-
Handbook of Clinical Neurology 2018Phenethylamine-induced hyperthermia can occur following exposure to several different types of illicit stimulants, such as amphetamine, methamphetamine,... (Review)
Review
Phenethylamine-induced hyperthermia can occur following exposure to several different types of illicit stimulants, such as amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine ("Molly"), synthetic cathinones ("bath salts"), and N-methoxybenyl ("NBOMe"), to name a few. Peripheral norepinephrine release mediated by these sympathomimetic agents induces a double-edged sword of heat accumulation through β-adrenoreceptor-dependent activation of uncoupling protein (UCP1 and 3)-regulated thermogenesis and loss of heat dissipation through α-adrenoreceptor-mediated vasoconstriction. Additionally, thyroid hormones are important determinants of the capacity of thermogenesis induced by phenethylamines through the regulation of free fatty acid release and the transcriptional activation of a host of metabolic genes, including adrenergic receptors and mitochondrial uncoupling proteins. Here, we review the central and peripheral mechanistic "triggers" of phenethylamine-induced hyperthermia and outline potential pharmacologic interventions for managing phenethylamine-induced hyperthermia based on these recently discovered hyperthermia mediators.
Topics: Animals; Body Temperature Regulation; Fever; Humans; Illicit Drugs; Mitochondrial Uncoupling Proteins; Norepinephrine; Phenethylamines; Substance-Related Disorders
PubMed: 30459028
DOI: 10.1016/B978-0-444-64074-1.00036-7 -
Der Ophthalmologe : Zeitschrift Der... May 2021Approximately 40% of all open-angle glaucomas do not show high intraocular pressure (IOP). Vascular risk factors play an important role in the pathogeneses of normal... (Review)
Review
BACKGROUND
Approximately 40% of all open-angle glaucomas do not show high intraocular pressure (IOP). Vascular risk factors play an important role in the pathogeneses of normal pressure glaucoma but high pressure glaucoma is also often accompanied by significant vascular components.
OBJECTIVE
What are the practice relevant possibilities of vascular glaucoma treatment?
MATERIAL AND METHODS
An evaluation of scientific articles from PubMed dealing with vascular glaucoma was carried out.
RESULTS
The treatment of vascular risk factors in glaucoma patients requires a thorough medical history regarding vascular symptoms (peripheral vasospasm, tinnitus, migraine etc.) and information on the presence of systemic diseases. Furthermore, a 24h blood pressure profile and the determination of the fat metabolism status represent important and simple examinations.
CONCLUSION
Besides optimizing systemic blood pressure, reducing an increased central retinal venous pressure, treatment with statins, calcium channel blockers, Ginkgo biloba extract, increased physical exercise and fluid replacement are options to ameliorate vascular conditions. An interdisciplinary cooperation with general practitioners and internists is an important component of holistic treatment.
Topics: Ethanolamines; Glaucoma; Humans; Intraocular Pressure; Phenethylamines
PubMed: 33026527
DOI: 10.1007/s00347-020-01239-7 -
International Journal of Molecular... Aug 2022Dofetilide is a rapid delayed rectifier potassium current inhibitor widely used to prevent the recurrence of atrial fibrillation and flutter. The clinical use of this...
Dofetilide is a rapid delayed rectifier potassium current inhibitor widely used to prevent the recurrence of atrial fibrillation and flutter. The clinical use of this drug is associated with increases in QTc interval, which predispose patients to ventricular cardiac arrhythmias. The mechanisms involved in the disposition of dofetilide, including its movement in and out of cardiomyocytes, remain unknown. Using a xenobiotic transporter screen, we identified MATE1 () as a transporter of dofetilide and found that genetic knockout or pharmacological inhibition of MATE1 in mice was associated with enhanced retention of dofetilide in cardiomyocytes and increased QTc prolongation. The urinary excretion of dofetilide was also dependent on the MATE1 genotype, and we found that this transport mechanism provides a mechanistic basis for previously recorded drug-drug interactions of dofetilide with various contraindicated drugs, including bictegravir, cimetidine, ketoconazole, and verapamil. The translational significance of these observations was examined with a physiologically-based pharmacokinetic model that adequately predicted the drug-drug interaction liabilities in humans. These findings support the thesis that MATE1 serves a conserved cardioprotective role by restricting excessive cellular accumulation and warrant caution against the concurrent administration of potent MATE1 inhibitors and cardiotoxic substrates with a narrow therapeutic window.
Topics: Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Humans; Mice; Phenethylamines; Sulfonamides
PubMed: 35955741
DOI: 10.3390/ijms23158607 -
Brain, Behavior and Evolution 2020Phenethylamines (e.g., methamphetamine) are a common source of drug toxicity. Phenethylamine-induced hyperthermia (PIH) can activate a cascade of events that may result... (Review)
Review
Phenethylamines (e.g., methamphetamine) are a common source of drug toxicity. Phenethylamine-induced hyperthermia (PIH) can activate a cascade of events that may result in rhabdomyolysis, coagulopathy, and even death. Here, we review recent evidence that suggests a potential link between the gut-brain axis and PIH. Within the preoptic area of the hypothalamus, phenethylamines lead to changes in catecholamine levels, that activate the sympathetic nervous system (SNS) and increase the peripheral levels of norepinephrine (NE), resulting in: (1) the loss of heat dissipation through α1 adrenergic receptor (α1-AR)-mediated vasoconstriction, (2) heat generation through β-AR activation and subsequent free fatty acid (FFA) activation of uncoupling proteins (UCPs) in brown and white adipose tissue, and (3) alteration of the gut microbiome and its link to the gut-brain axis. Recent studies have shown that phenethylamine derivatives can influence the composition of the gut microbiome and thus its metabolic potential. Phenethylamines increase the relative level of Proteuswhich has been linked to enhanced NE turnover. Bidirectional fecal microbial transplants (FMT) between PIH-tolerant and PIH-naïve rats demonstrated that the transplantation of gut microbiome can confer phenotypic hyperthermic and tolerant responses to phenethylamines. These phenethylamine-mediated changes in the gut microbiome were also associated with epigenetic changes in the mediators of thermogenesis. Given the significant role that the microbiome has been shown to play in the maintenance of body temperature, we outline current studies demonstrating the effects of phenethylamines on the gut microbiome and how these microbiome changes may mechanistically contribute to alterations in body temperature.
Topics: Animals; Gastrointestinal Microbiome; Hyperthermia; Phenethylamines; Rats; Thermogenesis
PubMed: 33472193
DOI: 10.1159/000512098 -
Forensic Toxicology Jan 2023The present review aims to provide an overview of methods for the quantification of 2,5-dimethoxy-amphetamines and -phenethylamines in different biological matrices,... (Review)
Review
PURPOSE
The present review aims to provide an overview of methods for the quantification of 2,5-dimethoxy-amphetamines and -phenethylamines in different biological matrices, both traditional and alternative ones.
METHODS
A complete literature search was carried out with PubMed, Scopus and the World Wide Web using relevant keywords, e.g., designer drugs, amphetamines, phenethylamines, and biological matrices.
RESULTS
Synthetic phenethylamines represent one of the largest classes of "designer drugs", obtained through chemical structure modifications of psychoactive substances to increase their pharmacological activities. This practice is also favored by the fact that every new synthetic compound is not considered illegal by existing legislation. Generally, in a toxicological laboratory, the first monitoring of drugs of abuse is made by rapid screening tests that sometimes can occur in false positive or false negative results. To reduce evaluation errors, it is mandatory to submit the positive samples to confirmatory methods, such as gas chromatography or liquid chromatography combined to mass spectrometry, for a more specific qualitative and quantitative analysis.
CONCLUSIONS
This review highlights the great need for updated comprehensive analytical methods, particularly when analyzing biological matrices, both traditional and alternative ones, for the search of newly emerging designer drugs.
Topics: Phenethylamines; Gas Chromatography-Mass Spectrometry; Amphetamines; Mass Spectrometry; Chromatography, Liquid
PubMed: 36652064
DOI: 10.1007/s11419-022-00638-6 -
Journal of Cardiovascular Pharmacology... Jan 2019Dofetilide is a class III antiarrhythmic agent approved by the Food and Drug Administration for the conversion of atrial fibrillation and atrial flutter and maintenance... (Review)
Review
Dofetilide is a class III antiarrhythmic agent approved by the Food and Drug Administration for the conversion of atrial fibrillation and atrial flutter and maintenance of sinus rhythm in symptomatic patients with persistent arrhythmia. Drug trials showed neutral mortality in post-myocardial infarction patients and those with heart failure. This is a review of postmarket data, including real-world efficacy and safety in a variety of populations. Dofetilide has been used off-label with success in patients with paroxysmal atrial fibrillation and atrial flutter, as well as atrial tachycardia and ventricular tachycardia. The real-world acute conversion rate of atrial fibrillation and atrial flutter is higher than that reported in clinical trials. Dofetilide has an acceptable safety profile when initiated (or reloaded) under hospital monitoring and dosed according to creatinine clearance. Dofetilide is well tolerated and a good choice for patients with acceptable renal function and a normal QT interval, especially if atrioventricular nodal blockade needs to be avoided.
Topics: Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Clinical Decision-Making; Heart Conduction System; Heart Rate; Humans; Patient Selection; Phenethylamines; Potassium Channel Blockers; Risk Factors; Sulfonamides; Treatment Outcome
PubMed: 29940780
DOI: 10.1177/1074248418784288 -
Drug and Alcohol Dependence Jul 2020Synthetic phenethylamines are widely abused drugs, comprising new psychoactive substances such as synthetic cathinones, but also well-known amphetamines such as... (Review)
Review
Synthetic phenethylamines are widely abused drugs, comprising new psychoactive substances such as synthetic cathinones, but also well-known amphetamines such as methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). Cathinones and amphetamines share many toxicodynamic mechanisms. One of their potentially life-threatening consequences, particularly of MDMA, is serotonin-mediated hyponatraemia. Herein, we review the state of the art on phenethylamine-induced hyponatremia; discuss the mechanisms involved; and present the preventive and therapeutic measures. Hyponatraemia mediated by phenethylamines results from increased secretion of antidiuretic hormone (ADH) and consequent kidney water reabsorption, additionally involving diaphoresis and polydipsia. Data for MDMA suggest that acute hyponatraemia elicited by cathinones may also be a consequence of metabolic activation. The literature often reveals hyponatraemia-associated complications such as cerebral oedema, cerebellar tonsillar herniation and coma that may evolve to a fatal outcome, particularly in women. Ready availability of fluids and the recommendation to drink copiously at the rave scene to counteract hyperthermia, often precipitate water intoxication. Users should be advised about the importance of controlling fluid intake while using phenethylamines. At early signs of adverse effects, medical assistance should be promptly sought. Severe hyponatraemia (<130 mmol sodium/L plasma) may be corrected with hypertonic saline or suppression of fluid intake. Also, clinicians should be made aware of the hyponatraemic potential of these drugs and encouraged to report future cases of toxicity to increase knowledge on this potentially lethal outcome.
Topics: Alcohol Drinking; Alkaloids; Amphetamine; Drinking; Humans; Hyponatremia; Illicit Drugs; N-Methyl-3,4-methylenedioxyamphetamine; Neurophysins; Phenethylamines; Protein Precursors; Vasopressins
PubMed: 32460203
DOI: 10.1016/j.drugalcdep.2020.108045 -
International Journal of Molecular... Dec 2020Psychedelic and stimulating phenethylamines belong to the family of new psychoactive substances (NPS). The acute toxicity framework has begun to be investigated, while...
Psychedelic and stimulating phenethylamines belong to the family of new psychoactive substances (NPS). The acute toxicity framework has begun to be investigated, while studies showing genotoxic potential are very limited or not available. Therefore, in order to fill this gap, the aim of the present work was to evaluate the genotoxicity by treating TK6 cells with 2C-H, 2C-I, 2C-B, 25B-NBOMe, and the popular 3,4-Methylenedioxymethylamphetamine (MDMA). On the basis of cytotoxicity and cytostasis results, we selected the concentrations (6.25-35 µM) to be used in genotoxicity analysis. We used the micronucleus (MN) as indicator of genetic damage and analyzed the MNi frequency fold increase by an automated flow cytometric protocol. All substances, except MDMA, resulted genotoxic; therefore, we evaluated reactive oxygen species (ROS) induction as a possible mechanism at the basis of the demonstrated genotoxicity. The obtained results showed a statistically significant increase in ROS levels for all genotoxic phenethylamines confirming this hypothesis. Our results highlight the importance of genotoxicity evaluation for a complete assessment of the risk associated also with NPS exposure. Indeed, the subjects who do not have hazardous behaviors or require hospitalization by using active but still "safe" doses could run into genotoxicity and in the well-known long-term effects associated.
Topics: Anisoles; Apoptosis; Cell Line; Cell Survival; Dimethoxyphenylethylamine; Flow Cytometry; Genes; Hallucinogens; Humans; Micronuclei, Chromosome-Defective; Micronucleus Tests; N-Methyl-3,4-methylenedioxyamphetamine; Phenethylamines; Psychotropic Drugs; Reactive Oxygen Species
PubMed: 33348640
DOI: 10.3390/ijms21249616 -
Therapeutic Drug Monitoring Apr 2016New psychoactive substances (NPSs) are substitutes for classical drugs of abuse and there are now compounds available from all groups of classical drugs of abuse. During... (Review)
Review
BACKGROUND
New psychoactive substances (NPSs) are substitutes for classical drugs of abuse and there are now compounds available from all groups of classical drugs of abuse. During 2014, the number of synthetic cathinones increased dramatically and, together with phenylethylamines, they dominate the NPS markets in the European Union. In total, 31 cathinones and 9 phenylethylamines were encountered in 2014. The aim of this article was to summarize the existing knowledge about the basic pharmacology, metabolism, and human toxicology of relevant synthetic cathinones and phenylethylamines. Compared with existing reviews, we have also compiled the existing case reports from both fatal and nonfatal intoxications.
METHODS
We performed a comprehensive literature search using bibliographic databases PubMed and Web of Science, complemented with Google Scholar. The focus of the literature search was on original articles, case reports, and previously published review articles published in 2014 or earlier.
RESULTS
The rapid increase of NPSs is a growing concern and sets new challenges not only for societies in drug prevention and legislation but also in clinical and forensic toxicology. In vivo and in vitro studies have demonstrated that the pharmacodynamic profile of cathinones is similar to that of other psychomotor stimulants. Metabolism studies show that cathinones and phenylethylamines are extensively metabolized; however, the parent compound is usually detectable in human urine. In vitro studies have shown that many cathinones and phenylethylamines are metabolized by CYP2D6 enzymes. This indicates that these drugs may have many possible drug-drug interactions and that genetic polymorphism may influence their toxicity. However, the clinical and toxicological relevance of CYP2D6 in adverse effects of cathinones and phenylethylamines is questionable, because these compounds are metabolized by other enzymes as well. The toxidromes commonly encountered after ingestion of cathinones and phenylethylamines are mainly of sympathomimetic and hallucinogenic character with a risk of excited delirium and life-threatening cardiovascular effects.
CONCLUSIONS
The acute and chronic toxicity of many NPSs is unknown or very sparsely investigated. There is a need for evidence-based-treatment recommendations for acute intoxications and a demand for new strategies to analyze these compounds in clinical and forensic cases.
Topics: Alkaloids; Animals; Drug-Related Side Effects and Adverse Reactions; Humans; Illicit Drugs; Phenethylamines; Psychotropic Drugs
PubMed: 26587869
DOI: 10.1097/FTD.0000000000000263 -
ACS Chemical Biology Sep 2020The chemosensory system of any animal relies on a vast array of detectors tuned to distinct chemical cues. Odorant receptors and the ion channels of the TRP family are...
The chemosensory system of any animal relies on a vast array of detectors tuned to distinct chemical cues. Odorant receptors and the ion channels of the TRP family are all uniquely expressed in olfactory tissues in a species-specific manner. Great effort has been made to characterize the molecular and pharmacological properties of these proteins. Nevertheless, most of the natural ligands are highly hydrophobic molecules that are not amenable to controlled delivery. We sought to develop photoreleasable, biologically inactive odorants that could be delivered to the target receptor or ion channel and effectively activated by a short light pulse. Chemically distinct ligands eugenol, benzaldehyde, 2-phenethylamine, ethanethiol, butane-1-thiol, and 2,2-dimethylethane-1-thiol were modified by covalently attaching the photoremovable protecting group (8-cyano-7-hydroxyquinolin-2-yl)methyl (CyHQ). The CyHQ derivatives were shown to release the active odorant upon illumination with 365 and 405 nm light. We characterized their bioactivity by measuring activation of recombinant TRPV1 and TRPA1 ion channels expressed in HEK 293 cells and the electroolfactogram (EOG) response from intact mouse olfactory epithelium (OE). Illumination with 405 nm light was sufficient to robustly activate TRP channels within milliseconds of the light pulse. Photoactivation of channels was superior to activation by conventional bath application of the ligands. Photolysis of the CyHQ-protected odorants efficiently activated an EOG response in a dose-dependent manner with kinetics similar to that evoked by the vaporized odorant amyl acetate (AAc). We conclude that CyHQ-based, photoreleasable odorants can be successfully implemented in chemosensory research.
Topics: Animals; Benzaldehydes; Eugenol; Female; HEK293 Cells; Humans; Hydroxyquinolines; Male; Mice; Odorants; Olfactory Mucosa; Phenethylamines; Sulfhydryl Compounds; TRPA1 Cation Channel; TRPV Cation Channels; Ultraviolet Rays
PubMed: 32865973
DOI: 10.1021/acschembio.0c00541