Team:KU Leuven/HP/Gold Integrated

Human practices

In HEKcite we create an oscillating HEK-cell, but for what purpose? Therapeutic drug monitoring is our answer. In the treatment of multiple severe diseases, a stable concentration of drugs is crucial. Steady blood levels determine therapeutic outcomes and increase survival rates. Currently, the most common therapeutic drug monitoring technique is blood sampling. For patients who need lifelong observation, the numerous hospital visits and frequent blood samplings can have a negative effect on the quality of life. Therefore, we develop a system that allows patients to determine the level of drugs at home. Furthermore, the ease of these measurements allows for daily or even continuous analysis.

Using this dynamic data collection instead of the static measurements performed in hospitals today, we might increase both therapeutic outcomes and quality of life of patients. In order to investigate the different views on our projects we talked to specialists in several fields where therapeutic drug monitoring is of great importance: transplantations, psychotics and epileptics. Three specialists have provided insights in how they expect our project will influence the lives of their patients and future treatments. We used this information to further shape our project.

Professor Diethard Monbaliu

Professor Monbaliu is a reputable abdominal transplant surgeon, at the department of microbiology and immunology at UZ Leuven. He is also responsible for a course on topographical and radiological anatomy and supervises several thesis students.

Professor Monbaliu confirmed our expectations that there is a need for a more dynamic measurement. In addition, he suspects that it could lead to a better evaluation of patients’ compliance. Together, these advances could result in fewer transplant rejections. He has also brought our attention to a novel and more prevalent immunosuppressant drug, tacrolimus. Finally, he mentioned that patient variability is an issue in his field, and that our device should take this into account. Want to learn more? Press for more details.

Before this meeting, we were investigating the immunosuppressant cyclosporine, as we thought this compound was commonly used after transplantations in order to reduce the chance of rejection. However, professor Monbaliu clarified that this is no longer the case. Instead, he brought our attention to the compound tacrolimus, which has taken cyclosporine’s place in transplantation medicine. Both drugs have the same mode of action, but tacrolimus has a better clinical outcome and less side effects. We were interested in using this novel drug for our research, but unfortunately, the compound is too expensive for us to use. Therefore, considering our financial situation and the input of the professor, we chose to use cyclosporine in our experiments.

Lastly, according to professor Monbaliu, a possible reduction of blood sampling could be a great advantage. However, he mentioned that every patient is different, which means that finding the optimal concentration of immunosuppressant for each patient could a challenge. As a result, our device should be calibrated individually for every patient. Together with professor Monbaliu, we suspect that the individual differences and the problems that go with them could be assessed during clinical studies. As soon as different patients and their different values can be assembled, it can lead to the procedures needed to determine the optimal drug concentration and calibrate our device.

Professor Chris Bervoets

Professor Chris Bervoets is a psychiatrist. He is responsible for the department of transcranial magnetic stimulation, the department of deep brain stimulation and the department of compulsive disorders within the UPC (University Psychiatric Center) of KU Leuven. Additionally, he conducts research on neuromodulatory treatments for various psychiatric disorders.

While investigating different branches in medicine that could benefit from improved therapeutic drug monitoring, our attention was drawn to psychiatry. In this field, there are several drugs, for example lithium, that affect ion channels and could therefore be measured directly by our system. These aspects spiked our interest, and to learn more we contacted the specialist professor Chris Bervoets, who gave us some valuable insights in the difficult world of psychiatry.

After explaining our project, professor Bervoets shared his enthusiasm about the possible advantages of our device. He mentioned three ways in which HEKcite could further shape the field of psychiatry.

First of all, he described the current problems concerning treatments using dopamine antagonists. These dopamine antagonist are blockers of the so-called dopamine receptors, and are used for a wide range of psychologic disorders, among which are depression, psychosis, and many more. At present, researches lack detailed information about the correct dosage of these dopamine antagonists: The amount of receptors that have to be occupied to achieve a certain clinical effect is not yet known. In some cases, doctors see a more favourable clinical outcome when patients take dopamine antagonists irregularly, while for other patients, this is not the case. Therefore, a better understanding of how the correct dosage correlates with dopamine receptor occupancy could be extremely valuable.

Nowadays, this occupancy can only be measured using expensive PET scans. If we could find a way to insert the dopamine receptor in our HEKcite cells and genetically design a correlation of the electric rhythm and the occupancy of the receptors, it could generate valuable information concerning different drug concentrations and their corresponding receptor occupancies. Not only would this measurement be less expensive than a PET scan, it would also provide a more dynamic measurement of the receptor occupancy, which could result in additional insights in dopamine antagonist metabolism.

Furthermore, Chris Bervoets told us about a novel way of clinical assessment, called the experience sampling method (ESM). Patients are asked to answer ten or more questions a day regarding their emotional status. The answers to these questions are then used to improve diagnosis or foresee psychotic episodes. Professor Bervoets suggests that our device could complement this method by combining the answers of the patients with the exact drug concentrations at a certain time. This could lead to a better comprehension of the connection between symptoms and drug dosage, and help further treatments.

Finally, professor Bervoets mentioned safety monitoring, which was our original motivation to investigate the field of psychiatry. With our device, we could verify the concentration of certain drugs that only have a small therapeutic range in which they are effective. Furthermore, Professor Bervoets explained to us that lithium may cause side effects even in the right doses. As a result, many patients visit the hospital unnecessarily. Our device could prevent these avoidable hospital visits by reassuring the patient that the experienced symptoms are due to a benign lithium intoxication. On the other hand, it could also warn the patients when their lithium concentrations are dangerously high and a hospital visit is required.

After discussing these interesting possibilities for our project, we asked professor Bervoets if he thinks whether patients would accept to undergo the implantation of a small device. He suspects that our project would most likely only reach a select group of patients. For instance, patients who experience severe symptoms are often treated by transcranial magnetic stimulation and are used to medical interventions. This group of patients would not mind a minor subcutaneous implantation, if this would decrease their symptoms. Additionally, our device could help determine which drug is most suitable for a patient and optimise doses to reduce side effects.

To conclude, professor Bervoets confirmed our speculations that therapeutic drug monitoring is important in psychiatry. Furthermore, he opened our eyes to other potential applications of HEKcite in this branch of medicine and research. We are very interested in investigating the correlation of ESM and drug concentrations and the possibilities of developing a system to analyse dopamine antagonists. However, due to time and resource constraints, we have to remain focussed on therapeutic drug monitoring. Thanks to professor Bervoets’ enthusiasm about the project and the possible applications, we have become even more motivated to investigate the possibilities of safety monitoring, and believe it could bring science and medicine a substantial step closer towards solving important problems in psychiatry.

Professor Wim Van Paesschen

Professor doctor Wim Van Paesschen is a neurosurgeon specialized in epilepsy. He also is head of the epilepsy research laboratory, part-time teaches at the faculty of medicine and supervises thesis students.

Professor Van Paesschen confirmed that therapeutic drug monitoring is necessary for anti-epileptics and mentioned the importance of verifying patient compliance. He also showed us that our project has more potential than even we imagined by giving some more examples of possible applications.

In light of our group focusing on drug monitoring as our target for human practices, anti-epileptic drugs seemed to be a quite interesting to research. Given that, we set a meeting with Doctor/Neurologist Wim Van Paesschen, a specialist in epilepsy. Prior to the meeting, our main interest was figuring out if drug monitoring was in fact needed for patients being treated from epilepsy, and it case it was, how could the concept of HEKcite come in handy for said patients. During the meeting, Prof. Van Paesschen showed a great deal of excitement and enthusiasm about the concept of HEKcite, assuring us that drug monitoring of anti-epileptics is indeed necessary, especially for patients suffering severe forms of epilepsy. There have been already various attempts to implement drug monitoring in epilepsy patients but none were quite successful. Since the concept of HEKcite mainly relies on different ion channels, his advice wasn’t to necessarily work with the most used anti-epileptics, but instead focus on those directly linked to the ion channels we are working with. Some of those include: Retigabine which opens potassium channels or ethosuximide which influences T-type calcium channels. Furthermore, some epileptics bind partially to albumin which hinders their activity. Nowadays laboratory tests can only measure the total concentration of anti-epileptics in the blood and not only the free, active concentration. Our system would be able to distinguish between the free, active versus the bound, non-active drug compounds. Another crucial point that was discussed during the meeting was what the patients would think/react to idea of an inserted monitoring device. He proceeded to say that field of “biosensors” is now a very interesting, growing field, and due to its simplicity and accuracy, it would be most welcome by patients. Prof. Van Paesschen was also so helpful, shedding light on a very important matter related to drug monitoring, that is, checking patients’ compliance. He mentioned how that is such a big problem especially with epilepsy patients, and that HEKcite could also be used to solve that problem. Last but not least, he gave a few suggestions for other useful applications that HEKcite could be used for. First of all he gave the idea of using our system as a form of personalized medicine. By using ion channels who contain the exact mutation of the patient, we could use our system to verify which drug is most effective specifically for the mutated channel of the patient. Next to this, he mentioned that epilepsy is often the result of multiple mutations in multiple channels. Our system could study the interactions between different ion channels and their mutation to further understand the mechanisms that can lead to epilepsy. These examples of the professor show again the diversity of our project and the great range of possible applications. All in all, the meeting was extremely helpful to us. We were able to leave the meeting with an answer to our original inquiry, that is, if the concept of HEKcite could be useful with patients with cases of epilepsy. We were also able to realize the full potential of the project and its various applications, giving us extra motivation and drive to move forward with our human practices.

professor Iemand anders

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Professor Victor Top

Always angry and disappointed with others. Mainly known as Victator.

Victator spotted in his natural habitat. His phone has our numbers. Will he or will he not call one of his slaves again? xoxo Gossip Girl

Before our meeting with professor Monbaliu, we were doing research on the immunosuppressant cyclosporine, which we thought was used most after transplantations to reduce the chance of rejection. However, professor Monbaliu clarified that it is not cyclosporine that is mostly used nowadays, but tacrolimus is. Both drugs have the same mode of action but tacrolimus has less side effects. We were interested in using tacrolimus for our research however the drug is too expensive for us to use. Therefore, considering the information professor Monbaliu gave us and our financial possibilities, we chose to use cyclosporine. Next to this, professor Monbaliu confirmed that there is a need for a more dynamic measurement and a better evaluation of patients’ compliance which could result in less transplant rejection.

Furthermore, the reduction of blood sampling is, according to the professor, a great advantage. However, a problem he brought to our attention was the fact that every patient is different which means that finding the optimal concentration of cyclosporine/tacrolimus is a challenge. Our device should thereby be calibrated individually for every patient. Bringing this information into account we considered that these differences and the problems that go with them could be assessed during clinical studies. Where different patients and their different values can be assembled, which can lead to procedures needed to determine the optimal drug concentration and calibrate our device.