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Circulation Oct 2015Hypokalemia is known to promote ventricular arrhythmias, especially in combination with class III antiarrhythmic drugs like dofetilide. Here, we evaluated the underlying...
BACKGROUND
Hypokalemia is known to promote ventricular arrhythmias, especially in combination with class III antiarrhythmic drugs like dofetilide. Here, we evaluated the underlying molecular mechanisms.
METHODS AND RESULTS
Arrhythmias were recorded in isolated rabbit and rat hearts or patch-clamped ventricular myocytes exposed to hypokalemia (1.0-3.5 mmol/L) in the absence or presence of dofetilide (1 μmol/L). Spontaneous early afterdepolarizations (EADs) and ventricular tachycardia/fibrillation occurred in 50% of hearts at 2.7 mmol/L [K] in the absence of dofetilide and 3.3 mmol/L [K] in its presence. Pretreatment with the Ca-calmodulin kinase II (CaMKII) inhibitor KN-93, but not its inactive analogue KN-92, abolished EADs and hypokalemia-induced ventricular tachycardia/fibrillation, as did the selective late Na current (INa) blocker GS-967. In intact hearts, moderate hypokalemia (2.7 mmol/L) significantly increased tissue CaMKII activity. Computer modeling revealed that EAD generation by hypokalemia (with or without dofetilide) required Na-K pump inhibition to induce intracellular Na and Ca overload with consequent CaMKII activation enhancing late INa and the L-type Ca current. K current suppression by hypokalemia and dofetilide alone in the absence of CaMKII activation were ineffective at causing EADs.
CONCLUSIONS
We conclude that Na-K pump inhibition by even moderate hypokalemia plays a critical role in promoting EAD-mediated arrhythmias by inducing a positive feedback cycle activating CaMKII and enhancing late INa. Class III antiarrhythmic drugs like dofetilide sensitize the heart to this positive feedback loop.
Topics: Action Potentials; Animals; Benzylamines; Computer Simulation; Hypokalemia; Male; Phenethylamines; Pyridines; Rabbits; Rats; Rats, Inbred F344; Sodium-Potassium-Exchanging ATPase; Sulfonamides; Triazoles; Ventricular Fibrillation
PubMed: 26269574
DOI: 10.1161/CIRCULATIONAHA.115.016217 -
Molecules (Basel, Switzerland) Jan 2021Conventional methods employed today for the synthesis of amides often lack of economic and environmental sustainability. Triazine-derived quaternary ammonium salts,...
Conventional methods employed today for the synthesis of amides often lack of economic and environmental sustainability. Triazine-derived quaternary ammonium salts, e.g., 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM(Cl)), emerged as promising dehydro-condensation agents for amide synthesis, although suffering of limited stability and high costs. In the present work, a simple protocol for the synthesis of amides mediated by 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and a -amine has been described and data are compared to DMTMM(Cl) and other CDMT-derived quaternary ammonium salts (DMT-Ams(X), X: Cl or ClO). Different -amines (Ams) were tested for the synthesis of various DMT-Ams(Cl), but only DMTMM(Cl) could be isolated and employed for dehydro-condensation reactions, while all CDMT/-amine systems tested were efficient as dehydro-condensation agents. Interestingly, in best reaction conditions, CDMT and 1,4-dimethylpiperazine gave -phenethyl benzamide in 93% yield in 15 min, with up to half the amount of -amine consumption. The efficiency of CDMT/-amine was further compared to more stable triazine quaternary ammonium salts having a perchlorate counter anion (DMT-Ams(ClO)). Overall CDMT/-amine systems appear to be a viable and more economical alternative to most dehydro-condensation agents employed today.
Topics: Amides; Amines; Benzamides; Carboxylic Acids; Chemistry Techniques, Synthetic; Perchlorates; Phenethylamines; Piperazines; Quaternary Ammonium Compounds; Solvents; Triazines
PubMed: 33401732
DOI: 10.3390/molecules26010191 -
Journal of the American Heart... May 2017Although atrial fibrillation (AF) is the most common abnormal heart rhythm and its prevalence continues to rise, there is a marked paucity of effective and safe...
BACKGROUND
Although atrial fibrillation (AF) is the most common abnormal heart rhythm and its prevalence continues to rise, there is a marked paucity of effective and safe antiarrhythmic drugs for AF. This study was done to test whether combined use of dofetilide and mexiletine exhibits not only a synergistic effect on AF suppression but also a safer profile in drug-induced ventricular proarrhythmias.
METHODS AND RESULTS
The effects of dofetilide plus mexiletine on atrial effective refractory period (ERP), AF inducibility, QT, and QT-related ventricular arrhythmias were studied using the isolated arterially perfused rabbit atrial and ventricular wedge preparations. Dofetilide or mexiletine alone mildly to moderately prolonged atrial ERP, but their combined use produced a markedly rate-dependent increase in atrial ERP. Dofetilide (3 nmol/L) plus mexiletine (10 μmol/L) increased the ERP by 28.2% from 72.2±5.7 to 92.8±5.9 ms (n=9, <0.01) at a pacing rate of 0.5 Hz and by 94.5% from 91.7±5.2 to 178.3±12.0 ms (n=9, <0.01) at 3.3 Hz. Dofetilide plus mexiletine strongly suppressed AF inducibility. On the other hand, dofetilide at 10 nmol/L produced marked QT and T prolongation, steeper QT-BCL and T-BCL slopes, and induced early afterdepolarizations and torsade de pointes in the ventricular wedges. Mexiletine at 10 μmol/L reduced dofetilide-induced QT and T prolongation, QT-BCL and T-BCL slopes, and abolished early afterdepolarizations and torsade de pointes.
CONCLUSIONS
In rabbits, combined use of dofetilide and mexiletine not only synergistically increases atrial ERP and effectively suppresses AF inducibility, but also markedly reduces QT liability and torsade de pointes risk posed by dofetilide alone.
Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Drug Synergism; Drug Therapy, Combination; Female; Heart Atria; Heart Rate; Heart Ventricles; In Vitro Techniques; Long QT Syndrome; Male; Mexiletine; Phenethylamines; Rabbits; Refractory Period, Electrophysiological; Risk Assessment; Sulfonamides; Time Factors; Torsades de Pointes
PubMed: 28522677
DOI: 10.1161/JAHA.117.005482 -
Pharmacology, Biochemistry, and Behavior Nov 2020Adolescent use of amphetamine and its closely related, methylated version methamphetamine, is alarmingly high in those who use drugs for nonmedical purposes. This raises... (Review)
Review
Adolescent use of amphetamine and its closely related, methylated version methamphetamine, is alarmingly high in those who use drugs for nonmedical purposes. This raises serious concerns about the potential for this drug use to have a long-lasting, detrimental impact on the normal development of the brain and behavior that is ongoing during adolescence. In this review, we explore recent findings from both human and laboratory animal studies that investigate the consequences of amphetamine and methamphetamine exposure during this stage of life. We highlight studies that assess sex differences in adolescence, as well as those that are designed specifically to address the potential unique effects of adolescent exposure by including groups at other life stages (typically young adulthood). We consider epidemiological studies on age and sex as vulnerability factors for developing problems with the use of amphetamines, as well as human and animal laboratory studies that tap into age differences in use, its short-term effects on behavior, and the long-lasting consequences of this exposure on cognition. We also focus on studies of drug effects in the prefrontal cortex, which is known to be critically important for cognition and is among the later maturing brain regions. Finally, we discuss important issues that should be addressed in future studies so that the field can further our understanding of the mechanisms underlying adolescent use of amphetamines and its outcomes on the developing brain and behavior.
Topics: Adolescent; Adolescent Behavior; Adolescent Development; Adult; Age Factors; Amphetamine; Amphetamine-Related Disorders; Animals; Brain; Central Nervous System Stimulants; Child; Cognition; Female; Humans; Male; Methamphetamine; Prefrontal Cortex; Sex Factors; Young Adult
PubMed: 32828971
DOI: 10.1016/j.pbb.2020.173016 -
Neuropharmacology May 2018Mephedrone is a synthetic cathinone and one of the most popular recreationally used new psychoactive substances. The aim of the present study was to characterize the...
BACKGROUND
Mephedrone is a synthetic cathinone and one of the most popular recreationally used new psychoactive substances. The aim of the present study was to characterize the in vitro pharmacology of novel analogs of mephedrone and related newly emerged designer stimulants.
METHODS
We determined norepinephrine, dopamine, and serotonin transporter inhibition potencies and monoamine release in transporter-transfected human embryonic kidney 293 cells. We also assessed monoamine receptor and transporter binding affinities.
RESULTS
Mephedrone analogs potently inhibited the norepinephrine transporter and, with the exception of 3-methylmethcathinone (3-MMC), inhibited the serotonin transporter more potently than the dopamine transporter. Similar to classic amphetamines, mephedrone analogs were substrate-type monoamine releasers. 5-(2-Aminopropyl)indole (5-IT) was a highly potent monoamine transporter inhibitor and a releaser of dopamine and serotonin. 4-Methylamphetamine (4-MA) mediated efflux of all three monoamines and inhibited the serotonin transporter more potently than the dopamine transporter, unlike amphetamine. N-methyl-2-aminoindane (N-methyl-2-AI) was a selective norepinephrine transporter inhibitor and norepinephrine releaser, whereas 5-methoxy-6-methyl-2-aminoindane (MMAI) was a selective serotonin transporter inhibitor and serotonin releaser. All of the drugs interacted with monoamine receptors.
CONCLUSION
The predominant actions on serotonin vs. dopamine transporters suggest that dimethylmethcathinones, 4-MA, and MMAI cause entactogenic effects similar to 3,4-methylenedioxymethamphetamine, whereas 3-MMC, 5-IT, and N-methyl-2-AI have more stimulant-type properties like amphetamine. Because of pharmacological and structural similarity to mephedrone, similar health risks can be expected for these analogs. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'
Topics: Biogenic Monoamines; Dose-Response Relationship, Drug; Gene Expression; HEK293 Cells; Humans; Methamphetamine; Neurotransmitter Transport Proteins; Protein Binding; Psychotropic Drugs; Transfection
PubMed: 28755886
DOI: 10.1016/j.neuropharm.2017.07.026 -
Molecules (Basel, Switzerland) Apr 2023The Amaryllidaceae species are well-known as a rich source of bioactive compounds in nature. Although has been studied for decades, its polar components were rarely...
The Amaryllidaceae species are well-known as a rich source of bioactive compounds in nature. Although has been studied for decades, its polar components were rarely explored. The current phytochemical investigation of Amaryllidaceae alkaloids from led to the identification of three previously undescribed compounds: -demethyl-norlycoramine (), (-)-2--pseudolycorine () and (+)-2--pseudolycorine (), together with eight known compounds: 6α-hydroxyhippeastidine (), 6β-hydroxyhippeastidine (), lycorine (), 2--lycorine (), zephyranthine (), ungeremine (), pancratistatin () and 9--demethyl-7--methyllycorenine (). Among the eight previously reported compounds, five were isolated from for the first time (compounds , , , and ). Compounds , , , , , and exhibited weak anti-SARS-CoV-2 activity (EC = 40-77 µM) at non-cytotoxic concentrations. Assessment of cytotoxicity on the Vero-E6 cell line revealed lycorine and pancratistatin as cytotoxic substances with CC values of 1.2 µM and 0.13 µM, respectively. The preliminary structure-activity relationship for the lycorine-type alkaloids in this study was further investigated, and as a result ring C appears to play a crucial role in their anti-SARS-CoV-2 activity.
Topics: Amaryllidaceae Alkaloids; COVID-19; Amaryllidaceae; Liliaceae
PubMed: 37049986
DOI: 10.3390/molecules28073222 -
Emergencias : Revista de La Sociedad... Jun 2022To detect the presence of unsuspected and/or undeclared cathinone and piperazine-type designer drugs in methamphetamine (METH) and amphetamine users treated in emergency... (Observational Study)
Observational Study
OBJECTIVES
To detect the presence of unsuspected and/or undeclared cathinone and piperazine-type designer drugs in methamphetamine (METH) and amphetamine users treated in emergency departments, and to compare clinical and toxicologic profiles.
MATERIAL AND METHODS
Retrospective observational study of emergency department patients treated for confirmed acute intoxication by recreational drugs (METH and amphetamines) between March 2019 and December 2020. We ordered high-performance liquid chromatography with tandem mass spectrometry to detect cathinones (methylone, fluoromethcathinone, mexedrone, fluoromethamphetamine, mephedrone, methylenedioxypyrovalerone) and synthetic piperazines (meta-chlorophenylpiperazine and trifluoromethylphenylpiperazine). Demographic, clinical, and toxicologic variables were analyzed with SPSS software (version 23).
RESULTS
Thirty-nine patients were included: 24 (61.5%) had used METH and 15 (38.5%) an amphetamine. Synthetic cathinones were detected in samples from 11 patients (28.2%), 10 (90.9%) in the METH group and 1 (9.1%) in the amphetamine group (P = .028). The METH users had taken mephedrone (8 patients) or methylone (2 patients); the amphetamine user had taken mephedrone. None of the patients had declared use of a cathinone; nor was use suspected. The mean (SD) number of substances involved was higher among users of cathinones (3.5 [1.13] vs 2.5 [1.40] in those who took no cathinones; P = .036). Among the cathinone users, 90.9% were men, 90.9% had used METH, and 45.5% had practiced chemsex. HIV positivity was significantly associated with cathinone use (in 45.5% vs 10.7% of those not using cathinones; P = .028). All 5 of the patients who had taken cathinones and also practiced chemsex were HIV positive. Significantly more patients who had taken cathinones presented with anxiety (72.7% vs 21.43%; P = .007). No differences in clinical management were found.
CONCLUSION
Detection of METH in intoxicated patients should raise suspicion of probable use of a synthetic cathinone. Patients in whom new psychoactive substances are detected should be kept under observation, and clinical protocols should include referring them to addiction treatment centers.
Topics: Alkaloids; Amphetamine; Emergency Service, Hospital; Female; Humans; Male; Methamphetamine; Piperazine; Piperazines
PubMed: 35736521
DOI: No ID Found -
The Journal of Pharmacology and... Jan 2021Dietary supplements often contain additives not listed on the label, including -ethyl homologs of amphetamine such as ,-diethylphenethylamine (DEPEA). Here, we examined...
Dietary supplements often contain additives not listed on the label, including -ethyl homologs of amphetamine such as ,-diethylphenethylamine (DEPEA). Here, we examined the neurochemical and cardiovascular effects of -ethylphenethylamine (AEPEA), -methyl--ethylphenethylamine (MEPEA), and DEPEA as compared with the effects of amphetamine. All drugs were tested in vitro using uptake inhibition and release assays for monoamine transporters. As expected, amphetamine acted as a potent and efficacious releasing agent at dopamine transporters (DAT) and norepinephrine transporters (NET) in vitro. AEPEA and MEPEA were also releasers at catecholamine transporters, with greater potency at NET than DAT. DEPEA displayed fully efficacious release at NET but weak partial release at DAT (i.e., 40% of maximal effect). In freely moving, conscious male rats fitted with biotelemetry transmitters for physiologic monitoring, amphetamine (0.1-3.0 mg/kg, s.c.) produced robust dose-related increases in blood pressure (BP), heart rate (HR), and motor activity. AEPEA (1-10 mg/kg, s.c.) produced significant increases in BP but not HR or activity, whereas DEPEA and MEPEA (1-10 mg/kg, s.c.) increased BP, HR, and activity. In general, the phenethylamine analogs were approximately 10-fold less potent than amphetamine. Our results show that -ethylphenethylamine analogs are biologically active. Although less potent than amphetamine, they produce cardiovascular effects that could pose risks to humans. Given that MEPEA and DEPEA increased locomotor activity, these substances may also have significant abuse potential. SIGNIFICANCE STATEMENT: The -ethyl homologs of amphetamine have significant cardiovascular, behavioral, and neurochemical effects in rats. Given that these compounds are often not listed on the ingredient labels of dietary supplements, these compounds could pose a risk to humans using these products.
Topics: Animals; Blood Pressure; Butylamines; Catecholamine Plasma Membrane Transport Proteins; Central Nervous System Stimulants; Dietary Supplements; Dopamine Plasma Membrane Transport Proteins; Dose-Response Relationship, Drug; Heart Rate; Male; Methamphetamine; Movement; Norepinephrine Plasma Membrane Transport Proteins; Phenethylamines; Rats; Rats, Sprague-Dawley
PubMed: 33082158
DOI: 10.1124/jpet.120.000129 -
Journal of the American Chemical Society May 2017The rate of hydrogen-deuterium exchange (HDX) in aqueous droplets of phenethylamine has been determined with submillisecond temporal resolution by mass spectrometry...
The rate of hydrogen-deuterium exchange (HDX) in aqueous droplets of phenethylamine has been determined with submillisecond temporal resolution by mass spectrometry using nanoelectrospray ionization with a theta-capillary. The average speed of the microdroplets is measured using microparticle image velocimetry. The droplet travel time is varied from 20 to 320 μs by changing the distance between the emitter and the heated inlet to the mass spectrometer and the voltage applied to the emitter source. The droplets were found to accelerate by ∼30% during their observable travel time. Our droplet imaging shows that the theta-capillary produces two Taylor cone-jets (one per channel), causing mixing to take place from droplet fusion in the Taylor spray zone. Phenethylamine (ϕCHCHNH) was chosen to study because it has only one functional group (-NH) that undergoes rapid HDX. We model the HDX with a system of ordinary differential equations. The rate constant for the formation of -NHD from -NH is 3660 ± 290 s, and the rate constant for the formation of -NHD from -NHD is 3330 ± 270 s. The observed rates are about 3 times faster than what has been reported for rapidly exchangeable peptide side-chain groups in bulk measurements using stopped-flow kinetics and NMR spectroscopy. We also applied this technique to determine the HDX rates for a small 10-residue peptide, angiotensin I, in aqueous droplets, from which we found a 7-fold acceleration of HDX in the droplet compared to that in bulk solution.
Topics: Deuterium Exchange Measurement; Nanotechnology; Particle Size; Phenethylamines; Spectrometry, Mass, Electrospray Ionization; Water
PubMed: 28481522
DOI: 10.1021/jacs.7b03541 -
Psychopharmacology Nov 2022Synthetic phenethylamine (PEA) analogs, such as β-methylphenethylamine (BMPEA) and N,α-diethylphenethylamine (DEPEA), are often found in dietary supplements, despite...
RATIONALE
Synthetic phenethylamine (PEA) analogs, such as β-methylphenethylamine (BMPEA) and N,α-diethylphenethylamine (DEPEA), are often found in dietary supplements, despite regulations prohibiting their sale. PEA analogs are structurally related to amphetamine, and we have shown that BMPEA and DEPEA produce cardiovascular stimulation mimicking the effects of amphetamine. However, few studies have examined behavioral effects of BMPEA, DEPEA, and other PEA analogs.
OBJECTIVES
Here, we examined the reinforcing effects of α-ethylphenethylamine (AEPEA, 1 mg/kg/injection), DEPEA (1 mg/kg/injection), and BMPEA (3 mg/kg/injection) as compared to amphetamine (0.1 mg/kg/injection) using a fixed-ratio 1 self-administration paradigm in male rats.
METHODS
Male rats were trained in self-administration chambers containing 2 nose-poke holes. A nose-poke response in the active hole delivered drug or saline, whereas a nose-poke response in the inactive hole had no programmed consequence. Four groups of rats were initially trained for 10 days with the doses noted above. Upon acquisition of drug self-administration, a dose-effect function was determined by training rats on 3 additional doses for 3 days each. A separate group of rats was trained with saline.
RESULTS
Male rats self-administered each PEA analog and amphetamine, as shown by significant increases in active responses versus inactive responses. Subsequent dose-response testing showed clear differences in potency of the compounds. Amphetamine showed a typical inverted U-shaped dose-effect function, peaking at 0.1 mg/kg/injection. AEPEA and DEPEA also showed inverted dose-effect functions, with each peaking at 0.3 mg/kg/injection. BMPEA did not show an inverted U-shaped dose-effect function, but active responding slowly increased up to a dose of 6 mg/kg/injection.
CONCLUSIONS
Taken together, our findings indicate that dietary supplements containing PEA analogs may have significant abuse liability when used recreationally.
Topics: Rats; Male; Animals; Rats, Sprague-Dawley; Amphetamine; Phenethylamines; Self Administration; Dietary Supplements; Dose-Response Relationship, Drug
PubMed: 36190536
DOI: 10.1007/s00213-022-06246-x