The opioid analgesic fentanyl has not been reported to interact with warfarin, but it is unclear whether the combination of fentanyl and warfarin can interfere with the therapeutic efficiency of the latter. In 30 patients who received both agents in combination at our institution, we compared the fluctuation of the warfarin dose-corrected international normalized ratio (INR per dose) before and after the fentanyl coadministration (via a transdermal patch). The INR per dose after the fentanyl coadministration was found to significantly increase as compared to that before the coadministration (1.22 ± 0.81 vs 2.40 ± 1.77, respectively; P < 0.001). The correlation between the INR per dose and serum albumin levels (Alb) revealed no significant correlation prior to the fentanyl coadministration (r = 0.011, P = 0.95); however, a significant negative correlation was observed after the fentanyl coadministration (r = -0.497, P = 0.005). The INR per dose × Alb after the coadministration of fentanyl was significantly increased compared to that before the coadministration (3.60 ± 2.58 vs 5.81 ± 3.59, respectively; P < 0.001). Our findings suggest that the combined use of fentanyl during warfarin administration affects the increase in INR. Because INR fluctuations are likely to occur in patients with decreased Alb, careful INR monitoring is required for these cases.

Breastfeeding is important for the mental and physical health of mothers and newborn babies. The amount of ethyl loflazepate, an antidepressant drug, excreted into breast milk is not well clarified. Here, we measured the plasma and breastmilk levels of ethyl loflazepate in two lactating women on the third day after delivery and their breastfed infants on the fourth day after birth. The metabolite in plasma and breastmilk was measured by liquid chromatography/mass spectrometry. The metabolite concentrations in the respective milks of case 1 were 35.1 ng/mL (relative infant dose was 2.3％) and the metabolite concentrations of case 2 were 35.0 ng/mL (relative infant dose was 3.9％). The metabolite concentrations in mothers’ and infants’ plasma of case 1 were 128.9 ng/mL (mother), 67.5 ng/mL (infant). The metabolite concentrations in mothers’ and infants’ plasma of case 2 were 99.9 ng/mL (mother), 28.2 ng/mL (infant). Adverse drug symptoms, such as respiratory disorder and drowsiness, were observed in the case 1 infant from immediately after birth to day 2 and in the case 2 infant from immediately after birth until discharge on day 8. The present case report can contribute to the pharmacotherapy in pregnant and postpartum women with depression.

In recent years, the GS1 data bar has been displayed on all ethical drugs to prevent medical accidents caused by dispensing errors. However, performing drug collation for oral drugs remains a challenge because the GS1 data bar is sometimes defective during the dispensing process. Our results showed that only 14.7％ of the drugs adopted by Kyushu University Hospital displayed a single GS1 data bar per tablet or slit, and measures were not taken to prevent GS1 data bar defects for most of the drugs. In addition, incidences of prescriptions containing less than one sheet of the press through package for counting dispensing, grinding, and one-dose package by hand were 54.5％, 71.6％, and 54.4％, respectively, suggesting that lack of the GS1 data bar occurred frequently in clinical settings. To promote the utilization of the GS1 data bar for oral drugs, pharmaceutical companies should address the GS1 data bar deficiency challenge and improve its design.

The results of clinical trials are essential for the advancement of evidence-based medicine (EBM). Our previous research using the Relative Citation Ratio (RCR), article-based citation metric developed by the National Institutes of Health (NIH), identified that the outcomes of clinical trials designed to have a high evidence level, such as large sized randomized trials, and those with novel interventions have higher scientific influence. In the present study, aiming to further investigate the factors that improve the scientific influence of clinical study results, we focused on randomized controlled trial (RCT) and evaluated the relationship between study design and RCR of drug intervention RCTs in patients with non-small cell lung cancer (NSCLC). Publications of drug intervention RCTs for NSCLC patients published between 2007 and 2016 were included. Clinical trial design factors were compared among three RCR categories with 50 trials in each: lowest RCR (LOW50), median RCR (50 NIH percentile [50NIH％ile]), and highest RCR (TOP50) group. The numbers of Phase 3, multi-country, for-profit company sponsored/supported, and statistically powered RCTs, which confirmed pre-defined differences between/among interventions, increased by more than 30％ from 50NIH％ile to TOP50. The number of novel interventions such as EGFR-TKI and Immune checkpoint inhibitors were also increased as RCR increased. Our results indicate quantitatively that the clinical trial design is an important factor that affects scientific influence of the RCT outcome. RCTs should be sufficiently large to generate statistically confirmatory outcomes, be conducted in multiple countries, and use newer drugs in order to better contribute to the progress of EBM.