Introduction
Collection of the literature
Anorectics in counterfeit weight loss products
Sibutramine
Fenfluramine
Metformin
Phentermine
Amfepramone (diethylpropion)
Methylphenidate
Modafinil
Rimonabant
Mitragynine
Other drug classes
Legal status
Anorectic | Legal status | Reference(s) |
---|---|---|
Sibutramine | Banned and withdrawn from markets due to the risk of major cardiac events | |
Fenfluramine | Removed from the market by the manufacturer due to association with serious health problems | [142] |
Phentermine | Schedule IV in the US, available by prescription only in many countries | [132] |
Metformin | Available by prescription only in many countries | [143] |
Buformin | Never approved for sale in the US, removed from markets in most countries due to increased risk of lactic acidosis. Available by prescription only in Romania1, Hungary2, Taiwan3 and Japan4 | |
Phenformin | Withdrawn from the market as an antidiabetic drug due to the high risk of fatal lactic acidosis | [148] |
Rimonabant | Never approved in the US, withdrawn from the market globally due to concerns over dangerous psychological side effects, including suicidality and depression | |
Amfepramone (diethylpropion) | Classified as Schedule IV controlled substance in the US and Canada1, Class C drug in the UK2, and available by prescription only in Australia3 and Germany4 | |
Methylphenidate | Designated Schedule II internationally1, the US2, Schedule III in Canada3 and Schedule 8 in Australia4. Controlled substance Class B in the UK5, Class B2 in New Zealand6, List II controlled substance of medical value in Sweden7, and controlled Psychotropics in Japan8 | |
Modafinil | Classified as Schedule IV controlled substance in the US1 and Sweden2, Schedule 4 prescription-only medicine in Australia3, Class I and Schedule 1 psychotropic drug in China4 and Japan5, respectively, and Schedule II controlled substance in the same class as morphine and cocaine in Russia6 | |
Mitragynine (plant / alkaloids) | Not listed under any schedules of the UNDC1; not approved for any medical use and under Schedule I consideration in the US2, controlled as Narcotic in Australia3 and New Zealand4; controlled as Designated substance in Japan5. Plant controlled in Europe6 and prohibited in the UK7 |
Detection of anorectics in counterfeit slimming products
Sample preparation for anorectics in counterfeit pharmaceuticals
Analytical methods for determination of counterfeit anorectics
Reference | Formulation and adulterants detected | Case | Clinical features | Extraction method | Analytical method | Outcome |
---|---|---|---|---|---|---|
Hughes (2019) [206] | Mitragynine | A 27-year-old man consumed quetiapine and mitragynine | Autopsy examination revealed dark fluid emanating from the mouth and intramuscular haemorrhage on cut sections of the tongue | N/A | HPLC | Death |
Alshaikhi et al. (2018) [207] | Herbal slimming product ‘Burning Fat Slimming Capsule’ obtained from the Internet Sibutramine | A 29-year-old woman was hospitalised 2 months after the ingestion of slimming product | Agitation and psychosis, nervousness, insomnia, hyperactivity, and obsession | N/A | HPLC | Treated and discharged |
Bunya et al. (2017) [208] | Thai-made weight loss capsule and tablets called “Hospital diet” bought on the Internet Sibutramine, hydrochlorothiazide, bisacodyl, chlorpheniramine, and a thyroid hormone | A 21-year-old woman, found unresponsive on a sidewalk, after taking only one day’s dose of weight loss pills from Thailand | Ventricular fibrillation with agonal breathing. Lack of response after 4 defibrillation attempts. Spontaneous circulation achieved 30 min after administering extracorporeal membrane oxygenation | N/A | N/A | Patient placed in intensive care. Automated cardioverter defibrillator implanted on day 42 and discharged on day 51 Clinical data excluded any other underlying pathology, including congenital causes |
Shapira et al. (2016) [209] | Dietary supplements “One Slim” and “Amana Care” purchased from a local pharmacy Sibutramine, phenolphthalein | A 26-year-old female admitted to emergency after ingestion of slimming dietary supplements for two weeks prior | Visual hallucinations, abnormal behaviour, hyperkinesia, tachycardia, dizziness, facial flushing | N/A | N/A | Patient responded well to haloperidol therapy and discharged |
Gunaydin et al. (2015) [210] | Herbal slimming product ‘La Jiao Shou Shen’ bought on the Internet Sibutramine | A 17-year-old female was admitted to the emergency department for the ingestion of weight loss products | Palpitation, dizziness, fatigue, and insomnia | N/A | N/A | Treated and discharged |
Vecchio et al. (2014) [211] | Herbal slimming product collected from patients Metformin | The study involved 66 patients hospitalised at the Pavia Poison Center from 2007 to 2011 for using metformin as a therapeutic agent for the management of type II diabetes | Mild gastroenteritis, neurological impairments, respiratory failure, hemodynamic disorder, acute heart failure, sepsis, severe pneumonia, post-surgical shock, lactic acidosis, and acute renal failure | N/A | HPLC | 17 deaths. Others treated and discharged |
Zhu et al. (2014) [57] | Metformin | 12 samples from anonymous real cases | N/A | N/A | LC–MS/MS | N/A |
Khazan et al. (2013) [212] | 9 herbal slimming products bought from the market Phencyclidine | 20 women using Chinese herbal slimming products were recruited for the study during spring 2010 in Iran | Dry mouth, hand tremor, increased blood pressure, tachycardia, arrhythmia, anxiety, diarrhoea, sleep disturbances, decreased appetite, euphoria, feeling hyper, and palpitations | N/A | Immunochromatographic assay | All 20 women declared their willingness to continue to use these products despite the reported side effects |
Heo and Kang (2013) [213] | Non-prescription weight loss formulation called “Slim-30” N-Desmethyl sibutramine | A 32-year-old male admitted with progressively worsening dyspnoea on exertion following continued use of unauthorised slimming pills for 7 months | High blood pressure, palpitation, pitting oedema in lower extremities, dilated cardiomyopathy with massive intracardiac thrombus | N/A | N/A | Good clinical response to treatment. Discharged in a stable condition and prescribed a beta-blocker, angiotensin-converting-enzyme inhibitor, and oral warfarin. One-month follow-up was required |
Lam et al. (2012) [214] | A slimming product obtained from the Internet Sibutramine, animal thyroid tissues, caffeine, and phenolphthalein | A 21-year-old woman was admitted at the hospital for overdose ingestion of an illicit slimming product. Patient t had been taking this medicine for 4 years for weight loss | Coma, fever with persistent sinus tachycardia | N/A | HPLC–DAD, LC–MS/MS | Treated and discharged |
Ching et al. (2012) [215] | Ku Le Kang, Yi Su Kang Jiao Nang, Jiang Tang Ning Jiao Nang, Xiao Ke Shu Ping – Jiang Tang Ning Jiao Nang, Tian Sheng Yi Bao, Tang Le Shi Shen Jiao Nang, Yi Zhi Ren Jiao Nang, Shen Ji Xi Jiao Wan, Ba Bao Xiao Ke Wan, Yi Huo Xiao Tang Ning Jiao Nang, Shen Shi Yi Huo Jiang Tang Ning Jiao Nang, Yi Dao Pai Du Jiao Nang, Jing Xue Wen Tang Jiao Nang, Tang Ke Wan Phenformin, metformin, rosiglitazone, glibenclamide, glimepiride, nateglinide | 27 cases of clinical toxicities associated with the use of herbal PCMs | Heart failure, severe Lactic acidosis, Hypoglycaemia, Renal impairment | N/A | N/A | Treated and discharged |
Tang et al. (2011) [22] | 81 slimming products sourced from the internet, OTC, friends, local slimming centres, and herbalists Sibutramine, N-desmethylsibutramine, N-bisdesmethylsibutramine, phenolthalein, fenfluramine,N-nitrosofenfluramine, anthraquinones, bisacodyl, hydrochlorothiazide, animal thyroid tissue, spironolactone | 66 cases of poisoning involving illicit slimming products between Jan. 2004 and Dec. 2009 | Severe to moderate poisoning presenting with: Liver failure, supraventricular tachycardia, palpitations, tremor, insomnia, myocardial infarction, hypertension, generalized weakness, dizziness, sweating | N/A | HPLC–UV GC–MS or LC–MS/MS, microscopy, immunoassay | One death. Others treated and discharged |
Vitalone et al. (2011) [216] | The Italian National Surveillance collected samples of slimming pills from patients Fluoxetine, metformin, and levothyroxine | 46 patients with adverse reaction due to ingestion of weight-loss products were admitted from April 2002 to June 2010 | Ventricular fibrillation, vomiting, and abdominal problems | N/A | HPLC–UV, HPLC–FLUOR, and ion-exchange chromatography | All patients were treated and discharged |
Chen et al. (2010) [52] | 20 proprietary herbal slimming products (bought from internet & OTC) Sibutramine, N-desmethylsibutramine, N-bisdesmethylsibutramine, phenolthalein, fenfluramine, mazindol, hydrochlorothiazide, spironolactone, caffeine, emodin, aloe-emodin, physcion | 16 patients hospitalised between Jan. 2004 to Oct. 2009 from taking herbal slimming formulation | Psychosis, auditory and visual hallucinations, persecutory ideas, suicidal ideation | N/A | HPLC (initial screening) GC–MS or LC–-MS/MS | Patients treated and discharged (recovery time range from 3 days to 3 months) |
Chong (2010) [217] | Herbal slimming pills Sibutramine, animal thyroid tissue, phenolphthalein, phentermine, paracetamol, oleanolic acid, caffeine, and N-bisdesmethylsibutramine | Two women aged 19 and 37 admitted with mania-like psychosis after taking non-prescription herbal weight loss pills | Sudden onset of paranoid ideations and self-harming behaviour, irritability, poor sleep, paranoid delusions, auditory and visual hallucinations | N/A | LC–MS/MS | Treated with quetiapine and Valproate (19 years old); and risperidone (37 years old) and discharged |
Müller et al. (2009) [218] | Lida Dai dai hua, slimming capsule Sibutramine | 17 cases of poisoning with a single product, said to be of purely herbal origin, that was bought over the Internet over 3 years in Göttingen and Freiburg | Malaise, tachycardia, headache, agitation, arterial hypertension, nausea, vomiting, dyspnoea, insomnia, left-sided chest pressure, elevated temperature, and, in two cases, psychosis | acidic hydrolysis and acetylation | GC–MS and HPLC–DAD | Treated and discharged |
Yim et al. (2008) [219] | Herbal slimming capsules bought in mainland China Sibutramine | A 37-year-old woman admitted at the Accident and Emergency Department in Hong Kong for taking herbal slimming pills 3 days before her admission | Retrosternal chest pain, nausea, sweating, myocardial infarction | N/A | LC–MS | Treated and discharged |
Poon et al. (2008) [220] | Two herbal weight loss product, Qing Zhi Mei and Chan Qing Chun, bought from a beauty salon and 0ver the counter Caffeine, anthraquinones, riboflavin, nicotinamide, pyridoxine, N-nitrosofenfluramine, fenfluramine, sibutramine, phenolphthalein propranolol, ephedrine, and animal thyroid tissue | Three patients, a 53-year-old woman, a 41-year-old man, and a 38-year-old woman were admitted in 2005 after taking herbal slimming product | Pulmonary hypertension, moderate aortic regurgitation, and prominent right heart failure, periodic paralysis. Patients showed factitious thyrotoxicosis | Uniform SPE | HPLC–DAD | Treated and discharged |
Ching et al. (2008) [149] | Herbal-based PCM: Yi Su Kang Jiau Nang, Xiang Lian Pian, Ching Shin Bei Dou Gen Pian and Yan Suan Shiau Bo Jiau Pian, Ku Le Kang, Shiau Ke Shu Ping–Jiang Tang Ning Jiau Nang, and Huo Yi Jiang Tang Dan, bought OTC Phenformin, glibenclamide, rosiglitazone | Four older women (57 -79 yr) and 2 older men (56 yr & 78 yr) with history of diabetes, defaulted follow-up of prescription and used PCM as alternative | Nausea, vomiting, hypoglycaemia, heart failure | Uniform SPE | LC–DAD, GC–MS and LC–MS/MS | Treated and discharged |
Yuen et al. (2007) [29] | 26 over-the-counter slimming products collected from 21 patients Sibutramine and its analogue, N-nitrosofenfluramine, nicotinamide, emodin, aloe-emodin, tiratricol, fenfluramine and its analogue, thyroxine, thyroid, mazindol, caffeine, hydrochlorothiazide, propranolol, dobutamine and phentermine | 42 patients hospitalised between September 2004 to December 2006 at the Hospital Authority Toxicology Reference Laboratory for consuming slimming products | Fulminant hepatic failure, pulmonary hypertension, moderate aortic regurgitation, right heart failure, and generalised body weakness | GC–MS or LC–MS/MS | All patients were treated and discharged | |
Hung and Chang (2006) [221] | Weight loss pill collected from the patient Phentermine, chlorpheniramine maleate | A 23-year-old woman was admitted at the emergency department for taking slimming pills for 3 consecutive days | Cardiac arrhythmia, lethargy, headache, dizziness, nausea, vomiting, dyspnoea, and palpitation | N/A | N/A | Treated and discharged |
Jung et al. (2006) [222] | A Chinese herbal weight loss product ‘LiDa Dai Dai Hua Jiao Nang’ bought from the Internet Sibutramine | A 20-year-old woman was admitted to the hospital for taking a Chinese herbal weight loss product for 6 days | Severe headache, vertigo, numbness | Methanol extraction, acid hydrolysis and methylation | GC–-MS, HPLC–DAD | Treated and discharged |
Lai et al. (2006) [223] | A Chinese slimming product (Shubao) bought from the West Midlands N-Nitrosofenfluramine | 4 patients hospitalised for taking a Chinese slimming pill between November 2003 and June 2004 | Severe acute hepatic injury | N/A | N/A | One patient received a liver transplant while the others fully recovered after discontinuing the herbal product |
Hsiao et al. (2005) [224] | ‘60 DNP’ capsules Dinitrophenol, caffeine, ibuprofen and acetaminophen | A 17-year-old female presented to the paediatric emergency department after ingesting diet pills 4 h prior | Vomiting, diaphoretic, tachycardia | N/A | UV/VIS | Death |
Lau et al. (2004) [225] | 39 capsules of Chinese dieting pills (Slim 10) were collected from the patients Fenfluramine, N-nitrosofenfluramine, nicotinamide, thyroxine | A 42 years old woman was hospitalised for consuming 4 bottles of dietary pills ‘Slim 10′ each containing 120 with only 39 capsules remaining at the time of her death | Acute hepatitis, severe jaundice, hepatic encephalopathy, coagulation, nosocomial sepsis, renal failure, and multi-organ failure | Methanol and dichloromethane | GC–MS, GC–MSD, GC–TEA, HPLC–DAD | Death |
Adachi et al. (2003) [226] | 2 dietary slimming products (Chinese herbal weight loss aids Chaso and Onshido) N-Nitrosofenfluramine | 12 patients were hospitalised at Keio University Hospital and other hospitals in Japan between April to July 2002 after taking weight loss products | Fatigue, appetite loss, hepatic encephalopathy, acute liver injury and hepatic failure | N/A | LC–MSD | One death, 1 patient underwent a liver transplant and the condition of the 10 patients improved after discontinuing the use of the products |
Nakadai et al. (2003) [227] | 10 Chinese slimming products obtained from patients N-Nitrosofenfluramine, fenfluramine, dexfenfluramine | 800 cases of liver damage were reported for taking Chinese diet aids in Japan from 2001 to summer 2002 | Liver damage | N/A | NMR, GC–MS, HPLC | N/A |
Corns and Metcalfe (2002) [228] | Herbal slimming capsules imported from mainland China: Ba Zhen Wan, Dan Gui Wan, Jiao Nang (Tiansu), Kang Gu Che Sheng Wan, Kintop, Qian Er, Shen Qi Da Bu Wan, Storm, Unnamed yellow tablets Fenfluramine | Three females (29, 41 and 46-year-olds) taken to the hospital after consuming weight loss formulations obtained from a herbalist | Hypertension, loss of weight, abdominal pain, rapid palpitation, nausea and visual hallucinations | N/A | GC–MS | Treated and discharged |