Ajuste de dosis según función renal en una paciente polimedicada incluida en el servicio de reacondicionamiento de medicamentos utilizando sistemas personalizados de dosificación (SPD) / Dose adjustment according to renal function in a polymedicated patient included in the medication reconditioning service using personalized dosing systems (SPD)

Paciente de 78 años, polimedicada e incluida en el servicio de Sistema Personalizado de Dosificación de Medicamentos (SPD). Al acudir a retirar su medicación nos informa que desde hace unos meses sufre cansancio, debilidad, mareos y confusión. Se realiza una revisión de la medicación, centrada en la dosificación de los medicamentos de metabolismo o eliminación renal, en función del valor de Filtrado Glomerular estimado de la paciente (FGe). Se realiza derivación al Médico de Atención Primaria (MAP) mediante un informe, en el que se recomienda la reducción de dosis de losartán y manidipino según el valor de FGe de la paciente. El MAP redujo la dosis de los antihipertensivos. Se efectuó seguimiento del caso, que permitió observar que la paciente dejó de presentar los síntomas descritos inicialmente.(AU)

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Background: The knowledge base on new psychoactive substances (NPS) is generally limited. This introduces new challenges and increased unpredictability in substance abuse treatment. Case presentation: A man in his thirties was submitted to detoxification after reportedly using flubromazolam, a high potency designer benzodiazepine, which he had purchased on the dark web. Extensive drug testing of serum, urine and hair, and the remains in a dropper bottle delivered by the patient, did not reveal flubromazolam or possible metabolites, but did reveal several common drugs of abuse, and 8-aminoclonazolam, a metabolite of clonazolam, another designer benzodiazepine sold on the dark web. The detoxification was uncomplicated. An excessive treatment protocol based on the patient's information, involving high preparedness and increased resources, both clinically and analytically, turned out to be unnecessary. Interpretation: The drug use and clinical course in this case proved to be more common than the unit prepared for. The case history illustrates both the challenges with users of NPS and the general unpredictability in substance abuse treatment.

Effects of the designer drug 4-methylamphetamine on core temperature and serotonin levels in the striatum and hippocampus of rats.

New psychoactive substances (NPS) are typically synthesized in clandestine laboratories in an attempt to chemically modify already federally regulated drugs in an effort to circumvent the law. Drugs derived from a phenethylamine pharmacophore, such as 4-chloroamphetamine and 3,4-methylenedioxymethamphetamine (MDMA), reliably induce thermogenesis and serotonergic deficits in the striatum and hippocampus of rodents. 4-methylamphetamine (4-MA), a relative newcomer to the NPS scene, was originally investigated in the mid-1900 s as a potential anorexigenic agent. With its phenethylamine pharmacophore, 4-MA was hypothesized to produce similar toxicological alterations as its chemical analogs. In the present study, three doses (1.0, 2.5, and 5.0 mg/kg, ip.) of 4-MA were administered to rats twice daily for two days. Core temperature data were calculated and analyzed as temperature area under the curve (TAUC). On the second day of dosing, a hypothermic response to 4-MA (2.5 and 5.0 mg/kg) was noted between 0.5 and 2.0 h post-treatment. Only the highest dose of 4-MA decreased body weight on the second day of treatment and maintained this reduction in weight for seven days after treatment ceased. None of the doses of 4-MA evaluated significantly altered serotonin levels in the hippocampus or striatum seven days after final treatment. The present findings demonstrate that the 4-methyl substitution to amphetamine generates a pharmacological and toxicological profile that differs from other similar phenethylamine analogs.

Metabolic characterization of 25X-NBOH and 25X-NBOMe phenethylamines based on UHPLC-Q-Exactive Orbitrap MS in human liver microsomes.

The types and quantities of new psychoactive substances synthesized based on structural modifications have increased rapidly in recent years and pose a great challenge to clinical and forensic laboratories. N-benzyl derivatives of phenethylamines, 25B-NBOH, 25E-NBOH, 25H-NBOH, and 25iP-NBOMe have begun to flow into the black market and have caused several poisoning cases and even fatal cases. The aim of this study was to avoid false negative results by detecting the parent drug and its metabolites to extend the detection window in biological matrices and provide basic data for the simultaneous determination of illegal drugs and metabolites in forensic and emergency cases. To facilitate the comparison of metabolic characteristics, we divided the four compounds into two groups of types, 25X-NBOH and 25X-NBOMe. The in vitro phase I and phase II metabolism of these four compounds was investigated by incubating 10 mg mL-1 pooled human liver microsomes with co-substrates for 180 min at 37 â„ƒ, and then analyzing the reaction mixture using ultrahigh-performance liquid chromatography-quadrupole/electrostatic field orbitrap mass spectrometry. In total, 70 metabolites were obtained for the four compounds. The major biotransformations were O-demethylation, hydroxylation, dehydrogenation, N-dehydroxybenzyl, N-demethoxybenzyl, oxidate transformation to ketone and carboxylate, glucuronidation, and their combination reactions. We recommended the major metabolites with high peak area ratio as biomarkers, B2-1 (56.61%), B2-2 (17.43%) and B6 (17.78%) for 25B-NBOH, E2-1 (42.81%), E2-2 (34.90%) and E8-2 (10.18%) for 25E-NBOH, H5 (49.28%), H2-1 (21.54%), and H1 (18.37%) for 25H-NBOH, P3-1 (10.94%), P3-2 (33.18%), P3-3 (14.85%) and P12-2 (23.00%) for 25iP-NBOMe. This is a study to evaluate their metabolic characteristics in detail. Comparative analysis of the N-benzyl derivatives of phenethylamines provided basic data for elucidating their pharmacology and toxicity. Timely analysis of the metabolic profiles of compounds with abuse potential will facilitate the early development of regulatory measures.

Post mortem blood bromazolam concentrations and co-findings in 96 coronial cases within England and Wales.

Bromazolam is a newly emerging benzodiazepine drug which is not licensed for medicinal use. It may be sourced as a New Psychoactive Substance (NPS) for its desired effects or be consumed unknowingly via counterfeit Xanax® or Valium® preparations. As part of our Coronial workload, we observed an increase in the detection of bromazolam from September 2021 to November 2022. We report a series of 96 cases in which bromazolam was quantitated by high resolution accurate mass - mass spectrometry (HRAM - MS) in post-mortem blood. The mean (SD) post-mortem blood bromazolam concentration from our case series was 64.6 ( ± 79.4) µg/L (range <1-425 µg/L). Routine toxicological screening results have also been reported; the most commonly encountered drugs taken in combination with bromazolam were cocaine, gabapentinoids and diazepam. In 48% of cases at least one further designer benzodiazepine drug was also present (etizolam, flualprazolam, flubromazolam, flubromazepam). It is essential that laboratories providing toxicological investigations are aware of the limitations of their assays; and inclusion of bromazolam within targeted screening panels using LC-MS/MS is encouraged. Bromazolam has not been associated with death in isolation from resulting toxic concentrations; however, it is likely to enhance adverse clinical effects when taken in combination with stimulant and/or centrally-acting depressant drugs (poly-drug deaths). Bromazolam, similar to other benzodiazepines, may also impair cognition and decision making skills.

Clozapine N-oxide, compound 21, and JHU37160 do not influence effortful reward-seeking behavior in mice.

RATIONALE: Clozapine N-oxide (CNO) has been developed as a ligand to selectively activate designer receptors exclusively activated by designer drugs (DREADDs). However, previous studies have revealed that peripherally injected CNO is reverse-metabolized into clozapine, which, in addition to activating DREADDs, acts as an antagonist at various neurotransmitter receptors, suggesting potential off-target effects of CNO on animal physiology and behaviors. Recently, second-generation DREADD agonists compound 21 (C21) and JHU37160 (J60) have been developed, but their off-target effects are not fully understood. OBJECTIVES: The present studies assessed the effect of novel DREADD ligands on reward-seeking behavior. METHODS: We first tested the possible effect of acute i.p. injection of low-to-moderate (0.1, 0.3, 1, 3 mg/kg) of CNO, C21, and J60 on motivated reward-seeking behavior in wild-type mice. We then examined whether a high dose (10 mg/kg) of these drugs might be able to alter responding. RESULTS: Low-to-moderate doses of all drugs and a high dose of CNO or C21 did not alter operant lick responding for a reward under a progressive ratio schedule of reinforcement, in which the number of operant lick responses to obtain a reward increases after each reward collection. However, high-dose J60 resulted in a total lack of responding that was later observed in an open field arena to be due to a sedative effect. CONCLUSIONS: This study provides definitive evidence that commonly used doses of CNO, C21, and J60 have negligible off-target effects on motivated reward-seeking but urges caution when using high doses of J60 due to sedative effects.

Hallucinating hallucinogens.

Fighting the designer drug epidemic with generative AI.

Flualprazolam and flubromazolam: Blood concentrations and prevalence of two novel psychoactive substances in forensic case work in Ontario, Canada.

Flualprazolam and flubromazolam are synthetic benzodiazepines that have not been approved for use in humans. They are categorized as novel psychoactive substances (NPS), and have been increasingly encountered in forensic case work. This report examines information from cases analyzed for flualprazolam and flubromazolam between July 1 and December 31, 2021 to identify the prevalence, trends and demographic data associated with these novel drugs in Ontario, Canada. Flualprazolam was identified in blood, serum or liver in 395 death investigations, 108 impaired driving and five sexual assault cases. Among all case types, blood concentrations were determined in 123 individuals aged 19-66 years. In impaired driving and sexual assault cases, flualprazolam blood concentrations ranged from <1.3 to 227 ng/mL (median 11.0 ng/mL), whereas a range of 3-59 ng/mL (median 6.8 ng/mL) was reported in death investigations. Flubromazolam was identified in blood, serum or liver in 137 death investigations, 55 impaired driving and one sexual assault case. Blood concentrations ranged from <1.3 to 323 ng/mL in 65 individuals, aged 14-61 years. In impaired driving and sexual assault cases, flubromazolam blood concentrations ranged from <1.3 to 323 ng/mL (median 7.7 ng/mL), which overlapped with the range of 2-220 ng/mL (median 8.0 ng/mL) reported in death investigations. Other drugs were frequently detected with flualprazolam and flubromazolam with opioids identified in more than 89% of positive flualprazolam and flubromazolam cases. These results demonstrated the prevalence of flualprazolam and flubromazolam in Ontario, Canada. Trends showed that over the 6-month period, as the number of flubromazolam cases decreased, the incidences of flualprazolam increased. An overlap in concentrations of these drugs was observed in both death investigations and cases involving living individuals. These data provide valuable information for the scientific community regarding the use of these drugs in antemortem and postmortem casework.

A head-to-head comparison of two DREADD agonists for suppressing operant behavior in rats via VTA dopamine neuron inhibition.

RATIONALE: Designer receptors exclusively activated by designer drugs (DREADDs) are a tool for "remote control" of defined neuronal populations during behavior. These receptors are inert unless bound by an experimenter-administered designer drug, commonly clozapine-n-oxide (CNO). However, questions have emerged about the suitability of CNO as a systemically administered DREADD agonist. OBJECTIVES: Second-generation agonists such as JHU37160 (J60) have been developed, which may have more favorable properties than CNO. Here we sought to directly compare effects of CNO (0, 1, 5, & 10 mg/kg, i.p.) and J60 (0, 0.03, 0.3, & 3 mg/kg, i.p.) on operant food pursuit. METHODS: Male and female TH:Cre + rats and their wildtype (WT) littermates received cre-dependent hM4Di-mCherry vector injections into ventral tegmental area (VTA), causing inhibitory DREADD expression in VTA dopamine neurons of TH:Cre + rats. All rats were trained to stably lever press for palatable food on a fixed ratio 10 schedule, and doses of both agonists were tested on separate days in counterbalanced order. RESULTS: All three CNO doses reduced operant rewards earned in rats with DREADDs, and no CNO dose had behavioral effects in WT controls. The highest J60 dose tested significantly reduced responding in DREADD rats, but this dose also increased responding in WTs, indicating non-specific effects. The magnitude of CNO and J60 effects in TH:Cre + rats were correlated and were present in both sexes. CONCLUSIONS: Findings demonstrate the usefulness of directly comparing DREADD agonists when optimizing behavioral chemogenetics, and highlight the importance of proper controls, regardless of the DREADD agonist employed.

Designer Drug, 25D-NBOMe, Has Reinforcing and Rewarding Effects through Change of a Dopaminergic Neurochemical System.

2-(2,5-Dimethoxy-4-methylphenyl)-N-(2-methoxybenzyl)_ethanamine (25D-NBOMe), an analogue of the 2C family, is a newly synthesized psychoactive substance. It acts as an agonist at the 5-HT2A receptor and has a similar mechanism to that of NBOMe compounds. However, the pharmacological mechanism for its rewarding and reinforcing effects has not been revealed. In the present study, intravenous self-administration (IVSA) test and conditioned place preference (CPP) test were performed to investigate whether 25D-NBOMe has abuse potential. We also evaluated the effects of 25D-NBOMe on neurochemical changes using western blot analysis and microdialysis. The IVSA test revealed increased self-administration in 25D-NBOMe (0.03 mg/kg)-treated rats. In addition, the CPP test revealed rewarding effects in 25D-NBOMe (1 mg/kg)-treated mice. In the neurochemical studies, 25D-NBOMe treatment affected the expression of dopamine (DA) receptor D1 (DRD1), DA receptor D2 (DRD2), tyrosine hydroxylase, DA transporter (DAT), and phospho-DAT (p-DAT) in the nucleus accumbens (NAc). In addition, microdialysis revealed that treatment with progressively increasing doses (1, 3, and 10 mg/kg) of 25D-NBOMe increased the extracellular levels of DA, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in the rat NAc. Taken together, our results show the abuse potential and neurochemical changes related to addictive behavior after administration of 25D-NBOMe.

Frequency of new psychoactive substances in hair and urine samples of individuals subject to drug testing in driving license regranting-A toxicological perspective.

In recent years, numerous new psychoactive substances (NPS) have emerged on the illicit drug market. The assumed non-detectability of these drugs is often a key motivation for individuals subject to drug testing, such as those in driving license regranting programs. In these programs, NPS are not routinely tested for, and thus, subjects who have to prove abstinence from common drugs of abuse might switch to NPS to avoid positive drug tests. The aim of the study was to determine the frequency of these substances in the hair and urine samples of individuals undergoing drug testing in driving license regranting. A total of 1037 samples (577 hair and 460 urine samples) collected from 949 subjects between February 2017 and December 2018 were retrospectively analyzed for designer drugs and synthetic cannabinoids by liquid chromatography-quadrupole-time-of-flight-mass spectrometry (LC-QTOF-MS). For a more sensitive analysis of synthetic cannabinoids and their metabolites, additional testing was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Overall, 42 hair and two urine samples, which were obtained from 40 subjects, tested positive for NPS resulting in a frequency of 4.2%. While synthetic cannabinoids were detected in all cases, designer drugs were only found in three of these cases. With regard to the 577 hair samples analyzed, 7.3% screened positive, whereas only 0.4% of the 460 tested urine samples contained NPS. The results of this study indicate that synthetic cannabinoid use seems to be popular among this population, and therefore, testing for synthetic cannabinoids should be requested more often preferably using hair analysis.

Chemogenetic modulation of astrocytes and microglia: State-of-the-art and implications in neuroscience.

Insights into the role astrocytes and microglia play in normal and diseased brain functioning has expanded drastically over the last decade. Recently, chemogenetic tools have emerged as cutting-edge techniques, allowing targeted and spatiotemporal precise manipulation of a specific glial cell type. As a result, significant advances in astrocyte and microglial cell function have been made, showing how glial cells can intervene in central nervous system (CNS) functions such as cognition, reward and feeding behavior in addition to their established contribution in brain diseases, pain, and CNS inflammation. Here, we discuss the latest insights in glial functions in health and disease that have been made through the application of chemogenetics. We will focus on the manipulation of intracellular signaling pathways induced by activation of the designer receptors exclusively activated by designer drugs (DREADDs) in astrocytes and microglia. We will also elaborate on some of the potential pitfalls and the translational potential of the DREADD technology.

Pharmacological insights emerging from the characterization of a large collection of synthetic cannabinoid receptor agonists designer drugs.

Synthetic cannabinoid receptor agonists (SCRAs) constitute the largest and most defiant group of abuse designer drugs. These new psychoactive substances (NPS), developed as unregulated alternatives to cannabis, have potent cannabimimetic effects and their use is usually associated with episodes of psychosis, seizures, dependence, organ toxicity and death. Due to their ever-changing structure, very limited or nil structural, pharmacological, and toxicological information is available to the scientific community and the law enforcement offices. Here we report the synthesis and pharmacological evaluation (binding and functional) of the largest and most diverse collection of enantiopure SCRAs published to date. Our results revealed novel SCRAs that could be (or may currently be) used as illegal psychoactive substances. We also report, for the first time, the cannabimimetic data of 32 novel SCRAs containing an (R) configuration at the stereogenic center. The systematic pharmacological profiling of the library enabled the identification of emerging Structure-Activity Relationship (SAR) and Structure-Selectivity Relationship (SSR) trends, the detection of ligands exhibiting incipient cannabinoid receptor type 2 (CB2R) subtype selectivity and highlights the significant neurotoxicity of representative SCRAs on mouse primary neuronal cells. Several of the new emerging SCRAs are currently expected to have a rather limited potential for harm, as the evaluation of their pharmacological profiles revealed lower potencies and/or efficacies. Conceived as a resource to foster collaborative investigation of the physiological effects of SCRAs, the library obtained can contribute to addressing the challenge posed by recreational designer drugs.

Non-fatal intoxications involving the novel benzodiazepine clonazolam: case series from the Emerging Drugs Network of Australia - Victoria project.

INTRODUCTION: Clonazolam is an unregistered novel benzodiazepine which emerged in global illicit drug markets in 2014. We describe the clinical features of four cases of non-fatal clonazolam mono-intoxications from patients presenting to emergency departments in Australia. CASES: Four patients aged between 16 and 19 years presented to hospital with a sedative toxidrome (Glasgow Coma Scale range 8-13) and elevated heart rate (median heart rate 100 beats per minute, range 92-105) following reported benzodiazepine exposure. Three patients reported the use of a large quantity (7-20 tablets) of Xanax®, a brand of alprazolam not commercially available in Australia. Two patients required nasopharyngeal airway insertion following the development of airway obstruction. The median time to return of a normal conscious state (Glasgow Coma Scale 15) was 23 h (range 5-30 h). Clonazolam (range 0.2-2.1 µg/L) and its main metabolite 8-aminoclonazolam (range 5.9-19.1 µg/L) were the only substances detected by liquid chromatography-tandem mass spectrometry in blood samples of all patients. CONCLUSION: Clonazolam intoxication resulted in sedation with mild sinus tachycardia. Three patients who reported multiple tablet exposures experienced prolonged sedation, and two of these patients developed airway obstruction. In this series, clonazolam was unknowingly ingested through possible illicit substitution within an unregulated counterfeit benzodiazepine product.

Designer benzodiazepine rat pharmacokinetics: A comparison of alprazolam, flualprazolam and flubromazolam.

Designer benzodiazepines, including flualprazolam and flubromazolam, are clandestinely produced to circumvent federal regulations. Although flualprazolam and flubromazolam are structurally similar to alprazolam, they do not have an approved medical indication. Flualprazolam differs from alprazolam by the addition of a single fluorine atom. Whereas, flubromazolam differs by the addition of a single fluorine atom and substitution of a bromine for a chlorine atom. The pharmacokinetics of these designer compounds have not been extensively evaluated. In the present study, we evaluated flualprazolam and flubromazolam in a rat model and compared the pharmacokinetics of both compounds to alprazolam. Twelve male, Sprague-Dawley rats were given a 2 mg/kg subcutaneous dose of alprazolam, flualprazolam and flubromazolam and plasma pharmacokinetic parameters were evaluated. Both compounds displayed significant two-fold increases in volume of distribution and clearance. Additionally, flualprazolam displayed a significant increase in half-life leading to a nearly double half-life when compared to alprazolam. The findings of this study demonstrate that fluorination of the alprazolam pharmacophore increases pharmacokinetic parameters including half-life and volume of distribution. The increase in these parameters for flualprazolam and flubromazolam leads to an overall increased exposure in the body and a potential for greater toxicity than alprazolam.