 Thank you for your interaction. Okay, good afternoon, everyone. And thank you for giving me the opportunity to be here to share my experience with you. I hope that at the end of my talk, you will be familiar with the pharmacovision system in Thailand and also know how pharmacovision and pharmacogenomics work together. I have divided my presentation in three parts. The first is the overview of the Thai pharmacovision system. The second is the Thai vigilant based pharmacovision data bed. And the third part is the pharmacovision and pharmacogenomics research. For the overview of the Thai pharmacovision system, I classify it into levels. The first level is the national level, the pharmacovision network and management. I classify it into levels, one with the national level and the second is the hospital level. And another part is the surveillance methods utilized in the pharmacovision. We do both passive and active methods. Let me introduce a little bit about Thailand. Thailand is a country in the Southeast Asia with a population of 65 million people divided in the 77 provinces. Pharmacovision was active in 1983 and the National Center was set up as a part of the Thai FDA at the same year. The year later, Thailand joined the official program for international drug monitoring as the 26th member in 1984. Right now, I think it's about 100 countries. This slide shows our network and the management at the national level. Someone called is the medical pharmacovision. Hospital is our main source of reports. About 1,000 to 1,500 setting reports to our center each year. Their reports are voluntary, not mandatory. But anyway, most of them are government hospitals and the government has the policy for them to report to us. For the company of marketing authority, it's mandatory for just early the new drug according to the safety monitoring program. And all the data that we analyze, if the signal is detected, it will proceed to consider the pharmacovision especially community to consider whether any measure should be implemented. For the communication measure, we can do immediately. But for the regulatory measure, we have to get the adoption from the drug community. Then Thai FDA will do the enforcement for that recreation. The AERI reporting system is the main system that the hospital used to report to us. Anyway, the other methods are welcome such as email, fax, seminal, and post-paste mail. Every month, we will send back the letter to acknowledgement and to inform how many reports that we receive from each hospital or each company and inform how the quality that they send to us. Each report will be classified by the component of the report. And for the routine, we will have a drug bulletin and also each year we will do the annual report. And in some situations, some of them will be feedback to the reporter. This safety monitoring is a condition for the new drug application only. So during two years, this program will be conducted for two years. During these two years, the company has to do the ADR monitoring. So they send us the report. For the individual report, they have to send up according to the timeline but every four months they have to summarize and send the summary to us. Now let's move to the hospital level. In the hospital, pharmacies pay the major role in this activity. When there is an ADR diagnosis, pharmacies will be notified to collect the data and do the assessment. Physicians in Thailand don't want to fill in any report. So pharmacies take care of this job. And after they do a causality assessment, they will feedback the result to the physician. Sometimes they have a discussion whether to agree with the result or not. At the same time, pharmacies will send the report to our center and try to minimize the risk by several methods. For example, they will provide the dark alert card to the patient. This card will document the suspected drug name, adverse drug reaction, and causality assessment level, and also the reporter. And recommend the patient how to use this card because it's very hard for the patient to remember the name, pieces, or English name. So we recommend them have to take this card every time when they see the doctor. Sometimes when the pharmacies will do the causality consultation, to do the patient consultation, to the patient who receives the medicine that can induce the serious cutaneous adverse drug reaction, this is the book for them. And this slide shows several many methods that we use to try to minimize the risk. This is the sticker to inform that this patient developed adverse drug reaction, this patient charge, medical record, and also patient bed. Some of you may have a question why we add on so many pairs because we would like to convey this message to the one who should know about that. And the information about it also input in the dispensing program to alert when the doctor prescribed the same medicine with the same patient who experienced the adverse drug reaction. Then the pharmacy will call back to confirm whether the doctor still would like to prescribe that medicine or not. The causality assessment method that the pharmacies use is the same as the USFDA, which is the old Uppsala monitoring method, and also Nalangzhou algorithm, and also the Thai algorithm. The Thai algorithm is modified from the visual UMC. For the surveillance method that we use, we use both passive and active methods. For the passive methods, spontaneous reporting is the main method that for all drug. And for the targeted spontaneous reporting is for some safety concerns or some drug of interest. For example, it's conditional approval new drug or herbal medicine, which is the national essential drug lead, and the medicine used in the public health program such as NGTB drug or ARV. For the active surveillance, the intensive hospital monitoring will be conducted for some products only. And I hope that this year or next year, the cohort even monitoring will be implemented for the new drug of NGTB. And for the registry, we conducted only one project. Because Thailand has a problem that the incident of the peerless aperture associated with illiteracy is higher than the other country in the world. For the type which way I will classify as shown on the slide. This slide shows the characteristics of our database. Right now, about 6 million reports were accumulated. Over half of them have been received in the last six years. About 50,000 reports were received each year. Only 2.1% of the reports were submitted by the company. Most of them come from the hospital, and about 20% of serious cases were received. During 1984 to 2014, about 18,000 reports were received. We can classify as HHS is the most adverse drug reaction that we receive. For the epidemoniclysis is the preferred term of the toxic epidemoniclysis. We use the base O, who are different from the beta. Similar, but not the same. But the pacification is the same. This slide shows the Steven Johnson syndrome. The total HHS and 10 report is 11,000 right now. The proportion of this report in Taiwee Tibet is about 1.8. This is the characteristic of the report. About half of them rank at the probable level. And 2% of them have a dead outcome. This slide shows the more suspected drug associated with HHS and 10. I think it's similar to the US FDA. And this slide shows the signal that our report contributes to generate signals. Two of them is Steven Johnson, this PTU. The number, this is five reports come from Thailand, from 12. And this is the signal generation that do by our Thai FDA. We found the steptomycin associated with the Steven Johnson syndrome in 2013. This slide shows the report in our last bed. Consistence with the publication from Africa. That indicated that an increasing list of the serious, serious cutaneous reactions associated with the use of the Taiwee acetalzone in person who with HIV. So, at the same time, our data can detect the signal. Even though the report didn't mention that this patient is HIV patient or not, but at the same time that the HIV epidemic in Thailand. This is public in the debate or within. For the research and publication that you see in our database. This is our colleagues' thesis. We evaluate reporting serious adverse drug reactions in Thailand against study of HHSN10. The study is a cross-sectional study. We select 14 selected hospitals from five legions of Thailand. We compare the report that our center received in 2005 compared with the report. How can I say? The ICD-10 compared to the report from this hospital. We retreat the case by using the ICD-10 computer-like system. And then verify with the patient medical record. The results show that the under-report is about 44 percent. And this cut-dance submission is about 8 percent. This slide shows the publication that you see in our database. Both of them. And now let's move to the last part. This picture shows our campus. And this one, even if I'm not here, but from the Dr. Wasan picture, confirm that I was there. And from the brainstorming, we found that the association between HHSN10 confirmed. And we estimate that if we... about 90 percent can be prevented by screening tests. So from the brainstorming, there are several... even come out. One is the proposal for the universal screen for carbamazepine. And they need the economic study. And also they need to develop the pharmacogenomic testing center. And at the same time, the pharmacogenomic network has been conducted. From the result, the testing for the neuropathic pain is not effective, but not for the epilepsy. Epilepsy is a borderline. And this is the nice center of the pharmacogenomic testing. And three-day quarantine turns around time for this service. And this slide shows the first announcement for the nationwide pharmacogenomic service. And the pilot-free testing for the all-carbamazepine presky in Bangkok. And for the study, 18 hospitals, which is our pharmacovigilane network, participate in the thyska pharmacogenomic-fed one study. And this slide shows how our center participates in this study. Every week, one of my colleagues will detect the case. And then inform the researcher, Dr. Sulakamed. And this slide shows the number of DNA samples collected based on the suspected drug. And I show this slide again because someone may think that because of carbamazepine testing, they do the case, but I think we have to find out. Further research have to conduct. I will end my talk with this slide. The collaborating with the pharmacovigilane team and pharmacogenomic team not just only benefit each other, for my opinion, I think it's benefit for the patient's safety as well. Thank you for your attention. And thank you, Dr. Sulakamed, for preparing the third part. Great. Thank you very much. Yes, Dr. Leader. That was very interesting. I noticed on a couple of slides one in the reported cases that the number of reported cases of cotrimoxazole, trimethoprimsulfa was exceeded considerably that of carbamazepine. And also in your collected DNA samples, you had a lot of cotrimoxazole samples. Do you think that's a function of an increased susceptibility in the Thai population, or does that reflect a use that's greater than what we might use in North America or Europe? I passed this to Dr. Sulakamed. Okay. I think there are several factors. First, we use a lot of surfamethoxazole because we have HIV epidemic. And this drug is used for opportunistic prophylaxis before we have a national antiretroviral program. So we have a lot of cases five, ten years ago back to more surfamethoxazole is recommended for the one who cannot afford the antiretroviral. So at that time, we use a lot. So we have a lot of cases with adverse drug reactions. And the second is that surfamethoxazole is the highly suspected drugs. When we treat the HIV infected patient, we usually give them multiple drugs. And then if you have multiple drugs and the pharmacist or the physician has to pick the causative drugs, then it will be the highly suspected. So it's become the first one. So every time we, I mean, anyone reported it become the first one that pick it to be the suspected drug. So that's the second. And the third one, we found some association with HLA class one with this surfamethoxazole in Thai population. And we are trying to publish the data. And probably we have some specific association with some HLA and Liu. So maybe these are the explaining factors. But it's the combination of surfamethoxazole and trimethoprim that you're giving? Or is it a combination? Yes. Is there much use of trimethoprim alone? We rarely use it. We usually use them together. I confirm that when pharmacists always think that south farm medicine is the suspected drug for the student and student. So the HLA always is the suspected drug for that report. I wonder if maybe Dr. Sirakameth or others could comment on the interaction between Stevens Johnson and HIV AIDS. And that it seems that patients with AIDS are at like, you know, a thousand fold increased risk. Or so particularly when their CD4 counts are low. Do you want to comment on that? So we have also the developing, which is the another drugs that cause Steve intense in our populations. And yes, we observed that Steven Tennis has a lot of hybrids in HIV population. But we do not know exactly why. So maybe it's a topic that we can study. Yes, Dr. Malkin. We used to have, we used to see a central number of cases related to never opinion, especially in France. And we had some suspect that at some point maybe patients of African origin may be more susceptible. We could not really prove that. But these were people living in the greater area of Paris where you have a higher population, deriving from these countries in Africa. But ever since there's other alternatives, we hardly see cases of the never opinion in Europe and central Europe. Our colleagues from South Africa report a completely different picture. The majority, this is let's say a governmental hospital run by the government. So everyone comes there, the poor people as well. Most of them are HIV infected plus have tuberculosis. So that means they have six, seven drugs, three or four for each of the conditions. And it's very difficult to identify the culprit one because they are kind of started pretty much at the same time. And they have developed a certain protocol how to deal with it. Because sometimes it's not easy to say whether it is one of the anti TB drugs or of the HIV drugs. So they stop everything and then step by step reintroduce the drugs. Because otherwise they would risk that the germs would be not sensitive to any medication anymore. So these are probably the people who could talk about this best. But of course, none is here right now. So in our prospective court study in Malawi, we followed a thousand patients from initiation of virupine for at least six months afterwards. At that time, the policies were not to start anti tuberculosis therapy at the same time. So these patients were started on triple therapy in terms of the virupine as Zidavidine and Stavidine at that time. So that because of the high risk of these hypersensitivity syndromes, the Malawian Ministry, National Health Ministry has changed the drugs now. If Averins is the commonly used drug, Stavidine is also gone because of peripheral neuropathy. But when we have done the work and this is also seen in northern European populations, the actual risk factor in terms of CD4 count is that you have to have a high CD4 count greater than 250 to be able to get the Stephen Johnson syndrome. I guess the pathogenetic point of view from that is that if you have too low a CD4 count, you don't actually have the immune system to be able to generate an immune response to start killing you off your skin cells. Just to follow on that, there is some data that also suggests with neuropeners. I think there's three or four separate studies that suggest in patients that are switching with undetectable HIV viral load that they don't get the reaction. So if they're virulogically suppressed or HIV is controlled, they don't seem to be at higher risk regardless of their CD4 count. So I think that's interesting. I just had a second question just regarding geography of Thailand and the diversity within it. I know northern Thailand has a lot more higher prevalence of specific Caucasian HLA alleles like HLA B5701. Do you see any signals across the country in terms of actually differences, potentially in terms of reporting of specific drug reactions based on that diversity? I'm not sure I get your question, but is this about the geographical distribution? Northern Thailand has different HLA representation like certain HLA B alleles like HLA B5701. The carriage rate there would be as high as 10% just like in Europeans. We did the determination of the regional distribution of HLA B specifically. And 1501 has a northern-souten gradation, but it's not so large difference. In the northern, we have like a 6% or something and then in the southern, we have 10%. But that's the only frequency. So if it's a carrier, it's turned out to be 12 to 20 ranging from the northern to the southern. But the southern has higher rate of prevalence of 1502. But for the 3505, it's about 3% distributed all over the country. There's no specific difference in the region, but the Indonesian population has a lot higher 35% or 5%. But then I think the question is, do you see a geographic influence of rates? I mean, I guess the numbers may be too low to see, but do you see different rates of SGS10? We don't see that, I think. What actually happens with regards to like health care in Thailand where patients access care as opposed to where they're from? There were two maps that we represent. And the first one is NICE Center for Pharmacogenomic Testing. And the other one is the 18 hospitals that participate in collecting the examples for these Stephen 10's cares. So that 18 hospitals is voluntarily working with us. So they are the hospitals that have adverse drug reaction pharmacists. So these pharmacists are interested in Stephen 10's more than the others. So they work with the patients and they get the sample for us to test in the research. And another thing is most of these hospitals are tertiary hospitals. So the Stephen Jensen case always refers to these hospitals. Dr. Wimun, could you go back to the slide, your wish base? The one that did. The one that from 2010 and then dropping the Stephen Jensen cases. Because one of our objective is to try to eradicate Stephen Jensen and 10. So in Thailand, can I say that now we are approaching that mode of eradication? And my question is what is the cause of dropping of Stephen Jensen and 10 because of the pharmacogenomic screening or because of the pharmacists in the hospital? Let me show another piece. It's not just only the Stephen Jensen case drop. It's the total, this one also drop. But anyway, I just see the proportion of the Stephen Jensen and 10 case is the same proportion as during we conduct the study from 2010 to 2012. It's about 1.6 to 1.7. It's still the same. And I think it's not just only the testing at the hospital. It's a policy that the pharmacists have to redo the Stephen Jensen case as much as they can. So whenever the doctor prescribe the drug that can induce the Stephen Jensen, they will give the counseling to the patient. How can the podium of the Stephen Jensen and ask the patient come as fast as they can to stop the drug? So I think this might be one of the factors that decrease the case. And the other one might be the testing. So I think we have to conduct the research to find out what is the real factor. So in Thailand it's quite interesting that in provinces, pharmacists are more powerful than clinicians. They have more say in Stephen Jensen how to prescribe the medication. But in Bangkok, doctors have a final say, not the pharmacists. Somehow that is debatable. We could find out the way. But anyhow, somehow the Stephen Jensen is dropping. Because for the drug safety, it's like the pharmacist's role to reduce the risk of the drug.