L’approche empirique En 1856, Claude Bernard a démontré que le curare bloque la jonction neuromusculaire, mais sans affecter le muscle lui même. Curare.

Présentation au sujet: "L’approche empirique En 1856, Claude Bernard a démontré que le curare bloque la jonction neuromusculaire, mais sans affecter le muscle lui même. Curare."— Transcription de la présentation:

1 L’approche empirique En 1856, Claude Bernard a démontré que le curare bloque la jonction neuromusculaire, mais sans affecter le muscle lui même. Curare is a mixture of naturally occurring alkaloids found in various South American plants and used as arrow poisons by indians. The most important component is tubucurarine. It does not survive the stomach and that’s why indians could eat the meat of curare poisened animals. Antagonist of Acetylcholine receptor and very effective at neuromuscular junction Le mot Curare vient en fait d'un mot en langue indigène «ourari» qui signifie la mort qui tue tout bas.

2 Atropa belladonna Plant très toxique. include dilated pupils, tachycardia, hallucinations, blurred vision, loss of balance, a feeling of flight, staggering, a sense of suffocation, paleness followed by a red rash, flushing, husky voice, extremely dry throat, constipation, urinary retention, and confusion. Utilisé en cosmétique Induit la dilatation des pupilles ce que rends les femmes plus attractives Bella donna = belle femme

3 Pitury SYDNEY RINGER, M.D.(around 1890)

4 QUITE recently a student of University College, London, whose, name we have unfortunately forgotten, gave us a small packet containing a few twigs and broken leaves of the powerful and interesting drug, Pituri. These we placed in Mr Gerard’s hands, and he kindly made first an extract from which he obtained a minute quantity of an alkaloid, and with this he made a solution containing one part of the alkaloid to twenty of water. The use of pituri is confined to the men of a tribe called Mallutha.. Before any serious undertaking, they chew these dried leaves, using about a tea-spoonful. A few twigs are burnt and the ashes mixed with the leaves. After a slight mastication the bolus is placed behind the ear (to increase it is supposed its strength), to be again chewed from time to time, the whole being at last swallowed. The native after this process is in a sufficiently courageous state either to transact business or to fight. When indulged in to excess, it is said to induce a condition of infuriation. In persons not accustomed to its use pituri causes severe headache.

5 Henry (Hallett) Dale Extraits de Claviceps purpurea, l’ergot de seigle, un champion qui produit des alcoloides polycyclique dont le dérivate LSD (lysergic acid diethylamide ) est le mieux connu, ainsi que ergotamine dans le traitement de migraine)

6 Dr George Oliver, a physician of Harrogate (1893),
Dr George Oliver, a physician of Harrogate (1893), employed his winter leisure in experiments on his family, using apparatus of his own devising for clinical measurements. In one such experiment he was applying an instrument for measuring the thickness of the radial artery; and, having given his son, who deserves a special memorial, an injection of an extract of the suprarenal gland, prepared from material supplied by the local butcher, Oliver thought that he detected a contraction He went up to London to tell Professor Schäfer what he thought he had observed, and found him engaged in an experiment in which the blood pressure of a dog was being recorded. Oliver was in no hurry, and urged only that a dose of his suprarenal extract should be injected into a vein when Schäfer’s own experiment was finished. And so, just to convince Oliver that it was all nonsense, Schäfer gave the injection, and then stood amazed to see the mercury mounting in the arterial manometer till the recording float was lifted almost out of the distal limb.

7 Alexander Fleming remarque un halo d’inhibition autour d’un moisissure bleu verte qui a contaminé une culture de Staphylococcus (bactérie). Il en conclut que la moisissure produit une substance qui inhibe la croissance bactérienne. Il cultive cette moisissure et découvre qu’il s’agit de Penicillium notatum.

8 Alexander Fleming

9 Two investigators at Oxford, Sir Howard Walter Florey and Ernst Boris Chain, brought penicillin's potential for medical use to fruition in 1939 and, along with Fleming, shared the 1945 Nobel Prize for Medicine.

10 Et qui a dit que les universités communiquent pas les fruits de leur travail?

11 Vers une approche rationnelle
Prix Nobel de médecine et physiologie en 1988 « For their discoveries of important principles for drug treatment » J Black (Kings College London) GB Elion (Wellcome) GH Hitchings (Wellcome)

12 Sir James W. Black realized the great pharmacotherapeutic potential of receptorblocking drugs and developed in 1964 the first clinically useful beta-receptorblocking drug, propranolol. This type of drug is now being used in the treatment of coronary heart disease (angina pectoris, myocardial infarction) and hypertension. In 1972 Black characterized a new group of histamine receptors, H2-receptors, and subsequently developed the first clinically useful H2-receptorantagonist, cimetidine. A new principle in the treatment of peptic ulcer was thereby introduced. Gertrude Elion and George Hitchings, who have collaborated since 1945, demonstrated differences in nucleic acid metabolism between normal human cells, cancer cells, protozoa, bacteria and virus. On the basis of such differences a series of drugs were developed that block nucleic acid synthesis in cancer cells and noxious organisms without damaging the normal human cells. Over the years Elion's and Hitchings' research philosophy has formed the basis for development of new drugs against a variety of diseases. During they developed thioguanine and 6-mercaptopurine against leukemia and pyrimethamine against malaria. Azathioprine, a drug that prevents rejection of transplanted organs and allopurinol which is used in the treatment of gout were developed in 1957 and 1963, respectively. An important discovery was that the chemotherapeutic effects of pyrimethamine and trimethoprim were markedly enhanced by sulphonamides. A recent, successful application of their research ideas is exemplified by acyclovir (1977), the first effective drug in the treatment of herpes virus infections.

13 propranolol (adrenaline-b receptor antagonist)

14 Cimetidine (Histamine-2 receptor antagonist)

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16 Anti-allergique anti-inflammatoire Anti-émétique (mal de voyage)

17 Mercaptopurine (purine analogue)

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19 Acyclovir (purine analogue)

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21 Infection d’une cellule épitheliale par le virus
EXPLOITABLE DIFFERENCE Infection d’une cellule épitheliale par le virus Herpes Simplex Acyclovir est uniquement actif dans les cellules infectées car elles expriment la thymidine kinase virale, essentiel pour l’activation de l’acyclovir

22 Zidovudine (AZT)

23 Le groupe azoture augmente la nature lipophile de l'AZT, lui permettant de traverser les membranes cellulaires facilement par diffusion et de traverser de ce fait également la barrière barrière hémato-encéphalique. Les enzymes cellulaires (kinases) convertissent l'AZT en la forme active du 5'-triphosphate. Les études ont prouvé que l'arrêt des brins d'ADN ainsi formées est le facteur spécifique dans l'effet inhibiteur. L’enzyme virale transcriptase inverse fabrique de l’ADN viral à partir de l’ARN du VIH en détournant des nucléotides normalement destinés à la cellule, cette synthèse de l’ADN viral lançant, en temps normal, alors la réplication du VIH dans la cellule

24 Nouvelles cibles pour les interventions thérapeutiques contre le cancer

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29 Leucémie chronique myéloïde
Cellules cancéreuses (myoblastes)

30 bcr-abl est un oncogène qui donne naissance à une protéine anormalement active. Cette protéine active est impliquée dans la prolifération excessive des globules blancs

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33 Médicament (inhibiteur de l’enzyme c-Abl)

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