Adherence to antiemetic guidelines in solid cancer patients receiving highly emetogenic chemotherapy in Korea.

BACKGROUND: Highly emetogenic chemotherapy (HEC) is known to induce nausea and vomiting (CINV) in approximately 90% of cancer patients undergoing this regimen unless proper prophylactic antiemetics are administered. This study aimed to analyze the use of a three-drug prophylactic antiemetic regimen during the first cycle of chemotherapy and assess the compliance rate with the National Comprehensive Cancer Network (NCCN) guidelines. METHODS: This retrospective study utilized data from the National Inpatient Sample database from 2016 to 2020 provided by the Health Insurance Review and Assessment Service. The claims data encompassed 10 to 13% of inpatients admitted at least once each year. Patients with solid cancers treated with two HEC regimens, namely anthracycline + cyclophosphamide (AC) and cisplatin-based regimens, were selected as the study population. We evaluated the use of a three-drug prophylactic antiemetic regimen, including a neurokinin-1 receptor antagonist, a 5-hydroxytryptamine-3 receptor antagonist, and dexamethasone and compliance with the NCCN guidelines. Multiple logistic regression was conducted to estimate the influence of variables on guideline adherence. RESULTS: A total of 3119 patients were included in the analysis. The overall compliance rate with the NCCN guidelines for prophylactic antiemetics was 74.3%, with higher rates observed in the AC group (87.9%) and lower rates in the cisplatin group (60.4%). The AC group had a 6.37 times higher likelihood of receiving guideline-adherent antiemetics than the cisplatin group. Further analysis revealed that, compared to 2016, the probability of complying with the guidelines in 2019 and 2020 was 0.72 times and 0.76 times lower, respectively. CONCLUSION: This study showed that a considerable proportion of HEC-treated patients received guideline-adherent antiemetic therapies. However, given the variations in adherence rates between different chemotherapy regimens (AC vs. cisplatin), efforts to improve adherence and optimize antiemetic treatment remain essential for providing the best possible care for patients experiencing CINV.

Underutilisation of prophylactic G-CSF in breast cancer patients receiving adjuvant docetaxel/cyclophosphamide chemotherapy.

Docetaxel/cyclophosphamide (TC) is a widely used adjuvant chemotherapy regimen, especially in patients with node-negative or low-risk node-positive breast cancer. Guidelines recommend the use of prophylactic granulocyte colony-stimulating factor (G-CSF) to prevent febrile neutropenia. In this study, we aimed to explore the use of G-CSF as a primary prophylactic and determine the factors influencing its use. This retrospective study used nationwide claims data from the National Inpatient Sample compiled by the Health Insurance Review and Assessment Service in South Korea from 2018. The claims data included 10% of inpatients admitted at least once in 2018 and 1% of outpatients who were not admitted. Female patients with breast cancer who received an adjuvant TC regimen after surgery were selected. Primary prophylactic G-CSF was defined as G-CSF prescribed within two days of the first cycle of TC. The factors influencing its utilisation were investigated using the chi-square test and a multiple logistic regression model. A total of 229 patients were included in the analysis. The proportion of patients who received primary prophylactic G-CSF treatment after the first cycle of TC was 55.5%. The factors positively influencing G-CSF utilization were patients' age ≥65 years, location (i.e. metropolitan areas), and the type of healthcare facility (i.e. non-tertiary hospitals). The use of prophylactic G-CSF in patients with breast cancer who received the adjuvant TC regimen was insufficient. The use of primary G-CSF prophylaxis should be emphasised to reduce the risk of febrile neutropenia among patients receiving a myelosuppressive TC regimen.

Oligonol Ameliorates CCl4-Induced Liver Injury in Rats via the NF-Kappa B and MAPK Signaling Pathways.

Oxidative stress is thought to be a key risk factor in the development of hepatic diseases. Blocking or retarding the reactions of oxidation and the inflammatory process by antioxidants could be a promising therapeutic intervention for prevention or treatment of liver injuries. Oligonol is a low molecular weight polyphenol containing catechin-type monomers and oligomers derived from lychee fruit. In this study, we investigated the anti-inflammatory effect of oligonol on carbon tetrachloride- (CCl4-) induced acute hepatic injury in rats. Oral administration of oligonol (10 or 50 mg/kg) reduced CCl4-induced abnormalities in liver histology and serum AST and serum ALT levels. Oligonol treatment attenuated the CCl4-induced production of inflammatory mediators, including TNF-α, IL-1ß, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) mRNA levels. Western blot analysis showed that oligonol suppressed proinflammatory nuclear factor-kappa B (NF-κB) p65 activation, phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein kinases (MAPKs) as well as Akt. Oligonol exhibited strong antioxidative activity in vitro and in vivo, and hepatoprotective activity against t-butyl hydroperoxide-induced HepG2 cells. Taken together, oligonol showed antioxidative and anti-inflammatory effects in CCl4-intoxicated rats by inhibiting oxidative stress and NF-κB activation via blockade of the activation of upstream kinases including MAPKs and Akt.

Hepatoprotective effects of zingerone on carbon tetrachloride- and dimethylnitrosamine-induced liver injuries in rats.

In this study, we investigated the hepatoprotective and anti-fibrotic effects of zingerone, one of the active components of ginger, against carbon tetrachloride (CCl4)- and dimethylnitrosamine (DMN)-induced liver injuries in rats, respectively. Oral administration of zingerone (10 mg/kg) reduced CCl4-induced abnormalities in liver histology, serum alanine aminotransferase and aspartate aminotransferase levels, and liver malondialdehyde levels. Zingerone treatment attenuated CCl4-induced increases in inflammatory mediators, including tumor necrosis factor-α, interleukin-1ß, cyclooxygenase-2, and inducible nitric oxide synthase mRNA levels. Western blot analysis showed that zingerone suppressed activation of nuclear factor-kappa B (NF-κB) p65 and phosphorylation of extracellular signal-regulated kinase, c-Jun NH2-terminal kinase, and p38 mitogen-activated protein kinases (MAPKs). Liver fibrosis induced by DMN (10 mg/kg, intraperitoneally) was ameliorated by administration of zingerone (10 and 20 mg/kg, orally). Zingerone treatment reduced DMN-induced elevation of hydroxyproline content and hepatic stellate cell activation. In conclusion, zingerone showed antioxidative and anti-inflammatory effects in CCl4-intoxicated rats by inhibiting oxidative stress and NF-κB activation via blockade of the activation of upstream MAPKs. Moreover, zingerone had hepatoprotective and anti-fibrotic effects against DMN-induced liver injury suggesting its usefulness in the prevention of liver inflammation and the development of hepatic fibrosis.

Epithelial-mesenchymal Transition is Associated with Acquired Resistance to 5-Fluorocuracil in HT-29 Colon Cancer Cells.

5-Fluorouracil (5-FU) is commonly used for the therapy of colon cancer; however, acquired resistance to 5-FU is a critical barrier to successful treatment and the primary cause of chemotherapy failure. Epithelialmesenchymal transition (EMT) is a process whereby cells undergo alterations in morphology and molecular characteristics promoting tumor progression and metastasis. Accumulating evidence shows that transition from epithelial to mesenchymal phenotype in cancer cells is associated with their resistance to chemotherapy. However, it is still poorly understood whether EMT is involved in acquired resistance to 5-FU. In this study, we developed an in vitro cell model, 5-FU-resistant HT-29 colon cancer cells, and characterized the differences in cellular morphology and molecular alterations between parental and resistant cells. In accord with mesenchymal-like morphology of 5-FU-resistant HT-29 cells, the expression of the mesenchymal marker fibronectin was significantly increased in these cells in comparision with that in the parental cells. Of interest, we also found a marked increase in the expression of EMT-inducing transcription factors Twist, Zeb1, and Zeb2. Finally, 5-FU-resistant cells showed enhanced migration in comparison with parental HT-29. Taken together, these results indicate that EMT could be associated with 5-FU resistance acquired by HT-29 cells. A specific role of each transcription factor found in this study will require further investigation.

Therapeutic duplicate prescribing in Korean ambulatory care settings using the National Health Insurance claim data.

BACKGROUND: Duplicate prescribing is known to occur across health systems and is one of the most frequent drug related problems. Therapeutic duplication (TD) increases the risk of adverse drug reactions without additional therapeutic benefits. OBJECTIVES: This study aimed to develop TD criteria concerning four drug categories which are acid-related disorder drugs, antimicrobials, antihypertensives, and lipid modifying drugs and to estimate the prevalence of therapeutic duplicate prescribing at the ambulatory care settings in Korea. METHODS: TD criteria were developed using the WHO anatomical therapeutic chemical classification and modified with an expert consensus panel using the Delphi method. The prevalence of TD including ingredient duplication (ID) of four drug categories was examined using National Health Insurance claim database including 15 million patients during one month in 2009 (December). TD was defined as prescribing medications within the same category in the developed TD criteria list. RESULTS: The numbers of patients who received acid-related disorder drugs, antimicrobials, antihypertensives, and lipid-modifying drugs in the study period were 10,049,292, 7,584,131, 4,349,945, and 1,425,292 respectively. In the field of acid-related disorder drugs prescribed, there were 0.3 % IDs and 2.5 % TDs within a prescription issued by one prescriber. There were 8.4 % IDs and 14.5 % TDs between prescriptions issued at different ambulatory visits. In the field of antimicrobial medicines, there were 0.1 % IDs and 2.6 % TDs within a prescription, while there were 5.0 % IDs and 7.6 % TDs between different prescriptions. Amongst the antihypertensives prescribed, there were 0.4 % IDs and 1.9 % TDs within a prescription, while there were 9.9 % IDs and 11.5 % TDs between prescriptions. Lastly, looking at lipid-modifying drugs prescribed, there were 0.3 % IDs and 0.5 % TDs within one prescription, while there were 8.9 % IDs and 9.4 % TDs between prescriptions. CONCLUSION: The prevalence of duplicate prescribing was substantial in the ambulatory care setting which is to be improved using the TD criteria developed from this study in the national drug utilization review system in Korea.

Inhibition of melanogenesis by 2-[4-(5-chlorobenzo[d]thiazol-2-yl)phenoxy]-2-methylpropanoic acid (MHY908).

Tyrosinase inhibitors might have potential use in cosmetic and medicinal products for the prevention of pigmentation disorders. However, only a few inhibitors are currently used due to their cytotoxicity, and lack of selectivity and stability. In this study, we synthesized several tyrosinase inhibitors and investigated their activity. To investigate the action of 2-[4-(5-chlorobenzo[d]thiazol-2-yl)phenoxy]-2-methylpropanoic acid (MHY908) specifically in the inhibition of melanogenesis, a mushroom tyrosinase activity assay was performed. We confirmed the inhibitory effect of MHY908 at various melanin concentrations using α-MSH-induced melanoma cells. Our results indicate that MHY908 potently inhibited mushroom tyrosinase activity (IC50 = 8.19 µM) in a dose-dependent manner. Through a docking simulation, we also analyzed its binding mode to inhibit tyrosinase activity. MHY908 also decreased melanin synthesis without inducing cytotoxicity. These results suggest that MHY908 is a good candidate for prevention and treatment of pigmentation disorders.

Transformation of Mouse Liver Cells by Methylcholanthrene Leads to Phenotypic Changes Associated with Epithelial-mesenchymal Transition.

Environmental pollutants such as polycyclic aromatic hydrocarbons (PAHs) have been implicated in cancer development and progression. However, the effects of PAHs on carcinogenesis are still poorly understood. Here, we characterized a mouse cancer cell line BNL 1ME A. 7R.1 (1MEA) derived by transformation of non-tumorigenic liver cell line BNL CL.2 (BNL) using 3-methylcholanthrene (3MC), a carcinogenic PAH. RT-PCR and immunoblot analysis were used to determine the expression level of mRNA and proteins, respectively. To determine functionality, cell motility was assessed in vitro using a transwell migration assay. Both mRNA and protein levels of E-cadherin were significantly decreased in 1MEA cells in comparison with BNL cells. While the expression levels of mesenchymal markers and related transcription factors were enhanced in 1MEA cells, which could lead to increase in cell motility. Indeed, we found that 7-day exposure of BNL cells to 3-MC reduced the level of the adhesion molecule and epithelial marker Ecadherin and increased reciprocally the level of the mesenchymal marker vimentin in a dose-dependent manner. Taken together, these results indicate that the process of epithelial-mesenchymal transition (EMT) may be activated during premalignant transformation induced by 3-MC. A mechanism study to elucidate the relation between 3-MC exposure and EMT is underway in our laboratory.