Comparative Neuropharmacology and Pharmacokinetics of Methamphetamine and Its Thiophene Analog Methiopropamine in Rodents.

Methiopropamine is a novel psychoactive substance (NPS) that is associated with several cases of clinical toxicity, yet little information is available regarding its neuropharmacological properties. Here, we employed in vitro and in vivo methods to compare the pharmacokinetics and neurobiological effects of methiopropamine and its structural analog methamphetamine. Methiopropamine was rapidly distributed to the blood and brain after injection in C57BL/6 mice, with a pharmacokinetic profile similar to that of methamphetamine. Methiopropamine induced psychomotor activity, but higher doses were needed (Emax 12.5 mg/kg; i.p.) compared to methamphetamine (Emax 3.75 mg/kg; i.p.). A steep increase in locomotor activity was seen after a modest increase in the methiopropamine dose from 10 to 12.5 mg/kg, suggesting that a small increase in dosage may engender unexpectedly strong effects and heighten the risk of unintended overdose in NPS users. In vitro studies revealed that methiopropamine mediates its effects through inhibition of norepinephrine and dopamine uptake into presynaptic nerve terminals (IC50 = 0.47 and 0.74 µM, respectively), while the plasmalemmal serotonin uptake and vesicular uptake are affected only at high concentrations (IC50 > 25 µM). In summary, methiopropamine closely resembles methamphetamine with regard to its pharmacokinetics, pharmacodynamic effects and mechanism of action, with a potency that is approximately five times lower than that of methamphetamine.

[Drug safety associated with the change of digitalis drug in Norway]. / Legemiddelsikkerhet ved bytte av digitalispreparat i Norge.

BACKGROUND In 2011, following a period with delivery problems, the only registered digitoxin drug in Norway was replaced with digoxin. As a result, approximately 21 000 patients had to replace digitoxin with digoxin. There are important pharmacokinetic differences between digitoxin and digoxin (the general term for both drugs is digitalis), which must be taken into account when changing therapy. The aim of this study was to investigate compliance of drug security, during the transition from digitoxin to digoxin in Norway.MATERIAL AND METHOD Enquiries addressed to the Norwegian Poison Information Centre and reports of fatal adverse effects to the Regional Drug Information Centres (RELIS) regarding intake of digitalis were analysed. Serum concentrations of digitoxin and digoxin analyzed at Oslo University Hospital were reviewed. All data sources were reviewed for the years 2010-2014 and patients > 20 years were included.RESULTS The total number of enquiries addressed to the Norwegian Poison Information Centre, fatal adverse drug reactions reported to RELIS, and patient samples in the toxic range analyzed at Oslo University Hospital increased from 2012, timewise related to the transition to digoxin.INTERPRETATION Despite extensive information from the Norwegian Medicines Agency, a small, transient increase was observed in the number of overdoses and reported deaths from digitalis related to change in therapy. The cause of the overdose was in many cases unknown. This study revealed several cases of incorrect dosage, simultaneous use of digitoxin and digoxin, and washout time that was insufficient or lacking before initiation of digoxin.

Blood concentrations of new designer benzodiazepines in forensic cases.

INTRODUCTION: A number of new designer benzodiazepines have reached the illegal drug market over the past years. Toxicological interpretation of concentrations of these drugs in blood is quite challenging as very limited human data have previously been published. The aim of this study was to report blood concentrations of new designer benzodiazepines in a population of drugged drivers as well as some other criminal offenders, and to relate this to clinical impairment. METHODS: The present material represents cases involving new designer benzodiazepines (clonazolam, diclazepam, flubromazepam, flubromazolam and pyrazolam) and etizolam, submitted for analyses during the period July 1, 2013-May 31, 2016. Analyses were performed using an ultra-performance liquid chromatography-tandem mass spectrometry method. Blood concentrations and results from the clinical test of impairment are reported. RESULTS: New designer benzodiazepines were detected in 77 cases during the study period. The median (range) concentrations were 0.012mg/L (0.00048-0.10) for flubromazolam (n=25), 0.055mg/L (0.0047-1.2) for flubromazepam (n=24), 0.013mg/L (0.0021-0.057) for diclazepam (n=15), 0.050mg/L (0.019-0.17) for etizolam (n=14), 0.0053mg/L (0.0019-0.011) for clonazolam (n=7) and 0.074mg/L for pyrazolam (n=1). In six cases, designer benzodiazepines were the only drugs detected in blood, and in two of those cases, the physician had given the conclusion of "considerably impaired" upon performing the clinical test for impairment. CONCLUSION: Given the lack of previously published data on human concentrations, results presented in this study could be helpful in interpretation of blood concentrations of new designer benzodiazepines. This is crucial for the assessment of the importance of toxicological results in suspected drugged drivers, rape victims, etc.

Methiopropamine in blood samples from drivers suspected of being under the influence of drugs.

OBJECTIVES: Methiopropamine (MPA; 1-(thiophen-2-yl)-2-methylaminopropane) belongs to the new psychoactive substances (NPS) that have emerged on the drug market in recent years. MPA appeared in 2011 and is an analogue of methamphetamine, sold as, for example, "Slush Eric" and "Blow." It is reported to have effects similar to those of methamphetamine, but the toxicity in humans is not known. Three fatal cases involving MPA have been reported. One analytical confirmed intoxication case has been published, and this supports the symptoms described by the users. The prevalence of recreational use of MPA is unknown, and no studies have reported the prevalence in driving under the influence of drug (DUID) cases. METHODS: We investigated the frequency of MPA in DUID cases received at our institute during a 12-week period and report the analytical method using an ultraperformance liquid chromatography.tandem mass spectrometry for quantification of MPA in whole blood. The analytical findings were compared to the results from a clinical test of impairment performed by a physician shortly after the driving episode. The samples were analyzed for 42 different psychoactive substances. RESULTS: MPA was detected in 10 DUID cases (0.8% of the cases), only from male drivers. Other drugs were detected concomitantly in all the cases. Two of the cases were traffic accidents. CONCLUSIONS: Our study shows that MPA is found in DUID cases and reveals that NPS are used among drivers and also proven in blood from drivers involved in traffic accidents. More studies are requested regarding the pharmacological and toxicological effects of MPA and other NPS. This is the first article that describes a method for analyzing and quantifying MPA in whole blood samples.

Concentrations of APINACA, 5F-APINACA, UR-144 and its degradant product in blood samples from six impaired drivers compared to previous reported concentrations of other synthetic cannabinoids.

A large number of new psychoactive substances are available at the illicit drug market and the synthetic cannabinoids (SCs) are among the substances that have led to serious side effects and death. Knowledge about common concentrations of these drugs are however sparse. Concentrations of APINACA and 5F-APINACA in biological matrixes have previously not been reported, and concentrations of UR-144 and its degradant product in blood samples from driving under the influence of drug (DUID) cases have not been published. The aims of this study were to report concentrations of APINACA, 5F-APINACA, UR-144 and UR-144 degradant from DUID cases analyzed at the Norwegian Institute of Public Health (NIPH), and also previously unpublished concentrations of AM-2201 in cases from our Institute. We have further summarized all the former published studies where concentrations of SCs have been reported, to compare with the results from these newer SCs. In whole blood from one driver we have found 5F-APINACA and from three drivers both APINACA and 5F-APINACA in concentrations from 0.24 to 24.5 and 0.9 to 6.5 µg/L, respectively, and UR-144 in two cases in concentrations of 0.22 and 0.47 µg/L. UR-144 degradant in a concentration of 0.15 µg/L was found in one of the cases. A summary of the literature reveals major deficiencies regarding concentrations of most of the SCs. The SCs most frequently detected in DUID cases were (n≥8) AM-2201, JWH-122, JWH-018 and JWH-210. In intoxication cases AM-2201 (n=517) was the most often detected SC, followed by JWH-122, JWH-210, UR-144, JWH-018, and MAM-2201 (n>100). Four studies regarding concentrations in autopsy cases have been published, and concentrations of four different SCs have been reported (JWH-018, JWH-073, JWH-210, AM-2201 and the metabolites of AM-2201; 4-OH-pentyl, JWH-018 5-OH-pentyl and JWH-018 pentanoic acid). Pharmacokinetic data are only available for JWH-018 (n=3), JWH-073 (n=1) and the metabolites of AM-2201; 4-OH-pentyl, 6-OH-indole, JWH-018 5-OH-pentyl and JWH-018 pentanoic acid (n=1).

Lethal poisonings with AH-7921 in combination with other substances.

AH-7921 is a synthetic µ-opioid agonist, approximately equipotent with morphine. We report the death of two young individuals after ingestion of AH-7921 in combination with other psychoactive drugs. In the first case a young man died shortly after ingesting Internet drugs. Toxicological analysis of post mortem peripheral blood revealed AH-7921 (0.43 mg/L), 2-FMA (0.0069 mg/L) and 3-MMC (0.0021 mg/L) as well as codeine (0.42 mg/L), codeine-6-glucuronide (0.77 mg/L) and acetaminophen (18.7 mg/L). The second case involved a young female found dead at home. The only positive finding at medicolegal autopsy was needle marks. Toxicological analysis revealed AH-7921 (0.33 mg/L), methoxetamine (MXE) (0.064 mg/L), etizolam (0.27 mg/L), phenazepam (1.33 mg/L), 7-aminonitrazepam (0.043 mg/L), diazepam (0.046 mg/L), nordiazepam (0.073 mg/L), and oxazepam (0.018 mg/L) in blood. In both cases intoxication with AH-7921 in combination with other psychoactive drugs was considered to be the cause of death.

Prevalence of synthetic cannabinoids in blood samples from Norwegian drivers suspected of impaired driving during a seven weeks period.

From early year 2000 different herbal products containing synthetic cannabinoids (SC) have appeared on the drug market all over the world, and new substances are frequently introduced. The prevalence of SC use in different populations is however still mainly unknown, also in Norway. This information is difficult to obtain, but studies of drivers suspected of driving under the influence of drugs (DUID), might provide important information. The aim of this study was to assess the prevalence of SC in drivers suspected of being under the influence of drugs in Norway, and investigate if SCs impair driving performance. For two periods of three and four weeks all blood samples from drivers suspected of DUID in Norway were analyzed for the presence of 12 and 18 different SCs, respectively. A new ultra performance liquid chromatography tandem mass spectrometry method was developed. A total of 726 cases were analyzed during our study period, and SCs were detected in 16 cases (2.2%) in total. The mean age of these drivers was 29.6 years. High concentrations of other psychoactive drugs were detected in all the blood samples where a SC was found. AM-2201 and JWH-018 were the most frequently detected SCs, each found in five cases. In addition RSC-4, JWH-122, JWH-081 and JWH-250 were detected. None of the drivers had reported using SCs prior to driving. Despite the limited number of SCs investigated in this 7 week study period, a considerable percent of the cases were positive. Other psychoactive drugs of abuse were always found concomitant with the SCs, and the age of these drivers indicates that experienced drug users also ingest SCs. Since other drugs were found in all the samples, the psychomotor impairment caused by the SCs is difficult to estimate. Our study shows the importance of screening analyses of biological samples from different populations to assess the prevalence of drug use, since self-reporting might be encumbered with significant under-reporting.

[Effect and occurrence of synthetic cannabinoids]. / Syntetiske cannabinoider--effekt og forekomst.

BACKGROUND: ''Spice'' is the term used for various products that contain synthetic cannabinoids. In recent years a growing number of products have been reported on the illegal market, also in Norway. The substances are sold over the internet as 'legal' cannabis. A number of the substances have gradually been classified as narcotics, also in Norway, but new variants continue to be developed. An overview is provided here of current knowledge of the efficacy and occurrence of synthetic cannabinoids. METHOD: The article is based on a discretionary selection of relevant articles found by means of a literature search in PubMed and on reports from Norwegian and European authorities and research institutions. RESULTS: Synthetic cannabinoids are a large group of drugs of abuse that have an effect similar to cannabis, but may be considerably more potent. The contents of the various Spice products vary with respect to potency, purity and the number and types of additives, and this implies a risk of unintentional overdose. There are reports from abroad of cardiac infarction in teenagers, severe psychoses, anxiety, unconsciousness and deaths following use. INTERPRETATION: Synthetic cannabinoids are marketed over the internet as legal and harmless cannabis, but can cause severe intoxication and death. There is a considerable need for more knowledge about the action and harmful effects of these substances.