Jak się tworzy leki? PARTNERZY

Co to jest? Co jest w środku? With a large capsule representing a medicine, ask students: What is it? What’s inside? (They will probably know that it’s a medicine): A medicine consists of an active substance or substances and excipients.

Co znajduje się w środku leku? You then open the capsule, which contains different objects representing the contents of a medicine: A chemical structure made from molecular models that represents the active substance, A plastic lemon that represents the aroma, A small packet of sugar, representing a nice flavour, A plastic strawberry, representing colour, Some coloured balls, to improve its appearance, Some plastic bubbles for protection, etc… The most important part of a medicine is the active ingredient, which is the biologically active substance that is capable of altering the metabolism of the cells that it affects. A medicine is a drug, or set of drugs, that have properties capable of preventing, treating, relieving or curing diseases or illnesses. Excipients are pharmacologically inactive substances. There are many kinds of excipient and their functions are: to improve flavour, colour and appearance, to make the medicine soluble or protect the active substance, etc.

Now imagine that the active substance is like a piece of a jigsaw puzzle. Ask: What do you think that this molecule does when it enters the body? (Students must think about what happens when we ingest a medicinal capsule and how it arrives at the right place to have an effect [digestive system, circulatory system, etc.]). The shape of the piece of the jigsaw should help us work out where it fits. If we imagine that it is an arrow, it has to have a target. We can then explain that the drug looks for its “target”, in this case a “therapeutical” target, to have an effect and cure the disease.

Składnik czynny środek farmaceutyczny Poszukiwanie celu terapeutycznego, aby uzyskać efekt i wyleczyć chorobę cel terapeutyczny The slide shows a drawing of a cell with some of its components. The purpose of the active substance is to find its therapeutic target, the place where we want the drug to act. In this case, the therapeutic target is a protein found in the cell’s membrane. 5

Składnik czynny Poszukiwanie celu terapeutycznego, aby uzyskać efekt i wyleczyć chorobę cel terapeutyczny As soon as the active substance reaches the therapeutic target, a series of reactions occur that provoke the desired cell response that could solve the problem. 6

Jak tworzy się leki? Going back to the initial capsule, we can ask students: How are medicines developed? What process should a drug follow to reach the market? How long do you think it takes to launch a medicine on the market?

FAZA BADAŃ KLINICZNYCH ETAPY POSZUKIWAŃ NOWEGO LEKU Poszukiwanie nowego leku to proces długi (trwa 10-25 lat), złożony i drogi, obejmujący wiele etapów. Badania i rozwój leku (2-10 lat) Badania przedkliniczne (2-6 lat) In vitro- In vivo FAZA BADAŃ KLINICZNYCH FAZA I  FAZA II  FAZA III Wprowadzenie leku na rynek FAZA IV The search for a medicine is a long, complex and very costly process (the phases are then briefly described, as they are explained in detail on the following slides). Launching a drug on the market is a very long process, taking an average of 20 years. It is very complex and requires huge economic investment. It consists of several stages: the first is the research and development of a possible drug candidate, the aim of which is to find a substance that could be a good active ingredient for the disease being studied. This stage is combined with the preclinical study stage, consisting of testing the drug candidate in cells and animals. If the results of these studies are positive and no side effects are detected, the drug candidate would enter the clinical development stage, which consists of testing it in humans. If this stage is passed, with no or very reduced side effects, the drug will reach the market.

? Kandydata na nowy lek można odkryć na wiele sposobów: JAK MOŻNA ODKRYĆ KANDYDATA NA NOWY LEK? Kandydata na nowy lek można odkryć na wiele sposobów: ? Mention that the purpose of the first research and development stage is to find a compound that could become a drug for a therapeutic target. Ask: How do scientists find compounds that are good drug candidates? (Encourage students to think about different ways in which to find a chemical compound that fits in the right place. Suggest that the therapeutic target is like a safe with a lock and that the drug candidate is the key to open that lock). How would you go about finding the key to the safe? (Encourage students to think about it and suggest possible solutions)

JAK MOŻNA ODKRYĆ KANDYDATA NA NOWY LEK? Kandydata na nowy lek można odkryć na wiele sposobów: Przypadek Szeroko zakrojone poszukiwania Racjonalne projektowanie Modyfikacja chemiczna A drug candidate can be discovered in different ways: One way would be to discover the key by chance or serendipity along the way. In the medicines world, there are many examples of drugs that have been discovered by chance. One example is Viagra. The drug was initially intended to reduce the blood pressure of people with hypertension. When it was tested in patients, it was found that the volunteers were enjoying the tests, despite its low anti-hypertensive effect. It was then discovered that one side effect (erection) was more important than its therapeutic effect. As there was no medicine available for erectile dysfunction at the time, that is how Viagra came about. Another procedure is massive screening: it consists of testing many different compounds (of animal, marine or vegetable origin, etc.) to see whether any of them are active in the disease under study. Chemical modification: this would be like having a key that doesn’t fit properly in the lock, but if we modify it (by filing it down or adding a piece, for example) we are able to create the key that opens the safe. Sometimes we want to improve the characteristics of a drug that we know is active, so we chemically modify part of the molecule to obtain the desired effect. Finally, rational design consists of making a mould of the lock and then making a key to fit it perfectly. In research labs, this can be done by studying the therapeutic target. For example, if we know the structure of the protein affected by the dysfunction, we can design a molecule to fit it.

I W TEN SPOSÓB MAMY KANDYDATA NA LEK Now that we have a drug candidate, ask: Do you think that we can go ahead and give it to patients? If not, why?

BADANIA PRZEDKLINICZNE Zanim środek farmaceutyczny będzie mógł zostać przebadany u ludzi, należy wykonać badania przedkliniczne, które są bardzo wyczerpujące i złożone: Takie badania przedkliniczne obejmują: Badania stabilności i toksyczności Badania in-vitro (białka, komórki, tkanki i narządy) Badania in-vivo (zwierzęta) ©Parc Científic Barcelona. Author: J. Planagumà Before testing a drug in humans, we have to conduct a thorough and complete preclinical study. This is what we call preclinical development. All these studies give us an idea of the drug’s efficacy and toxicity, helping us to detect possible undesirable side effects. They will also show us how the drug acts in the body (what the drug does to the body and what the body does to the drug – absorption, distribution, metabolism and the drug’s elimination)

BADANIA KLINICZNE Badania kliniczne to najdłuższy i najbardziej kosztowny etap procesu poszukiwań nowych leków. Obejmują one trzy fazy: FAZA III FAZA II FAZA I Zdrowi ochotnicy Osoby chore (100-300) (lek lub placebo) Osoby chore (1300-3000) Pewność i dawka If the preclinical development phase is successful, the drug is tested in humans in what is called clinical development. This is the longest and most costly stage in the process of searching for new medicines. It consists of three phases: In Phase I, the drug is tested in healthy volunteers. Ask: Why? (Because this will give us an idea of the drug’s safety and toxicity and the best route of administration. Also, remember that if it causes many side effects in a healthy person, it could be fatal in someone who is ill). In the second phase, the drug is tested in patients, administering the drug and a placebo at random. Do you know what a placebo is? Why do you think it is used? (A placebo is the medicine but without the active substance. We can then assess the psychological effects on the patients and discover whether an improvement is really due to the active substance. Short-term side effects are also assessed in this phase). And in the third phase, the drug is tested in a large number of patients, in different hospitals and countries. The idea is to assess its long-term effects. Skuteczność i działanie uboczne Działanie długoterminowe

I WRESZCIE...LEK ZOSTAJE WPROWADZONY NA RYNEK! Jeżeli lek przeszedł przez trzy fazy badań klinicznych, zostaje wprowadzony na rynek, ale badania nadal trwają (Faza IV) FAZA IV FAZA III The drug will reach the market if these 3 phases are successful. Once it is marketed, we can forget about it, can’t we? Ask: Do you think that we can? (Answer: NO. It then enters Phase IV, a period in which the long-term side effects will continue to be studied. This is a very important phase. Indeed, some drugs have eventually been found to be unsafe, and they were withdrawn from the market). RYNEK FAZA II FAZA I

POSZUKIWANIE LEKÓW NA CHOROBĘ PARKINSONA Projekt badawczy Parku Naukowego w Barcelonie Now that you know how medicines are obtained, we are going to explain a specific research project being conducted in Barcelona Science Park in which you will be participating today. The purpose of the project is to search for compounds for treating patients with Parkinson’s disease.

WPROWADZENIE - CZYM JEST CHOROBA PARKINSONA? Choroba Parkinsona to przewlekła i postępująca choroba układu ruchu charakteryzująca się następującymi objawami: Problemy z koordynacją Powolne ruchy Uogólnione drżenia To druga pod względem częstości choroba neurodegeneracyjna, która występuje u 1-2% osób w wieku powyżej 60 lat. Obecnie ponad 4 miliony osób na świecie cierpią na tę chorobę. The subject of Parkinson’s disease can be approached by asking the students whether they are familiar with the disease, what happens to people who have it and which cells or tissues are affected, etc.

WPROWADZENIE – PRZYCZYNY CHOROBY PARKINSONA Nasz mózg stanowi centrum kontroli nad ciałem, a komórki, które są odpowiedzialne za jego funkcjonowanie, to neurony. Samodzielna regeneracja tych komórek postępuje bardzo powoli. Neuroprzekaźniki to specjalne związki chemiczne,które umożliwiają „rozmowę” i komunikację między neuronami.

WPROWADZENIE – PRZYCZYNY CHOROBY PARKINSONA Przyczyny choroby Parkinsona nie są jeszcze znane, ale wiadomo, że jest ona spowodowana przez utratę lub nieprawidłowe działanie neuronów odpowiedzialnych za wytwarzanie neuroprzekaźnika o nazwie dopamina. Dopamina  Kontrola ruchu Niski poziom dopaminy  Problem z kontrolą ruchu Neuroprzekaźnik dopamina jest odpowiedzialny za przekazywanie sygnałów mających na celu kontrolę poruszania się naszych mięśni. W związku z tym niedobór dopaminy powoduje zaburzenie równowagi przekazywania między neuronami i dlatego neurony nie komunikują się w prawidłowy sposób. W wyniku tego następuje utrata funkcji mięśni.

WPROWADZENIE – LECZENIE CHOROBY PARKINSONA Sposób leczenia postępowania choroby obejmuje doustne podawanie leków. tyrozyna L-dopa dopamina Pęcherzyki z przekaźnikiem, dopaminą Obecnie najczęściej stosowanym lekiem jest lewodopa, inaczej L-dopa, zawierająca związek chemiczny, wykorzystywany przez mózg do produkcji dopaminy. synapsa There is currently no cure for Parkinson’s disease. All the medicines used are intended to mitigate its effects and improve the quality of life of both patients and their families. Because of its chemical structure, dopamine cannot reach the brain, as it does not pass through what is known as the blood-brain barrier, which is a natural protection barrier which prevents substances from reaching the brain. A compound called levodopa is therefore used. It does reach the brain, where it is transformed into dopamine. receptor dopaminy komórka receptorowa

WPROWADZENIE – LECZENIE CHOROBY PARKINSONA Stosowane są także inne leki, które naśladują działanie dopaminy w mózgu. Np.: bromokryptyna, lizuryd, pergolid, ropinirol,... dopamine związek naśladujący receptor receptor Besides indirectly administering dopamine, compounds that are very similar to dopamine are also used. They have the same therapeutic effect as dopamine. They’re like “dopamine synonyms”. Błona komórkowa Błona komórkowa Odpowiedź komórkowa Odpowiedź komórkowa

WPROWADZENIE – LECZENIE CHOROBY PARKINSONA Niestety te leki mają wiele działań ubocznych: Pojawienie się ruchów niezamierzonych i tików Depresja Halucynacje Ponadto wraz z upływem czasu takie leki przestają działać. Potrzebne są nowe leki, które będą mieć mniej działań ubocznych i będą aktywne przez dłuższy czas.

BADANIA, SYNTEZA LEKÓW DO LECZENIA CHOROBY PARKINSONA Naukowcy Platformy Chemii Kombinatorycznej Parku Naukowego w Barcelonie pracują obecnie nad syntezą nowych związków, które będzie można zastosować jako środki terapeutyczne w leczeniu chorób neurodegeneracyjnych, takich jak choroba Parkinsona lub schizofrenia, a które będą charakteryzować się: Lepszym działaniem Mniejszą toksycznością Platforma Chemii Kombinatorycznej

Leki przeciwparkinsonowe BADANIA, SYNTEZA LEKÓW DO LECZENIA CHOROBY PARKINSONA Aby zwiększyć skuteczność leków przeciw chorobie Parkinsona, obecnie podawany jest zestaw różnych leków. Celem badań jest synteza nowych cząsteczek, które będą bardziej skuteczne lub będą powodować mniej działań ubocznych. A drug cocktail is currently administered in an attempt to increase efficacy and reduce side effects. Besides the inconvenience for the patient, who has to take several tablets, this system of administration has a large number of side effects. The goal of this research group is to join two active drugs by a molecular chain, forming a single, more complex molecule. Only one medicine would have to be administered with this system. Leki przeciwparkinsonowe Zestaw leków 1 jedyny lek

BADANIA, SYNTEZA LEKÓW DO LECZENIA CHOROBY PARKINSONA Nowy lek This new drug would help the two drugs, now joined together, to reach the cell membrane at the same time. The effective dose will therefore be greater. In other words, there will be higher concentration of the drug close to the therapeutic target, resulting in an amplified cell response. The same cell response can thus be obtained with a smaller dose, with the advantage that a smaller quantity of drug will also reduce its side effects. Odpowiedź komórkowa

BADANIA, PROJEKTOWANIE I SYNTEZA NOWYCH CZĄSTECZEK XAC-COOH (±)-PPHT The two compounds that we are joining to form the drug are those shown on the slide.

W JAKI SPOSÓB NOWE CZĄSTECZKI SĄ SYNTETYZOWANE W LABORATORIUM? How do we synthesise these compounds in the lab? To obtain a chemical compound in the lab, we start with simple commercial compounds and use chemical reactions –such as reductions, oxidations, hydrolysis...) to obtain the desired product.

W JAKI SPOSÓB NOWE CZĄSTECZKI SĄ SYNTETYZOWANE W LABORATORIUM? przepłukanie w EtOH 3 dni This slide shows the synthesis of this compound, which is obtained through 7 stages in the lab.

W JAKI SPOSÓB NOWE CZĄSTECZKI SĄ SYNTETYZOWANE W LABORATORIUM? Reakcja chemiczna Each stage comprises a series of steps. The first is to carry out a chemical reaction, in which two or more compounds generate a third. This chemical reaction can be obtained manually or by using automatic instruments.

2. Izolacja i oczyszczenie produktu W JAKI SPOSÓB NOWE CZĄSTECZKI SĄ SYNTETYZOWANE W LABORATORIUM? 2. Izolacja i oczyszczenie produktu 3. Scharakteryzowanie produktu Once the reaction is complete, we have to check that we have done it properly: we first isolate the product, sometimes it’s necessary to purify it. It then has to be characterised to make sure that we have really obtained the desired product. This can be done with simple techniques, such as the thin-layer chromatography (TLC) that you will be using today, or using more complex instruments.

CO DZISIAJ BĘDZIEMY ROBIĆ?

W JAKI SPOSÓB NOWE CZĄSTECZKI SĄ SYNTETYZOWANE W LABORATORIUM? Reakcja chemiczna przepłukanie w EtOH 3 dni Today you will be participating in one of the 7 steps involved in the synthesis of the product under study.

 ?   CO DZISIAJ BĘDZIEMY ROBIĆ? Reakcja chemiczna Izolacja produktu metodą filtracji   ? As we mentioned earlier, each of these stages consists of 3 basic steps. Today, we will be producing the chemical reaction, isolating the product by vacuum filtration and then characterising it by thin layer chromatography. Students can now put on their lab coats and goggles. Encourage them to read the experimental protocol before starting to investigate.  Scharakteryzowanie produktu metodą chromatograficzną

Do badań!