Albert Yan-Wo Chan

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.

Inborn errors of metabolism and expanded newborn screening: review and update.

Abstract Inborn errors of metabolism (IEM) are a phenotypically and genetically heterogeneous group of disorders caused by a defect in a metabolic pathway, leading to malfunctioning metabolism and/or the accumulation of toxic intermediate metabolites. To date, more than 1000 different IEM have been identified. While individually rare, the cumulative incidence has been shown to be upwards of 1 in 800. Clinical presentations are protean, complicating diagnostic pathways. IEM are present in all ethnic groups and across every age. Some IEM are amenable to treatment, with promising outcomes. However, high clinical suspicion alone is not sufficient to reduce morbidities and mortalities. In the last decade, due to the advent of tandem mass spectrometry, expanded newborn screening (NBS) has become a mandatory public health strategy in most developed and developing countries. The technology allows inexpensive simultaneous detection of more than 30 different metabolic disorders in one single blood spot specimen at a cost of about USD 10 per baby, with commendable analytical accuracy and precision. The sensitivity and specificity of this method can be up to 99% and 99.995%, respectively, for most amino acid disorders, organic acidemias, and fatty acid oxidation defects. Cost-effectiveness studies have confirmed that the savings achieved through the use of expanded NBS programs are significantly greater than the costs of implementation. The adverse effects of false positive results are negligible in view of the economic health benefits generated by expanded NBS and these could be minimized through increased education, better communication, and improved technologies. Local screening agencies should be given the autonomy to develop their screening programs in order to keep pace with international advancements. The development of biochemical genetics is closely linked with expanded NBS. With ongoing advancements in nanotechnology and molecular genomics, the field of biochemical genetics is still expanding rapidly. The potential of tandem mass spectrometry is extending to cover more disorders. Indeed, the use of genetic markers in T-cell receptor excision circles for severe combined immunodeficiency is one promising example. NBS represents the highest volume of genetic testing. It is more than a test and it warrants systematic healthcare service delivery across the pre-analytical, analytical, and post-analytical phases. There should be a comprehensive reporting system entailing genetic counselling as well as short-term and long-term follow-up. It is essential to integrate existing clinical IEM services with the expanded NBS program to enable close communication between the laboratory, clinicians, and allied health parties. In this review, we will discuss the history of IEM, its clinical presentations in children and adult patients, and its incidence among different ethnicities; the history and recent expansion of NBS, its cost-effectiveness, associated pros and cons, and the ethical issues that can arise; the analytical aspects of tandem mass spectrometry and post-analytical perspectives regarding result interpretation.

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.

Risk of Vitamin A Toxicity From Candy-Like Chewable Vitamin Supplements for Children

Numerous vitamin supplements are available over-the-counter to the general public. Some such supplements are available as candy-like chewable preparations to encourage consumption by children. We report 3 cases of overdose of such preparations. Each patient had taken an estimated 200000 to 300000 IU of vitamin A. Their circulating vitamin A (retinol and retinyl palmitate) concentrations were monitored over a 6-month period. There were no clinical or biochemical complications noted. However, there were marked increases in both retinol and retinyl palmitate concentrations above age-related reference ranges. In particular, it took 1 to 3 weeks for the serum retinol concentrations to peak and many months for them to normalize. Parents should be warned about the dangers of excessive vitamin consumption. Clinicians should be aware of the late peak in serum retinol concentrations, which may lead to late complications of vitamin A overdose.

Nitrite-induced methaemoglobinaemia - aetiology, diagnosis and treatment.

A 41‐year‐old woman presented with the clinical features of methaemoglobinaemia after drinking Chinese herbal medicine. A life threatening methaemoglobin level of 68% was measured. Both clinical and laboratory diagnostic difficulties were encountered. The pitfalls of pulse oximeter, blood gas analysis and co‐oximeter interpretation during diagnosis and after methylene blue administration are discussed.

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.

Fatal viral infection-associated encephalopathy in two Chinese boys : a genetically determined risk factor of thermolabile carnitine palmitoyltransferase II variants

Influenza-associated encephalopathy (IAE) is a potentially fatal neurological complication of influenza infection usually in the presence of high and persistent fever. Thermolabile carnitine palmitoyltransferase II enzyme (CPT-II) predisposes IAE, so far only described in Japanese. As the genetic origins of Japanese and Chinese are alike, similar genetic risk factors in CPT-II are expected. We report the first two unrelated Chinese patients of thermolabile CPT-II variants that underlain the persistent high fever-triggered viral infection-associated encephalopathy, multi-organ failure and death. Elevated (C16:0+C18:1)/C2 acylcarnitines ratio and the CPT2 susceptibility variant allele [p.Phe352Cys; p.Val368Ile] were detected. The asymptomatic family members of one patient also had abnormal long-chain acylcarnitines. In our experience of biochemical genetics, the elevated (C16:0+C18:1)/C2 acylcarnitines ratio is unusual and specific for thermolabile CPT-II variants. Allele frequency of [p.Phe352Cys; p.Val368Ile] among Hong Kong Chinese was 0.104, similar to Japanese data, and [p.Phe352Cys] has not been reported in Caucasians. This may explain the Asian-specific phenomenon of thermolabile CPT-II-associated IAE. We successfully demonstrated the thermolabile CPT-II variants in patients with viral infection-associated encephalopathy in another Asian population outside Japanese. The condition is likely under-recognized. With our first cases, it is envisaged that more cases will be diagnosed in subsequent years. The exact pathogenic mechanism of how other factors interplay with thermolabile CPT-II variants and high fever leading to IAE, is yet to be elucidated. Fasting and decreased intake during illness may aggravate the disease. Further studies including high risk and neonatal screening are warranted to investigate its expressivity, penetrance and temperature-dependent behaviors in thermolabile CPT-II carriers. This may lead to discovery of the therapeutic golden window by aggressive antipyretics and L-carnitine administration in avoiding the high mortality and morbidity of IAE.

Non-invasive urinary screening for aromatic L-amino acid decarboxylase deficiency in high-prevalence areas: a pilot study.

BACKGROUND The diagnosis of aromatic L-amino acid decarboxylase (AADC) deficiency, one of the pediatric neurotransmitter disorders, is classically made with plasma enzyme level or cerebrospinal fluid (CSF) neurotransmitter profile, while both are technically demanding and the latter requires the invasive lumbar puncture. So far less than 100 cases have been reported worldwide with 20% from Taiwan. It was postulated that the condition might have been under-diagnosed among Chinese populations and a non-invasive screening tool should be developed in areas with high prevalence. METHODS Urine metabolic profiles performed by gas chromatography-mass spectrometry (GC-MS) in a 31-month period were retrospectively reviewed: those with vanilmandelic acid concentration lower than one percentile plus the presence of 3-o-methyldopa were defined as positive and the patients were further evaluated. RESULTS Among 1046 metabolic profiles (from 845 patients) reviewed, 3 profiles from 2 patients were screened positive: both cases had compatible CSF neurotransmitter profiles and the diagnosis was further confirmed by genetic analysis of DDC gene. 13 negative urinary metabolic profiles from 7 patients who had CSF neurotransmitters analyzed were identified as controls: all 7 CSF neurotransmitter profiles were not compatible for AADC deficiency. CONCLUSIONS The GC-MS-based urine metabolic profiling was shown to be a satisfactory screening tool for AADC deficiency. Further confirmation can be performed by mutation analysis in the DDC gene, thus avoiding risks of lumbar puncture. We advocate all ethnic Chinese patients presenting with dystonia have their urine organic acids analyzed before proceeding to CSF neurotransmitters analysis.

Aristolochic Acid Nephropathy: The Hong Kong Perspective

Aristolochic acid nephropathy (AAN) is a progressive tubulointerstitial nephropathy attributed to aristolochic acid (AA) toxicity. Five cases of AAN have been diagnosed in Hong Kong. Most were caused by the inadvertent substitution of innocuous herbs with Aristolochia species. Our findings contributed to the withdrawal of the AA-containing herbs and products in Hong Kong. This paper aims to review the topic of AAN from a Hong Kong perspective.