N. acuminatissima was selected to evaluate their anti-ßG activity. Among the isolates, demethoxydaibucarboline A (1) and quercetin (8) showed a strong bacterial ßG inhibitory effect with an inhibition ratio of about 80%. Methylneolitacumone A (2) and epicatechin (10) exhibited a moderate or weak inhibitory effect and the enzyme activity was less than 45% and 74%, respectively. These four compounds specifically inhibit bacterial ßG but not human ßG. Thus, they are expected to be used for the purpose of reducing chemotherapy-induced diarrhea (CID). The results suggest that the constituents of N. acuminatissima have the potential to be used as CID relief candidates. However, further investigation is required to determine their mechanisms of action.

Small intestinal mucosal injury and its risk factors in patients with gastrointestinal cancer who developed complicated fluoropyrimidine-induced diarrhea.

BACKGROUND: Diarrhea is a common adverse event of fluoropyrimidine-based chemotherapy. However, limited data are available on the frequency and risk factors of complicated chemotherapy-induced diarrhea (CID) and small intestinal mucosal damage. In this current study, we aimed to determine the incidence of complicated CID and mucosal injury among patients with complicated CID receiving fluoropyrimidine via small bowel capsule endoscopy (CE) and determined baseline risk factors associated with complicated CID. METHODS: In total, 536 patients with advanced or recurrent gastrointestinal cancer who received fluoropyrimidine-based chemotherapy were retrospectively analyzed. Diarrhea was evaluated using the Common Terminology Criteria for Adverse Events version 4. Complicated CID was defined according to the American Society of Clinical Oncology guidelines. To evaluate small intestinal mucosal injury in patients with complicated CID, CE was performed. Multivariate analysis was performed to identify risk factors for complicated CID. RESULTS: Total number of 32 (6%) patients developed complicated CID. Complicating symptoms were noted in 25 (78%) patients, with cramping, vomiting, and sepsis being observed in 15 (60%), 8 (32%), and 3 (12%) patients, respectively. Among the 13 patients who underwent CE, 11 (85%) showed abnormal findings. Multivariate analysis revealed that oral fluoropyrimidine administration was a risk factor for complicated CID (odds ratio 2.95; 95% confidence interval 1.06-8.19). CONCLUSIONS: Despite the relatively low incidence of complicated CID, mucosal injury of small intestine was common in patients with complicated fluoropyrimidine-induced diarrhea and oral fluoropyrimidine was an independent risk factor.

Ancient Chinese Medicine Herbal Formula Huanglian Jiedu Decoction as a Neoadjuvant Treatment of Chemotherapy by Improving Diarrhea and Tumor Response.

BACKGROUND: Diarrhea is a major gastrointestinal complication in cancer patients receiving chemotherapy. Prognosis and treatment of chemotherapy-induced diarrhea (CID) remain unsatisfactory. This study aims to explore the potential of an ancient Chinese Medicine herbal formula Huanglian Jiedu Decoction (HLJDD) as an adjuvant treatment on CID. METHOD: HLJDD extract was prepared by GMP manufacturing standard with quality and stability being checked. 5-fluorouracil (5-Fu) and irinotecan (CPT-11)-induced diarrhea model in mice was established and pre-, co- and post-treatment of HLJDD was implemented. Mechanism of action was explored by detecting related protein expression. In addition, the effect of HLJDD on diarrhea and tumor response induced by clinical regimens FOLFOX and FOLFIRI was measured in murine orthotopic colorectal cancer model. RESULTS: HLJDD exhibited consistency in quality and stability after 24-month storage. Pre-treatment of HLJDD, but not co-treatment or post-treatment, could significantly improve the diarrhea score, body weight loss and intestinal damage in 5-Fu- and CPT-11-treated mice. Pre-treatment of HLJDD reduced cell apoptosis in the intestine of chemotherapy-treated mice, and promoted renewal of intestinal cell wall. CD44 was predicted as the potential target of HLJDD-containing compounds in CID. HLJDD pre-treatment induced presentation of CD44-postive cells in the intestine of chemotherapy-treated mice, and initiated expression of stemness-associated genes. Transcriptional products of the downstream Wnt signaling of CD44 were elevated. Furthermore, pre-treatment of HLJDD could significantly improve the tumor response of clinical chemotherapy regimens FOLFOX and FOLFIRI in orthotopic colorectal cancer, and reduce diarrhea and intestinal damage. Conclusion: Our study suggests the potential of HLJDD as a neoadjuvant treatment of chemotherapy by reducing diarrhea and improving tumor response.

Gut microbial modulation in the treatment of chemotherapy-induced diarrhea with Shenzhu Capsule.

BACKGROUND: Gut microbiota plays a crucial role in the treatment of gastrointestinal (GI) diseases such as chemotherapy-induced diarrhea (CID). Shenzhu Capsule (SZC) is a Chinese herbal formula, which is composed of Renshen (rhizomes of Panax ginseng C. A. Mey.) and Baizhu (rhizomes of Atractylodes macrocephala Koidz.). Many Chinese traditional anti-diarrheal formulae that contain Renshen and Baizhu are capable of effectively alleviating CID. However, the efficacy in vivo and potential mechanism of SZC (the form of compatibility of Renshen and Baizhu) in the treatment of CID had not been elucidated. Here, this study aimed to investigate whether SZC exhibited the anti-diarrheal activity, and whether gut microbiota was involved in the therapeutic effect of SZC on CID. METHODS: High performance liquid chromatography (HPLC), gas chromatography-mass spectrometer (GC-MS) and infrared spectroscopy (IR) analyses were used to characterize the extracted components in SZC. The mice were orally administrated with SZC in a preventive mode on the first 2 days of this experiment, and then intraperitoneally injected with 5-FU (40 mg/kg/d) for 6 days. SZC treatment lasted until the 3rd day after the end of 5-FU chemotherapy. We investigated the effects of SZC on body weights, diarrhea, thymus/spleen indexes, colonic tissues, and gut microbiota. Colonic histology was examined by hematoxylin-eosin (HE) staining. 16S rDNA Amplicon Sequencing was used to analyze the gut microbial structure from fecal samples. RESULTS: SZC significantly increased the body weights and thymus/spleen indexes, alleviated diarrhea, and reversed histopathological changes of colons. In addition, gut microbiota analysis revealed that the overall structure of gut microbiota in CID mice was disturbed, but reversed to the normal state after SZC treatment. At genus level, SZC significantly inhibited the growth of some potential pathogens associated with diarrhea, such as Clostridiumm, Bacteroides, Parabacteroides, Alloprevotella, Acinetobacter and Pseudomonas. CONCLUSIONS: In our study, these data illustrated that SZC inhibited the growth of many potential pathogens during the alleviation of CID. Gut microbial modulation was associated with the anti-diarrheal activity of SZC.

Herbal Medicines for Irinotecan-Induced Diarrhea.

Irinotecan (CPT-11), a water-soluble derivative of camptothecin, belongs to the class of DNA topoisomerase I inhibitors and has been approved worldwide for the treatment of advanced colorectal cancer, lung cancer, and malignant lymphoma. Although CPT-11-based chemotherapy is widely used, severe gastrointestinal (GI) toxicity, especially late-onset diarrhea, is a common adverse reaction, limiting clinical application of the drug. The incidence of grade 3 or 4 diarrhea is high, with 20-40% of CPT-11-treated patients experiencing this adverse effect. High-dose loperamide and octreotide are generally recommended for treatment of CPT-11-induced diarrhea. However, in clinical practice, loperamide is associated with a significant failure rate and the beneficial effects of octreotide are controversial. An accumulating number of recent studies have suggested that medicinal herbs and their derived phytocompounds may be effective complementary treatments for CPT-11-induced diarrhea. In this mini-review, we briefly summarize currently available literatures regarding the formulae and herbs/natural products used as adjuvants in animal and clinical studies for the treatment of diarrhea caused by CPT-11.

Pharmacological inhibition of bacterial ß-glucuronidase prevents irinotecan-induced diarrhea without impairing its antitumor efficacy in vivo.

Irinotecan (CPT-11), a first-line chemotherapy for advanced colorectal cancer, causes serious diarrhea in patients receiving treatment. The underlying mechanism has been shown that the active metabolite of CPT-11, SN-38, is metabolized to the inactive metabolite SN-38 glucuronide (SN-38 G) during hepatic glucuronidation, and subsequently is exported into the intestine, where SN-38 G is hydrolyzed by bacterial ß-glucuronidase (ßG) to be SN-38, thus leading to intestinal toxicity. Thus, inhibition of the intestinal bacterial ßG activity is expected to prevent CPT-11-induced diarrhea. However, the effects of such inhibition on serum pharmacokinetics of SN-38, the key determinant of CPT-11 treatment, are uncertain. Here, we determined the effects of a potent E. coli ßG (eßG)-specific inhibitor pyrazolo[4,3-c]quinoline derivative (TCH-3562) for the potential use in preventing CPT-11-induced diarrhea. TCH-3562 exhibited efficacious inhibitory potency of endogenous ßG activity in two anaerobes, Eubacteriumsp. and Peptostreptococcus anaerobius. Oral administration of TCH-3562 also effectively reduced the bacterial ßG activity in mice intestine. Moreover, pharmacokinetic analysis of TCH-3562 revealed a relatively low amount of TCH-3562 was detected in the plasma whereas the majority of TCH-3562 was found in the feces. Importantly, co-treatment of CPT-11 and TCH-3562 did not decrease active SN-38 level in mice plasma. Finally, we established that TCH-3562 as an adjuvant treatment showed protective effects on CPT-11-induced diarrhea and had no negative effects on the therapeutic efficacy of CPT-11 in tumor-bearing mice. Therefore, inhibition of the intestinal bacterial ßG activity by the specific inhibitor, TCH-3562, is promising to prevent CPT-11-induced diarrhea while maintaining its anti-tumor efficacy that may have clinical potentials for the treatment with CPT-11.