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

The first case in HK

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

Clinical presentation & outcome Neuroglycopenia Dosage of glibenclamide SKY HIGH

The products Median dose of sildenafil 64mg and glibenclamide 70mg

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

Not only in HK

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

Besides hypoglycaemia…

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

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

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

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

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

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

Eventually patient’s relatives bring this back…….

Active ingredients – any problem?

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

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

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

Progress Progressively replace Potassium Rehydrate the patient K normalised CK normalised Thyroid function: normal Limb power restored back to normal Discharged from ICU on day 3

Analogues of erectile dysfunction drugs

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 Look for picture and diagrams

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

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

Phosphodiesterase-5 inhibitors Sildenafil Tadalafil Vardenafil

Proliferation of herbal products

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??

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?..” Sildenafil is a highly selective PDE-5 inhibitor, but how about this unknown compound

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

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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”

Case Series PIC_MS Age Symptoms QTc > 440ms Urine 09-12119 49 Dizziness, Sweating, Chest pain No Matrine +ve 09-12147 59 Dizziness, Sweating, Abdominal Pain Not sent to TRL 09-12203 36 Dizziness, Nausea, Vomiting 09-12562 Dizziness, Sweating, Nausea, Vomiting 09-12865 22 Dizziness, Nausea, Vomiting, Abdominal Pain 09-13090 24 Nausea, Dizziness Courtesy Dr. YC Chan, HKPIC

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

Thank You