healing ulcers liquorice extract (licorice) for > 2000 years in china.... helps ulcers heal...
TRANSCRIPT
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 fromworking. Licorice blocks this enzyme, and so theprostaglandins 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
OH
O
OH
HH
HO
H
O
The active ingredient was found in 1960 (a triterpenoid derived from glycyrrhizic acid)
COONa
HO
RO
RO = NaCOO(CH2)2COO-
Carbenoxolone
and was sold as CARBENOXOLONE the market leader for ulcer treatment for ~ 10 yrs, but had the side effects above.
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.
THE ANTI-HISTAMINES
In late 60's found that HISTAMINE is a signaling compound, which causes release of stomach acid.
N
NH
H2N
histamine
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.
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)
SMITH-KLINE-FRENCH launched TAGAMET (chemical name cimetidine) in Nov 1976
H-2 receptor ANTAGONIST
N
NH
SNHNH
NCN
cime tidine
fits lock and blocks it
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
LD50 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
An improvement was ZANTAC (ranitidine) 150mg twice per day
OMe2N S
NHNHMe
NO2
rani tidine
N
SNH2N
NH2 S N
NH2
SO2NH2
fami tidine
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
Need to find out more about a drug?
The CPS (Canadian Compendium of Pharmaceuticalsand Specialties) 2005 version in ELL 305 **especially good on approved usages, doses, side effectseg. Nizatidine is on page 162
The MERCK Index 13th Ed. in ELL 305good for a quick overview of almost all chemicalseg. Nizatidine is on page 1192
** updates thru http://www.pharmacists.ca/content/hcp/tools/drugnews/drugs.asp?Srch=ALL
Also in Canada: Nizatidine (2006)
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)
N
NH SN
O
OMe
MeOomeprazole
PRILOSEC (USA), LOSEC (Canada)
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
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)
Several new prazoles are now on the market:
PREVACID = lansoprazole
PEPTAZOL / PROTIUM = pantoprazole
PARIET / ACIPHEX = rabeprazole
N
NHS
N
CF2HOMeO
MeO
O
lansoprazole pantoprazole
N
NHS
N
OCF3
O ON
NHS
N
O (CH2)3OMe
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