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)

Using the Merck Index

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