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Neuroscience and Biobehavioral Reviews Dec 2023Methamphetamine use disorder (MUD) is a neuropsychiatric disorder characterized by binge drug taking episodes, intervals of abstinence, and relapses to drug use even... (Review)
Review
Methamphetamine use disorder (MUD) is a neuropsychiatric disorder characterized by binge drug taking episodes, intervals of abstinence, and relapses to drug use even during treatment. MUD has been modeled in rodents and investigators are attempting to identify its molecular bases. Preclinical experiments have shown that different schedules of methamphetamine self-administration can cause diverse transcriptional changes in the dorsal striatum of Sprague-Dawley rats. In the present review, we present data on differentially expressed genes (DEGs) identified in the rat striatum following methamphetamine intake. These include genes involved in transcription regulation, potassium channel function, and neuroinflammation. We then use the striatal data to discuss the potential significance of the molecular changes induced by methamphetamine by reviewing concordant or discordant data from the literature. This review identified potential molecular targets for pharmacological interventions. Nevertheless, there is a need for more research on methamphetamine-induced transcriptional consequences in various brain regions. These data should provide a more detailed neuroanatomical map of methamphetamine-induced changes and should better inform therapeutic interventions against MUD.
Topics: Animals; Methamphetamine; Amphetamine-Related Disorders; Rats; Disease Models, Animal; Central Nervous System Stimulants; Epigenesis, Genetic; Recurrence; Brain
PubMed: 38707245
DOI: 10.1016/j.neubiorev.2023.105440 -
Journal of Analytical Toxicology Jun 2024Illegal amphetamine is usually composed of a racemic mixture of the two enantiomers (S)- and (R)-amphetamine. However, when amphetamine is used in medical treatment, the...
Illegal amphetamine is usually composed of a racemic mixture of the two enantiomers (S)- and (R)-amphetamine. However, when amphetamine is used in medical treatment, the more potent (S)-amphetamine enantiomer is used. Enantiomer-specific analysis of (S)- and (R)-amphetamine is therefore used to separate legal medical use from illegal recreational use. The aim of the present study was to describe our experience with enantiomer-specific analysis of amphetamine in urine and oral fluid, as well as blood, and examine whether the distribution of the two enantiomers seems to be the same in different matrices. We investigated 1,722 urine samples and 1,977 oral fluid samples from prison inmates, and 652 blood samples from suspected drugged drivers, where prescription of amphetamine was reported. Analyses were performed using ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS-MS). The enantiomer separation was achieved by using a chiral column, and results from the method validation are reported. Samples containing <60% (S)-amphetamine were interpreted as representing illegal use of amphetamine. The distribution of the two enantiomers was compared between different matrices. In urine and oral fluid, the mean amount of (S)-amphetamine was 45.2 and 43.7%, respectively, while in blood, the mean amount of (S)-amphetamine was 45.8%. There was no statistically significant difference in the amount of (S)-amphetamine between urine and oral fluid samples and between urine and blood samples, but the difference was significant in blood compared to oral fluid samples (P < 0.001). Comparison of urine and oral fluid between similar populations indicated that enantiomers of amphetamine can be interpreted in the same way, although marginally higher amounts of (R)-amphetamine may occur in oral fluid. Oral fluid, having several advantages, especially during collection, could be a preferred matrix in testing for illegal amphetamine intake in users of medical amphetamine.
Topics: Humans; Amphetamine; Saliva; Stereoisomerism; Substance Abuse Detection; Tandem Mass Spectrometry; Chromatography, High Pressure Liquid; Central Nervous System Stimulants
PubMed: 38706158
DOI: 10.1093/jat/bkae038 -
Drug and Alcohol Review Jul 2024Contingency management (CM) is the most effective treatment for reducing methamphetamine use. We sought to understand why CM has not been taken up to manage...
INTRODUCTION
Contingency management (CM) is the most effective treatment for reducing methamphetamine use. We sought to understand why CM has not been taken up to manage methamphetamine use disorder in Australia.
METHODS
Six focus groups (4-8 participants per group) were conducted with health workers from agencies in Australia that provided drug-related health care to people who use methamphetamine. These agencies had no previous experience delivering CM for substance use. The potential acceptability and feasibility of implementing CM in their services were discussed.
RESULTS
Participants felt that it would be beneficial to have an evidence-based treatment for methamphetamine use disorder. This sentiment was offset by concerns that CM conflicted with a client-centred harm-reduction approach and that it dictated the goal of treatment as abstinence. It was also perceived as potentially coercive and seen to reify the power imbalance in the therapeutic relationship and therefore potentially reinforce stigma. There was also concern about the public's perception and the political acceptability of CM, who would fund CM, and the inequity of providing incentives only to clients with a methamphetamine use disorder. Some concerns could be ameliorated if the goals and structure of CM could be tailored to a client's needs.
DISCUSSION AND CONCLUSIONS
Many healthcare workers were keen to offer CM as an effective treatment option for people with methamphetamine use disorder, but CM would need to be sufficiently flexible to allow it to be tailored to client needs and implemented in a way that did not adversely impact the therapeutic relationship.
Topics: Humans; Australia; Amphetamine-Related Disorders; Methamphetamine; Health Personnel; Focus Groups; Harm Reduction; Attitude of Health Personnel; Behavior Therapy; Female; Male
PubMed: 38704742
DOI: 10.1111/dar.13853 -
Respiratory Physiology & Neurobiology Aug 2024The objective of this study is to explore the transport, size growth, and deposition of Salbutamol Sulphate (SS) using Computational Fluid Dynamics (CFD). A CT-based...
The objective of this study is to explore the transport, size growth, and deposition of Salbutamol Sulphate (SS) using Computational Fluid Dynamics (CFD). A CT-based realistic model of human airways from the oral cavity to the 5th generation of the lung was utilized as the computational domain. Four Test Cases (TC) with varying temperature and relative humidity (RH) under two inspiratory waveforms were considered to completely evaluate the impact of inhalation conditions on particle growth. Salbutamol Sulphate (SS) is a β2-adrenergic agonist and has been extensively used for asthma treatment. A monodispersed distribution of SS particles with an initial diameter of 167 nm was considered at the mouth inlet based on pharmaceutical data. Results indicated that inhalation of saturated/supersaturated air (RH>100%) leads to significant hygroscopic growth of SS particles with a factor of 10. In addition, the deposition efficiency of SS particles under the Quick and Deep (QD) inhalation profile was enhanced as the flow temperature and humidity increased. However, the implementation of Slow and Deep (SD) inspiratory waveform revealed that the same particle size growth is achieved in the respiratory system with lower deposition efficiency in the mouth-throat (less than 3%) and tracheobronchial airway (less than 2.18%). For the escaped particles form the right lung, in the SD waveform under TC 3, the maximum particle size distribution was for 600 nm particles with 25% probability. In the left lung, 30% of the particles were increased up to 950 nm in size. For the QD waveform in TC 3 and TC4, the most frequent particles were 800 nm with 36% probability. This holds practical significance in the context of deep lung delivery for asthmatic patients with enhanced deposition efficiency and large particle size. The findings of the present study can contribute to the development of targeted drug delivery strategies for the treatment of pulmonary diseases using hygroscopic dry powder formulations.
Topics: Humans; Albuterol; Computer Simulation; Administration, Inhalation; Bronchodilator Agents; Hydrodynamics; Models, Biological; Particle Size; Humidity; Wettability; Respiratory System; Lung
PubMed: 38703974
DOI: 10.1016/j.resp.2024.104271 -
Journal of Pharmaceutical and... Aug 2024We present a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying fenfluramine (FFA), its active metabolite norfenfluramine (norFFA),...
We present a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying fenfluramine (FFA), its active metabolite norfenfluramine (norFFA), and Epidyolex®, a pure cannabidiol (CBD) oral solution in plasma. Recently approved by the EMA for the adjunctive treatment of refractory seizures in patients with Dravet and Lennox-Gastaut syndromes aged above 2 years, FFA and CBD still do not have established therapeutic blood ranges, and thus need careful drug monitoring to manage potential pharmacokinetic and pharmacodynamic interactions. Our method, validated by ICH guidelines M10, utilizes a rapid extraction protocol from 100 µL of human plasma and a reversed-phase C-18 HPLC column, with deuterated internal standards. The Thermofisher Quantiva triple-quadrupole MS coupled with an Ultimate 3000 UHPLC allowed multiple reaction monitoring detection, ensuring precise analyte quantification. The assay exhibited linear responses across a broad spectrum of concentrations: ranging from 1.64 to 1000 ng/mL for both FFA and CBD, and from 0.82 to 500 ng/mL for norFFA. The method proves accurate and reproducible, free from matrix effect. Additionally, FFA stability in plasma at 4 °C and -20 °C for up to 7 days bolsters its clinical applicability. Plasma concentrations detected in patients samples, expressed as mean ± standard deviation, were 0.36 ± 0.09 ng/mL for FFA, 19.67 ± 1.22 ng/mL for norFFA. This method stands as a robust tool for therapeutic drug monitoring (TDM) of FFA and CBD, offering significant utility in assessing drug-drug interactions in co-treated patients, thus contributing to optimized patient care in complex therapeutic scenarios.
Topics: Humans; Cannabidiol; Tandem Mass Spectrometry; Drug Monitoring; Child; Fenfluramine; Chromatography, High Pressure Liquid; Epilepsy; Reproducibility of Results; Anticonvulsants; Child, Preschool; Chromatography, Liquid; Liquid Chromatography-Mass Spectrometry
PubMed: 38703746
DOI: 10.1016/j.jpba.2024.116174 -
CNS Neuroscience & Therapeutics May 2024This study aims to investigate the pharmacological effects and the underlying mechanism of cannabidiol (CBD) on methamphetamine (METH)-induced relapse and behavioral...
AIMS
This study aims to investigate the pharmacological effects and the underlying mechanism of cannabidiol (CBD) on methamphetamine (METH)-induced relapse and behavioral sensitization in male mice.
METHODS
The conditioned place preference (CPP) test with a biased paradigm and open-field test were used to assess the effects of CBD on METH-induced relapse and behavioral sensitization in male mice. RNA sequencing and bioinformatics analysis was employed to identify differential expressed (DE) circRNAs, miRNAs, and mRNAs in the nucleus accumbens (NAc) of mice, and the interaction among them was predicted using competing endogenous RNAs (ceRNAs) network analysis.
RESULTS
Chronic administration of CBD (40 mg/kg) during the METH withdrawal phase alleviated METH (2 mg/kg)-induced CPP reinstatement and behavioral sensitization in mice, as well as mood and cognitive impairments following behavioral sensitization. Furthermore, 42 DEcircRNAs, 11 DEmiRNAs, and 40 DEmRNAs were identified in the NAc of mice. The circMeis2-miR-183-5p-Kcnj5 network in the NAc of mice is involved in the effects of CBD on METH-induced CPP reinstatement and behavioral sensitization.
CONCLUSIONS
This study constructed the ceRNAs network for the first time, revealing the potential mechanism of CBD in treating METH-induced CPP reinstatement and behavioral sensitization, thus advancing the application of CBD in METH use disorders.
Topics: Animals; Cannabidiol; Male; Methamphetamine; MicroRNAs; Mice; RNA, Circular; RNA, Messenger; Mice, Inbred C57BL; Recurrence; Central Nervous System Stimulants; Nucleus Accumbens; Gene Regulatory Networks
PubMed: 38702929
DOI: 10.1111/cns.14737 -
BMC Pediatrics May 2024Cough variant asthma (CVA) is one of the most common causes of chronic cough in children worldwide. The diagnosis of CVA in children remains challenging. This study...
BACKGROUND
Cough variant asthma (CVA) is one of the most common causes of chronic cough in children worldwide. The diagnosis of CVA in children remains challenging. This study aimed to assess the diagnostic utility of impulse oscillometry (IOS) pulmonary function in children with CVA.
METHODS
This study included children aged 4 to 12 years diagnosed with CVA who underwent IOS pulmonary function and bronchodilation (BD) tests. A control group of healthy children was matched. Pre- and post-BD IOS parameters were recorded and presented as mean ± standard deviation or median. Receiver operating characteristic (ROC) curves were plotted, and the area under the curve (AUC) was calculated to evaluate the discriminatory potential of the IOS parameters for diagnosing CVA.
RESULTS
A total of 180 patients with CVA and 65 control subjects were included. The baseline IOS parameters in the CVA group, except X5%pred, were significantly greater compared to the control group. After inhalation of salbutamol sulfate, all IOS parameters improved significantly in the CVA group. However, Z5%pred, R5%pred, and R20%pred remained greater in the CVA group compared to the control group. The improvement rates of IOS parameters in the CVA group significantly surpassed those in the control group. The ROC curve results for pre-BD IOS parameters and the improvement rate during the BD test showed that the combinations of pre-Z5%pred+Z5% and pre-R5%pred+R5% achieved the highest AUC value of 0.920 and 0.898, respectively. The AUC values of these combined parameters surpassed those of individual ones.
CONCLUSIONS
This study highlights that children with CVA exhibit greater IOS parameters compared to healthy children. The changes in IOS parameters during the BD test provided valuable diagnostic information for CVA, and the combination of various parameters can help pediatricians accurately identify CVA in children.
Topics: Humans; Cough; Child; Asthma; Male; Female; Oscillometry; Child, Preschool; Case-Control Studies; ROC Curve; Albuterol; Respiratory Function Tests; Bronchodilator Agents; Cough-Variant Asthma
PubMed: 38702638
DOI: 10.1186/s12887-024-04749-4 -
American Journal of Physiology. Heart... Jul 2024Right ventricular failure (RVF) is a major cause of early mortality after heart transplantation (HT). Isoproterenol (Iso) has chronotropic, inotropic, and vasodilatory... (Observational Study)
Observational Study
Right ventricular failure (RVF) is a major cause of early mortality after heart transplantation (HT). Isoproterenol (Iso) has chronotropic, inotropic, and vasodilatory properties, which might improve right ventricle function in this setting. We aimed to investigate the hemodynamic effects of isoproterenol on patients with post-HT RVF. We conducted a 1-yr retrospective observational study including patients receiving isoproterenol (Iso) and dobutamine for early RVF after HT. A comprehensive multiparametric hemodynamic evaluation was performed successively three times: no isoproterenol, low doses: 0.025 µg/kg/min, and high doses: 0.05 µg/kg/min (henceforth, respectively, called no Iso, low Iso, and high Iso). From June 2022 to June 2023, 25 patients, median [interquartile range (IQR) 25-75] age 54 [38-61] yr, were included. Before isoproterenol was introduced, all patients received dobutamine, and 15 (60%) were on venoarterial extracorporeal membrane oxygenation (VA-ECMO). Isoproterenol significantly increased heart rate from 84 [77-99] (no Iso) to 91 [88-106] (low Iso) and 102 [90-122] beats/min (high Iso, < 0.001). Similarly, cardiac index rose from 2.3 [1.4-3.1] to 2.7 [1.8-3.4] and 3 [1.9-3.7] L/min/m ( < 0.001) with a concomitant increase in indexed stroke volume (28 [17-34] to 31 [20-34] and 33 [23-35] mL/m, < 0.05). Effective pulmonary arterial elastance and pressures were not modified by isoproterenol. Pulmonary vascular resistance (PVR) tended to decrease from 2.9 [1.4-3.6] to 2.3 [1.3-3.5] wood units (WU), = 0.06. Right ventricular ejection fraction/systolic pulmonary artery pressure (sPAP) evaluating right ventricle-pulmonary artery (RV-PA) coupling increased after isoproterenol from 0.8 to 0.9 and 1%·mmHg ( = 0.001). In conclusion, in post-HT RVF, isoproterenol exhibits chronotropic and inotropic effects, thereby improving RV-PA coupling and resulting in a clinically relevant increase in the cardiac index. This study offers a detailed and comprehensive hemodynamic investigation at the bedside, illustrating the favorable impact of isoproterenol on right ventricular-pulmonary arterial coupling and global hemodynamics. It elucidates the physiological effects of an underused inotropic strategy in a critical clinical scenario. By enhancing cardiac hemodynamics, isoproterenol has the potential to expedite right ventricular recovery and mitigate primary graft dysfunction, thereby reducing the duration of mechanical support and intensive care unit stay posttransplantation.
Topics: Humans; Isoproterenol; Heart Transplantation; Middle Aged; Male; Pulmonary Artery; Female; Ventricular Function, Right; Retrospective Studies; Adult; Hemodynamics; Aged; Ventricular Dysfunction, Right; Heart Failure; Dobutamine; Treatment Outcome; Heart Rate; Recovery of Function; Cardiotonic Agents
PubMed: 38700470
DOI: 10.1152/ajpheart.00200.2024 -
Angewandte Chemie (International Ed. in... May 2024β-Phenethylamines are widely represented in biologically and pharmacologically active organic small molecules. Here, we introduce N-pyridinium aziridines as latent dual...
β-Phenethylamines are widely represented in biologically and pharmacologically active organic small molecules. Here, we introduce N-pyridinium aziridines as latent dual electrophiles for the synthesis of β-phenethylamines. Bromide-promoted ring opening generates β-halopyridinium amines. Selective Ni-catalyzed C-C cross-coupling between organozinc nucleophiles and the benzylic C-Br electrophile affords a diverse family of β-functionalized phenethylaminopyridinium salts, and coupling is stereoconvergent in the presence of chiral ligands. Subsequent Ni-catalyzed reductive N-N bond activation within the β-functionalized phenethylaminopyridinium salts furnishes the products of formal olefin carboamination. Other reductive N-N cleavage reactions are demonstrated to provide access to free primary amines, alkylated amines, heterocycles, and products derived from N-centered radical chemistry. The developed reaction sequence can be implemented in the context of complex molecules and natural product derivatives. Together, the described results provide a general and modular synthesis of β-phenethylamines and significantly expand the utility of N-pyridinium aziridines as linchpins in chemical synthesis.
PubMed: 38699820
DOI: 10.1002/anie.202406335 -
Therapeutic Advances in Respiratory... 2024This summary describes the results of a clinical study called MANDALA that was published in the in 2022. In the MANDALA study, researchers looked at a new asthma rescue... (Review)
Review
This summary describes the results of a clinical study called MANDALA that was published in the in 2022. In the MANDALA study, researchers looked at a new asthma rescue inhaler that contains both and in a single inhaler (known as , AIRSUPRA™). This summary describes the results for people aged 18 yearsand older who took part in the study.
Topics: Humans; Asthma; Albuterol; Drug Combinations; Administration, Inhalation; Bronchodilator Agents; Budesonide; Adult; Middle Aged; Male; Female; Nebulizers and Vaporizers; Treatment Outcome; Adolescent; Young Adult; Aged; Anti-Asthmatic Agents
PubMed: 38698565
DOI: 10.1177/17534666241232264