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[11C]Cimbi-36 is a recently developed serotonin 2A (5-HT2A) receptor agonist positron emission tomography (PET) radioligand that has been successfully applied for human neuroimaging. Here, we investigate the test–retest variability of cerebral [11C]Cimbi-36 PET and compare [11C]Cimbi-36 and the 5-HT2A receptor antagonist [18F]altanserin. Sixteen healthy volunteers (mean age 23.9±6.4years, 6 males) were scanned twice with a high resolution research tomography PET scanner. All subjects were scanned after a bolus of [11C]Cimbi-36; eight were scanned twice to determine test–retest variability in [11C]Cimbi-36 binding measures, and another eight were scanned after a bolus plus constant infusion with [18F]altanserin. Regional differences in the brain distribution of [11C]Cimbi-36 and [18F]altanserin were assessed with a correlation of regional binding measures and with voxel-based analysis. Test–retest variability of [11C]Cimbi-36 non-displaceable binding potential (BPND) was consistently <5% in high-binding regions and lower for reference tissue models as compared to a 2-tissue compartment model. We found a highly significant correlation between regional BPNDs measured with [11C]Cimbi-36 and [18F]altanserin (mean Pearson's r: 0.95±0.04) suggesting similar cortical binding of the radioligands. Relatively higher binding with [11C]Cimbi-36 as compared to [18F]altanserin was found in the choroid plexus and hippocampus in the human brain. Excellent test–retest reproducibility highlights the potential of [11C]Cimbi-36 for PET imaging of 5-HT2A receptor agonist binding in vivo. Our data suggest that Cimbi-36 and altanserin both bind to 5-HT2A receptors, but in regions with high 5-HT2C receptor density, choroid plexus and hippocampus, the [11C]Cimbi-36 binding likely represents binding to both 5-HT2A and 5-HT2C receptors. •[11C]Cimbi-36 demonstrated excellent reproducibility as a 5-HT2A receptor agonist PET radioligand in healthy volunteers.•In vivo binding of [11C]Cimbi-36 and [18F]altanserin was highly correlated demonstrating that they both image 5-HT2A receptors in the human brain•In choroid plexus and hippocampus, [11C]Cimbi-36 binding exceeded [18F]altanserin binding suggesting high density of 5-HT2C receptors here.•[11C]Cimbi-36 may be used to detect both 5-HT2A and 5-HT2C receptor binding in the human brain

•Dofetilide administered intravenously has a rapid onset of action and the dose of dofetilide is proportional to the prolongation in cardiac repolarization as represented by an increase in QTc interval.•These findings suggest the potential clinical utility of an IV formulation of dofetilide. Dofetilide’s action is inhibition of the potassium channel (IKr) which causes a delay of repolarization as seen on the ECG as QTc prolongation and is its mechanism of antiarrhythmic action. Thus, the time to repolarization prolongation is critical in evaluating the onset of potential antiarrhythmic action. To determine the extent and time course of Dofetilide administered intravenously on cardiac repolarization. Methods: Dofetilide naive healthy subjects 18–45 years received a single dose of 500 mcg dofetilide administered IV over 2.5 hours by constant infusion rate. 12-lead digital Holters recorded the ECG and 20 blood samples were collected. A validated liquid chromatographic method measured dofetilide plasma concentration. The QT intervals were measured by the median beat method from 10‑sec recordings. The Bazett formula was used for QT correction (QTc). Dofetilide concentration continuously increased from the start to the end of the infusion, then gradually decreased. The QTc showed similar dynamics with very early prolongation. At 15 min 50 mcg dofetilide was administered, 1 tenth the recommended dose, with the QTc increasing by 11 ± 10 ms (p = 0.001) indicating early effect on repolarization. There was a strong linear correlation between dofetilide concentrations and QTc intervals (r = 0.95, p < 0.001) with every 1 nanogram increase in plasma concentration resulting in a 17 ms QTc prolongation. The early effect of IV dofetilide on cardiac repolarization suggests dofetilide clinically utility with an immediate antiarrhythmic action. Future clinical studies are indicated to determine optimum dosing, efficacy as well as safety. [Display omitted]

Bromo-DragonFLY, a new psychoactive substance (NPS) within the phenethylamine class, is noted for its exceptional potency and prolonged psychoactive effects. Despite its severe toxic reactions and fatalities, research on its human metabolic fate remains limited. This study predicts the absorption, distribution, metabolism, and excretion (ADME) of Bromo-DragonFLY using in silico methods. Results indicate high gastrointestinal absorption and potential blood-brain barrier penetration, enhancing its central nervous system effects. The compound shows significant plasma protein binding and involves multiple cytochrome P450 isoenzymes in its metabolism, with variability in phase I and II reactions. Predicted metabolites form through epoxidation, quinone formation, UGT conjugation, and N-dealkylation, exhibiting reactivity with proteins, DNA, and glutathione, contributing to its toxicological profile. Excretion is predicted mainly via renal pathways. These insights are crucial for understanding the toxicological risks of Bromo-DragonFLY, exemplifying the challenges posed by NPS.

To characterise the pharmacokinetics of dofetilide in patients and to identify clinically relevant parameter–covariate relationships. To investigate three different modelling strategies in covariate model building using dofetilide as an example: (1) using statistical criteria only or in combination with clinical irrelevance criteria for covariate selection, (2) applying covariate effects on total clearance or separately on non-renal and renal clearances and (3) using separate data sets for covariate selection and parameter estimation. Pooled concentration-time data (1,445 patients, 10,133 observations) from phase III clinical trials was used. A population pharmacokinetic model was developed using NONMEM. Stepwise covariate model building was applied to identify important covariates using the strategies described above. Inclusion and exclusion of covariates using clinical irrelevance was based on reduction in interindividual variability and changes in parameters at the extremes of the covariate distribution. Parametric separation of the elimination pathways was accomplished using creatinine clearance as an indicator of renal function. The pooled data was split in three parts which were used for covariate selection, parameter estimation and evaluation of predictive performance. Parameter estimations were done using the first-order (FO) and the first-order conditional estimation (FOCE) methods. A one-compartment model with first order absorption adequately described the data. Using clinical irrelevance criteria resulted in models containing less parameter–covariate relationships with a minor loss in predictive power. A larger number of covariates were found significant when the elimination was divided into a renal part and a non-renal part, but no gain in predictive power could be seen with this data set. The FO and FOCE estimation methods gave almost identical final covariate model structures with similar predictive performance. Clinical irrelevance criteria may be valuable for practical reasons since stricter inclusion/exclusion criteria shortens the run times of the covariate model building procedure and because only the covariates important for the predictive performance are included in the model.

The present study predicts effective doses of a set of phenethylamine (PEA) analogues that are frequently present in pre-workout and weight-loss food supplements, to prioritize these compounds for further risk assessment. In vitro determined EC 50 values of PEA analogues for multiple human adrenergic receptor (ADR) subtypes (ADRα 1A , α 1B , α 1D , α 2A , β 1 , β 2 ) and trace-amine associated receptor 1 (TAAR1) were extrapolated to human ED 50 values by using physiologically based kinetic (PBK) modelling-based reverse dosimetry combined with in silico and in vitro determined PBK model input parameters. The predicted ED 50 values of the studied PEAs for activation of ADRα 1A/B/D , ADRα 2A , ADRβ 1 and TAAR1 were within a range of 0.914–29.7 mg/kg body weight (bw), 139–234 mg/kg bw, 0.0839–38.8 mg/kg bw and 0.995–264 mg/kg bw, respectively. Comparison of the predicted ED 50 values with reported intake values revealed that particularly the exposure of the PEA analogues higenamine, isopropyloctopamine, β-methylphenethylamine and p-synephrine is in the same range or exceeds the predicted ED 50 values. This suggests that these PEAs can (in)directly affect the cardiovascular system after the intake of food supplements. These PEA analogues should therefore be considered as high priority compounds for further risk assessment. In conclusion, our study shows that the use of quantitative in vitro-to-in vivo extrapolation (QIVIVE) of adrenergic and TAAR1 potencies using a generic PBK model can serve as an efficient prioritization method for a whole set of chemical analogues.

New groups of synthetic “designer drugs” have increased in popularity over the past several years. These products mimic the euphoric effects of other well-known illicit drugs but are advertised as “legal” highs and are sold over the internet, at raves and night clubs, and in head shops. The 2C series drugs are ring-substituted phenethylamines that belong to a group of designer agents similar in structure to 3,4-methylenedioxy- N -methylamphetamine (MDMA, Ecstasy). Understanding the pharmacology and toxicology of these agents is essential in order to provide the best medical care for these patients. This review focuses on the pharmacology, pharmacokinetics, clinical effects, and treatment of 2C drug intoxication based on available published literature. Multiple names under which 2C drugs are sold were identified and tabulated. Common features identified in patients intoxicated with 2Cs included hallucinations, agitation, aggression, violence, dysphoria, hypertension, tachycardia, seizures, and hyperthermia. Patients may exhibit sympathomimetic symptoms or symptoms consistent with serotonin toxicity, but an excited delirium presentation seems to be consistent amongst deaths attributed to 2C drugs; at least five deaths have been reported in the literature in patients intoxicated with 2C drugs. 2C drugs are a group of designer intoxicants, many of which are marketed as legal, but may carry risks that consumers are unaware of. These drugs may be characterized by either serotonergic toxicity or a sympathomimetic toxidrome, but a presentation consistent with excited delirium is consistent amongst the reported 2C-related deaths. Treatment of 2C intoxication is primarily supportive, but immediate action is required in the context of excited delirium, hyperthermia, and seizure activity.

[11C]Cimbi-36 was recently developed as a selective serotonin 2A (5-HT2A) receptor agonist radioligand for positron emission tomography (PET) brain imaging. Such an agonist PET radioligand may provide a novel, and more functional, measure of the serotonergic system and agonist binding is more likely than antagonist binding to reflect 5-HT levels in vivo. Here, we show data from a first-in-human clinical trial with [11C]Cimbi-36. In 29 healthy volunteers, we found high brain uptake and distribution according to 5-HT2A receptors with [11C]Cimbi-36 PET. The two-tissue compartment model using arterial input measurements provided the most optimal quantification of cerebral [11C]Cimbi-36 binding. Reference tissue modeling was feasible as it induced a negative but predictable bias in [11C]Cimbi-36 PET outcome measures. In five subjects, pretreatment with the 5-HT2A receptor antagonist ketanserin before a second PET scan significantly decreased [11C]Cimbi-36 binding in all cortical regions with no effects in cerebellum. These results confirm that [11C]Cimbi-36 binding is selective for 5-HT2A receptors in the cerebral cortex and that cerebellum is an appropriate reference tissue for quantification of 5-HT2A receptors in the human brain. Thus, we here describe [11C]Cimbi-36 as the first agonist PET radioligand to successfully image and quantify 5-HT2A receptors in the human brain.

Schizophrenia is a chronic, severe and highly complex mental illness. Current treatments manage the positive symptoms, yet have minimal effects on the negative and cognitive symptoms, two prominent features of the disease with critical impact on the long-term morbidity. In addition, antipsychotic treatments trigger serious side effects that precipitate treatment discontinuation. Here, we show that activation of the trace amine-associated receptor 1 (TAAR1), a modulator of monoaminergic neurotransmission, represents a novel therapeutic option. In rodents, activation of TAAR1 by two novel and pharmacologically distinct compounds, the full agonist RO5256390 and the partial agonist RO5263397, blocks psychostimulant-induced hyperactivity and produces a brain activation pattern reminiscent of the antipsychotic drug olanzapine, suggesting antipsychotic-like properties. TAAR1 agonists do not induce catalepsy or weight gain; RO5263397 even reduced haloperidol-induced catalepsy and prevented olanzapine from increasing body weight and fat accumulation. Finally, TAAR1 activation promotes vigilance in rats and shows pro-cognitive and antidepressant-like properties in rodent and primate models. These data suggest that TAAR1 agonists may provide a novel and differentiated treatment of schizophrenia as compared with current medication standards: TAAR1 agonists may improve not only the positive symptoms but also the negative symptoms and cognitive deficits, without causing adverse effects such as motor impairments or weight gain.

Introduction 2C designer drugs have been in use since the 1970s, but new drugs continue to develop from substitutions to the base phenethylamine structure. This creates new clinical profiles and difficulty with laboratory confirmation. 2-(4-Iodo-2,5-dimethoxyphenyl)- N -[(2-methoxyphenyl)methyl]ethanamine (25I-NBOMe) is a relatively new 2C drug that is more potent than structural 2C analogs; exposure reports are rare. Testing for 2C drugs is developing; specific testing for new analogs such as 25I-NBOMe is a challenge. These drugs do not reliably trigger a positive result on rapid drug immunoassays. Additionally, most facilities with confirmatory testing capabilities will not identify 25I-NBOMe; methods for detecting 25I-NBOMe in biological samples have not been clearly described nor have optimal metabolic targets for detecting 25I-NBOMe ingestion. Case Report An 18-year-old female presented following use of 25I-NBOMe. She had an isolated brief seizure, tachycardia, hypertension, agitation, and confusion. She improved with intravenously administered fluids and benzodiazepines and was discharged 7 h postingestion. Urine was analyzed using quantitative LC-MS/MS methodology for 25I-NBOMe, 2-(4-chloro-2,5-dimethoxyphenyl)- N -[(2-methoxyphenyl)-methyl]ethanamine (25C-NBOMe), and 2-(2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25H-NBOMe). 25I-NBOMe was found at a concentration of 7.5 ng/mL, and 25H-NBOMe was detected as well. Additional testing was pursued to characterize the metabolism of 25I-NBOMe; the sample was reanalyzed with UPLC–time-of-flight mass spectrometry to identify excreted metabolites. The sample was additionally analyzed for the presence of 2,5-dimethoxy-4-iodophenethylamine (2C-I), 4-bromo-2,5-dimethoxyphenethylamine (2C-B), and 1-(2,5-dimethoxy-4-ethylphenyl)-2-aminoethane (2C-E). Discussion This is a report of a patient presenting following exposure to 25I-NBOMe, a dangerous member of the evolving 2C drug class. The exposure was confirmed in a unique manner that could prove helpful in guiding further patient analysis and laboratory studies.

To prolong the residence time of dosage forms within the gastrointestinal tract until all drug is released at the desired rate is one of the real challenges for oral controlled-release drug delivery systems. This study was designed to develop a controlled-release floating matrix tablet and floating raft system of Mebeverine HCl (MbH) and evaluate different excipients for their floating behavior and in vitro controlled-release profiles. Oral pharmacokinetics of the optimum matrix tablet, raft system formula, and marketed Duspatalin 200 mg retard as reference were studied in beagle dogs. The optimized tablet formula (FT-10) and raft system formula (FRS-11) were found to float within 34±5 sec and 15±7 sec, respectively, and both remain buoyant over a period of 12 h in simulated gastric fluid. FT-10 (Compritol/HPMC K100M 1:1) showed the slowest drug release among all prepared tablet formulations, releasing about 80.2% of MbH over 8 h. In contrast, FRS-11 (Sodium alginate 3%/HPMC K100M 1%/Precirol 2%) had the greatest retardation, providing sustained release of 82.1% within 8 h. Compared with the marketed MbH product, the C of FT-10 was almost the same, while FRS-11 maximum concentration was higher. The t was 3.33, 2.167, and 3.0 h for marketed MbH product, FT-10, and FRS-11, respectively. In addition, the oral bioavailability experiment showed that the relative bioavailability of the MbH was 104.76 and 116.01% after oral administration of FT-10 and FRS-11, respectively, compared to marketed product. These results demonstrated that both controlled-released floating matrix tablet and raft system would be promising gastroretentive delivery systems for prolonging drug action.