Roles of Health Technology Assessment for Better Health and Universal Health Coverage in Korea / 보건행정학회지

Health technology assessment (HTA) is defined as multidisciplinary policy analysis to look into the medical, economic, social, and ethical implications of the development, distribution, and use of health technology. Following the recent changes in the social environment, there are increasing needs to improve Korea's healthcare environment by, inter alia, assessing health technologies in an organized, timely manner in accordance with the government's strategies to ensure that citizens' medical expenses are kept at a stable level. Dedicated to HTA and research, the National Evidence-based Healthcare Collaborating Agency (NECA) analyzes and provides grounds on the clinical safety, efficacy, and economic feasibility of health technologies. HTA offers the most suitable grounds for decision making not only by healthcare professionals but also by policy makers and citizens as seen in a case in 2009 where research revealed that glucosamine lacked preventive and treatment effects for osteoarthritis and glucosamine was subsequently excluded from the National Health Insurance's benefit list to stop the insurance scheme from suffering financial losses and citizens from paying unnecessary medical expenses. For the development of HTA in Korea, the NECA will continue exerting itself to accomplish its mission of providing policy support by health technology reassessment, promoting the establishment and use of big data and HTA platforms for public interest, and developing a new value-based HTA system.

Association between research topics and disease burden in health technology assessment

The National Evidence-based Healthcare Collaborating Agency (NECA), an institution for health technology assessment in Korea, has used public solicitation of research topics since its establishment in 2009. This creates a necessity for examining whether a given research topic was selected to be considered when prioritizing healthcare technology assessment and distributing healthcare resources. This study aimed to investigate the relationship between the research topics suggested to NECA and the disease burden in Korea. To find the correlation between disease burden and 1,112 suggested topics and 91 performed topics that were classified by Human Research Classification System a linear auxiliary trend line and scatter plot were constructed using disability-adjusted life years (DALYs), and Pearson's correlation coefficients were calculated. The results suggested that cancer was most common, followed by cardiovascular diseases, among suggested research topics and research topics performed by NECA, as well as in terms of the ratio of performed to suggested topics. The correlation between research topic and disease burden index indicated a strong correlation with DALYs and years of life lost (YLLs). However, years lived with disability and research topic had no relationship. Suggested topics showed a greater correlation with YLLs than DALYs, whereas performed topics showed a greater correlation with DALYs than YLLs, showing that despite the fact that the diseases with a high burden from morbidity were appropriately considered with respect to selecting research topics, a statistically significant difference was not found. As the first Korean study to assess the correlation between research topics and disease burden, our results will be used as base data for prioritizing the allocation of healthcare resources in the future.

The Feasibility and Future Prospects of Robot-Assisted Surgery in Gastric Cancer: Consensus Comments from the National Evidence-based Collaborating Agency Round-Table Conference / 보건행정학회지

To establish an appropriate policy for robotic surgery in Korea, the National Evidence-based Collaborating Agency (NECA) and the Korean Society of Health Policy and Administration held a round-table conference (RTC) to gather opinions through a comprehensive discussion of scientific information in gastric cancer. The NECA RTC is a public discussion forum wherein experts from diverse fields and members of the lay public conduct in-depth discussions on a selected social issue in the health and medical field. For this study, representatives from the medical field, patient groups, industry, the press, and policy makers participated in a discussion focused on the medical and scientific evidence for the use of robotic surgery in gastric cancer. According to the RTC results, robotic surgery showed more favorable results in safety and efficacy than open surgery and it is similar to laparoscopy. When the cost-effectiveness of robotic surgery and laparoscopy is compared, robotic surgery costs are higher but there was no difference between the two of them in terms of effectiveness (pain, quality of life, complications, etc.). In order to resolve the high cost issue of the robotic surgery, a proper policy should be implemented to facilitate the development of a cost-effective model of the robotic surgery equipment. The higher cost of robotic surgery require more evidence of its safety and efficacy as well as the cost-effectiveness issues of this method. Discussions on the national insurance coverage of robotic surgery seems to be necessary in the near future.

Current Trend of Robotic Thoracic and Cardiovascular Surgeries in Korea: Analysis of Seven-Year National Data

BACKGROUND: Robotic surgery is an alternative to minimally invasive surgery. The aim of this study was to report on current trends in robotic thoracic and cardiovascular surgical techniques in Korea. METHODS: Data from the National Evidence-based Healthcare Collaborating Agency (NECA) between January 2006 and June 2012 were used in this study, including a total of 932 cases of robotic surgeries reported to NECA. The annual trends in the case volume, indications for robotic surgery, and distribution by hospitals and surgeons were analyzed in this study. RESULTS: Of the 932 cases, 591 (63%) were thoracic operations and 340 (37%) were cardiac operations. The case number increased explosively in 2007 and 2008. However, the rate of increase regained a steady state after 2011. The main indications for robotic thoracic surgery were pulmonary disease (n=271, 46%), esophageal disease (n=199, 34%), and mediastinal disease (n=117, 20%). The main indications for robotic cardiac surgery were valvular heart disease (n=228, 67%), atrial septal defect (n=79, 23%), and cardiac myxoma (n=27, 8%). Robotic thoracic and cardiovascular surgeries were performed in 19 hospitals. Three large volume hospitals performed 94% of the case volume of robotic cardiac surgery and 74% of robotic thoracic surgery. Centralization of robotic operation was significantly (p<0.0001) more common in cardiac surgery than in thoracic surgery. A total of 39 surgeons performed robotic surgeries. However, only 27% of cardiac surgeons and 23% of thoracic surgeons performed more than 10 cases of robotic surgery. CONCLUSION: Trend analysis of robotic and cardiovascular operations demonstrated a gradual increase in the surgical volume in Korea. Meanwhile, centralization of surgical cases toward specific surgeons in specific hospitals was observed.

Epidural steroid injection in spinal pain: a study on the NECA report

Epidural steroid injection (ESI) may be the most widely used interventional procedure in the management of low back pain (LBP). Its use has been supported by more than 45 placebo-controlled studies and dozens of systematic reviews. However the report Pain Reduction Efficacy of Injection Therapy in Chronic LBP by the National Evidence-Based Collaborating Agency (NECA) in 2010 is seen to have mis-concluded that ESI is not effective in the management of chronic LBP. The NECA report contains various descriptive and statistical errors. In this review, we have attempted to correct the errors in the NECA report. We also inform the rationale and evidence of ESI by the review of recent meta-analysis and work to inspire a proper use of ESI in the Republic of Korea.

National Evidence-based Collaborating Agency (NECA) Round-table Conference Consensus Statement: multidisciplinary responses to suicide, the first ranked cause of death in adolescents

The National Evidence-based Collaborating Agency (NECA) holds the NECA Round-table Conference that not only disseminates objective and systematic information on topics of social concern in public health care but also organizes discussions on core issues under dispute in the literature through panels composed of multidisciplinary experts. Accordingly, the Round-table Conference was composed of multidisciplinary experts including medical specialists in the areas of psychiatry and preventive medicine, psychiatric and mental health nursing, psychologists, social welfare experts, consultation experts, religious leaders, and government officials from the Ministry of Education, Science and Technology, and Ministry of Health and Welfare. The Round-table Conference, tasked with analysis of the actual status and causes of, and search for solutions for suicide in adolescents, has reached consensus on the current status, trend, risk factors and prevention factors, problems and issues in prevention and coping strategies, effective prevention and coping strategies and areas of research needed for the future. The Round-table Conference commented on the actual status and gravity of suicides in adolescents, and came to the agreement that mental health issues including stress from interpersonal relationships and depression are the key risk factors of suicide. It was further agreed that problems in the measures being implemented for each of the areas include lack of manpower and funding, and inadequate organic association and cooperation among relevant institutions. They also agreed that development of a government-initiated suicide prevention program for adolescents, association among relevant experts, and development, and management of practical guidelines that are of broad and practical use are important. Furthermore, the panels were in agreement that the mass media must comply with the recommended level of coverage in reporting of suicide as adolescents are greatly influenced by provocative mass media reports due to their strong impulsive dispositions.

Caffeine-induced endothelial cell death and the inhibition of angiogenesis / 대한해부학회지

Numerous studies have shown that adenosine or adenosine agonists can stimulate angiogenesis. However, the effect of caffeine (a known adenosine receptor antagonist) on angiogenesis has not been previously studied. Accordingly, this study was undertaken to examine the effect of caffeine on angiogenesis and to clarify the mechanism involved. Chick chorioallantoic membrane assays were used to investigate the effect of caffeine on angiogenesis and proliferation assays using human umbilical vein endothelial cells (HUVECs), were used to study its effects on specific aspects of angiogenesis. The expressions of caspase-3 and Bcl-2 were examined by western blotting, immunofluorescence staining was used to identify HUVEC morphological changes, and fluorescence activated cell sorting (FACS) and DAPI staining were used to detect HUVEC apoptosis. Caffeine was found to inhibit blood vessel formation dose-dependently and to inhibit the proliferation of HUVECs time- and dose-dependently. FACS analysis and DAPI staining showed that inhibitory effect of caffeine on HUVEC proliferation was the result of apoptosis and the up-regulation of thrombospondin-1 (TSP-1). Furthermore, TSP-1 levels were down-regulated by NECA but were unaffected by CGS21680, indicating that caffeine regulated TSP-1 expression via adenosine A2B receptor. In addition, caffeine up-regulated caspase-3 and down-regulated Bcl-2 at the protein level. These results suggest that the inhibitory effect of caffeine on angiogenesis is associated, at least in part, with its induction of endothelial cell apoptosis, probably mediated by a caspase-3 dependent mechanism.

Improving quality of healthcare in Korea

Korea has achieved a remarkable expansion in health coverage at modest costs relative to other Organization for Economic Cooperation and Development (OECD) countries. Hospitals are more accessible and equipped with more advanced medical technologies than in most other OECD countries. OECD Reviews of Health Care Quality seek to support the development of better policies to improve the quality of healthcare. In 2012, a report on Korea presented best practices and offered recommendations for improvement in the Korean health system. Korea's health care system needs to shift its focus from simply supporting an ever-continuing expansion of acute care services to quality of healthcare. First, Korea needs to strengthen the focus of governance to the quality of healthcare by establishing HIRA as an institutional champion for quality. Second, Korea must strengthen primary healthcare because in Korea it is woefully underdeveloped today. Third, Korea must use financing to drive improvements in quality of care. In reality, HIRA has used its power over healthcare providers to force them to accept financial constraints; it has not supported quality of all healthcare sectors. Without structural changes allowing for independent judgment on the quality at HIRA, NECA is more suitable for ensuring quality for all healthcare sectors. As suggested by the OECD report, Korea must strengthen primary healthcare by restoring patients' trust in health professionals. In using financing to drive improvements in quality of healthcare, Pay for Performance may be helpful, but that must be driven on a voluntary basis and with a great financial incentive.

Cardioprotective signaling cascade of A2 adenosine receptor agonist 5'-N-ethylcarboxaminidoadenosine against myocardial reperfusion injury / 대한마취과학회지

BACKGROUND: This experiments investigated the signaling cascade responsible for anti-infarct effect by an A2 adenosine receptor (AR) agonist 5'-N-Ethylcarboxaminidoadenosine (NECA). METHODS: Langendorff perfused isolated rat hearts were subjected to 30 minutes of regional ischemia and 120 minutes of reperfusion. Drugs were perfused for a period of 5 minutes before and 60 minutes after reperfusion. For comparison of cardioprotection among groups, area at necrosis (AN) and area at risk (AAR) were measured by triphenyltetrazolium chloride staining. RESULTS: NECA significantly attenuated AN/AAR (14.1 +/- 1.9%, P < 0.001) compared with control hearts (30.7 +/- 2.8%). Anti-infarct effect by NECA was attenuated by an A(2A)AR antagonist 8-(3-chlorostyryl)caffeine (23.7 +/- 3.4%, P < 0.05) and an A(2B)AR antagonist MRS1706 (29.9 +/- 3.3%, P < 0.001). Cardioprotection by NECA was blocked by a guanylyl cyclase inhibitor (23.1 +/- 2.9%, P < 0.05) and a protein kinase G (PKG) inhibitor KT5823 (30.3 +/- 3.2%, P < 0.001). Glycogen synthase kinase-3beta (GSK-3beta) inhibitor SB216763 attenuated the AN/AAR in both NECA with MRS (17.8 +/- 2.7%, P < 0.01 vs. control) and NECA with KT5823 treated hearts (8.2 +/- 1.8%, P < 0.001 vs. control). The mitochondrial permeability transition pore (mPTP) opener atractyloside also aborted NECA's anti-infarct effect (24.7 +/- 2.4% P < 0.05). CONCLUSIONS: The signaling pathway by NECA administered at reperfusion involves the activation of both A2AAR and A2BAR and cGMP/PKG pathway, which in turn depends on inactivation of GSK-3beta and inhibition of mPTP opening.

Adenosine Receptor Agonists Modulate Visceral Hyperalgesia in the Rat

BACKGROUND/AIMS: Adenosine is an endogenous modulator of nociception. Its role in visceral nociception, particularly in visceral hyperalgesia, has not been studied. The aim of this study was to determine the effects of adenosine receptor agonists in a model of visceral hyperalgesia. METHODS: The visceromotor response (VMR) in rats to colorectal distension (CRD; 80 mmHg, 20 seconds) was quantified by electromyographic recordings from the abdominal musculature. Three hours after the intracolonic administration of zymosan (25 mg/mL, 1 mL), VMRs to CRD were measured before and after either subcutaneous or intrathecal administration of an adenosine receptor agonist. RESULTS: Subcutaneous injection of 5'-N-ethylcarboxyamidoadenosine (NECA; an A1 and A2 receptor agonist), R(-)-N6-(2-phenylisopropyl)-adenosine (R-PIA; a selective A1 receptor agonist), or CGS-21680 hydrochloride (a selective A2a receptor agonist) dose-dependently (10-100 mg/kg) attenuated the VMR to CRD, although hindlimb weakness occurred at the higher doses tested. Intrathecal administration of NECA or R-PIA dose-dependently (0.1-1.0 microgram/kg) decreased the VMR, whereas CGS-21680 hydrochloride was ineffective over the same concentration range. Higher intrathecal doses of the A1/A2 receptor agonist NECA produced motor weakness. CONCLUSIONS: Adenosine receptor agonists are antihyperalgesic, but also produce motor weakness at high doses. However, activation of the spinal A1 receptor significantly attenuates the VMR to CRD without producing motor weakness.

Advances in the study of A2B adenosine receptor antagonists / 药学学报

A2B adenosine receptor is involved in the control of mast cell degranulation, interleukin-8 synthesis and cell growth. A2B adenosine receptor antagonists may serve as novel drugs for asthma, Alzheimer' s disease, cystic fibrosis and type-II diabetes. Therefore, seeking for the highly selective A2B adenosine receptor antagonists has been one of great interest. The molecular basis, structure-activity relationship of selective A2B adenosine receptor antagonists and their interactions with A2B adenosine receptor were reviewed.

Renin Release by Adenosine Agosists and Antagonists in Two-Kidney One Clip Goldblatt Hypertensive Rats / 대한내분비학회지

BACKGROUND: In two-kidney one clip Goldbaltt hypertensive rats(2K1C GHR), clipped kidney may be exposed to low pressure and unclipped kidney to high pressure. In addition, both kidneys may have a different amount of adenosine which is increased by ischemia and plays an important role for renin release. The aim of this study was to invstigate the responsmiveness for renin release to adenosine agonists and antagonist in clipped and unclipped kidney of 2K1C GHR. METHODS: Emplying kidney slices from both unclipped and unclipped kidney of 2K1C GHR, the alteration by adenosine agonists and antagonist of renin release was studied. RESULTS: The renal renin content and basal renin release from unclipped kidney slices were suppressed, whereas those from clipped kidney were augmented Adenosine Al receptor agonist, cyclohexyladenosne(CHA), phenylisopropyl adenosine(PIA) and adenosine caused a decrease in renin release from clipped kidney slices. Adenosine A2 receptor agonist, NECA, and nonspecific adenosine receptor aganist, 2-chloroadenosine(CA) caused an increase in renin release from clipped kidney slices. Adenosine receptor antagonist, 8-phenyltheophylline(8-PT) caused an increase in renin release from clipped kidney slices. In unclipped kidney, however, the renin release in response to NECA, CA or 8-PT was reversed and the decreasing effect of renin release to CHA and adenosine was slightly inereased. CONCLUSION: These results suggest that the responsiveness of adenosine receptors, which may participate in renin release is modified in clipped and unclipped kidney of 2K1C GHR.

Characteristics of A|1 and A|2 adenosine receptors upon the acetylcholine release in the rat hippocampus

As it has been reported that the depolarization induced acetylcholine (ACh) release is modulated by activation of presynaptic A1 adenosine heteroreceptor and various lines of evidence suggest the A2 adenosine receptor is present in the hippocampus. The present study was undertaken to delineate the role of adenosine receptors on the hippocampal ACh release. Slices from the rat hippocampus were equilibrated with (3H)choline and then the release amount of the labelled product, (3H)ACh, which was evoked by electrical stimulation (rectangular pulses, 3 Hz, 2 ms, 24 mA, 5 V/cm-1, 2 min), was measured, and the influence of various adenosine receptor-related agents on the evoked tritium outflow was investigated. And also, the drug-receptor binding assay was performed in order to confirm the presence of A1 and A2 adenosine receptors in the rat hippocampus. N-ethylcarboxamidoadenosine (NECA), a potent adenosine receptor agonist with nearly equal affinity at A1 and A2 adenosine receptors, in concentrations ranging from 1apprx30 muM, decreased the electrically-evoked (3H)ACh release in a concentration-dependent manner without affecting the basal rate of release. And the effect of NECA was significantly inhibited by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 2 micrometer), a selective A1 adenosine receptor antagonist, but was not influenced by 3,7-dimethyl-1-propargylxanthine (DMPX, 5 micrometer, a specific A2 adenosine receptor antagonist. N6-Cyclopentyladenosine (CPA), a selective A1 adenosine receptor agonist, in doses ranging from 0.1 to 10 micrometer, reduced evoked (3H)ACh release in a dose-dependent manner without the change of the basal release. And the effect of CPA was significantly inhibited by 2 micrometer DPCPX treatment. 2-P-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS-21680C), a potent A2 adenosine receptor agonist, in concentrations ranging from 0.1 to 10 micrometer, did not alter the evoked ACh release. In the drug-receptor binding assay, the binding of (3H)2-chloro-N6-Cyclopentyladenosine ((3H)CCPA) to the- A1 adenosine receptor of rat hippocampal membranes was inhibited by CPA (Ki = 1.22 nM), NECA (Ki=10.17 nM) and DPCPX (Ki-161.86 nM), but not by CGS-21680C (Ki=2,380 nM) and DMPX (Ki-22,367 nM). However, the specific binding of (3H)CGS-21680C to the A2 adenosine receptor was not observed. These results suggest that the A1 adenosine heteroreceptor play an important role in evoked ACh release, but the presence of A2 adenosine receptor is not confirmed in this study.

The role of adenosine receptors on acetylcholine release in the rat striatum

As it has been reported that the depolarization induced acetylcholine (ACh) release is modulated by activation of presynaptic A-1 adenosine heteroreceptor and various evidence suggest that indicate the A-2 adenosine receptor is present in the striatum, this study was undertaken to delineate the role of adenosine receptors on the striatal ACh release. Slices from the rat striatum were equilibrated with (3H)choline and then the release amount of the labelled product, (3H)ACh, which was evoked by electrical stimulation (rectangular pulses, 3 Hz, 2 ms, 24 mA, 5 Vcm-1, 2 min), was measured, and the influence of various agents on the evoked tritium outflow was investigated. And also, quantitative receptor autoradiography and drug-receptor binding assay were performed in order to confirm the presence and characteristics of A-1 and A-2 adenosine receptors in the rat striatum. Adenosine (10 ~ 100 micrometer) and N-6-cyclopentyladenosine (CPA, 1 ~ 100 micrometer) decreased the (3H)ACh release in a dose-dependent manner without changing the basal rate of release in the rat striatum. The reducing effects of ACh release by adenosine and CPA were abolished by 8-cyclopentyl-1,3-dipropy-lxanthine (DPCPX, 2 micrometer), a selective A-1 adenosine receptor antagonist, treatment. The effect of adenosine was potentiated markedly by 3,7-dimethyl-1-propargylxanthine (DMPX, 10 micrometer), a specific A-2 adenosine receptor antagonist. 2-P-(2-carboxyethyl)phenethylamimo-5'-N- ethylcarboxamidoadenosine hydrochloride (CGS-21680C), in concentrations ranging from 0.01 to 10 micrometer, a recently introduced potent A-2 adenosine receptor agonist, increased the(3 H)ACh release in a dose related fashion without changing the basal rate of release. These effects were completely abolished by DMPX (10 micrometer). In autoradiogaphy experiments, (3H)2-chloro-N-6-cyclopentyladenosine ((3 H)CCPA) bindings were highly localized in the hippocampus and the cerebral cortex. Additionally, lower levels of binding were found in the striatum. However, (3H)CGS-21680C bindings were highly localized in the striatal region with the greatest density of binding found in the caudate nucleus and putamen. Lower levels of binding were also found in the nucleus accumbens and olfactory tubercle. In drug-receptor binding assay, binding of (3H)CCPA to A-1 adenosine receptors of rat striatal membranes was inhibited by CPA (K-i = 1.6nM) and N-ethylcarboxamidoadenosine (NECA, K-i = 12.9 nM), but not by CGS-21680C (K-i = 2609.2 nM) and DMPX (K-i = 19,386 nM). In contrast, (3H)CGS-21680C binding to A-2 adenosine receptors was inhibited by CGS-21680C (K-i = 47.6 rim) and NECA (K-i = 44.9 nM), but not by CPA (K-i = 2099.2 nM) and DPCPX (K-i = 19,207 nM). The results presented here suggest that both types of A-1 and A-2 adenosine heteroreceptors exist and play an important role in ACh release in the rat striatal cholinergic neurons.

Renal effects of chronic treatment of adenosine analogues

Evidence for the existence of at least two subclasses of renal adenosine receptors has been presented. N-6-cyclohexyladenosine (CHA) is a relatively selective A-1 adenosine agonists, whereas 5'-N-ethylcarboxamidoadenosine (NECA) acts as a preferential agonist of A-2 adenosine receptor. N6-(L-2-phenylisopropyl)-adenosine (PIA) almost unselectively activates both A-1 and A-2 adenosine receptors at micromolar concentrations. During the characterization of adenosine receptor in the kidney, we have discovered a novel phenomenon, that is, an intramuscular administration of CHA for 3 days caused a diuresis and a suppression of urinary concentrating ability. To further characterize this novel phenomenon, an intramuscular administration of adenosine and other adenosine angonists, PIA and NECA, and prior treatment of adenosine antagonists, caffeine, theophylline and 1,3-diethyl-8-phenyl-xanthine (DPX) were performed. Systemic administration of CHA, PIA, and NECA for 3 days caused a suppression in heart rate, blood pressure and general motor activity without change in rectal temperature. Systemic administration of CHA, 0.5, 1 and 2 mg/kg/day, for 3 days caused a dose-dependent increase in urine volume and decrease in urinary osmolarity and free water reabsorption. This phenomenon was reversible and repeatable. Administration of adenosine (40 mg/kg/day) produced no apparent effect on the renal function, whereas PIA (2 mg/kg/day) produced an similar effect to CHA on the renal function. Systemic administration of NECA, 0.025, 0.05 and 0.25 mg/kg/day, for 3 days caused a dose-dependent increase in urine volume and dose-dependent increases in excreted amount of creatinine, urinary osmolarity and free water reabsorption. These renal effects of adenosine agonist were maximum at second day during the drug administration. In terms of increase in urine volume and the suppression of urinary concentrating ability, NECA was potent than CHA. Prior treatment of caffeine (50 mg/kg/day) or theophylline (50 mg/kg/day) abolished the diuretic effect of, CHA, whereas DPX (50 mg/kg/day) did not affect the CHA effect. CHA, 0.5 mg/kg/day, produced no change in plasma renin activity and plasma levels of aldosterone, epinephrine, and norepinephrine. These results suggest that this novel phenomenon produced by an activation of renal adenosine receptors plays an important role in urinary concentrating mechanism.