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Epilepsia Jun 2023To investigate the comparative antiseizure activity of the individual enantiomers of fenfluramine and its major active primary metabolite norfenfluramine in rodent...
OBJECTIVES
To investigate the comparative antiseizure activity of the individual enantiomers of fenfluramine and its major active primary metabolite norfenfluramine in rodent seizure models, and its relationship with the pharmacokinetics of these compounds in plasma and brain.
METHODS
The antiseizure potency of d,l-fenfluramine (racemic fenfluramine) was compared with the respective potencies of its individual enantiomers and the individual enantiomers of norfenfluramine using the maximal electroshock (MES) test in rats and mice, and the 6-Hz 44 mA test in mice. Minimal motor impairment was assessed simultaneously. The time course of seizure protection in rats was compared with the concentration profiles of d-fenfluramine, l-fenfluramine, and their primary active metabolites in plasma and brain.
RESULTS
All compounds tested were active against MES-induced seizures in rats and mice after acute (single-dose) administration, but no activity against 6-Hz seizures was found even at doses up to 30 mg/kg. Estimates of median effective doses (ED ) in the rat-MES test were obtained for all compounds except for d-norfenfluramine, which caused dose-limiting neurotoxicity. Racemic fenfluramine had approximately the same antiseizure potency as its individual enantiomers. Both d- and l-fenfluramine were absorbed and distributed rapidly to the brain, suggesting that seizure protection at early time points (≤2 h) was related mainly to the parent compound. Concentrations of all enantiomers in brain tissue were >15-fold higher than those in plasma.
SIGNIFICANCE
Although there are differences in antiseizure activity and pharmacokinetics among the enantiomers of fenfluramine and norfenfluramine, all compounds tested are effective in protecting against MES-induced seizures in rodents. In light of the evidence linking the d-enantiomers to cardiovascular and metabolic adverse effects, these data suggest that l-fenfluramine and l-norfenfluramine are potentially attractive candidates for a chiral switch approach leading to development of a novel, enantiomerically-pure antiseizure medication.
Topics: Rats; Mice; Animals; Fenfluramine; Norfenfluramine; Rodentia; Brain; Seizures
PubMed: 36995363
DOI: 10.1111/epi.17598 -
Advances in Pharmacology (San Diego,... 2024The 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...
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.
Topics: Humans; Synthetic Cathinone; Methamphetamine; Amphetamine; Central Nervous System Stimulants
PubMed: 38467489
DOI: 10.1016/bs.apha.2023.12.001 -
European Journal of Pharmacology Jul 2023The mechanism behind the reinstament of psychostimulant, as a major obstacle in addiction treatment is not fully understood. Controversial data are available in the... (Review)
Review
The mechanism behind the reinstament of psychostimulant, as a major obstacle in addiction treatment is not fully understood. Controversial data are available in the literature concerning the role of the endocannabinoid (eCB) system in regulating the relapse to psychostimulant addiction in preclinical studies. The current systematic review aims to evaluate eCB modulators' effect in the reinstatement of commonly abused psychostimulants, including cocaine, amphetamine, methamphetamine, and 3,4-methylenedioxymethamphetamine. By searching the PubMed, Web of Science, and Scopus databases, studies were selected. Then the studies quality was evaluated by the SYRCLE risk of bias tool. The results have still been limited to preclinical studies. Thirty-nine articles that employed self-administration and CPP as the most prevalent animal models of addiction were selected. This data indicates that cannabinoid receptor 1 antagonists and some cannabinoid receptor 2 agonists could suppress the reinstatement of cocaine and methamphetamine addiction in a dose-dependent manner. However, only AM251 was efficient to block the reinstatement of 3,4-methylenedioxymethamphetamine. In conclusion, cannabinoid receptor 1 antagonists and some cannabinoid receptor 2 agonists may have curative potential in the relapse of psychostimulant abuse. However, time, dose, and route of administration are crucial factors in their inhibitory impacts.
Topics: Animals; Endocannabinoids; N-Methyl-3,4-methylenedioxyamphetamine; Central Nervous System Stimulants; Cocaine; Methamphetamine; Amphetamine; Cannabinoid Receptor Antagonists; Recurrence; Receptors, Cannabinoid
PubMed: 36965745
DOI: 10.1016/j.ejphar.2023.175669 -
Journal of Dual Diagnosis Oct 2020Rhabdomyolysis is associated with methamphetamine, amphetamine, and methylenedioxymethamphetamine (MA) use. The aim of this study was to determine the frequency,...
Rhabdomyolysis is associated with methamphetamine, amphetamine, and methylenedioxymethamphetamine (MA) use. The aim of this study was to determine the frequency, severity, and risk factors of rhabdomyolysis associated with MA use. We reviewed patients with an MA-positive toxicology screen with and without diagnosed rhabdomyolysis based on initial creatine kinase (CK) concentration over a period of 6 years. Demographics, vital signs, disposition, diagnoses, and laboratory results were recorded. There were 7,319 patients with an MA-positive toxicology screen, of whom 957 (13%) were screened for rhabdomyolysis and included in the study. The majority were male, White, and middle-aged and smoked tobacco. Psychiatric (34%), neurological (15%), and trauma (13%) were the most common discharge diagnostic groups. The majority (55%) were admitted, and 8% were discharged to an inpatient psychiatric facility. Concomitant substance use included ethanol (10%) and cocaine (8%), and 190 (20%) had rhabdomyolysis with median (interquartile range) CK of 2,610 (1,530-6,212) U/L and range 1,020 to 98,172 U/L. There was significant difference in renal function between the rhabdomyolysis and non-rhabdomyolysis patients. Other differences included gender and troponin I concentration. A higher proportion of patients screening positive for both MA and cocaine use experienced rhabdomyolysis. Multiple logistic regression analysis revealed elevated troponin I, blood urea nitrogen, and/or creatinine concentration and male gender to be significant factors associated with rhabdomyolysis. The frequency of rhabdomyolysis in patients screening positive for MA was 20%. Factors associated with rhabdomyolysis in MA-positive patients included elevated troponin, blood urea nitrogen, creatinine concentration, and male gender. Clinicians caring for patients who screen positive for MA should also consider concomitant rhabdomyolysis, especially if renal/cardiac laboratory tests are abnormal and even if there is no history of injury, agitation, or physical restraint.
Topics: Amphetamine; Female; Humans; Male; Methamphetamine; Middle Aged; N-Methyl-3,4-methylenedioxyamphetamine; Retrospective Studies; Rhabdomyolysis
PubMed: 32644906
DOI: 10.1080/15504263.2020.1786617 -
Journal of Psychopharmacology (Oxford,... Sep 2020Recently, the recreational use of substituted phenethylamines has grown rapidly. Among these are 2-(3,5-dimethoxy-4-((2-methylallyl)oxy)phenyl)ethanamine (MAL) and...
BACKGROUND
Recently, the recreational use of substituted phenethylamines has grown rapidly. Among these are 2-(3,5-dimethoxy-4-((2-methylallyl)oxy)phenyl)ethanamine (MAL) and 2-(2,5-dimethoxy-4-methylphenyl)-2-methoxyethan-1-amine (BOD). However, studies characterizing their abuse potential are still lacking.
AIM
The purpose of this study was to investigate the abuse potential of MAL and BOD.
METHODS
The psychostimulant, reinforcing, and rewarding properties of MAL and BOD were analyzed using locomotor sensitization, self-administration, and conditioned place preference tests. Dopamine antagonists (i.e. SCH23390, haloperidol) were administered during conditioned place preference to evaluate the involvement of the mesolimbic dopamine system. Furthermore, dopamine-related protein expression in the nucleus accumbens and the ventral tegmental area was measured along with dopamine concentrations in the nucleus accumbens. Electroencephalography was conducted to determine effects of MAL and BOD on brain wave activity.
RESULTS
MAL induced psychostimulant effects and sensitization, while BOD induced locomotor depression in mice. Only MAL was self-administered by rats. Both drugs induced conditioned place preference in mice at different doses; dopamine receptor antagonists blocked MAL- and BOD-induced conditioned place preference. Both the compounds altered the expression of dopamine receptor D and D proteins in the nucleus accumbens and tyrosine hydroxylase (TH) and dopamine transporter in the ventral tegmental area, enhanced dopamine levels in the nucleus accumbens, and increased delta and gamma wave activities in the brain.
CONCLUSIONS
MAL may induce abuse potential via the mesolimbic dopaminergic system and possibly accompanied by alterations in brain wave activity. Moreover, the lack of rewarding and reinforcing effects in BOD suggest that this drug may have little to no capability to engender compulsive behavior, though having found to induce alterations in dopaminergic system and brain wave activities.
Topics: Animals; Behavior, Animal; Brain Waves; Central Nervous System Sensitization; Central Nervous System Stimulants; Conditioning, Psychological; Dopamine Antagonists; Locomotion; Male; Mice; Mice, Inbred C57BL; Nucleus Accumbens; Phenethylamines; Receptors, Dopamine D1; Receptors, Dopamine D2; Ventral Tegmental Area
PubMed: 32648801
DOI: 10.1177/0269881120936458 -
Molecules (Basel, Switzerland) Oct 2020Alkaloids are an important group of specialized nitrogen metabolites with a wide range of biochemical and pharmacological effects. Since the first publication on... (Review)
Review
Alkaloids are an important group of specialized nitrogen metabolites with a wide range of biochemical and pharmacological effects. Since the first publication on lycorine in 1877, more than 650 alkaloids have been extracted from Amaryllidaceae bulbous plants and clustered together as the Amaryllidaceae alkaloids (AAs) family. AAs are specifically remarkable for their diverse pharmaceutical properties, as exemplified by the success of galantamine used to treat the symptoms of Alzheimer's disease. This review addresses the isolation, biological, and structure activity of AAs discovered from January 2015 to August 2020, supporting their therapeutic interest.
Topics: Amaryllidaceae Alkaloids; Animals; Drug Discovery; Humans
PubMed: 33113950
DOI: 10.3390/molecules25214901 -
Forensic Toxicology Jan 2022This study aimed to validate a modified QuEChERS method followed by ultra-high performance liquid chromatography-tandem mass spectrometry to determine 79 new...
PURPOSE
This study aimed to validate a modified QuEChERS method followed by ultra-high performance liquid chromatography-tandem mass spectrometry to determine 79 new psychoactive substances (NPS) and other drugs in blood and urine.
METHODS
Prescription drugs (n = 23), synthetic cathinones (n = 13), phenethylamines (n = 11); synthetic cannabinoids (n = 8), amphetamines (n = 7) and other psychoactive substances (n = 17) were included in the method. 500 µL of biological fluid was extracted with 2 mL of water/ACN (1:1), 500 mg of anhydrous MgSO/NaOAc (4:1) added, followed by a supernatant cleanup with 25 mg of primary secondary amine and 75 mg of anhydrous MgSO. Quantification was done using matrix-matched calibration curves and deuterated internal standards.
RESULTS
The method was satisfactorily validated for blood and urine at limit of quantifications ranging from 0.4 to 16 ng/mL, and applied to the analysis of 54 blood (38 postmortem and 16 antemortem) and 16 antemortem urine samples from 68 forensic cases. All urine samples and 59.3% of the blood samples were positive for at least one analyte. Twenty-two analytes were detected in at least one biological sample, including the synthetic cathinones ethylone (222 ng/mL, antemortem blood), eutylone (246 and 446 ng/mL, urine), and N-ethylpentylone (597 and 7.3 ng/mL, postmortem and antemortem blood, respectively).
CONCLUSIONS
The validated method was shown to be suitable for the analysis of blood and urine forensic samples and an important tool to collect information on emerging drug threats and understanding the impact of NPS and other drugs in poisoning cases.
Topics: Tandem Mass Spectrometry; Chromatography, High Pressure Liquid; Body Fluids; Forensic Medicine; Central Nervous System Agents; Phenethylamines
PubMed: 36454493
DOI: 10.1007/s11419-021-00600-y -
Bioscience, Biotechnology, and... Jul 2022The aromatic diamine 2-(4-aminophenyl)ethylamine (4APEA) is a potential monomer for polymers and advanced materials. Here, 4APEA was produced by fermentation using...
The aromatic diamine 2-(4-aminophenyl)ethylamine (4APEA) is a potential monomer for polymers and advanced materials. Here, 4APEA was produced by fermentation using genetically engineered Escherichia coli (Masuo et al.2016). Optimizing fed-batch cultures of this strain produced the highest reported yield to date of 4APEA (7.2%; 3.5 g/L versus glucose) within 72 h. Appropriate aeration was important to maximize production and avoid unfavorable 4APEA degradation. Fermented 4APEA was purified from culture medium and polymerized with methylene diphenyldiisocyanate and hexamethylene diisocyanate to produce polyureas PU-1 and PU-2, respectively. The decomposition temperatures for 10% weight loss (Td10) of PU-1 and PU-2 were 276 °C and 302 °C, respectively, and were comparable with that of other thermostable aromatic polyureas. This study is the first to synthesize polyureas from the microbial aromatic diamine. Their excellent thermostability will be useful for the industrial production of heat-resistant polymer materials.
Topics: Diamines; Escherichia coli; Fermentation; Glucose; Hot Temperature; Metabolic Engineering; Phenethylamines
PubMed: 35612977
DOI: 10.1093/bbb/zbac077 -
Environmental Science & Technology Feb 2021The current study represents a comprehensive investigation of the occurrence and fates of trenbolone acetate (TBA) and metabolites 17α-trenbolone (17α-TBOH),...
The current study represents a comprehensive investigation of the occurrence and fates of trenbolone acetate (TBA) and metabolites 17α-trenbolone (17α-TBOH), 17β-TBOH, and trendione (TBO); melengesterol acetate (MGA); and the less commonly studied β-andrenergic agonist ractopamine (RAC) in two 8 month cattle feeding trials and simulated rainfall runoff experiments. Cattle were administered TBA, MGA, or RAC, and their residues were measured in fresh feces, pen floor material, and simulated rainfall runoff from pen floor surfaces and manure-amended pasture. Concentrations of RAC ranged from 3600 ng g, dry weight (dw), in pen floor to 58 000 ng g in fresh feces and were, on average, observed at 3-4 orders of magnitude greater than those of TBA and MGA. RAC persisted in pen floors (manure = 18-49 days), and contamination of adjacent sites was observed, likely via transport of windblown particulates. Concentrations in runoff water from pen floors extrapolated to larger-scale commercial feedlots revealed that a single rainfall event could result in mobilization of gram quantities of RAC. This is the first report of RAC occurrence and fate in cattle feedlot environments, and will help understand the risks posed by this chemical and inform appropriate manure-management practices.
Topics: Animals; Cattle; Manure; Phenethylamines; Soil Pollutants; Trenbolone Acetate
PubMed: 33450151
DOI: 10.1021/acs.est.0c06450 -
Biomolecules Sep 2022Ractopamine (RAC) is a synthetic phenethanolamine, β-adrenergic agonist used as a feed additive to develop leanness and increase feed conversion efficiency in different... (Review)
Review
Ractopamine (RAC) is a synthetic phenethanolamine, β-adrenergic agonist used as a feed additive to develop leanness and increase feed conversion efficiency in different farm animals. While RAC has been authorized as a feed additive for pigs and cattle in a limited number of countries, a great majority of jurisdictions, including the European Union (EU), China, Russia, and Taiwan, have banned its use on safety grounds. RAC has been under long scientific and political discussion as a controversial antibiotic as a feed additive. Here, we will present significant information on RAC regarding its application, detection methods, conflicts, and legal divisions that play a major role in controversial deadlock and why this issue warrants the attention of scientists, agriculturists, environmentalists, and health advocates. In this review, we highlight the potential toxicities of RAC on aquatic animals to emphasize scientific evidence and reports on the potentially harmful effects of RAC on the aquatic environment and human health.
Topics: Humans; Swine; Cattle; Animals; Animal Feed; Dissent and Disputes; Phenethylamines; Adrenergic beta-Agonists; Anti-Bacterial Agents
PubMed: 36291550
DOI: 10.3390/biom12101342