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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 -
Heliyon May 2024Infectious diseases can contribute to substance abuse. Here, a fatal case of borreliosis and substance abuse is reported. This patient had a history of multiple tick...
BACKGROUND
Infectious diseases can contribute to substance abuse. Here, a fatal case of borreliosis and substance abuse is reported. This patient had a history of multiple tick bites and increasing multisystem symptoms, yet diagnosis and treatment were delayed. He experimented with multiple substances including phencyclidine (PCP), an N-methyl-d-aspartate (NMDA) receptor antagonist that opposes NMDA agonism caused by infection. During PCP withdrawal, he committed one homicide, two assaults, and suicide.
METHODS
Brain tissue was obtained from autopsy and stained for microglial activation and quinolinic acid (QA). Immunoflouresence (IFA) and fluorescence hybridization (FISH) were used to identify the presence of pathogens in autopsy tissue.
RESULTS
Autopsy tissue evaluation demonstrated in the pancreas by IFA and heart by IFA and FISH. Activated microglia and QA were found in the brain, indicating neuroinflammation. It is postulated that PCP withdrawal may exacerbate symptoms produced by -induced biochemical imbalances in the brain. This combination may have greatly increased his acute homicidal and suicidal risk. Patient databases also demonstrated the risk of homicide or suicide in patients diagnosed with borreliosis and confirmed multiple symptoms in these patients, including chronic pain, anxiety, and anhedonia.
CONCLUSIONS
Late-stage borreliosis is associated with multiple symptoms that may contribute to an increased risk of substance abuse and addictive disorders. More effective diagnosis and treatment of borreliosis, and attention to substance abuse potential may help reduce associated morbidity and mortality in patients with borreliosis, particularly in endemic areas.
PubMed: 38779029
DOI: 10.1016/j.heliyon.2024.e31159 -
Biomolecules Jul 2020Memantine, an -methyl-d-aspartate (NMDA) receptor antagonist approved for treating Alzheimer's disease, has a good safety profile and is increasingly being studied for... (Review)
Review
Memantine, an -methyl-d-aspartate (NMDA) receptor antagonist approved for treating Alzheimer's disease, has a good safety profile and is increasingly being studied for possible use in a variety of non-dementia psychiatric disorders. There is an abundance of basic and clinical data that support the hypothesis that NMDA receptor hypofunction contributes to the pathophysiology of schizophrenia. However, there are numerous randomized, double-blind, placebo-controlled clinical trials showing that add-on treatment with memantine improves negative and cognitive symptoms, particularly the negative symptoms of schizophrenia, indicating that memantine as adjunctive therapy in schizophrenia helps to ameliorate negative symptoms and cognitive deficits. It remains unclear why memantine does not show undesirable central nervous system (CNS) side effects in humans unlike other NMDA receptor antagonists, such as phencyclidine and ketamine. However, the answer could lie in the fact that it would appear that memantine works as a low-affinity, fast off-rate, voltage-dependent, and uncompetitive antagonist with preferential inhibition of extrasynaptic receptors. It is reasonable to assume that the effects of memantine as adjunctive therapy on negative symptoms and cognitive deficits in schizophrenia may derive primarily, if not totally, from its NMDA receptor antagonist activity at NMDA receptors including extrasynaptic receptors in the CNS.
Topics: Animals; Antipsychotic Agents; Drug Combinations; Excitatory Amino Acid Antagonists; Humans; Memantine; Receptors, N-Methyl-D-Aspartate; Schizophrenia
PubMed: 32751985
DOI: 10.3390/biom10081134 -
Translational Psychiatry Jun 2021Stimulant dependence is heritable, but specific genetic factors underlying the trait have not been identified. A genome-wide association study for stimulant dependence...
Stimulant dependence is heritable, but specific genetic factors underlying the trait have not been identified. A genome-wide association study for stimulant dependence was performed in a discovery cohort of African- (AA) and European-ancestry (EA) subjects ascertained for genetic studies of alcohol, opioid, and cocaine use disorders. The sample comprised individuals with DSM-IV stimulant dependence (393 EA cases, 5288 EA controls; 155 AA cases, 5603 AA controls). An independent cohort from the family-based Collaborative Study on the Genetics of Alcoholism (532 EA cases, 7635 EA controls; 53 AA cases, AA 3352 controls) was used for replication. One variant in SLC25A16 (rs2394476, p = 3.42 × 10, odds ratio [OR] = 3.70) was GWS in AAs. Four other loci showed suggestive evidence, including KCNA4 in AAs (rs11500237, p = 2.99 × 10, OR = 2.31) which encodes one of the potassium voltage-gated channel protein that has been linked to several other substance use disorders, and CPVL in the combined population groups (rs1176440, p = 3.05 × 10, OR = 1.35), whose expression was previously shown to be upregulated in the prefrontal cortex from users of cocaine, cannabis, and phencyclidine. Analysis of the top GWAS signals revealed a significant enrichment with nicotinic acetylcholine receptor genes (adjusted p = 0.04) and significant pleiotropy between stimulant dependence and alcohol dependence in EAs (p = 3.6 × 10), an anxiety disorder in EAs (p = 2.1 × 10), and ADHD in both AAs (p = 3.0 × 10) and EAs (p = 6.7 × 10). Our results implicate novel genes and pathways as having roles in the etiology of stimulant dependence.
Topics: Black or African American; Autoantigens; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Membrane Transport Proteins; Polymorphism, Single Nucleotide; Substance-Related Disorders; White People
PubMed: 34226506
DOI: 10.1038/s41398-021-01440-5 -
Korean Journal of Anesthesiology Apr 2021Initially known as CI-581, ketamine was first synthesized in 1962 as a replacement from phencyclidine. It has since been used as an anesthetic and analgesic. In... (Review)
Review
Initially known as CI-581, ketamine was first synthesized in 1962 as a replacement from phencyclidine. It has since been used as an anesthetic and analgesic. In addition, it has bronchodilating, sedative, and amnestic properties, preserving airway reflexes and sympathetic nervous system tone. Since the discovery of ketamine, it has been a major topic of discussion due to controversies regarding its usage in particular sets of patients. In the past 50 years, despite its potential benefits, it is not commonly used because of concerns of "emergence phenomenon," its use as a substance of abuse, and its systemic side effects. Since 2012, three World Health Organization reviews on ketamine have addressed its international control. Researchers have been studying this wonder drug for a decade worldwide. Many myths of ketamine regarding emergence phenomenon and its use in traumatic brain injury and open eye injury have been disproved in recent times. It is becoming popular in pre-hospital settings, critical care, emergency medicine, low-dose acute pain services, and adjuvant in regional anesthesia techniques. This review highlights the current consensus on the various applications of ketamine in the literature.
Topics: Analgesics; Anesthesia, Local; Humans; Hypnotics and Sedatives; Ketamine
PubMed: 33423410
DOI: 10.4097/kja.20663 -
Brain Sciences Sep 2020Sex and gender deeply affect the subjective effects and pharmaco-toxicological responses to drugs. Men are more likely than women to use almost all types of illicit... (Review)
Review
Sex and gender deeply affect the subjective effects and pharmaco-toxicological responses to drugs. Men are more likely than women to use almost all types of illicit drugs and to present to emergency departments for serious or fatal intoxications. However, women are just as likely as men to develop substance use disorders, and may be more susceptible to craving and relapse. Clinical and preclinical studies have shown important differences between males and females after administration of "classic" drugs of abuse (e.g., Δ9-tetrahydrocannabinol (THC), morphine, cocaine). This scenario has become enormously complicated in the last decade with the overbearing appearance of the new psychoactive substances (NPS) that have emerged as alternatives to regulated drugs. To date, more than 900 NPS have been identified, and can be catalogued in different pharmacological categories including synthetic cannabinoids, synthetic stimulants (cathinones and amphetamine-like), hallucinogenic phenethylamines, synthetic opioids (fentanyls and non-fentanyls), new benzodiazepines and dissociative anesthetics (i.e., methoxetamine and phencyclidine-derivatives). This work collects the little knowledge reached so far on the effects of NPS in male and female animal and human subjects, highlighting how much sex and gender differences in the effects of NPS has yet to be studied and understood.
PubMed: 32899299
DOI: 10.3390/brainsci10090606 -
Journal of Integrative Neuroscience Jan 2022Locomotor hyperactivity induced by psychotomimetic drugs, such as amphetamine and phencyclidine, is widely used as an animal model of psychosis-like behaviour and is...
Locomotor hyperactivity induced by psychotomimetic drugs, such as amphetamine and phencyclidine, is widely used as an animal model of psychosis-like behaviour and is commonly attributed to an interaction with dopamine release and N-methyl-D-aspartate (NMDA) receptors, respectively. However, what is often not sufficiently taken into account is that the pharmacological profile of these drugs is complex and may involve other neurotransmitter/receptor systems. Therefore, this study aimed to assess the effect of three antagonists targeting different monoamine pathways on amphetamine- and phencyclidine-induced locomotor hyperactivity. A total of 32 rats were pre-treated with antagonists affecting dopaminergic, noradrenergic and serotonergic transmission: haloperidol (0.05 mg/kg), prazosin (2 mg/kg) and ritanserin (1 mg/kg), respectively. After 30 min of spontaneous activity, rats were injected with amphetamine (0.5 mg/kg) or phencyclidine (2.5 mg/kg) and distance travelled, stereotypy and rearing recorded in photocell cages over 90 min. Pre-treatment with haloperidol or prazosin both reduced amphetamine-induced hyperactivity although pre-treatment with ritanserin had only a partial effect. None of the pre-treatments significantly altered the hyperlocomotion effects of phencyclidine. These findings suggest that noradrenergic as well as dopaminergic neurotransmission is critical for amphetamine-induced locomotor hyperactivity. Hyperlocomotion effects of phencyclidine are dependent on other factors, most likely NMDA receptor antagonism. These results help to interpret psychotomimetic drug-induced locomotor hyperactivity as an experimental model of psychosis.
Topics: Adrenergic alpha-1 Receptor Antagonists; Akathisia, Drug-Induced; Amphetamine; Animals; Behavior, Animal; Central Nervous System Stimulants; Disease Models, Animal; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Male; Phencyclidine; Psychoses, Substance-Induced; Rats; Rats, Sprague-Dawley; Serotonin Antagonists
PubMed: 35164453
DOI: 10.31083/j.jin2101017 -
Journal of Psychiatric Research May 2021The approval of intranasal esketamine for treatment-resistant depression marks the next step in our understanding of and ability to treat treatment-resistant depression.... (Review)
Review
The approval of intranasal esketamine for treatment-resistant depression marks the next step in our understanding of and ability to treat treatment-resistant depression. The origin of ketamine is rooted in the search for a phencyclidine analog that could be used as a pre-surgical anesthetic with less emergence delirium. Following its inception, ketamine has been used in a variety of contexts. However, it was the seminal Berman et al., 2000 study, which published positive findings from the first human trial using subanesthetic intravenous ketamine for depression. Since then, a large body of research has investigated ketamine's various proposed antidepressant mechanisms of action, and the role its pharmacokinetic properties and route of administration play in producing its antidepressant effects. The results of this research were the eventual approval of intranasal esketamine for treatment-resistant depression by the U.S. Food and Drug Administration (FDA) in March 2019. By identifying and utilizing predictors of response, we can continue to refine our approach to treating treatment-resistant depression and optimize patient response to intranasal esketamine. In this article, we look at the history, pharmacology, landmark studies, and future implications of intranasal esketamine for treatment-resistant depression.
Topics: Administration, Intranasal; Depression; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Humans; Ketamine
PubMed: 33647726
DOI: 10.1016/j.jpsychires.2021.02.020 -
Cureus Nov 2023Ketamine is a phencyclidine (PCP) derivative, which primarily acts as a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. Ketamine serves as an analgesic... (Review)
Review
Ketamine is a phencyclidine (PCP) derivative, which primarily acts as a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. Ketamine serves as an analgesic and a dissociative sedative that produces potent analgesia, sedation, and amnesia while preserving spontaneous respiratory drive. It is rapidly gaining acceptance in the management of pain as multiple studies have demonstrated its reliable efficacy and a wide margin of safety. This article reviews some of these studies, the history of ketamine, and its pharmacological and pharmacokinetic properties. The article also discusses the use of ketamine in the trauma setting, including joint reductions, procedures, sedation, and pain control, as well as dosing recommendations.
PubMed: 37920424
DOI: 10.7759/cureus.48099 -
Frontiers in Neural Circuits 2022Abnormally high-amplitude hippocampal gamma activity (30-100 Hz) in behaving animals is seen after a hippocampal seizure, following injection of phencyclidine (PCP) or... (Review)
Review
Abnormally high-amplitude hippocampal gamma activity (30-100 Hz) in behaving animals is seen after a hippocampal seizure, following injection of phencyclidine (PCP) or ketamine, and transiently in a delirium stage during induction of general anesthesia. High-amplitude hippocampal gamma activity in behaving rats is associated with hyperactive behavior and impairment in sensorimotor gating and sensory gating. The medial septum is necessary for the high-amplitude gamma activity and abnormal behaviors observed following a hippocampal seizure or injection of PCP/ketamine. Glutamatergic projection of the hippocampus to the nucleus accumbens (NAC) and dopaminergic transmission in NAC is necessary for abnormal behaviors. Large hippocampal gamma waves are suggested to contribute to seizure-induced automatism following temporal lobe seizures, and the schizophrenia-like symptoms induced by PCP/ketamine. Low-amplitude gamma activity is found during general anesthesia, associated with loss of consciousness in humans and loss of righting reflex in animals. Local inactivation or lesion of the medial septum, NAC, and brain areas connected to the septohippocampal-NAC system attenuates the increase in hippocampal gamma and associated behavioral disruptions induced by hippocampal seizure or PCP/ketamine. Inactivation or lesion of the septohippocampal-NAC system decreases the dose of anesthetic necessary for gamma decrease and loss of consciousness in animals. Thus, it is proposed that the septohippocampal-NAC system serves to control consciousness and the behavioral hyperactivity and neural dysfunctions during psychosis.
Topics: Animals; Consciousness; Electroencephalography; Gamma Rays; Hippocampus; Humans; Ketamine; Psychotic Disorders; Rats; Rats, Long-Evans; Seizures; Unconsciousness
PubMed: 35874429
DOI: 10.3389/fncir.2022.895000