Earticle

Background: Small-molecule tyrosine kinase inhibitors (TKIs) have had major impacts on anticancer therapy by targeting the catalytic activities of dysregulated tyrosine kinases. TKIs have not presented traditional toxicities; however, some serious adverse effects, including hepatotoxicity, have been documented in clinical trials and post-marketing surveillance. Although TKI-induced hepatotoxicity can cause severe clinical complications in patients, the underlying mechanism is still unclear. Methods: Studies on TKI-induced hepatotoxicity were identified by Pubmed search, and relevant articles were reviewed. Results: Immunoallergic reaction, cytochrome P (CYP) 450 polymorphisms, and formation of reactive metabolites are under consideration as mechanisms of TKI-induced hepatotoxicity. Host protein-drug metabolite conjugates are recognized as antigens by class II major histocompatibility complexes and are believed to cause liver injuries. Polymorphisms in CYP, which influences TKI metabolism, can slow TKI metabolism and may induce development of hepatotoxicity. The formation of reactive metabolites during drug metabolism can induce hepatotoxicity by directly causing cytotoxicity, leading to cell dysfunction, and indirect toxicity by mediating secondary immune reactions. Concurrent use of various medications with TKI can also cause hepatotoxicity by affecting drug transporter or enzyme activities. Conclusion: Periodic monitoring of patients taking TKIs and risk/benefit reassessments though post marketing surveillance are necessary to prevent hepatotoxicity.

Objective: The aim of this study was to analyze the status of split tablet prescription in South Korea. Methods: We conducted this analysis using 2016 National Patient Sample data from the Health Insurance Review and Assessment Service. We computed split tablet prescription rates by sex and age and determined which medicine and medical specialties had the highest split tablet prescribing rates. Results: The proportion of prescriptions that included split tablets was 15.6% (n=6,687,35). The proportion of prescriptions that included split tablets was higher for females (56.7%) than for males (43.3%), while that of prescriptions including split tablets versus total prescriptions for each sex was higher for males (16.4%) than for females (14.9%) (p<0.001). In the age group under 19 years, the proportion of prescriptions including split tablets (53.7%) was more than half of the total. The highest tablet splitting rate was found to be 89.9% for formoterol fumarate (40 μg), and pseudoephedrine hydrochloride (60 mg) had the highest number of prescriptions. Pediatrics (65.6%) was the medical field with the highest rate of split tablet prescription. Conclusion: Split tablets were most prescribed to pediatric patients. To minimize the use of split tablets, it is necessary to develop lower dose tablets and establish a policy that promotes prescription of these lower-dose tablets.

Background: In South Korea, as an aged society, an understanding of dementia and its risk factors is important from clinical and healthcare policy perspectives. Relationship between cognitive impairment and body weight or weight changes have been reported, but these were contradictory. We have evaluated the association between weight changes and cognitive decline using national level longitudinal data. Methods: Data from the Korean Longitudinal Study of Ageing from 2006 to 2012 were used. Association between weight changes and decline in cognitive function as measured by K-MMSE (the Korean version of the Minimental state examination) score was assessed by multivariate logistic regression. Weight changes were calculated from 1st wave and 3rd wave survey data, and classified into five groups as stable, increases, decreases of >10%, or 5%-10%. Results: About 37% of the total participants (n=4,512) were 65 years or older. These participants made up the largest proportion of the groups with weight change exceeding 10%. Multivariate logistic regression analyses revealed that weight changes exceeding 10% (10% increase vs stable, adjusted OR [aOR] 1.47, 95% confidence interval (CI) 1.11-1.95; 10% decrease vs stable, aOR 1.44, 95% CI 1.11-1.88) were significant predictive factors for decline in cognitive function. In subgroup analyses, the association between weight changes and cognitive decline was significant in males aged over 65 years and in normal BMI groups. Conclusion: Weight changes, both increases and decreases exceeding 10% of baseline, were significantly associated with declines in cognitive function among older adults in South Korea.

Background: Glutamate is implicated in the pathophysiology of migraine, a common neurological disorder. Therefore, glutamate receptor antagonists (GluRAs) have been suggested as a novel migraine treatment that are able to overcome the limitations of triptans. Objective: The aim of this study was to perform a meta-analysis to assess the efficacy of GluRAs for patients with migraine. Method: The PubMed, Cochrane Library, CINAHL, and Clinical Trial.gov databases were searched for randomized placebo-controlled trials of the efficacy of GluRAs for patients with migraine conducted up to August 2019. Two independent reviewers screened the literature according to inclusion and exclusion criteria and performed quality assessment and data extraction. Review Manager 5.3 software was used for the meta-analysis. Results: Three studies involving a total of 206 patients were included in the final analysis. Compared with placebo, GluRAs significantly improved the pain-free response at 2 hours (odds ratio [OR]=3.85, 95% confidence intervals [CIs]=1.63-9.09) and the 24-hour sustained pain freedom (OR=7.40; 95% CIs=2.36- 23.20). The use of rescue medications with GluRAs was lower compared to that with placebo, but the difference was not significant (OR=0.39, 95% CI=0.10-1.47). Conclusion: Our meta-analysis showed that GluRAs were more effective than placebo for patients with migraine.

Background: Patients with cardiovascular risks are recommended to use statins and antiplatelet agents to prevent major cerebrocardiovascular events (MACCE). Antiplatelet agents also possess anti-inflammatory and antioxidant effects, in addition to their inhibitory activity on platelets. The differences in clinical outcomes in ischemic heart disease (IHD) based on the type of antiplatelet therapy combined with statin treatment were investigated in this study. Methods: We conducted a retrospective cohort study using electronic medical records of IHD patients from January 2010 to December 2014 at Ajou University Hospital. Patients on combination therapy of antiplatelet drugs and statins were grouped based on antiplatelet drug types: clopidogrel, cilostazol, or sarpogrelate. Propensity score matching was applied to balance the baseline of the groups of clopidogrel vs. cilostazol and the groups of clopidogrel vs. sarpogrelate. The incidence and risk of MACCE as primary outcomes were assessed between the groups of antiplatelet drugs. Results: Among the approximately 128,500 patients with IHD, 1,049 patients had taken a combination therapy of statin and antiplatelet agents. The cohorts of patients administered clopidogrel, cilostazol, or sarpogrelate were 906, 79, and 64, respectively. The incidence of MACCE was not significantly different among the cohorts (p=0.58), and there were no differences between clopidogrel vs. cilostazol (p=0.72) or clopidogrel vs. sarpogrelate (p=1.00) after propensity score matching. Conclusion: There was no difference in the incidence of MACCE based on the type of antiplatelet drug (clopidogrel, cilostazol, or sarpogrelate) in combination with a statin in patients with IHD.

Backgrounds: With the globalization of drug development, multi-regional clinical trials (MRCTs) have emerged to facilitate rapid availability of medicines to patients worldwide. The present study aimed to has explored attitudes and perceptions towards adopting the Korean MRCT guideline. Methods: An online survey, consisting of 16 questions, classified into two subjects, was administered to stakeholders in Korea. Most quantitative components were measured using the Likert scales. A content analysis of the qualitative components was carried out to identify the keywords in open-ended responses. Results: A total of 94 survey responses were analyzed: 51 participants from pharmaceutical companies, 11 from clinical research organizations, and 21 from clinical trial centers. The content of the guideline was rated as appropriate for clarity, acceptability, and applicability (96.8, 96.8, and 93.6%, respectively). The local environmental impact of the systemic/political, academic/technical, and industrial/economical aspects of the guideline was rated as appropriate at 95.7, 97.9, and 91.5%, respectively. The suggested adoption period was 1~2 years (40, 42.6%). The concept and individuals’ domestic circumstances were the key problems affecting the clarity, applicability, and local environmental impact of the guideline. Conclusion: The Korean MRCT guideline was well-developed. Their overall impact on the local environmental impact of MRCTs in Korea was expected to be beneficial, but methods are needed to minimize the negative impacts. The findings of this study can inform the priorities for the future adoption of the guideline in Korea.

Background: Rheumatoid arthritis is highly prevalent in overweight patients with type 2 diabetes mellitus and can be reduced by physical activity via altered proinflammatory parameters. However, the association between the frequency of physical activity and the prevalence of rheumatoid arthritis in prediabetic patients remains unclear and was evaluated in this study. Methods: Utilizing the Korean National Health Insurance Sharing Service database, 58,391 adults, who met the research criteria and underwent a general medical check-up between 2009 and 2013, were selected for this study. To analyze the data, a logistic regression with a proc survey logistic procedure was used. Results: The study revealed that the cumulative rheumatoid arthritis prevalence was lower in prediabetic patients compared to that in the control group (OR, 0.64; 95% CI, 0.483-0.840; p=0.001). More frequent physical activity (>3 days/week) was significantly associated with a reduced rheumatoid arthritis prevalence in both groups (OR, 0.28; 95% CI, 0.039-0.521; p=0.044 vs. OR, 0.15; 95% CI, 0.063-0.237; p=0.007). Additionally, a 3.8-fold higher risk of rheumatoid arthritis development was observed in prediabetic adults with less frequent baseline physical activity (≤2 days/week). Overall, in prediabetes, the prevalence of rheumatoid arthritis was associated with the frequency of physical activity and not with the fasting plasma glucose levels. Conclusion: More frequent physical activity is associated with a low risk of developing rheumatoid arthritis in prediabetic patients. Thus, further studies are needed to confirm the clinical outcomes of frequent physical activity in rheumatoid arthritis prevention and control.

Background: At the end of the‘Waste Drug Disposal Project’, collection and disposal of waste drugs remain a social issue. Objective: This study aimed to provide suggestions to improve the drug waste management system in Korea by comparing domestic and overseas relevant programs. Methods: This is a comparative study between South Korea, Australia, Canada, France, and the US. These overseas countries were selected because they have been operating waste drug management programs continuously to date. Comparison was conducted by a pre-determined analysis frame including legal regulation, enforcement program and its performance. Results: All selected countries except Australia had legal regulations on drug wastes. The US had the largest variety of drug waste disposal methods. Canada had recommended that pharmacies actively participate in drug waste withdrawal programs. France had the largest variety of methods to promote relevant programs, including window sticker, SNS, and app, as well as the highest level of awareness and participation. Australia had the lowest level of awareness and participation in pharmaceutical waste management programs. Pharmaceutical companies took responsibility of paying for these programs in the selected overseas countries. Conclusion: Further efforts should be made to establish a clear guideline including the role of pharmaceutical companies, and to develop various methods for the public to be aware of appropriate ways of disposing drug wastes in Korea.