CYP1A2 polymorphism and theophylline clearance in Korean non-smoking asthmatics.

BACKGROUND: Theophylline is mainly metabolized by cytochrome P450 (CYP) 1A2 and CYP2E1 which show inter-individual variations. However, the underlying mechanism remains unknown in humans. We investigated the relationship between differences in theophylline clearance and genetic polymorphisms in the CYP1A2 and CYP2E1 gene in 89 Korean asthmatic patients. METHODS: Polymerase chain reaction (PCR) was performed on the 5'-flanking region of those genes. PCR products were directly sequenced and confirmed using the SNaP shot method. We determined whether the detected SNPs affected gene transcription using electrophoretic mobility shift assay (EMSA). Theophylline clearance (mL/kg/h) was assessed by using a Bayesian approach. RESULTS: Genetic polymorphisms were identified at 7 sites in the CYP1A2 gene and at 10 sites in the CYP2E1. Among them, subjects with genotypes (GA+AA) of the -3860G>A polymorphism were found to show higher theophylline clearance than those with genotypes GG (29.11 ± 0.91 mL/kg/h vs. 26.12 ± 0.80 mL/kg/h, p = 0.014). This polymorphic site was revealed to be a protein binding site by conducting EMSA on nuclear hepatocyte extracts. CONCLUSION: In conclusion, increased theophylline clearance was significantly related to the -3860G>A polymorphism, which could be associated with increased CYP1A2 inducibility in Korean non-smoking asthmatics.

Assessment of pharmacoeconomic evaluations submitted for reimbursement in Korea.

OBJECTIVE: To assess the quality of pharmacoeconomic evaluations (PEs) submitted with new drug applications for reimbursement and to investigate the role of PEs for coverage decisions in Korea. METHODS: Forty-seven PEs that were submitted by pharmaceutical companies for coverage decisions between June 2005 and December 2009 were included in this study. To assess their appropriateness with regard to the PE guidelines, we used the Health Insurance Review and Assessment services (HIRA) checklist consisting of 20 items based on the PE guidelines. We also evaluated the results for coverage decisions, as "recommended," "recommended with restricted use," or "not recommended," based on the incremental cost-effectiveness ratio and the range of uncertainty. RESULTS: On average, 14 of the 20 items on the HIRA checklist were fulfilled (70.9%, range 35.0%-100%). The compliance rate for the following items was above 70%: presentation of perspectives and evaluation methods, a sufficient time horizon, and appropriateness of comparators and health outcomes. The compliance rate for the following items was below 70%: omission of objectives for the study, inappropriate target population, unclear selection process for effectiveness and cost, inappropriate cost estimation, insufficient justification of generalizability, and description of study limitations. The range of incremental cost-effectiveness ratios per quality-adjusted life-years of PEs from a societal perspective varied from dominant to 59K USD (n = 13): it consisted of dominant to 28K USD for "recommended" submissions (n = 6), 8K to 20K USD for "recommended with restricted use" submissions (n = 4), and 13K to 59K for "not recommended" ones (n = 3). CONCLUSIONS: Our study showed that most PEs in this study have reached an adequate level for coverage decisions. Overall barriers associated with a lack of relevant evidence could account for the low compliance rate with specific items in the PE guidelines. PEs with good quality submitted for coverage decisions have played an important role for selecting cost-effective drugs.

Evaluation on the first 2 years of the positive list system in South Korea.

OBJECTIVE: The South Korean positive list system in pharmaceutical reimbursement was introduced by the Health Care System Reform Act implemented in December 2006. This study introduces this positive list system (PLS), and reports on an evaluation of two years of operation. In addition, decision-making factors are evaluated and current issues and solutions discussed. METHODS: We analyzed 91 submissions with reimbursement decisions completed by December 31, 2008. Submission characteristics and relevant factors related to decision criteria were identified by the decision outcomes (recommended/rejected). RESULTS: Under the new system, Health Insurance Review and Assessment service (HIRA) recommended 64 submissions for reimbursement and rejected 27 submissions. For recommended submissions, 59 met all criteria and 5 were recommended based on the rule of rescue. The primary reason for rejection was unacceptable cost-effectiveness. The likelihood of recommendation was found to be significantly elevated if a drug was superior to its comparator, if treatment cost was not greater than that of its comparator, or if the number of recommended decisions made by other committees increased. CONCLUSIONS: The South Korean PLS has stabilized during the 2 years after its introduction. The recommended submissions were qualified in all decision-making criteria used. Among the various decision criteria, clinical benefit and cost-effectiveness were the main drivers of reimbursement decisions. In addition, there is a certain degree of consistency between the reimbursement decisions of HIRA and other countries.

Inhibition of nitric oxide production in lipopolysaccharide-activated RAW 264.7 macrophages by Jeju plant extracts.

Nitric oxide (NO) produced in large amounts by inducible nitric oxide synthase (iNOS) is known to be responsible for the vasodilation and hypotension observed during septic shock and inflammation. Thus, inhibitors of iNOS may be useful candidates for the treatment of inflammatory diseases accompanied by the overproduction of NO. In this study, we prepared alcoholic extracts of Jeju plants and screened them for their inhibitory activity against NO production in lipopolysaccharide (LPS)-activated macrophages. Among the 260 kinds of plant extract tested, 122 extracts showed potent inhibitory activity towards NO production by more than 25% at a concentration of 100 µg/mL. Plants such as Malus sieboldii, Vaccinium oldhamii, Corylus hallaisanensis, Carpinus laxiflora, Styrax obassia, and Securinega suffruticosa showed the most potent inhibition (above 70%) at a concentration of 100 µg/mL. The cytotoxic effects of the plant extracts were determined by colorimetric MTT assays and most plant extracts exhibited only moderate cytotoxicity at 100 µg/mL. Therefore, these plants should be considered promising candidates for the further purification of bioactive compounds and would be useful for the treatment of inflammatory diseases accompanying overproduction of NO.