Gemcitabine (GEM) plus albumin-bound paclitaxel (nab-paclitaxel, nab-PTX) combination chemotherapy, known as GN-therapy, has demonstrated efficient anti-tumor effect and statistically significant overall survival of patients with metastatic or locally advanced pancreatic ductal adenocarcinoma (PDAC) compared with GEM monotherapy. This regimen was approved in 2014 as a standard care treatment option for patients with PDAC in Japan. While severe neutropenia is a frequent adverse effect of GN-therapy, the frequency in 2nd-line use is still poorly understood. Thus, we retrospectively investigated clinical data to compare the frequency of adverse effects between 1st-line and 2nd-line use and the risk factor for sever neutropenia in PDAC patients treated with GN-therapy.
We analyzed 52 patients who received GN-therapy for advanced PDAC. The endpoint of the survey was the occurrence of neutropenia. Risk factors significantly related to severe neutropenia were identified using logistic regression analysis. Of the 52 patients studied, the mean age ± SD was 65.7 ± 9.4 years, and 32 (61.5％) were male. The frequency of severe neutropenia was not different in 1st-line (65.4％) and 2nd-line use (57.7％) (P = 0.776) and thus 2nd-line use of GN-therapy can be as safe and effective for PDAC as 1st-line use is. In the univariate and multivariate analysis, our data suggests that low level-absolute count of white blood cells (WBC), neutrophils (ANC) and alanine aminotransferase (ALT) are important predictive risk factors for severe neutropenia in patients with PDAC after the first course of GN-therapy and can make chemotherapy for PDAC more relevant and individualized.
Inflammatory bowel disease (IBD) is referred to as uncontrolled mucosal inflammation resulting from an abnormal immune response against unknown environmental triggers. Fibrosis is considered to be an important feature in the progression of IBD and the most likely mechanism involved in the activation of fibroblasts is epithelial-mesenchymal transition (EMT). Bokusoku is the main component of the Japanese Kampo medicine Jumihaidokuto, and is mainly prescribed for various inflammatory diseases. We examined the beneficial effect of bokusoku in IBD associated with fibrosis and inflammation of the intestinal mucosal membrane. We used C57BL/6 female mice, divided into three groups, all of which received 3％ dextran sulphate sodium (DSS) in drinking water during the experimental period (8 days). Standard group mice received sulphasalazine 80 mg/kg/day po, treatment group mice received bokusoku 100 mg/kg/day po and the DSS control group received an equal volume of distilled water. Normal control group mice received plain drinking water. Bokusoku treatment significantly alleviated fibrosis and inflammation by regulating EMT and decreased the expression of pro-inflammatory cytokines associated with the disease pathogenesis and can thus be considered a potent agent for the treatment of colitis.
Ramucirumab (RAM) is a monoclonal antibody of human vascular endothelial growth factor receptor 2 (VEGFR-2). In Japan, it is indicated for combination therapy with paclitaxel (PTX) for advanced/recurrent gastric cancer that cannot be curatively resected. However, the development of severe neutropenia due to RAM administration is considered to be one of the major side effects. Therefore, the principal aims of the present study were to examine whether the risk of neutropenia increases due to RAM + PTX combination therapy compared with PTX monotherapy in Japanese patients with gastric cancer and to elucidate the risk factors of neutropenia due to RAM + PTX combination therapy.
At the Osaka International Cancer Institute, we retrospectively investigated myelosuppression in 26 patients who received RAM + PTX combination therapy and in 25 patients who received PTX monotherapy for advanced/recurrent gastric cancer that cannot be curatively resected. The expression of neutropenia of all grades and of grade 3 or higher were significantly higher in the RAM + PTX group (P < 0.001 and P = 0.045, respectively). Investigation of the risk factors in patients with expression of neutropenia of grade 3 or higher revealed that a low initial lymphocyte count was a risk factor (P = 0.021); that is, the results suggest that neutropenia may be enhanced by administering RAM in combination with PTX. When RAM + PTX combination therapy is administered in patients with a low initial lymphocyte count, it may be necessary to consider measures against infectious diseases and administration of granulocyte-colony stimulating factor (G-CSF) agents, for example.
Trazodone is an antidepressant having hypnotic and sedative effects. It has recently been applied for the treatment of insomnia in elderly patients and inpatients with delirium. Because the only commercially available dosage of trazodone is tablet form in Japan, trazodone is not applicable for patients who have difficulty taking oral medication; these patients are very common among the above patient population. Therefore, we attempted to develop rectal suppositories of trazodone to facilitate its administration in patients who cannot take medicines orally. The suppositories were prepared using Witepsol W-35 as the base. Trazodone tablets and prepared suppositories were administrated to 5 healthy adult volunteers, and the days of administration were separated by a one-week washout period. Serum concentration was measured using liquid chromatography tandem-mass spectrometry (LC-MS/MS). In oral administration, the maximum serum concentration (Cmax), time to Cmax (tmax), and area under the concentration-time curve from 0 to 8 h (AUC0→8) were 570.91 ± 129.49 ng/mL, 1 h, and 2,499.50 ± 546.19 h·ng/mL, respectively. In rectal administration, Cmax was not clear and serum concentration was almost sustained, AUC0→8 was 1,727.70 ± 435.25 h·ng/mL. Pharmacokinetic parameters revealed the sustained absorption of trazodone in suppository, absorption and serum drug concentrations after rectal administration were lower than those after oral administration, which might prevent adverse effects. The results of this study suggest that trazodone suppositories prepared using Witepsol as the base might be safely applicable and useful for patients who find it difficult to take oral medicine.
Hydroxychloroquine sulfate (HCQ) is widely prescribed in the long-term treatment of systemic lupus erythematosus (SLE) and cutaneous lupus erythematosus (CLE). In Japan, the indications for SLE and CLE were obtained at 2015. We report a case of atrioventricular block (AVB) during HCQ therapy in a 29-year-old woman with SLE. On admission, her lupus nephritis was exacerbated and the administration of HCQ was started. Electrocardiography during HCQ treatment revealed second-degree AVB and sinus tachycardia. HCQ was then discontinued and the second-degree AVB disappeared, while first-degree AVB remained. Although, HCQ-induced AVB has been reported mainly in Europe and North America, no cases were observed in a Japanese phase III clinical trial and no case reports on HCQ-induced AVB have been reported in Japan. It seems that adverse cardiac events occur frequently when the duration and total dosage of HCQ are increased. The present case shows the need for monitoring of cardiac function to avoid life-threatening cardiac conduction disturbance.
Hepatotoxicity associated with the administration of voriconazole (VRCZ) is a treatment-related adverse event that necessitates discontinuation of administration in some cases. This study is aimed at investigating the clinical features of VRCZ-induced hepatotoxicity in pediatric patients, including the status of hepatic damage before the administration of VRCZ.
Demographic and laboratory data were retrieved retrospectively from the medical records of 13 Japanese pediatric patients who underwent VRCZ therapy. Based on this study and other studies, we examined the relationship between the ratio of patients with hematologic malignancy / solid tumors to the underlying disease and the occurrence of VRCZ-induced hepatotoxicity.
There have been 10 cases (76.9％) with hepatic damage before the administration of VRCZ. VRCZ-induced hepatotoxicity was observed in 11 cases (84.6％), 7 cases (63.6％) of which were severe. The median values of time to the occurrence of VRCZ-induced hepatotoxicity and time to becoming severe were 5 and 7 days respectively after the first dose of VRCZ. As the ratio of patients with hematologic malignancy / solid tumors to the underlying disease increased, the occurrence of VRCZ-induced hepatotoxicity tended to increase (P < 0.01). Of the liver function tests, an abnormal increase in aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transferase occurred with high probability in patients diagnosed as having VRCZ-induced hepatotoxicity.
These results suggest that VRCZ-induced hepatotoxicity may occur with high probability early after initiating the administration of VRCZ in pediatric patients. We therefore recommend frequent liver function tests in pediatric patients treated with VRCZ, at least around the first 5 days.