Dr. AMC Kwan Department of Intensive Care Pamela Youde Nethersole Eastern Hospital

1. HKEC Toxicology Interest Group MeetingAdulteration of male erectile dysfunction health products - not simply hypoglycaemia Dr. AMC Kwan Department of Intensive Care Pamela Youde Nethersole Eastern Hospital

2. The first case in HK

3. Subsequent review in HK • 68 cases in Dec/07-Sept/08 • 2/68 admitted 2 times • 1/68 admitted 3 times • Age: 39-87 • Only 1/68 had DM • 0/68 had been prescribed with glibenclamide/sildenafil

4. Clinical presentation & outcome • Neuroglycopenia • Dosage of glibenclamide • SKY HIGH

5. The products

6. Dosages • Recommended dosage of glibenclamide • 2.5mg-15mg • Recommended dosage of Sildenafil • 25mg-100mg • Quantitative analysis of the samples • Glibenclamide • 70mg • Sildenafil • 64mg (range 0.05 -198mg) • Some of the sildenafil content <10mg

7. Not only in HK

8. Not only in HK • One of the most extensive list of adulterated (sildenafil/analogues )health products ~300 products

9. Besides hypoglycaemia…

10. Case history • M/51 • Hypertension • on Atenolol and Natrilix for 3 yrs • Also on herbal medicine for “health enhancement” • Presented to AED for generalised muscle weakness x 2 days

11. Further history taking • Muscle weakness • Myalgia • Barely able to walk • Was able to go hiking 1 wk before • No URI/trauma/systemic upset • Afebrile all along

12. Physical examination BP 165/72 P 104 SaO2 98% on RA Conscious and alert Oriented and coherent speech Limb power 2/5, normal jerks Chest, abdomen, respiratory -> unremarkable Euthyroid, no thyrotoxic eyesigns, no palpable goitre

13. Initial Lab tests • Initial blood results • WCC 15, Hb 12.6 PLT 175 • RFT: 142/1.5/6.9/123 • ABG: 7.489/4.51/16.5/29/1.5 • CK 1314

14. What is the problem? • Simply Natrilix induced hypokalaemia? • Any other drugs? • Thyrotoxic periodic paralysis? • Conn’s syndrome?

15. Progress • Admitted to ICU for close monitoring • Detailed drug history traced • Atenolol 100mg QD • Natrilix 2.5mg QD • Estazolam 1mg nocte • Proprietary herbs -> pending

18. Eventually patient’s relatives bring this back…….

19. Active ingredients – any problem?

20. Response from HKPIC • 甘草 • Known to cause hypokalaemia from pseudohyperaldosteronism in chronic use • Other ingredients are not expected to cause hypokalaemia • Suggest • Stop強力三鞭海狗丸 • If hypokalaemia does not recur it is likely the presentation is largely related to強力三鞭海狗丸 in particular甘草 • Consult HA TRL for chemical analysis of the PCM as Western Drug adulteration is not uncommonly found

21. Liquorice • Contain isoflavones (Phytoestrogens) • Lower the amount of serum testosterone • “for reducing high sex drive in men”

22. Liquorice induced pseudohyperaldosteronism • Liquorice contain glycyrrhetinic acid甘草酸 • Block 11β-hydroxysteroid dehydrogenase type II • Bind to mineralocorticoid receptors • Elevated level of cortisol (in collecting duct) • Cross react and activate mineralocorticoid receptor • Retain Na • Lose K • Those with underlying HT are more sensitive to the inhibition of 11β-hydroxysteroid dehydrogenase type II by liquorice

23. Progress • Progressively replace Potassium • Rehydratethe patient • K normalised • CK normalised • Thyroid function: normal • Limb power restored back to normal • Discharged from ICU on day 3

24. Analogues of erectile dysfunction drugs

25. Drug analogues • Structually similar compunds of existing drugs • Chemically modified • +/- functional groups • MAY retain corresponding pharmacological actions • Drug analogues WITHOUT drug testing process • Analogues of psychoactive drugs • Anabolic steroids • Anti-obesity drugs • Unpredictable side effect profile

26. Case report • M/28 • Good past health • No Family history of neurological disorder • Presented to RH AED for unsteady gait and frequent fall x 1 wk • Full limb power • Unsteady gait • Fail to perform heel-toe-walking • Unremarkable jerks

27. Case report • CT brain: no focal lesion • Blood parameters: all normal • Progress • All neurological symptom subsided on day 2 admission • Brought back the drugs • Took health products for 8 consecutive days prior the onset of symptom • Working Diagnosis: Drug-related Ataxia • Chemical analysis: Acetildenafil

28. Phosphodiesterase-5 inhibitors Sildenafil Tadalafil Vardenafil

30. Proliferation of herbal products

31. Problems • No formal studies have been performed to assure the safety and efficacy of the analogues • Unpredictable safety profile • Parent compound vs Analogues -> similar effect??

32. Acetildenafil • Drug analogue of sildenafil • No animal study • No human trial • No report of toxicity in literature • No one knows whether it’s safe or not • “…Is the ataxia related to the inhibitory action of PDE inhibitor in CNS?..”

33. The never-ending story • Analogues are not difficult to create • Once the presence of an analogue is exposed, it becomes Obsolete • Soon replaced by another analogue • 58小時轟天炮 • 白金裝超強配方58小時轟天炮 • 58小時轟天炮第三代特強版 • 58小時轟天炮第三代白金裝特強版

34. END

35. Under-recognised social threat • NOT Pharmaceuticals in HK • NOT controlled by local legislation • NO effective surveillance system and control measure so far • NO compulsory disclosure of all active ingredients • “legal loophole”

39. Case Series Courtesy Dr. YC Chan, HKPIC

40. Take home message • Always think of adulteration of “health enhancement products”-not ONLY hypoglycaemia • The dosage of oral hypoglycaemics can be SKYHIGH • Same drug- different contents; Same content –different drugs • NO assumption – age, content, dosage • Always consider this DDx…….and ask the patient tactfully, as men usually, if not always, claimed they have a normal sexual function

41. Thank You