2 Qu’y a-t-il à l’intérieur ? Qu’est-ce que c’est ?Qu’y a-t-il à l’intérieur ?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.
3 Qu’y a-t-il à l’intérieur d’un médicament ? 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.
4 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.
5 Il cherche la cible thérapeutique pour agir et soigner la maladie Principe actifmédicamentCible thérapeutiqueIl cherche la cible thérapeutique pour agir et soigner la maladieThe 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
6 Il cherche la cible thérapeutique pour agir et soigner la maladie Principe actifIl cherche la cible thérapeutique pour agir et soigner la maladieAs 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
7 Comment les médicaments sont-ils mis au point ? 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?
8 DÉVELOPPEMENT CLINIQUE ÉTAPE DANS LA RECHERCHE D’UN MÉDICAMENTLa recherche d’un médicament est un processus long (entre 10 et 25 ans), complexe et coûteux, qui comporte différentes étapes.R + Ddu MÉDICAMENT(2-10 ans)ÉTUDESPRÉCLINIQUES(2-6 ans)In vitro-In vivoDÉVELOPPEMENT CLINIQUEPHASE I PHASE II PHASE IIILancementdumédicamentPHASE IVThe 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.
9 ? Un candidat médicament peut être découvert de différentes manières : COMMENT DÉCOUVRE-T-ON UN CANDIDAT MÉDICAMENT ?Un candidat médicament peut être découvert de différentes manières :?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)
10 COMMENT DÉCOUVRE-T-ON UN CANDIDAT MÉDICAMENT ? Un candidat médicament peut être découvert de différentes manières :Modification chimiqueHasardSélection de masseConception rationnelleA 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.
11 NOUS AVONS MAINTENANT UN CANDIDAT MÉDICAMENT Now that we have a drug candidate,ask:Do you think that we can go ahead and give it to patients?If not, why?
13 (médicament ou placebo) DÉVELOPPEMENT CLINIQUELe développement clinique est l’étape la plus longue et la plus chère dans le processus de recherche de nouveaux médicaments. Il comporte trois phases :PHASE IIIPHASE IIPHASE IVolontaires sainsMalades( )(médicament ou placebo)Malades( )Sécurité et doseIf 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.Efficacité eteffetsindésirablesEffetsà longterme
14 ET ENFIN… LE MÉDICAMENT ARRIVE SUR LE MARCHÉ ! Une fois que le médicament a passé les trois phases cliniques, il est lancé sur le marché, mais l’étude continue encore (Phase IV).PHASE IVPHASE IIIThe 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).MARCHÉPHASE IIPHASE I
15 pour LA MALADIE DE PARKINSON RECHERCHE de MÉDICAMENTSpour LA MALADIE DE PARKINSONProjet de recherche du Parc scientifique de BarceloneNow 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.
16 INTRODUCTION – QU’EST-CE QUE LA MALADIE DE PARKINSON ? La maladie de Parkinson est un trouble chronique et progressif du mouvement qui secaractérise par :des difficultés de coordination,des mouvements ralentis,un tremblement généralisé.C’est la deuxième maladie neurodégénérative la plus fréquente. Elle touche 1 à 2 % des personnes âgées de 60 ans. Actuellement, plus de 4 millions de personnes sont touchées dans le monde.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.
17 INTRODUCTION – MALADIE DE PARKINSON, CAUSES Notre cerveau est le centre de contrôle du corps et les cellules chargées de son fonctionnement s’appellent « neurones ». Ces cellules s’autorégénèrent très lentement.Les neurotransmetteurs sont des composés chimiques spéciaux qui permettent aux neurones de « parler » et de communiquer entre elles.
18 INTRODUCTION – MALADIE DE PARKINSON, CAUSES Les causes de la maladie de Parkinson ne sont pas encore connues, mais on sait que la maladie est provoquée par une perte ou un fonctionnement incorrect des neurones chargées de produire le neurotransmetteur dopamine.Dopamine Contrôle du mouvementNiveaux faibles de dopamine Difficulté dans le contrôledu mouvementLa dopamine est le neurotransmetteur chargé de transmettre les signaux pour contrôler le mouvement de nos muscles.Un déficit en dopamine provoque donc un déséquilibre dans la transmission neuronale qui entraîne une mauvaise communication entre les neurones. Cela provoque la perte de la fonction musculaire.
19 INTRODUCTION – MALADIE DE PARKINSON, TRAITEMENT La progression de la maladie est traitée avec la prise de médicament par voie orale.tyrosineL-dopadopamineVésicules contenant le transmetteur dopamineLe médicament le plus utilisé aujourd’hui est la levodopa, ou L-dopa, qui consiste en un composé chimique que le cerveau utilise pour fabriquer la dopamine.synapseThere 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.récepteur de dopaminecellule réceptrice
20 INTRODUCTION – MALADIE DE PARKINSON, TRAITEMENT On utilise également certains médicaments qui imitent l’effet de la dopamine dans le cerveau.Ex. : bromocriptine, lisuride, pergolide , ropinirole, etc.dopamineimitateurrécepteurrécepteurBesides 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”.Membrane cellulaireMembrane cellulaireRéponse cellulaireRéponse cellulaire
21 INTRODUCTION – MALADIE DE PARKINSON, TRAITEMENT Malheureusement, ces médicament ont de nombreux effets indésirables :apparition de mouvements involontaires et tics,dépression,hallucinations.De plus, ces médicaments n’ont plus d’effet avec le temps.Il est nécessaire de fabriquer de nouveaux médicaments qui aient moins d’effets indésirables et qui soient actifs pendant plus longtemps.
22 RECHERCHE, SYNTHÈSE DE MÉDICAMENTS POUR LE TRAITEMENT DE LA MALADIE DE PARKINSON Sur la plateforme de chimie combinatoire du Parc scientifique de Barcelone, les scientifiques travaillent sur la synthèse de nouveaux composés pouvant être utilisés comme agents thérapeutiques dans le traitement de maladies neurodégénératives comme le Parkinson ou la schizophrénie qui sont :plus actifs,moins toxiques.
23 Cocktail de médicaments RECHERCHE, SYNTHÈSE DE MÉDICAMENTS POUR LE TRAITEMENT DE LA MALADIE DE PARKINSONAfin d’accroître l’efficacité de ces antiparkinsoniens, on administre aujourd’hui un cocktail de médicaments.L’objectif est de synthétiser de nouvelles molécules qui soient plus efficaces ou qui présentent moins d’effets indésirables.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.AntiparkinsoniensCocktail de médicaments1 seul médicament
24 RECHERCHE, SYNTHÈSE DE MÉDICAMENTS POUR LE TRAITEMENT DE LA MALADIE DE PARKINSON Nouveau médicamentThis 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.Réponse cellulaire
25 RECHERCHE, CONCEPTION ET SYNTHÈSE DE NOUVELLES MOLÉCULES AADXAC-COOH(±)-PPHTThe two compounds that we are joining to form the drug are those shown on the slide.
26 COMMENT SYNTHÉTISE-T-ON CES NOUVELLES MOLÉCULES DANS LE LABORATOIRE ? 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.
27 COMMENT SYNTHÉTISE-T-ON CES NOUVELLES MOLÉCULES DANS LE LABORATOIRE ? reflux dans EtOHjoursThis slide shows the synthesis of this compound, which is obtained through 7 stages in the lab.
28 COMMENT SYNTHÉTISE-T-ON CES NOUVELLES MOLÉCULES DANS LE LABORATOIRE ? Réaction chimiqueEach 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.
29 2. Isolement et purification du produit COMMENT SYNTHÉTISE-T-ON CES NOUVELLES MOLÉCULES DANS LE LABORATOIRE ?2. Isolement et purification du produit3. Caractérisation du produitOnce 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.
31 COMMENT SYNTHÉTISE-T-ON CES NOUVELLES MOLÉCULES DANS LE LABORATOIRE ? Réaction chimiquereflux dans EtOHjoursToday you will be participating in one of the 7 steps involved in the synthesis of the product under study.
32 ? QU’ALLONS-NOUS FAIRE AUJOURD’DUI ? Réaction chimique Isolement du produit par filtration?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..Caractérisation du produit par chromatographie