First reported case in the UK of acute prolonged neuropsychiatric toxicity associated with analytically confirmed recreational use of phenazepam.

PURPOSE: There is increasing evidence from around Europe of the availability and misuse of long-acting benzodiazepines such as phenazepam. There is little information on the acute toxicity of these compounds; we describe here a case of analytically confirmed phenazepam-related acute toxicity. CASE REPORT: A 42-year-old man with no previous medical or psychiatric history was brought to the Emergency Department by his friends because he had developed prolonged ongoing confusion and disorientation following use of up to three different "legal high" powders. There was no obvious medical cause for this acute confusion and disorientation. His symptoms continued for approximately 60 h after suspected use. Subsequent toxicological analysis of a serum sample confirmed use of phenazepam (concentration 0.49 mg/L); no other drugs were detected during an extensive analytical screening. CONCLUSION: This is the second case of analytically confirmed acute toxicity related to phenazepam in Europe. This adds to the scant published information on the acute toxicity of this drug, and will provide healthcare and legislative authorities with further information on which to base advice and consideration of the need for its control.

Methoxetamine associated reversible cerebellar toxicity: three cases with analytical confirmation.

CONTEXT: There have been recent concerns about increasing use and accessibility of methoxetamine, a ketamine derivative. Few data are available to describe the clinical features associated with methoxetamine exposure. We report three cases that presented to hospital with acute neurological toxicity associated with analytically confirmed methoxetamine exposure. CASE DETAILS: A 19-year-old male presented with severe truncal ataxia, nystagmus, incoordination and reduced conscious level several hours after nasal insufflation of what was initially thought to be ketamine. Features of cerebellar toxicity persisted for 3-4 days before gradual recovery. Two more patients aged 17 and 18 years presented with severe cerebellar ataxia, imbalance and reduced conscious level 40 minutes after nasal insufflation of methoxetamine (MXE). Both had slurred speech, incoordination and cerebellar ataxia that resolved within 24 hours. Serum methoxetamine concentrations were 0.24 mg/L, 0.45 mg/L and 0.16 mg/L, respectively, and no other drugs were identified on an extended toxicological screen. DISCUSSION: Methoxetamine may cause rapid onset of neurological impairment, characterised by acute cerebellar toxicity. Spontaneous recovery was observed, but the duration of recovery may extend to several days. Presentation with an acute cerebellar toxidrome should alert clinicians to the possibility of methoxetamine exposure.

Risk of caffeine toxicity associated with the use of 'legal highs' (novel psychoactive substances).

PURPOSE: Caffeine has desired stimulant effects similar to but weaker than both classical recreational drugs and novel psychoactive substances. This study was undertaken to determine the caffeine content of a sample of novel psychoactive substances, and we discuss the implications for the management of acute recreational drug toxicity. METHODS: Six novel psychoactive products ('legal highs') that were not declared to contain caffeine were purchased from different Internet suppliers; one additional product was supplied by the UK police force. Analysis of these products was undertaken using infrared spectroscopy (IR), gas chromatography with mass spectrometry (GC-MS) and liquid chromatography with tandem mass spectrometry (LC-MS-MS) to identify the active ingredient(s) and measure the caffeine content of the product. RESULTS: All seven products, which weighed approximately 1 g each, contained only caffeine as the active pharmacological compound. There was significant variation in the percentage caffeine content (<2 to 96%), with four powders containing very significant caffeine contents of 87-96%. CONCLUSION: This study shows that individuals are at risk of significant caffeine toxicity related to the high caffeine content of some novel psychoactive substances. Clinicians, including clinical pharmacologists, need to be aware of this to ensure that the management of acute recreational drug toxicity is appropriate and that over-correction of any hypokalaemia does not occur.

Acute toxicity associated with the recreational use of the ketamine derivative methoxetamine.

PURPOSE: Long-term regular use of ketamine has been reported to be associated with severe symptomatic urinary tract problems. Methoxetamine, an arylcyclohexylamine derivative of ketamine, is marketed as a "bladder safe" derivative of ketamine, and no cases of acute toxicity following analytically confirmed methoxetamine use have been reported to date. We report here a case series of three individuals with acute toxicity related to the analytically confirmed use of methoxetamine. CASE SERIES: Three patients aged between 28 and 42 years presented to the Emergency Department (ED) on unrelated occasions having used methoxetamine. Clinical features were suggestive of a "dissociative/catatonic" state similar to that seen with ketamine; in addition, they had clinical features of acute sympathomimetic toxicity with significant tachycardia and hypertension. All were managed with low-dose benzodiazepines and discharged home once their symptoms/signs had settled. TOXICOLOGICAL SCREENING: Serum collected at the time of presentation to the ED was analysed qualitatively and quantitatively by gas chromatography-mass spectrometry. Serum concentrations ranged from 0.09 to 0.2 mg/L; in addition, detectable levels of 6-APB/5-APB were found in one of the patients. CONCLUSIONS: These three analytically confirmed cases demonstrate that acute methoxetamine-related toxicity is associated with both "dissociative" and "sympathomimetic" clinical features. The information from these three cases is useful to clinical pharmacologists, not only in managing individuals with acute methoxetamine toxicity but also in advising the appropriate legislative authorities on the risk of acute harm related to methoxetamine use. Further work is needed to determine whether methoxetamine is more "bladder friendly" than ketamine, as has been suggested by those marketing methoxetamine.

Energy-1 ('NRG-1'): don't believe what the newspapers say about it being legal.

A 31-year-old man purchased the legal high Energy-1 (NRG-1) over the internet; this was advertised as containing the compound naphthylpyrovalerone (NPV), which at the time was currently legally available in the UK. He ingested 1 g of this substance and developed a prolonged high associated with palpitations, sweating and insomnia. Analysis of both the powder and serum samples from the patient demonstrated that he ingested two classified recreational drugs ß-keto-N-methylbenzodioxolylpropylamine (butylone) and methylenedioxypyrovalerone (MDPV) rather than the legal substance NPV. Users of legal highs need to be aware that legal highs purchased over the internet may contain illegal substances and therefore they may be liable for prosecution if found in possession of these substances. Future educational campaigns aimed at recreational drug and legal high users should include reference to the potential legal implications of buying these substances.

Mephedrone: use, subjective effects and health risks.

AIMS: To assess the patterns of use, subjective effect profile and dependence liability of mephedrone, supported by corroborative urine toxicology. DESIGN: Cross-sectional structured telephone interview. SETTING: UK-based drug users associated with the dance music scene. PARTICIPANTS: A total of 100 mephedrone users, recruited through their involvement with the dance music scene. MEASUREMENTS: Assessment of pattern of use, acute and after effects, DSM dependence criteria and gas chromatography-mass spectrometry urinalysis. FINDINGS: Mephedrone consumption results in typical stimulant-related subjective effects: euphoria, increased concentration, talkativeness, urge to move, empathy, jaw clenching, reduced appetite and insomnia. Thirty per cent of the sample potentially met criteria for DSM-IV dependence and there was evidence of a strong compulsion to use the drug (47% had used the drug for 2 or more consecutive days). Self-reported recent consumption of mephedrone was confirmed by toxicological analysis in all of the 14 participants who submitted a urine sample. CONCLUSION: Mephedrone has a high abuse and health risk liability, with increased tolerance, impaired control and a compulsion to use, the predominant reported dependence symptoms.

Variability in the 3,4-methylenedioxymethamphetamine content of 'ecstasy' tablets in the UK.

BACKGROUND: Toxicity, such as hyperpyrexia, associated with the use of 3,4-methylenedioxymethamphetamine (MDMA; 'ecstasy') appears to be related to serum MDMA concentrations. However, there does not appear to be a similar association with the number of tablets ingested, suggesting variation in the tablet content of MDMA. Although work has shown this variation in other areas of the world, no studies have reported on the variation of MDMA content in UK ecstasy tablets. METHODS: Ecstasy tablets seized from individuals attending nightclubs were analysed qualitatively to determine if they contained MDMA and quantitatively to determine the MDMA content per tablet. RESULTS: The mean amount of MDMA hydrochloride in 101 seized ecstasy tablets was 58.7±22.9 mg per tablet, with a range of 20 mg to 131 mg per tablet. The majority (96.0%) of tablets contained less than 100 mg MDMA per tablet. There appeared to be a bimodal distribution of MDMA content at approximately 20-40 mg per tablet and 60-80 mg per tablet. CONCLUSION: There is variability in the MDMA content of ecstasy tablets in the UK. This variability could potentially put users at increased risk of acute harm due to inadvertent excess ingestion of MDMA, as they are unaware of the differences in the MDMA content. Repeat sampling and quantification of MDMA content of ecstasy tablets in the UK will allow better education of users about the potential harms associated with the variability in the MDMA content. In addition, it will provide information to allow the monitoring of changes in not only the MDMA content, but also other adulterants, in ecstasy tablets.

Analysis of recreational drug samples obtained from patients presenting to a busy inner-city emergency department: a pilot study adding to knowledge on local recreational drug use.

INTRODUCTION: Routine toxicological screening is not undertaken in individuals presenting to emergency departments (ED) with acute recreational drug toxicity, because it does not usually alter an individual patient's management. Localised information on the types of recreational drugs being used is often not available. The pilot study described here looks at the analysis of presumed recreational drugs in the possession of individuals presenting to the ED with acute recreational drug toxicity. METHODS: Suspected recreational drug samples were handled as controlled drugs and transported to a Home Office approved laboratory. Samples were initially categorised on the basis of their physical appearance; liquid samples were analysed by infrared spectrophotometry and non-liquid samples were analysed by gas chromatography-mass spectrometry. RESULTS: A total of 33 (12 liquid and 21 non-liquid) samples was analysed in this pilot study. Liquid samples were shown to contain either γ-butyrolactone or isopropyl nitrite. 19% of non-liquid samples (12% of total samples) did not contain any drugs and 23% contained legal pharmaceutical agents. Of the remaining samples, they contained both 'classic' and 'novel' recreational drugs. Only 33.3% of crystalline substances contained methamphetamine. DISCUSSION: This pilot study has shown that analysing samples obtained in the ED can contribute to clinicians' knowledge of local drug epidemiology. Extension of this approach in areas with a high prevalence of recreational drug use, with appropriate funding, may be useful in monitoring drug trends and detecting novel emerging drugs.

Energy-1 ('NRG-1'): don't believe what the newspapers say about it being legal.

A 31-year-old man purchased the legal high Energy-1 (NRG-1) over the internet; this was advertised as containing the compound naphthylpyrovalerone (NPV), which at the time was currently legally available in the UK. He ingested 1 g of this substance and developed a prolonged high associated with palpitations, sweating and insomnia. Analysis of both the powder and serum samples from the patient demonstrated that he ingested two classified recreational drugs ß-keto-N-methylbenzodioxolylpropylamine (butylone) and methylenedioxypyrovalerone (MDPV) rather than the legal substance NPV. Users of legal highs need to be aware that legal highs purchased over the internet may contain illegal substances and therefore they may be liable for prosecution if found in possession of these substances. Future educational campaigns aimed at recreational drug and legal high users should include reference to the potential legal implications of buying these substances.

Case series of individuals with analytically confirmed acute mephedrone toxicity.

CONTEXT: Previous reports of acute toxicity/harm associated with mephedrone use have been based on self-reported mephedrone use; toxicological screening has not been undertaken in these cases to determine whether mephedrone has been used. OBJECTIVE: To report the first case series of analytically confirmed mephedrone-related acute toxicity. MATERIALS AND METHODS: Serum samples were collected from individuals presenting to an emergency department (ED) with acute toxicity related to self-reported mephedrone use. Toxicological analysis, by gas-chromatography coupled with mass-spectrometry and liquid chromatography with tandem mass-spectrometry was performed to qualitatively confirm mephedrone use. Symptoms/signs of acute mephedrone toxicity and basic physiological parameters were extracted from the routine ED records. RESULTS: Acute mephedrone-related toxicity was analytically confirmed in seven male patients; the mean ± SD age was 24.6 ± 6.5 years (range 16-36 years). Agitation (four patients) was the most common symptom/sign reported; other common symptoms/signs included: palpitations (two patients); chest pain (two patients); self-limiting pre-hospital seizures (one patient) and headaches (one patient). The mean heart rate was 109.1 ± 21.8 (range 80-140) beats per minute; one patient had a "severe" tachycardia (heart rate of ≥ 140 bpm). The mean systolic blood pressure was 153.0 ± 39.6 (range 110-210) mmHg; three patients had clinically significant hypertension (systolic blood pressure ≥ 160 mmHg). DISCUSSION: These analytically confirmed acute mephedrone toxicity presentations had clinical features of toxicity consistent with an acute sympathomimetic toxidrome (e.g. hypertension, tachycardia and agitation). These findings are similar to the pattern of toxicity seen with other sympathomimetic recreational drugs such as 3,4-Methylenedioxymethamphetamine (MDMA) and cocaine. CONCLUSION: The process for determining whether a novel psychoactive substance should be controlled often relies on demonstrated/proven acute harm associated with its use. It is important that clinical toxicologists undertake appropriate biological sampling and toxicological analyses in suspected cases of "novel psychoactive drug" toxicity. This will ensure that both clinicians and legislative authorities are informed of the confirmed pattern of toxicity associated with these drugs.

Recreational use of mephedrone (4-methylmethcathinone, 4-MMC) with associated sympathomimetic toxicity.

INTRODUCTION: Cathinone is a pharmacologically active alkaloid that can be extracted from the leaves of the khat plant (Catha edulis). There are synthetic derivatives of cathinone entering the recreational drug market, including mephedrone (4-methylmethcathinone, 4-MMC). There are discrepancies in the legal status of both the khat plant and its extracted alkaloids between the UK and the USA. CASE REPORT: A 22-year-old man purchased 4 g of mephedrone powder over the Internet from a chemical supplier based in China. He initially ingested 200 mg of the mephedrone orally, with no perceived clinical effects, and thereafter injected the remaining 3.8 g intramuscularly into his thighs. Shortly after the injection, he developed palpitations, "blurred tunnel vision," chest pressure, and sweating and felt generally unwell; he presented to hospital with continuing features of sympathomimetic toxicity. His symptoms settled over the next 4 h after a single dose of oral lorazepam. Qualitative analysis of the urine and serum sample was undertaken using gas chromatography with mass spectrometric (GC/MS) detection, both positive for the presence of 4-methylmethcathinone. Quantitative analysis of the serum sample was undertaken by liquid chromatography with tandem mass spectrometric detection; the estimated mephedrone concentration was 0.15 mg/l. Routine toxicological analysis of the serum and urine specimens using a broad GC/MS toxicology screen did not detect any other drugs or alcohol. DISCUSSION: This is the first case of isolated 4-MMC toxicity, with confirmatory analytical findings. It is important that clinical toxicologists and emergency physicians work together to ensure a better understanding of the toxicity of novel/emerging drugs such as 4-MMC.

Delayed onset of seizures and toxicity associated with recreational use of Bromo-dragonFLY.

INTRODUCTION: Many countries have specific legislation, such as the Controlled Substances Act (1970) in the United States and the Misuse of Drugs Act (1971) in the United Kingdom to control recreational drugs. There is a growing market and supply of "novel" recreational drugs, which include the misuse of pharmaceutical compounds and research chemicals. These are often not covered under current legislation, despite the fact that they often have both similar chemical structures and/or clinical effects to controlled recreational drugs. CASE REPORT: A male patient presented to an emergency department with delayed onset of severe agitation, hallucinations, and tonic-clonic seizures following the use of Bromo-dragonFLY and an unknown white powder. He settled following IV benzodiazepines and supportive care, and was discharged with no evidence of long-term sequelae. Analysis of the white powder by gas chromatography/mass spectrometry (GC/MS), ultraviolet/visible spectrophotometry (UV/VIS) and thin layer chromatography (TLC) showed the presence of Bromo-dragonFLY (1-(8-bromobenzo[1,2-b;4,5-b']difuran-4-yl)-2-aminopropane); serum analysis by GC/MS and liquid chromatography with tandem mass spectrometry (LC/MS/MS) confirmed that a combination of Bromo-dragonFLY (0.95 ng/mL), ketamine (20 ng/mL) and cannabis had been used by the patient. No other recreational drugs were detected in an extensive toxicological screen of serum and urine samples. DISCUSSION: This is the first confirmed case to be reported of toxicity with delayed onset of severe agitation, hallucinations and tonic-clonic seizures associated with recreational use of Bromo-dragonFLY (1-(8-bromobenzo[1,2-b;4,5-b']difuran-4-yl)-2-aminopropane) in combination with ketamine and cannabis. In our view, this case provides further support for the need for a systematic approach to toxicological screening of patients with recreational drug toxicity, to identify emerging drugs and provide evidence for legislative authorities to assist in revising the legal status of emerging recreational drugs.

The identification of potent, selective and CNS penetrant furan-based inhibitors of B-Raf kinase.

Modification of the potent imidazole-based B-Raf inhibitor SB-590885 resulted in the identification of a series of furan-based derivatives with enhanced CNS penetration. One such compound, SB-699393 (17), was examined in vivo to challenge the hypothesis that selective B-Raf inhibitors may be of value in the treatment of stroke.

4-acyl-1-(4-aminoalkoxyphenyl)-2-ketopiperazines as a novel class of non-brain-penetrant histamine H3 receptor antagonists.

A series of ketopiperazines were prepared and evaluated for their activity as histamine H 3 antagonists. From investigation of the tertiary basic center in the aminopropyloxyphenyl template, the 2( R)-methylpyrrolidine was identified as the most potent amine. In the more rigid piperidineoxyphenyl template the N-cyclobutyl group was the most potent amine. The 4-fluorobenzyol, 4-cyanobenzoyl, and 2,4-difluorobenzoyl groups provided good pharmacokinetic profiles for the various amides. The PSA and log D values of these compounds suggested low brain penetration. The compounds had very high selectivity over other receptors and did not inhibit hepatic cytochrome P450, indicating low drug-drug interaction potential. Compound 22i was identified as the best compound of this series based on its overall profile of high potency, selectivity, low brain penetration, lack of CYP450 inhibition, high oral bioavailability, and pharmacokinetic properties.

The identification of potent and selective imidazole-based inhibitors of B-Raf kinase.

A novel triarylimidazole derivative, SB-590885 (33), bearing a 2,3-dihydro-1H-inden-1-one oxime substituent has been identified as a potent and extremely selective inhibitor of B-Raf kinase.

(1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: a novel class of potent MSK-1-inhibitors.

A novel series of imidazo[4,5-c]pyridines bearing a 1,2,5-oxadiazol-3-ylamine functionality has been developed. These are potent inhibitors of mitogen and stress-activated protein kinase-1.

(1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: further optimisation as highly potent and selective MSK-1-inhibitors.

The novel imidazo[4,5-c]pyridine 1,2,5-oxadiazol-3-yl template affords an excellent start point for identification of inhibitors of a number of protein kinases. Here we report on its optimisation for mitogen and stress-activated protein kinase-1 (MSK-1) inhibitory activity, and selectivity over other kinases.

Optimal conditions for the papain digestion of polyclonal ovine IgG for the production of bio-therapeutic Fab fragments.

In the present paper, we describe a rapid method for the determination of optimum conditions for papain digestion of polyclonal ovine IgG (purified by Na(2)SO(4) precipitation) for the production of bio-therapeutic Fabs (antigen-binding fragments). To determine the optimum conditions for digestion, a factorial approach to the design of experiments was undertaken. The resulting experimental data were used to construct the mathematical models using Design Expert 6.06(R) (Stat-Ease, Minneapolis, MN, U.S.A.) to predict the optimum conditions for a robust IgG digestion step. Optimum conditions were evaluated experimentally, and the applicability of the conditions for large-scale manufacture of bio-therapeutic Fab fragments was assessed. The results and methods described in the present paper suggest that, provided the time and temperature are maintained at the high settings evaluated (24 h, 40 degrees C), the modelled data predict IgG digestion close to 100% for all the papain concentrations used. Provided papain is used at >2.5% (w/w), either time and/or temperature may be reduced. The results and methods described in the present paper may also be applicable to the generation of therapeutic Fab fragments from other immunoglobulins, including monoclonal antibodies purified from mammalian cell culture.

Optimised affinity purification of polyclonal antibodies from hyper immunised ovine serum using a synthetic Protein A adsorbent, MAbsorbent A2P.

This report describes the applicability of a synthetic chromatography adsorbent for large-scale purification of polyclonal immunoglobulin G from hyper immunised ovine serum. Under optimised conditions, MAbsorbent A2P was shown to bind approximately 27 mg mL(-1) of ovine immunoglobulin from undiluted serum, with eluted IgG purities of >95%, minor levels of albumin (approximately 1%) and undetectable levels of leached ligand in the purified preparations. The results presented here indicate that the optimised affinity capture of immunoglobulin from ovine serum using MAbsorbent A2P is a feasible alternative to Protein A chromatography or sodium sulphate precipitation for the initial capture of antibodies from undiluted serum.