In this study, an efficient, reproducible, and reliable stability indicating reverse-phase high-performance liquid chromatography (HPLC) method has been developed for the simultaneous quantification of Tegafur (TGFR), Gimeracil (GMRL), and Oteracil (ORCL) in bulk and dose formulation with a shorter run time (6min).TFGR, GMRL, and ORCL were separated using an isocratic method on a Waters C18 (250 mm x 4.6 mm × 5 µm) column with a mobile phase containing methanol and phosphate buffer (0.1M KH2PO4, pH 4.0) in a 50:50 (v/v) ratio. The detection wavelength was 275 nm and the flow rate was 1 mL/min. The new method demonstrated excellent linearity for TFGR (10 to 30µg/ml), GMRL (2.9 to 8.7µg/ml), and ORCL (7.9 to 23.70µg/ml). The method was found to be precise and accurate, with an RSD of 0.057% to 0.183% and a recovery rate of 98.66% to 100.52%. Stress degradation experiments have demonstrated that this method can be utilized to estimate TFGR, GMRL, and ORCL in the presence of their degradants. The method is suitable for determining TFGR, GMRL, and ORCL in bulk and capsule formulation (Tegonat).

The combined use of tegafur (TAR), gimeracil (GAR), and oteracil (OAR) is often employed for the therapy of malignant tumors. A high-performance liquid chromatography (HPLC) approach was developed to consistently and precisely measure GAR, OAR, and TAR in a combined pharmaceutical formula that uses a shorter operation time. The separation followed by assessment of GAR, OAR and TAR is done with C18 (Waters, USA) column (250; 4.6 mm; temperature 25˚C) and the mobile phase ratio used included 60% vol (0.1 M NaHSO4): 40% vol (methanol). Upon applying stress conditions, International Council for Harmonisation (ICH) recommended to GAR, OAR and TAR. The HPLC findings pointed out the nonexistence of any interference between the drugs under test and the degradation compounds. The stability indicating quality was established by the peak purity results for GAR, OAR, and TAR, which disclose that the test peaks (GAR, OAR, and TAR) were homogenous in all stress settings examined. From stability studies, we found that GAR showed significant degradation when rendered to dry heat, while TAR and OAR exhibited significant degradation after being exposed to acidic conditions. The suggested approach could potentially be implemented to assess the stability of GAR, OAR, and TAR under stress environments as well as to perform quality control checks on the three mentioned drugs in capsule doses.

Tegafur (TF) is one of the most important clinical antitumor drugs with poor water solubility, severely reducing its bioavailability. This work develops new cocrystals to improve the solubility of TF and systematically investigates the intermolecular interactions to provide new insights into the formation of cocrystal and changes in physicochemical properties. In this paper, two new 1:1 cocrystals of TF with 2,4 dihydroxybenzoic acid (2,4HBA) and p-nitrophenol (PNP) were synthesized. The cocrystal products were identified and characterized by various solid state analysis techniques. And the high performance liquid chromatography (HPLC) was conducted to determine the solubility and dissolution rate of TF and cocrystals. Moreover, the quantum chemistry calculations of crystal structure provided theoretical support for the results. Compared with pure TF, the solubility and dissolution rate of TF-2,4HBA is significantly increased in a pH 6.8 buffer at 37°C. Under accelerated storage conditions (40°C, 75% RH), all cocrystal exhibits excellent stability over 8weeks. Hirshfeld surface (HS) analysis, atoms in molecules (AIM) analysis, interaction region indicator (IRI) analysis, molecular electrostatic potential surface (MEPS) analysis and frontier molecular orbital (HOMO-LUMO) analysis were integrated to understand the hydrogen bonding interaction more comprehensively. The simulation results are in good agreement with the experimental data. The results show that the analysis of physical and chemical properties of TF-PNP cocrystal and TF crystal by quantum chemistry method is reliable at molecular level. These results are helpful to provide guiding methods in the cocrystal development and theoretical study of tegafur.

Objective: This investigation entitles the development and authentication of a rapid, selective and explicit RP-HPLC technique to assay tegafur (TGR), gimeracil (GMR), and oteracil (OTR) simultaneously in bulk and formulations of capsule type. Methods: The separation, detection and assessment of TGR, GMR and OTR were achieved using a C18 Agilent Zorbax (25 cm; 4.6 mm; 5 µm particle dimension) reverse phase column. The acetonitrile (40% by volume) and 0.1% triethylamine in distilled water (pH 2.5, 60% by volume) was utilized as mobile phase. The validation of the method and degradation study was performed as per the strategy given by ICH. Results: The retention periods in Agilent Zorbax column for OTR, TGR, and GMR were 2.458 min, 7.236 min and 8.629 min, respectively. Linearity was seen in the concentration series of 5.0-30.0 µg/ml (TGR), 1.45-8.70 µg/ml (GMR), and 3.95-23.70 µg/ml (OTR). The regression coefficient was greater than 0.999. The LOQ values were 0.606 µg/ml (TGR), 0.175 µg/ml (GMR), and 0.478 µg/ml (OTR). The percent comparative standard deviation (exactness) values were bestowed to be 0.243%-0.676%, 0.293%-1.894% and 0.269%-0.615% for TGR, GMR and OTR, respectively. The percent recoveries (accuracy) were in the range of 100.044%-100.493 for TGR, 99.730%-100.335% for GMR and 100.064%-100.543% for OTR. Conclusion: The research results of the degradation investigation proved the technique's specificity as well as stability indicating feature. The process could be used for routine evaluation of OTR, TGR, and GMR in formulations of capsule type.

High drug carrying efficiency of boron-doped Triazine based covalent organic framework toward anti-cancer tegafur; a theoretical perspective

Calorimetric and spectroscopic studies of interactions of PPI G4 dendrimer with tegafur in aqueous solutions

In this work, the potential of BN, AlN, and CN nanotubes as the drug delivery systems of Tegafur (TG) was investigated by the density functional theory (DFT). The doping effect of Si atom on the adsorption of TG drug on the surface of the BN, AlN, and CN nanotubes was investigated. The structural parameters, the interaction energies, and the electronic properties of formed complexes were evaluated. The strength of interactions in complexes was investigated using interaction energies, geometric parameters, topological properties, and the reduced density gradient analysis (RDG). The results show that the tendency of TG drug for interaction with doped and non-doped AlN nanotubes is the most. Also, the Si-doped nanotubes have a stronger interaction with the TG drug. The NBO analysis was performed to evaluate the charge transfer in complexes. Some of the quantum molecular descriptors were used for the investigation of reactivity of nanotubes to TG drugs. The application of pure/doped nanotubes as drug delivery systems was investigated after the interaction of Tegafur drug on the surface of nanotubes in the presence of the water solvent. It seems that the selected nanotubes can be used as drug delivery systems for the transfer of TG drugs in living organisms. Compared to pristine nanotubes, Si-doped nanotubes could be a better candidate for delivering TG drugs to target cells.

Payload delivery of anticancer drug Tegafur with the assistance of graphene oxide nanosheet during biomembrane penetration: Molecular dynamics simulation survey

Objective To evaluate the recent efficacy and safety of gemcitabine combined with S-1 in the treatment of advanced biliary tract cancer. Methods From August 2014 to May 2017, 27 patients with advanced biliary tract cancer confirmed by pathology in the First People's Hospital of Zhengzhou received gemcitabine(1 000mg/m2, day 1 and 8) and S-1(80mg/m2, day 1-14) every three weeks.The recent efficacy and toxicities were observed after two cycles of chemotherapy. Results All of the 27 patients were evaluated, 1 patient(3.7%) achieved CR, 6 patients(22.2%) with PR, 12 patients(44.4%) with SD, 8 patients(29.6%) with PD.The total response rate was 25.9%(7/27), the disease control rate was 70.4%(19/27). The main toxicities were gastrointestinal reactions and myelosuppression, no chemotherapy-related death was observed. Conclusion Gemcitabine combined with S-1 in the treatment of advanced biliary tract cancer is safe and effect. Key words: Digestive system neoplasms; Biliary tract neoplasms; Bile duct neoplasms; Drug therapy; Antineoplastic combined chemotherapy protocols; Adverse effects; Gemcitabine; Tegafur

Objective To analyze the clinical efficacy and safety of tegafur combined with oxaliplatin and gemcitabine combined with cisplatin in the treatment of advanced triple negative breast cancer. Methods Seventy-eight female patients with metastatic triple negative breast cancer who has afailed treatment with anthracycline/taxanes from January 1, 2012 to December 31, 2015 in PLA 309 Hospital were randomly divided into SOX group (38 cases) and GP group (40 cases) by computer generated random numbers. Results The objective response rates of SOX group and GP group were 31.5% (12/38) and 32.5% (13/40), and the disease control rates were 65.8% (25/38) and 70.0% (28/40), respectively.There was no significant difference between the two groups (P value was 1.000 and 0.809). The median progression-free survival time of GP group and SOX group was 6.6 and 5.5 months respectively, and there was a significant difference between the two groups (P=0.044). Adverse reactions in both groups included bone marrow suppression, gastrointestinal reactions and so on.The incidence rate of digestive tract reaction was 23.7% (9/38) in SOX group and 27.5% (11/40) in GP group.There was no significant difference between the two groups (P=0.699). The incidence rate of bone marrow suppression was 28.9% (11/38) and 30.0% (12/40), respectively.There was no significant difference between the two groups (P=0.920). Conclusion Tegafur combined with oxaliplatin and gemcitabine combined with cisplatin are effective drugs for the treatment of metastatic triple negative breast cancer, and the adverse reactions are tolerable. Key words: Triple negative breast cancer; Tegafur; Oxaliplatin; Gemcitabine; Cisplatin

Clinical effects and prognostic analysis of radical surgery for primary gallbladder cancer

Objective To investigate the clinical efficacy of tegafur, gimeracil and oteracil porassium capsules combined with oxaliplatin in the treatment of patients with advanced gastric cancer and liver metastases. Methods From January 2012 to February 2017, 125 patients with advanced gastric cancer and liver metastases in the Second People's Hospital of Jiande were selected and randomly divided into control group and observation group.The control group(63 cases) was treated with tegafur, gimeracil and oteracil porassium capsules.The observation group(62 cases) was treated with tegafur, gimeracil and oteracil porassium capsules combined with oxaliplatin.The clinical efficacy of the two groups was evaluated, and the adverse reactions during the treatment were recorded.The serum levels of matrix metalloproteinase 9 (MMP-9) and vascular endothelial growth factor (VEGF) were measured before and after treatment. Results The total effective rate of the observation group was 80.64%(50/62), which was significantly higher than 57.14%(36/63) of the control group (χ2=8.294, P=0.015). The incidence rate of adverse reaction in the observation group was 22.58%(14/62), which was significantly lower than 47.61%(30/63) in the control group (χ2=8.588, P=0.003). After treatment, the levels of MMP-9 and VEGF in the two groups were significantly lower than those before treatment (all P=0.000). The MMP-9 and VEGF levels in the observation group were significantly lower than those in the control group(t=14.203, 1.560, P=0.000, 0.000). Conclusion The efficacy of tegafur, gimeracil and oteracil porassium capsules combined with oxaliplatin in the treatment of advanced gastric cancer with liver metastasis is significant and has less adverse reactions. Key words: Stomach neoplasms; Neoplasm metastasis; Matrix metalloproteinase 9; Vascular endothelial growth factors; Antineoplastic combined chemotherapy protocols; Ticino; Oxaliplatin

Green tea has attracted great interest as a cancer prevention agent. Interactions of tea polyphenols with serum albumin may influence the efficacy of drugs. The interactions of (–)-epigallocatechin-3-gallate (EGCG), (–)-epicatechin-3-gallate (ECG), and tegafur (TF) alone or in combination with human serum albumin (HSA) at pH 7.4 and different temperatures were investigated by spectroscopic methods, isothermal titration calorimetry (ITC), and molecular docking. The binding affinities to HSA were ranked in the order of EGCG > ECG > TF, and the interactions were spontaneous and exothermic. Ternary system studies showed that the presence of one component hindered the binding of another component to HSA. The secondary structures of HSA were slightly altered in the presence of the ligands. Site marking experiments and molecular docking showed that EGCG and ECG mainly bound to subdomain IIA and ΙΙΙA while TF bound to subdomain ΙΙA and ΙB. Results indicated that the existence of ECG and EGCG would influence the binding of TF to HSA and can increase the free concentration of TF. Obtained results would provide beneficial information about possible interference upon simultaneous co-administration of the tea components and drugs.Communicated by Ramaswamy H. Sarma

Objective To investigate the clinical efficacy and safety of re-radiotherapy combined with TS-1 (tegafur gimeracil oteracil potassium capsule) in treatment of local recurrent esophageal carcinoma. Methods A total of 63 esophageal carcinoma patients who recurred after the first course radiation treatment admitted to Jiangdu People′s Hospital of Yangzhou during January 1, 2012 to June 30, 2015 were retrospec-tively analyzed. Twenty-seven of them treated with re-radiotherapy combined with TS-1 were deemed as the research group and 36 of them treated with radiotherapy alone were deemed as the control group based on diffe-rent treatment. Then the clinical efficacy and adverse reactions of the two groups were compared. Results The objective response rates were 77.8% (21/27) and 50.0% (18/36) respectively in the research group and control group, and the difference was statistically significant (χ2=5.048, P=0.025). The median survival time in the two groups were 21.6 months and 13.7 months, the 1-year (74.1%) and 2-year (44.4%) survival rates of the research group were both higher than those of the control group (52.8% and 30.6%, respectively), and the difference was statistically significant (χ2=6.086, P=0.013). The major adverse effects of the research group and control group during the treatment were radiation oesophagitis (92.6% vs. 80.5%), radiation pneumonia (18.5% vs. 19.4%), myelosuppression (96.3% vs. 77.8%) and gastrointestinal reactions (25.9% vs. 19.4%). Most of them were 1-2 grade, and there were no statistically significant differences (χ2=0.975, P=0.323; χ2=0.009, P=0.926; χ2=2.941, P=0.086; χ2=0.375, P=0.540). Conclusion The treatment of re-radiotherapy combined with TS-1 for local recurrent esophageal carcinoma can improve the efficacy and prolong survival period, and the adverse reactions are tolerable. Key words: Esophageal neoplasms; Radiotherapy, intensity-modulated; Recurrence; Tegafur gimeracil oteracil potassium capsule

Comment on: Short-term effect of metronomic chemotherapy of low dose Tegafur on patients with primary hepatic carcinoma after radiofrequency ablation.

To evaluate the short-term efficacy and safety of neoadjuvant synchronous chemoradiotherapy (paclitaxel plus carboplatin regimen) in stage III adenocarcinoma of esophagogastric junction (AEG). Forty cases clinically diagnosed as stage III AEG were prospectively enrolled at the Department of Gastrointestinal Oncology Surgery, the First Affiliated Hospital of Hebei North University from December 2014 to November 2017 and then were randomly divided into paclitaxel plus carboplatin combined with synchronous radiotherapy group(neoadjuvant group) and direct operation group. Inclusion criteria was as follows:(1) AEG was diagnosed by gastroscopic biopsy and III stage was confirmed by ultrasound endoscopy and spiral CT;(2) physical strength score ≥70, and age ≤75 years old; (3) no contraindications of chemoradiotherapy and operation. Exclusion criteria was as follows:(1) patients voluntarily withdrew or refused the treatment;(2) occurrence of severe anaphylaxis; (3) uncontrollable events happened during treatment and treatment was unable to continue;(4) tumor developed obviously during treatment. Preoperative neoadjuvant synchronous chemoradiotherapy used TP regimen: paclitaxel 80 mg/m², drug concentration-time area under curve of carboplatin= 1.5 mg×ml⁻¹×min⁻¹, once per week for 9 weeks; radiotherapy began at the second week, 40 Gy/20 F, completed within 4 weeks. Operative procedure of both groups was radical resection of cardiac cancer(D2). Postoperative chemotherapy regimen was oral Tegafur(Gimeracil and Oteracil potassium). The side effects, diet situation, change of gastroscopic image after treatment in patients of neoadjuvant group were observed and efficacy evaluation of chemotherapy was performed according to solid tumor efficacy evaluation criteria of US National Cancer Institute. Operation-associated parameters, including R0 resection rate, lymph node metastasis, operative mortality and postoperative complications, were compared between two groups. There were no significant differences in baseline information between the two group (all P>0.05). One case in neoadjuvant group was excluded because of perforation at lesion site 7 weeks after chemotherapy. The side effects of 19 cases in neoadjuvant group were mainly alopecia (100%) and marrow inhibition (68.4%), while 3-4 degree side effects were alopecia(8/19,42.1%), leukopenia (3/19, 15.8%) and neutropenia(3/19, 15.8%). Complete remission was observed in 4 cases; partial remission was observed in 13 cases and stable disease in 2 cases, with an objective response rate of 89.5% and a disease control rate of 100%. Before neoadjuvant chemotherapy, 16 cases were difficult to take liquid diet and 3 cases received liquid diet only, while after 12 weeks of neoadjuvant chemotherapy, all the 19 cases received normal diet. Besides, after neoadjuvant chemotherapy, gastroscopic examination showed close healing of cardiac ulcer, disappearance of swelling, and renewal of normal mucosa. Compared to direct operation group, neoadjuvant group had less number of positive lymph node (4.9±3.6 vs. 8.8±2.8, P<0.05) and higher R0 resection rate (94.7% vs. 50.0%, P<0.05). Total number of harvested lymph node was not significantly different between two groups (19.1±2.5 vs. 18.6±7.0, t=0.326, P=0.746). There was no surgical death in either group. One case in direct operation group developed postoperative inflammatory obstruction. No associated complication was found in neoadjuvant group. Paclitaxel plus carboplatin combined with synchronous radiotherapy can elevate the R0 resection rate of patients with stage III esophagogastric junction adenocarcinoma, without increasing operative mortality and postoperative complications.

Objective To investigate the application value of π-shaped esophagojejunostomy in totally laparoscopic total gastrectomy. Methods The retrospective and descriptive study was conducted. The clinicopathological data of 3 patients who underwent totally laparoscopic total gastrectomy in the Beijing Friendship Hospital of Capital Medical University between October 2016 and March 2017 were collected. Patients received π-shaped Roux-en-Y esophagojejunostomy. Patients who were diagnosed with Ⅱ and above stages by pathological examination underwent postoperative adjuvant chemotherapy with oxaliplatin + tegafur gimeracil oteracil. Observation indicators: (1) surgical and postoperative recovery situations; (2) follow-up and survival situations. The follow-up using outpatient examination and telephone interview was performed to detect postoperative adjuvant therapy and survival up to March 2018. Results (1) Surgical and postoperative recovery situations: 3 patients underwent successfully totally laparoscopic total gastrectomy, and π-shaped Roux-en-Y esophagojejunostomy was also performed. Case 1 had injury of spleen vessel when No 11p lymph nodes were dissected and then received successful hemostasis, and case 2 and 3 didn′t have complication. Operation time, digestive tract reconstruction time, volume of intraoperative blood loss, time to anal exsufflation and postoperative drainage-tube removal time of case 1, 2 and 3 were respectively 376 minutes, 290 minutes, 284 minutes and 26 minutes, 30 minutes, 24 minutes and 500 mL, 100 mL, 200 mL and 2 days, 3 days, 3 days and 4 days, 4 days, 5 days. Case 3 with left pleural effusion was cured by puncture and drainage treating, and case 1 and 2 didn′t have complication. Three patients were not complicated with anastomotic stoma-related complicaions. Results of postoperative pathological examination: number of lymph node dissected and TNM staging of case 1, 2 and 3 were respectively 20, 17, 20 and T1aN0M0 staging, T3N3M0 staging, T1bN0M0 staging. Duration of hospital stay in case 1, 2 and 3 was respectively 7 days, 8 days and 11 days. (2) Follow-up and survival situations: 3 patients were followed up, and follow-up time of case 1, 2 and 3 was respectively 18 months, 16 months, 12 months. During the follow-up, case 2 received postoperative adjuvant therapy, and then underwent palliative treatment of Paclitaxel and Xeloda after the case was rechecked out multiple liver metastases at postoperative month 12. Case 1 and 3 had disease-free survival. Conclusion The π-Shaped esophagojejunostomy is safe and feasible for totally laparoscopic total gastrectomy, and it can be used as an alternative to digestive tract reconstruction. Key words: Gastric neoplasms; Total gastrectomy; Digestive tract reconstruction; Esophagojejunostomy; Laparoscopy

Comprehensive theoretical prediction of the dynamics and stability properties of Tegafur pharmaceutical agent on the Graphene based nanostructures in aqueous environment

Objective To evaluate the short-term effect of tegafur combined with oxaliplatin in the treatment of advanced colorectal cancer and its impact on long-term prognosis. Methods 70 patients with advanced colorectal cancer were selected.The patients were randomly divided into tegafur group (oxaliplatin plus tegafur) and capecitabine group (oxaliplatin combined with capecitabine) according to the digital table, 35 cases in each group, The short-term efficacy, side effects, 2-year survival rate and median survival time were compared between the two groups. Results The total effective rate of the tegafur group was 85.71%, which of the capecitabine group was 77.14%, but the difference was not statistically significant between the two groups (χ2=0.850, P=0.356). After treatment, the levels of VEGF in the two groups were significantly lower than those before treatment (t=21.694, 20.558, P=0.305, 0.249). There was no statistically significant difference between the two groups (t=0.998, 1.242, P=0.281, 0.307). The 1-year survival rate was 51.43% and the 2-year survival rate was 25.71% of the tegafur group, compared with 45.71% and 17.14% in the capecitabine group, the differences were not statistically significant (χ2=0.229, 0.764, P=0.632, 0.382). The median survival time of the tegafur group was 13.5 months, which of the capecitabine group was 13.0 months, there was no statistically significant difference (Z=1.304, P=0.752). The incidence rate of hand-foot syndrome of the tegafur group was 5.71%, which was lower than 22.86% of the capecitabine group (χ2=4.163, P=0.027). Conclusion The efficacy of tegafur combined with oxaliplatin in the treatment of advanced colorectal cancer is similar to capecitabine plus oxaliplatin, with a slightly lower complication rate. Key words: Colorectal neoplasms; Tegafur; Oxaliplatin

Objective To analyze the clinical efficacy and toxic reaction of Tegafur, Gimeraciland Oteracil Potassium Capsule combined with Gemcitabine chemotherapy for patients with radical resection for advanced gallbladder carcinoma. Methods The clinical dataof 135 patients with advanced gallbladder cancer who were admitted to the 1st Affiliated Hospital of Zhengzhou University and supported after the gastrectomy by the pathology from June 2007 to June 2012 were retrospectively analyzed. All patients were divided into three groups by different therapeutic regimens, operation groups (Radical resection or Extended radical resection of gallbladder carcinoma) with 47 cases, chemotherapy A group (Tegafur, Gimeracil and Oteracil Potassium Capsule combined with Gemcitabine chemotherapy after Radical resection or Extended radical resection of gallbladder carcinoma) with 52 cases, and chemotherapy B group (5-Fluorouracil combined with Oxaliplatin chemotherapy after Radical resection or Extended radical resection of gallbladder carcinoma) with 36 cases. We collected the dates of all patients with the median survival time and the 1, 3 and 5-year survival rate after operation, and counted the rate of major toxic reaction after chemotherapy. Results There were no significant differences in the general date of three groups (sex, age, tumor size, CA19-9, CA125, TNM stages, with or without cholecystolithiasis, operation methods, operation complication), The chemotherapy A group and chemotherapy B group had no differenceswiththe median survival time and 1, 3 and 5-year survival rate after operation. There were significant differences in the median survival time and 3, 5-year survival rate after operation between the operation group and chemotherapy A group (or between the operation group and chemotherapy B group ). There were significant differences in the rate of whole toxic reaction and the rate of toxic reaction beyond Ⅲ degree between chemotherapy A group and chemotherapy B group. Conclusions The treatment of Tegafur, Gimeracil and Oteracil Potassium Capsule combined with Gemcitabine chemotherapy for patients with radical resection of advanced gallbladder carcinoma has a lower rate of whole toxic reaction and rate of toxic reaction beyond Ⅲ degree than 5-Fluorouracil combined with Oxaliplatin chemotherapy, and for patients with advanced gallbladder carcinoma, the frontal treatment can obviously prolong the median survival time and effectively improve the 3 and 5-year survival rate after operation. Key words: Advanced gallbladder carcinoma; Radical resection of gallbladder carcinoma; Tegafur, Gimeracil and Oteracil Potassium Capsule; Gemcitabine; 5-Fluorouracil; Oxaliplatin