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Biomedicine & Pharmacotherapy =... Jun 2022We investigated the protective effects of ephedra herb (HEPH) on adriamycin-induced testicular toxicity in rats and explored the potential mechanisms underlying these...
OBJECTIVE
We investigated the protective effects of ephedra herb (HEPH) on adriamycin-induced testicular toxicity in rats and explored the potential mechanisms underlying these effects.
METHODS
A rat model of adriamycin injury was established, and sperm motility-related indicator and oxidative stress levels in the testis were evaluated. Serum levels of sex hormones and levels of testicular cell apoptosis were detected by enzyme-linked immunosorbent assay and flow cytometry, respectively. Western blotting (WB), immunofluorescence analyses, and reverse transcription-polymerase chain reaction (RT-PCR) were performed to evaluate the gonadotropin-releasing hormone (GnRH) signalling pathway- and meiosis-related genes and proteins. In subsequent in vitro experiments, adriamycin was used to stimulate GC-1 cells, which were treated with HEPH, ephedrine, or pseudoephedrine. Cell viability was assessed using flow cytometry to detect apoptosis and reactive oxygen species, whereas the GnRH signalling pathway and levels of meiosis-related genes and proteins were evaluated by InCell WB, a high-content imaging system, and RT-PCR.
RESULTS
Per in vivo experiments, HEPH restored testicular weight and function, sperm characteristics, serum and tissue hormonal levels, and antioxidant defences and significantly activated the GnRH signalling pathway- and meiosis-related protein levels. All protective effects of HEPH against adriamycin-induced injury were antagonised by the GnRH antagonist cetrorelix. In vitro, HEPH, ephedrine, and pseudoephedrine significantly reduced adriamycin-induced GC-1 cell apoptosis and reactive oxygen species levels and increased the expression of GnRH signalling pathway- and meiosis-related proteins. The effect of pseudoephedrine was greater than that of ephedrine, and these findings may be an important basis for understanding the effects of HEPH.
Topics: Animals; Doxorubicin; Ephedra; Ephedrine; Gonadotropin-Releasing Hormone; Male; Pseudoephedrine; Rats; Reactive Oxygen Species; Sperm Motility; Testis
PubMed: 35658231
DOI: 10.1016/j.biopha.2022.113061 -
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 -
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 -
British Journal of Pharmacology Nov 2021Human pharmacokinetic studies of lung-targeted drugs are typically limited to measurements of systemic plasma concentrations, which provide no direct information on lung...
BACKGROUND AND PURPOSE
Human pharmacokinetic studies of lung-targeted drugs are typically limited to measurements of systemic plasma concentrations, which provide no direct information on lung target-site concentrations. We aimed to evaluate lung pharmacokinetics of commonly prescribed drugs by sampling different lung compartments after inhalation and oral administration.
EXPERIMENTAL APPROACH
Healthy volunteers received single, sequential doses of either inhaled salbutamol, salmeterol and fluticasone propionate (n = 12), or oral salbutamol and propranolol (n = 6). Each participant underwent bronchoscopies and gave breath samples for analysis of particles in exhaled air at two points after drug administration (1 and 6, 2 and 9, 3 and 12, or 4 and 18 h). Lung samples were taken via bronchosorption, bronchial brush, mucosal biopsy and bronchoalveolar lavage during each bronchoscopy. Blood samples were taken during the 24 h after administration. Pharmacokinetic profiles were generated by combining data from multiple individuals, covering all sample timings.
KEY RESULTS
Pharmacokinetic profiles were obtained for each drug in lung epithelial lining fluid, lung tissue and plasma. Inhalation of salbutamol resulted in approximately 100-fold higher concentrations in lung than in plasma. Salmeterol and fluticasone concentration ratios in lung versus plasma were higher still. Bronchosorption- and bronchoalveolar-lavage-generated profiles of inhaled drugs in epithelial lining fluid were comparable. For orally administered drugs, epithelial-lining-fluid concentrations were overestimated in bronchoalveolar-lavage-generated profiles.
CONCLUSION AND IMPLICATIONS
Combining pharmacokinetic data derived from several individuals and techniques sampling different lung compartments enabled generation of pharmacokinetic profiles for evaluation of lung targeting after inhaled and oral drug delivery.
Topics: Albuterol; Fluticasone; Humans; Lung; Pharmaceutical Preparations; Salmeterol Xinafoate
PubMed: 34250588
DOI: 10.1111/bph.15621 -
The International Journal on Drug Policy Mar 2023Changes to drug markets can affect drug use and related harms. We aimed to describe market trends of heroin, methamphetamine, cocaine and ecstasy in Australia following...
BACKGROUND
Changes to drug markets can affect drug use and related harms. We aimed to describe market trends of heroin, methamphetamine, cocaine and ecstasy in Australia following the introduction of COVID-19 pandemic-associated restrictions.
METHODS
Australians residing in capital cities who regularly inject drugs (n ∼= 900 each year) or regularly use ecstasy and/or other illicit stimulants (n ∼= 800 each year) participated in annual interviews 2014-2022. We used self-reported market indicators (price, availability, and purity) for heroin, crystal methamphetamine, cocaine, and ecstasy crystal to estimate generalised additive models. Observations from the 2014-2019 surveys were used to establish the pre-pandemic trend; 2020, 2021 and 2022 observations were considered immediate, short-term and longer-term changes since the introduction of pandemic restrictions.
RESULTS
Immediate impacts on market indicators were observed for heroin and methamphetamine in 2020 relative to the 2014-2019 trend; price per cap/point increased (β: A$9.69, 95% confidence interval [CI]: 2.25-17.1 and β: A$40.3, 95% CI: 33.1-47.5, respectively), while perceived availability (adjusted odds ratio [aOR] for 'easy'/'very easy' to obtain: 0.38, 95% CI: 0.24-0.59 and aOR: 0.08, 95% CI: 0.03-0.25, respectively) and perceived purity (aOR for 'high' purity: 0.36, 95% CI: 0.23-0.54 and aOR: 0.33, 95% CI: 0.20-0.54, respectively) decreased. There was no longer evidence for change in 2021 or 2022 relative to the 2014-2019 trend. Changes to ecstasy and cocaine markets were most evident in 2022 relative to the pre-pandemic trend: price per gram increased (β: A$92.8, 95% CI: 61.6-124 and β: A$24.3, 95% CI: 7.93-40.6, respectively) and perceived purity decreased (aOR for 'high purity': 0.18, 95% CI: 0.09-0.35 and 0.57, 95% CI: 0.36-0.90, respectively), while ecstasy was also perceived as less easy to obtain (aOR: 0.18, 95% CI: 0.09-0.35).
CONCLUSION
There were distinct disruptions to illicit drug markets in Australia after the COVID-19 pandemic began; the timing and magnitude varied by drug.
Topics: Humans; Methamphetamine; Heroin; Cocaine; Australia; Pandemics; COVID-19; N-Methyl-3,4-methylenedioxyamphetamine; Surveys and Questionnaires
PubMed: 36822010
DOI: 10.1016/j.drugpo.2023.103976 -
Psychopharmacology Jun 2022Novel psychedelics (NPs) are an expanding set of compounds, presenting new challenges for drug policy and opportunities for clinical research. Unlike their classical...
BACKGROUND
Novel psychedelics (NPs) are an expanding set of compounds, presenting new challenges for drug policy and opportunities for clinical research. Unlike their classical derivatives, little is known regarding their use profiles or their subjective effects.
AIMS
The purpose of this study was to compile usage patterns and adverse event rates for individual NPs belonging to each of three main psychedelic structural families. Targeting the most widely used representatives for each class, we expanded on their phenomenological distinctions.
METHODS
A two-part survey was employed. We investigated the prevalence of novel phenethylamines, tryptamine and lysergamides in NP users (N = 1180), contrasting the type and incidence of adverse events (AEs) using a set of logistic regressions. Honing in on 2-4-Bromo-2,5-dimethoxyphenyl)ethanamine (2C-B) (48.6%), 1-propionyl-lysergic acid diethylamide (1P-LSD) (34.2%) and 4-Acetoxy-N,N-dimethyltryptamine (4-AcO-DMT) (23.1%), we examined their phenomenological separability using a gradient boosting (XGBoost) supervised classifier.
RESULTS
Novel phenethylamines had the highest prevalence of use (61.5%) seconded by tryptamines (43.8%) and lysergamides (42.9%). Usage patterns were identified for 32 different compounds, demonstrating variable dosages, durations and a common oral route of administration. Compared to phenethylamines, the odds for tryptamines and lysergamides users were significantly less for overall physical AEs. No significant differences in overall psychological AEs were found. Overall model area under the curve (AUC) stood at 0.79 with sensitivity (50.0%) and specificity (60.0%) for 2C-B ranking lowest.
CONCLUSION
NP classes may hold distinct AE rates and phenomenology, the latter potentially clouded by the subjective nature of these experiences. Further targeted research is warranted.
Topics: Hallucinogens; Humans; Lysergic Acid Diethylamide; Phenethylamines; Tryptamines
PubMed: 35487983
DOI: 10.1007/s00213-022-06142-4 -
Circulation Research Apr 2020Drug-induced proarrhythmia is so tightly associated with prolongation of the QT interval that QT prolongation is an accepted surrogate marker for arrhythmia. But QT...
RATIONALE
Drug-induced proarrhythmia is so tightly associated with prolongation of the QT interval that QT prolongation is an accepted surrogate marker for arrhythmia. But QT interval is too sensitive a marker and not selective, resulting in many useful drugs eliminated in drug discovery.
OBJECTIVE
To predict the impact of a drug from the drug chemistry on the cardiac rhythm.
METHODS AND RESULTS
In a new linkage, we connected atomistic scale information to protein, cell, and tissue scales by predicting drug-binding affinities and rates from simulation of ion channel and drug structure interactions and then used these values to model drug effects on the hERG channel. Model components were integrated into predictive models at the cell and tissue scales to expose fundamental arrhythmia vulnerability mechanisms and complex interactions underlying emergent behaviors. Human clinical data were used for model framework validation and showed excellent agreement, demonstrating feasibility of a new approach for cardiotoxicity prediction.
CONCLUSIONS
We present a multiscale model framework to predict electrotoxicity in the heart from the atom to the rhythm. Novel mechanistic insights emerged at all scales of the system, from the specific nature of proarrhythmic drug interaction with the hERG channel, to the fundamental cellular and tissue-level arrhythmia mechanisms. Applications of machine learning indicate necessary and sufficient parameters that predict arrhythmia vulnerability. We expect that the model framework may be expanded to make an impact in drug discovery, drug safety screening for a variety of compounds and targets, and in a variety of regulatory processes.
Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiotoxicity; Cardiotoxins; Computer Simulation; Drug Discovery; ERG1 Potassium Channel; Female; Humans; Long QT Syndrome; Machine Learning; Male; Moxifloxacin; Myocytes, Cardiac; Phenethylamines; Protein Structure, Secondary; Sulfonamides; Topoisomerase II Inhibitors
PubMed: 32091972
DOI: 10.1161/CIRCRESAHA.119.316404 -
Scientific Reports Sep 2023Natural phenethylamines are trace amine neurotransmitters associated with dopamine transmission and related illnesses such Parkinson's disease, and addiction. Synthetic...
A molecular analysis of substituted phenylethylamines as potential microtubule targeting agents through in silico methods and in vitro microtubule-polymerization activity.
Natural phenethylamines are trace amine neurotransmitters associated with dopamine transmission and related illnesses such Parkinson's disease, and addiction. Synthetic phenethylamines can have psychoactive and hallucinogenic effects due to their high affinity with the 5-HT receptor. Evidence indicates phenethylamines can directly alter the microtubule cytoskeleton being structurally similar to the microtubule destabilizing agent colchicine, however little work has been done on this interaction. As microtubules provide neuron structure, intracellular transport, and influence synaptic plasticity the interaction of phenethylamines with microtubules is important for understanding the potential harms, or potential pharmaceutical use of phenethylamines. We investigated 110 phenethylamines and their interaction with microtubules. Here we performed molecular docking of these compounds at the colchicine binding site and ranked them via binding energy. The top 10% of phenethylamines were further screened based on pharmacokinetic and physicochemical properties derived from SwissADME and LightBBB. Based on these properties 25B-NBF, 25C-NBF, and DMBMPP were tested in in vitro microtubule polymerization assays showing that they alter microtubule polymerization dynamics in a dose dependent manner. As these compounds can rapidly cross the blood brain barrier and directly affect cytoskeletal dynamics, they have the potential to modulate cytoskeletal based neural plasticity. Further investigations into these mechanisms are warranted.
Topics: Phenethylamines; Molecular Docking Simulation; Polymerization; Microtubules; Colchicine
PubMed: 37658096
DOI: 10.1038/s41598-023-41600-9