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Journal of Analytical Toxicology Feb 2023Maternal drug use during pregnancy is a significant concern. Drug-exposed newborns are often born premature and may suffer from birth defects, neonatal abstinence...
Maternal drug use during pregnancy is a significant concern. Drug-exposed newborns are often born premature and may suffer from birth defects, neonatal abstinence syndrome and cognitive and developmental delays. Because of this, testing of neonatal specimens is carried out to assess fetal drug exposure during pregnancy. Umbilical cord tissue (UC) and meconium are commonly used specimens for this purpose. However, comprehensive studies comparing drug positivity rates and concentration in the two specimen types are lacking. To this end, 4,036 paired UC and meconium specimens originating from 13 states within the USA were identified, and retrospective analysis of drug positivity rates and drug concentration was performed for 31 analytes in 5 drug classes. Testing for 11-Nor-9-carboxy-tetrahydrocannabinol (THC-COOH) is a separate orderable for UC specimen at our laboratory, so a second data set was created for evaluation of this drug analyte with 2,112 paired UC and meconium specimens originating from 11 states. Testing of UC was performed by semi-quantitative liquid chromatography-tandem mass spectrometry (LC-MS-MS) assays, whereas, for meconium, an immunoassay-based screening preceded LC-MS-MS confirmation tests. Results generated for UC and meconium specimens were therefore compared for a total of 32 drug analytes from 6 drug classes. Drug concentrations for analytes were higher in meconium compared to UC, with the exception of phencyclidine. Despite this, the positivity rates for individual analytes were higher in UC, with the exception of THC-COOH and cocaine. Furthermore, analysis for multidrug positivity revealed that THC-COOH and opioids were the most common multidrug combination detected in both matrices. In conclusion, this study suggests that for most drug compounds, UC was more analytically sensitive to assess neonatal drug exposure by current methodologies. Additionally, by demonstrating that meconium has higher drug concentrations for most compounds, this study sets the stage for developing more sensitive assays in meconium.
Topics: Infant, Newborn; Pregnancy; Humans; Female; Meconium; Retrospective Studies; Substance Abuse Detection; Cocaine; Umbilical Cord
PubMed: 35707888
DOI: 10.1093/jat/bkac037 -
International Journal of Molecular... May 2022Mental illness modeling is still a major challenge for scientists. Animal models of schizophrenia are essential to gain a better understanding of the disease... (Review)
Review
Mental illness modeling is still a major challenge for scientists. Animal models of schizophrenia are essential to gain a better understanding of the disease etiopathology and mechanism of action of currently used antipsychotic drugs and help in the search for new and more effective therapies. We can distinguish among pharmacological, genetic, and neurodevelopmental models offering various neuroanatomical disorders and a different spectrum of symptoms of schizophrenia. Modeling schizophrenia is based on inducing damage or changes in the activity of relevant regions in the rodent brain (mainly the prefrontal cortex and hippocampus). Such artificially induced dysfunctions approximately correspond to the lesions found in patients with schizophrenia. However, notably, animal models of mental illness have numerous limitations and never fully reflect the disease state observed in humans.
Topics: Animals; Antipsychotic Agents; Behavior, Animal; Disease Models, Animal; Hippocampus; Humans; Prefrontal Cortex; Schizophrenia
PubMed: 35682647
DOI: 10.3390/ijms23115968 -
International Journal of Environmental... May 2022Psychedelics represent a unique subset of psychoactive substances that can induce an aberrant state of consciousness principally via the neuronal 5-HT2A receptor. There...
BACKGROUND
Psychedelics represent a unique subset of psychoactive substances that can induce an aberrant state of consciousness principally via the neuronal 5-HT2A receptor. There is limited knowledge concerning the interest in these chemicals in Poland and how they changed during the pandemic. Nonetheless, these interests can be surveyed indirectly via the web.
OBJECTIVES
We aim to conduct a spatial-temporal mapping of online information-seeking behavior concerning cannabis and the most popular psychedelics before and during the pandemic.
METHODS
We retrieved online information search data via Google Trends concerning twenty of the most popular psychedelics from 1 January 2017 to 1 January 2022 in Poland. We conducted Holt-Winters exponential smoothing for time series analysis to infer potential seasonality. We utilized hierarchical clustering analysis based on Ward's method to find similarities of psychedelics' interest within Poland's voivodships before and during the pandemic.
RESULTS
Twelve (60%) psychedelics had significant seasonality; we proved that psilocybin and ayahuasca had annual seasonality (-value = 0.0120 and = 0.0003, respectively), and four substances-LSD, AL-LAD, DXM, and DOB-exhibited a half-yearly seasonality, while six psychedelics had a quarterly seasonal pattern, including cannabis, dronabinol, ergine, NBOMe, phencyclidine, and salvinorin A. Further, the pandemic influenced a significant positive change in the trends for three substances, including psilocybin, ergine, and DXM.
CONCLUSIONS
Different seasonal patterns exist for psychedelics, and some might correlate with school breaks or holidays in Poland. The pandemic induced some changes in the temporal and spatial trends. The spatial-temporal trends could be valuable information to health authorities and policymakers responsible for monitoring and preventing addictions.
Topics: COVID-19; Cannabis; Hallucinogens; Humans; Lysergic Acid Diethylamide; Pandemics; Poland; Psilocybin
PubMed: 35682204
DOI: 10.3390/ijerph19116619 -
Pharmacotherapy Jul 2022Ketamine, an anesthetic available since 1970, and esketamine, its newer S-enantiomer, provide a novel approach for the treatment of depression and other psychiatric... (Review)
Review
Ketamine, an anesthetic available since 1970, and esketamine, its newer S-enantiomer, provide a novel approach for the treatment of depression and other psychiatric disorders. At subanesthetic doses, the two drugs, along with their older congener, phencyclidine (PCP), induce a transient, altered mental state by blocking the N-methyl-D-aspartate (NMDA) receptor for glutamate, the primary excitatory neurotransmitter in the mammalian central nervous system. This multidisciplinary review examines the pharmacology/direct effects on consciousness, effectiveness in depression and acute suicidality, and safety of these fast-acting NMDA antagonists. To capture the essence of 60 years of peer-reviewed literature, we used a semi-structured approach to the subtopics, each of which required a different search strategy. We review the evidence for the three primary reported benefits of the two clinical drugs when used for depression: success in difficult-to-treat patients, rapid onset of action within a day, and immediate effects on suicidality. Key safety issues include the evidence-and lack thereof-for the effects of repeatedly inducing this altered mental state, and whether an adequate safety margin exists to rule out the neurotoxic effects seen in animal studies. This review includes evidence from multiple sources that raise substantial questions about both safety and effectiveness of ketamine and esketamine for psychiatric disorders.
Topics: Animals; Depression; Humans; Ketamine; Mammals; N-Methylaspartate; Phencyclidine; Receptors, N-Methyl-D-Aspartate
PubMed: 35665948
DOI: 10.1002/phar.2707 -
Nature Structural & Molecular Biology Jun 2022Excitatory signaling mediated by N-methyl-D-aspartate receptor (NMDAR) is critical for brain development and function, as well as for neurological diseases and...
Excitatory signaling mediated by N-methyl-D-aspartate receptor (NMDAR) is critical for brain development and function, as well as for neurological diseases and disorders. Channel blockers of NMDARs are of medical interest owing to their potential for treating depression, Alzheimer's disease, and epilepsy. However, precise mechanisms underlying binding and channel blockade have remained limited owing to challenges in obtaining high-resolution structures at the binding site within the transmembrane domains. Here, we monitor the binding of three clinically important channel blockers: phencyclidine, ketamine, and memantine in GluN1-2B NMDARs at local resolutions of 2.5-3.5 Å around the binding site using single-particle electron cryo-microscopy, molecular dynamics simulations, and electrophysiology. The channel blockers form different extents of interactions with the pore-lining residues, which control mostly off-speeds but not on-speeds. Our comparative analyses of the three unique NMDAR channel blockers provide a blueprint for developing therapeutic compounds with minimal side effects.
Topics: Binding Sites; Ketamine; Memantine; Molecular Dynamics Simulation; Receptors, N-Methyl-D-Aspartate
PubMed: 35637422
DOI: 10.1038/s41594-022-00772-0 -
Pharmacology Research & Perspectives Jun 2022Fenfluramine (FFA) has potent antiseizure activity in severe, pharmacoresistant childhood-onset developmental and epileptic encephalopathies (e.g., Dravet syndrome). To... (Review)
Review
Fenfluramine (FFA) has potent antiseizure activity in severe, pharmacoresistant childhood-onset developmental and epileptic encephalopathies (e.g., Dravet syndrome). To assess risk of drug interaction affecting pharmacokinetics of FFA and its major metabolite, norfenfluramine (nFFA), we conducted in vitro metabolite characterization, reaction phenotyping, and drug transporter-mediated cellular uptake studies. FFA showed low in vitro clearance in human liver S9 fractions and in intestinal S9 fractions in all three species tested (t > 120 min). Two metabolites (nFFA and an N-oxide or a hydroxylamine) were detected in human liver microsomes versus six in dog and seven in rat liver microsomes; no metabolite was unique to humans. Selective CYP inhibitor studies showed FFA metabolism partially inhibited by quinidine (CYP2D6, 48%), phencyclidine (CYP2B6, 42%), and furafylline (CYP1A2, 32%) and, to a lesser extent (<15%), by tienilic acid (CYP2C9), esomeprazole (CYP2C19), and troleandomycin (CYP3A4/5). Incubation of nFFA with rCYP1A2, rCYP2B6, rCYP2C19, and rCYP2D6 resulted in 10%-20% metabolism and no clear inhibition of nFFA metabolism by any CYP-selective inhibitor. Reaction phenotyping showed metabolism of FFA by recombinant human cytochrome P450 (rCYP) enzymes rCYP2B6 (10%-21% disappearance for 1 and 10 µM FFA, respectively), rCYP1A2 (22%-23%), rCYP2C19 (49%-50%), and rCYP2D6 (59%-97%). Neither FFA nor nFFA was a drug transporter substrate. Results show FFA metabolism to nFFA occurs through multiple pathways of elimination. FFA dose adjustments may be needed when administered with strong inhibitors or inducers of multiple enzymes involved in FFA metabolism (e.g., stiripentol).
Topics: Animals; Cytochrome P-450 Enzyme System; Dogs; Drug Interactions; Fenfluramine; Humans; Microsomes, Liver; Norfenfluramine; Rats
PubMed: 35599345
DOI: 10.1002/prp2.958 -
Proceedings of the National Academy of... May 2022Environmental perturbations during the first years of life are a major factor in psychiatric diseases. Phencyclidine (PCP), a drug of abuse, has psychomimetic effects,...
Environmental perturbations during the first years of life are a major factor in psychiatric diseases. Phencyclidine (PCP), a drug of abuse, has psychomimetic effects, and neonatal subchronic administration of PCP in rodents leads to long-term behavioral changes relevant for schizophrenia. The cerebellum is increasingly recognized for its role in diverse cognitive functions. However, little is known about potential cerebellar changes in models of schizophrenia. Here, we analyzed the characteristics of the cerebellum in the neonatal subchronic PCP model. We found that, while the global cerebellar cytoarchitecture and Purkinje cell spontaneous spiking properties are unchanged, climbing fiber/Purkinje cell synaptic connectivity is increased in juvenile mice. Neonatal subchronic administration of PCP is accompanied by increased cFos expression, a marker of neuronal activity, and transient modification of the neuronal surfaceome in the cerebellum. The largest change observed is the overexpression of Ctgf, a gene previously suggested as a biomarker for schizophrenia. This neonatal increase in Ctgf can be reproduced by increasing neuronal activity in the cerebellum during the second postnatal week using chemogenetics. However, it does not lead to increased climbing fiber/Purkinje cell connectivity in juvenile mice, showing the complexity of PCP action. Overall, our study shows that administration of the drug of abuse PCP during the developmental period of intense cerebellar synaptogenesis and circuit remodeling has long-term and specific effects on Purkinje cell connectivity and warrants the search for this type of synaptic changes in psychiatric diseases.
Topics: Animals; Connective Tissue Growth Factor; Disease Models, Animal; Hallucinogens; Mice; Neurons; Phencyclidine; Proto-Oncogene Proteins c-fos; Purkinje Cells; Receptors, Phencyclidine; Schizophrenia; Synapses
PubMed: 35588456
DOI: 10.1073/pnas.2122544119 -
Biomedicine & Pharmacotherapy =... Jun 2022GABA receptors containing α6 subunits (α6GABARs) in the cerebellum have -been implicated in schizophrenia. It was reported that the GABA synthesizing enzymes were...
GABA receptors containing α6 subunits (α6GABARs) in the cerebellum have -been implicated in schizophrenia. It was reported that the GABA synthesizing enzymes were downregulated whereas α6GABARs were upregulated in postmortem cerebellar tissues of patients with schizophrenia and in a rat model induced by chronic phencyclidine (PCP). We have previously demonstrated that pyrazoloquinolinone Compound 6, an α6GABAR-highly selective positive allosteric modulator (PAM), can rescue the disrupted prepulse inhibition (PPI) induced by methamphetamine (METH), an animal model mimicking the sensorimotor gating deficit based on the hyper-dopaminergic hypothesis of schizophrenia. Here, we demonstrate that not only Compound 6, but also its structural analogues, LAU463 and LAU159, with similarly high α6GABAR selectivity and their respective deuterated derivatives (DK-I-56-1, DK-I-58-1 and DK-I-59-1) can rescue METH-induced PPI disruption. Besides, Compound 6 and DK-I-56-I can also rescue the PPI disruption induced by acute administration of PCP, an animal model based on the hypo-glutamatergic hypothesis of schizophrenia. Importantly, Compound 6 and DK-I-56-I, at doses not affecting spontaneous locomotor activity, can also rescue impairments of social interaction and novel object recognition in mice induced by chronic PCP treatments. At similar doses, Compound 6 did not induce sedation but significantly suppressed METH-induced hyperlocomotion. Thus, α6GABAR-selective PAMs can rescue not only disrupted PPI but also hyperlocomotion, social withdrawal, and cognitive impairment, in both METH- and PCP-induced animal models mimicking schizophrenia, suggesting that they are a potential novel therapy for the three core symptoms, i.e. positive symptoms, negative symptoms, and cognitive impairment, of schizophrenia.
Topics: Animals; Disease Models, Animal; Humans; Methamphetamine; Mice; Phencyclidine; Rats; Receptors, GABA-A; Schizophrenia; gamma-Aminobutyric Acid
PubMed: 35483195
DOI: 10.1016/j.biopha.2022.113022 -
Expert Opinion on Drug Safety Jun 2022Racemic ketamine, a derivative of phencyclidine, has been used as a dissociative anesthetic since 1970. In 2000, the first randomized controlled trial showed a rapid... (Review)
Review
INTRODUCTION
Racemic ketamine, a derivative of phencyclidine, has been used as a dissociative anesthetic since 1970. In 2000, the first randomized controlled trial showed a rapid relief of depressive symptoms. Since then, intravenous ketamine and intranasal S-ketamine have been validated for the treatment of depression and suicidal ideation following dose-response and double-blind placebo-controlled clinical trials. In clinical practice, after dose titration and with repeated treatments, patients may experience approximately 2-3 weeks of symptomatic relief from depression.
AREAS COVERED
Areas covered in this narrative review include mechanism of action, dosing, safety, and tolerability. Some attention is paid to the possibility of R-ketamine as a future antidepressant.
EXPERT OPINION
We recommend further investigation into treatment dosing and frequency strategies as well as approaches that prolong the therapeutic effects. The current fixed dosing of esketamine for obese individuals may be insufficient. Additional investigation into co-administration with somatic and neuromodulation treatments needs investigation. Finally, continuing to monitor research subjects and patients long-term for the emergence of adverse effects on cognition or other organ systems is critical.
Topics: Administration, Intranasal; Antidepressive Agents; Depression; Depressive Disorder, Treatment-Resistant; Humans; Ketamine; Randomized Controlled Trials as Topic
PubMed: 35475388
DOI: 10.1080/14740338.2022.2069749 -
The International Journal of... Aug 2022Immunological markers and related signaling molecules in the blood are altered in schizophrenia mouse models, in acutely relapsed patients with schizophrenia, and in...
BACKGROUND
Immunological markers and related signaling molecules in the blood are altered in schizophrenia mouse models, in acutely relapsed patients with schizophrenia, and in persons at a clinically high risk for subsequently developing psychosis, highlighting their potential as prognostic and theranostic biomarkers. Therefore, we herein aimed to identify novel potential biomarkers in the serum that are associated with purinergic signaling.
METHODS
To our knowledge, this is the first study to assess the correlations among the levels of human serum adenine nucleotides (ATP, ADP), adenosine, P2X7 receptor, and disease activity in patients hospitalized due to an acute relapse of schizophrenia (n = 53) and healthy controls (n = 47). In addition, to validate these findings using a reverse translational approach, we examined the same parameters in an acute phencyclidine-induced schizophrenia mouse model.
RESULTS
We found consistently elevated levels of ATP, ADP, interleukin (IL)-6, and IL-10 in both schizophrenia groups compared with the controls. The levels of adenosine, IL-1β, IL-12, and C-reactive protein were also increased in the human patient samples. Moreover, ATP and ADP were significantly positively correlated with the Positive and Negative Symptom Scale item "lack of judgment and insight"; IL-1β, IL-12, and tumour necrosis factor alpha were significantly positively correlated with "tension" and "depression"; and "disorientation" and "poor attention" were correlated significantly with IL-6 and IL-8.
CONCLUSIONS
Our study suggests the promising potential of blood purines and inflammatory markers as future prognostic tools.
Topics: Adenosine; Adenosine Diphosphate; Adenosine Triphosphate; Biomarkers; Humans; Interleukin-12; Interleukin-1beta; Interleukin-6; Purines; Schizophrenia
PubMed: 35443035
DOI: 10.1093/ijnp/pyac026