RESUMO
With the rapid proliferation of online businesses, national authorities are facing challenges managing the online supply of illegal health products due to the anonymity of the internet, increasing number of global syndicates, new technologies, and inability to enforce against overseas sellers. This paper describes these challenges and the Health Sciences Authority's regulatory approaches to tackle the online sales of illegal health products. These include partnering with platform administrators to remove illegal online postings, leveraging technological tools and relevant legislation, empowering consumers to make informed decisions, and fostering closer collaborations across different jurisdictions to combat online pharmaceutical crimes.
Assuntos
Comércio , Internet , Humanos , Comércio/legislação & jurisprudênciaRESUMO
INTRODUCTION: Messenger ribonucleic acid (mRNA) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines have been associated with myocarditis/pericarditis, especially in young males. We evaluated the risk of myocarditis/pericarditis following mRNA vaccines by brand, age, sex and dose number in Singapore. METHODS: Adverse event reports of myocarditis/pericarditis following mRNA vaccines received by the Health Sciences Authority from 30 December 2020 to 25 July 2022 were included, with a data lock on 30 September 2022. Case adjudication was done by an independent panel of cardiologists using the US Centers for Disease Control and Prevention case definition. Reporting rates were compared with expected rates using historical data from 2018 to 2020. RESULTS: Of the 152 adjudicated cases, males comprised 75.0%. The median age was 30 years. Most cases occurred after Dose 2 (49.3%). The median time to onset was 2 days. Reporting rates were highest in males aged 12-17 years for both primary series (11.5 [95% confidence interval [CI] 6.7-18.4] per 100,000 doses, post-Dose 2) and following booster doses (7.1 [95% CI 3.0-13.9] per 100,000 doses). In children aged 5-11 years, myocarditis remained very rare (0.2 per 100,000 doses). The reporting rates for Booster 1 were generally similar or lower than those for Dose 2. CONCLUSIONS: The risk of myocarditis/pericarditis with mRNA vaccines was highest in adolescent males following Dose 2, and this was higher than historically observed background rates. Most cases were clinically mild. The risk of myocarditis should be weighed against the benefits of receiving an mRNA vaccine, keeping in mind that SARS-CoV-2 infections carry substantial risks of myocarditis/pericarditis, as well as the evolving landscape of the disease.
RESUMO
Background: The real-world safety profile of COVID-19 mRNA vaccines remains incompletely elucidated. Methods: We performed a nationwide post-market safety surveillance analysis in Singapore, on vacinees aged 5 years and older, through mid-September 2022. Observed-over-expected (O/E) analyses were performed to identify potential safety signals among eight shortlisted adverse events of special interest (AESIs): strokes, cerebral venous thrombosis (CVT), acute myocardial infarction, myocarditis/pericarditis, pulmonary embolism, immune thrombocytopenia, convulsions and appendicitis. Self-controlled case series analyses (SCCS) were performed to validate signals of concern, occurring within 42 days of vaccination. Findings: Elevated risks were observed on O/E analyses for the following AESIs: myocarditis/pericarditis, [rate ratio (RR): 3.66, 95 % confidence interval (95 % CI): 2.71 to 4.94], appendicitis [RR: 1.14 (1.02 to 1.27)] and CVT [RR: 2.11 (1.18 to 3.77)]. SCCS analyses generated corroborative findings: myocarditis/pericarditis, [relative incidence (RI): 6.96 (3.95 to 12.27) at 1 to 7 days post-dose 2], CVT [RI: 4.30 (1.30 to 14.20) at 22 to 42 days post-dose 1] and appendicitis [RI: 1.31 (1.03 to 1.67) at 1 to 7 days post-dose 1]. Booster dose 1 continued to be associated with higher rates of myocarditis/pericarditis on O/E analysis [RR: 2.30, (1.39 to 3.80) and 1.69, (1.11 to 2.59)] at 21- and 42-days post-booster dose 1, respectively. Males aged 12 to 17 exhibited highest risks of both myocarditis/pericarditis [RI: 6.31 (1.36 to 29.3)] and appendicitis [RI: 2.01 (1.12 to 3.64)] after primary vaccination. Similarly, CVT was also predominantly observed in males aged above 50 (11 out of 16 cases), within 42-days of vaccination. Interpretation: Our data suggest that myocarditis/pericarditis, appendicitis and CVT are associated with primary vaccination using COVID-19 mRNA vaccines. Males at specific ages exhibit higher risks for all three AEs identified. The risk of myocarditis/pericarditis continues to be elevated after booster dose 1.
RESUMO
INTRODUCTION: Despite reports suggesting an association between COVID-19 mRNA vaccination and pericarditis and myocarditis, detailed nationwide population-based data are sparsely available. We describe the incidence of pericarditis and myocarditis by age categories and sex after COVID-19 mRNA vaccination from a nationwide mass vaccination programme in Singapore. METHODS: The incidence of adjudicated cases of pericarditis and myocarditis following COVID-19 mRNA vaccination that were reported to the vaccine safety committee between January to July 2021 was compared with the background incidence of myocarditis in Singapore. RESULTS: As of end July 2021, a total of 34 cases were reported (9 pericarditis only, 14 myocarditis only, and 11 concomitant pericarditis and myocarditis) with 7,183,889 doses of COVID-19 mRNA vaccine administered. Of the 9 cases of pericarditis only, all were male except one. The highest incidence of pericarditis was in males aged 12-19 years with an incidence of 1.11 cases per 100,000 doses. Of the 25 cases of myocarditis, 80% (20 cases) were male and the median age was 23 years (range 12-55 years) with 16 cases after the second dose. A higher-than-expected number of cases were seen in males aged 12-19 and 20-29 years, with incidence rates of 3.72 and 0.98 case per 100,000 doses, respectively. CONCLUSION: Data from the national registry in Singapore indicate an increased incidence of pericarditis and myocarditis in younger men after COVID-19 mRNA vaccination.
Assuntos
COVID-19 , Miocardite , Pericardite , Adolescente , Adulto , COVID-19/epidemiologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miocardite/complicações , Miocardite/etiologia , Pericardite/epidemiologia , Pericardite/etiologia , RNA Mensageiro , SARS-CoV-2 , Vacinação/efeitos adversos , Vacinas Sintéticas , Adulto Jovem , Vacinas de mRNARESUMO
In April 2013, the Ministry of Health and Health Sciences Authority of Singapore jointly issued recommendations for HLA-B*15:02 genotyping before starting carbamazepine (CBZ) in new patients of Asian ancestry as standard of care. The Ministry of Health also approved a 75% subsidy for HLA-B*15:02 genotyping to all patients on subsidy at public healthcare institutions. To understand the impact of these regulatory decisions, we researched the usage patterns for CBZ and levetiracetam, the trend of Stevens-Johnson syndrome/toxic epidermal necrolysis [Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN)] reports associated with antiepileptic drugs and the take-up rates of HLA-B*15:02 tests in Singapore. In the 5-year post-policy period, we found that the annual number of reported SJS/TEN cases associated with all antiepileptic drugs was significantly decreased by 57% (p = 0.015); SJS/TEN cases associated with CBZ and phenytoin reduced by 92% and 42% respectively. New CBZ users decreased by 31% while new levetiracetam users approximately doubled. The annual number of HLA-B*15:02 tests conducted increased from 444 to approximately 1,200. Regulatory recommendations for HLA-B*15:02 genotyping as standard of care coupled with government subsidy for the test had contributed to a reduction in CBZ SJS/TEN in Singapore by >90%, in line with that observed in other Asian countries with similar policies. Additionally, the number of phenytoin-SJS/TEN cases also declined. Taken together, this represents a successful example of precision medicine through implementation of a genotyping program to reduce a rare but serious adverse drug reaction among at-risk individuals, while preserving the availability of an effective and low-cost medicine for the broader population.
RESUMO
Background: In Singapore, the Health Sciences Authority (HSA) reviews an average of 20,000 spontaneous adverse event (AE) reports yearly. Potential safety signals are identified manually and discussed on a weekly basis. In this study, we compared the use of four quantitative data mining (QDM) methods with weekly manual review to determine if signals of disproportionate reporting (SDRs) can improve the efficiency of manual reviews and thereby enhance drug safety signal detection.Methods: We formulated a QDM triage strategy to reduce the number of SDRs for weekly review and compared the results against those derived from manual reviews alone for the same 6-month period. We then incorporated QDM triage into the manual review workflow for the subsequent two 6-month periods and made further comparisons against QDM triage alone.Results: The incorporation of QDM triage into routine manual reviews resulted in a reduction of 20% to 30% in the number of drug-AE pairs identified for further evaluation. Sequential Probability Ratio Test (SPRT) detected more signals that mirror human manual signal detection than the other three methods.Conclusions: The adoption of QDM triage into our manual reviews is a more efficient way forward in signal detection, avoiding missing important drug safety signals.
Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Mineração de Dados/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Humanos , SingapuraRESUMO
PURPOSE: To describe the magnetic resonance (MR) imaging findings associated with severe hypoglycemia after consumption of an illegal sexual enhancement product (Power 1 Walnut) adulterated with glibenclamide, an oral hypoglycemic agent used to treat diabetes mellitus. MATERIALS AND METHODS: Institutional review board approval was obtained for this retrospective study. Records in eight male patients with severe hypoglycemia of unknown cause, without prior treatment for diabetes, and with positive blood toxicology results for glibenclamide were reviewed. MR imaging included diffusion-weighted imaging and, in some patients, MR angiography, dynamic contrast material-enhanced perfusion MR imaging, and MR spectroscopy. RESULTS: In seven patients, there were hyperintense abnormalities on diffusion-weighted and T2-weighted images in the hippocampus and cerebral cortex, sparing the subcortical white matter and cerebellum. Three patients had abnormalities of the splenium of the corpus callosum, and one had widespread involvement, including the caudate nucleus, basal ganglia, and internal capsule bilaterally. In three patients, unilateral cortical involvement, which did not conform to the typical cerebral arterial territories, was noted. In one patient, perfusion MR imaging showed slightly increased relative cerebral blood volume, and MR spectroscopy revealed no evidence of abnormal lactate in the affected cerebral cortex. CONCLUSION: Diffusion-weighted MR imaging findings in patients with severe hypoglycemia showed typical lesions in the hippocampus and cerebral cortex, but the caudate nucleus and basal ganglia were involved in only the most severely affected patient. The splenium of the corpus callosum and internal capsule were also abnormal in three patients, and unilateral cortical lesions could be distinguished from acute ischemic stroke by the pattern of involvement and MR angiographic, perfusion, and spectroscopic findings.
Assuntos
Encéfalo/efeitos dos fármacos , Imagem de Difusão por Ressonância Magnética , Contaminação de Medicamentos , Glibureto/toxicidade , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/toxicidade , Drogas Ilícitas/toxicidade , Processamento de Imagem Assistida por Computador , Angiografia por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Fitoterapia , Piperazinas/toxicidade , Sulfonas/toxicidade , Vasodilatadores/toxicidade , Adulto , Idoso , Volume Sanguíneo/efeitos dos fármacos , Encéfalo/patologia , Transtornos Cerebrovasculares/induzido quimicamente , Transtornos Cerebrovasculares/diagnóstico , Coma/induzido quimicamente , Coma/diagnóstico , Transtornos da Consciência/induzido quimicamente , Transtornos da Consciência/diagnóstico , Dominância Cerebral/fisiologia , Escala de Coma de Glasgow , Humanos , Hipoglicemia/diagnóstico , Ácido Láctico/metabolismo , Masculino , Pessoa de Meia-Idade , Purinas/toxicidade , Estudos Retrospectivos , Convulsões/induzido quimicamente , Convulsões/diagnóstico , Citrato de SildenafilaRESUMO
A risk management plan (RMP) contains an overview of important safety concerns associated with the use of a therapeutic product (TP) and proposed pharmacovigilance activities to monitor and manage these safety concerns in the post-approval stage. The Health Sciences Authority (HSA) of Singapore has legislated its requirements for RMPs as part of its product life cycle approach in the management of safety concerns associated with TPs. Under the Health Product (Therapeutic Products) Regulations enacted in November 2016, companies may be required to implement RMPs under the direction of HSA to help ensure that the benefits of TPs outweigh their risks. In this commentary, we present a case study on the local RMP for Dengvaxia®, the world's first dengue vaccine, which has been approved for use in Singapore. We hope that this article raises awareness among healthcare professionals about the concept of RMPs and how RMPs are implemented locally.
Assuntos
Vacinas contra Dengue/uso terapêutico , Dengue/prevenção & controle , Gestão de Riscos/métodos , Adolescente , Adulto , Criança , Pessoal de Saúde , Humanos , Pessoa de Meia-Idade , Segurança do Paciente , Farmacovigilância , Medição de Risco , Singapura/epidemiologiaRESUMO
The objective of this study is to collate and analyse adverse event reports associated with the use of complementary health products (CHP) submitted to the Health Sciences Authority (HSA) of Singapore for the period 2010-2016 to identify various trends and signals for pharmacovigilance purposes. A total of 147,215 adverse event reports suspected to be associated with pharmaceutical products and CHP were received by HSA between 2010 and 2016. Of these, 143,191 (97.3%) were associated with chemical drugs, 1,807 (1.2%) with vaccines, 1,324 (0.9%) with biological drugs (biologics), and 893 (0.6%) with CHP. The number of adverse event reports associated with Chinese Proprietary Medicine, other complementary medicine and health supplements are presented. Eight hundred and ninety three adverse event reports associated with CHP in the 7-year period have been successfully collated and analyzed. In agreement with other studies, adverse events related to the "skin and appendages disorders" were the most commonly reported. Most of the cases involved dermal allergies (e.g., rashes) associated with the use of glucosamine products and most of the adulterated products were associated with the illegal addition of undeclared drugs for pain relief. Dexamethasone, chlorpheniramine, and piroxicam were the most common adulterants detected. Reporting suspected adverse events is strongly encouraged even if the causality is not confirmed because any signs of clustering will allow rapid regulatory actions to be taken. The findings from this study help to create greater awareness on the health risks, albeit low, when consuming CHP and dispelling the common misconception that "natural" means "safe." In particular, healthcare professionals and the general public should be aware of potential adulteration of CHP. The analysis of spontaneously reported adverse events is an important surveillance system in monitoring the safety of CHP and helps in the understanding of the risk associated with the use of such products. Greater collaboration and communication between healthcare professionals, regulators, patients, manufacturers, researchers, and the general public are important to ensure the quality and safety of CHP.
Assuntos
Contaminação de Medicamentos , Disfunção Erétil/tratamento farmacológico , Glibureto/efeitos adversos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Drogas Ilícitas/efeitos adversos , Extratos Vegetais/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Carbolinas/química , Cromatografia Líquida de Alta Pressão , Surtos de Doenças , Glibureto/isolamento & purificação , Humanos , Hipoglicemia/epidemiologia , Hipoglicemiantes/isolamento & purificação , Masculino , Pessoa de Meia-Idade , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/isolamento & purificação , Piperazinas/isolamento & purificação , Extratos Vegetais/efeitos adversos , Purinas/isolamento & purificação , Citrato de Sildenafila , Singapura/epidemiologia , Sulfonas/isolamento & purificação , Tadalafila , Adulto JovemRESUMO
OBJECTIVE: To evaluate the specific contact lens-related or other factors that may contribute to the outbreak of Fusarium keratitis. METHODS: A case-control study was conducted of Fusarium keratitis in contact lens users in Singapore from March 1, 2005, to May 31, 2006, and included 61 patients with Fusarium keratitis and 188 population-based and 179 hospital-based control subjects. Interviewers asked about contact lens solution use and other risk factors. RESULTS: Patients with Fusarium keratitis were more likely to use ReNu contact lens solutions (Bausch & Lomb, Rochester, NY) 58 [95.1%] of 61 cases) than were either population-based (62 [34.3%] of 181) or hospital-based (50 [30.1%] of 166) control subjects. After controlling for age, sex, contact lens hygiene, and other factors, the use of ReNu with MoistureLoc significantly increased the risk of Fusarium keratitis (odds ratio, 99.3; 95% confidence interval, 18.4-535.4; P<.001), and the risk was 5 times higher compared with the risk with use of ReNu MultiPlus, a multipurpose solution (odds ratio, 21.5; 95% confidence interval, 4.0-115.5; P<.001). CONCLUSIONS: The use of ReNu contact lens solutions significantly increased the risk of contact lens-related Fusarium keratitis in Singapore. Our data support the recall of ReNu MultiPlus from the Singapore market and the need for further investigations into the role of ReNu MultiPlus in the development of Fusarium keratitis in other populations.
Assuntos
Lentes de Contato/efeitos adversos , Úlcera da Córnea/etiologia , Fusarium/isolamento & purificação , Micoses/etiologia , Adolescente , Adulto , Estudos de Casos e Controles , Soluções para Lentes de Contato/efeitos adversos , Desinfecção/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Singapura/epidemiologiaRESUMO
INTRODUCTION: Most Countries have pharmacovigilance (PV) systems in place to monitor the safe use of health products. The process involves the detection and assessment of safety issues from various sources of information, communicating the risk to stakeholders and taking other relevant risk minimization measures. OBJECTIVES: This study aimed to assess the PV status in Association of Southeast Asian Nation (ASEAN) countries, sources for postmarket safety monitoring, methods used for signal detection and the need for a quantitative signal detection algorithm (QSDA). Comparisons were conducted with centres outside ASEAN. METHODS: A questionnaire was sent to all PV centres in ASEAN countries, as well as seven other countries, from November 2015 to June 2016. The questionnaire was designed to collect information on the status of PV, with a focus on the use of a QSDA. RESULTS: Data were collected from nine ASEAN countries and seven other countries. PV activities were conducted in all these countries, which were at different stages of development. In terms of adverse drug reaction (ADR) reports, the average number received per year ranged from 3 to 50,000 reports for ASEAN countries and from 7000 to 1,103,200 for non-ASEAN countries. Thirty-three percent of ASEAN countries utilized statistical methods to help detect signals from ADR reports compared with 100% in the other non-ASEAN countries. Eighty percent agreed that the development of a QSDA would help in drug signal detection. The main limitation identified was the lack of knowledge and/or lack of resources. CONCLUSION: Spontaneous ADR reports from healthcare professionals remains the most frequently used source for safety monitoring. The traditional method of case-by-case review of ADR reports prevailed for signal detection in ASEAN countries. As the reports continue to grow, the development of a QSDA would be useful in helping detect safety signals.
Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Algoritmos , Povo Asiático , Pessoal de Saúde , Humanos , Farmacovigilância , Inquéritos e QuestionáriosRESUMO
INTRODUCTION: The ability to detect safety concerns from spontaneous adverse drug reaction reports in a timely and efficient manner remains important in public health. OBJECTIVE: This paper explores the behaviour of the Sequential Probability Ratio Test (SPRT) and ability to detect signals of disproportionate reporting (SDRs) in the Singapore context. METHODS: We used SPRT with a combination of two hypothesised relative risks (hRRs) of 2 and 4.1 to detect signals of both common and rare adverse events in our small database. We compared SPRT with other methods in terms of number of signals detected and whether labelled adverse drug reactions were detected or the reaction terms were considered serious. The other methods used were reporting odds ratio (ROR), Bayesian Confidence Propagation Neural Network (BCPNN) and Gamma Poisson Shrinker (GPS). RESULTS: The SPRT produced 2187 signals in common with all methods, 268 unique signals, and 70 signals in common with at least one other method, and did not produce signals in 178 cases where two other methods detected them, and there were 403 signals unique to one of the other methods. In terms of sensitivity, ROR performed better than other methods, but the SPRT method found more new signals. The performances of the methods were similar for negative predictive value and specificity. CONCLUSIONS: Using a combination of hRRs for SPRT could be a useful screening tool for regulatory agencies, and more detailed investigation of the medical utility of the system is merited.
Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Bases de Dados Factuais/estatística & dados numéricos , Probabilidade , Teorema de Bayes , Humanos , Razão de Chances , Medição de Risco , Índice de Gravidade de Doença , SingapuraRESUMO
The Health Sciences Authority launched a pharmacogenetics initiative in 2008 to facilitate evaluation of pharmacogenetics associations pertinent for Chinese, Malays and Indians in Singapore. The aim was to reduce the incidence and unpredictability of serious adverse drug reactions, with a focus on serious skin adverse drug reactions. This paper describes the gathering of evidence and weighing of factors that led to different genotyping recommendations for HLA-B*15:02 with carbamazepine and HLA-B*58:01 with allopurinol, despite both having strong genetic associations. Translation of pharmacogenomics at a national level requires careful deliberation of the prevalence of at-risk allele, strength of genetic associations, positive predictive value, cost-effectiveness and availability of alternative therapies. Our experience provides a perspective on translating genomic discoveries in advancing drug safety.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Dermatopatias/induzido quimicamente , Pele/efeitos dos fármacos , Alelos , Alopurinol/efeitos adversos , Carbamazepina/efeitos adversos , Análise Custo-Benefício/métodos , Antígenos HLA-B/genética , Humanos , Farmacogenética/métodos , Singapura , Dermatopatias/genéticaRESUMO
OBJECTIVES: Quantitative data mining methods can be used to identify potential signals of unexpected relationships between drug and adverse event (AE). This study aims to compare and explore the use of three data mining methods in our small spontaneous AE database. METHODS: We consider reporting odds ratio (ROR), Bayesian Confidence Propagation Neural Network (BCPNN) and Gamma Poisson Shrinker (GPS) assuming two different sets of criteria: (1) ROR-1.96SE>1, IC-1.96SD>0, EB05>1 (2) ROR-1.96SE>2, IC-1.96SD>1, EB05 >2. Count of drug-AE pairs ≥3 was considered for ROR and GPS. RESULTS: The Health Sciences Authority, Singapore received 151,180 AE reports between 1993 and 2013. ROR, BCPNN and GPS identified 2,835, 2,311 and 2,374 significant drug-AE pairs using Criterion 1, and 1,899, 1,101 and 1,358 respectively using Criterion 2. The performance of the three methods with respect to specificity, positive predictive value and negative predictive value were similar, although ROR yielded a higher sensitivity and larger area under the receiver operating characteristic curve. ROR and GPS picked up some potential signals which BCPNN missed. CONCLUSIONS: The defined threshold used for ROR (Criterion 1) is a useful screening tool for our small database. It may be used in conjunction with GPS to avoid missed signals.
Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Mineração de Dados/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Teorema de Bayes , Bases de Dados Factuais , Humanos , Singapura/epidemiologiaRESUMO
α and ß asarones are natural constituents of some aromatic plants, especially species of the genus Acorus (Araceae). In addition to reports of beneficial properties of asarones, genotoxicity and carcinogenicity are also reported. Due to potential toxic effects of ß-asarone, a limit of exposure from herbal products of ~2 µg/kg body weight/day has been set temporarily until a full benefit/risk assessment has been carried out by the European Medicines Agency. Therefore, it is important to monitor levels of ß-asarone in herbal products. In this study, we developed a simple, rapid and validated GC-MS method for quantitative determination of asarones and applied it in 20 pediatric herbal products after detecting high concentrations of ß-asarone in a product suspected to be implicated in hepatotoxicity in a 3 month old infant. Furthermore, targeted toxicological effects were further investigated in human hepatocytes (THLE-2 cells) by employing various in vitro assays, with the goal of elucidating possible mechanisms for the observed toxicity. Results showed that some of the products contained as much as 4-25 times greater amounts of ß-asarone than the recommended levels. In 4 of 10 samples found to contain asarones, the presence of asarones could not be linked to the labeled ingredients, possibly due to poor quality control. Cell-based investigations in THLE-2 cells confirmed the cytotoxicity of ß-asarone (IC50 = 40.0 ± 2.0 µg/mL) which was associated with significant lipid peroxidation and glutathione depletion. This observed cytotoxic effect is likely due to induction of oxidative stress by asarones. Overall, the results of this study ascertained the usability of this GC-MS method for the quantitative determination of asarones from herbal products, and shed light on the importance of controlling the concentration of potentially toxic asarones in herbal products to safeguard consumer safety, especially when the target consumers are young children. Further investigations of the toxicity of asarones are warranted.
RESUMO
Orlistat (tetrahydrolipostatin) is a lipase inhibitor which is used, in conjunction with appropriate dietary control, for the treatment of obesity. It is generally deemed to be a safe drug, which mainly exerts a topical action on the stomach and small bowel, with negligible systemic absorption and oral bioavailability. Consequently, its adverse effects have largely been limited to relatively mild gastrointestinal disorders. However, there have been recent, published reports of non-fatal acute hepatitis and systemic hypertension associated with its use. The present case concerns a 62-year-old male who died from massive hepatocellular necrosis, consistent with drug-induced, fulminant hepatitis, associated with the use of oral orlistat, presumably administered at the recommended daily dose of 360 mg. It is postulated that this may represent a rare idiosyncratic reaction to the drug.
Assuntos
Fármacos Antiobesidade/efeitos adversos , Lactonas/efeitos adversos , Falência Hepática/induzido quimicamente , Fármacos Antiobesidade/metabolismo , Fármacos Antiobesidade/uso terapêutico , Evolução Fatal , Humanos , Lactonas/metabolismo , Lactonas/uso terapêutico , Falência Hepática/patologia , Masculino , Pessoa de Meia-Idade , Necrose , OrlistateRESUMO
A 42-year-old female developed fulminant hepatic failure after having ingested an undetermined quantity of a herbal product over a period of approximately four months prior to the onset of her illness. Clinically, the cause of liver failure was assessed to be drug-induced and she eventually underwent total hepatectomy, with porto-caval shunting, in anticipation of a living-unrelated liver transplant. Unfortunately, her condition deteriorated and she died less than 48 hours post-operatively, approximately three weeks post-admission. An autopsy showed that the subject was deeply jaundiced and severely obese (BMI: 47.1 kg m(-2)), with evidence of diffuse haemorrhage, including the presence of 1.35 l of blood in the peritoneal cavity. The liver had been removed and was later recovered as a formalin-fixed specimen which was markedly contracted, comprising multiple micronodules interspersed with extensive areas of dense fibrotic tissue. Histologically, there was massive necrosis of the hepatic parenchyma, such that the residual hepatocytes were disposed as nodules displaying variable cellular regeneration and ballooning degeneration, attended by florid ductal proliferation and mixed inflammatory infiltrates. Infective, autoimmune, metabolic, vascular, neoplastic and most other natural causes of massive hepatocellular necrosis were effectively excluded. Analysis of the post-mortem blood samples yielded fluconazole, metronidazole, frusemide, lignocaine and tramadol, (therapeutic agents administered to the patient during her last illness). Subsequent analysis of the residual capsules revealed that they were adulterated by fenfluramine, N-nitrosofenfluramine (1.3-1.6 mg per capsule), nicotinamide (13.3-15.6 mg per capsule) and thyroid extract. None of the herbal ingredients is currently known to be hepatotoxic and much the same applies to fenfluramine, nicotinamide (except when taken in mega-doses) and thyroid extract. However, as nitrosamines are known to be variably hepatotoxic, it would be reasonable to surmise that, in the absence of a more plausible cause of liver damage, N-nitrosofenfluramine was the likely cause of massive hepatocellular necrosis in this instance.