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17. Medicines, Drugs - part 2

17. Medicines, Drugs - part 2. The Pharmaceutical Industry.

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17. Medicines, Drugs - part 2

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  1. 17. Medicines, Drugs - part 2

  2. The PharmaceuticalIndustry Worldwide, in 2007,~ $800 billion was spent on legal/ ethical 'medications‘ (doesn't include vitamins/minerals/herbals). By 'continent': N.America ~44%, W.Europe ~25%, Japan ~16%, Latin America ~ 6%, Asia Pacific ~4%, other ~6% NB. Where is Africa?? No money; not important!

  3. OTC - from A(antacids) to Z(zits) OTC = Over The Counter, ie. non-prescription North Americans self-medicate ~10x/mo/person Est. ~75% of all 'illnesses' are treated from the drug-store shelves. In USA ('97) there were: 144 categories; ~2000 compounds(some 'inactive') ~300,000 formulations/products.

  4. Over The Counter (OTC) Cold Medications Type of IngredientName Decongestant Pseudoephedrine Antitussive Dextromethorphan (cough suppressant) Expectorant Guaifenesin (loosen fluids in cough) Analgesic/Antipyretic Acetaminophen (diminish pain/fever) Antihistamine Chlorpheniramine Caffeine Stimulant

  5. OTC - Common Sense • Choose single-ingredient products, specific for your condition • Save $$ - choose generics • Read labels; follow instructions • Pay attention to cautions and interactions with alcohol or other medications • Always mention OTC preparations to your MD Or…. take chicken soup, gargle with salt/water, use a water vaporizer and get some sleep

  6. Psychology and Drug Price Expensive placebo’s work better than cheap ones! • Double blind study: 2 placebos. Patients told cost of “new pain reliever” (10 cents vs 2.50 $per pill) • Pain relief much higher in group taking the expensive pill • Globe and Mail: March 2008

  7. The Business of Wellness Research/Development-synthesis 20 - 25% (~ 35% on Human Clinical Evaluation for DIN - Drug Identification Number) Production/Scale-Up ~20% Patents/Licensing ~10% (17 yrs for a 'brand name' patent) + ‘delays’ Marketing (Advertising) ~10% For every: 10,0000 - starting compounds 10 - to preclinical trials 5 - to human trials 1 - to market

  8. New Product Development* 12 -15 years(7 yrs. of ‘clinical trials’) $300 - $400 million 3 of 10 'pay back' 'block-buster' = $1 billion(life-time sales) Some Companies: AstraZeneca, Bayer, Bristol Myers/ Squibb, Glaxo-Smith-Kline, Warner Lambert Hoffman LaRoche, Novartis, Merck(US), Pharmacia, Pfizer, G D Searle, Eli Lilly In Canada: Merck Frosst, BioChem Pharma,(Apotex#) Ratiopharm#. Proprietary/'Brand-name'* vs Generic#.

  9. Brand/Trade - only by manufacturer (proprietary) ie Tylenol , Motrin Generic - generally accepted 'chemical name' (for 'easy' recognition by health professionals) ie acetaminophen, ibuprophen

  10. Patent protection • Brand name is protected in perpetuity • Active component has protection for 17 years in Canada • After that, Generic Co’s can make the drug and sell it under another name • Many legal disputes (IP law) Gowlings in Ottawa • Polymorphs (different crystalline forms) can be patented • New applications of old drugs can be patented

  11. Brand names! • Who thinks them up? • Big business!! • But getting tougher to find simple ones : beware of similarities • Some are brilliant “Viagra” “Levitra” Celebrex (anti-inflammatory)

  12. World Top 10 prescription drugs in 2008 • Lipitor Pfizer : lowers cholesterol 13.8B$ • Plavix BMS: atherosclerotic events 8.3 • Nexium AstraZeneca :Acid reflux symptoms 7.7 • Serentide GlaxoSmith Kline :asthma 7.5 • Enbrel Amgen: rheumatoid arthritis 5.6 • Seroquel AstraZeneca: bipolar disorder,schizophrenia 5.1 • Zyprexa Eli Lilly: schizophrenia 5.1 • Risperdal J&J : schizophrenia 5.0 • Remicade Centocor: Crohn’s Disease, Rheumatoid arth. 4.7 • Singulair Merck: asthmas, Allergies 4.6 • Overall sales increase vs. 2007: 8.3%

  13. Steroids Compounds with a common tetracyclic structure and a variety of physiological functions depending on functional group arrangement. Cholesterol(animal fat)

  14. Are all steroids anabolic? • Consider cholesterol, cortisone etc.

  15. Stanozolol (Ben Johnson ’88 Olympics) Anabolic Steroids Promote rapid muscle growth & stamina (more workouts) 4-Androstene-3,17-dione (Mark McGuire 90’s)

  16. Detection: Mass Spectrometry of Drug metabolites in urine • Each compound has a unique “pattern”

  17. Male Sex Hormones (Androgens) Testosterone: also in females ,but only~2 % of level in males; biosynthesized from cholesterol; affects libido in both! Androsterone

  18. The next generation of cheating • Idea-just take more testosterone: undetectable because the body makes it anyway!

  19. Doping in Sports: Testosterone • Floyd Landis tests positive for abnormal amounts of testosterone: forfeits Tour de France cycling championship in July 2006

  20. The tests and the Dope • Testosterone (T) is an anabolic (muscle enhancing steroid) • Epi-testosterone (E) is a stereoisomer, differing only in stereochemistry of the chiral centre in the D-ring, BUT it has no anabolic effects • If T is administered, the excretion rate of urinary T increases and that of E decreases

  21. Measure the T/E ratio in urine! • The average for adult men is 1, and very rarely exceeds 4 • Landis had a T/E ratio of 11. • Based on this test, he looks guilty • But he claimed someone tampered with his urine

  22. Adding epitestosterone • Some have tried to beat the Urine T/E ratio test by taking in additional E • Thus another test needed to be developed

  23. Kinetic Isotope Effect (KIE) • Biggest effect is in C-H vs C-D bond breakage • Rates of C-D bond breaking can be up to 7 times slower than C-H • Effects for 12C-H vs. 13C-H are obviously smaller, but bonds involving the heavier isotope are always harder to break

  24. Other bonds to be broken • 13C-O vs. 12C-O • 13C-12C vs 12C-12C

  25. Experimentally • Rates of 12C vs 13C have been measured to differ by up to 8% in one reaction: 12C is always faster • So enrichment 12C/13C =1.08 for one reaction • If 5 reactions: enrichment =1.08x1.08x1.08x1.08x1.08 ie. 1.46 or 46%!

  26. Isotope ratio test (new ~2004) • Synthetically derived T has a slightly lower amount of the 13C isotope than does T produced in the body (Because more reactions needed to make it synthetically than in the body) : 13C isotope reacts more slowly than 12C). • This is the well known Kinetic Isotope effect! • Mass spectrometry (detects isotopic abundances) used to measure the 13C to 12C ratio in testosterone Landis also failed this test………..verdict GUILTY

  27. Manny Ramirez : LA Dodgers

  28. May 12, 2009 Manny gets caught! • Urine showed elevated testosterone level • Also high testosterone/epitestosterone ratio; between 4:1 and 10:1 • Synthetic or “Manny made”? • World anti-doping lab (Montreal) asked to do carbon isotope test-find low 12C/13C ratio • Result: Manny used synthetic testosterone • 50 game suspension (without pay) by MLB

  29. Female Sex Hormones (Estrogens) Estrone Estradiol Progesterone (‘pregnancy hormone)

  30. Steroids cont’d: Evolution of the BC pill • 1st step (1960’s) progesterone (pregnancy hormone, prevents ovulation) was administered • Worked well if injected, but not effective if taken orally; not acceptable for mass use • Synthesis of “progesterone like” compds • Similar structure except for D ring substituents

  31. Progestins • Stopped ovulation • Could be taken orally • But small amount of “breakthrough bleeding” • Inclusion of a small amount of estrogen controls this • “Combination Pill” : Progestin and estrogen • Dosage 1/day for 21 days, off for 7, can miss one

  32. ‘The Pill’ (Birth Control) Ethynylestradiol (synthetic estrogen) + Norethindrone (synthetic progestin)

  33. Side effects of the Pill • “minor”: headaches, some dizziness • “major” : combined with smoking, risk of blood clots • Risk increases with age and long term use

  34. The morning after pill RU-486 • Blocks the implantation of a fertilized egg in the uterine wall • Developed in France

  35. Antibacterials and Antibiotics Many OTC and some prescription: growing problem of resistance to antibiotics!

  36. Dr. Joseph Lister • UK 1871 • found that mould inhibited growth of bacteria • “discovered” antiseptic surgery by killing bacteria • “Listerine” named after him

  37. Listerine and other mouthwashes • Often contain up to 25% alcohol • Long term use of high alcohol mouthwashes increases risk of oral cancer • Does Listerine kill germs? Yes, but many more remain • Salt water rinse an effective alternative • Or use enzyme based ones

  38. Serious infections: gingivitis, trench mouth • Require much stronger mouthwash than any OTC available: See your Dentist or MD • Careful tooth brushing and flossing and thorough rinsing with water are best preventative measures

  39. Sulfa Drugs: the 1st antibacterials • Benzene sulfonamides-not antibiotics, but did inhibit bacterial growth by disrupting folic acid synthesis • Developed in Germany 1932 (1st wonder drugs) could be applied as powders to wounds in the field WWII. • Superceded by less toxic antibiotics in 1944

  40. Antibiotics - the Wonder Drugs Antibiotic = a compound that kills bacteria (by destroying bacterial cell walls. isolated from moulds or bacteria, eg. penicillins, cephalosporins, erythromycin, streptomycin, but sometimes 'synthetic', eg. chloramphenicol, fluoroquinolones Antibacterial agent = antimetabolite (starves the bacteria, often of folic acid), eg. sulfa drugs

  41. Discovery of penicillin(20th century’s most important one?) 1928 , Alexander Fleming grew Staphylococcus bacteria on an agar medium • Noticed inhibition of bacterial growth around a blue-green mould accidental contaminant

  42. 1928-1940 • Fleming grew a pure mould culture: discovered it was Penicillium notatum • Later isolated the pure chemical “antibiotic”component, named it “penicillin” • But needed a good large scale source of the mould

  43. Antibiotics – Mass production of penicillin -following a world-wide search, a mouldy canaloupe in Peoria Ill, in 1942 was found to contain the highest quality penicillin! Led to mass production(start of Pfizer) 2.3 million tons available to Allied Soldiers for the Normandy invasion in 1944.

  44. Penicillins('28-'44) - the -Lactams Penicillin – the general structure The first class of 'broad spectrum' antibiotics; still the most prescribed worldwide.

  45. Alexander Fleming 1881-1955 • Nobel Prize for Medicine/Physiology in 1945 • Knighted in 1944

  46. Penicillin from fermentation • Pharmaceutical grade obtained

  47. The Process • Start “cold stored” penicillium culture on agar plate • Transfer to “shake flasks” ,with food (Sugars) and nutrients (ammonium salts), aa’s needed for growth • Resulting suspension can be transferred to seed tanks for further growth • Transfer to larger fermentation tank (30,000 gallons) • After 3-5 days , isolation • Temp, pH, mixing essential, sterilized air pumped in.

  48. Semi-synthetic derivatives • Original penicillin was excreted too rapidly-urine recycling in early patients for recovery of the drug • Chemists modify original structure for different properties and bio-availablity

  49. the 'Evolution' of Penicillins - 1 step ahead! penicillin G penicillin V ampicillin amoxicillin methicillin cloxacillin oxacillin

  50. Incapacitating those 'Nasty Bugs' Varied structures indicate varied 'mechanisms' to kill bacteria. eg. • -lactams(penicillins) - breakdown cell walls • tetracyclines/erythromycin/streptomycin - inhibit various aspects of protein synthesis • fluoroquinolones('cipro') - inhibit DNA replication

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