Clinical features associated with ADB-BUTINACA exposure in patients attending emergency departments in England.

OBJECTIVE: Synthetic cannabinoid receptor agonists (SCRA) are commonly encountered new psychoactive substances. Here we report the recent detection of ADB-BUTINACA in samples from patients attending United Kingdom emergency departments with toxicity after suspected drug misuse and describe the associated clinical features. METHODS: Consenting adults (≥16 y) presenting to participating hospitals with toxicity after suspected drug misuse have been included in the Identification Of Novel psychoActive substances (IONA) study since March 2015. Demographic and clinical features are recorded and blood and/or urine samples analysed using high-resolution accurate mass liquid chromatography-mass spectrometry. RESULTS: By December 2021, analytical data were available for 1279 IONA participants and ADB-BUTINACA was detected in at least one sample from 10 (9 males, age range 16-51 median 45 years), all presenting since February 2021. Smoking 'spice' was reported by four patients, two had ingested edible "cannabis" gums and four reported heroin use (2 intravenous, 1 smoked, 1 route not known). Co-use of pregabalin (oral) and crack cocaine (smoked) were also reported. In 3 cases ADB-BUTINACA was the only substance detected, while in seven other substances of misuse were also detected including other SCRA, opioids, benzodiazepines cocaine and pregabalin. Clinical features reported in these 2 groups respectively included reduced level of consciousness (3/3, 6/7), agitation (0/3, 4/7), tachycardia (0/3, 3/7), seizures (1/3, 1/7), hallucinations (1/3, 1/7), hypotension (1/3, 1/7). Metabolic acidosis (1/3, 0/7) and respiratory acidosis (1/3, 0/7), All 10 patients recovered with supportive care, including intubation and ventilation for one case. The median length of hospital stay was 19 h (range 2.6-131 h). CONCLUSIONS: ADB-BUTINACA has recently emerged as a drug of misuse in England. Clinical features of toxicity are consistent with those of other SCRA and include reduced level of consciousness, respiratory and/or metabolic acidosis, seizures, confusion and hallucinations.

Toxicoepidemiology and predictors of death in 2,4-dinitrophenol (DNP) toxicity.

INTRODUCTION: 2,4-Dinitrophenol (DNP) is a highly toxic industrial chemical that is sometimes misused to reduce body fat. Toxicity following ingestion of DNP has recently become more common in the United Kingdom. This research was performed to document the frequency of DNP toxicity as reported to poisons centres in the United States (US) and United Kingdom (UK) and to identify the clinical features associated with fatality. METHODS: Calls to UK and US poisons centres involving systemic exposure to DNP were extracted for the 12 calendar years 2007-2018. These were analysed using univariate and multivariate statistical techniques. RESULTS: There were 204 cases (n = 86, US; n = 118, UK) of systemic DNP exposure identified, of which 86% were under the age of 40 and 71% were males. Over the study period the incidence of reported DNP toxicity was higher in the United Kingdom than the United States (1.78 vs. 0.26 cases per million population) and annual case numbers have increased in both countries since 2011. Case fatality was high and did not differ significantly between countries (US 11.6%; 95% CI: 6.4-20.1%: UK 16.9%; 95% CI: 11.3-24.7%; X2(1) = 1.12, p = 0.29). Univariate analysis demonstrated significant associations between risk of death and the presence of hypoglycaemia (OR = 17.1, 95% CI 1.7-174.3), hypertonia (OR = 12.9, 95% CI 3.5-47.6), acidosis (OR = 12.5, 95% CI 4.8-32.9), raised lactate (OR = 8.3, 95% CI 2.4-28.4), hyperpyrexia (OR = 6.5, 95% CI 2.8-15.2), tachycardia (OR = 6.4, 95% CI 2.5-16.4), agitation or confusion (OR = 6.0, 95% CI 2.6-13.7), hypertension (OR = 5.6, 95% CI 1.9-16.4) and tachypnoea/dyspnoea (OR = 2.8, 95% CI 1.2-6.1). After backwards stepwise logistic regression, the following were retained as significant independent predictors of mortality: acidosis (OR = 5.4, 95% CI: 1.8 - 16.5), tachycardia (OR = 3.6, 95% CI: 1.2 - 11.0), agitation/confusion (OR = 3.4, 95% CI: 1.2 - 9.7) and hyperpyrexia (OR = 2.8, 95% CI: 1.0 - 7.4). DISCUSSION: DNP toxicity is uncommonly reported to poisons centres but has recently become more frequent in the United States and United Kingdom. Tachycardia, hyperpyrexia, acidosis, and agitation/confusion are independent risk factors for mortality and their presence should prompt rapid escalation to an intensive care environment for aggressive supportive treatment and monitoring.

Effect of the UK Psychoactive Substances Act 2016 on episodes of toxicity related to new psychoactive substances as reported to the National Poisons Information Service. A time series analysis.

BACKGROUND: There have been recent increases in use of new psychoactive substances (NPS) associated with acute health harms including hospital presentations due to toxicity and increasing numbers of deaths. In response, the UK Government enacted generic legislation on 26th May 2016 (the Psychoactive Substances Act) making it an offence to produce, possess with intent to supply, supply, import or export, or possess within a custodial setting a psychoactive substance. We studied the impact of this Act on monthly frequency of enquiries made by health professionals to the UK National Poisons Information Service (NPIS) about NPS. We also studied five commonly used 'conventional' drugs of misuse that had been controlled prior to January 2009. METHOD: Anonymised clinical enquiries to the NPIS and accesses to the poisons information database TOXBASE were reviewed retrospectively from January 2009 to December 2018 to ascertain the trends in reported toxicity for NPS, cocaine, heroin, cannabis, amphetamines and MDMA. Data were analysed using interrupted time series analysis with the date of the PSA used as an independent predictor. RESULTS: Over the period of study there were 3,866 NPIS telephone enquiries and 79,271 TOXBASE user accesses made by UK health professionals concerning NPS. There were increases in monthly TOXBASE accesses (t = 7.408, P < 0.0001) and telephone enquiries (t = 4.74, P < 0.001) over the pre-specified period January 2009 to May 2016. Comparing the period after the PSA with that before, there were significant reductions in TOXBASE accesses (t = -3.327, P < 0.001) and telephone enquiries (t = -6.97, P < 0.001), although reductions started before May 2016. There were no significant changes for the five conventional drugs. There were significant reductions in telephone enquiries (t = -3.418, P < 0.001) and non-significant reductions in TOXBASE accesses (t = -1.713, P = 0.089) for NPS between June 2016 and December 2018. Increases in telephone enquiries for cocaine and reductions TOXBASE accesses for MDMA were also observed over that period. CONCLUSIONS: There have been significant recent reductions in NPIS enquiry activity relating to NPS; although these began before enactment of the PSA in May 2016.

Synthetic cannabinoid receptor agonists: classification and nomenclature.

Introduction: The emergence of novel psychoactive substances has changed the epidemiology of drugs used recreationally throughout Europe and have posed significant challenges for clinicians, researchers and regulators. Synthetic cannabinoid receptor agonists have made up a large proportion of these novel psychoactive substances. Developed for legitimate scientific research, synthetic cannabinoid receptor agonists are potent agonists at CB1 and CB2 receptors and there have been many case reports of severe or fatal toxicity following their recreational use. At least 180 analytically confirmed compounds belonging to this group of drugs have been reported in Europe as of January 2019. Synthetic cannabinoid receptor agonists have a complex molecular structure, consisting of four pharmacophore components termed the 'core', 'tail', 'linker' and 'linked' groups. This structural complexity offers multiple opportunities for chemical modification to evade drug control legislation based on chemical structure, and this explains the large numbers of individual products that have been detected.Objectives: To discuss the chemical structure of synthetic cannabinoid receptor agonists and to describe the different nomenclature used to identify individual compounds thereby increasing understanding of their chemical heterogenicity and the potential relevance of their molecular structure to the risk of toxicity.Methods: The European Database on New Drugs (EDND) and EMCDDA-Europol annual implementation reports (2010-2017) was searched for compounds with known agonist activity at CB1 and/or CB2 receptors. Information on the different names and chemical structures of each compound was extracted and analysed for patterns. PUBMED, Google Scholar and MEDLINE databases were searched, in addition to non-peer reviewed sources, for data on structure, structure-activity relationships and nomenclatures for each compound.Nomenclature of synthetic cannabinoid receptor agonists: The structural complexity of synthetic cannabinoid receptor agonists presents challenges for nomenclature. There are several nomenclature systems in use.Colloquial and clandestine names: Non-scientific names (e.g. AKB-48, 2NEI, XLR-11) have been used to refer to specific compounds and most have probably been invented by vendors, presumably for the purpose of successful marketing of recreational products, however such names do not convey useful information about structure.Systematic chemical names: Each compound has a systematic chemical name that describes its exact structure; however, it is complex, unwieldy, inaccessible to non-chemists and not suitable for routine communication or clinical use.Serial names: Represent iterative designations assigned to compounds produced as a series in a laboratory (e.g. 'WIN-', 'HU-', 'CP-', 'JWH-' and 'AM-'). This nomenclature does not provide structural information or reflect structural similarities between compounds.Systematic abbreviated names: Succinctly describe each compound utilising structural pharmacophores. The chemical motif in each pharmacophore group is assigned a unique code-letter and assembled into a name with the format of 'Linked Group - TailCoreLinker'. Frequently encountered groups include indole and indazole cores, amino-acid-like like groups, most notably methyl-3,3-dimethylbutanoate (MDMB), methanone linker groups and pentyl, 5-fluoropentyl and 4-fluorobenzyl tails. There has been inconsistent usage of this nomenclature, likely due to a lack of consensus and identification of code-letters for several chemical motifs.Emerging compounds and practices: Tricyclic carbazole and γ-carbolinone core analogues have been identified and may represent the next significant structural analogues to emerge onto the recreational market. There is a need to establish basic pharmacological and toxicological data for these analogues.Conclusions: There is a need for international consensus on the nomenclature used to name synthetic cannabinoid receptor agonists to ensure precise and effective communication between professional groups in the clinic and for the purposes of research and regulation, especially with the emergence of analogues of existing compounds and novel structural motifs. A well-defined nomenclature system also supports quick and accurate communication of the structure-activity of these compounds, potentially highlighting compounds that carry a significant risk of toxicity.

Pregnancy outcomes following maternal venlafaxine use: A prospective observational comparative cohort study.

BACKGROUND: Venlafaxine is a serotonin noradrenaline reuptake inhibitor used to treat major depressive episodes and anxiety disorders. The primary aim of this study was to investigate spontaneous abortion risks following gestational exposure. METHODS: This prospective observational comparative cohort study utilised data collected by the UK Teratology Information Service (UKTIS) between 1995 and 2018. The study sample included 281 venlafaxine exposed pregnancies matched to antidepressant unexposed (n = 1405) and SSRI exposed (n = 843) comparator groups. RESULTS: After correction for variation in competing outcome rates and the stage of pregnancy at reporting, no statistically significant differences in the hazard of spontaneous abortion was observed following gestational venlafaxine use compared with either antidepressant unexposed (HR 1.28, 95% CI; 0.850-1.94) or SSRI exposed (HR 1.03, 95% CI; 0.681-1.57) pregnancies. CONCLUSIONS: No conclusive evidence is provided from this study that venlafaxine increases the risk of adverse pregnancy or fetal outcomes.

Sensitivity of the UK Clinical Practice Research Datalink to Detect Neurodevelopmental Effects of Medicine Exposure in Utero: Comparative Analysis of an Antiepileptic Drug-Exposed Cohort.

INTRODUCTION: Electronic healthcare data have several advantages over prospective observational studies, but the sensitivity of data on neurodevelopmental outcomes and its comparability with data generated through other methodologies is unknown. OBJECTIVES: The objectives of this study were to determine whether data from the UK Clinical Practice Research Datalink (CPRD) produces similar risk estimates to a prospective cohort study in relation to the risk of neurodevelopmental disorders (NDDs) following prenatal antiepileptic drug (AED) exposure. METHODS: A cohort of mother-child pairs of women with epilepsy (WWE) was identified in the CPRD and matched to a cohort without epilepsy. The study period ran from 1 January 2000 to 31 March 2007 and children were required to be in the CPRD at age 6 years. AED exposure during pregnancy was determined from prescription data and children with an NDD diagnosis by 6 years were identified from Read clinical codes. The prevalence and risk of NDDs was calculated for mother-child pairs in WWE stratified by AED regimen and for those without epilepsy. Comparisons were made with the results of the prospective Liverpool and Manchester Neurodevelopment Group study which completed assessment on 201 WWE and 214 without epilepsy at age 6 years. RESULTS: In the CPRD, 1018 mother-child pairs to WWE and 6048 to women without epilepsy were identified. The CPRD identified a lower prevalence of NDDs than the prospective study. In both studies, NDDs were more frequently reported in children of WWE than women without epilepsy, although the CPRD risk estimate was lower (2.16 vs. 0.96%, p < 0.001 and 7.46 vs. 1.87%, p = 0.0128). NDD prevalence differed across AED regimens but the CPRD data did not replicate the significantly higher risk of NDDs following in utero monotherapy valproate exposure (adjusted odds ratio [ORadj] 2.02, 95% confidence interval [CI] 0.52-7.86) observed in the prospective study (ORadj 6.05, 95% CI 1.65-24.53). CONCLUSION: It was possible to identify NDDs in the CPRD; however, the CPRD appears to under-record these outcomes. Larger studies are required to investigate further.

Pregnancy outcomes after maternal varenicline use; analysis of surveillance data collected by the European Network of Teratology Information Services.

Varenicline is a smoking cessation aid for which limited data exist concerning safety during human pregnancy. This multicentre prospective observational comparative cohort study was undertaken using surveillance data collected by the European Network of Teratology Information Services. The study sample consisted of 89 varenicline exposed pregnancies and two matched comparator groups; 267 non-teratogen exposed (NTE) controls and 78 exposed to nicotine replacement therapy or bupropion (NRT/B) for smoking cessation. For all exposed pregnancies, varenicline use only occurred in the first trimester, with a considerable proportion discontinuing use in the very early stages of pregnancy. The major congenital malformation rate (n=2/89, 2.25%) was in keeping with the expected background rate (2-4%), and was not significantly increased for first trimester varenicline-exposed infants in comparison with non-exposed controls (vs. NTE: OR 2.02, 95%CI 0.166 to 17.9, vs. NRT/B: OR 0.874, 95%CI 0.0620 to 12.3). However, the small sample size produced very imprecise risk estimates.

Impact of reducing the threshold for acetylcysteine treatment in acute paracetamol poisoning: the recent United Kingdom experience.

BACKGROUND: On 3 September 2012, the licensed indication for acetylcysteine was changed in the United Kingdom (UK) so that all patients with a plasma paracetamol concentration above a "100 mg/L" (4 h post ingestion) nomogram treatment line after an acute paracetamol (acetaminophen) overdose should be treated. This is a lower threshold than that used in the United States, Canada, Australia, and New Zealand. Here we report the impact of this change in the UK on the management of patients with acute overdose in different paracetamol concentration ranges. METHODS: This is a cohort study, consisting of a retrospective analysis conducted on prospectively collected audit data in three UK hospitals. Following appropriate ethical and data protection authority approval, data for patients presenting within 24 h of an acute timed single paracetamol overdose were extracted. Numbers of admissions and use of antidote in relation to different paracetamol concentration bands (< 100 mg/L; 100-149 mg/L; 150-199 mg/L; and ≥ 200 mg/L at 4 h) were analyzed for one-year periods before and after the change. RESULTS: Comparing the year before with the year after the change, there was no change in the numbers of patients presenting to hospital within 24 h of acute timed paracetamol overdose (1246 before and 1251 after), but more patients were admitted (759 before and 849 after) and treated with acetylcysteine (389 before and 539 after). Of the 150 additional patients treated with acetylcysteine in the year following the change, 114 (76%, 95% CI: 68.4-82.6) were in the 100-149 group and 9 (6.0%, 95% CI: 2.8-11.1) in the 150-199 group. CONCLUSIONS: Changes to national guidelines for managing paracetamol poisoning in the UK have increased the numbers of patients with acute overdose treated with acetylcysteine, with most additional treatments occurring in patients in the 100-149 mg/L dose range, a group at low risk of hepatotoxicity and higher risk of adverse reactions.

Using poisons information service data to assess the acute harms associated with novel psychoactive substances.

Novel psychoactive substances (NPS) can cause significant acute toxicity but usually little is known about their toxicity when they enter the recreational drug scene. Current data sources include online user forums, user questionnaires, case reports/series, and deaths; however, these are limited by their focus on sub-populations and generally include severe cases and specific geographical areas. Approximately 54% of countries have at least one poisons information service (in 2012 there were 274 worldwide) providing advice to healthcare professionals and/or the public on poisoning. They provide advice on recreational drug and NPS toxicity. In 2012, 2.5% of telephone enquiries to the UK National Poisons Information Service and 2.4% of enquiries to US poisons centres related to recreational drugs. Data are collected at population level and can be used to complement other data sources with clinical details on acute NPS toxicity and geographical/time patterns of toxicity. Like other acute NPS toxicity data, poisons centre data should be interpreted within their limitations, notably the absence of analytical confirmation and reliance on secondary reporting of clinical features. This manuscript demonstrates the breadth and depth of poisons information service data in the literature with a focus on mephedrone and synthetic cannabinoid-receptor agonists. In our opinion it would be possible to develop a more robust and systematic reporting system using a network of poisons information services both within and across countries that would be complimentary to other datasets on acute NPS toxicity and allow more accurate data triangulation.

National toxicovigilance for pesticide exposures resulting in health care contact - An example from the UK's National Poisons Information Service.

BACKGROUND: Although there are extensive systems in place for pharmacovigilance, similar systems for detecting adverse health effects relating to pesticide exposure are rare. In 2004, the National Poisons Information Service (NPIS) pesticide surveillance study was implemented to identify cases requiring health care contact in the UK. This report describes the epidemiology of pesticide exposures reported to poison centres in the UK over a 9-year period. METHODS: Data on exposures were gathered through monitoring access to the NPIS's online clinical toxicology database TOXBASE(®) and through monitoring calls to the four NPIS units (Edinburgh, Cardiff, Newcastle and Birmingham). Severity was judged by both caller and NPIS staff. RESULTS: During the 9 years, 34,092 enquiries concerning pesticides were recorded; 7,804 cases of pesticide exposure were derived from these enquiries. Exposures were predominantly unintentional and acute (6,789; 87.0%); 217 (2.8%) and 755 (9.7%) were chronic unintentional and acute deliberate self-harm exposures, respectively. The majority of cases occurred in children, especially the 0-4 year age group The minimum incidence of pesticide exposure requiring health care contact was 2.0 cases/100,000 population per year. Reported numbers were 6- to 25-fold greater than those picked up through other UK pesticide toxicovigilance schemes. There were 81 cases of severe toxicity and 38 cases of fatal exposure. Deliberate self-harm accounted for 62.3% of severe cases and 79% of deaths. Aluminium phosphide, paraquat, diquat and glyphosate were responsible for most severe and fatal cases. CONCLUSIONS: The data gathered from this pesticide surveillance study indicate that poison centre resources can usefully monitor pesticide exposures resulting in health care contact in the UK. The NPIS may usefully be one component of the UK's response to European legislation requiring surveillance of complications resulting from pesticide use.

Pregnancy outcome following maternal use of zanamivir or oseltamivir during the 2009 influenza A/H1N1 pandemic: a national prospective surveillance study.

OBJECTIVE: To conduct enhanced surveillance for signals of teratogenesis following use of the neuraminidase inhibitors zanamivir and oseltamivir in the treatment or post-exposure prophylaxis of 2009 A/H1N1 influenza during pregnancy. DESIGN: Prospective cohort study, using national surveillance data collected by the UK Teratology Information Service (UKTIS) during the 2009 A/H1N1 pandemic. SETTING: United Kingdom. POPULATION: Pregnant women who were reported to UKTIS by healthcare professionals seeking advice about exposure to zanamivir and oseltamivir or to other non-teratogenic drugs. METHODS: Pregnancy outcomes were collected for prospectively reported pregnancies exposed to zanamivir (n = 180) or oseltamivir (n = 27), and compared with a reference group of 575 prospectively reported pregnancies exposed to non-teratogenic drugs over the same period. MAIN OUTCOME MEASURES: Rates of major congenital malformation, preterm delivery and low birth weight. RESULTS: No significant differences in overall rates of major malformation in live-born infants [adjusted odds ratios (aOR): zanamivir 0.37 (95% confidence interval 0.02-2.70); oseltamivir aOR 0.81 (0.05, 14.15)], preterm delivery [aOR: zanamivir 0.95 (0.45, 1.89); oseltamivir aOR 1.68 (0.38, 5.38)] or low birth weight [aOR: zanamivir 0.94 (0.25, 2.90); oseltamivir aOR 4.12 (0.59, 17.99)] were observed following exposure at any gestation. No major malformations were reported in 37 zanamivir or eight oseltamivir first trimester exposures. CONCLUSION: These surveillance data do not provide a signal that use of zanamivir or oseltamivir in pregnancy is associated with an increased risk of the adverse pregnancy outcomes studied but the data are too limited to state conclusively that there is no increase in risk.

Patterns of presentation and clinical toxicity after reported use of alpha methyltryptamine in the United Kingdom. A report from the UK National Poisons Information Service.

OBJECTIVE: To characterise the patterns of presentation, clinical effects and possible harms of acute toxicity following recreational use of alpha methyltryptamine (AMT) in the United Kingdom, as reported by health professionals to the National Poisons Information Service (NPIS) and to compare clinical effects with those reported after mephedrone use. METHODS: NPIS telephone enquiries and TOXBASE user sessions, the NPIS online information database, related to AMT were reviewed from March 2009 to September 2013. Telephone enquiry data were compared with those for mephedrone, the recreational substance most frequently reported to the NPIS, collected over the same period. RESULTS: There were 63 telephone enquiries regarding AMT during the period of study, with no telephone enquiries in 2009 or 2010, 19 in 2011, 35 in 2012 and 9 in 2013 (up to September). Most patients were male (68%) with a median age of 20 years. The route of exposure was ingestion in 55, insufflation in 4 and unknown in 4 cases. Excluding those reporting co-exposures, clinical effects recorded more frequently in AMT (n = 55) compared with those of mephedrone (n = 488) users including acute mental health disturbances (66% vs. 32%; Odds Ratio [OR], 4.00; 95% Confidence Intervals [CI], 2.22-7.19), stimulant effects (66% vs. 40%; OR, 2.82; 95% CI 1.57-5.06) and seizures (14% vs. 2%; OR, 9.35; 95% CI 3.26-24.18). CONCLUSIONS: Although still infrequent, toxicity following reported exposure to AMT has been encountered in the United Kingdom since January 2011. Stimulant features, acute mental health disturbances and seizures are more frequently reported than in those presenting following reported use of mephedrone.

Guidelines for laboratory analyses for poisoned patients in the United Kingdom.

To enable consistency of investigation and the establishment of best practice standards, consensus guidelines were formulated previously by the UK National Poisons Information Service and the Association for Clinical Biochemistry. These joint guidelines have now been updated to reflect current best practice. The types of laboratory investigation required for poisoned patients are categorized as either (a) essential common laboratory investigations or (b) specific toxicological assays, and also as either (i) common or (ii) specialist or infrequent. Tests in categories (a) and (bi) should be available 24 hours per day, with a maximum turnaround time of 2 h. For the specialist assays, i.e. category (bii), availability and turnaround times have been specified individually. The basis for selection of these times has been clinical utility. The adoption of these guidelines, along with the use of the National Poisons Information Service (0844 8920111) and its online poisons information resource TOXBASE(®) (www.toxbase.org) enable the poisoned patient to receive appropriate, 'best practice' investigations according to their clinical needs and will avoid unnecessary investigations.

Clinical characteristics of mephedrone toxicity reported to the U.K. National Poisons Information Service.

OBJECTIVE: To describe the patterns and clinical features of toxicity related to recreational use of mephedrone and other cathinones in the U.K. using data collected by the National Poisons Information Service (NPIS). METHODS: The number of accesses to TOXBASE, the NPIS online poisons information database, details of consecutive cases uploaded onto TOXBASE and the number and details of telephone enquiries made to the NPIS by health professionals in the U.K. were collected for the period March 2009 to February 2010. RESULTS: Over the year of study there were 2901 TOXBASE accesses and 188 telephone enquiries relating to cathinones, the majority relating to mephedrone (TOXBASE 1664, telephone 157), with a month-on-month increase in numbers. In 131 telephone enquiries concerning mephedrone, alone or in combination with alcohol, common clinical features reported included agitation or aggression (n=32, 24%, 95% CI 18% to 33%), tachycardia (n=29, 22%, 95% CI 16% to 30%), confusion or psychosis (n=18, 14%, 95% CI 9% to 21%), chest pain (n=17, 13%, 95% CI 8% to 20%), nausea (n=15, 11%, 95% CI 7% to 18%), palpitations (n=14, 11%, 95% CI 6% to 18%), peripheral vasoconstriction (n=10, 8%, 95% CI 4% to 14%) and headache (n=7, 5%, 95% CI 2% to 11%). Convulsions were reported in four cases (3%, 95% CI 1% to 8%). One exposed person died following cardiac arrest (1%, 95% CI 0% to 4%), although subsequent investigation suggested that mephedrone was not responsible. CONCLUSIONS: Toxicity associated with recreational mephedrone use is increasingly common in the UK. Sympathomimetic adverse effects are common and severe effects are also reported. Structured data collected by the NPIS may be of use in identifying trends in poisoning and in establishing toxidromes for new drugs of abuse.

Suicide attempts in a prospective cohort of patients with schizophrenia treated with sertindole or risperidone.

The incidence of suicide attempts (fatal and non-fatal) was analysed in a prospective cohort of patients with schizophrenia randomly assigned to sertindole (4905 patients) or risperidone (4904 patients) in a parallel-group open-label study with blinded classification of outcomes (the sertindole cohort prospective study--SCoP). The total exposure was 6978 and 7975 patient-years in the sertindole and risperidone groups, respectively. Suicide mortality in the study was low (0.21 and 0.28 per 100 patients per year with sertindole and risperidone, respectively). The majority (84%) of suicide attempts occurred within the first year of treatment. Cox's proportional hazards model analysis of the time to the first suicide attempt, reported by treating psychiatrists and blindly reviewed by an independent expert group according to the Columbia Classification Algorithm of Suicide Assessment (both defining suicide attempts by association of suicidal act and intent to die), showed a lower risk of suicide attempt for sertindole-treated patients than for risperidone-treated patients. The effect was statistically significant with both evaluation methods during the first year of randomized treatment (hazard ratios [95% CI]: 0.5 [0.31-0.82], p=0.006; and 0.57 [0.35-0.92], p=0.02, respectively). With classification by an independent safety committee using a broader definition including all incidences of intentional self-harm, also those without clear suicidal intent, the results were not significant. A history of previous suicide attempts was significantly associated with attempted suicides in both treatment groups.

Influenza A/H1N1v in pregnancy: an investigation of the characteristics and management of affected women and the relationship to pregnancy outcomes for mother and infant.

BACKGROUND: In April 2009 a novel influenza A virus (AH1N1v) of swine origin (swine flu) emerged, spreading rapidly and achieving pandemic status in June 2009. Pregnant women were identified as being at high risk of severe influenza-related complications and as a priority group for vaccination against AH1N1v. Limited information was available about the maternal and fetal risks of AH1N1v infection or of antiviral drug or AH1N1v vaccine use in pregnancy. OBJECTIVES: To assess rates of and risk factors for adverse outcomes following AH1N1v infection in pregnancy and to assess the adverse effects of the antiviral drugs and vaccines used in prevention and management. METHODS: Prospective national cohort studies were conducted to identify pregnant women who were (1) suspected to be infected with AH1N1v or being treated with antiviral medication in primary care; (2) vaccinated against AH1N1v; and (3) admitted to hospital with confirmed AH1N1v. Characteristics of women with influenza-like illness (ILI) in primary care were compared with those of women without symptoms accepting or declining immunisation. Characteristics of women admitted to hospital with confirmed AH1N1v infection in pregnancy were compared with a historical cohort of over 1200 women giving birth in the UK who were uninfected with AH1N1v. Outcomes examined in hospitalised women included maternal death, admission to an intensive care unit, perinatal mortality and preterm birth. Risk factors for hospital and intensive care unit admission were examined in a full regression model. RESULTS: The weekly incidence of ILI among pregnant women averaged 51/100,000 over the study period. Antiviral drugs were offered to 4.8% [95% confidence interval (CI) 4.0% to 5.9%] and vaccination to 64.8% (95% CI 64.7% to 68.9%) of registered pregnant women. Ninety pregnant women with ILI presenting in primary care were reported to the research team, 55 of whom were prescribed antiviral drugs and in 42 (76%) cases this was within 2 days of symptom onset. After comparison with 1329 uninfected pregnant women offered vaccination, pre-existing asthma was the only maternal factor identified as increasing risk of ILI presentation [adjusted odds ratio (OR) 2.0, 95% CI 1.0 to 3.9]. Maternal obesity and smoking during pregnancy were also associated with hospital admission with AH1N1v infection. Overall, 241 pregnant women were admitted to hospital with laboratory-confirmed AH1N1v infection. Eighty-three per cent of these women were treated with antiviral agents, but only 6% received antiviral treatment before hospital admission. Treatment within 2 days of symptom onset was associated with an 84% reduction in the odds of admission to an intensive therapy unit (OR 0.16, 95% CI 0.08 to 0.34). Women admitted to hospital with AH1N1v infection were more likely to deliver preterm; a three times increased risk was suggested compared with an uninfected population cohort (OR 3.1, 95% CI 2.1 to 4.5). CONCLUSIONS: Earlier treatment with antiviral agents is associated with improved outcomes for pregnant women and further actions are needed in future pandemics to ensure that antiviral agents and vaccines are provided promptly to pregnant women, particularly in the primary care setting. Further research is needed on longer-term outcomes for infants exposed to AH1N1v influenza, antiviral drugs or vaccines during pregnancy.

Electrocardiographic effects of methylphenidate overdose.

OBJECTIVES: Stimulants used in the management of attention-deficit hyperactivity disorder have been associated with an increased risk of sudden cardiac death. One mechanism could involve drug-induced repolarization delay, reflected as prolongation of the QT interval on the electrocardiogram, which has been described in some recipients of methylphenidate in therapeutic doses. Because QT prolongation is usually dose-related, this study was performed to investigate effects of methylphenidate overdose on the QT interval. METHODS: Adults with methylphenidate overdose identified retrospectively were matched for sex and heart rate with a control subject with overdose of a noncardiotoxic substance, mainly acetaminophen. Notes were reviewed for clinical details and coingestants. Admission 12-lead electrocardiograms were individually calibrated and analyzed using a manual digitizer in a blinded manner by a single investigator. Mean QRS and QT intervals were calculated and differences between groups were analyzed. RESULTS: Twenty-three cases of methylphenidate overdose (median reported dose 120 mg, range 40-1,500 mg) were identified (10 males, 13 females, mean age 27.8 years). There were multiple coingestants. Level of consciousness and mean hemodynamic variables were within normal limits for all cases. Symptoms recorded in cases included anxiety (32%), dilated pupils (20%), abdominal pain (16%), vomiting (12%), palpitations (12%), and chest pain (8%). No arrhythmias were recorded. Mean heart rate was 92.4/min in methylphenidate cases and 93.8/min in the heart rate-matched controls. There were no significant differences between the groups in mean QRS (cases 86.1, controls 86.2, mean difference 0.1, 95% confidence interval = -5.1 to 5.0 ms) or mean QT intervals (cases 354, controls 355, mean difference -0.8, 95% confidence interval = -10.7 to 9.2 ms). CONCLUSIONS: Methylphenidate overdose is unlikely to have substantial effects on the QRS or QT intervals.

Safety of sertindole versus risperidone in schizophrenia: principal results of the sertindole cohort prospective study (SCoP).

OBJECTIVE: To explore whether sertindole increases all-cause mortality or cardiac events requiring hospitalization, compared with risperidone. METHOD: Multinational randomized, open-label, parallel-group study, with blinded classification of outcomes, in 9858 patients with schizophrenia. RESULTS: After 14147 person-years, there was no effect of treatment on overall mortality (sertindole 64, risperidone 61 deaths, Hazard Ratio (HR) = 1.12 (90% CI: 0.83, 1.50)) or cardiac events requiring hospitalization [sertindole 10, risperidone 6, HR = 1.73 (95% CI: 0.63, 4.78)]: Of these, four were considered arrhythmia-related (three sertindole, one risperidone). Cardiac mortality was higher with sertindole (Independent Safety Committee (ISC): 31 vs. 12, HR=2.84 (95% CI: 1.45, 5.55), P = 0.0022; Investigators 17 vs. 8, HR=2.13 (95% CI: 0.91, 4.98), P = 0.081). There was no significant difference in completed suicide, but fewer sertindole recipients attempted suicide (ISC: 68 vs. 78, HR=0.93 (95% CI: 0.66, 1.29), P = 0.65; Investigators: 43 vs. 65, HR=0.67 (95% CI: 0.45, 0.99), P = 0.044). CONCLUSION: Sertindole did not increase all-cause mortality, but cardiac mortality was higher and suicide attempts may be lower with sertindole.

Factors affecting drug concentrations and QT interval during thioridazine therapy.

The objective of this study was to investigate factors affecting steady-state plasma concentrations of thioridazine. A cross-sectional study of patients receiving chronic thioridazine was employed. Common allelic variants of CYP2D6 and CYP2C19, as well as thioridazine and metabolite concentrations and QTc intervals, were determined. In 97 patients, dose-corrected plasma concentrations (C/Ds) of thioridazine and metabolites were correlated with age but not sex or CYP2C19 genotype. Patients with no functional CYP2D6 alleles (n=9) had significantly higher C/D for thioridazine (P=0.017) and the ring sulfoxide metabolite and a significantly higher thioridazine/mesoridazine ratio compared with those with >/=1 functional CYP2D6 allele (n=82). Smokers had significantly lower C/D for thioridazine, mesoridazine, and sulforidazine and significantly lower thioridazine/ring sulfoxide ratios than non-smokers. QTc interval was not significantly affected by CYP2D6 or CYP2C19 genotypes. Plasma concentrations of thioridazine are influenced by age, smoking, and CYP2D6 genotype, but CYP2D6 genotype does not appear to influence on-treatment QTc interval.