Drug Analogues – the Chemical Structure of Existing Drugs an Under-Recognized Threat to the Society

HA Management Committee on Toxicology Services Commissioned Training in Toxicology 2007 What is drug analogue?

• Drug analogue is created by modifying Drug Analogues – the chemical structure of existing drugs An Under-recognized Threat to the Society

Dr WT Poon MSc, MRCP(UK), FHKAM(Pathology) HA Toxicology Reference Lab

What is it for? Like Father, Like Son

• Strategy used by drug companies • To find new drugs with similar pharmacology as the parent drug

Diazepam Nitrazepam

Similar structure = Similar pharmacology

• Drugs with similar structures may not • It is prudent to test the safety & efficacy share similar efficacy / toxicity before a new drug analogue is marketed for human use

Paracetamol (PANADOL) Phenacetin

withdrawn in 1980 due to carcinogenicity & renal toxicity

1 Drug testing process Drug testing process

Preclinical Preclinical Testing Testing •Perform cell-culture and animal experiments to Phase 1 Phase 1 obtain safety data: Clinical Trial Clinical Trial – Toxicity – Carcinogenicity Phase 2 Phase 2 Clinical Trial Clinical Trial – Teratogenicity

Phase 3 Phase 3 Clinical Trial Clinical Trial

Post marketing Post marketing surveillance surveillance

Drug testing process Drug testing process

Preclinical Preclinical Testing • Small no. healthy volunteers Testing • Several hundred health- • Small dosage impaired patients Phase 1 Phase 1 • To find out effectiveness of Clinical Trial • To obtain information about: Clinical Trial – drug absorption and metabolism the drug in treating disease

Phase 2 – effects on organs and tissues Phase 2 Clinical Trial – dose related side effects Clinical Trial

Phase 3 Phase 3 Clinical Trial Clinical Trial

Post marketing Post marketing surveillance surveillance

Drug testing process Drug testing process

Preclinical Preclinical Testing • Involves thousands of Testing • Clinical trials prior to health-impaired patients marketing only identify Phase 1 • Treatment and control arms Phase 1 common adverse effects Clinical Trial Clinical Trial • To assess efficacy and risk- (≧ 1:250)

Phase 2 benefit ratio Phase 2 Clinical Trial Clinical Trial

Phase 3 Phase 3 Clinical Trial Clinical Trial

Post marketing Post marketing surveillance surveillance

2 Drug testing process Vioxx (Rofecoxib)

Preclinical Testing • Detect rare or long-term • approved by the FDA in adverse effects over a much 1999 Phase 1 larger patient population and Clinical Trial timescale than was possible • In Sep 2004, drug during the initial clinical trials company voluntarily Phase 2 withdrew it because of Clinical Trial reports of heart attack • Such adverse effects may and stroke associated Phase 3 result in the withdrawal or with long-term, high- Clinical Trial restriction of a drug dosage use

Post marketing surveillance

Drug testing is lengthy & costly Thalidomide disaster

• On average, it takes 9.5 years and costs US$ 802 million to license a new drug Why All The • PharmaceuticalTrouble?? companies quite often research and test 10,000-30,000 different substances before one could be successfully introduced into the market

Illicit drug analogue What is the risk?

• Illicit drug analogues are marketed for • Have not undergone formal testing - human consumption without the above- potential adverse effects are numerous & mentioned testing process unpredictable

ALL users would become guinea pigs!!

3 Under-recognized threat to the society • Often disguised as health supplements or herbal products – readily available to the public

• Analogues are difficult to detect by ordinary laboratory methods – problem is easily missed

損肝減肥藥 Laboratory Findings

•F/34 • A MAJOR unidentified peak was seen: • Good past health – Did not match with any drug / herbal toxin in • Took herbal slimming product for 6 weeks our analytical system • Developed fulminant liver failure & required liver transplantation • Further work-up revealed its identity: • Listed ingredients of the herbal product: N-nitroso-fenfluramine – 黃精, 人參, 山楂, 絞股藍, 巴戟天, 海藻, 綠茶, 決明子, 首烏, 北芪, 檳榔, 萊服子.

N-nitroso-fenfluramine Comparison

• Analogue of fenfluramine Fenfluramine Fenfluramine: N-nitroso-fenfluramine: • Valvular problem • Hepatotoxicity • Associated with > 800 cases • Not associated with • Nephrotoxicity of liver damage in Japan hepatotoxicity • No weight reduction • Similar cases reported in • Known appetite effect !! Singapore and U.K. suppressant

• fatalities or fulminant hepatic failure reported

N-nitroso- fenfluramine

4 N-nitroso-fenfluramine

• If N-nitrosofenfluramine were an investigational drug for formal evaluation, it would have been abandoned already

• M/28, good past health •P/E • Unsteady gait X 1 week – Failed heel-toe walking • Fell several times – Tend to fall – No other cerebellar signs • CT brain: Normal

Herbal pill

• “Malaise” • Claimed for male erectile • Took herbal pill 8 days before admission dysfunction – From convenient store • Labeled to contain herbal – Recommended by friend ingredients only

• Drug induced ataxia suspected •“不含昔多芬”

5 昔多芬 Laboratory findings

• 昔多芬 = Sildenafil • No sildenafil detected • For male erectile dysfunction • Phosphodiesterase (type 5) inhibitor Æ • However, acetildenafil was detected !! cGMP↑Æ vasodilation Æ erection

• Side effects: – headache, dyspepsia, flushing, myalgia, rhinitis • NO ataxia

Any adverse effects associated Acetildenafil with acetildenafil reported? • NOT a marketed drug !! • No report in literature • Illicit drug analogue of sildenafil •Does NOT mean no adverse effects !!

Share similar pharmacology as sildenafil? – No formal testing done • May not be so… – As a concealed ingredient, no post-marketing • The patient deny erectile dysfunction BEFORE surveillance taking the herbal pill • But he had erectile dysfunction AFTER !!!

Ataxia related? Human distribution of PDEs

O • Sildenafil is highly specific N O HN O N for PDE type 5 S N N N O • Structure of acetildenafil is Sildenafil modified and may lead to:

Æ loss of PDE5 specificity O N N O HN N Æ inhibit other PDEs N N

Acetildenafil Carson CC, Lue TF. Phosphodiesterase type 5 inhibitors for erectile dysfunction. BJU Int. 2005;96(3):257-80.

6 Adverse effects of Acetildenafil? Illicit analogue problem in H.K.

• NO one knows !! • Limited market survey • Need formal animal and human studies • male erectile dysfunction health products • Before that, the drug analogue should not available in Hong Kong be allowed for use in humans • Twenty products were bought over the counter • Claim 100% herbal • Tested for erectile dysfunction drugs and analogues

Results

• 1 was found to contain sildenafil • 10 contain illicit drug analogues: – Acetildenafil (Sildenafil analogue) – Hydroxy acetildenafil (Sildenafil analogue) – Hydroxy homo sildenafil (Sildenafil analogue) – Piperidenafil (Vardenafil analogue)

The story did not end… Legal loophole

• Product similar to the Laboratory Findings: • The H.K. Pharmacy and Poisons Ordinance only one taken by patient provides control on adulteration of health was available in some •NO acetildenafil / sildenafil products with registered drugs stores and on internet was found •Piperidenafil was detected !! • These illicit durg analogues are NOT regarded “Do not contain as “drugs” acetildenafil”

• Their use in health products is therefore not under legal regulation

7 Summary How to control the problem?

• Problem of illicit drug analogue is huge: • In Hong Kong, drugs of abuse are banned – Slimming agent based on chemical structure only – Male erectile dysfunction product – Others … • If a chemical is similar in structure to an already banned drug, it too is banned. E.g. • Adverse effects are largely unpredictable ecstasy • Their use is not under legal regulation • The same principle could apply to illicit analogues of other drug classes

Acknowledgements

Supervisors: Dr. Albert Chan Dr. Tony Mak

Scientific Development: Mr. C K Lai Mr. Y H Lam

Staff buying these products (embarrassing!): Karen, Solvil, Vanessa, SW