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1.
Adv Pharmacol ; 99: 1-33, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38467478

RESUMO

The availability of monoamine neurotransmitters in the brain is under the control of dopamine, norepinephrine, and serotonin transporters expressed on the plasma membrane of monoaminergic neurons. By regulating transmitter levels these proteins mediate crucial functions including cognition, attention, and reward, and dysregulation of their activity is linked to mood and psychiatric disorders of these systems. Amphetamine-based transporter substrates stimulate non-exocytotic transmitter efflux that induces psychomotor stimulation, addiction, altered mood, hallucinations, and psychosis, thus constituting a major component of drug neurochemical and behavioral outcomes. Efflux is under the control of transporter post-translational modifications that synergize with other regulatory events, and this review will summarize our knowledge of these processes and their role in drug mechanisms.


Assuntos
Anfetamina , Dopamina , Humanos , Anfetamina/farmacologia , Transporte Biológico , Dopamina/metabolismo , Neurotransmissores , Processamento de Proteína Pós-Traducional
2.
Adv Pharmacol ; 99: 125-144, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38467479

RESUMO

Use of amphetamines during adolescence, a critical period of brain development and reorganization, may lead to particularly adverse outcomes that are long-lasting. Similarly, female users may be uniquely vulnerable to certain aspects of drug use. A recognition of the role of use during adolescence and sex on outcomes of amphetamine and methamphetamine exposure are of critical importance in understanding and treating substance use disorders. This chapter highlights what human research, which has been largely epidemiological, suggests about sex and age differences in drug use patterns and outcomes. We also discuss work in laboratory animals that has typically utilized rats or mice exposed to drugs in a non-contingent manner (i.e., involuntarily) or through volitional self-administration. Lastly, we draw attention to the fact that advancing our understanding of the effects of amphetamine and methamphetamine use, the development of problematic drug taking, and the mechanisms that contribute to relapse will require an emphasis on inclusion of age and sex as moderating factors in future studies.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas , Metanfetamina , Transtornos Relacionados ao Uso de Substâncias , Adolescente , Feminino , Humanos , Ratos , Camundongos , Animais , Anfetaminas/efeitos adversos , Metanfetamina/efeitos adversos , Anfetamina
3.
Adv Pharmacol ; 99: 61-82, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38467489

RESUMO

The synthetic cathinones are man-made compounds derived from the naturally occurring drug cathinone, which is found in the khat plant. The drugs in this pharmacological class that will be the focus of this chapter include mephedrone, MDPV, methcathinone and methylone. These drugs are colloquially known as "bath salts". This misnomer suggests that these drugs are used for health improvement or that they have legitimate medical uses. The synthetic cathinones are dangerous drugs with powerful pharmacological effects that include high abuse potential, hyperthermia and hyperlocomotion. These drugs also share many of the pharmacological effects of the amphetamine class of drugs including methamphetamine, amphetamine and MDMA and therefore have high potential to cause damage to the central nervous system. The synthetic cathinones are frequently taken in combination with other psychoactive drugs such as alcohol, marijuana and the amphetamine-like stimulants, creating a situation where heightened pharmacological and neurotoxicological effects are likely to occur. Despite the structural features shared by the synthetic cathinones and amphetamine-like stimulants, including their actions at monoamine transporters and receptors, the effects of the synthetic cathinones do not always match those of the amphetamines. In particular, the synthetic cathinones are far less neurotoxic than their amphetamine counterparts, they produce a weaker hyperthermia, and they cause less glial activation. This chapter will briefly review the pharmacology and neurotoxicology of selected synthetic cathinones with the aim of delineating key areas of agreement and disagreement in the literature particularly as it relates to neurotoxicological outcomes.


Assuntos
Estimulantes do Sistema Nervoso Central , Metanfetamina , Humanos , Catinona Sintética , Metanfetamina/efeitos adversos , Anfetamina , Estimulantes do Sistema Nervoso Central/efeitos adversos
4.
Adv Pharmacol ; 99: 35-59, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38467486

RESUMO

The dopamine transporter (DAT) is a key site of action for cocaine and amphetamines. Dysfunctional DAT is associated with aberrant synaptic dopamine transmission and enhanced drug-seeking and taking behavior. Studies in cultured cells and ex vivo suggest that DAT function is sensitive to membrane cholesterol content. Although it is largely unknown whether psychostimulants alter cholesterol metabolism in the brain, emerging evidence indicates that peripheral cholesterol metabolism is altered in patients with psychostimulant use disorder and circulating cholesterol levels are associated with vulnerability to relapse. Cholesterol interacts with sphingolipids forming lipid raft microdomains on the membrane. These cholesterol-rich lipid raft microdomains serve to recruit and assemble other lipids and proteins to initiate signal transduction. There are two spatially and functionally distinct populations of the DAT segregated by cholesterol-rich lipid raft microdomains and cholesterol-scarce non-raft microdomains on the plasma membrane. These two DAT populations are differentially regulated by DAT blockers (e.g. cocaine), substrates (e.g. amphetamine), and protein kinase C providing distinct cholesterol-dependent modulation of dopamine uptake and efflux. In this chapter, we summarize the impact of depletion and addition of membrane cholesterol on DAT conformational changes between the outward-facing and the inward-facing states, lipid raft-associated DAT localization, basal and induced DAT internalization, and DAT function. In particular, we focus on how the interactions of the DAT with cocaine and amphetamine are influenced by membrane cholesterol. Lastly, we discuss the therapeutic potential of cholesterol-modifying drugs as a new avenue to normalize DAT function and dopamine transmission in patients with psychostimulant use disorder.


Assuntos
Cocaína , Proteínas da Membrana Plasmática de Transporte de Dopamina , Humanos , Proteínas da Membrana Plasmática de Transporte de Dopamina/química , Dopamina/metabolismo , Anfetamina/farmacologia , Cocaína/farmacologia , Colesterol/química , Colesterol/metabolismo
5.
Exp Neurol ; 374: 114718, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38336285

RESUMO

Executive function, including working memory, attention and inhibitory control, is crucial for decision making, thinking and planning. Lisdexamfetamine, the prodrug of d-amphetamine, has been approved for treating attention-deficit hyperactivity disorder and binge eating disorder, but whether it improves executive function under non-disease condition, as well as the underlying pharmacokinetic and neurochemical properties, remains unclear. Here, using trial unique non-matching to location task and five-choice serial reaction time task of rats, we found lisdexamfetamine (p.o) enhanced spatial working memory and sustained attention under various cognitive load conditions, while d-amphetamine (i.p) only improved these cognitive performances under certain high cognitive load condition. Additionally, lisdexamfetamine evoked less impulsivity than d-amphetamine, indicating lower adverse effect on inhibitory control. In vivo pharmacokinetics showed lisdexamfetamine produced a relative stable and lasting release of amphetamine base both in plasma and in brain tissue, whereas d-amphetamine injection elicited rapid increase and dramatical decrease in amphetamine base levels. Microdialysis revealed lisdexamfetamine caused lasting release of dopamine within the medial prefrontal cortex (mPFC), whereas d-amphetamine produced rapid increase followed by decline to dopamine level. Moreover, lisdexamfetamine elicited more obvious efflux of noradrenaline than that of d-amphetamine. The distinct neurochemical profiles may be partly attributed to the different action of two drugs to membranous catecholamine transporters level within mPFC, detecting by Western Blotting. Taken together, due to its certain pharmacokinetic and catecholamine releasing profiles, lisdexamfetamine produced better pharmacological action to improving executive function. Our finding provided valuable evidence on the ideal pharmacokinetic and neurochemical characteristics of amphetamine-type psychostimulants in cognition enhancement.


Assuntos
Estimulantes do Sistema Nervoso Central , Dimesilato de Lisdexanfetamina , Ratos , Animais , Dimesilato de Lisdexanfetamina/farmacologia , Função Executiva , Dopamina , Estimulantes do Sistema Nervoso Central/efeitos adversos , Dextroanfetamina/efeitos adversos , Dextroanfetamina/farmacocinética , Anfetamina/farmacologia , Catecolaminas , Cognição
6.
J Atten Disord ; 28(5): 936-944, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38321936

RESUMO

OBJECTIVE: Stimulant medications are the main treatment for Attention Deficit Hyperactivity Disorder (ADHD), but overall treatment efficacy in adults has less than a 60% response rate. This study aimed to identify neural and cognitive markers predictive of longitudinal improvement in response to stimulant treatment in drug-naïve adults with ADHD. METHOD: We used diffusion tensor imaging (DTI) and executive function measures with 36 drug-naïve adult ADHD patients in a prospective study design. RESULTS: Structural connectivity (measured by fractional anisotropy, FA) in striatal regions correlated with ADHD clinical symptom improvement following stimulant treatment (amphetamine or methylphenidate) in better medication responders. A significant positive correlation was also found between working memory performance and stimulant-related symptom improvement. Higher pre-treatment working memory scores correlated with greater response. CONCLUSION: These findings provide evidence of pre-treatment neural and behavioral markers predictive of longitudinal treatment response to stimulant medications in adults with ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central , Metilfenidato , Adulto , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico por imagem , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Imagem de Tensor de Difusão , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Estudos Prospectivos , Metilfenidato/farmacologia , Metilfenidato/uso terapêutico , Anfetamina/uso terapêutico , Resultado do Tratamento , Cognição
7.
Expert Rev Neurother ; 24(4): 421-432, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38391788

RESUMO

INTRODUCTION: Amphetamine preparations are one of the two categories of stimulant medications approved for the treatment of attention deficit hyperactivity disorder (ADHD). Optimal treatment of ADHD aims to reduce core symptoms for as much of the waking hours as possible, leading to longer-acting delivery formats. In addition, the pediatric population commonly has difficulty swallowing pills and manufacturers have developed a variety of options to facilitate this concern. These include chewable tablets, capsules that may be sprinkled on soft food, liquids and transdermal patches. AREAS COVERED: This article reviews the once-daily extended-release preparations currently available for amphetamine compounds, their pharmacodynamics, and common adverse effects. EXPERT OPINION: There is an extensive evidence base supporting use of amphetamine preparations in the treatment of ADHD. Rapid onset of action and a favorable side effect profile make these widely used. The availability of once-daily extended-release chewable tablets, capsules that can be opened and sprinkled, and liquid formulations provides clinicians with multiple options to meet the specific needs of patients with difficulty swallowing whole pills.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central , Metilfenidato , Humanos , Criança , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Anfetamina/uso terapêutico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Metilfenidato/uso terapêutico , Preparações de Ação Retardada/uso terapêutico , Comprimidos/uso terapêutico
8.
J Chromatogr A ; 1718: 464709, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38350352

RESUMO

The different behavior of enantiomers of chiral compounds in non-isotropic environments (among them in living organism) is well known. On the other hand, the importance of a kinetic isotope effect in the biomedical field has become evident during past few decades. Thus, separation of both, enantiomers and isotopologues is now critical. Only very few published studies have attempted the simultaneous separation of enantioisotopologues. In this article we report baseline separation of partially deuterated isotopologues of a few amphetamine derivatives in high-performance liquid chromatography (HPLC) using achiral columns. In addition, the simultaneous separations of enantiomers and isotopologues (i.e. enantioisotopologues) were attempted on polysaccharide-based chiral columns. For several compounds the isotope effect was tunable and could be switched from a "normal" to "inverse" by making changes to the mobile-phase composition. A stronger isotope effect was observed in acetonitrile-containing mobile phases compared to methanol-containing ones with both chiral and achiral columns. In a separation system where both "normal" and "inverse" isotope effects were observed the "normal" isotope effect was favored in polar organic solvents while increasing content of the aqueous component in the reversed-phase (RP) mobile phase favored an "inverse" isotope effect. This observation indicates that polar, hydrogen bonding-type noncovalent interactions are involved in the "normal" isotope effect, while apolar hydrophobic-type interactions are mostly responsible for the "inverse" isotope effect.


Assuntos
Anfetamina , Polissacarídeos , Cromatografia Líquida de Alta Pressão/métodos , Polissacarídeos/química , Solventes/química , Isótopos , Estereoisomerismo
9.
eNeuro ; 11(2)2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38355299

RESUMO

A current hypothesis to explain the limited recovery following brain and spinal cord trauma stems from the dogma that neurons in the mammalian central nervous system lack the ability to regenerate their axons after injury. Serotonin (5-HT) neurons in the adult brain are a notable exception in that they can slowly regrow their axons following chemical or mechanical lesions. This process of regrowth occurs without intervention over several months and results in anatomical recovery that approximates the preinjured state. During development, serotonin is a trophic factor, playing a role in both cell survival and axon growth. Additionally, some studies have shown that stroke patients treated after injury with serotonin selective reuptake inhibitors (SSRIs) appeared to have improved recovery. To test the hypothesis that serotonin can influence the regrowth of 5-HT axons, mice received a high dose of para-chloroamphetamine (PCA) to induce widespread retrograde degeneration of 5-HT axons. Then, after a short rest period to avoid any interaction with the acute injury phase, SSRIs were administered daily for 6 or 10 weeks. Using immunohistochemistry in 5-HT transporter-GFP BAC transgenic mice, we determined that while PCA led to a rapid initial decrease in total 5-HT axon length in the somatosensory cortex, visual cortex, or area CA1 of the hippocampus, treatment with either fluoxetine or sertraline (two different SSRIs) did not affect the recovery of axon length. These results suggest that chronic SSRI treatment does not affect the regrowth of 5-HT axons and argue against SSRIs as a potential therapy following brain injury.


Assuntos
Inibidores Seletivos de Recaptação de Serotonina , Serotonina , Humanos , Adulto , Camundongos , Animais , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Anfetamina , Fluoxetina/farmacologia , Axônios/fisiologia , Prosencéfalo , Camundongos Transgênicos , Mamíferos
10.
Sci Rep ; 14(1): 3596, 2024 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-38351286

RESUMO

Abuse of amphetamine-type stimulants is linked to cardiovascular adverse effects like arrhythmias, accelerated atherosclerosis, acute coronary syndromes and sudden cardiac death. Excessive catecholamine release following amphetamine use causes vasoconstriction and vasospasms, over time leading to hypertension, endothelial dysfunction or even cardiotoxicity. However, immediate vascular pathomechanisms related to amphetamine exposure, especially endothelial function, remain incompletely understood and were analyzed in this study. Pharmaco-pathological effects of acute d-amphetamine-sulfate (DAM) were investigated ex vivo using contraction-force measurements of rat carotid artery rings and in vitro using label-free, real-time electrochemical impedance spectroscopy (EIS) on endothelial and smooth muscle cells. Specific receptor and target blocking was used to identify molecular targets and to characterize intracellular signaling. DAM induced vasodilation represented by 29.3±2.5% decrease in vascular tone (p<0.001) involving vascular endothelial growth factor receptor (VEGF-R) and protease activated receptor 1 (PAR-1). EIS revealed that DAM induces endothelial barrier disruption (-75.9±1.1% of initial cellular impedance, p<0.001) also involving VEGF-R and PAR-1. Further, in response to DAM, Rho-associated protein kinase (ROCK) mediated reversible contraction of actin cytoskeleton resulting in endothelial barrier disruption. Dephosphorylation of Serine1177 (-50.8±3.7%, p<0.001) and Threonine495 (-44.8±6.5%, p=0.0103) of the endothelial NO synthase (eNOS) were also observed. Blocking of VEGF-R and PAR-1 restored baseline eNOS Threonine495 phosphorylation. DAM induced vasodilation, enhanced vascular permeability and actin cytoskeleton contraction and induced eNOS hypophosphorylation involving VEGF-R, PAR-1 and ROCK. These results may contribute to a better understanding of severe adverse cardiovascular effects in amphetamine abuse.


Assuntos
Receptor PAR-1 , Doenças Vasculares , Ratos , Animais , Receptor PAR-1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Anfetamina/farmacologia , Permeabilidade Capilar , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Quinases Associadas a rho/metabolismo , Doenças Vasculares/metabolismo , Endotélio Vascular/metabolismo , Citoesqueleto de Actina/metabolismo , Células Cultivadas
11.
J Pharm Biomed Anal ; 241: 115996, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38330785

RESUMO

BACKGROUND AND AIM: Non-medical use of Pregabalin (PGB) is a growing concern in many countries because of the serious consequences associated with their abuse. Judicial cases within the probation system, multiple drug users, and patients in treatment programs administered PGB at higher doses than suggested, commonly without prescription. For this reason, it is important to analyze PGB by adding it to the routine analysis scale in determining whether PGB is used for medical purposes or abuse. In this study, PGB analyzed (single or multiple substance use, concomitant substances) in urine samples of forensic and clinical cases by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In addition to the sociodemographic and clinical characteristics of pregabalin-positive cases, the results were evaluated separately from a clinical and forensic perspective. METHODS: All urine samples which was admitted to Addiction Toxicology Laboratory from 'drug abuse probation system' (forensic cases, n = 640) and from various departments of our hospital (clinical cases, n = 371) between December 2022 and April 2023. Screening analysis were carried out by immunoassay in total 1011 cases. LC-MS/MS method simultaneously analyzed amphetamine, benzoilecgonine, cocaine, codeine, metamphetamine, morphine, 3,4-metilenedioksi-N-metilamfetamin (MDMA), 11-nor-9-karboksi-Δ9-tetrahidrokannabinol and pregabalin in urine samples. PGB was added to the our routine substance screening analysis scale in December 2022 to detect pregabalin use. RESULTS: PGB was detected in 12.3% of probabition cases and 13.2% of clinical cases. The mean age of PGB positive cases was 26.55 ± 7,52 years old, predominantly males (%85,9). Single PGB was detected in 53.2% of forensic cases (n = 42), and 38.7% of clinical cases (n = 19). The most common substance detected concomitantly with PGB was amphetamine type stimulants (ATSs:amphetamine, methamphetamine, ecstasy/MDMA etc.) (22.8% of forensic cases and 46.9% of clinical cases), followed by concomitant cannabis use (24.1% of forensic cases and 26.5% of clinical cases). Concomitant opioid use was rare (1.3% of forensic cases and 4.1% of clinical cases). Detection of PGB was significantly different across months on which the samples were collected (x2 = 82.8, df=4, p < 0.001). CONCLUSION: Inconsistently with previous studies suggesting opioids as the most prevalant substances concominant with PGB, our results showed that stimulants (especially ATSs) were the most prevelant substances concominant with PGB, followed by cannabis. High proportion of PGB detection in probabition cases, frequently as a single substance abuse takes attention. These results suggest that PGB, may be used to avoid legal consequences. It is important for laboratories to be aware that they need to make changes as addition of newly abused substances in their analysis panels, when necessary, as differences between regions and cultures affect substance use patterns.


Assuntos
Estimulantes do Sistema Nervoso Central , Alucinógenos , Metanfetamina , N-Metil-3,4-Metilenodioxianfetamina , Transtornos Relacionados ao Uso de Substâncias , Masculino , Humanos , Feminino , N-Metil-3,4-Metilenodioxianfetamina/análise , Pregabalina , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Anfetamina/urina , Estimulantes do Sistema Nervoso Central/urina , Alucinógenos/análise , Transtornos Relacionados ao Uso de Substâncias/diagnóstico , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Detecção do Abuso de Substâncias/métodos
12.
J Toxicol Sci ; 49(1): 9-26, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38191192

RESUMO

Amphetamine-type stimulants are abused worldwide, and methamphetamine (METH) accounts for a large majority of seized abused drug cases. Recently, the paternal origin of health and disease theory has been proposed as a concept wherein paternal factors influence descendants. Although METH abuse is more common among males, its effects on their descendants were not examined. Therefore, we investigated the effects of paternal METH exposure on F1 and F2 levels in a mouse model. Sires were administered METH for 21 days and mated with female mice to obtain F1 mice. Growth evaluations (number of births, survival rate, body weight, righting reflex, cliff avoidance tests, and wire-hanging maneuver) were performed on F1 mice. Upon reaching six weeks of age, the mice were subjected to spontaneous locomotion, elevated plus-maze, acute METH treatment, and passive avoidance tests. Additionally, RNA-seq was performed on the striatum of male mice. Male F1 mice were mated with female mice to obtain F2 mice. They were subjected to the same tests as the F1 mice. Paternal METH exposure resulted in delayed growth and decreased memory function in F1 mice, overweight in F2 mice, decreased METH sensitivity, and reduced anxiety-related behaviors in female F2 mice. Enrichment analysis revealed significant enrichment of terms related to behavior in F1 and protein folding in F2. These results indicated that the effects of paternal METH exposure vary across generations. The effects of paternal factors need to be examined not only in F1, but also in F2 and beyond.


Assuntos
Estimulantes do Sistema Nervoso Central , Metanfetamina , Feminino , Masculino , Animais , Camundongos , Metanfetamina/toxicidade , Anfetamina , Estimulantes do Sistema Nervoso Central/toxicidade , Peso Corporal , Corpo Estriado
13.
Ecotoxicol Environ Saf ; 270: 115900, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38176186

RESUMO

A thorough understanding of the degradation of chemical biomarkers in wastewater after the sampling is critical in the surveillance of illicit drug use based on the back-calculation technique. Herein, three temperatures, eight groups of matrices, and acidification were applied to simulate the preservation condition of 21 illicit drugs, their metabolites, and cotinine for a 240-day stability study. It was proved that the temperature, matrices, and acidification play vital roles in their stability in wastewater. Most of them demonstrated high stability (transformation rates < 20%) during room temperature for 45 days, and the transformation rates decreased while the storage temperature reduced. The stability of the target compounds such as cocaine (COC), 6-monoacetylmorphine (6-MAM), and amphetamine (AM) is influenced by matrices. Acidification prevented the majority of analytes from transforming, making it a feasible solution for preservation after sampling. A model that combined the effects of temperature and matrix was developed to back-calculate the concentration of target compounds during the postsampling process. The feasibility of this model was validated by correcting the loss of COC and 6-MAM from 24.2% and 16.2% to 2.98% and 2.77%. This study simulated a typical large-scale sampling and storage scenario. The effect of the temperature, pH, and matrix on in-sample stability and the postsampling analysis of selected target compounds was investigated for the first time in this study.


Assuntos
Cocaína , Drogas Ilícitas , Poluentes Químicos da Água , Águas Residuárias , Drogas Ilícitas/análise , Cotinina , Anfetamina/análise , Cocaína/análise , Poluentes Químicos da Água/análise
14.
J Chromatogr A ; 1715: 464628, 2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38183783

RESUMO

In this study, a novel supramolecular deep eutectic solvent consisting of sulfated-ß-CD and citric acid (S-ß-CD-CA) is reported for the first time. This innovative system was evaluated as a sole chiral selector in capillary electrophoresis for the enantioseparation of six fluorine-substituted amphetamine analogs, yielding remarkable outcomes. Baseline separations of all amphetamine analogs under study were achieved in less than 21.00 min using the S-ß-CD-CA as the chiral selector. It was observed that the addition of 0.050 % v/v S-ß-CD-CA into the background electrolyte resulted in the baseline separation of five out of the six fluorine-substituted amphetamine analogs, while in the case of the para-substituted amphetamine analog, 4-fluoramphetamine (4-FA), a higher percentage (0.15 % v/v) was required to achieve baseline enantioseparation. These findings emphasized the potential of this new supramolecular system in providing a class of solvents with promising chiral recognition properties.


Assuntos
beta-Ciclodextrinas , Anfetamina , Solventes Eutéticos Profundos , Flúor , Solventes , Eletroforese Capilar/métodos , Sulfatos , Estereoisomerismo
15.
Ugeskr Laeger ; 186(2)2024 Jan 08.
Artigo em Dinamarquês | MEDLINE | ID: mdl-38235724

RESUMO

This is a case report of two men aged 39 and 43 years with dissection of the coeliac trunk involving the splenic arteries causing splenic infarction. One case was associated with an increase in abdominal pressure during defaecation and the other occurred during treatment with methylphenidate. Based on the published 43 cases, risk factors include male sex, increased intraabdominal pressure or increased vascular pressure. Methylphenidate most likely increased the blood pressure, and dissections of other arteries have been described during treatment with this and the similar drug amphetamine.


Assuntos
Artéria Celíaca , Metilfenidato , Humanos , Masculino , Anfetamina , Pressão Sanguínea , Artéria Esplênica , Adulto
16.
Environ Pollut ; 344: 123355, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38228265

RESUMO

Cocaine, methamphetamine, ectasy (3,4-methylenedioxy amphetamine (MDMA)) and ketamine are among the most consumed drugs worldwide causing cognitive, oxidative stress and cardiovascular problems in humans. Residue levels of these drugs and their transformation products may still enter the aquatic environment, where concentrations up to hundreds of ng/L have been measured. In the present work we tested the hypothesis that psychotropic effects and the mode of action of these drugs in D. magna cognitive, oxidative stress and cardiovascular responses are equivalent to those reported in humans and other vertebrate models. Accordingly we expose D. magna juveniles to pharmacological and environmental relevant concentrations. The study was complemented with the measurement of the main neurotransmitters involved in the known mechanisms of action of these drugs in mammals and physiological relevant amino acids. Behavioural cognitive patters clearly differentiate the 3 psychostimulant drugs (methamphetamine, cocaine, MDMA) from the dissociative one ketamine. Psychostimulant drugs at pharmacological doses (10-200 µM), increased basal locomotion activities and responses to light, and decreased habituation to it. Ketamine only increased habituation to light. The four drugs enhanced the production of reactive oxygen species in a concentration related manner, and at moderate concentrations (10-60 µM) increased heartbeats, diminishing them at high doses (200 µM). In chronic exposures to environmental low concentrations (10-1000 ng/L) the four drugs did not affect any of the behavioural responses measured but methamphetamine and cocaine inhibited reproduction at 10 ng/L. Observed effects on neurotransmitters and related metabolites were in concern with reported responses in mammalian and other vertebrate models: cocaine and MDMA enhanced dopamine and serotonin levels, respectively, methamphetamine and MDMA decreased dopamine and octopamine, and all but MDMA decreased 3 MT levels. Drug effects on the concentration of up to 10 amino acids evidence disruptive effects on neurotransmitter synthesis, the urea cycle, lipid metabolism and cardiac function.


Assuntos
Cocaína , Drogas Ilícitas , Ketamina , Metanfetamina , N-Metil-3,4-Metilenodioxianfetamina , Humanos , Animais , N-Metil-3,4-Metilenodioxianfetamina/toxicidade , Drogas Ilícitas/toxicidade , Dopamina , Cardiotoxicidade , Metanfetamina/toxicidade , Anfetamina , Cocaína/toxicidade , Neurotransmissores , Aminoácidos , Mamíferos
17.
J Cardiovasc Pharmacol ; 83(3): 243-250, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38181215

RESUMO

ABSTRACT: Amphetamine derivatives are used worldwide legally or illegally and intoxications may be accompanied by cardiac arrhythmias. Here, we tested contractile effects of cumulative applied (±)-amphetamine, pseudoephedrine, nor-pseudoephedrine (cathine), and cathinone in electrically stimulated (1 Hz) human right atrial preparations (HAP) and mouse left atrial preparations and in spontaneously beating mouse right atrial preparations. In mouse atrial preparations, amphetamine increased force of contraction and beating rate in a concentration- and time-dependent manner, starting at 1 µM in left atrial preparations to 157.1% ± 3.0% and right atrial preparations to 146.6% ± 9.8% at 10 µM, respectively [mean ± standard error of the mean (SEM); n = 5; P < 0.05]. Pseudoephedrine, cathine, or cathinone alone were ineffective in mouse atrial preparations but after pre-incubation with the phosphodiesterase IV inhibitor rolipram (0.1 µM), a positive inotropic effect was noted (mean ± SEM: pseudoephedrine: 112.3% ± 9.8%; cathine: 109.0% ± 4.3%; cathinone: 138.3% ± 21.2%). The effects of all drugs were greatly attenuated by 10 µM cocaine or 10 µM propranolol treatments. However, In HAP, not only amphetamine (to a mean ± SEM of 208% ± 32%) but also pseudoephedrine (to a mean ± SEM of 287% ± 60%), cathine (to a mean ± SEM of 234% ± 52%), and cathinone (to a mean ± SEM of 217% ± 65%) increased force of contraction without the need of phosphodiesterase inhibition. The contractile effects in HAP were attenuated by 10 µM cocaine and antagonized by 10 µM propranolol. We conclude that amphetamine, pseudoephedrine, cathine, and cathinone act probably via release of noradrenaline from cardiac stores as indirect sympathomimetic agents in mouse and more pronounced in human atrial preparations.


Assuntos
Alcaloides , Anfetamina , Cocaína , Fenilpropanolamina , Humanos , Anfetamina/farmacologia , Pseudoefedrina/farmacologia , Propranolol/farmacologia , Contração Miocárdica
18.
J Atten Disord ; 28(5): 810-819, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38214178

RESUMO

OBJECTIVE: To examine the effects of triple beaded mixed amphetamine salts (TB MAS) on ADHD and executive dysfunction symptoms throughout the day in adults with DSM-5 ADHD. METHOD: This was a 6 week, single-blind, placebo-lead in trial of TB MAS (12.5-37.5 mg/day); all participants received 2 weeks of single-blind placebo); one individual was a placebo responder and was discontinued. One of these 18 dropped after 1 week on 12.5 mg/day, while all others completed the trial and received 37.5 mg/day TB MAS. RESULTS: There were significant effects of TB MAS on all clinical measures, including investigator overall symptoms (AISRS); self-report overall (ASRS), time-sensitive ADHD (TASS) scores throughout the day, impairment (CGI) and executive function scores (BRIEF-A). TB MAS was generally well tolerated. CONCLUSIONS: This study extends prior findings of TB MAS to adults with DSM-5 ADHD; it further re-validates findings of efficacy of TB MAS throughout the day.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central , Adulto , Humanos , Anfetamina/uso terapêutico , Estimulantes do Sistema Nervoso Central/efeitos adversos , Sais/uso terapêutico , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Método Simples-Cego , Preparações de Ação Retardada/uso terapêutico , Método Duplo-Cego , Relação Dose-Resposta a Droga , Resultado do Tratamento
19.
J Atten Disord ; 28(5): 847-860, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38293912

RESUMO

BACKGROUND: Research examining the potential effects of stimulant exposure in childhood on subsequent development of substance use disorder (SUD) have focused on differences in the brain reward system as a function of risk. METHODS: 18 drug naïve children ages 7 to 12 years (11 High Risk [ADHD + ODD/CD]; 7 Low Risk [ADHD only]), underwent fMRI scans before and after treatment with mixed amphetamine salts, extended release (MAS-XR). We examined correlations between clinical ratings and fMRI activation at baseline and following treatment as a function of risk status. RESULTS: High Risk children had higher activation than Low Risk children at baseline during both the Reward and Surprising Non-Reward conditions. Treatment produced strong differential effects on brain activation pertinent to group and reward outcome. CONCLUSIONS: Findings support the hypothesized role of reward mechanisms in SUD risk, and suggest that stimulant treatment may have differential effects on reward processing in relation to SUD risk.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central , Transtornos Relacionados ao Uso de Substâncias , Criança , Humanos , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Anfetamina/efeitos adversos , Encéfalo/diagnóstico por imagem , Recompensa
20.
Int J Neuropsychopharmacol ; 27(2)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38174899

RESUMO

BACKGROUND: Rats emit 50-kHz ultrasonic vocalizations (USVs) in response to nonpharmacological and pharmacological stimuli, with addictive psychostimulants being the most effective drugs that elicit calling behavior in rats. Earlier investigations found that dopamine D1-like and D2-like receptors modulate the emission of 50-kHz USVs stimulated in rats by the acute administration of addictive psychostimulants. Conversely, information is lacking on how dopamine D1-like and D2-like receptors modulate calling behavior in rats that are repeatedly treated with addictive psychostimulants. METHODS: We evaluated the emission of 50-kHz USVs in rats repeatedly treated (×5 on alternate days) with amphetamine (1 mg/kg, i.p.) either alone or together with (1) SCH 23390 (0.1-1 mg/kg, s.c.), a dopamine D1 receptor antagonist; (2) raclopride (0.3-1 mg/kg, s.c.), a selective dopamine D2 receptor antagonist; or (3) a combination of SCH 23390 and raclopride (0.1 + 0.3 mg/kg, s.c.). Calling behavior of rats was recorded following pharmacological treatment, as well as in response to the presentation of amphetamine-paired cues and to amphetamine challenge (both performed 7 days after treatment discontinuation). RESULTS: Amphetamine-treated rats displayed a sensitized 50-kHz USV emission during repeated treatment, as well as marked calling behavior in response to amphetamine-paired cues and to amphetamine challenge. Antagonism of D1 or D2 receptors either significantly suppressed or attenuated the emission of 50-kHz USVs in amphetamine-treated rats, with a maximal effect after synergistic antagonism of both receptors. CONCLUSIONS: These results shed further light on how dopamine transmission modulates the emission of 50-kHz USVs in rats treated with psychoactive drugs.


Assuntos
Anfetamina , Estimulantes do Sistema Nervoso Central , Ratos , Animais , Anfetamina/farmacologia , Dopamina , Antagonistas de Dopamina/farmacologia , Racloprida , Ultrassom , Vocalização Animal , Estimulantes do Sistema Nervoso Central/farmacologia
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