Tony Wing Lai Mak

Two cases of severe intoxication associated with analytically confirmed use of the novel psychoactive substances 25B-NBOMe and 25C-NBOMe

Abstract Context. A new group of novel psychoactive substance, the N-methoxybenzyl (NBOMe) derivatives of substituted phenethylamine, has recently emerged on the drug market, among which 25I-NBOMe and 25B-NBOMe have previously been implicated in clinical intoxications and fatalities. We report two cases of acute intoxication associated with these substances. Case details. Two male patients (17 and 31 years of age) had ingested drugs labelled as ‘NBOMe’ or ‘Holland film’ and developed confusion, agitation, hypertension, tachycardia, hyperthermia, sweating and dilated pupils. Other features included convulsion, rhabdomyolysis and deranged liver function. The patients required benzodiazepines and other drugs for the control of symptoms. Urine samples from both patients were analysed using liquid-chromatography tandem mass spectrometry (LC-MS/MS) following glucuronidase digestion and solid-phase extraction. Identification was based upon comparison of the retention time and enhanced product ion scan with reference standards. In both urine samples, 25B-NBOMe was detected. Additionally, 25C-NBOMe was identified in one of the urine samples. Discussion. The NBOMe compounds are highly potent 5HT2A receptor agonists and are also agonists at alpha-adrenergic receptors, which likely account for their serotonergic and sympathomimetic symptoms. The clinical testing of NBOMe drugs is not commonly available. Clinicians as well as laboratory staff play an important role in facilitating the detection of this group of potentially dangerous emerging drugs.

Identification of a novel vardenafil analogue in herbal product

A new herbal health product marketed for enhancing erectile function, namely Power58 Platinum, was purchased over-the-counter in Hong Kong. The product was tested for adulteration with sildenafil, tadalafil, and vardenafil as well as their structurally modified analogues. A new analogue of vardenafil, in which the N-ethylpiperazine ring and the sulphonyl group were removed from the vardenafil structure, was identified in the product.

Case series on a diversity of illicit weight-reducing agents: from the well known to the unexpected

AIMS To provide an overview of illicit weight-reducing agents found in over-the-counter slimming products ingested by poisoned patients. METHODS The clinical details and analytical findings of slimming products involved in poisoning cases between 2004 and 2009 were reviewed. RESULTS Sixty-six (including one fatal) poisoning cases were encountered. Eighty-one products were analysed and found to contain undeclared prescription weight-loss drugs, drug analogues, banned drugs, drugs used for an inappropriate indication or animal thyroid tissue, with up to six illicit agents within the same product. Many products were readily available from shops or the Internet. CONCLUSIONS A rich diversity of illicit, potentially harmful weight-reducing agents was found in over-the-counter slimming products.

Simultaneous detection of 93 conventional and emerging drugs of abuse and their metabolites in urine by UHPLC-MS/MS

Novel psychoactive substances (NPS) are becoming increasingly popular worldwide in recent years, some of which have been reported to cause considerable harm and even fatalities. Currently, simultaneous screening for a comprehensive panel of conventional and novel drugs of abuse is not widely available in most clinical laboratories. The aim of this study was to establish a chromatography/mass spectrometry-based analytical system for the simultaneous detection of conventional drugs of abuse and NPS in urine. Sample preparation entails enzyme digestion and solid phase extraction; analytes were then detected by liquid-chromatography tandem mass spectrometry (LC-MS/MS) with multiple reaction monitoring. Forty-seven conventional drugs (28 parent drugs, 19 metabolites) and 46 NPS analytes (44 parent drugs, two metabolites) are covered by the established method, which has been validated according to international guidelines. The method was then applied to 964 urine samples collected from drug abusers and the results revealed the presence of two NPS - TFMPP and methcathinone - as well as conventional drugs of abuse. To conclude, an LC-MS/MS method has been established that allows the simultaneous detection of over 90 conventional as well as novel psychoactive substances and metabolites in urine samples. The method was successfully applied to authentic specimens revealing the presence of conventional as well as novel drugs of abuse in the local population.

Simultaneous detection of 22 toxic plant alkaloids (aconitum alkaloids, solanaceous tropane alkaloids, sophora alkaloids, strychnos alkaloids and colchicine) in human urine and herbal samples using liquid chromatography-tandem mass spectrometry.

A liquid chromatography-tandem mass spectrometry method for simultaneous detection of 22 toxic plant alkaloids, including aconitum alkaloids and their hydrolyzed products (aconitine, hypaconitine, mesaconitine, yunaconitine, crassicauline A, benzoylaconine, benzoylmesaconine, benzoylhypaconine, deacetylyunaconitine, deacetylcrassicauline A), solanaceous tropane alkaloids (atropine, anisodamine, scopolamine, anisodine), sophora alkaloids (matrine, sophoridine, oxymatrine, cytisine, N-methylcytisine), strychnos alkaloids (brucine, strychnine) and colchicine, in herbal and urine samples was developed and validated. Following sample preparation by liquid-liquid extraction, chromatographic separation was achieved on Eclipse XDB C8 column. Identification was based on two multiple reaction monitoring transitions and the relative ion intensity. Method selectivity was demonstrated. The limits of detection were 5ng/mL for all analytes, except 50ng/mL for cytisine. The herbal matrix effects ranged from 89% to 118%, whereas the urine matrix effects were between 91% and 109% for all analytes except cytisine (57%) and N-methylcytisine (67%). The urine extraction recovery ranged from 74% to 110% for all analytes, except cytisine (15%) and oxymatrine (30%). With the good extraction efficiency of the other major sophora alkaloids, the relatively low extraction recovery of the minor sophora alkaloids cytisine and oxymatrine did not affect identification of sophora alkaloids as a group. Carry-over was minimal at less than 0.1%. The method was successfully applied in analysis of 170 cases of suspected herbal poisoning, with aconitum alkaloids, sophora alkaloids, solanaceous tropane alkaloids, and strychnos alkaloids being detected in 53, 42, 18, and 6 cases, respectively.

Aconite poisoning over 5 years: a case series in Hong Kong and lessons towards herbal safety.

AbstractBackground: Aconite poisoning is a severe, life-threatening poisoning related to the use of traditional Chinese medicine (TCM). Despite current legislation, repeated poisoning cases are steadily encountered. Objective: The aim of the study was to summarize the clinical features and to elucidate the causative and contributory factors leading to aconite poisoning. Methods: This study was conducted within the Hospital Authority Toxicology Reference Laboratory, which is the sole tertiary referral clinical toxicology laboratory in Hong Kong. This retrospective study reviewed all confirmed aconite poisoning cases handled by a clinical toxicology laboratory between April 2004 and July 2009. The diagnosis in all cases was confirmed biochemically by detecting aconitum alkaloids in urine specimens. Additionally, herbal specimens were morphologically identified and herbal formulae were studied and transcribed. The cause of poisoning for each case was determined whenever possible. Results: Fifty-two cases were examined in this aconite poisoning case series. Neurological, cardiovascular and gastrointestinal toxicities were encountered in 49 (94.2%), 46 (88.5%) and 31 (59.6%) patients, respectively. The poisoning was severe in 6 (11.5%) patients, moderate in 17 (32.7%) patients and mild in 29 (55.8%) patients. Amongst 44 patients (84.6%) in whom the underlying reasons of poisoning could be determined, four major causes were found. These included overdose- prescription of a higher than recommended dosage of aconite herbs in 17 (32.7%) cases; ‘hidden’ poisoning (the aconite herb was not prescribed but dispensed inadvertently) in 17 (32.7%) cases; usage of inadequately processed herbs in 7 (13.5%) cases; and dispensary error in 2 (3.9%) cases. No case fatality was recorded. Conclusion: In the majority of cases in this series, the causes of poisoning can be traced to poor-quality herbs, poor quality of prescription practice, or dispensary errors. The quality issues of TCM practice should be critically addressed to minimize this poisoning threat.

Causality assessment of herb-induced liver injury using multidisciplinary approach and Roussel Uclaf Causality Assessment Method (RUCAM).

Objective. To evaluate an algorithmic approach involving a multidisciplinary team for causality assessment of suspected herb-induced liver injury (HILI) cases and to compare the causality score using this multidisciplinary approach and Roussel Uclaf Causality Assessment Method (RUCAM). Methods. A team consisting of hepatologist, clinical toxicologist, analytical toxicologist, and Chinese medicine (CM) pharmacist was formed to do causality assessment based on a protocol for suspected HILI cases. The likelihood of the diagnosis of individual case was first assessed systematically by a hepatologist and clinical toxicologist independently after collecting information about four aspects: (1) clinical course, (2) exclusion of alternative causes, (3) quality of the prescription and herbal product by examining the CM prescriptions and analysis of biological and herb samples, (4) scientific support on comprehensive literature review on English and Chinese medical database, and subsequently concluded in a consensus meeting held by the multidisciplinary team. The final causality score of each patient was compared with the likelihood of causality as assessed by RUCAM. Results. Between 2005 and 2007, 48 consecutive patients with suspected HILI were enrolled and 21 patients were excluded due to the establishment of an alternative cause of liver impairment or the lack of any information on the herbs taken. Twenty-seven patients were recruited, among them 15 consumed Chinese herbal medicines, 10 used proprietary Chinese medicinal products, and 2 used both. The concordance between the causality assessment of the hepatologist and clinical toxicologist was moderate (weighted κ = 0.48, 95%CI 0.30–0.66). The causality assessment process concluded that the likelihood of HILI was “highly probable” in 5 cases and “probable” in 12, whereas there were 5 “highly probable” and 16 “probable” cases as assessed by RUCAM. The causality assessment by the multidisciplinary approach and RUCAM also showed moderate agreement (weighted κ = 0.51, 95%CI 0.22–0.81). Conclusion. A multidisciplinary approach using defined algorithms is a scientific approach in causality assessment for HILI. Further study is needed to assess its accuracy and applicability.

Bromadiolone toxicokinetics: Diagnosis and treatment implications

Introduction. Ingestion of bromadiolone can lead to prolonged and life-threatening coagulopathy. Traditional treatment of bromadiolone intoxication relies on the coagulation profile. Currently, there is scanty information on bromadiolone elimination kinetics and half-life. Case Report. We report a case of bromadiolone poisoning in a 40-year old female who, by history, ingested four 42.5-gram bags of rat poison (0.005% bromadiolone), equivalent to 8.5 mg bromadiolone (0.17 mg/kg body weight), four days prior to admission. On admission, her prothrombin time was 92.0 seconds, international normalized ratio was 5.7, and activated partial thromboplastin time was 50.2 seconds with no bleeding on clinical examination. The first plasma bromadiolone level (5 days post-ingestion) was 92 ng/mL. Serial measurement of plasma bromadiolone levels confirmed the diagnosis and demonstrated that bromadiolone obeys the elimination kinetic of a two-compartment model with a rapid, fairly steep decline phase (half-life 3.5 days) followed by a slower termination phase (half-life 24 days). Plasma bromadiolone level of less than 10 ng/mL in our patient was associated with a consistently normal coagulation profile without vitamin K1 therapy. Conclusions. There is a lack of information on the toxicodynamics and toxicokinetics of bromadiolone in humans; further studies are needed before the plasma bromadiolone level can serve as one of the logical and safe therapeutic endpoints for vitamin K1 therapy.

2,4-Dinitrophenol: A threat to Chinese body-conscious groups

2,4-Dinitrophenol (2,4-DNP), a yellowish compound, has historically been used in the manufacture of dyes, explosives, and fungicides. As it uncouples mitochondrial oxidative phosphorylation, the compound was also used as an antiobesity agent early in the past century. The compound was subsequently banned by the United States Food and Drug Administration in 1938 due to its potentially fatal adverse effects, including hyperthermia, cataract, agranulocytosis, hepatoxicity, nephrotoxicity, and cardiotoxicity. However, the popularity of 2,4-DNP as a slimming aid has appeared to increase again in recent years. The Hong Kong Hospital Authority Toxicology Reference Laboratory recently confirmed two cases of self-administered 2,4-DNP with different clinical presentations to hospitals in the area. Here we describe those two cases, in an attempt to underscore the potential of misuse of this substance by body-conscious groups among the Chinese population.

Severe rhabdomyolysis and acute kidney injury associated with methoxphenidine.

Methoxphenidine (1-[1-(2-methoxyphenyl)-2-phenylethyl] piperidine), also known as 2-MeO-diphenidine or MXP, is a diarylethylamine compound believed to have dissociative effects.[1] It has emerged as a ‘‘research chemical’’ or ‘‘legal high’’ since 2013. Little is known about its pharmacology and only a few cases of toxicity have been reported.[2–4] We report a case of severe rhabdomyolysis and acute kidney injury (AKI) associated with its exposure. A 35-year-old man, with a history of hypothyroidism, Wolff-Parkinson-White Syndrome, adjustment disorder and alcohol dependence, was brought to the emergency department (ED) after being found somnolent on the street with retrograde amnesia for the events in the past 13–15 h. He denied any recent alcohol drinking, drug overdose or abuse. His current medications included thyroxine and quetiapine. He took a few tablets of over-the-counter promethazine (dose unknown) three days before presentation. He denied any muscle pain or weakness. At ED, he was noted to have slurring of speech and hypertension (179/95 mmHg). Minor abrasions, bruises and superficial lacerations were found over his body. No compartment syndrome, limb ischemia, or particular toxidrome was identified. Neurological, cardiovascular, chest and abdominal examinations were otherwise unremarkable. Both ECG and CT brain were normal. Laboratory tests revealed severe rhabdomyolysis (serum creatine kinase [CK] 146860 U/L; reference interval 65–355 U/L), renal impairment (serum creatinine 141 lmol/L; reference interval 67–109 lmol/L) and myoglobinuria, along with elevated alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase levels and mild hypokalemia. Bedside urine toxicology immunoassay (Abon Biopharm, Hangzhou, China) was positive for benzodiazepines and tricyclic antidepressants, but negative for cocaine, amphetamines, tetrahydrocannabinol, opioids, barbiturates, phencyclidine and ketamine. Ethanol was undetectable in patient’s serum. Analysis of patient’s urine collected at ED using liquid chromatography–tandem mass spectrometry showed prominent peaks of methoxphenidine and its metabolites (hydroxy-2-methoxydiphenidine, dihydroxy-2-methoxydiphenidine and hydroxyl-O-demethyl-2methoxydiphenidine), as well as small peaks of methylphenidate metabolite, tramadol and lorazepam (close to the lower limits of detection for the latter two, which were 50 and 100 ng/mL, respectively). The patient was hospitalized for intravenous hydration and urine alkalization. His CK level peaked at 200660 U/L 9.5 h after presentation and serum creatinine reached 512 lmol/L on day eight. Further workup for AKI, including a renal ultrasound and autoimmune markers, was unremarkable. The patient remained asymptomatic and requested to leave our hospital on day five. On day fifteen, his CK and serum creatinine fell to 380 U/L and 230 lmol/L, respectively. He defaulted all subsequent appointments. The most striking feature of this case was severe rhabdomyolysis with AKI, which was likely multi-factorial,[5] since it was out of proportion to the observed injuries. Prolonged immobilization, severe agitation and unwitnessed seizure after drug exposure were possible. Despite being denied or forgotten by the patient, methoxphenidine exposure was confirmed analytically. Patient’s clinical presentation, including somnolence, hypertension, amnesia and slurred speech, was consistent with its exposure.[2,3] Mild rhabdomyolysis has been reported in a case of methoxphenidine abuse with opisthotonus,[2] but it was not seen in our patient. Arguably, the other drugs detected in the patient’s urine might also be contributory, but only small peaks were found. Given the unknown time of drug exposure, multiple drugs exposed, and long unwitnessed time before hospital presentation, it is difficult to estimate the relative contribution of each of the drugs identified. Yet, based on the compatible clinical presentation and analytical result, we believe methoxphendine played a significant role in this case.