1. HEALING ULCERS Liquorice extract (licorice) for > 2000 years in China.... helps ulcers heal Prostaglandins are natural hormones that help heal holes in the stomach wall, but an enzyme (15-hydroxyprosta- glandin dehydrogenase) stops the prostaglandins from working. Licorice blocks this enzyme, and so the prostaglandins stick around longer, make ulcers heal. HOWEVER chemistry always has a price, licorice causes cortisol to bind to a protein causing sodium to be retained, increases BP, water retention, (*) head aches, lethargy,.... (*) Addison’s disease is caused by a deficiency of cortisol, so liquorice helps that

2. The active ingredient was found in 1960 (a triterpenoid derived from glycyrrhizic acid) and was sold as CARBENOXOLONE the market leader for ulcer treatment for ~ 10 yrs, but had the side effects above.

3. BISMUTH COMPOUNDS (1786 on) PEPTOBISMOL today 1920's surge in use because also a syphilis treatment Use rebounded in 1980's: Peptic ulcer patients have larger than normal amounts of BACTERIUM ‘Helicobacter pylori’ (H. pylori), especially type O blood, where bacterium links to stomach wall via a sugar. Bismuth salts(*) inhibit this linking, and so with Amoxicillin (a penicillin) which kills the bacteria, have been used to treat ulcers since about 1990. (*)Bismuth salicylate, carbonate or basic nitrate.

4. THE ANTI-HISTAMINES In late 60's found that HISTAMINE is a signaling compound, which causes release of stomach acid. an AMINE In 1972, the receptor (H-2), was recognized; different from the H-1 receptor that causes allergies. Eating, stress,.... causes histamine to be released, which on triggering the H-2 receptor starts acid secretion.

5. Thus an H-2 receptor ANTAGONIST was needed which would bind to the receptor stronger than histamine itself, but not promote the release, i.e. block the receptor [an AGONIST binds and promotes the effect] RECEPTORs are like LOCKS, if an appropriate KEY (CHEMICAL) is inserted, the LOCK will OPEN (the RECEPTOR will TURN ON) AGONIST: chemical that binds to a receptor and turns it on (a key that goes in the lock and turns) ANTAGONIST: chemical that binds the receptor but does not turn it on (like a key that fits but jams the lock)

6. SMITH-KLINE-FRENCH launched TAGAMET (chemical name cimetidine) in Nov 1976 H-2 receptor ANTAGONIST fits lock and blocks it

7. By 1983 Tagamet world-wide sales were 1B$ (7000 ulcer related deaths in US in 1982) Heals ca. 70-80% ulcers in 4 weeks; requires 3 doses per day of 150-300 mg LD 50 mice (rats) 2.6 (5) g/kg orally (lethal dose to kill 50% of population) essentially non-toxic cf. aspirin = ~0.4 g/kg in people Generic cimetidine available in 90’s and now as an OTC ‘over-the-counter’ drug, usually in lower doses, eg. 100mg Tagamet-HB

8. An improvement was ZANTAC (ranitidine) 150mg twice per day and then PEPCID-AC and MAALOX-H2 (famitidine) OTC drugs now in 75mg or 100 mg doses Few side effects: mild diarrhea, skin rash ~ 4 to 9x more effective than cimetidine

9. Need to find out more about a drug? The CPS (Canadian Compendium of Pharmaceuticals and Specialties) 2005 version in ELL 305 ** especially good on approved usages, doses, side effects eg. Nizatidine is on page 162 The MERCK Index 13 th Ed. in ELL 305 good for a quick overview of almost all chemicals eg. Nizatidine is on page 1192 ** updates thru http://www.pharmacists.ca/content/hcp/tools/drugnews/drugs.asp?Srch=ALL http://www.pharmacists.ca/content/hcp/tools/drugnews/drugs.asp?Srch=ALL Also in Canada: Nizatidine (2006)

10. Using the Merck Index

12. TURNING OFF THE ACID PUMP Histamine is one of the signals that starts acid secretion, however acid is not stored but generated by passage of protons across a membrane (H + one way, K + the other). This is caused by an ATP-ase enzyme: blocking this enzyme, reduces the amount of acid pumped ASTRA ZENECA were the first to patent Omeprazole for this purpose, and in 1989 launched as: PRILOSEC (USA), LOSEC (Canada)

13. Advantage: One 20 mg pill per day; self limiting - does not stop acid, reduces it STOPS acid reflux into esophagus (Zollinger-Ellison syndrome), very low (4g/kg) toxicity, few side effects. Disadvantage: $2 per pill

14. By 2001, (PRI)LOSEC was THE #2 DRUG overall, with sales of $6.1B but it has now dropped out of the top 10 due to competition from generics: eg. apo-omeprazole in Canada (2003)(APO=Apotex) And from NEXIUM (Mg salt of the S-enantiomer) ‘The Purple Pill’ has captured >40% of US market thanks to heavy advertising (this does protect AZ’s patents!). 2008: Nexium 7.7B$ (No. 3 prescribed drug in US)

15. Several new prazoles are now on the market: PREVACID = lansoprazole PEPTAZOL / PROTIUM = pantoprazole PARIET / ACIPHEX = rabeprazole Starting June 2003: BC Pharmacare changed coverage of PPI (proton pump inhibitors) for GERD (gastroesophageal reflux disease) LOSEC had to be approved by Pharmacare once per year; forced to try PARIET = ACIPHEX(USA) = rabeprazole, (Japan) is 40% cheaper than LOSEC but approval waived